Elias Jabbour and Hagop Kantarjian
I. MYELOPROLIFERATIVE NEOPLASMS (MPNs)
The MPNs are clonal disorders of pluripotent hematopoietic stem cells or of lineage-committed progenitor cells. MPNs 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 patients with polycythemia vera [PV]). 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 MPNs now appears related to “switched-on” tyrosine kinase signaling pathways. For chronic myelogenous leukemia (see Chapter 19), this arises from the t(9;22) translocation and the BCR-ABL gene product. For the MPNs 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 patients with PV and in 30% to 50% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). Positivity for JAK2 V617F gives important diagnostic confirmation for MPN, though negative results do not exclude MPN.
A. Polycythemia vera (PV)
1. Diagnosis. PVmust 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.). PV is suspected in patients with hemoglobin levels greater than 18.5 g/dL in men or 16.5 g/dL in women or hemoglobin levels greater than 17 g/dL in men or 15 g/dL in women if associated with a documented and sustained increase of at least 2 g/dL from an individual's baseline value. Diagnostic evaluation begins with peripheral JAK2 V617F mutation screen and measurement of serum erythropoietinlevels. This is because JAK2 is present in 97% of patients with PV and is not associated with other causes of increased hemoglobin/ hematocrit levels; similarly, a subnormal serum erythropoietin level is expected and encountered in more than 90% of patients with PV but not in secondary or apparent polycythemia. However, neither the absence of JAK2 nor the presence of a normal erythro-poietin level rules out the diagnosis of PV.
The presence of a JAK2 V617F in suspected PV is highly supportive of the diagnosis, regardless of the serum erythropoietin level. In the absence of a JAK2 V617F mutation, the serum erythropoietin level is useful to guide further evaluation. If the serum erythropoietin level is subnormal, a JAK2 exon 12 mutation screen should be performed. In the setting of a negative JAK2 mutation and a normal erythropoietin level, the diagnosis of PV is unlikely and evaluation should focus on secondary causes of erythrocytosis.
The diagnosis of PV requires meeting either both major criteria and one minor criterion or the first major criterion and two minor criteria:
Hemoglobin greater than 18.5 g/dL in men, 16.5 g/dL in women, or other evidence of increased red cell volume
Presence of JAK2 V617F or other functionally similar mutation such as JAK2 exon 12 mutation.
Bone marrow biopsy showing hypercellularity for age with trilineage myeloproliferation
Serum erythropoietin level below the normal reference range
Endogenous erythroid colony formation in vitro.
2. Aims of therapy. PV is generally an indolent disorder with the decision to treat based on risk stratification. Low-risk patients (i.e., those with no history of thrombosis, age less than 60 years, or platelets below 1 × 106/μL) are usually treated with phlebotomy and/or aspirin (ASA). The goal of phlebotomy is to keep the hematocrit level below 45% in men and below 42% in women. Initially, phlebotomy is used to reduce hyperviscosity by decreasing the red cell mass, and subsequent phlebotomies help maintain the red cell mass in a normal range. For patients with high-risk features (i.e., history of thrombosis, or an age greater than 60 years), treatment consists of phlebotomy, ASA, and/or cytoreductive therapy with hydroxyurea. Control of hypertension and diabetes and avoidance of smoking are also important.
3. Treatment regimens
a. 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; the goal is getting thehematocrit to 40% to 45%. Te blood count is then checked monthly, and phlebotomy is repeated as needed to maintain the hematocrit at no more than 45%. Rapid lowering of the hematocrit may also be achieved in emergency situations by erythropheresis. Elective surgery should be deferred until the hematocrit has been stable at no more than 45% for 2 to 4 months. Platelet function should be evaluated before surgery or invasive procedures.
b. Antithrombotic therapy. Concomitantly with phlebotomy, use of low-dose ASA is now widely regarded as standard therapy, following a large European study (ECLAP) utilizing 100 mg ASA daily that showed an approximately 60% reduction in thrombotic events. Higher doses of ASA (325 mg daily) carry risk of bleeding, especially in patients with platelet counts greater than 1.5 × 106/μL, in whom acquired von Willebrand disease may be seen. The exact thrombogenic role of platelets in MPNs is not clear, but hydroxyurea and anagrelide have been shown to lower platelet counts and reduce the risk of thrombosis.
