20 - Chronic 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 20 - Chronic Leukemias

Chapter 20

Chronic Leukemias

Peter White

Paul R. Walker

The chronic leukemias have traditionally been grouped together to underscore their differences from the more aggressive acute leukemias, but their course is not necessarily indolent; paradoxically, the possibility for achieving cure of these disorders has been more limited than with some acute leukemias. There have been two recent advances that have greatly impacted the understanding and treatment of the chronic leukemias. First is the recognition that treating to an absent (negative) minimal residual disease (MRD) state, as assessed by either polymerase chain reaction (PCR) in chronic myelogenous leukemia (CML) or flow cytometry in chronic lymphocytic leukemia (CLL), has improved durability of response as compared to just traditional morphologic responses and remissions. CML patients are best served when treated to and monitored for negative MRD, and the same may prove true for CLL as well. Second is the sobering understanding that the stem cell population of the chronic leukemias appear to be differentially resistant to treatment that is very effective in the progeny population. This resistance of the often dormant stem cell population limits treatment effectiveness of control, and is a barrier to cure.

I. Chronic myelogenous leukemia

CML is a relatively uncommon disorder, accounting for 15% of adult leukemias in the United States. The median age at diagnosis is 53 years. Less than 10% of cases are under 20 years of age. There is a slight male predominance. Ionizing radiation is the only known causative factor. There are no known genetic susceptibility factors.

The pathognomonic finding is the Philadelphia (Ph) chromosome, involving a reciprocal translocation between chromosomes 9 and 22, t(9;22) (q34;q11), resulting in a hybrid BCR-ABL gene. The BCL-ABL fusion protein encoded by this gene results in permanently switched-on tyrosine kinase signaling activity and in leukemogenesis. The activated BCR-ABL tyrosine kinase becomes both the cause and perpetuator, allowing unregulated proliferation of the CML clone. It is not the sole factor, however. Amultitude of other secondary and associated BCR-ABL-induced abnormalities in CML cells affect proliferation and differentiation; activation of mitogenic signaling pathways; altered cellular adhesion; inhibition of apoptosis; and downstream Ras, mitogenactivated protein kinase (MAPK), Myc, Phosphatidylinositol 3 (PI-3) kinase, and Janus kinase signal transducer and activator of transcription (STAT) pathways. It is now recognized that there are two distinct compartments of CML cells. Myeloid progeny, including erythroid-megakaryocyte-granulocyte lineages, carry the Ph chromosome (Ph+) and actively proliferate. There is also a Ph+ stem cell population of pluripotential myeloid progenitor cells. This stem cell population is often dormant and resistant to

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treatment, but must be eradicated, or at least kept dormant, to cure CML.

A. Diagnosis

The typical clinical picture is of a middle-aged patient with a total white blood cell (WBC) count more than 25,000 and peripheral smear differential spectrum of circulating immature and mature granulocytic progeny (the peripheral blood will look like bone marrow) with basophilia and palpable splenomegaly. Splenic and/or constitutional symptoms may be present. Palpable lymphadenopathy is absent. The bone marrow is hypercellular with myeloid hyperplasia. Dysplastic changes are minimal. Mild increased reticulum can be seen.

Diagnosis requires identification of either the Ph chromosome or the BCR-ABL fusion product. The neutrophil leukocyte alkaline phosphatase (LAP) score is low in CML; in contrast, it is elevated in leukemoid reactions and other reactive leukocytosis states. If there are no other clinical or hematologic findings to suggest CML, LAP can be helpful as a negative discriminator. However, it is never absolute or diagnostic.

The Ph chromosome can be identified in 95%of CML patients by standard bone marrow cytogenetic techniques or by fluorescence in situ hybridization (FISH) (which does not require dividing cells) of bone marrow or peripheral blood. An initial bone marrow is recommended for diagnostic confirmation and assessment of additional cytogenetic abnormalities. Assessing the BCR-ABL transcript in peripheral blood by PCR techniques can identify the small fraction of patients who are Ph-negative by routine cytogenetics. PCR has evolved into a very important way to assess and monitor response to treatment.

The differential diagnosis does include a heterogeneous group of typical clinical picture but Ph chromosome /BCRABL negative patients including some with chronic myelomonocytic leukemia and chronic neutrophilic leukemia. The latter is a rare clonal myeloproliferative disorder of the elderly. In contrast to CML, these Ph-patients lack basophilia and also have elevated LAP scores.

B. Classification

CML is characterized by three evolutionary phases, each carrying a different clinical and hematologic picture, natural history, and treatment outcome.

  • Chronic phase is the usual initial presentation of CML. 85% of patients present at diagnosis in the chronic phase. This is marked by immature myeloid cells in the peripheral blood and marked granulocytic hyperplasia in the marrow, but myeloblasts are less than 10% in both peripheral blood and bone marrow. Absolute eosinophilia and basophilia are typically present (in contrast to reactive leukocytosis). The chronic phase will typically run an indolent course of 3 to 5 years before progressing to the accelerated phase, even without treatment.

  • Accelerated phase is a transition process to the blast phase. It is poorly defined but is usually marked by loss of previously controlled WBC counts and clonal evolution with the development of new chromosomal abnormalities in addition to the persisting or reemerged Ph chromosome. Peripheral blood counts show one or more of the following: blasts equal to or more than 15%, blasts plus promyelocytes equal to or more than 30%, basophils more than 20%, or fall in platelet count to less than or equal to 100,000/ L,

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    unrelated to ongoing treatment. These laboratory findings are often accompanied by the reemergence or progression of symptoms such as fever, bone pain, and fatigue, or worsening splenomegaly. Median survival before imatinib was just 18 months, but now with imatinib it can exceed 4 years.

  • Blastic phase, also called blast crisis, is the progressed transformation of CML to acute leukemia. It is defined by the acute leukemia criteria of more than 20% marrow blasts. However, patients with 20% to 29% blasts seem to carry a better prognosis than those meeting the older criteria of more than 30% blasts. The majority, 50% to 70% of cases, will show a myeloid phenotype (acute myelogenous leukemia [AML]), but 25% lymphoid (acute lymphocytic leukemia [ALL]), and 5% an undifferentiated phenotype. Recent studies have identified BCR-ABL kinase domain mutations in 30% to 40% of these patients. Persistence of the Ph chromosome including additional Ph chromosomes and other cytogenetic abnormalities will be present. Extramedullary tumor masses (chloromas) can occur in both the accelerated and blastic phases. Durable response to chemotherapy, using various acute leukemia regimens, is typically poor, and median survival in blast phase is 3 to 6 months. ALL will respond better and has a better prognosis than AML evolutions. A chronic phase remission can occur with treatment as the blastic progeny clone is eradicated but the chronic phase Ph + stem cell persists.

