19 - Acute Leukemias
Editors: Skeel, Roland T.
Title: Handbook of Cancer Chemotherapy, 7th Edition
Copyright 2007 Lippincott Williams & Wilkins
> Table of Contents > Section III - Chemotherapy of Human Cancer > Chapter 19 - Acute Leukemias
function show_scrollbar() {}
Chapter 19
Acute Leukemias
Olga Frankfurt
Martin S. Tallman
I. General features of acute leukemias
The acute leukemias are a heterogeneous group of disorders characterized by clonal proliferation and abnormal differentiation of neoplastic hematopoietic progenitor cells. Accumulation of immature hematopoietic cells, or blasts, in the bone marrow and peripheral blood, ultimately leads to inhibition of normal hematopoiesis. If left untreated, acute leukemias are rapidly fatal.
Over the last 40 years, significant therapeutic advances have been made, and many patients can now be cured of their disease. The general treatment approach for most patients with acute leukemia includes eradication of the leukemic clone with intensive systemic chemotherapy, followed by some form of consolidation and, in certain cases, maintenance therapy. Despite this strategy, many patients younger than 55 years and most of the older adults die from their disease.
Numerous questions regarding optimal therapeutic strategies for the patients with acute leukemia remain unanswered. Hence, all patients with acute leukemia ought to be considered candidates for clinical trials and should be treated in centers where appropriate intensive and comprehensive care can be provided.
A. Epidemiology
The incidence of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) is 2.7 and 1.5/100,000 population, respectively, and is slightly higher in men than in women. Sixty percent of ALL patients are children, with a peak incidence in the first 5 years of life. The second peak emerges after the age of 60 years. The incidence of AML rises exponentially after the age of 40 years, with the median age of disease presentation being 68 years. The median age of patients diagnosed with acute promyelocytic leukemia (APL), a distinct subtype of AML, is 40 years and the incidence of the disease does not increase with advanced age. While, in general, the incidence of acute leukemias is slightly higher in the populations of European descent, the incidence of APL is higher among patients of Spanish origin.
B. Etiology and risk factors of acute leukemias
Although the association of the acute leukemias with various infectious, genetic, environmental, and socioeconomic factors has been evaluated extensively, the etiology remains obscure in most cases.
Infection. There is a strong association between Epstein-Barr virus (EBV), a deoxyribonucleic acid (DNA) virus causing infectious mononucleosis, with Burkitt's lymphoma/leukemia.
Genetic factors have been implicated in the pathogenesis of acute leukemia on the basis of epidemiologic studies showing the 25% increase risk of ALL within 1 year in a monozygotic twin of an affected infant. There is also
P.447
a fourfold increase in the risk of developing leukemia in dizygotic siblings. The risk of developing acute leukemia is significantly higher in patients with Down and Klinefelter syndromes, and conditions with excessive chromosome fragility such as Fanconi's anemia, ataxia telangiectasia, and Bloom's syndrome.Exposures to chemotherapy and radiation significantly increase the risk of developing acute leukemias. AML with chromosome5 and/or 7 abnormality has been reported to occur 2 to 9 years after therapy with alkylating agents. Topoisomerase inhibitors have been linked to the development of AML and ALL with 11q23 aberration, characteristically 1 to 3 years after the exposure. An increased incidence of acute leukemias has been reported after the radiation exposure such as atomic bomb explosion, Chernobyl accident, and therapeutic radiation. Increased incidence of leukemia has been linked to the exposure to gasoline, benzene, tobacco, diesel, motor exhaust, and electromagnetic fields.
C.
Clinical features of acute leukemias are shown in Table 19.1.
D. Diagnosis and classification
The acute leukemias are divided into AML and ALL, on the basis of the morphologic, immunohistochemical, and immunophenotypic characteristics of the stem cell of origin. Although the peripheral blood smear may be highly suggestive of the diagnosis, examination of the bone marrow aspirate and core biopsy is essential to confirm the diagnosis and to determine the extent of the disease. Cytogenetic analysis and molecular studies may aid in establishing an accurate diagnosis, estimate prognosis, and guide therapy.
Acute myeloid leukemia (AML)
Classification. Currently, two pathologic classifications are used to define AML. Morphology-based French American British (FAB) classification devised in 1976, utilizes cytochemical stains and, more recently, immunophenotyping by flow cytometry to differentiate myeloid from lymphoid blasts (Tables 19.2 and 19.3). According to FAB classification, eight subcategories of AML are established on the basis of the type of cell involved and the degree of differentiation (Table 19.4).
A more recent World Health Organization (WHO) classification created in 1999 generated 17 subclassifications of AML, based on the presence of dysplasia, chromosomal translocations, and molecular markers (Table 19.4). Additional changes included decrease of the diagnostic threshold to 20% blasts (from the original FAB classification of 30%, hence eliminating RAEB-t category of myelodysplastic syndrome [MDS]) and the diagnosis of AML regardless of the percentage of marrow blasts in marrows with evidence of abnormal hematopoiesis and clonal cytogenetic abnormalities such as t(8;21), t(15;17), and t(16;16) or inv(16).
Prognostic factors in AML. Cytogenetic information is the single most important prognostic factor for predicting the rate of remission, relapse, and overall survival (OS) (Table 19.5). On the basis of the recent analysis of 1,213 patients with AMLtreated with Cancer and Leukemia Group B (CALGB) protocols, the 5-year survival for patients with favorable, intermediate, and poor risk cytogenetics was 55%, 24%, and 5%, respectively. FLT3 gene aberrations, in the form of internal tandem duplication (ITD) or mutation at the activation loop position 835 (D835), are the most common genetic abnormality in AML, and has been reported to confer a poor prognosis. In the recent series, 5-year survival of patients with a normal karyotype and the presence of FLT3 mutations was 20% as compared to that of 42% for patients with normal karyotype and absence of FLT3 mutation. Although currently the information regarding FLT3 status is unlikely to change the initial therapy, it may do so in the future, as FLT3 kinase inhibitors become part of the armamentarium of agents active against AML. ITD of the MLL (mixed lineage leukemia or myeloid lymphoid leukemia) gene has also been associated with poor prognosis in patients with normal karyotype.
P.448
Table 19.1. Clinical features of acute leukemias
Clinical and Laboratory Features Signs and Symptoms Anemia Pallor, fatigue, exertional dyspnea, CHF Neutropenia Fever, infection Thrombocytopenia Petechiae, ecchymosis, retinal hemorrhages Leukocytosis (10% of patients with WBC >100,000/ L) Hepatomegaly, splenomegaly, lymphadenopathy (more common in ALL)
Bone pain (40% 50% of children with ALL, 5% 10% of adults)
Gingival hypertrophy (particularly M4, M5)
Leukemia cutis
Solitary mass or granulocytic sarcoma (<5% of AML at presentation), composed of leukemia myeloid cells in any organ, including bones, breast, skin, small bowel, and mesentery, and obstruction lesions of genitourinary and hepatobiliary tracts)Leukostasis Dyspnea, hypoxia, mental status changes Mediastinal mass (80% of patients with T-cell ALL, rare in AML) Cough, dyspnea, chest pain CNS involvement (<1% in AML at presentation, 3% 5% of adult ALL) Headache, diplopia, cranial neuropathies, particularly CN VI, VIII, papilledema, nausea, vomiting Elevated PT, PTT, low fibrinogen Intracranial bleeding, DIC (particularly in APL) Acute renal failure (uncommon), acidosis, hyperkalemia, hyperphosphatemia, hypocalcemia, elevated LDH and uric acid levels Tumor lysis syndrome CHF, congestive heart failure; WBC, white blood cell; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CN, cranial nerve; PT, prothrombin time; PTT, partial thromboplastin time; APL, acute promyelocytic leukemia; DIC, disseminated intravascular coagulation; LDH, lactate dehydrogenase. P.449
Table 19.2. Antigens commonly demonstrated by flow cytometry techniques
Cell Lineage Antigens Lymphoid B CD19, CD20, cytoplasmic CD22, CD23, CD79a Lymphoid T CD1, CD2, cytoplasmic CD3, CD4, CD5, CD7, CD8 Myelomonocytic Myeloperoxidase, CD11c, CD13, CD14, CD33, CD117 (c-Kit) Erythrocytic Glycophorin A Megakaryocytic von Willebrand factor, GPIIb (CD41), GPIIIa (CD61) NK cells CD16, CD56 Nonlineage specific TdT, HLD-DR NK, natural killer; TdT, terminal deoxynucleotidyl transferase; HLD-DR, human leukocyte differentiation antigen-DR. Additionally, advanced age, antecedent hematologic disorder, and prior exposure to chemotherapy/radiation are well-established factors associated with lower rates of
P.450
complete remission (CR) and long-term survival. Although 40% to 60% of older AML patients achieve a CR, only 5% to 16% are alive at 5 years.Table 19.3. Common histochemical stains that characterize the non lymphoid cells
Sudan Black B (myeloblasts, promyelocytes)
Peroxidase (myeloblasts, promyelocytes)
Nonspecific esterases that are inhibited by sodium fluoride (monoblasts)
Periodic acid-Schiff (pronormoblasts in erythroleukemia)Table 19.4. World Health Organisation classification of acute myeloid leukemia (AML) (simplified)
AML with recurrent cytogenetic translocations - AML with t(8;21) (q22;22); AML1/ETO)
- Acute promyelocytic leukemia t(15;17)(q22;q12) (PML/RAR- ) and variants
- AML with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22); (CBF /MYH11)
- AML with 11q23 (MLL) abnormalities
AML with multilineage dysplasia - With prior MDS
- Without prior MDS
AML and MDS, therapy related - Alkylating agent related
- Epipodophyllotoxin related
- Other types
AML not otherwise categorized (correlated with FAB subtype) - AML minimally differentiated (FAB M0)
- AML without maturation (FAB M1)
- AML with maturation (FAB M2)
- Acute myelomonocytic leukemia (FAB M4)
- Acute monocytic leukemia (FAB M5)
- Acute erythroid leukemia (FAB M6)
- Acute megakaryocytic leukemia (AmegL; FAB M7)
- Acute basophilic leukemia
- Acute panmyelosis with myelofibrosis
Acute biphenotypic leukemias MDS, myelodysplastic syndrome; MLL, myeloid lymphoid leukemia; FAB, French American British. Adult ALL
The diagnosis and classification of ALL are based on cell morphology, immunohistochemistry, as well as immunophenotypic and cytogenetic features. Marrow involvement with more than 25% lymphoblasts is used to differentiate ALL from lymphoblastic lymphoma, in which the preponderance of tumor bulk is in nodal structures. Approximately 70% to 75% of adult ALL cases are of precursor B-cell origin, 20% to 25% are of T-cell origin, and 5% are of mature B-cell origin (or Burkitt-type leukemia, FAB L3).
Precursor B-cell ALL may be further subdivided into early precursors B-ALL, common ALL, and pre-B ALL. Precursor B-cell ALL cells are terminal deoxynucleotidyl transferase (TdT) positive and commonly express CD19, CD10 (the common ALL antigen or CALLA), and HLA-DR, but lack surface immunoglobulin.
Mature B-cell ALL, or Burkitt-cell leukemia, is associated with translocation of c-myc gene of chromosome 8 and the immunoglobulin heavy-chain gene on chromosome 14q32 in 80% of the cases or with the light-chain gene on the chromosome 2p11 or 22q11 in the other 20%. The recent increase in the incidence of Burkitt's leukemia/lymphoma is attributed to its association with human immunodeficiency virus (HIV) infection. Mature B-cell ALL cells are always positive for the membrane immunoglobulin with light chain restriction and commonly positive for CD10, CD19, CD20, CD22, and CD79b.
T-Cell ALL arises from stage I (prothymocyte) and stage II thymocytes. Immunologic markers classically suggesting T-cell lineage are CD2 (sheep red blood cell receptor), CD3, CD7, CD38 (panthymocyte), and CD71 (transferrin receptor). The TdT can be demonstrated in T-cell (through thymocyte) lineage.
P.451
Table 19.5. Acute myeloid leukemia prognostic groups based on cytogenetics at presentationa
Favorable - t(15;17) with any other abnormality
- inv(16) or t(16;16)b or del(16q) with any other abnormality
- t(8;21)b without del(9q) or complex karyotype
Intermediate - +8c, - Y, +6, del(12p) or normal karyotype
Unfavorable - - 5 or del(5q), - 7 or del(7q), inv(3q), abnormalities of 11q23, 20q, 21q, del(9q), t(6;9), t(8;21) with del(9q) or with complex karyotype, t(9;22), abnormalities of 17p, complex karyotype (three or more abnormalities)
Unknown - All other clonal chromosomal aberrations with less than three abnormalities
aDetermined by conventional cytogenetic techniques, fluorescent in situ hybridization, or polymerase chain reaction.
bKaryotype in these two groups is part of core-binding factor-type acute leukemia.
cSome evidence suggests that trisomy 8 confers an unfavorable prognosis.Prognostic features in ALL
Clinical features. Specific biologic and clinical features of ALL predict response to therapy, remission duration, and disease-free survival (DFS), and help determine the intensity of the induction and postremission therapy. In multivariate analysis, age older than 60 years is associated with a particularly poor prognosis, with shorter remission durations, and worse survival. Presenting white blood cell (WBC) counts of more than 30,000/ L is an adverse prognostic factor predicting shorter remission durations that
P.452
pertains more to precursor B-lineage ALL (threshold WBC count >50,000 to 100,000/ L may be important for T-cell ALL). Time required to achieve CR (>4 weeks) following induction chemotherapy has been demonstrated to be an adverse prognostic factor in some but not other clinical trials. A recent report from the GIMEMA (Gruppo Italiano per le Malattie Ematologiche dell_Adulto, [Italian Group for Adult Hematologic Diseases]) ALL group demonstrated that response (defined as peripheral blast count of >1,000/ L on day 10) to 7 days of initial prednisone treatment before induction was prognostic in predicting disease favorable outcome in adult ALL patients.The poor outcome associated with T-cell ALL and the expression of myeloid antigens on lymphoblasts, noted in 30% to 35% of adults with ALL, are overcome by the newer multiagent intensive induction regimens. In fact, the German Multicenter Studies for Adult ALL (GMALL) group has reported superior long-term event-free survival (EFS) of 50% to 60% for the group of T-ALL patients. Favorable prognostic factors in T-lineage ALL include mediastinal mass, younger age, and CD10 antigen expression. Earlier studies using immunophenotypic subclassification of leukemic cells had demonstrated mature B-cell ALL (FAB L3) to be associated with shorter remission rates and worse survival. Survival rates have improved significantly in adults with Burkitt's ALL through regimens adapted from childhood protocols using shorter, intensive, multiagent chemotherapy regimens, which have resulted in long-term survival rates of more than 50% in this group of patients.