c. 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 compared with phlebotomy alone. Most alkylating agents carry a high risk of inducing a secondary myelodys-plastic syndrome (MDS) or leukemia and should no longer be used. Currently recommended choices are as follows:
(1) Hydroxyurea 10 to 30 mg/kg by mouth daily. Weekly blood cell counts are required initially, with dose adjustments to maintain the hematocrit at no more than 45%, the platelet count at 100,000 to 500,000/μL, and the white blood cell (WBC) count at greater than 3000/μL. Side effects are usually minimal, but long-term use may cause painful leg ulcers and aphthous stomatitis. For younger patients and cases difficult to control with hydroxyurea, acceptable alternatives include the following.
(2) Interferon-α is usually effective in controlling hematocrit, platelet count, and splenomegaly and in relieving pruritus. The starting dose is 1 to 3 × 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.
(3) Radioactive phosphorus (32P) 2.3mCi/m2intravenously(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 an 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.
(4) 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.
(5) Anagrelide selectively inhibits platelet production, and platelets start to fall in 7 to 14 days. Te WBC count is unaffected; hemoglobin may fall slightly. Responses to anagrelide have been reported in more than 80% of patients with MPNs, and thrombotic risk is reduced. Recommended starting dose is 0.5 mg by mouth once a day. 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.
d. 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-α is also frequently effective. ASA is often helpful for erythromelalgia (hot, red, painful digits) and is commonly used to prevent thrombosis.
4. Evolution and outcome. The median survival in patients with PV exceeds 15 years and the 10-year risk of developing either myelofibrosis (MF; 4% and 10%, respectively) or acute myeloid leukemia (AML; 2% and 6%, respectively) is relatively low. To date, drug therapy has not been shown to favorably affect these figures. Therefore, at present, drugs should not be used with the intent to either prolong survival or prevent disease transformation into AML or MF.
B. Essential thrombocythemia (ET)
1. Diagnosis. Diagnosis of ET requires a persistent elevation of the platelet count above 450 × 103/μL plus the absence of known causes of reactive or secondary thrombocytosis (e.g., iron deficiency, malignancy, chronic inflammatory disease). After excluding obvious causes of reactive thrombocytosis (iron deficiency, trauma, infection, etc.), peripheral blood testing for the JAK2 V617F mutation is helpful. The presence of JAK2 V617F confirmsclonal thrombocytosis but careful review of the peripheral blood smear and bone marrow histology with cytogenetics must also be performed to confirm the diagnosis of ET. Chronic myeloid leukemia (CML) can often present with thrombocytosis, therefore the presence of BCR–ABL must be excluded. As stated previously, the absence of JAK2 does not rule out the possibility of ET given that a large proportion of patients do not carry the mutation. Only 4% of patients with ET without a JAK2 V617F mutation will have a mutation in the MPL gene; however, if present, it does suggest clonal thrombocytosis. 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. Deep venous thrombosis is uncommon. The risk of hemorrhagic problems is significant, particularly with a platelet count greater than 1500 × 103/μL. The diagnosis of ET requires meeting four criteria, as follows:
Sustained platelet count of at least 450 × 103/μL
Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes. No significant increase or left-shift of neutrophil granulopoiesis or erythropoiesis.
Not meeting World Health Organization (WHO) criteria for PV or primary myelofibrosis, BCR–ABL-positive CML, or MDS or other myeloid neoplasm
Demonstration of JAK2 V617F or other clonal marker or, in the absence of JAK2 V617F, no evidence of reactive thrombocytosis
2. Treatment regimens. Given its typically indolent course, the primary goal of treatment in patients with ET is the prevention of complications from thrombocytosis, such as microvascular disturbances or hemorrhagic events caused by acquired von Willebrand disease. ASA therapy is often used to reduce microvascular symptoms for patients with all risk categories. Hydroxyurea, to reduce platelet counts, in combination with low-dose ASA, has been shown to decrease the risk of arterial thrombosis in patients with high-risk ET, such as those older than 60 years with platelets greater than 1000 × 103/μL or a history of hypertension, diabetes requiring treatment, or ischemia, thrombosis, embolism, or hemorrhage related to ET. For patients with ET whose platelet counts are refractory to therapy with ASA or other salicylates, therapy with interferon-α (including in pegylated preparations), anagrelide, or hydroxyurea can be used. Anagrelide was developed to prevent platelet aggregationbut was subsequently found to reduce platelet counts in ET and PMF when used at low dose.
