21 - Myeloproliferative Diseases and Myelodysplastic Syndromes

Editors: Skeel, Roland T.

Title: Handbook of Cancer Chemotherapy, 7th Edition

> Table of Contents > Section III - Chemotherapy of Human Cancer > Chapter 21 - Myeloproliferative Diseases and Myelodysplastic Syndromes

Chapter 21

Myeloproliferative Diseases and Myelodysplastic Syndromes

Peter White

Paul R. Walker

I. Myeloproliferative diseases

The myeloproliferative diseases (MPDs) are clonal disorders of pluripotent hematopoietic stem cells or of lineage-committed progenitor cells. MPDs are characterized by autonomous and sustained overproduction of morphologically and functionally mature granulocytes, erythrocytes, or platelets. Although one cellular element is most strikingly increased, it is not uncommon to have modest or even major elevations in other myeloid elements (e.g., thrombocytosis and leukocytosis in polycythemia vera [P. vera]). Bone marrow aspirates and biopsy specimens typically show hyperplasia of all myeloid lineages (panmyelosis). Morphologic maturation and cellular function are essentially normal, although platelet dysfunction occasionally contributes to bleeding. The overproduction of blood elements in the MPDs now appears related to switched on tyrosine kinase signaling pathways. For chronicmyelogenous leukemia (discussed in Chapter 20), this arises from the t(9;22) translocation and the BCR-ABL gene product. For the MPDs discussed in this chapter, a single nucleotide mutation in the gene for JAK2, a tyrosine kinase normally activated by erythropoietin and other cytokines, plays an analogous role. JAK2 V617F is present in 74% to 97% of P. vera patients, and in 30% to 50% of patients with essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). Positivity for JAK2 V617F gives important diagnostic confirmation for MPD, though negative results do not exclude MPD.

A. Polycythemia vera (P. vera)

Diagnosis. P. vera must be distinguished from relative or spurious polycythemia (normal red blood cell [RBC] mass, decreased plasma volume) and from secondary erythrocytosis (increased RBC mass due to hypoxia, carboxyhemoglobinemia, inappropriate erythropoietin syndromes with tumors or renal disease, etc.).