C. Prognosis

Separation of these three stages is imprecise, and approximately 25% of patients progress directly from chronic phase to blast phase. Moreover, the duration of the chronic phase is difficult to predict, although a number of factors indicate an increased risk for progression, including greater age, splenomegaly, elevated platelet counts, and higher numbers of peripheral blood myeloblasts, eosinophils, or basophils. The Sokal prognostic system and the Hasford classification utilize a formula factoring in age, spleen size, and the hematologic picture to assign three risk (low-intermediate-high) groups of differing prognosis with 5-year survivals of 76%, 55%, and 25%. Both were developed in patient cohorts treated with interferon, however. No prognostic system has been validated in the imatinib era, limiting their usefulness. Regardless of pretreatment characteristics, the most important and best prognostic predictor is the quality of the MRD response to treatment, as measured by the degree of cytogenetic and molecular response.

D. Therapy

The imatinib/gleevec era has revolutionized the treatment of CML but also ushered in some questions of treatment uncertainty. Targeting and inhibiting the BCRABL mitogenic pathway with imatinib has achieved dramatic cytogenetic and molecular levels of responses with prolonged disease control never before seen in CML. However, it still appears that imatinib can just control, but not completely eradicate and cure, the stem cell clone. This leaves open the question of on whom and when the transplant should be done. It is clear that imatinib is the starting point in treating chronic phase CML and that close molecular monitoring of the

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BCR-ABL transcript is important to best manage an individual with CML.

  • Imatinib (Gleevec) is a small molecule inhibitor of the BCR-ABL tyrosine kinase. In interferon-refractory patients, the rate of complete cytogenetic responses at 40 months was 52%. In the landmark phase III IRIS study in newly diagnosed patients comparing 400 mg imatinib to the then standard interferon/cytarabine, 96% of the imatinib-treated patients had complete hematologic response, 76% a complete cytogenetic response, and 43% major molecular responses with a 3-log decrease in BCRABL messenger ribonucleic acid (mRNA) transcripts; all of these are far better than the interferon combination, demonstrating convincing superiority of imatinib. As the imatinib experience grows, several initial unknowns are becoming clear. Dose can be an issue. 800 mg does seem to achieve a more rapid BCR-ABL molecular response; 60% versus 39% 3-log reduction, and 26% as compared to 4% complete molecular response with the 800 mg as compared to 400 mg dosing in early follow-up. However, a recent update from the IRIS trial indicates that with ongoing time and treatment the major molecular response rate increased to 75% at 49 months median follow-up in those patients achieving a complete cytogenetic response at 12 months. It is not clear if the 800-mg dose is ultimately superior to 400 mg. A phase III trial of this dosing comparison is ongoing. A 3-log BCR-ABL mRNA response by quantitative PCR does translate into more durable disease control as compared to less than a 3-log decrease. The deeper the molecular response, the longer the clinical response. Additional kinase mutations or other constitutive pathway stimulation can cause imatinib resistance. It is now known that imatinib has limited effectiveness on the dormant stem cell. Durable control but not cure is the treatment goal with imatinib. The exact median time frames of disease control and overall survival (OS) with imatinib are unknown. It remains hopeful that survival will exceed 15 years in responding patients, and ongoing advances in therapy may push that even longer.

    • The initial management of early phase CML:

      • Imatinib 400mg oral daily is the standard initial dosing in chronic phase disease; 800 mg is the standard dose in accelerated phase.

        Treatment is best given continuously, and dosing lower than 300 mg daily is ineffective.

      • Hydroxyurea 1 to 2 g daily is given as well if the WBC count is more than 100, 000/ L or massive splenomegaly is present.

      • Allopurinol 300 mg daily is often used until counts normalize.

      Imatinib is overall well tolerated. Nausea, peripheral and periorbital edema, muscle cramps, diarrhea, weight gain, and fatigue can occur, but all usually grade 1 to 2. Nausea can be lessened by taking the drug with a large glass of water and a full meal. Muscle cramps can be

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      lessened by tonic water and calcium. Imatinib inhibits and is metabolized through the CYP450 pathway causing potential drug interactions. Liver toxicity can also occur. Myelosuppression is the most common grade 3 to 4 toxicity with neutropenia and thrombocytopenia forcing treatment interruption or dose reduction at times, in particular during the first few months of treatment. Granulocyte colony-stimulating factor (G-CSF) can be used to maintain adequate dose intensity in the face of grade 3 or 4 neutropenia. Congestive heart failure is rare. It may be related to imatinib inhibition of Abl, which may be related to mitochondrial function in the heart.

      Maintaining imatinib dosing at higher than 300 mg daily is pharmacologically important to achieve effective inhibitory plasma concentrations.

    • Treatment and disease monitoring is used to assess for early hematologic treatment toxicity and to evaluate the ongoing and ultimate disease response, with the treatment goal of MRD measured by a complete cytogenetic response and a 3-log reduction molecular response. A reasonable approach, modifiable to an individual patient and case, is:

      • Complete blood cell count (CBC) weekly until stable, then every 4 to 6 weeks.

      • Marrow cytogenetics at diagnosis, at 6 and 12 months of initial treatment, and yearly with ongoing treatment.

      • Peripheral blood quantitative reverse transcriptase PCR(RT-PCR) for BCR-ABL mRNA at diagnosis and every 3 months with ongoing treatment.

      The timing and level of response are important management milestones. The earlier a cytogenetic and molecular response, the better and longer the ultimate response will be. A partial cytogenetic response (1% 35% Ph positive metaphases) by 3 to 6 months predicts an 80% to 95% likelihood of achieving an eventual complete cytogenetic response. Quantitative PCR on peripheral blood is the monitoring method of choice.