a. Hydroxyurea 10 to 30 mg/kg by mouth daily, with dosage adjustments on the basis of weekly blood counts, should give satisfactory response in 2 to 6 weeks. Its use in combination with low-dose ASA may give optimal protection against arterial thrombosis and evolution to myelofibrosis.
b. Anagrelide can be areasonable alternative to hydroxyurea and perhaps is preferable in younger patients. Anagrelide plus ASA was inferior to hydroxyurea plus ASA in a large recent trial, however. Tis agent should not be used in pregnancy.
c. Interferon-α. Most patients with ET respond to this agent, at an initial dose of 3 × 106 U/day subcutaneously (SC). Maintenance doses of 3 × 106 U three times weekly usually suffice. Pegylated interferon at an initial dose of 1.5 to 4.5 μg/kg/wk SC seems comparable in efficacy and side effects. Use of interferon in pregnancy is considered safe.
d. 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.
e. 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. ASA may be useful in pregnant patients, in whom the preceding agents are contraindicated.
3. Evolution and outcome. The course of ET is often indolent, particularly in young patients. The median survival exceeds 15 years, and some patients appear to have normal life expectancy. Transformation to PMF, MDS, or acute leukemia occurs in 5% to 10%. Trombosis is the major cause of ET-related death.
C. Primary myelofibrosis (PMF)
1. Diagnosis. Tis 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 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 patients with PMF. An abnormal karyotype is also demonstrable in approximately 50% and connotes shortened survivaltime. Other adverse prognostic factors include advanced age, anemia, WBC count of less than 4000/μL or greater than 30,000/μL, thrombocytopenia, blasts in peripheral blood, and hypercatabolic symptoms (weight loss, night sweats, fever). Diseases causing secondary marrow fibrosis, such as metastatic carcinoma, hairy-cell leukemia, and granulomatous infections, must be excluded. Similar to ET, the presence of a JAK2 V617F or an MPL mutation can be helpful to rule out reactive marrow fibrosis. However, the absence of both of these molecular markers does not exclude the presence of an MPN. Terefore, causes of reactive marrow fibrosis must be excluded in cases where no clonal marker is found. Again, bone marrow histology in combination with other clinical and laboratory features helps to establish the diagnosis of PMF. BCR–ABL should be performed to rule out the presence of CML and criteria for another myeloid neoplasm should not be met. Te minor criteria, which help to establish a diagnosis of PMF, include leukoerythroblastosis, increased serum lactate dehydrogenase, anemia, and palpable splenomegaly. Major causes of death in PMF include marrow failure, infection, portal hypertension, and leukemic transformation. Cases of MDS with marrow fibrosis are easily confused with PMF. Postpolycythemic myelofibrosis is clinically indistinguishable but carries a poor prognosis, evolving to acute leukemia in 25% to 50% of patients (compared to 5% to 20% for de novo PMF). Acute megakaryoblastic leukemia (M7) may also present with a myelofibrotic picture and be confused with PMF.
The diagnosis ofPMF requires meeting all three major criteria and two minor criteria:
Presence of megakaryocyte proliferation and atypia, accompanied by either reticulin or collagen fibrosis; or, in the absence of significant reticulin fibrosis, the megakaryocyte changes must be accompanied by an increased marrow cellularity characterized by granulocytic proliferation and often decreased erythropoiesis (i.e., prefibrotic cellular-phase disease)
Not meeting WHO criteria for PV, CML, MDS, or other myeloid disorders
Demonstration of JAK2 V617F or other clonal marker (e.g., MPL W515K/L); or, in the absence of the above clonal markers no evidence of secondary bone marrow fibrosis.
