Jeffrey Klotz, Ankur R. Parikh and Minoo Battiwalla
The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterized by ineffective hematopoiesis and a variable tendency to progress to acute myelogenous leukemia (AML). Increasingly, MDS is diagnosed incidentally when modestly abnormal blood counts trigger a bone marrow examination.
MDS is a disease of older adults; the median age is in the mid-60s. Estimates of its incidence range from 4 to 160 per 100,000 people, and in the elderly the rate may be 10-fold higher, making MDS a relatively common hematologic disease.1-3 In a well-characterized population study that included bone marrow biopsies for all subjects, the incidence of MDS in males 80 years or older was 35 per 100,000 people.4 Death due to MDS occurs from the complications of cytopenias and/or progression to AML, but many patients will succumb first to comorbidities of the elderly.
Myelodysplasia of the marrow can also be seen in aplastic anemia, especially as a late event after immunosuppressive treatment, in the course of Fanconi anemia, and with paroxysmal nocturnal hemoglobinuria (PNH) and T-large granular lymphocyte lymphoproliferative (T-LGL) disorders, and preceding AML (Fig. 7.1).
ETIOLOGY AND PATHOGENESIS
MDS is related to the accumulation of somatic mutations in a hematopoietic stem cell. In the majority of cases (85%), MDS is a de novo phenomenon with no definitive antecedent cause. In secondary MDS (15%), prior chemotherapy (alkylating agents and topoisomerase inhibitors) and ionizing radiation are clearly etiologic; the latency period between exposure and the development of secondary MDS is typically 2 to 10 years. Radiation has been implicated in the marrow failure syndromes historically reported in occupationally and accidentally exposed individuals and in atomic bomb victims; solvents and smoking are also associated. For most MDS, age is the dominant risk factor. Indeed, childhood MDS is exceedingly rare (incidence rate = 0.01/100,000); it can be seen de novo or in patients with a history of acquired or constitutional aplastic anemia, especially Fanconi anemia.
The bone marrow is typically hypercellular, implying that ineffective hematopoiesis rather than absence of stem cells results in the cytopenias. In general, early MDS (refractory anemia) is characterized by an increased susceptibility to apoptosis, while late MDS (in transition to leukemia) is associated with reduced apoptosis. Although the principal defect is in the hematopoietic stem cells, immunological factors and the bone marrow microenvironment contribute to the bone marrow failure. There are significant abnormalities in apoptosis, cytokine profiles, angiogenesis, and the T-cell repertoire. Specific mutations, in particular, abnormalities in chromosome 7 and a complex karyotype, predispose to leukemic transformation. In contrast, 5q-, del 20q, and -Y are recurrent chromosomal abnormalities not associated with a high risk of transformation.
FIGURE 7.1 Myelodysplastic syndromes. AML, acute myelogenous leukemia; FA, Fanconi anemia; MDS, myelodysplastic syndrome; SAA, severe aplastic anemia;T-LGL,T-cell large granular lymphocytic leukemia. Suggested schema for management of MDS.
Advances continue to be made in refining the understanding of the molecular mechanisms underlying specific MDS subtypes. In addition to the identification of haploinsufficiency of the RPS14 gene for the phenotype of del(5q), the importance of cyclin D1 in trisomy 8, and the high frequency of uniparental disomy by single nucleotide polymorphism (SNP) arrays in patients with normal metaphase cytogenetics, more recent insights include the frequent identification of specific somatic mutations in approximately 50% of MDS patients including the majority of patients with normal cytogenetics, the strong association of SF3B1 mutations in MDS syndromes characterized by ringed sideroblasts, and recurrent mutations in DNMT3A implicating epigenetic alterations in the pathogenesis of MDS.5-11
CLINICAL FEATURES
Patients present with symptoms due to cytopenias, usually anemia. Approximately 17% of patients with unexplained anemia aged 65 or older (“Anemia of the Elderly”) have peripheral blood count abnormalities consistent with MDS.12,13 Lymphadenopathy and splenomegaly are absent. The clinical course is variable: patients may be asymptomatic or have mild anemia progressing to transfusion dependence over many years while others have an aggressive course with multilineage involvement and rapid evolution to acute leukemia.