Cytogenetic abnormalities. Similar to AML, cytogenetic abnormalities are one of the most important factors predicting outcome in ALL. Approximately half the number of patients with ALL have cytogenetic abnormalities, which usually take the
P.453
form of translocation rather than deletion as seen more commonly in AML (Table 19.6).
Table 19.6. Adverse prognostic factors in B-lineage acute lymphoblastic leukemia (ALL)
Older age High WBC Cytogenetics: t(9;22), t(4;11), t(1:19), 9p21,11q23 Immunophenotype: mature B-ALLa, null-cell ALL (non-T, non-CALLA) Delayed time to CR (>4 weeks)b WBC, white blood cell; CALLA, common ALL antigen; CR, complete remission.
aHas poor prognosis when treated with conventional ALL regimes. However, with modern regimens prognosis has improved.
bWas not shown to be a predictor of worse outcome in recent MRC UALL XII/ECOG E2993.Philadelphia (Ph+) chromosome. The t(9;22), one of the most ominous cytogenetic abnormalities in ALL, results in the formation of the BCR/ABL fusion gene with tyrosine kinase activity. This translocation, referred as Philadelphia chromosome, is the most common cytogenetic abnormality, found in up to 30% of adults with ALL, as compared with 5% of children. The BCR/ABL fusion protein in ALL is smaller with a molecular mass of 185 or 190 kDa as compared with the 210-kDa BCR/ABL protein seen in almost all chronic myelogenous leukemia (CML) patients (including blast crisis). The abnormal fusion protein upregulates tyrosine kinase activity and affects the downstream signaling pathways. In the recent update of the German ALL trials, 37% of patients were Ph+, with 77% showing the p190 and 23% showing p210 proteins. Although patients with Ph+ALL may attain morphologic remission (82%) with conventional chemotherapy, most will have persistent molecular disease. The median survival of 6 to 14 months and long-term DFS of 0% to 10%, depend in part on intensity of induction and consolidation therapy. Patients who do achieve a molecular remission have longer remission duration (30 vs. 12 months).
Other translocations associated with poor outcomes involve the mixed-lineage leukemia (MLL) gene on chromosome 11q23, partnered with several other chromosomes including 4q21, 9q22, and 19q13. Translocation t(4;11), the most common rearrangement of 11q23, occurs in approximately 10% of adult patients and is common among infants with ALL. Adults with this translocation tend to be older, have organomegaly, higher WBC count, and central nervous system (CNS) involvement.
Favorable cytogenetics. ALL patients with t(10;14) karyotype (or other abnormality involving 14q (11 13)), Del (12p), or t(12p) (without associated Philadelphia chromosome) have a better prognosis, with long-term DFS rates exceeding 70% to 75%. Furthermore, rearrangement of the TEL gene (12q13) in children with precursor B-cell ALL was demonstrated to be a favorable genetic marker, with a 5-year DFS of 91% in one study.
Acute mixed-lineage and stem cell leukemias. With the expansion of immunophenotyping panels, use of electron microscopy and gene rearrangement studies for the characterization of acute leukemia, increasing degrees of infidelity of myeloid and lymphoid markers is demonstrated. Cases in which differentiation betweenAML and ALL is difficult are described by the WHO as acute leukemia of ambiguous lineage and are divided in three subgroups: undifferentiated acute leukemia, lacks all of the specific markers such as myeloperoxidase, CD3, cytoplasmic CD22, and cytoplasmic CD79a; bilineal acute leukemia, is characterized by dual blasts population, with each population expressing markers of a distinct lineage; and biphenotypic acute leukemia, characterized by blasts
P.454
coexpressing lineage-specific antigens from two lineages. However, the coexpression of one or two lineage-associated antigens is not a sufficient criterion to diagnose biphenotypic leukemia and may produce well-defined syndromes that do not alter the basic cellular lineage (e.g., CD13/CD33 ALL, CD7 AML, TdT AML).In stem cell leukemia, the cells express only rudimentary hematopoietic markers (e.g., Ia antigen, TdT, CD34). The identification of entities such as CD13/CD33 ALL and stem cell leukemia may be of prognostic importance and have therapeutic implications.
II. Initial support
Once the diagnosis of acute leukemia has been established, the next 24 to 48 hours are spent preparing the patient for the initiation of cytotoxic chemotherapy. The following issues need to be addressed in almost all individuals facing induction chemotherapy.
A. Hyperleukocytosis, leukostasis, and leukapheresis
Hyperleukocytosis, defined as an absolute blast count of more than 100,000/ L, predisposes to rheologic complications. Leukostasis, manifesting as cerebral and cardiopulmonary dysfunction due to vascular obstruction and/or vessel wall necrosis with hemorrhage, occurs almost exclusively in AML and represents an oncologic emergency. Given the increased risk of early death with hyperleukocytosis, steps to rapidly reduce the blast counts should be undertaken as soon as the diagnosis is made. In the hemodynamically stable patient, leukapheresis is the most rapid way to lower the blast count. The goal of the leukapheresis session is to lower the blast count to less than 100,000/ L if possible. With very high blast counts (>200,000/ L), decreasing the blast count by 50% may have to be the initial goal because mathematic modeling suggests that prolonged leukapheresis after a 3-L exchange does not significantly decrease the blast count further. Leukapheresismay be repeated daily. Systemic chemotherapy should be initiated immediately after emergent leukapheresis or if leukapheresis cannot be performed. Hydroxyurea 3 to 5 g/m2/day split into three doses daily is most commonly used. Hydroxyurea is stopped at the time more specific induction chemotherapy is initiated. In patients presenting with hyperleukocytosis, an allopurinol dose of 600 mg b.i.d. is well tolerated for the first 2 days, followed by 300 mg b.i.d. for 2 to 3 days. Emergent cranial radiation for hyperleukocytosis and cranial nerve palsies is another treatment modality that may be used.
Blood transfusions in the anemic patient with hyperleukocytosis should be undertaken with great caution as aggressive packed RBC (PRBC) transfusion in such patients may precipitate symptoms of hyperviscosity. Unless the patient has symptoms due to anemia, a hematocrit of 20% to 25% is a reasonable goal.
B. Hydration and correction of electrolyte imbalance
Dehydration needs to be corrected and adequate urine output maintained to prevent renal failure due to the deposition of cellular breakdown products resulting from the tumor lysis syndrome (TLS). In the absence of cardiac disease, normal saline with or without 5% dextrose is infused to maintain the urine output at more than 100 mL/hour. The concomitant use
P.455
of loop diuretics may be necessary in patients with congestive heart failure.
A variety of electrolyte abnormalities, such as hypocalcemia, hyperphosphatemia, and hyperkalemia may occur in patients with acute leukemia. Hypocalcemia may cause potentially lethal cardiac (ventricular arrhythmias, heart block) and neurological (hallucination, seizures, coma) complications. In an asymptomatic patient with laboratory evidence of hypocalcemia and hyperphosphatemia, calcium replacement is not recommended, because it may precipitate metastatic calcifications. However, in a patient with symptomatic hypocalcemia, calcium gluconatemay be carefully administered to correct the clinical symptoms. Hyperkalemia, defined by a potassium level of greater than 6 mmoL/L, caused bymassive cellular degradation, may precipitate significant neuromuscular (muscle weakness, cramps, paresthesias) and potentially life-threatening cardiac (asystole, ventricular tachycardia, and ventricular fibrillation) abnormalities. Patients should be treated with oral sodium potassium exchange resin such as Kayexalate 15 to 30 g every 6 hours and combined glucose/insulin therapy.
Serum electrolytes, uric acid, phosphorus, calcium, and creatinine should be monitored several times a day, depending on the severity of the clinical condition and degree of metabolic abnormality. Early hemodialysis may be required in patients who develop oliguric renal failure or recalcitrant electrolyte disturbances. The electrocardiogram(ECG) should be obtained and cardiac rhythm monitored while these abnormalities are corrected.
C. Prevention of uric acid nephropathy
Hyperuricemia is common at presentation and may also occur with the tumor lysis caused by chemotherapy. Allopurinol is the mainstay of prevention of uric acid nephropathy. The usual initial adult dose is 300 mg (150 mg/m2) twice a day for 2 to 3 days, which is then decreased to 300 mg once a day. Allopurinol should be stopped after 10 to 14 days to lessen the risk of rash and hepatic dysfunction. If chemotherapy needs to be initiated urgently, allopurinol at a dose of 600 mg twice a day is well tolerated for 1 to 2 days. With the advent of allopurinol, the role of urine alkalinization has become less clear. Although urine alkalinization increases uric acid solubility, it decreases the solubility of urinary phosphates and may promote phosphate deposition in patients susceptible to TLS (e.g., B-cell ALL and T-cell lymphoblastic leukemia). A commonly employed method of urine alkalinization is to hydrate the patient with D5W, to which two syringes of sodium bicarbonate (44 mEq of NaHCO3 per syringe) have been added per liter.
Recombinant urate oxidase rasburicase, which recently became available in the United States, is a safe and effective alternative to allopurinol. Although the recommended dose of rasburicase is 0.15 to 0.2 mg/kg/day for 5 days, at our institution, an excellent control of hyperuricemia was achieved with a lower dose of 3 mg/day. Administration of 3 mg of rasburicase to 18 patients with hyperuricemia secondary to leukemia/lymphoma resulted in the normalization of the uric acid in 11 patients with just a single dose of rasburicase, in 6 patients with two doses and in 1 patient with three doses.
P.456
D. Correction of coagulopathy
Hemostatic defect secondary to thrombocytopenia may be potentiated by the presence of consumption coagulopathy, (disseminated intravascular coagulation [DIC]). Life-threatening bleeding complications are particularly common in patients with APL, due to the presence of DIC and primary fibrinolysis (see Section V.B.). Lysozyme released from monoblasts in M4 and M5 subtypes of AML may trigger a clotting cascade leading to consumption coagulopathy. In ALL, therapy with L-asparaginase may lead to DIC. Additionally, sepsis may contribute to coagulopathy in newly diagnosed patients with acute leukemias. Frequent monitoring of coagulation parameters and adequate replacement with cryoprecipitate or fresh frozen plasma products in appropriate patients is critical (see Chapter 29).
E. Blood product support
Most patients with acute leukemiapresent with evidence of bonemarrow failure. Symptomatic anemia, hemoglobin less than 8 g/dL, thrombocytopenia less than 10,000/ L, as well as signs of bleeding must be corrected. The threshold for platelet transfusion may be lower if conditions known to increase the risk of bleeding such as severe mucositis, fever, anemia, and coagulopathy are present. Blood products should be leucoreduced to decrease the risk of febrile nonhemolytic transfusion reaction, alloimmunization to human leucocyte antigens, which may lead to subsequent refractoriness to platelet transfusion, and transmission of cytomegalovirus (CMV). Additionally, blood products should be irradiated to reduce the risk of transfusion-related graftversus-host disease (GVHD). Patients who are potential candidates for hematopoietic stem cell transplant (HSCT) should be screened for CMV and receive CMV-negative blood until CMV status is determined (see Chapter 29).
F. Human leukocyte antigen (HLA) typing
Patients who are candidates for HSCT should be HLA typed before the initiation of therapy, because chemotherapy-induced severe myelosuppression will not leave enough lymphocytes for HLA typing. However, occasionally an inadequate number of circulating lymphocytes and the presence of blast cells preclude the ability to carry out HLA typing before initial therapy. HLA-matched platelet transfusions may need to be administered to patients who develop alloimmunization and become refractory to pooled or single-donor platelets.
G. Fever or infection
Patients frequently have a fever or an infection at initial diagnosis. The approach to fever and infection is discussed in Chapter 28. The cardinal rule is that all patients with acute leukemia and fever are presumed to have an infection until proved otherwise. Given the additional myelosuppressive and immunosuppressive effects of chemotherapy, severe infections should be treated aggressively before initiating chemotherapy. However, the antibiotic treatment frequently needs to be administered concurrently with induction chemotherapy. Patients with acute leukemia need a careful physical examination daily. There should be close attention toward potential sites of infection, including the fundi, sinuses, oral cavity, intertriginous areas, perineum (attempts are made to avoid internal rectal examination during
P.457
neutropenia), and catheter sites. A dental consultation at the time of diagnosis is often useful.
H. Vascular access
Because of the need for several sites of venous access for at least 1 month, a multiple-lumen implantable catheter (e.g., Hickman catheter or peripherally inserted central catheter [PICC] line) must be placed as soon as possible (except in patients suspected to have APL). An implantable port is not recommended for leukemic patients because there is higher risk of infection and hematoma at the access site. Because of the coagulopathy in patients with APL, the placement of a long indwelling catheter is avoided until the coagulopathy has been corrected. A risk of life-threatening bleeding in patients with APL is present even if most or all of the routine coagulation studies are normal.