Increased serum lactate dehydrogenase level
2. Treatment regimens. PMF has a much more aggressive course than ET and PV, and treatments include androgen preparations (e.g., fluoxymesterone or danazol), corticosteroids, erythropoietin, and lenalidomide. Splenectomy should be considered for patients with portal hypertension, to improve anemia (due to sequestration) or for symptomatic relief of abdominal pain or problems with alimentation. Radiation therapy may be beneficial for palliative relief; however, a significant increase in the risk of neutropenia and infection is seen.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the only curable treatment option for patients with PMF. Tis option should be considered in young patients with intermediate-/high-risk PMF. For patients older than 60 years of age, a reasonable option would be a reduced-intensity conditioning regimen. Studies assessing the efficacy of JAK kinase inhibitors are ongoing and, in the setting of clinical benefit, may eventually change the course of the disease. Intervention is indicated in the following situations.
a. Anemia. Androgens (e.g., testosteroneenanthate 600 mg intramuscularly weekly or fluoxymesterone 10 mg by mouth two or three times a day for men; danazol 400 to 600 mg by mouth daily for women) are recommended and reduce transfusion requirements in 30% to 50% of patients. Corticosteroids (e.g., prednisone 40 mg/m2 by mouth daily) should be tried if overt hemolysis is present. Erythropoietin is helpful in a small percent of patients but requires large doses; response is unlikely if serum erythropoietin level is greater than 200 mU/mL. In limited studies, improvement in cytopenias or transfusion requirements has been reported in 20% to 50% of patients with PMF receiving low-dose thalidomide (50 mg/day) or lenalidomide (5 to 10 mg/day).
PMF patients routinely become transfusion-dependent; early institution of iron-chelating agents is advisable.
b. 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. The first option for control by myelosuppressive therapy is hydroxyurea, given as for PV. Melphalan (2.5 mg by mouth 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-α produces responses in some cases as well.
Radiation 50 to 200 cGy is effective in improving splenomegaly but causes cytopenias in 40% of patients. Radiation occasionally is indicated for extramedullary hematopoietic tumors causing compression syndromes or for bone pain.Splenectomy is indicated in carefully selected cases but carries significant perioperative mortality and morbidity from bleeding, sepsis, and postoperative thrombocytosis.
c. Curative intent. Allo-HSCT from appropriately matched donors appears to be potentially curative, but transplant-related mortality is high in patients with PMF who are older than 45 years. Younger patients with expected survival of no more than 5 years may be reasonable candidates. Engraftment rates are equal to those in other hematologic disorders, and a “graft versus myelofibrosis” effect has been demonstrated. Encouraging early results with nonmyeloablative allo-HSCT suggest that this modality may be the most appropriate option and is feasible in older patients with PMF.
3. Novel therapies
a. JAK2 inhibitors. The discovery of theJAK pathways in patients with PMF led to the conduct of several clinical studies with JAK2 inhibitors. INCB018424 is a JAK2 inhibitor in advanced clinical trials. It is a potent selective inhibitor of JAK1 and JAK2, has demonstrated encouraging clinical activity in a phase I/II study in over 100 patients with PMF and MF post PV/ET. INCB018424 was associated with 50% or greater reduction in splenomegaly in 35% of patients treated with 10 mg twice a day or 50 mg once a day, and in 59% of patients dosed with 25 mg twice a day. Patients experienced rapid improvement of well-being, and weight gain was most pronounced in patients with the lowest body mass index values at baseline. Tis may be due to the associated profound reductions in inflammatory cytokines in virtually all patients. Te treatment was well tolerated, the primary toxicity being grade 3 or 4 reversible thrombocytopenia.
b. Immunomodulatory agents (IMiDs). These agents have engendered an interesting clinical activity in a subset of patients with PMF, including improvements in anemia, thrombocytopenia, and splenomegaly, thought to be due to their effect on bone marrow environment. Thalidomide and lenalidomide induced responses in 16% to 34% ofpatients. The combination of lenalidomide and prednisone may be more effective and safer than single-agent IMiD therapy. New agents like pomalidomide are under study.
c. Hypomethylating agents. Azacitidine and decitabine are being assessed in ongoing clinical trials.
II. MYELODYSPLASTIC SYNDROMES (MDSs)
This is a diverse group of hematopoietic stem cell clonal neoplasms characterized by ineffective hematopoiesis and dysplastic morphologic changes in one or more lineages. The disease has a median ageof 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 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 microenviroment, 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 half of cases also having complex cytogenetic changes involving three or more chromosomes.