Proper formulation of major and minor criteria to establish the diagnosis of P. vera is a topic of some discussion at present. Proposed modifications of the original criteria of the Polycythemia Vera Study Group incorporate the following elements:
- A1. Increased RBC mass: more than 125% of predicted normal by direct measurement of blood volume; or by inference if hematocrit is more than 60% for men or more than 56% for women, or if multiple phlebotomies are required to lower hematocrit to normal range
- A2. Normal arterial O₂ saturation ( 92%)
- A3. Splenomegaly
- A4. Abnormal karyotype (other than t 9;22), JAK2 V617F, or other clonality marker
- B1. Thrombocytosis more than 400,000/ L
- B2. Neutrophilic leukocytosis more than 10,000/ L
- B3. Hypercellular bone marrow with panmyelosis
- B4. Subnormal serum erythropoietin level and/or no rise following phlebotomy
- B5. Spontaneous growth of erythroid colonies in vitro in the absence of erythropoietin (test is expensive and not widely available)
- A1 + A2 + either A3 or A4 establishes diagnosis of P. vera
- A1 + A2 + two or more B criteria establishes diagnosis of P. vera
An erythropoietin level in the low normal range showing no rise after phlebotomy is consistent with P. vera. An elevated erythropoietin level at presentation is strong evidence against P. vera. Splenomegaly is present in 70% of P. vera cases, but borderline enlargement on ultrasound is of questionable significance. Panmyelosis (hyperplasia of all nonlymphoid marrow elements) is present in 80% of cases but may be difficult to quantify; clusters of megakaryocytes strengthen the case for P. vera (or other MPD). Marrow karyotype is abnormal in 10% to 20% of patients at diagnosis; iron stores are typically absent.
Aims of therapy. Thrombosis (stroke, myocardial infarct, and deep venous thrombosis [DVT]) is a major cause of morbidity in P. vera, due to increased blood viscosity and other factors. Lowering the hematocrit to 40% to 45% by phlebotomy reduces the risk of thrombosis; concomitant use of phlebotomy and hydroxyurea or other myelosuppressive agents may be advisable, particularly if platelet counts are markedly elevated. It is especially important to maintain good long-term control of hematocrit and platelets in the elderly and in those with a history of thrombosis. Control of hypertension and diabetes, and avoidance of smoking are also important.
Treatment regimens
- Phlebotomy. Removal of 350 to 500 mL of blood every 2 to 4 days (less often in the elderly or in patients with cardiac disease) is the standard initial approach; goal is to lower hematocrit to 40% to 45%. The blood count is then checked monthly, and phlebotomy is repeated as needed to maintain the hematocrit at less than or equal to 45%. Rapid lowering of the hematocrit may also be achieved in emergency situations by erythroapheresis. Elective surgery should be deferred until the hematocrit has been stable at less than or equal to 45% for 2 to 4 months. Platelet function should be evaluated before surgery or invasive procedures.
- Antithrombotic therapy. Concomitantly with phlebotomy, use of low-dose aspirin is now widely regarded as standard therapy, following a large European study, the ECLAP (European collaboration on low-dose aspirin in polycythemia) trial that showed approximately 60% reduction in thrombotic events utilizing 100 mg ASA daily. Higher doses of aspirin (325 mg daily) carry risk of bleeding, especially in patients with platelet counts
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  more than 1.5 x 106/ L, in whom acquired von Willebrand's disease may be seen. The exact thrombogenic role of platelets in MPDs is not clear, but hydroxyurea and anagrelide have been shown to lower platelet counts and reduce the risk of thrombosis.
- Myelosuppressive agents. Myelosuppressive agents are indicated in conjunction with phlebotomy for persistent thrombocytosis, recurrent thrombosis, enlarging spleen, or similar problems. They may also reduce the risk of progression to myelofibrosis as compared with phlebotomy alone. Most alkylating agents carry a high risk of producing myelodysplastic syndrome (MDS) or leukemia and should no longer be used. Currently recommended choices are as follows:
  - Hydroxyurea 10 to 30 mg/kg PO daily. Weekly blood cell counts are required initially, with dose adjustments to maintain the hematocrit at less than or equal to 45%, the platelet count at 100,000 to 500,000/ L, and the white blood cell (WBC) count at more than 3,000/ L. Side effects are usually minimal, but long-term use may cause painful leg ulcers and aphthous stomatitis. The risk of leukemia may be slightly increased as well. For younger patients and cases difficult to control with hydroxyurea, acceptable alternatives include the following:
  - Interferon is usually effective in controlling hematocrit, platelet count, and splenomegaly and in relieving pruritus. The starting dose is 1 to 3 x 10⁶ U/m² three times weekly (pegylated interferon once weekly may also be an option see Section I.B.2.c.). Common side effects include myalgia, fever, and asthenia, usually controlled with acetaminophen. Leukemogenic effects are presumably absent, but high cost is a deterrent to long-term use.
  - Radioactive phosphorus (³²P) 2.3 mCi/m² IV (5 mCi maximum single dose). Repeat in 12 weeks if the response is inadequate (25% dose escalation optional). Lack of response after three doses mandates a switch to other forms of therapy. Use of ³²P entails approximately 10% risk of leukemia by 10 years, and it is best reserved for the elderly and patients refractory to other modalities. Supplemental phlebotomies may be required for patients with satisfactory platelet and WBC counts but with rising hematocrit levels.
  - Busulfan appears to have less leukemogenic potential than other alkylating agents and is appropriate in patients whose disease is not controlled by other treatments or in the elderly. It is best given in short courses over several weeks (to avoid prolonged marrow suppression) at 2 to 4 mg/day.
  - Anagrelide selectively inhibits platelet production, and platelets start to fall in 7 to 14 days. The WBC count is unaffected; hemoglobin may fall slightly. Responses to anagrelide have been reported in more than 80% of patients with all MPDs, and thrombotic risk is reduced. Recommended starting
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    dose is 0.5 mg PO q.i.d. Average dose for control is 2.4 mg daily. Side effects include headache (44%), palpitations, diarrhea, asthenia, and fluid retention. It should be used with caution in cardiac patients and is contraindicated in pregnancy.
- Ancillary treatments. To control hyperuricemia, allopurinol 300 mg/day is usually effective. Pruritus is a frequent problem, but usually abates with myelosuppressive therapy. Cyproheptadine 5 to 20 mg/day or paroxetine 20 mg/day may be helpful; interferon is also frequently effective. Aspirin is often helpful for erythromelalgia (hot, red, painful digits) and is commonly used to prevent thrombosis.
Evolution and outcome. Themedian survival time for patients with P. vera is approximately 10 years. One third of deaths is caused by thrombosis. The risk of leukemia is low (~1.5%) in patients treated by phlebotomy alone. Many patients progress to a spent phase, with increasing splenomegaly and stable or falling hematocrit, or develop postpolycythemic myelofibrosis. The risk of leukemia is markedly elevated in such patients.