      There is a significant correlation between the molecular response at 3 months and cytogenetic response at 12 months. At 42 months of follow-up, those patients with a complete cytogenetic response by 12 months and a major molecular response (>3-log reduction in BCRABL mRNA) had a progression-free survival of 98% as compared to 90% if less than 3-log reduction and 75% for patients without a complete cytogenetic response. There is no absolute latest point in time at which a patient should have a complete cytogenetic response before considering an altered treatment approach. That must be individualized based up age and other viable treatment options available. In a young patient who is a transplant candidate, if there is not an early optimal response within 6 to 12 months, consideration of this alternative therapy is appropriate.

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    • Imatinib resistance can either be primary or secondary. Primary hematologic resistance without a complete hematologic response occurs in approximately 5% of patients. Primary cytogenetic resistance, failing to achieve a partial cytogenetic response at 6 months or complete cytogenetic response at 12 months, will occur in 15% of patients. After 42 months of follow-up, 16% of patients treated on the IRIS study developed secondary resistance or progressed overtly. In patients previously treated with interferon, 26% in chronic phase developed resistance or progression. Imatinib resistance is much higher in accelerated (73%) and blast phases (95%). Causes of resistance can either be BCR-ABL dependent or independent. Acquired kinase domain mutation in BCR-ABL is the most frequent mechanism, preventing the conformal binding of imatinib to the ABL kinase domain, and causing BCR-ABL reactivation. A small number of cases can be due to BCR-ABL overproduction, overcoming the imatinib inhibition effect. The BCR-ABL independent resistance develops through alternate pathways with SRC activation implicated in some cases. Imatinib resistance will be identified by either overt hematologic progression or now more frequently by a 1-log increase in the BCR-ABL q-PCR result of the peripheral blood. At that time, a repeat bone marrow with cytogenetics and screening for the new kinase mutations, if that technology is available, should be performed. At this time, the main purpose outside of a clinical trial would be to identify the T3151 mutation that does not respond to alternative kinase inhibitors.

      The management of imatinib resistance has no single strategy. Just changes in mutation alone may not absolutely warrant a change in therapy in circumstances when a different therapy may be more toxic or not accessible. Overt phase progression forces a treatment change, as the current therapy is ineffective. Mutation changes are clearly a harbinger of phase progression but in a variable time frame. Optimal control has been lost but just at a biologic and not yet clinical level. Imatinib dose escalation up to 800 mg can be undertaken; however, tolerance and durability are limiting factors. The addition of a conventional agent, either interferon or cytarabine, could also be undertaken but this is best utilized if just a suboptimal initial response has occurred. An allogeneic stem cell transplant in a transplant candidate would remain an option.

    • Imatinib alternatives. The best approach for patients resistant to imatinib seems to be the new small molecule ABL kinase inhibitors, dasatinib (BMS-354825) and AMN107. Both are being actively investigated with exciting preliminary results. AMN107 is a derivative of imatinib and has shown 40% overall and 13% cytogenetic responses in resistant chronic phase and accelerated phase disease but is less effective in blastic phase. Dasatinib, structurally unrelated to imatinib, binds both the

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      ABL kinase domain and also inhibits SRC family kinases. Dasatinib has been granted U.S. Food and Drug Administration (FDA) approval for second-line use in CML. Single-arm studies of extensively pre-treated patients have shown major cytogenetic responses in 45% of chronic phase disease and major hematologic responses in 59% accelerated phase and 31% blast phase CML. It is premature to know response durability.

      • Dasatinib (Sprycel) is given as 70 mg PO twice daily for initial dosing. Doses are adjusted up or down in 20-mg increments as needed; doses above 90 to 100 mg b.i.d. have not been investigated in clinical trials. Fluid retention including pleural and pericardial effusions, bleeding, febrile neutropenia, and diarrhea are the most frequent grade 3/4 adverse events.

  • Allogeneic stem cell transplant. This remains the only known curative treatment for CML. A current debate and dilemma is on whom and when the transplant should be done. The earlier the disease at the time of transplant, the better the outcome: 5-year survival rates will range from 60% to 80% in chronic phase disease to 25% to 40% in accelerated phase, and 10% in blastic phase. Early chronic phase is better than the late phase In the interferon era, transplanting within 12 months of diagnosis was the aim. Now with the better responses and tolerance of imatinib, that is not as clear. Recent data from the Fred Hutchinson transplant experience indicates that transplanting within 24 months of diagnosis maintains a maximal outcome. A younger age is also better but even this is in flux with reduced-intensity conditioning transplant regimens increasing the age of potential transplant recipients. Treatment-related mortality, let alone the tremendous morbidities, does increase with age. Graft-versus-leukemia effect appears crucial to achieve a cure, indicating the need for immune effects to eradicate the CML stem cell. For those transplant candidate patients not achieving an optimal cytogenetic and molecular response, the decision to transplant is easy, with no other hope of durability, let alone curability. Likewise in potential transplant candidates who relapse on imatinib, stepping to transplant is an easy decision. However, there is still significant mortality and morbidity even in young patients and the disease is less curable as time goes on. There are no absolute guidelines at this point in time. As the imatinib experience extends, clearer guidelines and direction may identify those who should be transplanted at initial diagnosis. In patients younger than 30 years, this should still be a prime consideration even in the imatinib era. The Gratwohl score (Table 20.1) can give a sense of the outcome and mortality of a transplant in groups by factoring in disease stage, age, donor type and gender, and timing with transplant-related mortality ranging from 20% in favorable groups but more than 50% in unfavorable settings. However, as with all of the prognostic models, these were developed in the pre-imatinib era, limiting applicability, particularly in

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    patients achieving a major or complete molecular response with imatinib. Only with a full and candid discussion with the patient regarding currently available data imatinib does not appear to eradicate the CML stem cell; it can only be viewed as control, although durable, and not curative therapy; and upon disease progression the cure rate of transplant does decrease can the best decision for an individual be made. Early referral to a transplant center of all potential transplant candidates can help the initial understanding of the rigors of a transplant and also best facilitate the timeliness of implementation.

    Table 20.1. Gratwohl score for predicting transplant outcome

    Score 0 1 2
    Donor type Related Matched, unrelated
    Disease state Chronic Accelerated Blastic; second chronic
    Age <20 year 20 40 year >40 year
    Donor/recipient gender M/M; F/F; M/F F/M
    Time from diagnosis <12 months >12 months
    Score 0 1 2 3 4 5 6
    Survival at 5 years (%) 72 70 62 48 40 18 22
    Transplant mortality (%) 20 23 31 46 51 71 73

    Treatment of relapse after a transplant can still be successful with augmentation of the graft-versus-leukemia effects with donor lymphocyte infusions. Recent use of imatinib in this setting has also been effective, suggesting a certain degree of potential synergism between imatinib and the graft-versus-leukemia effect.