The typical clinical picture is an elderly patient with macrocytic anemia, with or without thrombopenia and neutropenia. Initial diagnostic studies needed are complete blood count with differential and peripheral smear review, bone marrow aspirate and biopsy with cytogenetics, reticulocyte count, serum erythropoietin level prior to transfusion, serum iron-total iron binding capacity-ferritin, B12 and folate levels, along with human immunodeficiency virus status if a clinical concern, and human leukocyte antigen (HLA) typing in young patients if a candidate for transplant or aggressive immunosuppressive therapy. Tere is no single diagnostic test, however. A confirmed diagnosis is made from the hematologic picture of cytopenias and dysplastic lineage morphology supported by associated marrow cytogenetic findings, if abnormal. Te 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 red blood cells, 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 cy-topenias. The bone marrow is most often hypercellular (but 10% to 20% will be hypocellular) with a low reticulocyte count. Abnormal localization of immature precursors 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, PMF if marrow fibrosis is present, and paroxysmal nocturnal hemoglobinuria.
The French-American-British (FAB) classification for MDS put forth in 1982 continues to be useful (Table 20.1). More recently, WHO modified this classification to better correlate with more homogeneous subsets and natural histories (Table 20.2). The major changes (1) lowered the percentage of marrow blasts to define full blown acute myelogenous leukemia at greater than or equal to 20%, removing refractory anemia with excess blasts (RAEB) in transformation 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.
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 20.3) assigns a score based on the percent 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. However, recent studies have highlighted issues with the IPSS model in relation to the exclusion of many subgroups that now represent a large proportion of patients with MDS (e.g., secondary MDS, chronic myelomonocytic leukemia with leukocytosis, prior therapy) and its lack of applicability to most patients on investigational programs, because many would have received prior therapies and would have had MDS for a significant length of time. A multivariate analysis ofprognostic factors in 1915 patients with MDS identified the following adverse, independent factors as continuous and categoric values (p 0.001): poor performance status, older age, thrombocytopenia, anemia, increased bone marrow blasts, leukocytosis, chromosome 7 or complex (S3) abnormalities, and prior transfusions. The new MDS prognostic model divides patients into four prognostic groups with significantly different outcomes (Table 20.4). The new model accounts for duration of MDS and prior therapy. It is applicable to any patient with MDS at anytime during the course of MDS.
The management of MDS is guided by the scoring systems previously elucidated including patient s age, IPSS category, serum erythropoietin level, cytogenetics if 5q- present, and by assessing HLA status in a candidate for allo-HSCT or immunosuppressive therapy. All patients should receive appropriate blood product transfusion support.
1. General approach
a. 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).
Azacitidine, decitabine, or lenalidomide if no clinical response to growth factors.
b. High-risk patients (IPSS intermediate-2 and high):
If young and a donor available, allo-HSCT.
If not a transplant candidate, azacitidine, decitabine, or lenalidomide.
c. 5q- cytogenetics: lenalidomide.
d. MDS with hypoplastic features:
Antithymocyte globulin (ATG)
2. 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 greater than 15% ringed sideroblasts. These growth factors need to be continued to maintain the achieved benefit.
a. Recombinant human erythropoietin 40,000 to 60,000 units SC 2 to 3 times weekly; taper to smallest effective dosing schedule if response, and continue.
b. Darbepoetin 150 to 300 μg SC weekly. If an inadequate or no response to the erythropoietin analog alone and clinically still indicated, add G-CSF.
c. G-CSF (filgrastim) 1 to 2 μg/kg SC two to three times weekly, with the erythropoietin analog.
3. Specific agents
a. Azacitidine 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 to conventional care, azacitidine showed a survival improvement (24 months versus 15 months) and improved quality-of-life parameters. It is now approved by the U.S. Food and Drug Administration (FDA) in all types of MDS at the dose of 75 mg/m2 SC or IV daily for 7 days every 28 days with a possibility of continuing treatment as long as there is a favorable benefit/tolerance balance. The most common toxicity is myelosuppression with a 20% treatment-related infection rate. It is generally very well tolerated and can be administered in the outpatient setting.