B. Essential thrombocythemia (ET)

Diagnosis. Diagnosis of ET requires a persistent elevation of the platelet count above 600,000/ L plus the absence of known causes of reactive or secondary thrombocytosis (e.g., iron deficiency, malignancy, chronic inflammatory disease). To exclude other MPDs, hematocrit and RBC mass should be normal, myelofibrosis absent and t(9;22) absent. Marrow aspiration and biopsy should be performed to assess hyperplasia of megakaryocytes, evaluate iron stores and fibrosis, and exclude MDS, in particular 5q- syndrome. Overall cellularity is clearly increased in approximately 70% of patients, and marked megakaryocytic hyperplasia is seen in 65%. Abnormal karyotype is found in less than 10% of patients. Approximately 50% have the JAK2 V617F mutation, and these patients may closely resemble P. vera clinically. Moderate leukocytosis is common. Palpable splenomegaly is present in less than 50% of patients. Platelet function studies may show either spontaneous aggregation or impaired response to agonists. Microvascular occlusion may cause digital gangrene, transient ischemic attacks, visual complaints, and paresthesias. Large-artery thrombotic episodes are also common. DVT is uncommon. The risk of hemorrhagic problems is significant, particularly with platelet count more than 1.5 x 106/ L.
Treatment regimens. Observation alone or low-dose ASA is considered a reasonable course in younger, symptom free patients with less than 1 x 106 platelets/ L. Therapy to lower platelet count to less than 400 x 103/ L should be undertaken in the elderly and in patients otherwise at increased risk for hemorrhagic or thrombotic complications. Options include the following:
- Hydroxyurea 10 to 30 mg/kg PO daily, with dosage adjustments on the basis of weekly blood counts, should give satisfactory response in 2 to 6 weeks. Its use in
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  combination with low-dose ASA may give optimal protection against arterial thrombosis and evolution to myelofibrosis. Possible teratogenic and leukemogenic effects should be kept in mind.
- Anagrelide (see Section I. A.3.c.5) can be a reasonable alternative to hydroxyurea, and is perhaps preferable in younger patients. Anagrelide plus ASA was inferior to hydroxyurea plus ASA in a large recent trial, however. This agent should not be used in pregnancy.
- Interferon . Most ET patients respond to this agent, at an initial dose of 3 x 106 U/day SC. Maintenance doses of 3 x 106 U three times weekly usually suffice. Pegylated interferon at an initial dose of 1.5 to 4.5 g/kg/week SC seems comparable in efficacy and side effects. Use of interferon in pregnancy is considered safe. As noted in Section I.A.3.c.2, side effects and expense are potential problems. Effectiveness in reducing thrombosis is uncertain.
- Platelet apheresis. Platelet apheresis may be indicated in emergent situations (e.g., cerebral ischemia), but the effect is usually short-lived.
- ³²P and alkylating agents. These agents are effective but carry increased risk of secondary leukemia. Nitrogen mustard (mechlorethamine 0.15 to 0.3 mg/kg [6 to 12 mg/m²] IV) can be helpful when rapid reduction in platelet count is needed. Busulfan 2 to 4 mg/day initial dose is appropriate in selected elderly patients resistant to other agents.
- Aspirin (ASA) 81 to 325 mg/day may control erythromelalgia and similar vaso-occlusive problems but is contraindicated in patients with a history of hemorrhagic symptoms, and with platelet counts more than 1 x 10⁶/ L. ASA may be useful in pregnant patients in whom the preceding agents are contraindicated. Its routine use in ET is a matter of debate.
- Stem cell transplantation (SCT). Experience with this modality is quite limited, but transplant may be a consideration in a young patient with poor control and major complications.
Evolution and outcome. The course of essential thrombocythemia is often indolent, particularly in young patients. The median survival exceeds 10 years, and some patients appear to have normal life expectancy. Transformation to myelofibrosis, MDS, or acute leukemia occurs in 5 to 10%. Thrombosis is the major cause of ET-related death.

C. Idiopathic myelofibrosis (IMF) also called agnogenic myeloid metaplasia

Diagnosis. This is a clonal disorder of the hematopoietic stem cell, marked by an intense reactive (nonclonal) fibrosis of the marrow; splenomegaly (frequently massive), reflecting ectopic hematopoiesis in the spleen and portal hypertension; and the presence of immature granulocytes and nucleated RBCs in the peripheral blood (leukoerythroblastic blood picture) plus teardrop RBCs and giant
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platelets. Mild to moderate elevations of WBC and platelet counts are common initially; cytopenias dominate later on.