DIAGNOSTIC STUDIES
Minimum diagnostic criteria for MDS require unexplained persistent cytopenia(s), and either evidence of clonality (such as with a cytogenetic abnormality) or unambiguous dysplastic marrow morphology (dysplasia in at least 10% of the cells of one of the myeloid lineages or excess blasts).14,15
Peripheral blood smear typically shows macrocytosis; hypogranular neutrophils; sometimes with Pelger-Huet nuclei and other abnormal nuclear patterns; and circulating micromegakaryocytes. Significant numbers of large granular lymphocytes should raise suspicion of a T-LGL/MDS overlap syndrome.
Bone marrow biopsy is frequently hypercellular but may be frankly hypocellular or fibrotic in about 20% of MDS. Moderate to severe bone marrow fibrosis, while variably characterized histologically, is an important adverse prognostic feature .16,17 Abnormal localization of immature precursors (ALIPs) near bony trabeculae is characteristic. Increase in myeloblasts and dysplastic morphology in the white cell and/or the megakaryocytic lineages can be seen on the aspirate smear. Mononuclear, small, or dysplastic megakaryocytes are evidence of MDS. Erythroid dysplasia alone is less specific, but large numbers of ringed sideroblasts identify a specific MDS subtype.
Chromosome analysis of marrow cells is critical; abnormal cytogenetics strongly influence prognosis. Even in the absence of conclusive morphologic dysplasia, a presumptive diagnosis of MDS can be made in the presence of specific recurring chromosomal abnormalities including -5 and -7.15 However, approximately 50% of MDS patients will have a normal karyotype by routine metaphase cytogenetics.18Karyotyping should be repeated periodically as chromosome patterns can evolve. Fluorescent in situ hybridization (FISH) analysis may provide more subtle information than karyotyping alone. A chromosome breakage test for Fanconi anemia is recommended for younger patients even if physical examination is normal. SNP array karyotyping and somatic mutation testing, while currently used only in the research setting, may become more widely available as the prognostic significance of specific molecular abnormalities is clarified.
Flow cytometry has limited utility; blasts enumeration, critical to prognosis, can be assessed by routine morphology. Nevertheless, expert flow cytometry can be highly specific in diagnosing MDS, and may offer useful phenotypic information. 19
HLA typing is needed to evaluate younger patients for allotransplantation and may provide predictive information for responsiveness to immunosuppression.
CLASSIFICATIONS
Accurate classification and prognosis for this highly heterogeneous disorder is necessary to individualize therapy.
The first validated classification, the French-American-British (FAB; expanded in 1982) was based on morphology (Table 7.1). This scheme recognized that the risk of leukemic progression was proportional to the blast count in the marrow.
The International Prognostic Scoring System (IPSS; Table 7.2), derived from analyses of outcomes in large series of patients, combined information from cytogenetics, cytopenias, and blast count to generate a prognostic score.20These values separate out median survivals for patients with low risk (5.7 years), intermediate-1 (3.5 years), intermediate-2 (1.2 years), and high-risk (0.4 years) MDS. A revised IPSS (IPSS-R) has recently been proposed by the International Prognostic Working Group for Prognosis in MDS (IWG-PM) that places greater emphasis on poor-risk cytogenetics, more precisely characterizes cytopenias, and places patients in five clinical risk groups.
The WHO classification (Table 7.3) attempts to better define risk and separate individual syndromes.15 Some of the deficiencies of the FAB are addressed by including the prognostic relevance of cytopenias and karyotypic information in addition to blast counts. (Table 7.3). RAEB-t is discarded and the threshold for defining AML is lowered to 20% blasts. However, this distinction may be misleading, as older adults with 20% to 30% blasts (WHO-AML) had superior outcomes compared with conventional care when treated with azacitidine, an MDS therapy. 21
5q- syndrome is one of several specific MDS syndromes. Deletion of 5q, between bands q31 and q33, is separate in the WHO classification. 5q- usually manifests as anemia, with or without mild neutropenia and platelet counts either preserved or elevated. The prognosis is relatively good. Several cytokines, growth factors, and their receptors are found at the 5q locus; Haploinsufficiency of ribosomal gene RPS14 has been identified as potentially causative. Lenalidomide (Celgene Corporation, Summit, NJ), a thalidomide analog, is especially efficacious in 5q- syndrome.