b. 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 compared to supportive care confirmed significant response rates (17% complete or partial response 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 score, or not previously treated. Overall survival was prolonged in patients responding to decitabine compared to nonresponders (23.5 months versus 13.7 months). It is now approved by the FDA for use in MDS. Decitabine was originally approved at the dose of 15 mg/m2 as a 3-hour infusion IV every 8 hours for 3 consecutive days (9 total doses) every 6 weeks × four cycles continuously, as long as it is 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 were evaluated. Te M.D. Anderson experience has reported overall clinical benefit in 76% of patients treated with a modified schedule of 20 mg/m2IV over 1 hour daily for 5 consecutive days every 4 weeks. The efficacy of this regimen was confirmed in the ADOPT trial. Decitabine is currently approved in the United States at the dose of 20 mg/m2 IV over 1 hour daily for 5 consecutive days every 4 weeks.
c. Lenalidomide is a thalidomide-related immunomodulator with greater potency. It has with 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 those patients with RAEB responding also demonstrated decreased blast counts. It is approved by the FDA in patients with 5q- MDS. Lenalidomide 10 mg orally daily is given continuously so long as this dose is tolerated; the dose can be reduced to a 21 out of 28 day schedule or 5-mg dosing if persistent or severe hematologic toxicity occurs. Marrowsuppression with neutropenia and thrombocytopenia, the most frequent toxicity, is dose dependent and requires dose interruption in over half of patients. Other systemic side effects include low-grade pruritus, diarrhea, rash, and fatigue.
4. Allogeneic hemapoietic stem cell transplant (allo-HSCT). 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 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 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.
5. 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 complete responses in 50% to 60% of patients with MDS, 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 young patients with high-risk disease serving as a bridge to an allo-HSCT. 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 an every 12-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. The effectiveness, tolerability, and availability of azacitidine and decitabine have now largely supplanted the use of low-dose chemotherapies in MDS.
6. Immunotherapy. 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 patients with MDS, namely those who are younger, with hypocellular marrow, normal cytogenetics, shorter duration of transfusion dependency, and those who are HLA DR15 positive.
ATG 40 mg/kg per day × 4 days (common toxicities include infusion reactions, serum sickness [coadministration of prednisone may alleviate this] and immunosuppression).
Other immunosuppressive agents have been tried with mixed success. Prednisone is occasionally helpful in improving cytopenias (approximately 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 with dose adjustments to maintain serum levels of 100 to 300 ng/mL.
Alemtuzumab given at the dose of 10 mg IV daily was recently used in 21 patients with MDS. Responses were reported in 74%: five out of seven patients with abnormal cytogenetics achieved a complete cytogenetic response. Te estimated 3-year relapse-free survival is 50%.
7. Other agents have shown some limited hematologic benefit in MDS. However, with the availability of azacitidine, 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 methyltransferase epigenetic pathways alone and in combination are being evaluated in clinical trials.
8. Supportive care
a. Anemia. RBC transfusions will become needed in most patients with MDS to maintain quality of life. A hemoglobin goal (usually above 9 g/dL) must be individualized based on symptom need and improvement. Leukocyte-depleted packed RBC should be used in all patients, with cytomegalovirus (CMV)-negative (if the patient is CMV negative) and irradiated blood products in potential allo-HSCT candidates.
b. 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 institution of a chelating agent when the ferritin is greater than 2500 μg/L. The treatment goal is to lower ferritin to less than 1000 μg/L.
Deferoxamine (Desferal) 1 to 2 g by overnight (8 to 12 hrs) infusion SC 5 to 7 nights per 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 deferoxamine with nausea and vomiting, diarrhea, pyrexia, and abdominal pain but also potential increased serum creatinine. Te availability of this more convenient oral chelator will likely greatly improve this aspect of supportive care in MDS.
c. 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 patients with MDS, and its short-term use may be appropriate in infected, severely neutropenic patients; indications for long-term use of G-CSF are limited.
d. Bleeding. Symptomatic thrombocytopenia requires platelet transfusion support. Single-donor platelets delay alloimmunization, but this will eventually develop in the majority (30% to 70%) of patients, limiting subsequent platelet transfusion increments. Tere is not an absolute thrombocytopenia transfusion threshold, but platelet counts below 10,000/μL carry a spontaneous central nervous system hemorrhage risk. Two additional adjuncts to thrombocytopenic bleeding control are as follows:
Aminocaproic acid 4 g IV over 1 hour, followed by 1 gram/ 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 μg/kg/day can raise platelet counts in selected patients with bone marrow failure.
The authors are indebted to Drs. Peter White and Paul R. Walker, who contributed to previous editions of this chapter. Several sections in this revision of the handbook represent their work.
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