JAK2 V617F mutation is present in approximately 50% of IMF patients. An abnormal karyotype is also demonstrable in approximately 50%, and connotes shortened survival time. Other adverse prognostic factors include advanced age, anemia, WBC less than 4,000/ L or more than 30,000/ L, thrombocytopenia, blasts in peripheral blood, and hypercatabolic symptoms (weight loss, night sweats, fever). Major causes of death in IMF include marrow failure, infection, portal hypertension, and leukemic transformation. Diseases causing secondary marrow fibrosis, such as metastatic carcinoma, hairy cell leukemia, and granulomatous infections, must be excluded. Cases of MDS with marrow fibrosis are easily confused with IMF. Postpolycythemic myelofibrosis is clinically indistinguishable but carries a poor prognosis, evolving into acute leukemia in 25 to 50% of patients (as compared to 5% 20% for de novo IMF). Acute megakaryoblastic leukemia (M7) may also present with a myelofibrotic picture and be confused with IMF.
Treatment regimens. The median survival time is 5 years, but symptom-free patients may do well without treatment for a number of years. Intervention is indicated in the following situations:
- Anemia. Androgens (e.g., testosterone enanthate 600 mg IM weekly or fluoxymesterone 10 mg PO b.i.d. or t.i.d. for men; danazol 400 to 600 mg PO daily for women) are recommended and they reduce transfusion requirements in 30 to 50% of patients. Corticosteroids (e.g., prednisone 40 mg/m² PO daily) should be tried if overt hemolysis is present. Erythropoietin is helpful in a small percentage of patients but requires large doses; response is unlikely if serum erythropoietin level is more than 200 mU/mL. In limited studies, improvement in cytopenias or transfusion requirements has been reported in 20 to 50% of IMF patients receiving low-dose thalidomide (50 mg/day) or lenalidomide (5 10 mg/day).
  
  IMF patients routinely become transfusion-dependent; early institution of iron-chelating agents is advisable (see discussion under Section II.D.8.).
- Splenomegaly. Massive splenomegaly may lead to cytopenias, portal hypertension, variceal bleeding, abdominal pain, or compression of adjacent organs. Anorexia, fatigue, and hypercatabolic complaints may be prominent. First option for control by myelosuppressive therapy is hydroxyurea, given as for P. vera (see Section I.A.3.c). Melphalan (2.5 mg PO three times weekly, with escalations up to 2.5 mg daily as tolerated), and busulfan (2 mg/day in older patients) can also be considered. Interferon produces responses in some cases, but its role is not clearly established in IMF.
  
  Radiation, 50 to 200 cGy, is effective in improving splenomegaly but causes cytopenias in 40% of patients. Radiation is occasionally indicated for extramedullary hematopoietic tumors causing compression syndromes
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  or for bone pain. Splenectomy is indicated in carefully selected cases but carries significant perioperative mortality and morbidity from bleeding, sepsis, and postoperative thrombocytosis. Splenectomy may also increase the risk of blast transformation.
- Curative intent. Myeloablative allogeneic marrow or stem cell transplantation (SCT) from appropriately matched donors appears to be potentially curative, but transplant-related mortality is high in IMF patients older than 45 years. Younger patients with an expected survival of less than or equal to 5 years may be reasonable candidates. Engraftment rates are equal to those in other hematologic disorders, and graft vs myelofibrosis effect has been demonstrated. Encouraging early results with nonmyeloablative SCT suggest that this modality may be the most appropriate option, and that it is feasible in older IMF patients.

II. Myelodysplastic syndromes (MDS)

This is a diverse group of hematopoietic stem cell clonal neoplasms that is characterized by ineffective hematopoiesis and dysplastic morphologic changes in one or more lineages. The disease has a median age of 65 to 70 years, is the most frequent hematologic malignancy in the over-65 age-group, and affects 20,000 to 30,000 cases annually in the United States. For the population over 60 years of age, the incidence is 1 in 500. Eighty percent of cases occur de novo and have no specific etiology or known cause. In the remaining 20% of cases, an association with prior chemotherapy use can be identified, most frequently high-dose alkylator or topoisomerase-II inhibitor-based regimens, or exposure to radiation. Whether a specific inciting cause can be identified or not, the pathophysiologic process of MDS is deoxyribonucleic acid (DNA) damage in a pluripotential bone marrow stem cell with a dynamic balance of secondary and associated changes in proliferation, differentiation, and apoptosis intrinsic cellular pathways along with extrinsic marrow microenvironment, angiogenic, cytokine, and immune effects. Clonal cytogenetic abnormalities can be identified in 40% to 50% of de novo cases, most typically a loss of chromosome material involving chromosomes 5, 7, 11, 20, or Y; or trisomy of chromosome 8. Cytogenetic abnormalities in chromosomes 5 or 7 will be identifiable in 95% of therapy-related cases, with one half also having complex cytogenetic changes involving three or more chromosomes.