I. Suppression of menses
A serum beta human chorionic gonadotropin ( -hCG) assay (pregnancy test) should be done in all premenopausal women before initiation of chemotherapy. It may be desirable to prevent menses during chemotherapy to avoid severe menorrhagia due to thrombocytopenia. Medroxyprogesterone (Provera) 10 mg twice a day may be started 5 to 7 days before the expected starting time of the next menstrual period. It may be increased to 10 mg three times a day or higher if breakthrough bleeding occurs. Depo-Provera is contraindicated in the thrombocytopenic and neutropenic patient.
J. Birth control and fertility
Given the potential teratogenic effects of cytotoxic chemotherapy, appropriate measures for preventing conception must be addressed with women of reproductive age undergoing chemotherapy. Although there are no clear data linking chemotherapy in the male partner to teratogenic effects in the fetus, it is prudent to suggest that appropriate birth control measures be undertaken in this situation as well. Late effects of chemotherapy, such as infertility, need to be considered in younger patients. Sperm cryopreservation should be offered to men of reproductive age before initiation of chemotherapy. Gonadal function in women seems to be less affected by cytotoxic chemotherapy. Cryopreservation of the fertilized eggs is currently available, whereas cryopreservation of unfertilized eggs may be conducted on an investigational basis. Treatment with a gonadotropin-releasing hormone (GnRH) agonist analog to induce a temporary prepubertal milieu is an additional option that may be considered in women of reproductive age.
K. Psychosocial support
Patients with acute leukemia are usually previously healthy individuals who have suddenly had to accept the possibility of their own imminent mortality. Intensive psychological and spiritual support by the health care team, family, and religious leaders is critical for maintaining the patient's sense of well-being (see Chapter 33).
III. Therapeutic principles and approach to therapy of acute leukemia
A. Therapeutic aim
The goals of chemotherapy are to eradicate the leukemic clone and to re-establish normal hematopoiesis in the bone marrow. Long-term survival is seen only in patients in whom a CR is attained. Although leukemia therapy is toxic and infection is the major cause of death during therapy, the median survival time of untreated (or unresponsive)
P.458
acute leukemia is 2 to 3 months, and most untreated patients die of bone marrow failure and its complications. The doses of chemotherapy are never reduced because of cytopenias, as lowered doses still produce the unwanted side effects (further marrow suppression) without having as great a potential for eradicating the leukemic clone and ultimately improving marrow function.
B. Forms of chemotherapy
Induction chemotherapy is initial intensive chemotherapy given in an attempt to eradicate the leukemic clone and to induce a complete remission (CR). The term CR depicts patients who achieve recovery of normal peripheral blood counts with recovery of bone marrow cellularity, including the presence of less than 5% blast cells, in the absence of extramedullary disease. The aim of induction chemotherapy is to reduce the leukemia cell population by several logs from the clinically detectable leukemia tumor burden of 1011 to 1012 cells, commonly seen at diagnosis, to below the morphologically detectable level of 109 cells. It is important to note that because achievement of initial CR represents only a 3- to 6-log leukemia cell reduction, a substantial leukemia cell burden persists, and patients usually relapse within months if further therapy is not administered.
Postremission chemotherapy is administered subsequently to achieve a CR in a further attempt to eradicate the residual, but often undetectable, leukemic clone. In a younger patient population, considering the relatively high rate of CR after the induction, future advances are likely to bemade through improved postremission therapy. Patients older than 60 years, tend to achieve a suboptimal CR rate of 40% to 60% and poor 5-year OS of approximately 10%, and should be enrolled in investigational protocols aimed at improving induction and consolidation therapy.
Consolidation therapy involves repeated courses of the same drugs at similar or higher doses as those used to induce the remission, which are given soon after the remission has been achieved (2 3 weeks after the recovery of blood counts). Consolidation often requires further hospitalization.
Maintenance therapy pertains primarily to ALL, and includes low doses of drugs designed to be administered on an outpatient basis for up to 2 years. In AML, this strategy applies only to APL.
Definition of response is based on the peripheral blood counts and the status of the recovered bone marrow. If the marrow is hypoplastic, it is imperative to repeat the bone marrow biopsy to document remission upon recovery.
Complete response (complete remission, CR) is the return of the complete blood count to a normal absolute neutrophil count (ANC) of more than 1,500/ L and to a platelet count of more than 100,000/ L in conjunction with a normal bone marrow, that is, normal cellularity, less than 5% blasts or promyelocytes and promonocytes, an absence of obvious leukemic cells and
P.459
absence of extramedullary disease. Presence of minimal residual disease (MRD) as determined by flow cytometry or polymerase chain reaction (PCR) analysis is a predictor of the relapse. Relapse rates range from 0% in patients with less than 10-4 leukemic cells detected at the completion of the induction to 14% in those with 10-3 to 10-4 to 89% in patients with 1% residual disease.Partial response (PR) is the persistence of morphologically identifiable residual leukemia (5% 15% leukemic cells in the bone marrow).
IV. Therapy for adult AML (other than APL) (Table 19.7)
The day that induction chemotherapy is started is arbitrarily called day 1. Bone marrow aspiration and biopsy are repeated on approximately days 10 to 14. If the bone marrow is severely hypoplastic with fewer than 5% residual blasts or if the bone marrow is aplastic, no further chemotherapy is given, and the patient is supported until bone marrow recovery occurs (usually 1 3 weeks). A bone marrow examination is repeated 2 weeks later (~days 26 28). Once a CR has been documented, the potential benefit of further consolidation therapy should be determined on an individual basis.
A. Induction therapy
Factors that influence the choice of the initial chemotherapeutic agents include the patient's age, cardiac function, and performance status. Age 60 has traditionally been considered a cut-off point for recommending the induction chemotherapy because of higher prevalence of unfavorable cytogenetics, antecedent myelodysplasia, expression of multidrug-resistant protein as well as frequency and severity of comorbid conditions affecting the ability to tolerate intensive chemotherapy. The initial drug doses outlined in the following text are based on the presence of normal hepatic and renal functions and do not require modification for depressed (or elevated) peripheral blood counts.
P.460
Table 19.7. Therapeutic options for acute myeloid leukemia other than acute promyelocytic leukemia (outside of a clinical trial)a | ||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||
7 + 3 Cytarabine and anthracycline induction. During the last 30 years, a series of clinical trials have identified an induction regimen of cytarabine (Ara-C) and anthracycline that is now considered standard (Table 19.8). The most widely used combination includes cytarabine 100 mg/m2 by continuous IV infusion for 7 days and daunorubicin (DNR) 45 to 60 mg/m2/day IV for 3 days (known as 7 + 3). Although many investigators have strong personal biases regarding the choice of anthracycline or anthracenedione for induction therapy, we would consider daunorubicin, idarubicin, and mitoxantrone as essentially equivalent choices on the basis of current data. All three should be considered potentially cardiotoxic.
Dose intensification. The merit of cytarabine dose intensification has been explored in several clinical trials. On thewhole, it appears that induction therapy with HDAC (high-dose Ara-C) plus DNR is associated with greater toxicity than SDAC (standard dose Ara-C) plus DNR, but without improvement in CR rate or survival. Hence, the addition of HDAC to induction regimens outside the clinical trial remains controversial.
Other regimens. Many permutations to the standard 7 + 3 regimen have been studied over the years in attempts to improve the CR rate of induction therapy and prolong survival. Except in the unfavorable subgroup of patients, defined by lactate dehydrogenase (LDH) values greater than 700 U/L, more than 40% blasts in the day- 16 bone marrow, and unfavorable cytogenetics, in which TAD-HAM (thioguanine, cytarabine, and daunorubicin followed by HDAC and mitoxantrone) is associated with a
P.461
higher CR rate (65% vs. 49%) and 5-year survival (25% vs. 18%), these permutations do not provide lasting benefit.Table 19.8. Commonly administered induction regimens in acute myeloid leukemia
7 + 3 Cytarabine and anthracycline
Cytarabine 100 mg/m2/24 h continuous IV infusion on days 1 7 and
Daunorubicin 45 to 60 mg/m2 IV bolus on days 1 3 or
Idarubicin 12 mg/m2 IV bolus on days 1 3 or
Mitoxantrone 12 mg/m2 IV bolus on days 1 3
HDAC induction regimens for patients with cardiac disease
Cytarabine 2 3 g/m2 IV infusion over 1 2 h every 12 h for 12 doses, or
Cytarabine 2 3 g/m2 IV infusion over 2 h every 12 h on days 1, 3, 5HDAC, high-dose cytarabine (ara-C). The use of an anthracycline or an anthracenedione is contraindicated in patients with severe underlying cardiac disease, particularly if the patient has had a recent myocardial infarction or has an ejection fraction of less than 50%. The choice of therapy in this situation is HDAC, although the optimum dose and schedule of HDAC therapy are not known (i.e., number of doses, dosage, and infusion rate) (see Table 19.8).
Residual disease. Patients who have residual disease at day 28 should be considered primary treatment failures and have alternative therapy initiated. If a significant response has been demonstrated at the day-10 to day- 14 marrow (>50% 60% reduction in leukemic infiltration) but residual leukemia persists, a second course of similar chemotherapy (or an alternative regimen such as HDAC) is given. Patients with persistent significant involvement of leukemia on day 10 to 14 (<40% 50% leukemic reduction) should receive an alternative chemotherapy regimen. There is no dose modification for the second course based on blood cell counts. The doses of drugs may be decreased for the second cycle if the total dose of anthracycline would be cardiotoxic or hepatic dysfunction attributed to the chemotherapy develops.
Common HDAC toxicities. Neurotoxicity (cerebellar dysfunction, somnolence) occurs more frequently in older patients and as the number of doses of HDAC increases. Renal and hepatic dysfunction contributes to the development of neurotoxicity. One- to 2-hour infusions are generally recommended as opposed to the original infusion rate over 2 to 3 hours, as the neurotoxicity appears to be decreased with shorter infusion times.
Reducing the dose of cytarabine in the face of renal dysfunction may decrease the risk of neurotoxicity. The following schema has been suggested to decrease neurotoxicity in the face of renal dysfunction. For a baseline serum creatinine level of 1.5 to 1.9 mg/dL or an increase in serum creatinine of 0.5 to 1.2 mg/dL from baseline, reduce the cytarabine to 1 g/m2/dose. For a baseline serum creatinine of more than 2 mg/dL or an increase of serum creatinine of greater than 1.2 mg/dL from baseline, reduce the cytarabine dose to 100 mg/m2/day.
Because cytarabine is secreted in tears, ulcerative keratitis can be prevented by instilling eye drops (saline, methylcellulose, or steroid) every 4 hours while awake, and Lacri-Lube ophthalmic ointment (Allergan Pharmaceuticals) at bedtime, starting at the time HDAC is initiated and continuing for 2 to 3 days after the last dose of HDAC.
B. Postremission therapy
Despite attaining a CR, most patients with AML relapse, necessitating further therapy aimed at eradication of the residual yet undetected leukemic clone. There are three general treatment strategies for postremission therapy: consolidation chemotherapy, autologous hematopoietic stem cell transplantation (auto-HSCT), or allogeneic (allo) HSCT. Although the optimum postremission strategy remains
P.462
to be defined, almost all younger adults with AML benefit from further therapy. The type of postremission therapy should be determined on the basis of prognostic factors, particularly age and cytogenetics at diagnosis. Patients with AML in first CR should be considered candidates for experimental protocols examining postremission therapy options. For patients who cannot be enrolled in protocol studies, the approach to postinduction therapy used as a guide at Northwestern University is shown in Table 19.9. Consolidation should be initiated when the peripheral blood counts have returned to normal (ANC >1,500/ L and platelet count >100,000/ L), marrow cellularity is normal, infections have resolved, and mucositis has cleared.
Table 19.9. High-dose cytarabine (ara-C) consolidation regimens | |
|---|---|
|
AML with favorable cytogenetics, or so-called corebinding factor (CBF) leukemias, includes t(8;21), inv(16), and t(16;16) cytogenetics. There is increasing evidence that several courses of HDAC represent the best treatment option for this group of patients. The treatment-related mortality (TRM) of standard allo-HSCT makes this option currently prohibitive in this group of patients. Elevated WBC count (specifically, WBC index: WBC x [% of marrow blasts/100]) has been demonstrated to be an important prognostic factor in multivariate analysis for DFS and OS in t(8;21) AML. The French AML Intergroup reported the 3-year DFS and OS for t(8;21) patients with low WBC index (<2.5) to be 74% and 74%, respectively, as compared with the high WBC index (20 or above) group of 33% and 47%, respectively. Further clinical trials may identify a subset of AML patients with t(8;21), such as high WBC index, that may benefit from more intensive postremission therapy.
Current data suggest that HDAC offers a distinct advantage over standard-dose cytarabine consolidation in patients younger than 60 years. More than 40% to 50% of patients will be in a continuous CR 5 years after consolidation with HDAC.
AML with intermediate-risk cytogenetics. Longterm survival for patients presenting with intermediate cytogenetics is 40% to 45%. For patients younger than 60 years, data support the use of allo-HSCT as a postremission therapy. The largest collection of prospective cohort data in this subgroup by the Medical Research Council
P.463
(MRC) documented superior 3-year relapse rates of 18% for allo-HSCT, 35% for auto-SCT, and 55% for chemotherapy consolidation, and 3-year survival rates of 65%, 56%, and 48%, respectively. The U.S. Intergroup Study did not demonstrate advantage for allogeneic HSCT, although analysis was based on a much smaller cohort of patients. The optimal timing of allogeneic HSCT is yet to be established, although retrospective data collected from the International Bone Marrow Transplant Registry (IBMTR) demonstrated lack of additional benefit from receiving consolidation chemotherapy before matched sibling HSCT in first CR. In other words, patients in postinduction CR may proceed immediately to allogeneic HSCT.Patients who do not have an HLA-identical sibling should receive consolidation chemotherapy incorporating HDAC or similar therapy. The optimal number and duration of HDAC has not been established, but 2 to 3 g/m2 is recommended for two to four cycles in younger patients. In healthy patients, this may be followed by auto-HSCT. Autologous HSCT has been studied in this subgroup of patients but has not been shown to represent an advantage over consolidation chemotherapy alone in randomized studies conducted during the last decade.