    Autologous stem cell transplants, just utilizing highdose cytotoxic chemotherapy and a marrow rescue without any graft-versus-leukemia effects, have not shown any durable benefit. Nonmyeloablative stem cell transplants with reduced-intensity conditioning are an expanding option for the older population but are still fraught with significant mortality and graft-versus-host disease.

  • Interferon and cytarabine no longer have a role as primary therapy in CML given the results of the IRIS trial and availability of imatinib. However, studies of combination regimens of imatinib and either interferon and/or cytarabine are ongoing with early phase II studies showing significant molecular responses. A differential mechanism of effect of interferon as compared to imatinib may be on the stem cell.

  • Accelerated phase CML may still respond to higher (800 mg) dosing of imatinib; however, it is usually much

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    less responsive, and with higher resistance and progression than chronic phase disease. An allogeneic stem cell transplant is arguably the only chance of prolonged survival. Clinical trials should be utilized if accessible.

  • Blastic phase CML is notoriously resistant to any treatment including allogeneic stem cell transplants. Determining whether the blastic phase conversion is to AML or ALL will direct the induction chemotherapy approach. Continuing imatinib with either the ALL or AML induction regimen is safe and well tolerated and appears to improve durability. Clinical trials, if available, should be offered to the patient.

II. Chronic lymphocytic leukemia (CLL)

CLL is marked by the accumulation of a clone of morphologically mature but immunologically nonfunctional or aberrant B lymphocytes in the peripheral blood, bone marrow, spleen, and lymph nodes. Unlike CML, failure of apoptosis rather than cell proliferation accounts for most of this excess accumulation. Over 90% of CLL lymphocytes are in a quiescent G0 phase of the cell cycle, and the doubling time for circulating lymphocytes is prolonged. The clinical course is typically indolent, and median survival time is in excess of 10 years for patients presenting with earlystage disease. Stage alone does not reliably predict survival for individual patients, however, and characteristics such as abnormal karyotype and unmutated state of immunoglobulin heavy chain genes may foretell more rapid progression.

CLL is the most common form of leukemia in Western societies (though not in Asia), with an annual incidence in the United States of 2.7 cases/100,000 individuals. Incidence in males is twice that in females. Owing to unidentified hereditary factors, relatives of CLL patients have a threefold increased risk of developing CLL or similar lymphoid neoplasms. Median age at diagnosis in the United States is over 70 years; approximately 10% of patients are younger than 50 years.

A. Diagnosis

Accepted diagnostic criteria require (1) sustained lymphocytosis equal to or more than 5, 000/ L; (2) marrow lymphocytosis equal to or more than 30% of nucleated cells; and (3) phenotypic demonstration of monoclonality, with lymphocytes typically positive for CD5, CD19, CD20 (weak), and CD23, but negative for CD10. Surface Ig is demonstrable but dim on flow cytometry, with monoclonality for either or light chains. Marrow evaluation is not required if (1) and (3) are fulfilled, but it provides a baseline for evaluation of treatment, and the pattern of infiltration has prognostic import (nodular or interstitial good, diffuse bad). The lymphocytes in CLL are morphologically mature and virtually indistinguishable from normal lymphocytes, although a few prolymphocytes with a prominent nucleolus may be found. Numerous prolymphocytes suggest transformation to prolymphocytic leukemia (seen in ~10% of advanced-stage CLL cases) or de novo prolymphocytic leukemia, a separate group of B-cell and T-cell neoplasms. Differential diagnosis of CLL also includes other lymphoid neoplasms such as hairy cell leukemia (HCL), mantle cell lymphoma, large granular lymphocytic leukemia, adult T-cell leukemia/lymphoma, follicle center cell lymphoma, and S zary syndrome. Morphologic

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features and phenotypic patterns on flow cytometry are the key to separating these entities.

Table 20.2. Modified Rai Staging System for chronic lymphocytic leukemia

Stage (risk) Criteria Median Survival Time (years)
0 (low risk) Lymphocytosis only (in blood and bone marrow) >10
I, II (intermediate risk) Lymphocytosis plus adenopathy or lymphocytosis plus splenomegaly or hepatomegaly 6
III, IV (high risk) Lymphocytosis plus anemia (hemoglobin <11 g/dL) or thrombocytopenia (platelets <100 x 103/ L) <2

B. Staging and prognosis

Clinical stage is prognostically important, and should be assessed in all patients at diagnosis, utilizing either the five-tier Rai system or the three-tier Binet system (see Tables 20.2 and 20.3). Initial evaluation should also include serum lactate dehydrogenase (LDH) and 2-microglobulin (elevations unfavorable) and quantitation of serum Ig levels (hypogammaglobulinemia develops in 70% of patients as CLL evolves).

Table 20.3. Binet Staging System for chronic lymphocytic leukemia

Stage No. of Lymphoid Areas Involveda Anemia or Thrombocytopeniab Median Survival (years)
A 0 2 No >7
B 3 5 No <5
C 0 5 Yes <3
aFive areas are designated: cervical, axillary, inguinal, spleen, and liver. Bilateral involvement of regional nodes does not increase the number of areas designated.
bAnemia is defined as hemoglobin <10 g/dL, platelets <100 x 103/ L.

Independent of stage, the following features also carry unfavorable prognostic import: diffuse pattern of marrow infiltrate; doubling time of peripheral blood lymphocytes less than 1 year; expression of CD38 and/or zeta-associated protein 70 (ZAP-70) by lymphocytes; and unmutated state of Ig variable-region genes. Abnormal karyotype is frequently demonstrable by cytogenetics or FISH (conveniently performed on peripheral blood); trisomy 12, 17p-, and 11q- are unfavorable; normal

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karyotype is neutral; and 13q- is favorable. Testing for these risk factors is not considered essential, and their role as guides to management decisions is not yet clear.