A. Diagnosis

The typical clinical picture is of an elderly patient with macrocytic anemia, with or without thrombopenia and neutropenia. Initial diagnostic studies needed are complete blood count (CBC) with differential and peripheral smear review, bone marrow aspirate and biopsy with cytogenetics, reticulocyte count, serum erythropoietin level before transfusion, serum iron-TIBC-ferritin, B12 and folate levels, along with human immunodeficiency virus (HIV) status if there is clinical concern, and human leukocyte antigen (HLA) typing in young patients if the patient is a candidate for transplant or aggressive immunosuppressive therapy. There is no single diagnostic test, however. A confirmed diagnosis is made from the hematologic picture of cytopenias and

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dysplastic lineage morphology supported by associated marrow cytogenetic findings, if abnormal. The typical dysplastic features seen in the marrow and peripheral blood include megaloblastoid precursors, budding and irregular nuclear outline of normoblasts, hypochromia and basophilic stippling of RBCs, iron-laden sideroblasts, hyposegmentation (bilobed Pelger-Huet like forms are characteristic) and hypogranularity of neutrophils, hypolobar and/or micromegakaryocytes, and hypogranular platelets. Platelet and neutrophil functional abnormalities exist, further contributing to the symptomatic cytopenias. The bone marrow is most often hypercellular (but 10% 20% will be hypocellular) with a low reticulocyte count. Abnormal localization of immature precursors (ALIP) is often seen on the marrow core biopsy. A variable number of myeloblasts will be seen from less than 5% up to 20%. Differential diagnosis includes B12 and folate deficiency, lead poisoning, and alcohol abuse in patients with sideroblastic anemia, aplastic anemia in patients with hypoplastic marrows, IMF (ideopathic myelofibrosis or agnogenic myeloid metaplasia) if marrow fibrosis is present, and paroxysmal nocturnal hemoglobinuria (PNH).

B. Classification

The French-American-British (FAB) classification for MDS put forth in 1982 continues to be useful (Table 21.1). More recently the World Health Organization (WHO)modified this classification to better correlate with more homogeneous subsets and natural histories (Table 21.2). The major changes (1) lowered the percentage of marrow blasts to

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define full blown acute myelogenous leukemia at less than or equal to 20%, removing refractory anemia with excess blasts in transformation (RAEB-t) as a category; (2) separated out the 5q- syndrome, given its different clinical picture and treatment; and (3) moved chronic myelomonocytic leukemia to a separate category of myelodysplastic/myeloproliferative disease.

Table 21.1. Myelodysplastic Syndrome subtypes: French-American-British classification

FAB Subtype	% Marrow Blasts	% Peripheral Blood Blasts	Other Findings	Median Survival (months)
Refractory anemia (RA)	< 5	1		43
Refractory anemia with ring sideroblasts (RARS)	< 5	1	15% ring sideroblasts	73
Refractory anemia with excess blasts (RAEB)	5 20	< 5		12
Refractory anemia with excess blasts in transformation (RAEB-t)^a	20 30 or	5 or	Presence of Auer rods	5
Chronic myelomonocytic leukemia (CMML)	20	< 5	Monocytes >1,000/ L	20
^aIn a subsequent revised scheme, RAEB-t cases are reclassified as acute leukemia.

Table 21.2. World Health Organization classification of myelodysplastic syndrome and pertinent features

Subtype	Blood Findings	Bone Marrow Findings
RA	Anemia; no blasts	Erythroid dysplasia only; <5% blasts
RARS	Anemia; no blasts	RA + 15% or greater ringed sideroblasts
RCMD	Bi- or pancytopenia; no blasts	Dysplasia in >10% cells in two or more lineages
RCMD-RS	RCMD	RCMD + 15% or greater ringed sideroblasts
RAEB		Uni- or multilineage dysplasia plus
RAEB-1	No Auer rods and <5% blasts;	No Auer rods and 5 9% blasts
RAEB-2	Auer rods or 5 19% blasts	Auer rods or 10 19% blasts
MDS-U	Cytopenias; no blasts	Unilineage dysplasia in granulocytes or megakaryocytes; <5% blasts
MDS with isolated del(5q-)	Anemia; <5% blasts	Normal to increased megakaryocytes
RA, refractory anemia; RARS, refractory anemia with ringed sideroblasts; RCMD, refractory cytopenia with multilineage dysplasia; RCMD-RS, refractory cytopenia with multilineage dysplasia and increased ringed sideroblasts; RAEB, refractory anemia with excess blasts; MDS-U, myelodysplastic syndrome, unclassified.