Hypocellular MDS, while not categorized in any schema, may be easily confused with aplastic anemia, and patients may respond more favorably to immunosuppression with ATG.
Idiopathic cytopenia of undetermined significance (ICUS) and idiopathic dysplasia of uncertain significance (IDUS) are two recently described syndromes characterized by meaningful cytopenias and dysplasia, respectively, which do not meet the minimum diagnostic criteria for MDS.22 While the natural history of these conditions is not yet well characterized, in some cases they may precede a myeloid malignancy and warrant serial follow-up.
Chronic myelomonocytic leukemia (CMML) is biologically distinct, now classified as a myelodysplastic/myeloproliferative neoplasm by the WHO, which is discussed in other chapters.
Therapy-related (or secondary) MDS is an important subtype, constituting about 15% of cases in most series. This subtype has the highest rate of progression (75%) to acute leukemia, is difficult to treat, and rapidly fatal. Almost all patients have recurrent chromosomal abnormalities: deletions in chromosomes 5 and/or 7 occur at a mean interval of 4 to 5 years after exposure to alkylating agents, and 11q23 abnormalities follow in a shorter time period after topoisomerase II inhibitors. A very high frequency of therapy-related MDS is seen in patients who have undergone high-dose chemotherapy with autologous stem cell rescue (up to 19% at 10 years), more likely due to the cumulative prior therapy, especially alkylating agents, rather than the autotransplant itself. Overall, median survival is only 9 months.
MDS can be associated with large granular lymphocytosis (LGL). Significant numbers of circulating T-LGLs should prompt suspicion of this overlap syndrome; the diagnosis is confirmed by a clonal pattern of T-cell receptor gene rearrangement. Cases of T-LGL/MDS may have hematological responses to therapy directed against the T-LGL component, such as cyclosporine (CsA) or monoclonal antibody to CD52 (Campath); HLA-DR4 is a strong predictor of responsiveness.
Pediatric MDS is unusual and should lead to evaluation for genetic syndromes, such as Fanconi anemia, MonoMAC syndrome, Bloom syndrome, neurofibromatosis type 1, Schwachman syndrome, Pearson disease, Kostmann syndrome, familial monosomy 7, and constitutional chromosomal abnormalities.
THERAPY
Therapeutic strategies combine supportive care, suppression of the MDS clone and its leukemic progeny, efforts to improve bone marrow function, and curative attempts with allogeneic stem cell transplantation. Optimum management often requires the application of some or all of these approaches, preferably in the context of a research protocol (Table 7.4). Evidence-based decisions may be constrained by the clinical heterogeneity of MDS and the paucity of adequate data from clinical trials.
Supportive Care
Cytopenias are the single most important contributor to mortality.
Supportive care to maintain adequate peripheral counts and to prevent or treat infections is critical to the patient with MDS. Even moderate degrees of anemia may not be well tolerated by the elderly, especially in the presence of cardiopulmonary disease, and maintenance of higher hemoglobin levels (>9 g/dL) can improve the quality of life without altering transfusion frequency. Iron chelation should be considered in patients who are younger, without serious comorbidities, and who are in favorable diagnostic categories.
Leukodepletion of blood products and single-donor platelet transfusions reduce the risk of eventual alloimmunization to platelets. If a prophylactic regimen is adopted, 10,000/µL is usually an adequate platelet transfusion threshold. Aminocaproic acid may be a useful adjunct in patients who are refractory to platelet transfusions although this has not been studied in clinical trials.
Neutrophils may be dysfunctional in MDS. Infections in the setting of neutropenia must be treated promptly and aggressively.