C. Approach to therapy

The standard approach is to withhold treatment in asymptomatic early-stage patients. Conventional chemotherapy in this setting confers no survival advantage over a watch-and-wait strategy. Indications to initiate treatment include systemic symptoms (fatigue, weight loss, night sweats, recurrent infections), significant cytopenias due to marrow suppression or autoimmune processes, symptomatic or progressive lymphadenopathy, marked splenomegaly, rapid lymphocyte-doubling time (<6 months), and extreme lymphocytosis. There is no firm consensus, but a lymphocyte count of equal to or greater than 150,000/ L is frequently used as a treatment threshold. Hyperviscosity or leukostasis syndromes are rare under 800,000/ L, however. Duration of treatment depends on response, but in most cases treatment is discontinued after clinical control of the disease is achieved. There is no evidence that prolonged maintenance therapy improves OS.

Standardized criteria, developed by a National Cancer Institute (NCI) Working Group, to classify response are as follows:

  • Complete remission (CR). No evidence of clinical disease for more than 2 months. Requires CBC with lymphocytes less than 4,000/ L, neutrophils equal to or more than 1,500/ L, platelets equal to or more than 100,000/ L, hemoglobin equal to ormore than 11 g/dL; marrow lymphocytes less than or equal to 30% with no lymphoid nodules; and no constitutional symptoms, hepatosplenomegaly, or palpable lymphadenopathy.

  • Partial remission (PR). 50% or greater reduction in peripheral blood lymphocytes, 50% or greater reduction in adenopathy and/or hepatosplenomegaly plus at least one of the following: (a) 50% or greater improvement in platelet and hemoglobin levels, (b) platelets 1,000/microliter or higher, or (c) hemoglobin 11 g/dL or higher. Improvement in clinical stage (e.g., from Binet C to B) may also be considered a PR. Patients who achieve CR except for persistence of lymphoid nodules in marrow are classified as nodular PR.

  • Stable disease. Patients who fail to meet the criteria for PR but do not show evidence of progression (e.g., no increasing lymphadenopathy) are considered to have stable disease.

D. Specific regimens

  • Nucleosides

    • Fludarabine. This nucleoside analog is now commonly used as first-line therapy. In a large trial of intermediate- and high-risk (Rai stage I to IV) CLL patients, fludarabine gave 20% CR and 43% PR versus 4% CR and 33% PR for chlorambucil, formerly regarded as the standard agent. Time to progression was also longer following fludarabine: 25 versus 14 months. Importantly, however, there was no OS advantage for fludarabine, which also causes greater myelotoxicity and immunosuppression (with prolonged decreases in

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      CD4 lymphocytes). Chlorambucil thus continues to be considered appropriate for first-line treatment. For chlorambucil failures, fludarabine provides effective salvage, with 46% response rate, in contrast to 7% response to chlorambucil given after fludarabine failure. Patients with fludarabine-induced remissions lasting for equal to or greater than 12 months show reasonable response rates if retreated with fludarabine upon relapse, but combination therapy (see following text) is generally more effective. The recommended regimen formonotherapy is as follows:

      • Fludarabine 25 mg/m2/day IV (10- to 30-minute infusion) on days 1 to 5, every 28 days, repeated for six to ten cycles. Dose reductions for renal impairment are required (see Chapter 4). Patients with no response after two cycles should be considered for alternative therapies. Allopurinol is given for 10 to 14 days in advanced-stage patients; patients with very high tumor mass are monitored for tumor lysis syndrome. Cytopenias and immunosuppression are major side effects. Reversible neurologic toxicity is occasionally seen. To avoid transfusion-related graft-versus-host disease, blood products should be irradiated. Prophylaxis against Pneumocystis and My-cobacterium tuberculosis should be considered in selected patients.

    • Cladribine. This nucleoside is approved for use in HCL (see following text). Its efficacy in CLL seems comparable to that of fludarabine, with 40% to 60% response rates in previously untreated patients. It is of little benefit in fludarabine-refractory patients. Recommended dose is

      • Cladribine 0.12 to 0.14 mg/kg (~5 mg/m2) IV as a 2-hour infusion on days 1 to 5; repeat every 4 weeks. As with fludarabine, discontinue if no response is seen after two cycles. Toxicity is similar to that of fludarabine, including prolonged immunosuppression.

    • Pentostatin. Approved for hairy cell leukemia, this nucleoside appears to have efficacy similar to the other nucleosides in CLL, and may be less myelotoxic. Recommended dose is

      • Pentostatin 4 mg/m2 by IV bolus or by 20- to 30-minute infusion, given weekly 3, then every 2 weeks 3, then once a month. Precautions regarding immunosuppression apply as with fludarabine and cladribine. Do not use with fludarabine.

  • Alkylating agents

    • Chlorambucil is still considered an appropriate first-line treatment, especially in the frail elderly. It is well tolerated, with minimal nausea and no alopecia; reversible myelotoxicity is the major side effect. Prolonged use may lead to myelodysplastic syndromes. Palliative responses will be seen in most CLL patients, though not necessarily meeting the criteria for PR as detailed in the

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      preceding text; CR occurs in a modest percentage. It is not effective for salvage after fludarabine or cladribine failure. Dosing schedule may be either continuous or intermittent:

      • Chlorambucil 2 to 6 mg PO daily, with adjustments according to biweekly CBC, or

      • Chlorambucil 0.4 to 0.7 mg/kg (15 26 mg/m2) PO given as single dose on day 1, or divided over days 1 to 4. Repeat treatment every 2 to 4 weeks depending on myelotoxicity. The intermittent schedule may be less myelotoxic and have better patient compliance. Combination of chlorambucil with prednisone, once popular, is of questionable benefit.

    • Cyclophosphamide is equally effective as chlorambucil but carries risks of cytopenias, nausea, alopecia, and hemorrhagic cystitis.

      • Continuous dose is 50 to 100 mg PO daily;

      • Intermittent dose is 500 to 750 mg/m2 PO or IV every 3 to 4 weeks.

      To avoid cystitis, morning dosing and 2 to 3 L of daily PO fluid intake are indicated.

  • Steroids

    • Prednisone 40 to 80 mg daily for 5 to 7 days, repeated every 4 weeks may be useful in patients who cannot tolerate myelotoxic agents, and is also used routinely for autoimmune complications. The preferred schedule is intermittent dosing, but continuous maintenance dosing is often needed for control of autoimmune hemolysis or thrombopenia. Hyperglycemia, psychiatric reactions, osteoporosis, and immunosuppression are hazards. A transient initial rise in lymphocyte count is not unusual, followed by a fall, with subsequent improvement in lymphadenopathy and splenomegaly.