AML with unfavorable cytogenetics. Despite the CR rates of up to 60%, this group of AML patients has the poorest long-term outcome, with reported 5-year OS of 11% (3% 20%) depending on the specific cytogenetic abnormality found at diagnosis (i.e., 3% 5% of patients with monosomy 5 and complex karyotype are alive at 3 years). The U.S. Intergroup Study demonstrated a significant longterm survival advantage for patients with unfavorable cytogenetics who received allo-HSCT for consolidation as compared with auto-HSCT or conventional chemotherapy. Although the total number of patients analyzed in this and similar trials has been small, matched-sibling allogeneic HSCT likely represents the therapy with the best current potential to prevent relapse. Moreover, select reports in younger patients have demonstrated long-term survival rates of 35% to 45% in patients undergoing mismatched sibling allo-HSCT and matched unrelated donor (MUD) HSCT. Despite 100-day mortality rates of approximately 35% to 40%, these strategies may represent the best therapeutic choice for select patients because of the dismal longterm outcome with unfavorable cytogenetics. Low-intensity myeloablative or nonmyeloablative HSCT procedures have allowed less fit and older patients to proceed to allogeneic HSCT for consolidation, but these techniques should still be considered investigational. For less fit patients or patients without a suitable matched donor, enrollment in experimental clinical trials testing novel strategies should be aggressively pursued. Alternative-donor transplantation is an area of active investigation.
C. Acute megakaryocytic leukemia
AmegL (FAB M7) is a rare AML subtype (1% 2%) not encompassed in the unfavorable group that has very poor long-term outcome. The Eastern Cooperative Oncology Group (ECOG) described 20 AmegL
P.464
cases out of 1,649 patients with newly diagnosed AML. The median age of patients described was 42 years, and 50% of patients entered CR with a median OS of 10.4 months (two patients remain alive). There have been only anecdotal reports of allo-HSCT for patients with AmegL. Novel therapeutic strategies are needed, including agents such as arsenic trioxide (As2O3), which has recently been demonstrated to inhibit growth and survival in megakaryocytic leukemia cell lines.
D. Relapsed AML
Significant number of patients with AML who achieve a remission will ultimately have a relapse. The goals of therapy for these patients vary from achievement of second CR with intensive chemotherapy and/or HSCT to best supportive care. The success of achieving a second CR varies greatly, depending less on cytogenetic characteristics but more on duration of first CR, age, and active comorbidities of the patient. The median duration of second CR is usually less than 6 months without HSCT, with long-term DFS rates of less than 10 months. Moreover, most standard salvage chemotherapy regimens induce significant toxicity. Survival is improved in patients who proceed to allo-HSCT with long-term OS rates that may approach 30% to 40%. Unfortunately, because of the lack of suitable availability of donors and patient morbidities, many patients are not eligible for allogeneic HSCT.
Options for the reinduction therapy include the immunoconjugate agent gemtuzumab ozogamicin (GO), intensive chemotherapy with conventional agents, investigational therapies on a clinical trial, immediate HSCT for the individual with a suitable allogeneic donor or cryopreserved autologous stem cells available, palliative-intent chemotherapy, or best supportive care. Individuals who relapsed after an allo-HSCT may be eligible for donor lymphocyte infusions as an immunologic maneuver to generate a graft-versus-leukemia (GVL) effect. The determination of the optimal therapy depends in part on the duration of the first remission, whether HSCT is planned, if a second CR is achieved, and the manner in which the relapse was detected. Individuals with remission less than 6 to 12 months in duration are best treated with investigational agents on clinical trials or, if feasible, immediate HSCT depending on the marrow blast percentage. Individuals with a remission greater than 18 to 24 months may be treated with more conventional salvage treatment that commonly includes a HDAC-containing regimen.
Gemtuzumab ozogamicin (GO), a recombinant humanized monoclonal anti-CD33 antibody conjugated to a highly potent antitumor antibiotic calicheamicin, is U.S. Food and Drug Administration (FDA) approved for the treatment of patients older than 60 years with CD33+ AML in first relapse who are not candidates for cytotoxic therapy. Most AML blast cells (80% 90%) express the CD33 surface antigen, whereas pluripotent hematopoietic stem cells/tissues and nonhematopoietic cells do not. After administration, GO is believed to be internalized into lysosomes, where the calicheamicin dissociates from the antibody, migrates to the nucleus
P.465
and causes double-stranded DNA breaks. Three multicenter trials demonstrated an overall response (OR) rate of 30% (16% CR with full platelet recovery) characterized by 5% or less blasts in the bone marrow, recovery of neutrophil count to 1,500/ L, and RBC and platelet transfusion independence following two doses of GO. Median relapse-free survival (RFS) was 6.8 months, median survival was 5.9 months, 1-year OS was 31%, and no differences were noted in age or duration of first remission. (Of note, patients with myelodysplasia or first CR of less than 3 months were excluded from the study.) Additionally, there is data to suggest efficacy of GO in CD33-AML patients.GO has been generally well tolerated with the most common side effect that patients experienced being a transient infusion-related syndrome (fevers, chills/rigors, nausea, pain, and hypotension). Notwithstanding, a significant minority of patients treated with GO have developed hepatic toxicity manifested as weight gain, ascites, jaundice, and abnormalities in the hepatic transaminases. A direct association of GO with liver injury may be confounded by prior and/or concomitant antileukemic cytotoxic therapies received by patients, but reports including patients who had received no prior antileukemic cytotoxic therapy (including patients who received single-agent GO) have infrequently documented significant liver injury. Results of liver histologic examination in five of seven patients who died with persistent liver dysfunction demonstrated sinusoidal injury with extensive sinusoidal fibrosis, centrilobular congestion, hepatocyte necrosis, and striking deposition of sinusoidal collagen, suggesting that GO targets CD33+ cells residing in hepatic sinusoids.
The risk of veno-occlusive disease (VOD) like syndrome appears to be higher in patients who proceed to allo-HSCT within 3 to 4 months of exposure to GO. Currently, the combination of GO with various chemotherapeutic and biologic agents as well as its role in eliminating MRD is being evaluated in clinical trials. Three recent studies, utilizing GO with intensive chemotherapy demonstrated a CR rate of approximately 85%.
Standard chemotherapy. The selection of conventional salvage therapy, the optimal dose of cytarabine, and the benefits of the addition of an anthracycline or other agents all remain important unanswered issues.
New agents and investigational strategies. Many new agents with diverse putative mechanisms of actions are currently evaluated in clinical trials.
In phase I and II studies, a novel nucleoside analog clofarabine, induced a 16% CR rate in patents with relapsed AML. When clofarabine was combined with cytarabine, the OR rate was 32% with CR rate of 22%. When clofarabine was administered to previously untreated older patients with AML, the CR was 60%.
Farnesyl transferase inhibitors (FTI), which interfere with retinoic acid syndrome (RAS) signaling pathway have activity in patients with newly diagnosed and refractory AML. In a recent study of older patients with newly diagnosed AML, orally administered FTI Zarnestra induced OR (CR + PR) of 39%, with CR 20% and median CR duration of 6.4 months.
The protein kinase C active agent bryostatin is actively being evaluated before and after HDAC therapy.
Internal tandem duplications (ITDs) of the receptor tyrosine kinase FLT3 gene have been found in 20% to 30% of patients with AML and are believed to confer a poor prognosis. Tyrosine kinase inhibitors that are active against FLT3 are being examined. So far, their success has been modest, with a 50% reduction in the peripheral blasts noted in 70% of patents and 50% bone marrow blast reduction in 10% of AML patients in one clinical trial. Some patients without ITD or activating loop mutation have responded to FLT3 inhibitors. Current clinical trials are evaluating FLT3 inhibitors in combination with chemotherapy.
Troxacitabine, a novel dioxolane nucleoside analog was shown to induce 26% responses in patients with relapsed/refractory AML.
Transcriptional therapy, histone deacetylase inhibitors (HDAC) and DNA hypomethylating agents are being studied in high-risk MDS and AML patients.
The proteasome inhibitor bortezomib appears to have single agent activity in leukemia and has in vitro synergistic activity with HDAC inhibitors.
Inhibition of P-glycoprotein (Pgp)-mediated cellular export of anthracyclines by Zosuquidar are being explored. The ECOG recently completed a prospective randomized trial of induction chemotherapy with and without Zosuquidar. Although addition of PSC-833, another multidrug resistance inhibitor, to anthracycline therapy provided no benefits over standard therapy, combination of Zosuquidar with GO in elderly patients who are not candidates for cytotoxic therapy is still being investigated.
A high level of expression of antiapoptotic protein BCL-2, confers poor prognosis on AML patients. Addition of BCL-2 inhibitor Genasense to chemotherapy resulted in a 45% CR rate.
P.466
Options for reinduction therapy. Depending on prior therapy, age, and perceived ability to tolerate subsequent systemic treatment, chemotherapeutic options using commercially available drugs would include the following:
Gemtuzumab ozogamicin. 9 mg/m2 as a 2-hour IV infusion is used on days 1 and 15. No dose adjustments for anemia or thrombocytopenia should be made. Benadryl may be administered before infusion. Acetaminophen has the potential to contribute
P.467
to hepatotoxicity (increased free radicals) and theoretically should be avoided.7 + 3. Up to half of patients who undergo induction with the 7 + 3 regimen respond to a repeat course of 7 + 3. Patients who relapse within 6 to 12 months of the last chemotherapy are unlikely to respond to the same regimen again. Therefore, a different regimen should be considered.
HDAC. Fifty percent to 70% of patients respond to HDAC. Although HDAC combination regimens may have a slightly higher response rate (RR), their increased toxicity may not make them significantly better than single-agent HDAC. Patients who relapse within 6 to 12 months of HDAC intensification are unlikely to have a significant response to further HDAC.
HDAC (see Table 19.9)
HDAC plus anthracycline, for example, HDAC 3 g/m2 IV infusion over 2 hours every 12 hours on days 1 to 4, plus mitoxantrone 10 mg/m2/day IV on days 2 to 5 or 2 to 6.
CAT
Cyclophosphamide 500 mg/m2 IV every 12 hours on days 1 to 3,
Topotecan 1.25 mg/m2/day by continuous infusion on days 2 to 6, and
Cytarabine 2 g/m2 IV over 4 hours daily for 5 days on days 2 to 6.
MEC. A variation of MEC currently used by the ECOG is as follows:
Etoposide 40 mg/m2/day IV infusion over 1 hour on days 1 to 5, followed immediately by
Cytarabine 1 g/m2/day IV infusion over 1 hour on days 1 to 5, and
Mitoxantrone 4 mg/m2/day IV sidearm push on days 1 to 5, given after completion of HDAC each day.
MEC may produce significant gastrointestinal and cardiac toxicity. It is not recommended for patients older than 60 years or those with borderline cardiac function.
ME. Mitoxantrone 10 mg/m2/day IV on days 1 to 5 and etoposide 100 mg/m2/day IV on days 1 to 5 represents an active and well-tolerated combination that is commonly used for relapsed or refractory leukemia.
High-dose etoposide 70 mg/m2/hour continuous IV infusion for 60 hours and high-dose cyclophosphamide 50 mg/kg (1,850 mg/m2)/day IV infusion over 2 hours on days 1 to 4 is a highly toxic but active regimen that does not require bone marrow support. It is active against HDAC-resistant AML (30% CR). This regimen may be useful for young patients who are good candidates for allogeneic HSCT while waiting for an unrelated donor search to be completed.
E.
CNS prophylaxis may be considered in patients at high risk of CNS recurrence such as patients with WBC more
P.468
than 50,000/ L or those with myelomonocytic (FAB M4) or monocytic (FAB M5) differentiation. Patients treated with HDAC (>7.2 g/m2) do not require intrathecal (IT) therapy as they achieve therapeutic drug level in the cerebrospinal fluid (CSF). If required, IT therapy with methotrexate (MTX) 12 mg or Ara-C 30 mg is used. For patients with CNS involvement (uncommon on presentation) chemotherapy should be administered through Ommaya catheter with 30 mg of hydrocortisone.
F. AML in older adults
AML is a disease of older adults as the median age of diagnosis is 68 years. Despite the refinements in supportive care and chemotherapy programs, the long-term survival rates have improved little over the last 30 years for patients older than 55 years. Standard remission induction and postremission therapy result in median DFS of 10 months and rare long-term survival. Because of the effects of comorbid disease and age on normal physiology, older adults are less able to withstand the inherent toxicity of induction chemotherapy than young adults. There are also intrinsic differences in the biology of AML in older adults: a higher percentage of the leukemic cells express P-glycoprotein (Pgp) at diagnosis (71% vs. 35% in younger patients) and existence of an overt or covert antecedent hematologic disorder that predispose to drug resistance. Moreover, AML in older adults is associated with a greater number of high-risk cytogenetic abnormalities (i.e., abnormalities of chromosomes 5 and 7 and complex karyotypes). As reported by the MRC, the favorable cytogenetic risk group (see Table 19.5) was less common in patients older than 55 years (7% vs. 26% in patients younger than 55 years), whereas complex karyotypes were more common (13% vs. 6%). Furthermore, patients older than 55 years with complex karyotype predicted a poor outcome with OS of 2% at 5 years. The MRC recognized a predictive hierarchical cytogenetic classification for older adults similar to previous analysis for younger patients, although 5-year OS for favorable cytogenetic group patients older than 55 was 34% compared with 65% for younger patients (13% and 41%, respectively, for intermediate cytogenetic risk).