C. Prognosis

Acute leukemia transformation potential and survival correlate to some degree with both the FAB and WHO classifications, but even more so with the International Prognostic Scoring System (IPSS). The IPSS (Table 21.3) assigns a score based on the percentage of marrow blasts, initial marrow cytogenetics, and the number of peripheral cytopenias to provide a better prognostic risk stratification for an individual; the IPSS can be very helpful in guiding management decisions. Although not included in the IPSS, age of the patient is also of major prognostic impact (e.g., median survival for low-risk patients is 11.8 years for age less than 60 years vs. 3.9 years for age more than 70 years). The natural history is one of ultimate transformation to acute myeloblastic leukemia (AML) or progressive bone marrow failure fraught with refractory symptomatic cytopenia-related complications.

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Table 21.3. International Prognostic Scoring System (IPSS) for myelodysplastic syndrome

Prognostic Factor	Score Value
Prognostic Factor	0	0.5	1.0	1.5	2.0
% Marrow blasts	<5	5 10		11 20	21 30
Karyotype^a	Good	Intermediate	Poor
Cytopenias^b	0 1	2 3
Risk category	Total score		Median survival (years)
Low	0		5.7
Intermediate-1	0.5 1.0		3.5
Intermediate-2	1.5 2.0		1.2
High	2.5		0.4
Note that the IPSS conforms to the French-American-British classification and includes refractory anemia with excess blasts in transformation patients who would be classified as acute myeloblastic leukemia under the WHO system. ^aGood, normal karyotype, - Y, 5q-, or 20q-. Poor, chromosome 7 abnormal (monosomy, 7q-, etc.); or complex (three separate abnormalities). Intermediate, all other abnormal karyotypes. ^bCytopenias defined by hemoglobin <10 g/dL, neutrophils <1,500/ L, and platelets <100,000/ L.

D. Therapy

The management of MDS is guided by the patient's age, IPSS category, serum erythropoietin level, cytogenetics if 5q- is present, and by assessing HLA status in a candidate for stem cell transplant or immunosuppressive therapy. All patients should receive appropriate blood product transfusion support.

General approach
- Low-risk patients (IPSS low and intermediate-1):
  - If serum erythropoietin level is less than 500 mU/ml, treat with growth factors (erythropoietin analog, adding granulocyte colony-stimulating factor (G-CSF) if no hematocrit response)
  - Azacytidine, decitabine, or lenalidomide if no clinical response to growth factors
- High-risk patients (IPSS Intermediate-2 and higher):
  - If young and a donor available, allogeneic stem cell transplant
  - If not a transplant candidate, azacytidine, decitabine, or lenalidomide
- 5q-cytogenetics Lenalidomide
- HLA-DR 15 positive (younger patients with a hypoplastic marrow):
  - ATG (antithymocyte globulin) or
  - Cyclosporine A