  • Monoclonal antibodies

    • Rituximab is a chimeric (mouse human) monoclonal antibody specific against CD20, a surface glycoprotein present on neoplastic and on mature normal B lymphocytes. It is thought to cause cell lysis through complement and antibody-dependent cellular cytotoxicity. CD20 expression on CLL lymphocytes is typically weak, but responses (usually PR) have been reported in 25% of patients previously treated with fludarabine or chlorambucil, utilizing standard rituximab doses. Escalated dosing may produce higher responses, but expense is significant. Rituximab is also utilized in combination with fludarabine, cyclophosphamide, and other agents for salvage therapy. The standard dosage is as follows:

      • Rituximab 375 mg/m2 IV weekly 4 (or 4 to 8). Infusions are started at 50 mg/hour for the first hour and then escalated at 50 mg/hour increments every 30 minutes as tolerated up to 400 mg/hour.

      Infusion reactions are routinely seen, consisting of transient chills and fever, often accompanied by nausea,

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      dyspnea, or flushing; hypotension occurs in approximately 10% of patients. Interrupting the infusion, until symptoms subside, will usually allow infusion to be resumed at half the previous rate, and then slowly escalated to complete the scheduled dose. Subsequent infusions can usually be given at an initial rate of 100 mg/hour, with 100-mg/hour increments at 30-minute intervals, up to 400 mg/hour. Pretreatment with acetaminophen and diphenhydramine is recommended, and epinephrine should also be on hand to treat rare anaphylactic reactions. With high tumor burden, a more ominous syndrome with vomiting, hypotension, and dyspnea may be seen, because of massive release of cytokines from damaged lymphocytes. Rarely, tumor lysis syndrome has also occurred. To minimize these problems, patients with lymphocyte counts more than 50, 000/ L may be given 50 mg rituximab on day 1, a dose of 150 mg on day 2, and the remaining on day 3, to total 375 mg/m2. When feasible, lymphocyte count should be reduced by other agents before rituximab. Myelotoxicity with rituximab is minimal, and severe cytopenias are rare. Circulating normal B lymphocytes are depleted, but not T lymphocytes; immunosuppression has not been a major problem.

    • Alemtuzumab (Campath-1H). This is a humanized chimeric monoclonal antibody targeted against CD52, a surface glycoprotein expressed on normal and neoplastic B and T lymphocytes. Cell death results from apoptosis, complement activation, and antibody-dependent cell-mediated cytotoxicity. Alemtuzumab induces profound immunosuppression, with gradual return of CD4 lymphocytes over many months; opportunistic infections are common, including cytomegalovirus (CMV) and fungi. Severe anemia, neutropenia, and/or thrombocytopenia are seen in 50% to 70% of cases, with recovery typically in 3 to 4 weeks; rare cases of fatal pancytopenia are reported. As with rituximab, infusion-related chills, fever, and nausea are common; pretreatment with acetaminophen/diphenhydramine is recommended. Anti-infection prophylaxis with trimethoprim sulfa DS b.i.d. 3 days/week and famciclovir 250 mg b.i.d. or valacyclovir 500 mg b.i.d. daily should accompany alemtuzumab treatment and be continued until CD4 T-cell count is equal to or more than 200/ L, or for a minimum of 2 months after therapy. All blood products for transfusion should be irradiated. Monitoring CMV antigen blood levels may be advisable. Alemtuzumab is indicated for use in patients with fludarabine-refractory CLL. In a pivotal trial, response rate was 33% (2% CR, 31% PR); median time to progression was 9.5 months for responders. Recommended schedule is

      • Alemtuzumab 3 mg as a 2-hour IV infusion is given on day 1 with close monitoring of vital signs. Repeat 3 mg daily until infusion reaction is minimal, then escalate to 10 mg; repeat 10 mg daily until tolerated, then escalate to 30 mg (30 mg level

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        usually reached within 7 days); continue 30 mg three times weekly (Monday, Wednesday, Friday). Total weekly dose should not exceed 90 mg. Continue up to 12 weeks depending on clinical response; discontinue after achieving CR (marrow reassessment needed), or for serious toxicity, for progressive disease, or if disease is stable for more than 4 to 6 weeks. Off-label use of subcutaneous alemtuzumab (dose: 30 mg SC, 3 weekly) may be useful in patients intolerant of infusions; minor injection-site reactions are common. Alemtuzumab may also be appropriate as first-line therapy for selected patients with 17p- or p53 mutations, who respond poorly to fludarabine and alkylators. Its use in CR patients to clear the marrow of MRD is under study, and may improve OS.

  • Combination chemotherapy. Enthusiasm has waned for the use of steroids combined with chlorambucil or fludarabine, and little advantage has been found in utilizing lymphoma regimens such as COP or CHOP. There is currently great interest, however, in various combinations involving rituximab, alemtuzumab, fludarabine, pentostatin, and cyclophosphamide. These combinations have resulted in significantly higher percentages of CR, when used either as first-line therapy or as salvage for relapsing or refractory CLL. Progression-free survival is lengthened, and evidence suggests that OS is improved in patients achieving CR, when marrow is negative for MRD by molecular or cytofluorometric techniques. Options include the following:

    • Fludarabine 30 mg/m2 IV on days 1 to 3 and cyclophosphamide 250 mg/m2 IV on days 1 to 3 (both given as separate 30-minute infusions); cycle repeated every 28 days, up to six cycles, depending on response. As first-line treatment in a phase III trial of younger (<66 years) CLL patients, this combination gave 24% CR versus 7% CR for fludarabine alone.

    • Fludarabine 25 mg/m2 IV on days 1 to 3; cyclophosphamide 200 mg/m2 IV on days 1 to 3; and mitoxantrone 6 mg/m2 IV on day 1; given every 4 weeks for up to six cycles. In a small phase 2 study of relapsed and refractory CLL, CR was 50% (including 17% MRD-negative) and PR 28%.

    • Fludarabine 25 mg/m2 IV on days 1 to 5 of each cycle plus rituximab 375 mg/m2 IV on days 1 and 4 of cycle one, and on day 1 only of cycles two to six; repeat every 28 days for six cycles, followed by consolidation (after 2-month observation interval) with rituximab 375 mg/m2 IV once weekly 4. In a recent phase 2 study of treatment-naive patients, this concurrent schedule gave 47% CR versus 28% CR in patients treated sequentially (rituximab given only after completion of the fludarabine).