The decision to forgo therapy in an older patient with AML should not be made a priori based solely on age; rather, the decision to treat or not to treat should be based on more substantive factors such as the presence of comorbid disease, performance status before diagnosis, quality of life before diagnosis, and projected long-term survival.
Induction therapy. In older AML patients, only one randomized study has ever shown a survival advantage of remission-induction therapy as compared to low-dose therapy or supportive care. The survival advantage of 10 weeks was almost exactly the time of hospitalization required for the induction and one cycle of consolidation chemotherapy.
In general, 55% to 70% of elderly patients without complex karyotype cytogenetics can achieve a CR with induction chemotherapy (20% 30% for complex karyotypes). Although attenuated doses of 7 + 3 have been recommended in the past, full-dose therapy is now generally recommended in older adults without significant comorbidities,
P.469
in part owing to improvements in supportive care. Continuous attempts have been made to improve the efficacy of this regimen by varying the doses of Ara-C and/or anthracycline; comparing one anthracycline or anthracenedione with another; combining with other chemotherapeutic agent; using growth factors as priming agents or as supportive care. Improved CR rates in many of the phase II studies were not confirmed in the randomized phase III trials.Standard 7 + 3
Cytarabine 100 mg/m2/day or 200 mg/m2/day IV continuous infusion on days 1 to 7, and
Daunorubicin 45 to 60 mg/m2/day IV bolus for 3 days or Idarubicin 8 to 12 mg/m2/day IV bolus for 3 days.
Modified HDAC decreases the cytarabine dose in an attempt to diminish the neurotoxicity that is dose-limiting in older adults. Modified HDAC is generally believed to be more toxic than the 7 + 3 regimen. We do not routinely recommend the use of HDAC for induction in older patients given the lack of data supporting improved remission rate and the significantly increased morbidity and mortality associated with HDAC during the induction period. In selected older patients with excellent performance status and a decreased ejection fraction, one can consider using modified HDAC. Although the optimum dose and schedule are not known, 1.5 to 2 g/m2 IV over 2 hours every 12 hours for 8 to 12 doses may be used.
Postremission therapy. Older patients may tolerate one to two cycles of lower doses of HDAC (1.5 g/m2 every 12 hours days 1, 3, and 5) than is usually given for younger adults, although a beneficial impact of HDAC consolidation chemotherapy on long-term outcome is not proved. The CALGB trial of varying doses of cytarabine (100 mg/m2/day, 400 mg/m2/day, and 3 g/m2) reported similar 5-year DFS and OS within each arm (each <15% and 8%, respectively). Other reports have demonstrated that prolonged consolidation courses (over four cycles) will likely not benefit long-term outcomes. Current experimental therapeutic strategies include incorporation of less intensive therapy, such as GO, FTIs, and bcl-2 antisense oligonucleotides into consolidation (and induction) therapy. Autologous HSCT may be considered for fit patients, although, as in younger patients, the optimal timing of this therapy is not known. Low-intensity allogeneic HSCTs have been performed in older patients, but this modality should still be considered experimental in this setting. In a recent series of 122 patients with AML who underwent nonmyeloablative allogeneic HSCT, the 2-year DFS was 44% in related and 63% in unrelated donor transplant recipients. Outside of the clinical trial, treatment options include the following:
HDAC 1.5 g/m2 IV infusion over 1 to 2 hours every 12 hours on days 1, 3, and 5 (better tolerated) for one to two monthly courses (with careful attention to cerebellar toxicity and to renal function; if either is noted to be apparent, HDAC should be immediately discontinued).
Cytarabine 100 mg/m2/day for 5 days for two to three courses but there are no data to show that these strategies are effective.
P.470
Overall, there is no definitive data showing that postremission therapy benefits older adults.
Newer therapeutic approaches include GO, BCL-2 inhibitors, FLT3 inhibitors, and FTI inhibitors, hypomethylating agents, and histone deacetylase inhibitors. Older adults are increasingly offered an option of undergoing nonmyeloablative (mini)-HSCT as a postremission therapy. Although most of the studies evaluating mini-HSCT are limited to single-institution experience, they show feasibility of this potentially curative approach in the older patient population.
V. Acute promyelocytic leukemia (APL)
APL is a distinct subtype of AML, designated m3 by the FAB classification. It accounts for 10% to 15% of cases of adult AML in the general population and 20% to 25% of AML cases in Latin America. The median age at presentation (40 years) is significantly lower than that of patients diagnosed with other AML subtypes (68 years). Owing to the remarkable sensitivity of APL to anthracyclines, all-trans retinoic acid (ATRA), and arsenic trioxide (ATO), it has become the most curable acute leukemia in adults, with cure rates exceeding 80% with contemporary therapeutic strategies. Despite a good overall outlook in APL, several factors adversely affect the outcome in this disease:
Age (>50 60)
Male gender
High WBC (>10,000/ L)
CD56 expression (not in all the studies)
A. Cytogenetic abnormalities and prognostic factors
The characteristic molecular genetic abnormality in APL is a balanced reciprocal translocation between the gene for retinoic acid receptor (RAR ) located on chromosome 17 and the gene for the promyelocytic leukemia (PML) located on chromosome 15, resulting in 2 hybrid gene products PML-RAR and RAR -PML. PML-RAR fusion protein, detectable by PCR technique, is essential for the diagnosis and identification of MRD. Four alternative chromosomal translocations have been identified (PLZF-RAR , NPM-RAR , NuMA-RAR , STAT5b-RAR ).
B. Management of coagulopathy in APL
Coagulopathy, a peculiar presenting feature of APL, must be managed aggressively at the suspicion of APL diagnosis, as it results in a high rate of spontaneous and potentially fatal hemorrhage. Pooled data through the late 1980s suggested that under the best of circumstances with cytotoxic induction chemotherapy, 5% of APL patients would die of CNS hemorrhage within the first 24 hours of hospitalization and another 20% to 25% would die of CNS hemorrhage during induction chemotherapy. With intensive supportive care and the introduction of all-trans retinoic acid (ATRA) therapy, the most recent studies suggest that less than 5% of patients will die of hemorrhage during induction chemotherapy, although overall induction mortality in APL remains approximately 10%. Regardless of clinical manifestations, essentially all patients with APL have laboratory
P.471
features of DIC. Management guidelines for coagulopathy in APL:
Initiate ATRA-based therapy at the suspicion of APL diagnosis.
Monitor DIC panel at least daily.
Maintain fibrinogen level at 100 to 150 mg/dL with cryoprecipitate transfusions.
Maintain platelet count at 30 to 50,000/ L.
Avoid central line placement.
Avoid aminocaproic acid.
C. APL therapy
On the basis of cumulative experience of multiple cooperative groups, therapy for APL should include simultaneous administration of ATRA and anthracycline-based chemotherapy for induction, ATRA and chemotherapy for consolidation and a combination of ATRA and chemotherapy for maintenance (for high-risk subgroups of patients).
ATRA, a vitamin A derivative, is able to induce a high rate (85%) of short-lived clinical remissions by promoting cell maturation, differentiation, and apoptosis without producing marrow hypoplasia. Two large randomized clinical trials have demonstrated that the addition of ATRA to chemotherapy during induction results in improved EFS and OS, as compared with the use of chemotherapy alone. Additionally concomitant and extended administration of ATRA with chemotherapy resulted in superior CR rates (87% vs. 70%), reduced 4-year relapse rate (20% vs. 36%), and superior 4-year OS (71% vs. 52%) as compared to the sequential administration of ATRA and chemotherapy.
In patients with APL, anthracycline monotherapy can induce 50% to 99% CR with 50% to 60% relapse rate and 30% to 40% survival rate at 2 years. Although the choice of anthracycline is still debated, in the ATRA era, idarubicin is more frequently used as amonotherapy, whereas daunorubicin is mainly used in combination with other drugs (typically cytarabine). However, the dose of anthracycline appears to be important. A retrospective analysis by the Southwestern Oncology Group (SWOG) suggested that a higher dose of daunomycin (70 mg/m2/day vs. 45 mg/m2/day) resulted in improved CR rate, OS, and DFS.
The role of cytarabine in the induction and consolidation regimens for APL remains controversial, as several retrospective analyses failed to show the difference in the rate of CR with its addition. Long-term outcome data from the PETHEMA (Spanish Cooperative Group for the Study of Hematologic Malignancies) studies also suggested that cytarabine could be safely omitted during induction and consolidation with excellent CR, DFS, and OS rates. However, the recent trial conducted by the European APL Group aimed at comparing daunorubicin and ATRA with and without Ara-C was closed prematurely because of the increased rate of relapse in daunorubicin/ATRA arm. Hence, the role of Ara-C in induction and consolidation remains unclear, except for the patients with high-risk disease, where intermediate dose Ara-C appears important.
In the pre-ATRA era several studies showed a definitive benefit of maintenance chemotherapy. Since the ATRA became
P.472
standard therapy, a combination of ATRA and low-dose chemotherapy was shown to be superior to ATRA alone, chemotherapy alone, and observation, in terms of relapse rate and DFS. However, two recent studies showed no advantage of maintenance therapy in patients who achieved a molecular remission after the 3-day cycle of consolidation. The optimal schedule, dose, and duration of maintenance therapy as well as a patient population most likely to benefit from maintenance are still under investigation.
Induction
ATRA 45 mg/m2/day PO is divided into two doses with food given every day until CR (no longer than 90 days) plus an anthracycline, either daunorubicin 45 to 60 mg/m2/day for 3 days or idarubicin 12 mg/m2 every other day for 4 days. In the modified regimen used by the PETHEMA group, the fourth dose of idarubicin was omitted in patients older than 70 years.
It appears reasonable to initiate treatment with ATRA first for 2 to 3 days in patients with clinical evidence of bleeding to ameliorate the coagulopathy before initiating anthracycline-based therapy, provided the WBC count is not high (<10,000/ L). Otherwise, concurrent ATRA plus anthracycline-based therapy has been routine practice and may have the advantage of decreasing the incidence of RAS (see the following text). With ATRA and anthracycline, hematologic CR rate of greater than 90% are expected. Patients, who do not achieve a hematologic CR by 90 days, should be treated with alternative therapy. Presence of MRD (50% after induction) as determined by RT-PCR does not appear to have prognostic implications and does not warrant change in therapeutic approach. The role of cytarabine in induction remains unclear.
Consolidation. The goal of consolidation therapy is an achievement of molecular remission as determined by the RT-PCR, as it has been convincingly correlated with the improved outcome. Two to three cycles of anthracycline-based chemotherapy may be given, as in the North American Intergroup trial:
Daunorubicin 50 to 60 mg/m2/day IV for 3 days, or
Idarubicin 5 mg/m2/day on days 1 to 4 (consolidation no. 1), mitoxantrone 10 mg/m2/day on days 1 to 5 (consolidation no. 2), and idarubicin 12 mg/m2 on day 1 only (consolidation no. 3), as in PETHEMA regimen or
Daunorubicin 60 mg/m2/day IV for 3 days and Ara-C 200 mg/m2/day IV for 7 days, as in European APL 93 regimen
The addition of ATRA may be considered, and if PCR negative state is not achieved at the completion of consolidation, a salvage regimen should be initiated (HDAC or intermediate dose Ara-C, arsenic trioxide, GO or a clinical trial).
Maintenance
ATRA 45 mg/m2/day PO, divided into two doses with food for 15 days every 3 months (or 7 days on/7 days off)
P.473
plus 6-mercaptopurine 90 to 100 mg/m2/day plus MTX 10 to 15 mg/m2/week all for 2 years, orATRA 45 mg/m2/day, PO, divided into two doses with food for 1 year, or
ATRA 45 mg/m2/day, divided into two doses with food for 15 days every 3 months for 2 years.
Follow-up of PCR for PML-RAR every 3 to 6 months for 2 years and then every 6 months for 2 years has been considered in the past. However, because contemporary strategies now result in a relapse rate of only 5% to 20%, this schedule may not be necessary in all patients but can rather be carried out in high-risk patients.
Retinoic acid syndrome (RAS) is a complication of ATRA therapy, which manifests by unexplained fever, weight gain, respiratory distress, pericardial and pleural effusion, periodic hypotension, and acute renal failure. Typically, RAS occurs between the second day and the third week of ATRA therapy, with the incidence between 5% to 27% and a mortality (of those who develop RAS) between 5% and 29%. Although a rising WBC count may be a risk factor for RAS, it may occur with a WBC count below 5,000/ L. If the WBC count is more than 5,000 to 10,000/ L on presentation, ATRA and chemotherapy should be given concurrently. If the WBC count rises to more than 10,000/ L during ATRA monotherapy, induction chemotherapy should added. Regardless of the WBC count or the risk of neutropenic sepsis, at the first sign of RAS, dexamethasone (10 mg IV twice a day) should be initiated. If the symptoms are mild, ATRA may be continued concomitantly with steroids under careful observations. However, if the symptoms are severe or do not respond to steroid therapy, ATRA should be temporarily discontinued. Several uncontrolled trials reported a very low-mortality rate with the prophylactic corticosteroid therapy in patients with leukocytosis; however, no prospective randomized studies were conducted to address this issue.