Growth factors are frequently used in MDS and are used at the lowest doses that maintain a response.23 Combinations of erythropoietin and granulocyte colony-stimulating factor (G-CSF) are synergistic, with hematological improvements in 40% of low-grade MDS patients.24 Growth factor combinations can be effective even when individual factors have failed to improve blood counts. Patients requiring fewer than 2 units of red blood cells per month and a serum erythropoietin level less than 500 U/L have a higher probability of response (>70%) to erythropoietin plus G-CSF according to an established predictive model.24-26 Erythropoietin and G-CSF therapy do not appear to hasten leukemic progression, but there is also little evidence for a positive impact on survival. Thrombopoietin agonists are in clinical trials in thrombocytopenic MDS patients but have raised concerns of leukemogenesis. Romiplostim (Amgen, Thousand Oaks, CA) was used in early clinical trials in patients with MDS and severe thrombocytopenia but an increased rate of progression to AML was observed. Eltrombopag (GlaxoSmithKline, Philadelphia, PA) is currently being used in clinical trials in patients with low and high-risk MDS.
Table 7.4 Therapeutic Strategies for Myelodysplastic Syndrome
Supportive care
Transfusion
Antimicrobials
Iron chelation
Treatments aimed at improving bone marrow function
Growth factors (erythropoietin, G-CSF, GM-CSF)
Immunosuppression (ATG, cyclosporine, alemtuzumab)
Anti-cytokine approaches (lenalidomide)
Anti-apoptosis (ON 01910.Na)
Treatments directed at the abnormal clone
Low intensity chemotherapy (hydroxyurea, low dose ara-C,VP-16)
Intermediate intensity chemotherapy (clofarabine)
Induction regimens (anthracycline/ara-C combinations, FLAG, ADE)
DNA methyltransferase inhibitors (5-azacitidine, decitabine)
Histone deacetylase inhibitors
Farnesyl transferase Inhibitors
Curative attempts (stem cell transplantation)
Myeloablative transplantation
Reduced intensity conditioning
ADE, Ara-C daunorubicin etoposide; ATG, antithymocyte globulin; FLAG, Fludarabine Ara-C G-CSF; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte monocyte colony-stimulating factor.
Stem Cell Transplant
Allotransplant is the only curative therapy. Favorable transplant outcomes are more likely in younger patients, those with a short interval between diagnosis and transplant, and patients with HLA identical siblings.27 Generally, patients with IPSS risk of Int-2 or High would benefit from allogeneic transplant as soon as a donor is identified whereas those with IPPS risk of Low of Int-1 would benefit from waiting till progression.28 Survival outcomes after transplant from HLA-matched unrelated donors have been similar to conventional allotransplant from matched siblings; the improvement is in part attributed to use of high-resolution HLA typing to screen for HLA disparity at the allele level.27 Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) document that survival rates decrease precipitously in advanced stage MDS; survival is approximately 30% for both HLA-matched related and unrelated transplants, which is comparable or slightly worse than transplant outcomes for a similar age group with AML. The IPSS score also predicts relapse and survival; patients with low-risk disease (low risk/Int-1 by IPSS) have significantly lower relapse rates (13% vs. 43%) and better disease-free survival (55% vs. 28%) than do patients with high-risk MDS.29 Therefore, the decision for transplantation requires balancing the probability of disease progression and complications against the morbidity and mortality incurred with transplant (highest in the first year following the procedure). While allotransplant remains the treatment of choice in younger patients, until recently transplant was not feasible for older adults because of higher treatment-related mortality with advanced age; as most patients with MDS are diagnosed in their 60s, the age limit eliminated the only curative option. With the advent of reduced intensity regimens (RIC) that employ less myelosuppression with more intense immunosuppression, older patients with MDS are now being transplanted. RIC regimens offer less treatment-related mortality but at the expense of more disease relapse.
Specific Therapies: DNA Methyltransferase Inhibitors
The DNA methyltransferases function to hypermethylate the CpG promoter regions of many tumor suppressor genes and decrease their gene expression. Hypermethylation is one of many epigenetic modifications that can influence gene expression. In malignancy (such as in MDS), acquired hypermethylation of tumor suppressor genes downregulates expression, increasing the potential for dysplastic growth. Two agents that inhibit hypermethylation are 5-azacitidine (Vidaza, Celgene Corporation, Summit, NJ) and its active metabolite 5-aza-2′-deoxyazacitidine (Decitabine or Dacogen, Eisai Inc, Woodcliff Lake, NJ). At low doses they induce cellular differentiation by inhibiting DNA methyltransferase, while at higher doses these analogs of cytidine can be incorporated into DNA (decitabine) or both RNA and DNA (azacitidine) to exert a direct cytostatic effect.