    • Fludarabine 25 mg/m2 IV on days 2 to 4 and cyclophosphamide 250 mg/m2 IV on days 2 to 4, plus Rituximab 375 mg/m2 IV on day 1, in cycle one. In subsequent cycles (every 28 days), rituximab dose is

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      500 mg/m2 on day 1, with fludarabine 25 mg/m2 on days 1 to 3 and cyclophosphamide 250 mg/m2 on days 1 to 3. In previously untreated CLL, this combination has been reported to produce CR in 70%, nodular PR in 10%, and PR in 15% of patients. In previously treated patients, CR was 25%, nodular PR was 16%, and PR was 32%. A significant percentage of patients in CR have no MRD detectable by molecular techniques. The impact of these responses on OS is unknown as yet.

    • Fludarabine plus alemtuzumab. Cycle 1: after dose escalation of alemtuzumab to 30 mg (see Section II.D.4.b), fludarabine 30 mg/m2 IV over 15 to 30 minutes on days 1 to 3, plus alemtuzumab 30 mg IV over 2 hours on days 1 to 3. Subsequent cycles (every 28 days, up to a total of 6, as tolerated): fludarabine 30 mg/m2 on days 1 to 3, plus alemtuzumab 30 mg over 4 hours on day 1 (no preceding lead-in escalation), then 30 mg over 2 hours on days 2 and 3. In a phase 2 study of 36 relapsed or refractory subjects, CR rate was 30% and PR was 53%, with acceptable toxicity.

    • Pentostatin 2 mg/m2, cyclophosphamide 600 mg/m2 and rituximab 375 mg/m2 each given once every 21 days for 6 cycles (except cycle 1 when rituximab is given at 100 mg/m2 day 1 and 375 mg/m2 on days 3 and 5 of the first week of therapy) has yielded 91% response rate with 41% complete responses.

  • Transplantation. The role of SCT for CLL is in a state of flux. There is suggestive evidence that a significant fraction of patients may be cured following allo-SCT, since survival plateaus can be seen in various series, but transplant-related mortality, mostly due to graft-versushost disease, has been in the 25% to 50% range. Graftversusleukemia effect is important in achieving CR, and detection of MRD after transplant does not necessarily predict for clinical relapse. Nonmyeloablative SCT allows for allografting at more advanced age and with low transplant-related mortality, and currently seems preferable to myeloablative regimens, especially if there are multiple comorbidities. Autologous SCT appears feasible even in patients older than 70 years and achieves approximately 80% CR, with 40% to 70% OS at 4 years, but relapse rate is high and there is no plateau in the survival curve, suggesting that cure is not achievable with current techniques. Improved purging methods to remove CLL cells contaminating the harvested stem cells may be helpful, but the absence of graft-versus-leukemia effect will likely remain an obstacle to long-term success for autografting.

  • Radiation therapy. For patients with refractory cytopenias or abdominal symptoms attributable to massive splenomegaly, low-dose radiation (e.g., 10 Gy delivered in multiple fractions) provides improvement in most patients, though sometimes with significant worsening of cytopenias because of poorly understood remote suppression of bone marrow. Median duration of responses has been reported as 12 months. Radiation is also occasionally indicated for

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    bulky lymphadenopathy with compression of veins, nerve roots, ureters, and so on.

  • Splenectomy. On rare occasions, splenectomy is indicated for relief of cytopenias or abdominal symptoms. Operative mortality historically has been approximately 10%, but may be lower with laparoscopic techniques. Response is unpredictable, but significant improvement in platelet count is seen in most patients.

  • New therapies. Lenolidomide 25 mg daily has been reported to result in clinical response in over half of treated patients with relapsed or refractory CLL.

E. Complications

  • Autoimmune syndromes. Despite hypogammaglobulinemia and a poor antibody response to vaccines, approximately 15% of CLL patients develop autoimmune hemolytic anemia, and an equal number have a positive Coombs test without overt hemolysis. The antibodies are typically polyclonal immunoglobulin G (IgG), of indeterminate specificity. Hemolytic anemia is an indication for chemotherapy of the CLL, regardless of stage. Alkylating agents are considered preferable to fludarabine, and steroids are routinely given (e.g., prednisone 1 mg/kg PO daily initially). Recent reports indicate a role for rituximab as well. The following combination seems reasonable:

    • Rituximab 375 mg/m2 on day 1, and Cyclophosphamide 750 to 1,000 mg/m2 IV on day 2, and Dexamethasone 12 mg IV on days 1 and 2, and then 12 mg PO on days 3 to 7; repeat monthly.

    Antibody-mediated thrombopenia occurs in approximately 2% of CLL patients. Steroids and alkylating agent are recommended, with or without rituximab. Pure red cell aplasia is another autoimmune entity occasionally seen in CLL. Steroids and cyclosporine are recommended.

  • Infections. Hypogammaglobulinemia contributes to recurrent infections in CLL, typically with streptococci, staphylococci, and other pyogenic organisms. In patients further immunosuppressed by chemotherapy, organisms such as fungi, Pneumocystis, Listeria, Mycobacteria, and CMV can pose formidable problems. Replacement therapy with pooled globulin has been controversial, in part due to expense, but its use seems justifiable in patients who have had recurrent and/or life-threatening infections. The dose is as follows:

    • Globulin 400 mg/kg IV every 3 to 4 weeks; lower doses of 200 to 250 mg/kg every 4 weeks may also provide protection at more acceptable costs.

    Immunizations utilizing dead vaccines (e.g., antipneumococcal vaccine) are appropriate but usually elicit poor antibody responses.

  • Transformations. Unlike CML, CLL only rarely evolves to acute leukemia. Instead, up to 10% of CLL patients develop an aggressive large cell lymphoma or immunoblastic lymphoma, arising either de novo or from the original CLL clone. This is referred to as Richter's syndrome. Onset of fever and other systemic symptoms,

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    rising LDH, and localized enlargement of lymph nodes often herald this ominous situation. Node biopsy is usually required to confirm the diagnosis. Chemotherapy utilizing regimens for intermediate- or high-grade lymphoma is appropriate but usually of marginal benefit. Median survival is approximately 5 months following recognition of Richter's syndrome.