Relapsed APL
Arsenic trioxide (ATO, As2O3). Approximately 10% to 30% of patients treated with a combination of ATRA and chemotherapy eventually relapse. Although second remissions with standard therapy are common, particularly if the last exposure to ATRA occurred more than 6 to 12 months before relapse, they are not durable. Several clinical trials show that ATO has remarkable activity in this patient population leading to its FDA approval in this setting. Preclinical mechanisms of action of ATO include apoptosis and APL cell differentiation. Chinese investigators demonstrated CR rates of at least 85% and 2-year DFS of 40% in patients with relapsed APL. A U.S. multicenter study of ATO for induction and consolidation therapy for relapsed APL confirmed the high CR rates and long-term survival, and most importantly, 85% rate of molecular remission after the completion of the consolidation therapy. Combination of arsenic trioxide with other active agents (ATRA,
P.474
chemotherapy, GO) for the relapsed APL (induction and consolidation phases) are actively being studied.ATO, either alone or in combination with ATRA, results in remission rates in excess of 90% in previously untreated patients. Incorporation of ATO into the consolidation regimen of first CR has been evaluated by the U.S. Intergroup APL trial (the results are pending). The most significant toxicities associated with ATO therapy include ventricular arrhythmia caused by the prolongation of QT interval, hyperleukocytosis, and APL differentiation syndrome.
Other therapies. Despite the high initial CR rates in relapsed disease, many patients relapse following arsenic-based treatment. Results of retrospective studies have demonstrated that HSCT may be an effective option at this point or upon achievement of second CR following ATO therapy, particularly autologous HSCT when molecular negative cells are harvested and reinfused.
A high rate of CD33 expression on the promyelocytes and in vitro activity of GO in ATRA and ATO-resistant leukemia cell lines provided a rationale for GO therapy in patients with APL. In patients with evidence of molecular relapse, single-agent GO reinstated the molecular remission in 14 out of 16 patients while 2 patients suffered from the disease progression. Combination of GO and ATRA in previously untreated patients resulted in 88% CR rate.
HSCT is routinely considered as a postconsolidation modality in second CR (CR2). However, most studies of HSCT in CR2 were conducted before introduction of ATO. Considering that most of the patients with relapsed and refractory disease can be successfully treated with ATO without introducing transplant-related toxicity, the optimal timing of the transplant is unclear.
Treatment regimens for relapsed APL
Arsenic trioxide
Induction 0.15mg/kg IV over 2 hours daily until bone marrow remission occurs, up to a cumulative maximum of 60 doses. Bone marrow biopsy should be obtained on or before day 28 of therapy, and subsequently weekly until CR.
Consolidation start 3 to 4 weeks after completion of the induction therapy at 0.15 mg/kg IV over 2 hours daily for 5/7 days, for a cumulative total of 25 doses.
Maintain potassium levels more than 4 mEq/L and magnesium levels more than 1.8 mg/dL. Monitor the heart frequently with an ECG. If QTc interval remains normal the ECG frequency may be reduced to once every 2 weeks. Monitor WBC count and for signs of APL syndrome. Institute steroids (dexamethasone 10 mg IV b.i.d.) at the earliest suggestion of the APL syndrome.
HSCT. Patient should be referred for the evaluation for HSCT, with options being allo-HSCT if the patient
P.475
fails to achieve a molecular remission and auto-HSCT if in a molecular remission.
VI. Secondary AML
AML that develops after exposure to the alkylating agent is characterized by cytogenetic abnormalities involving chromosomes 5 and/or 7, a long latency (7 10 years), and, frequently, an antecedent MDS. Patients who develop AML following exposure to topoisomerase II inhibitors have a rearrangement of chromosome 11q23 (MLL), a relatively short latency period (2 3 years), and myelomonocytic or monocytic differentiation. High-dose chemotherapy with HSCT has been increasingly implicated in the pathogenesis of secondary leukemias. In one study, the estimated cumulative probability of developing therapy-related MDS or AML was approximately 8.6% 2.1% at 6 years among 612 patients undergoing high-dose chemotherapy and HSCT for Hodgkin's disease and non Hodgkin's lymphoma. The most important risk factor appears to be large cumulative doses of alkylating agents. However, patient age and previous radiotherapy, particularly total-body irradiation as part of the conditioning regimen, are additional risk factors.
Although up to 50% of patients with therapy-related AML may achieve a CR with chemotherapy, the median remission duration is approximately 5 months. Recent data suggest that secondary AML with favorable cytogenetics has an RR similar to that of de novo AML with the same cytogenetic features. Therapeutic options include supportive care, 7 + 3, HDAC, or other chemotherapy regimens. Younger patients with secondary AML should be considered for allo-HSCT in first remission. All patients should be treated on a clinical trial if at all possible. Amonafide, a topoisomerase II inhibitor that has shown promising activity in patients with AML, particularly AML arising on the background of MDS, is being evaluated in combination with ARA-C in clinical trials.
VII. AML during pregnancy
The outcomes of both the mother and the fetus must be considered when discussing the therapeutic options for a pregnant woman who develops AML. Therapeutic abortion must be considered if AML develops during the first trimester. If therapeutic abortion is not an option or if AML develops during the second or third trimester, induction chemotherapy may be undertaken. Although there is a slightly increased risk of premature labor and fetal death, in most cases 7 + 3 appears to be well tolerated by both the patient and the fetus.
VIII. Role of HSCT in AML (see also Chapter 5)
A. Allogeneic
Matched-sibling allogeneic HSCT has emerged as an important and potentially curative postremission strategy for many AML patients. Initial studies in patients with relapsed and refractory disease have administered high-dose chemotherapy (cyclophosphamide and total-body irradiation) followed by the HLA-matched sibling bone marrow derived stem cells, curing 10% to 15% of patients, who would otherwise have died of the disease. Similar studies conducted in patients in first CR increased cure rate to approximately 50% despite a treatment-related mortality (TRM) rate of approximately 20%. Multiple studies from single institutions and cooperative groups have confirmed these results. As discussed
P.476
in Chapter 5, the important benefit attributable to the success of this strategy is the phenomenon of GVL effect whereby the donor cells recognize the recipient's cells, including leukemia cells, as foreign, with resulting cytotoxicity.
B. Autologous
The lack of a suitable HLA-matched donor and TRM limit the application of allogeneic transplantation. Alternatively, autologous HSCT is potentially available to all patients and has very low TRM rates (currently 3% or less in contemporary series and in a recent ECOG trial where there were no transplant-related deaths among 60 consecutive patients studied).
C. Matched unrelated donors (MUD)
MUD transplant registries have grown, and this, coupled with more sensitive tissue-typing techniques, has become an effective approach for more patients. However, there are limitations to this strategy, including donor availability, length of time to identify the donor, and significant TRM (historically, approximately 30% 35%), and the exact role of MUD transplantation in patients with AML has not been established.
D. Haploidentical transplantation
Another alternative donor is a haploidentical family member. Almost every patient will have such a suitable donor available, and there is little reason for delay in proceeding to transplant beyond that present for an HLA-matched sibling donor transplant. This treatment is associated with delayed immune reconstitution and opportunistic infections, particularly CMV. Nevertheless, this approach is promising and warrants further research.
E. Umbilical cord transplants
Finally, hematopoietic stem cells procured from umbilical cords from related and unrelated donors can also restore hematopoiesis with acceptable risks of GVHD. This approach has been limited by the size of the recipient because it has often been difficult to collect enough stem cells. Simultaneous use of two umbilical cord transplants and ex vivo expansion of stemcells is an area of active research that may expand the application of umbilical cell transplantation.
F. Clinical trials of HSCT in AML
Several studies have compared prospectively the benefits of intensive consolidation with HDAC, autologous, and HLA-matched HSCT.
A recent European Organisation for Research and Treatment of Cancer (EORTC)/GIMEMA trial compared auto-HSCT with matched siblingHSCT for patients younger than 46 years, stratified by the cytogenetic risk. In the favorable risk group, the DFS for auto-HSCT and allo-HSCT were 66% and 62%, respectively, whereas treatment related mortality (TRM) was 6% and 17%, respectively. The outcome of patients treated with auto-HSCT was similar to the ones achieved with several cycles of HDAC. Hence, several cycles of consolidation HDAC chemotherapy is recommended for patients with favorable cytogenetics. Patients with intermediate cytogenetics achieved a 4-year DFS of 48.5% for allo-HSCT and 45% for auto-HSCT, similar to the 5-year DFS in patients treated with intermediate or high-dose cytarabine of 41%. For patients with high-risk cytogenetics or secondary AML, allo-HSCT produces DFS of 43%, similar to DFS for MUD HSCT reported by the IBMTR. In contrast the outcome of auto-HSCT was once again similar to the outcome of chemotherapy with poor DFS of 18%. Several
P.477
clinical trials are exploring the utility of reduced intensity allogeneic HSCT as a consolidation strategy in patients older than 60 years.
IX. Therapy for adult ALL (Tables 19.10 and 19.11)
Over the last 30 years, significant advances have been made in the management of adult ALL. Current therapeutic strategies incorporate a more intensive induction and postremission regimens and take into account biologic and clinical features of the disease.
P.478
P.479
P.480
P.481
P.482
P.483
P.484
Despite an excellent initial response to therapy (CR 80% 90%), the overall long-term DFS is 35% to 50% in adult patients with ALL. Most chemotherapeutic regimens for ALL have been developed as complete programs without testing the contributions of the individual components, and have not been compared with one another in a rigorous prospective randomized manner. All patients undergoing therapy for ALL should be enrolled in clinical trials.
Table 19.10. Initial therapeutic options for acute lymphoblastic leukemia outside a clinical triala | |||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |||||||||||||||||||||||||||||
Table 19.11. Examples of regimens frequently used for the management of acute lymphoblastic leukemia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The goals of intensified therapy are to eliminate leukemia cells, as determined by light microscopy and flow cytometry, before the emergence of drug-resistant clones, to restore normal hematopoiesis, and to provide adequate chemoprophylaxis for the sanctuary sites such as CNS. A typical ALL regimen consists of induction, consolidation/intensification, and maintenance; CNS prophylaxis is usually administered during induction and consolidation.
A. Induction
The addition of an anthracycline to the standard pediatric ALL induction regimen of vincristine, prednisone, and L-asparaginase increased CR rates in adults from 50 60% to 70 90% and median duration of the disease remission to approximately 18 months. In some studies dexamethasone has been substituted for prednisone because of its higher in vitro activity and better CNS penetration. Although L-asparaginase proved to be of value in the pre anthracycline era, its role in anthracycline-based adult programs is unclear. Given the significant toxicity of L-asparaginase, many investigators no longer recommend its use, particularly in older patients.
Attempts to further improve the outcome of patients with ALL led to the incorporation of agents such as cytarabine, cyclophosphamide, etoposide, mitoxantrone, and MTX in the induction and postinduction therapy. It is unclear if intensification with additional agents or the use of multiple phases of induction therapy improved CR rates in the unselected patients; however, it may benefit certain subgroups.
The use of growth factors during induction may alleviate complications of prolonged bone marrow suppression and avoid delays in delivering dose-intensive chemotherapy. In a double-blind, randomized trial conducted by the CALGB, administration of granulocyte colony-stimulating factor (G-CSF) shortened the duration of neutropenia from 29 days in the placebo group to 16 days in the G-CSF group. The CR rates were higher with G-CSF (90% vs. 81%), whereas induction mortality was higher in the placebo group (11% vs. 4%).
B.
Consolidation therapy typically includes three to eight cycles of non cross-resistant drugs administered after remission induction. As mentioned in the preceding text, no randomized studies have compared the existing regimens.
C. Maintenance
The benefit of therapy in adult ALL patients is unclear. In patients with low-risk disease, who enjoy outcomes similar to pediatric patients, maintenance therapy appears to be justified. Considering that more than half the number of the high-risk patients have a relapse while undergoing maintenance therapy, alternative strategies of eradicating MRD are urgently needed. The utility of
P.485
maintenance therapy has been questioned for T-cell ALL patients and it is not given for patients with mature B-cell ALL.
The traditional maintenance regimen is given for 2 to 3 years and includes daily doses of 6-mercaptopurine (6-MP), weekly doses of MTX, and monthly doses of vincristine and prednisone. Dose intensification or extension of maintenance beyond 3 years does not appear to be of benefit, whereas its omission has been associated with shorter DFS.
D. Minimal residual disease (MRD) in ALL
The aim of induction therapy in ALL is to reduce the leukemia cell population from 1011 to 1012 cells to below the cytologically detectable level of 109 cells. At this point, a substantial leukemia cell burden (i.e., MRD) persists and patients relapse within months without subsequent therapy. As described in the preceding text, standard ALL protocols require approximately 2 to 3 years of systemic therapy. Most ALL patients in continuous CR for 7 to 8 years are considered cured, although late relapses have been reported. Various techniques such as flow cytometry and PCR, using either fusion transcript resulting from the chromosomal abnormalities or patient-specific junctional regions of rearranged Ig and TCR genes, can be used to detect approximately one to five blasts per 100,000 nucleated cells. There is a significant correlation between the presence of MRD and early disease recurrence, particularly with greater than 10-2 residual blasts per 2 x 105 mononuclear bone marrow cells immediately after disease remission or greater than 10-3 at a later time. Although it is clear that MRD positivity is associated with increased rate of disease recurrence, large randomized studies are needed to incorporate MRD results into the treatment paradigm for adults with ALL.
E. CNS leukemia
CNS leukemia prophylaxis is an essential part of ALL therapy, as it has clearly been shown to reduce the incidence of CNS disease. Although uncommon at diagnosis (>10%), without CNS-directed therapy, 50% to 75% of patients will develop CNS disease. Depending on the protocol, CNS prophylaxis includes IT chemotherapy with MTX, Ara-C, and steroids, high-dose systemic chemotherapy with MTX, Ara-C, L-asparaginase, craniospinal irradiation (RT), or a combination of both. None of the combinations have been definitively proven to be superior to the others. The role of cranial RT has become controversial, because of the significant neurologic complications such as seizures, intellectual and cognitive impairment, dementia, and development of secondary CNS malignancy.