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Growth factors. Erythropoietin analogs, either epoetin or darbepoetin, can effectively achieve a meaningful hemoglobin improvement in 15% to 25% of patients. In patients with a serum erythropoietin level less than 500 mU/mL, a trial of an erythropoietin analog is indicated. Low-risk patients do respond better than high-risk patients. Usually higher dosing than used in chemotherapy-associated anemias is needed. An adequate therapeutic trial of 8 to 12 weeks is appropriate. G-CSF can be synergistic with erythropoietin therapy, enhancing the erythroid response rate potential up to 40%. This synergism is particularly effective in patients with more than 15% ringed sideroblasts. These growth factors need to be continued to maintain the achieved benefit.
- Recombinant human erythropoietin 40,000 to 60,000 units SC 2 to 3 times weekly; taper to least effective dosing schedule if response, and continue, or darbepoetin 150 to 300 g/kg SC weekly. If there is an inadequate or no response to the erythropoietin analog alone and if still indicated clinically, add G-CSF (granulocyte colony-stimulating factor)
- G-CSF (filgrastim) 1 to 2 g/kg subcutaneously 2 to 3 times weekly, with the erythropoietin analog
Specific Agents
- Azacytidine is a hypomethylating agent inhibiting DNA methyltransferase reversing the epigenetic silencing of gene transcription. The exact mechanism of action in MDS is most likely multifactorial. In a landmark phase III trial compared azacytidine to supportive care only, azacytidine showed a 60% hematologic response rate, prolonged the time to leukemic transformation or death (21 vs. 13 months), and improved quality-of-life parameters. It is now approved by the U.S. Food and Drug Administration (FDA) for use in all types of MDS.
  - Azacitidine 75 mg/m² SC daily for 7 days every 28 days continuing treatment as long as a favorable benefit/tolerance balance. Increase to 100 mg/m²/day can be considered if there is no response. The most common toxicity is myelosuppression with a 20% treatment-related infection rate. It is generally very well tolerated and can be administered as an outpatient.
- Decitabine (Dacogen) is another hypomethylating agent DNA methyltransferase inhibitor that has shown significant activity in MDS. Initial European phase II studies showed 50% hematologic response rates, notably even higher in IPSS high-risk patients. A landmark phase III trial that compared decitabine to supportive care confirmed significant response rates (17% complete response (CR) or partial response (PR) by International Working Group criteria, plus an additional 13% with hematologic improvement) and a longer time to acute leukemia transformation or death, in particular among those patients with an IPSS intermediate-2/high-risk
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  score, or not previously treated. Overall survival was prolonged in patients responding to decitabine as compared to nonresponders (23.5 vs. 13.7 months). It is now approved by the FDA for use in MDS.
  - Decitabine 15 mg/m² as a 3-hour IV infusion every 8 hours for 3 consecutive days (9 total doses) every 6 weeks x 4 cycles; continue treatment as long as effective. Myelosuppression with cytopenic complications is an expected and frequent toxicity of decitabine, especially in the already cytopenic MDS patient. Other side effects include nausea, diarrhea, or constipation and cough. More convenient dosing schedules are being evaluated; the MD Anderson experience has reported overall clinical benefit in 76% of patients treated with a modified schedule of 20 mg/m² IV over 1 hour daily for 5 consecutive days every 4 weeks. It is not known if either DNA methyltransferase inhibitor is superior to the other.
- Lenalidomide is a thalidomide-related immunomodulator with greater potency. It has a wide range of biologic effects including suppression of angiogenesis, inhibition of inflammatory cytokines, potentiation of immune pathways, and other cellular ligand-induced responses. A landmark phase II study showed dramatic erythroid responses in erythropoietin-resistant patients. Major erythroid responses and cytogenetic responses occurred in 83% of patients with a 5q-deletion, but were not limited to this 5q-subset. Overall, 68% of patients with a low IPSS score, 50% with intermediate-1 IPSS, and over half of patients with normal cytogenetics, had erythroid responses. High-risk MDS patients had a much less frequent hematologic response (20%) but the refractory anemia with excess blasts (RAEB) patients responding also demonstrated decreased blast counts. It is approved by the FDA in patients with 5q- MDS.
  - Lenalidomide 10 mg orally daily is continued so long as this dose is tolerated; the dose is reduced to a 21 out of 28-day schedule or 5-mg dosing if persistent or severe hematologic toxicity occurs. Marrow suppression with neutropenia and thrombocytopenia, the most frequent toxicity, is dose dependent and requires dose interruption in over half the number of patients. Other systemic side effects include low grade pruritus, diarrhea, rash, and fatigue.
  Thalidomide remains an option in treating MDS, but now with the availability of the more potent and potentially less toxic lenalidomide, it will likely find minimal use.
Allogeneic stem cell transplantation. This remains the only curative therapy but is limited to younger patients and preferably with a matched related donor. Treatment-related mortality and chronic morbidity remain very high. Given that the older age-group with MDS, less than 10% of patients are considered transplant candidates. It should always be considered in younger patients in IPSS high-risk or
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intermediate-2-risk category with suitable sibling donors. Transplant studies show disease-free survival ranges from 29% to 40%, nonrelapse mortality of 37% to 50%, and relapse even with a sibling donor of 23% to 48%. Reduced-intensity conditioning transplants appear to carry promise for use in an older population but are still fraught with significantly high mortalities. The use of autologous SCT (high-dose chemotherapy with stem cell rescue) is limited to transformed or transforming acute leukemia.