    Another 10% of CLL cases evolve into the picture of prolymphocytic leukemia, showing larger, less mature lymphocytes with a prominent nucleolus. Chemotherapy is generally unsatisfactory, with reported median survival of 9 months. Distinction must be made between (a) CLL undergoing prolymphocytic transformation and (b) de novo prolymphocytic leukemia, a heterogeneous group of B-cell and T-cell neoplasms showing characteristic immunophenotypes on flow cytometry. By convention, diagnosis of de novo prolymphocytic leukemia requires more than 55% prolymphocytes. These patients respond poorly to chemotherapy, although some success is seen with nucleosides or with CHOP as used in non Hodgkin's lymphoma. Alemtuzumab shows promising response rates in T-cell prolymphocytic leukemia.

III. Hairy cell leukemia (HCL)

HCL is an uncommon B-cell neoplasm characterized by mononuclear cells with villiform cytoplasmic projections, usually visible in peripheral blood smears and in marrow aspirates, though increased marrow reticulin often results in a dry tap. There is a strong male predominance; median age at presentation is in the sixth decade.

A. Diagnosis

Pancytopenia is present in approximately 50% of patients and cytopenia of at least one element in virtually all. Neutropenia and monocytopenia can be profound, leading to recurrent infections by a wide variety of organisms including Mycobacteria and fungi. Splenomegaly is present in 90% of patients and may be massive; palpable lymphadenopathy is uncommon.

Characteristic morphology and flowcytometry pattern (monoclonality for / light chains; positivity for CD11c, CD20, CD22, CD25, and CD103), plus strong positivity for tartrateresistant acid phosphatase (TRAP), establish the diagnosis and distinguish HCL from the similar entity of splenic lymphoma with villous lymphocytes, and from B-cell prolymphocytic leukemia. A variant form of HCL may also cause confusion. This presents with cells that are negative for CD25 and CD103, negative or weakly positive for TRAP, and have prominent nucleoli; this variant group responds less well to treatment.

B. Therapy

Some patients remain asymptomatic and do not initially require treatment. Indications for initiating chemotherapy includemarked cytopenias, recurrent infections, symptomatic splenomegaly, or other systemic complications.

  • Splenectomy will reverse cytopenias but is reserved for urgent situations such as uncontrolled infection, severe refractory cytopenias, and unresponsive splenic pain.

  • Interferon (IFN- ) produces a response in the majority of patients, but CRs are uncommon, response is slow, and relapse is frequent. IFN- is largely superseded by purine analogs.

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  • Cladribine is a nucleoside or purine analog, currently considered the treatment of choice, with 75% to 90% CR following one cycle of treatment. However, MRD can be detected in 25% to 50% of patients in CR, and relapse rate is approximately 35%. Median time to relapse for all responders (PRs and CRs) was 42 months in a recent Scripps Clinic follow-up. Retreatment with cladribine gives approximately 60% second CR. OS at 10 years is approximately 90%. It is not yet clear if permanent cure is achieved. Standard dosage is as follows:

    • A single cycle of cladribine 0.1 mg/kg/day as continuous IV infusion over 7 days. Alternatively, a 5-day regimen may be used:

    • Cladribine 0.12 to 0.14 mg/kg (~5mg/m2) IV as a 2-hour IV infusion days 1 to 5.

    Cytokine fever and worsening of cytopenias may accompany treatment. Prolonged immunosuppression is to be expected, and CD4 T-cells remain low over many months.

  • Pentostatin is also a nucleoside analog with response rates comparable to cladribine, but multiple cycles are required to reach CR. Cytopenias, fever, and immunosuppression are major side effects. Recommended dose is as follows:

    • Pentostatin 4 mg/m2 by IV bolus every 2 weeks until CR (median eight courses required).

  • Rituximab. Hairy cells strongly express CD20, and respectable response rates are reported in both relapsing and previously untreated HCL. Four to eight infusions of rituximab 375 mg/m2 weekly have been utilized. CRs with a strikingly high percentage of negative MRD have recently been reported in a small series of HCL patients (most previously untreated) who received cladribine followed by rituximab. It is not yet clear how this impacts survival.

  • BL-22 is a recombinant immunotoxin containing an anti-CD22 immunoglobulin variable domain fused to truncated pseudomonas exotoxin. Both classic and variant HCL cells are CD22+. An NCI study of cladribine-resistant patients had a 69% CR. This is available through the NCI for compassionate use.

  • Relapsed disease. There is no absolute paradigm, and second-line treatment must be individualized. In purine analog-sensitive disease, retreatment with cladribine or pentostatin can still be very effective. Primary or consolidation use of rituximab would be a strong consideration. In cladribine-resistant disease, the BL-22 immunotoxin would be the best option.

Suggested Readings

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Goldman JM, Hughes T, Radich J, et al. Continuing reduction in level of residual disease after 4 years in patients with CML in chronic phase responding to first-line imatinib in the IRIS study. Blood 2005;106:163a.

Goldman JM, Melo JV. Chronic myeloid leukemia advances in biology and new approaches to treatment.N Engl J Med 2003;349: 1451 1464.

Gratwohl A, Hermans J, Goldman JM, et al. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic leukemia working party of the European group for blood and marrow transplantation. Lancet 1998;352:1087 1092.

Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003;349: 1423 1432.

Shah NP. Chronic myeloid leukemia loss of response to imatinib: mechanisms and management. Hematology (American Society of Hematology Education Program) 2005:183 187.

Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase II study. Blood 2002;99:1928 1937.

Chronic Lymphocytic Leukemia and Hairy Cell Leukemia

Byrd JC, Rai K, Peterson BL, et al. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia. Blood 2005;105:49 53.

Chadha P, Rademaker AW, Mediratta P, et al. Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA): long-term followup of the Northwestern University experience. Blood 2005;106: 241 246.

Cheson BD, Bennett J, Grever M, et al. National Cancer Institute Sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996;87:4990 4997.

Eichhorst BF, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 2006; 107:885 891.

Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 2002;99:3554 3561.

Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 2005;23:4079 4088.

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Handbook of Cancer Chemotherapy
Handbook of Cancer Chemotherapy
ISBN: 0781765315
EAN: 2147483647
Year: 2007
Pages: 37

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