In adults, features that correlate with high-risk of development of CNS disease include mature B-cell ALL, serum LDH higher than 600 IU/L, and a proliferative index more than 14% (% S phase + G2M phase).
The commonly used regimens for CNS prophylaxis include the following:
MTX, 12 mg/m2 (maximum 15 mg), diluted in preservative-free saline, given IT once a week for 6 weeks. Some investigators also give 10 mg of hydrocortisone succinate IT to prevent lumbar arachnoiditis.
P.486
The IT MTX is given in an in-and-out manner. One to 2 mL of the MTX solution is injected into the spinal canal. Then, 0.5 to 1 mL of spinal fluid is withdrawn back into the syringe. This in-and-out process is repeated until all of the MTX has been given. This method is used to ensure that the MTX is actually given into the subarachnoid space. Leucovorin 5 to 10 mg may be given orally every 6 h for four to eight doses to ameliorate the mucositis, although this is usually not needed unless the patient is receiving concurrent systemic MTX. Complications of MTX include chemical arachnoiditis and leukoencephalopathy.
In the MD Anderson Hyper-CVAD regimen, IT MTX 12 mg on day 2 and cytarabine 100 mg on day 8 of each of eight cycles was administered to high-risk patients and on each of four cycles in low-risk patients.
Cranial irradiation with IT MTX has usually been initiated within 2 weeks of attaining a CR when classic maintenance is given. Cranial irradiation is usually given to the cranial vault (anteriorly to the posterior pole of the eye and posteriorly to C2) in 0.2 Gy fractions for a total of 18 to 24 Gy. The spine is not irradiated because marrow toxicity significantly limits the ability to give further chemotherapy. Common acute complications of radiation include stomatitis, parotitis, alopecia, marrow suppression, and headaches.
CNS leukemia therapy is similar to CNS prophylaxis.
Cranial irradiation is usually given to a total of 30 Gy in 1.5 to 2 Gy fractions.
IT chemotherapy is given in the manner described for CNS prophylaxis and is repeated every 3 to 4 days, with appropriate laboratory studies being done with each lumbar puncture (LP). When blast cells are no longer seen on the cytospin preparation, two more doses of IT drug are given, usually followed by a monthly maintenance IT injection.
Some investigators advocate either a simultaneous or alternating administration of IT Ara-C and MTX. The use of systemic therapy with high-dose cytarabine 1 to 3 g/m2 IV infusion over 2 hours every 12 hours is also effective for the treatment of CNS leukemia. A practical approach is to initiate IT chemotherapy until the time that the HDAC is started. Further IT therapy can then be given on the basis of the results of subsequent CSF analysis after the HDAC is completed. A slow-release formulation of Ara-C (DepoCyt) that maintains cytotoxic concentrations for approximately 14 days has been demonstrated to be effective for the treatment of lymphomatous meningitis and solid tumors and is under evaluation in acute leukemia.
Guidelines for the management and prophylaxis of CNS disease. Obtain the diagnostic LP once the leukemic blasts are cleared from the peripheral blood (to preclude the CNS contamination in the event of traumatic LP). The first dose of IT chemotherapy could be given at the same time. Presence of lymphoblasts in the CSF
P.487
(>5 lymphocytes/ L and blasts on the differential or any lymphoblasts in the CSF) usually signifies CNS disease, although false-negative results are possible with predominantly cranial nerve involvement by leukemia. Patients presenting with clinical symptoms consistent with CNS involvement, such as headache, altered sensorium, and cranial nerve (particularly VI) palsy warrant an immediate CNS imaging and LP because neurologic dysfunction is most amenable to therapy within the first 24 hours. Infectious meningitis must also be excluded in the immunocompromised host. Consider Ommaya placement for patients with diagnosed CNS involvement or patients at high risk of developing CNS (as they will require longer CNS therapy). Isolated CNS relapse usually heralds bone marrow relapse if systemic therapy is not changed. Therefore, isolated CNS relapse is usually treated with systemic reinduction chemotherapy and IT chemotherapy, followed by cranial irradiation.
F. PrecursorB-cell lineage and T-cell acute lymphoblastic leukemia (ALL)
Although T-cell ALL previously had a poor prognosis with standard induction and maintenance chemotherapy, with the advent of more intensive chemotherapy regimens, RRs and long-term DFS are comparable with those for precursor B-cell ALL. RR of 100% and projected longterm DFS of 59% were demonstrated by the regimen devised by Linker et al. in 2002 for T-cell ALL. CALGB 8811 protocol produced a 100% CR rate with a 3-year RFS of 63% for a similar group of patients. Precursor B-cell and T-cell ALLs are treated with similar regimens in most contemporary protocols.
G.
Mature (Burkitt) B-cell ALL is rare, constituting 2% to 4% of cases of adult ALL, and is associated with HIV syndrome. Characteristic clinical features include frequent CNS involvement, lymphadenopathy, splenomegaly, and high serum LDH levels. Current pediatric studies designed specifically for B-cell ALL, utilizing shorter duration, dose-intensive systemic chemotherapy and early CNS prophylaxis/treatment, have substantially improved the CR rate to approximately 90% and the DFS to 50% to 87%.
With the use of these therapeutic strategies in children as a template, clinical trials with young adults have demonstrated long-term survival rates of 70% to 80%. The German BFM group reported the improvement of CR rate from 44% to 74%, the probability of DFS from 0% to 71%, and the OS from 0% to 51% when the intensive treatment was compared with a standard ALL regimen. Hyper-CVAD regimen modeled by the MD Anderson Cancer Center after the total therapy B (see Hyper-CVAD, Table 19.11) induced a CR of 90% and cure rate of 70% in patients younger than 60, and a CR rate of 67% with cure rate of only 15% in older patients.
Addition of anti-CD20 antibody rituximab to the Hyper-CVAD regimen induced CR in 86% of patients, with 3-year OS, EFS, and DFS of 89%, 80%, and 88% respectively. Nine elderly patients achieved a CR with a 3-year OS rate of 89% (one patient died from infection in CR).
Hyper-CVAD therapy in combination with highly active antiretroviral therapy (HAART) regimen in HIV-positive patients
P.488
resulted in a CR rate of 92%, with more than 50% of patients alive at 2 years after the diagnosis. The outcome appeared to be improved in patients taking HAART medications early in the course of the therapy.
Recommendations for management of mature B-cell ALL include
R-Hyper-CVAD therapy or
MRC/ECOG regimen, or
CALGB regimen
One should also consider HIV testing and CNS prophylaxis.
H. Therapy for Ph+ ALL
Although the rates of CR in patients with Ph+ ALL are only slightly less than in those with Ph disease (60% 80%), the long-term DFS is less than 10%. In the CALGB 8461 study, the CR rate in Ph+ ALL was 79% and 5-year remission duration was 8% (vs. 38% in diploid ALL). Currently, allo-HSCT is recommended for Ph+ ALL patients in first remission as the only modality shown to provide long-term DFS. The MRC/ECOG international prospective ALL group compared the outcomes of Ph+ ALL patients treated with matched sibling allo-HSCT, matched unrelated allo-HSCT, auto-HSCT, and consolidation/ maintenance chemotherapy. The 5-year RR was lower in allo-HSCT group (29%) than with auto-HSCT/chemotherapy group (81%), whereas the 5-year survival rates were 43% and 19%, respectively. The treatment-related mortality (TRM), not surprisingly, was higher in the patients undergoing allo-HSCT; 43% for matched unrelated allo-HSCT; 37% for matched sibling HSCT; 14% for auto-HSCT; and 8% for chemotherapy.
Imatinib mesylate (Gleevec), a potent selective inhibitor of the bcr-abl tyrosine kinase, has been shown in phase I and II clinical trials to have substantial (CR 20% 58%), albeit nonsustained (42 123 days) activity in patients with relapsed and refractory Ph+ ALL. Administration of imatinib to 20 patients with Ph+ ALL relapsed after the allo-HSCT induced a CR in 55%. Incorporation of imatinib in the first-line chemotherapy regimen, such as Hyper-CVAD, is associated with the hematologic CR rates consistently higher than 90%, with concurrent administration resulting in greater antileukemic efficacy. Of interest, imatinib monotherapy in previously untreated patients results in the CR rate of approximately 95%, without the associated toxicity of chemotherapy.
Dasatinib (BMS-354825, Bristol-Myers Squibb) is a novel, oral kinase inhibitor that targets bcr-abl and SRC kinases, shows activity in Gleevec resistant Ph+ ALL, and had recently been FDA approved for CML. In a resent study 70% (seven out of ten) of patients with Ph+ ALL and CML with lymphoid blast crisis achieved a major hematologic response with dasatinib. Dasatinib is currently being evaluated in combination with chemotherapy for patients with Ph+ ALL.
I. ALL in older adults
The therapeutic advances and improved outcomes in children and young adults with ALL did not occur in older ALL patients. Likely reasons include fundamental biologic differences in the spectrum of ALL in this patient population, presence of coexisting medical conditions and decreased ability to tolerate intensive chemotherapy.
P.489
Additionally, older patients have been frequently excluded from the clinical trials. The outcomes of older ALL patients treated on the five sequential CALGB studies as compared to their younger counterparts have been demonstrated. The CR rate decreases from 90% in patients younger than 30 years to 81% in patients between 30 and 59 years, and to 57% in those older than 60 years; the 3-year OS is estimated to be 58%, 38%, and 12%, respectively. On the basis of the data provided by the Hoelzer and Pagano et al., from 1990 to 2004, for patients older than 60 years treated with intensive chemotherapy, the weighted mean CR rate was 56%; 23% suffered from early mortality and 30% had primary refractory disease.
In a randomized clinical trial evaluating the use of growth factors during chemotherapy for ALL, older patients enjoyed the greatest benefit. Therefore, it is recommended to administer growth factors during ALL treatment in older adults.
Full doses of VPD-based induction protocols are used in elderly patients with ALL. Some investigators decrease the dose of vincristine by 50%. The MRC UKALLIIX/ECOG E2993 and CALGB 8811 regimens should be considered for patients who are thought to be able to tolerate more intensive therapy.
Underlying cardiac disease may preclude the use of an anthracycline for induction therapy. An active program is MOAD, which is given in sequential 10-day courses (minimum three, maximum five) until remission is achieved (see Table 19.11) Once a CR has been attained, two additional courses of MOAD are given.
J. Salvage therapy for ALL
Although a second remission can usually be achieved in 10% to 50% of adults with ALL, it tends to be short lived (6 7 months). If a second remission can be attained, suitable patients with relapsed ALL should be evaluated for the HSCT. Salvage therapies typically include combinations of vincristine, steroids, and anthracyclines; combinations of MTX and L-asparaginase; and HDAC-containing regimens. Novel agents are incorporated into the salvage regimens continuously. None of the programs used for relapse is distinctly superior to the others, and any perceived differences are likely attributable to the usual biases of study selection.
7 + 3 (cytarabine and daunorubicin) as used for the induction of AML is active in ALL. Vincristine and prednisone may be added.
Etoposide and cytarabine are given every 3 weeks for up to three courses until marrow hypoplasia and remission are achieved. They are then repeated monthly until relapse. Etoposide 60 mg/m2 IV every 12 hours on days 1 to 5, and Cytarabine 100 mg/m2 IV bolus every 12 hours on days 1 to 5.
HDAC-based regimens have been reported to induce CR rates in 17% to 70% of patients.
HDAC as a single agent has modest activity in ALL, with a CR rate of approximately 34% and a median remission duration of 3.6 months. The addition of idarubicin or mitoxantrone increases the RR to 60%, but the median response time remains 3.4 months.
Cytarabine and fludarabine comprise an active noncardiotoxic combination. The median response duration is 5.5 months. Neurotoxicity is low. A second course can be given in 3 weeks if needed.
Induction
Cytarabine 1 g/m2/day IV over 2 hours on days 1 to 6, and
Fludarabine 30 mg/m2/day IV over 30 minutes, 4 hours before cytarabine on days 2 to 6.
Consolidation is given monthly for two to three courses.
Cytarabine 1 g/m2/day IV over 2 hours on days 1 to 4, and
Fludarabine 30 mg/m2/day IV over 30 minutes, 4 hours before cytarabine on days 1 to 4.
Maintenance
6-Mercaptopurine 50 mg PO t.i.d., and MTX 20 mg/m2/week PO.
FLAG-IDA (fludarabine, cytarabine, G-CSF, and idarubicin) induced a 39% CR rate in patients with relapsed/ refractory ALL. The responders have received the second cycle followed by allo-HSCT and achieved a DFS of 6 months (7 38 months) and OS of 9 months (7 38 months).
Fludarabine 30 mg/m2/day IV over 30 minutes on days 1 to 5, and
Cytarabine 2 g/m2/day IV over 4 hours on days 1 to 5, and
Idarubicin 10 mg/m2/day days 1 to 3, and
G-CSF 5 g/kg SC 24 hours after the completion of chemotherapy and until neutrophil regeneration.
Hyper-CVAD (see Table 19.11) therapy achieves CR rates similar to a combination of HDAC, mitoxantrone, and granulocyte-macrophage colony-stimulating factor (GM-CSF) (44% vs. 30%); however the survival is improved.
L-asparaginase was administered in combination with MTX, anthracyclines, vinca alkaloids, and prednisone with RR ranging from 33% to 79% and median DFS from 3 to 6 months.
Sequential MTX and L-asparaginase resulted in significant stomatitis (dose-limiting toxicity); 23% of treated patients had allergic reactions to L-asparaginase.
Induction
MTX 50 to 80 mg/m2 IV on day 1, and
L-Asparaginase 20,000 IU/m2 IV 3 hours after MTX on day 1, followed by
MTX 120 mg/m2 IV on day 8, and
L-Asparaginase 20,000 IU/m2 IV on day 9.