Azacitidine is currently approved for use for patients with all FAB subtypes. The landmark trial that demonstrated efficacy of 5-azacitidine, CALGB 9221, was a randomized trial of 5-azacitidine versus best supportive care. The data from this trial was re-analyzed using the WHO classification for MDS and the International Working Group response criteria.30 Overall response rate was 47%.31 Although the complete and partial remission rates were low (10% and 1%, respectively), there was a significant improvement in overall survival, time to leukemia progression, and quality of life.32,33 In responders, median time to first response was three cycles and 90% responded by the sixth cycle. While worsening cytopenias were seen in many patients, there was no increase in infection or bleeding. A definitive phase III trial (Aza-001) compared Azacitidine (75 mg/m2/day × 7 days q4 weeks) versus a choice of three conventional regimens (best supportive care, low dose Ara-C or Ara-C + Daunorubicin) for Int-2 to High IPSS risk patients.34 Patients were treated until disease progression. A significant survival benefit for azacitidine treatment was seen over conventional care regimens (24.5 months vs. 15 months median overall survival). Clinical trials exploring the efficacy of oral azacitidine in MDS are ongoing.35
Decitabine is FDA approved for the treatment of IPSS scored intermediate-1 or higher risk patients. At a dose of 15 mg/m2 given intravenously inpatient every 8 hours for 3 days every 6 weeks, a phase III trial demonstrated a statistically significant overall response rate (17% vs. 0%) and improvement in quality of life compared to supportive care alone but only a nonstatistically significant trend toward improved overall survival or time to leukemogenesis.36 An alternative outpatient dosing schedule of 20 mg/m2 given intravenously once daily for 5 consecutive days every 4 weeks demonstrated similar efficacy.37 A subsequent EORTC trial comparing the 3-day dosing schedule versus best supportive care in intermediate or high-risk MDS demonstrated improvements in progression-free survival and AML transformation but no impact on overall survival.38
Dose and schedule optimization of the demethylating agents are ongoing. If tolerated, patients should receive an extended course of therapy (e.g., up to six cycles) before deeming it ineffective. Maintenance therapy is important and hematological responses are not a precondition for a survival benefit. Demethylating agents should now be considered a standard of care in Int-2 and high IPSS patients who are not transplant candidates or as a bridge to allogeneic BMT.26
Specific Therapies: Immunomodulatory Agents
Lenalidomide is an oral analog of thalidomide with far greater potency, superior safety, and established efficacy in MDS. Lenalidomide is approved for use in patients with transfusion-dependent anemia and low or intermediate-1 risk MDS with deletion 5q with or without other cytogenetic abnormalities. A landmark clinical trial in MDS patients demonstrated rapid responses (median time to response 4.6 weeks) including cytogenetic response and complete transfusion independence in 67% of patients with isolated deletion 5q.39 A confirmatory randomized phase III study comparing lenalidomide to best supportive care in low or intermediate-1 risk MDS with deletion 5q demonstrated similar results.40 Approximately 50% of patients with deletion 5q experienced grade 3 or 4 neutropenia or thrombocytopenia early in the course of treatment. Those patients who had a greater platelet and neutrophil decline while on therapy had an increased transfusion independence response which suggests a direct cytotoxic effect of lenalidomide specific to the deletion 5q clone.41 Fifty percent of patients will have a clinical and cytogenetic relapse after 2 to 3 years of treatment. A recent study suggests that there may be a small deletion 5q stem cell population that persists despite treatment with lenalidomide accounting for the relapse rate.42 Lenalidomide is indicated in patients with lower risk MDS with deletion 5q and transfusion dependence. Patients who lack deletion 5q demonstrated a 26% transfusion-independence response rate.43
Immunosuppression