Intensive chemotherapy. There is no clear consensus regarding the role of intensive chemotherapy in MDS. Its use is typically restricted to patients in IPSS intermediate and high-risk groups. Induction chemotherapy utilizing acute leukemia type regimens (e.g., anthracycline/cytosine arabinoside) can induce CRs in 50% to 60% of MDS patients, but remissions tend to be brief and outcomes correlate strongly with karyotype associated chemoresistance mechanisms. Topotecan, a topoisomerase I inhibitor, has been postulated to have selectively favorable effectiveness in MDS, but its role is not well established as responses are brief and myelotoxicity is very high. The role of intensive chemotherapy in treating MDS is limited to overtly transformed acute leukemia or bridging selected patients to an allogeneic transplant. In hopes of minimizing toxicity, low-dose chemotherapy has been utilized, most notably with cytarabine at doses of 5 to 20 mg/m² daily, as a q12 hour SC injection, continued for 10 to 20 days. Hematologic responses are seen in 20% to 30% of patients, but without any significant survival benefit, and serious marrow suppression may result. Melphalan given at a dose of 2 mg PO daily, continued until progressive disease, toxicity, or response is seen, has been recently reported to give 40% response rate with minimal side effects, though patients with hypercellular marrow (the majority of MDS) or complex cytogenetic abnormalities do poorly. The effectiveness, tolerance, and availability of azacytidine, decitabine, and lenalidomide have now largely supplanted the use of low-dose chemotherapies in MDS.
Antithymocyte globulin (ATG). The immunosuppressive effects of ATG can be quite effective achieving transfusion independence along with other cytopenia responses in one third of a select subset of MDS patients, namely those who are younger, with hypocellular marrow, normal cytogenetics, shorter duration of transfusion dependency, and those who are HLA DR-15 positive.
- ATG 40 mg/kg/day x 4 days (common toxicities include infusion reactions, serum sickness (co-administration of prednisone may alleviate this), and immunosuppression).
Other immunosuppressive agents have been tried with mixed success. Prednisone is occasionally helpful in improving cytopenias (~10% response rate overall), particularly in those patients with evidence of hemolysis. Cyclosporine has shown high response rates in limited studies, utilizing 5 to 6 mg/kg/day initially, then monitored
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with dose adjustments to maintain serum levels of 100 to 300 ng/mL.
Other agents have shown some limited hematologic benefit in MDS. However, now with the availability of azacytidine, decitabine, and lenalidomide, and with a very narrow therapeutic index for either amifostine or arsenic trioxide, their use should be rare except in a clinical trial. Pyridoxine 100 to 200 mg daily is a reasonable trial in patients with increased ringed sideroblasts; however, benefit is infrequent. Developmental therapies targeting angiogenesis, apoptosis, cytokine, farnesyl transferase, tyrosine kinase, and histone deacetylase or other DNA methyl transferase epigenetic pathways, alone and in combination, are being evaluated in clinical trials.
Supportive care
- Anemia. RBC transfusions will become needed in most MDS patients to maintain quality of life. Hemoglobin goal (usually more than 9 g/dL) must be individualized on the basis of symptom, need, and improvement. Leukocyte-depleted packed RBCs should be used in all patients, with cytomegalovirus (CMV) negative blood if the patient is CMV negative, and irradiated blood products in potential SCT candidates.
- Iron overload and chelation therapy. Secondary hemochromatosis with cardiac, hepatic, endocrine, and hematopoietic dysfunction can develop after 20 to 30 units of red cell transfusion. Chelation therapy can improve visceral and marrow function, and should be a strong consideration in patients with an ongoing transfusion need who are expected to survive several years, as well as in patients with overt iron overload-related visceral dysfunction. Monitoring of ferritin levels should begin at a 20- to 30-unit transfusion threshold, with the institution of a chelating agent when the ferritin is more than 2,500 g/L. The treatment goal is to lower ferritin to less than 1,000 g/L.
  - Desferrioxamine (Desferal) 1 to 2 g by overnight (8 12 hours) SC infusion 5 to 7 nights/week; or
  - Deferasirox (Exjade) 20 mg/kg oral daily dispersed in water or orange/apple juice taken on an empty stomach. Toxicities are similar to desferrioxamine with nausea/vomiting, diarrhea, pyrexia, and abdominal pain but also with potential increased serum creatinine. The availability of this more convenient oral chelator will likely greatly improve this aspect of supportive care in MDS.
- Infections. Neutropenia and neutrophil dysfunction contribute to a high risk of bacterial infections in MDS. Antibiotics remain the mainstay of management, but prophylactic antibiotics are of unknown benefit. G-CSF can raise the neutrophil count in 90% of MDS patients, and its short-term use may be appropriate in infected, severely neutropenic patients; indications for long-term use of G-CSF are limited.
- Bleeding. Symptomatic thrombocytopenia requires platelet transfusion support. Single-donor platelets delay alloimmunization, but this will eventually develop in most (30% to 70%) patients, limiting subsequent platelet transfusion increments. There is no absolute thrombocytopenia transfusion threshold, but platelet counts below 10,000 carry a spontaneous central nervous system hemorrhage risk. Two additional adjuncts to thrombocytopenic bleeding control are given:
  - Aminocaproic acid 4 g IV over 1 hour, followed by 1 g/hour continuous infusion; or orally in a similar dosing schedule; or by a more convenient 2- to 4-g schedule orally every 4 to 6 hours. Tachyphylaxis and loss of antifibrinolytic stabilization will often occur after 48 consecutive hours of therapy.
  - Interleukin-11/oprelvekin is a thrombopoietic cytokine that has increased platelet counts after chemotherapy. A low-dose regimen of 10 g/kg/day can raise platelet counts in selected patients with bone marrow failure.