Repeat day 8 and 9 doses for MTX and L-asparaginase every 7 to 14 days until remission is attained.
Maintenance is repeated every 2 weeks.
MTX 10 to 40 mg/m2 IV on day 1, and
L-Asparaginase 10,000 IU/m2 IV on day 1.
P.490
P.491
K. Hematopoietic stem cell transplantation in acute lymphoblastic leukemia (ALL)
Autologous hematopoietic stem cell transplantation for patients in first remission appears to offer no advantage over chemotherapy, on the basis of the data from the small prospective trials reported to date and preliminary prospective randomized MRC/ECOG ALL data, because of high rates of relapse.
Allogeneic matched-sibling hematopoietic stem cell transplantation. Patients receiving matched sibling HSCT in first CR reach a survival rate of 50% (20% 81%). Prior studies have not demonstrated an advantage with allogeneic HSCT as compared to standard chemotherapy for ALL patients without high-risk features in first CR. However, many of these trials have lacked sufficient numbers of patients, have used varied patient selection criteria, or did not allow for direct, prospective comparisons.
According to the data collected by the IBMTR 9-year DFS was not different for patients treated with chemotherapy and allo-HSCT (32% vs. 34%). High treatment-related mortality (TRM) in HSCT group was the main reason for poor outcome, whereas recurrence rate was twice as high in the chemotherapy group (66% vs. 30%).
The benefit of allo-HSCT in high-risk ALL patients was shown by a large French multicenter trial (LALA87) that compared the allo-HSCT with chemotherapy or auto-HSCT in first CR. Although 5-year OS was not significantly different (48% vs. 35%, p = 0.08) for patients with high-risk disease, both 5-year OS (44% vs. 22%) and DFS (39% vs. 14%) were significantly better with allo-HSCT. Similarly, the 10-year OS for high-risk group was 44% with allo-HSCT and only 11% in the chemo/auto-HSCT arm, whereas in the standard-risk population the corresponding numbers were 49% and 39% (p = 0.6), respectively.
Results from the prospective International MRC/ECOG ALL Trial have demonstrated favorable results for Ph negative patients treated with matched-sibling allo-HSCT as compared with a combined cohort of auto-HSCT and consolidation chemotherapy. The actuarial 5-year EFS for the allo-HSCT is 54% as compared with 34% for the chemotherapy/auto-HSCT group (100-day mortality for Ph negative patients in allo-HSCT arm was 21%). This survival advantage for allo-HSCT included patients with standard risk ALL disease (defined as Ph negative, younger than 36 years, time to CR <4 weeks, and WBC count <30,000/ L for B-cell lineage and <100,000/ L for T-cell lineage) with 5-year EFS rates and 5-year relapse rates of 66% and 17%, respectively, versus 45% and 50%, respectively, for the chemotherapy/auto-HSCT group. Particular subgroups of patients with good long-term EFS such as chromosome 12 and 14 abnormalities (and possibly thymic ALL patients) may not benefit from allo-HSCT in first CR. Further evaluation is warranted to determine the optimal intensity of postremission therapy for this patient population. Despite the high risk of early toxicity, matched-sibling allo-HSCT
P.492
should be considered for most ALL patients in first CR, including standard-risk patients.Matched unrelated donor (MUD) hematopoietic stem cell transplantation. As less than 30% of suitable ALL patients have an HLA-matched sibling donor, MUD HSCT is a viable option available to younger (40 50 years old) patients. Although treatment-related mortality (TRM) remains unacceptably high (40% 50% at 100 days), the outcomes have been improving, in part through the use of better matching at the HLA loci with molecular rather than serologic methods. The National Marrow Donor Program reported on 127 high-risk, defined as presence of t(9;22), t(4;11), or t(1;19), ALL patients, who received a MUD HSCT between 1988 and 1999. The cumulative TRM incidence at 2 years was 61% (54% in first CR, 75% in second CR, and 64% in primary induction failure), whereas the OS at 2 years from transplant was 40%, 17%, and 5%, respectively. The DFS for patients transplanted in CR1 is 32% at 4 years with a 13% cumulative incidence of relapse.
On the basis of the available data, we advocate the use of MUD HSCT for physically fit Ph-positive patients in first CR, if a matched-sibling donor is not available.
Alternative-donor hematopoietic stem cell transplantation. Mismatched family member and haploidentical HSCTs have been evaluated and are options, but these procedures should still be considered experimental in ALL.
L. Novel and experimental strategies for the therapy of ALL
It is unlikely that altering the sequence of currently available chemotherapeutic agents or increasing their intensity will produce a qualitative improvement in the outcome of adult patients with ALL. A number of experimental approaches that are currently being evaluated in clinical trials include monoclonal antibodies, farnesyl transferase inhibitors, tyrosine kinase inhibitors, antimetabolites, and other agents.
Suggested Readings
Amadori S, Suciu S, Stasi R, et al. Gemtuzumab ozogamicin (Mylotarg) as single-agent treatment for frail patients 61 years of age and older with acute myeloid leukemia: final results of AML-15B, a phase 2 study of the European Organisation for Research and Treatment of Cancer and Gruppo Italiano Malattie Ematologiche dell'Adulto Leukemia Groups. Leukemia 2005;19:1768 1773.
Andersen MK, Larson RA, Mauritzson N, et al. Balanced chromosome abnormalities inv(16) and t(15;17) in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes Chromosomes Cancer 2002;33:395 400.
Annino L, Vegna ML, Camera A, et al. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood 2002;99:863 871.
Bishop JF, Matthews JP, Young GA, et al. Intensified induction chemotherapy with high dose cytarabine and etoposide for acute myeloid leukemia: a review and updated results of the Australian Leukemia Study Group. Leuk Lymphoma 1998;28:315 327.
Blume KG, Forman SJ, Snyder DS, et al. Allogeneic bone marrow transplantation for acute lymphoblastic leukemia during first complete remission. Transplantation 1987;43:389 392.
P.493
Byrd JC, Mrozek K, Dodge RK, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002;100(13):4325 4336.
Cave H, van der Werff ten Bosch J, Suciu S, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer Childhood Leukemia Cooperative Group. N Engl J Med 1998;339:591 598.
Chessells JM, Hall E, Prentice HG, et al. The impact of age on outcome in lymphoblastic leukaemia; MRC UKALL X and XA compared: a report from the MRC Paediatric and Adult Working Parties. Leukemia 1998;12:463 473.
Cortes J, Thomas D, Rios A, et al. Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and highly active antiretroviral therapy for patients with acquired immunodeficiency syndrome-related Burkitt lymphoma/leukemia. Cancer 2002;94:1492 1499.
Dombret H, Gabert J, Boiron JM, et al. Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia results of the prospective multicenter LALA-94 trial. Blood 2002;100:2357 2366.
Durrant IJ, Prentice HG, Richards SM. Intensification of treatment for adults with acute lymphoblastic leukaemia: results of U.K. Medical Research Council randomized trial UKALL XA. Medical Research Council Working Party on Leukaemia in Adults. Br J Haematol 1997;99:84 92.
Faderl S, Gandhi V, O'Brien S, et al. Results of a phase 1 2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood 2005;105:940 947.
Faderl S, Jeha S, Kantarjian HM. The biology and therapy of adult acute lymphoblastic leukemia. Cancer 2003;98:1337 1354.
Faderl S, Kantarjian HM, Talpaz M, et al. Clinical significance of cytogenetic abnormalities in adult acute lymphoblastic leukemia. Blood 1998;91:3995 4019.
Foroni L, Coyle LA, Papaioannou M, et al. Molecular detection of minimal residual disease in adult and childhood acute lymphoblastic leukaemia reveals differences in treatment response. Leukemia 1997;11:1732 1741.
Goldman SC, Holcenberg JS, Finklestein JZ, et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood 2001;97(10):2998 3003.
Goldstone A, Prentice HG, Durant J. Allogeneic transplant (related or unrelated donor) is the preferred treatment for the adult Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Results from the International ALL trial (MRC UKALLXII/ECOG E2993). Blood 2001;98:856a.
Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999;17:3835 3849.
P.494
van der Holt B, Lowenberg B, Burnett AK, et al. The value of the MDR1 reversal agent PSC-833 in addition to daunorubicin and cytarabine in the treatment of elderly patients with previously untreated acute myeloid leukemia (AML), in relation to MDR1 status at diagnosis. Blood 2005;106(8):2646 2654.
Ichimura M, Ishimura T, Belsky JL. Incidence of leukemia on atomic bomb survivors belonging to fixed cohort in Hiroshima and Nagasaki, 1950 1971: radiation dose, years after exposure, age at exposure, and type of leukemia. J Radiat Res 1987;19:262 282.
Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.NEngl J Med 2006;354:2542 2551.
Kantarjian HM, O'Brien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 2000;18:547 561.
Kell WJ, Burnett AK, Chopra R, et al. A feasibility study of simultaneous administration of gemtuzumab ozogamicin with intensive chemotherapy in induction and consolidation in younger patients with acute myeloid leukemia. Blood 2003;102:4277 4283.
Koller CA, Kantarjian HM, Thomas D, et al. The hyper-CVAD regimen improves outcome in relapsed acute lymphoblastic leukemia. Leukemia 1997;11:2039 2044.
Larson RA, Dodge RK, Burns CP, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 1995;85:2025 2037.
Mortuza FY, Papaioannou M, Moreira IM, et al. Minimal residual disease tests provide an independent predictor of clinical outcome in adult acute lymphoblastic leukemia. J Clin Oncol 2002;20:1094 1104.
Ottmann OG, Druker BJ, Sawyers CL, et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 2002;100: 1965 1971.
Ottmann O, Wassmann B, Gokbuget N, et al. A randomized phase II study comparing Imatinib with chemotherapy as induction therapy in elderly patients with newly diagnosed Philadelphia-positive acute lymphoid leukemia(Ph+ ALL). Hematol J 2004;5:S112. Ottmann O, Wassmann B, Pfeifer H. Activity of the ABL-tyrosine kinase inhibitor Gleevec (STI571) in Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) relapsing after allogeneic stem cell transplantation (allo-SCT). Blood 2001;98:589.
Robison LL, Neglia JP. Epidemiology of Down Syndrome and childhood acute leukemia. Prog Clin Biol Res 1987;246:19 32.
Rowe JM, Buck G, Burnett AK, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial:MRC UKALL XII/ECOG E2993. Blood 2005;106:3760 3767.
Rowe JM, Neuberg D, Friedenberg W. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood 2004;103:479 485.
Rowe JM, Tallman MS. Intensifying induction therapy in acute myeloid leukemia: has a new standard of care emerged? Blood 1997;90:2121 2126.
Sebban C, Lepage E, Vernant JP, et al. Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. French Group of Therapy of Adult Acute Lymphoblastic Leukemia. J Clin Oncol 1994;12:2580 2587.
P.495
Sievers EL. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acutemyeloid leukaemia in first relapse. Expert Opin Biol Ther 2001;1:893 901.
Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of pre-remission and post-remission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000;96:4075 4083.
Specchia G, Pastore D, Carluccio P, et al. FLAG-IDA in the treatment of refractory/relapsed adult acute lymphoblastic leukemia. Ann Hematol 2005;84(12):792 795.
Suki S, Kantarjian H, Gandhi V, et al. Fludarabine and cytosine arabinoside in the treatment of refractory or relapsed acute lymphocytic leukemia. Cancer 1993;72(7):2155 2160.
Tallman MS, Neuberg D, Bennett JM, et al. Acute megakaryocytic leukemia: the Eastern Cooperative Oncology Group experience. Blood 2000;96(7):2405 2411.
Tallman MS, Rowlings PA, Milone G, et al. Effect of postremission chemotherapy before human leukocyte antigen-identical sibling transplantation for acute myelogenous leukemia in first complete remission. Blood 2000;96(4):1254 1258.
Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinibresistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006;354(24):2531 2541.
Thiebault A, Vernant JP, Degos L, et al. Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation. A follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am 2000;14:1353 1366.
Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002;99:4326 4335.
Thomas X, Boiron JM, Huguet F, et al. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol 2004;22(20):4075 4086.
Thomas D, Cortes J, Giles FJ. Combination of Hyper-CVAD with imatinib mesylate (STI571) for Philadelphia (Ph-) positive adult lymphoblastic leukemia (ALL) or chronic myelogenous leukemia in lymphoid blasts phase (CML-LBP). Blood 2001;98:803a.
Tilly H, Castaigne S, Bordessoule D, et al. Low-dose cytarabine versus intensive chemotherapy in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol 1990;8(2):272 279.
Trifilio S, Tallman M, Singhal S, et al. Low-dose recombinant urate oxidase (Rasburicase) is effective in hyperuricemia. Blood 2004;104:3312 (American Society of Hematology Annual Meeting abstracts.) San Diego.
Vignetti M, Fazi P, Meloni G, et al. Dramatic improvement in CR rate and CR duration with Imatinib in adult and elderly Ph+ ALL patients: results of the GIMEMA Prospective Study LAL0201. Blood 2004;104:2739 (American Society of Hematology Annual Meeting abstracts) San Diego.
Wadleigh M, Richardson PG, Zahrieh D, et al. Prior gemtuzumab ozogamicin exposure significantly increases the risk of venoocclusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood 2003;102(5):1578 1582.
P.496
Wassmann B, Pfeifer H, Goekbuget N, et al. Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL). Blood 2006;108:1469 1477.
Weick JK, Kopecky KJ, Appelbaum FR, et al. A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group Study. Blood 1996;88(8):2841 2851.
WetzlerM, Dodge RK, Mrozek K, et al. Prospective karyotype analysis in adult acute lymphoblastic leukemia: the cancer and leukemia Group B experience. Blood 1999;93(11):3983 3993.