Horse antithymocyte globulin (hATG) at 40 mg/kg/day × 4 days produces hematological responses in about one-third of patients with low-risk MDS.44 Subjects who are less than 50 years of age, with a shorter duration of red cell transfusion dependence and who are HLA-DR15+ are most likely to respond to immunosuppression.45 In a retrospective analysis of 129 MDS patients treated with antithymocyte globulin (ATG) and/or CsA, younger age was the most significant factor favoring response to therapy.46 Other favorable factors affecting response were HLA-DR15 positivity and combination ATG plus CsA treatment. CsA (5 mg/kg/day for 3 months, tapered to a low maintenance dose thereafter) may be effective, especially in T-LGL/MDS patients who are HLA-DR4 positive. Alemtuzumab (Campath) is an alternative choice for immunosuppressive therapy, which was recently shown to improve blood counts and induce cytogenetic remissions in selected patients with intermediate-1 MDS.47
Specific Therapies: Histone Deacetylase Inhibitors, Multi-Kinase Inhibitors
Histone Deacetylase (HDAC) inhibitors inhibit deacetylation of histone lysine tails, resulting in relaxation of chromatin and decreased transcription of the involved DNA. The compounds have activity in AML and MDS. HDAC inhibitors currently under investigation include valproic acid, suberoylanilide hydroxamic acid (vorinostat), depsipeptide, phenylbutyrate, MGCD0103, MS-275, and LBH589. HDAC inhibitors as single-agent therapy do not have a strong favorable impact on disease, but early results from phase I/II trials suggest a synergistic response with the combination of DNA methyltransferase inhibitors and HDAC inhibitors. Dosing regimens, toxicity, and impact on disease are under ongoing investigation.48
ON 01910.Na (Onconova) is a multi-kinase inhibitor that selectively induces mitotic arrest leading to apoptosis in cancer cells and blasts. Recent phase I/II trials have shown encouraging responses in high-risk MDS patients no longer responding to DNA methyltransferase inhibitors.49 A phase III trial is currently ongoing (NCT01241500 from ClinicalTrials.gov).
Failure of DNA Methyltransferase Inhibitor-Based Therapy
Although the DNA methyltransferase inhibitors (azacitidine and decitabine) represent the standard of care for transplant-ineligible high-risk MDS patients, not all patients will respond and most responders will experience disease progression within 2 years of response.34 In this situation, the prognosis is poor with no definitive standard salvage option.50 Clinical trials are preferred for such patients and current studies using various agents including ezatiostat (TLK199), ON 01910.NA, clofarabine, and alemtuzumab are ongoing.51 Switching hypomethylating agents may be considered if there is no response or disease progression after initial response but this approach has not yet been validated in significant patient numbers.52
Chemotherapy
Many guidelines have suggested a role for standard intensive induction chemotherapy with regimens typically used for AML to eliminate the neoplastic clone. However, no prospective studies show long-term survival benefit and this approach should be discouraged outside the context of a clinical trial. While advanced MDS often demonstrates high response rates to induction chemotherapy, it is usually followed by the virtual certainty of relapse (up to 90%). Likely futile efforts to eradicate an MDS clone have to be balanced against the risk of further reduction of the marrow reserve. Low intensity chemotherapy (hydroxyurea or etoposide) may be useful for cytoreduction with a palliative goal once MDS transforms, especially in the aged patient.
SUMMARY
The past decade has seen a significant growth in treatment options for MDS. When evaluating a patient, many factors need to be considered in the decision to treat, including age, comorbidities, karyotype, HLA status, prognostic-risk assessment, and availability of sibling and unrelated donor matches (Fig. 7.2). Targeted therapies have not yet made a clear long-term impact on survival. Growth factors should be tried on low-risk patients with MDS if erythropoietin level is low. Lenalidomide can be used in patients with deletion 5q and hypomethylating agents should be reserved for patients with higher risk MDS or as a bridge to stem cell transplant. Clinical and laboratory research in MDS is robust and may continue to yield therapeutic advances. When possible, patients should always be referred to a clinical trial to further define the heterogenous nature of MDS and improve therapeutic options for disease subsets.
FIGURE 7.2 Risk-adjusted schema for management of MDS. When deciding upon treatment of MDS, a careful prognostic assessment is essential. Age and comorbidities also influence treatment options that are realistic. Note that 5-azacitidine is approved for use in patients with all FAB types and IPSS scores. Decitabine is approved for patients with IPSS scores that are intermediate-1 or higher.
References