- Email: [email protected]
Alternative Treatments for Myelodysplastic Syndromes
Alternative Treatments for Myelodysplastic Syndromes Mikkael Sekeresa and Alan Listb Selecting the most appropriate treatment for patients with myelodysplastic syndromes (MDS) requires careful consideration of several factors. Most patients with MDS are in the 7th or later decade of life and often have comorbid health problems influencing treatment tolerance. Poor-prognosis MDS, as indicated by unfavorable cytogenetics or an increased percentage of myeloblasts, warrants more aggressive interventions than more indolent forms, which might remain stable for many years without treatment. The only curative treatment for MDS is allogeneic stem cell transplantion; however, only a small percentage of patients are candidates for this aggressive treatment. Traditional management for most patients with MDS is supportive care with red blood cell and platelet transfusions or hematopoietic growth factor support and antibiotics for infections. More detailed scrutiny of the processes involved in the MDS phenotype has stimulated investigation into identifying alternate therapeutic options that are effective and better tolerated. Herein, we summarize an array of novel treatments in development for the management of MDS. Semin Hematol 42:S32-S37 © 2005 Elsevier Inc. All rights reserved.
T
he myelodysplastic syndromes (MDS) are a collection of stem cell malignancies that share features of cytologic dysplasia in myeloid, erythroid, or megakaryocytic cells, which result in ineffective hematopoiesis and peripheral blood cytopenias.7 At one time, MDS was thought to be a precursor to leukemic transformation. It is now clear that only a percentage of MDS progresses to acute myeloid leukemia (AML) and that MDS can be divided into several prognostically distinct categories on the basis of cytogenetic characteristics, bone marrow morphology, blast percentages, and number of cytopenias present.1 More than leukemic transformation, the greater morbidity and mortality concerns for patients with MDS are anemia, hemorrhage, and infection.25 The two morphologic classification systems that are most commonly used to describe the varied types of MDS are the French-American-British (FAB)9 and the World Health Organization (WHO).18 Both rely on morphologic characteristics and the presence of myeloblasts in specific threshold
aDepartment
of Hematology and Medical Oncology, The Cleveland Clinic Foundation, Cleveland, OH. bDivision of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, and Department of Medicine, University of South Florida, Tampa, FL. Address correspondence to Mikkael Sekeres, MD, MS, Assistant Professor of Medicine, Department of Hematology and Medical Oncology, The Cleveland Clinic Foundation, 9500 Euclid Ave, Desk R 35, Cleveland, OH 44195. E-mail: [email protected]
S32
0037-1963/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.seminhematol.2005.05.008
percentages to delineate the different subtypes of MDS. The five categories into which MDS is divided under the FAB system are: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-t), and chronic myelomonocytic leukemia (CMML). The principal differences between the FAB and WHO classifications are the elimination of the RAEB-t classification from the WHO classification, where patients with ⱖ20% myeloblasts are now considered to have AML; the subdivision of the FAB RAEB group into RAEB-1 and RAEB-2 in the WHO system, using a blast threshold of less than or greater than 10%; the addition of two new categories, refractory cytopenia with multilineage dysplasia (RCMD), which acknowledges the importance of dysplasia in non-erythroid lineages, and RCMD with ringed sideroblasts (RCMD/RS); and the recognition of the importance of cytogenetics in identifying 5q⫺ syndrome as a distinct subgroup.30 Even though the FAB and WHO nomenclatures can distinguish among the diverse diseases that comprise MDS, these classification systems provide little insight into prognosis or potential response to therapy for the various morphologic types. To develop a system that provides greater prognostic discrimination, the International MDS Risk Analysis Workshop performed an analysis of more than 800 patients with primary MDS to identify those disease characteristics predictive of AML transformation and survival. The analysis singled out
Alternative treatments for MDS
S33
Table 1 International Prognostic Scoring System17 Characteristic Karyotype* Good Intermediate Poor Cytopenia 0/1 2/3 % Bone marrow blasts <5 5–10 11–20 21–30 Risk group Low Intermediate 1 (INT-1) Intermediate 2 (INT-2) High
Pathobiology of MDS
Point Value 0 0.5 1.0 0 0.5 0 0.5 1.5 2.0 Total points 0 0.5-1.0 1.5-2.0 >2.5
*Good-risk cytogenetics include normal, del (5q) only, del (20q) only, ⴚY. Intermediate-risk cytogenetics include ⴙ8, single miscellaneous, double abnormalities. Poor-risk cytogenetics include complex (ie, >3 anomalies) or chromosome 7 abnormalities.
percentage of bone marrow blasts, cytogenetic abnormalities, and number of cell linages affected by cytopenias as factors that are signficantly predictive for AML evolution in a multivariate analysis. As shown in Table 1, the International Prognostic Scoring System (IPSS) assigns weighted values to these features in accordance with the corresponding prognostic power. The IPSS divides MDS patients, regardless of morphologic type, into discrete risk groups, as shown in Table 1, based on their total point score.17 An aggregate IPSS ⱕ1.0 places a patient in one of the two lower risk groups (Low and INT-1), whereas an aggregate IPSS of 1.5 or higher would indicate placement in one of two higher risk groups (INT-2 and High). The IPSS provides more reliable patient stratification by incorporating relevant and easily obtainable prognostic variables, without relying on bone marrow blast percentage alone as do the FAB and WHO pathologic classifications schemas. The more accurate assessment of risk provided by the IPSS permits therapeutic decisions within a framework of cohesive goals commensurate with the level of risk for leukemic transformation and expected survival, and establishes a context for standardizing the evaluation of clinical trials for this heterogeneous disease.11 Treatment options for patients with MDS range from supportive care and low-intensity treatments for those with low and INT-1 IPSS, to aggressive chemotherapy or even stem cell transplantation with curative intent for eligible patients at the highest risk (INT-2 and high risk), whose age and performance status do not earmark them as poor candidates for treatment. Although MDS remains a challenging disorder to manage, encouraging developments are emerging directed by the delineation of pathobiologic features underlying the disease.
Like its clinical presentation, the pathobiology of MDS varies depending on the risks posed by the disease. Although the precise biological mechanisms have not been described with unequivocal precision, several lines of evidence provide a basis for developing new therapeutic interventions. Some of the effectors that have been implicated in the disease process are catalogued in Table 2. A number of the genes involved in regulation of hematopoiesis are located on the long arm of chromosome 5, and clonal abnormalities on chromosomes 5 and 7 are common findings in MDS. The clonal basis for the development of MDS lends credence to the view that MDS is, in fact, a cancer, and is considered by many to be a subtype of leukemia. The events culminating in MDS are initiated by abnormalities in the genome of pluripotent stem cells in the bone marrow. Excessive apoptosis is predominant in low-risk or early MDS, where there is a hypercellular marrow in the presence of peripheral blood cytopenias. Under these circumstances, an inhospitable milieu in the bone marrow microenvironment is maintained by the presence of angiogenic factors, such as vascular endothelial growth factor, and proapoptotic, inflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣), interleukin (IL)-1, IL-6, transforming growth factor-, and soluble fas ligand.2 In advanced stages of MDS where there is a preponderance of blasts, activation of oncogenes and the inactivation of tumor-suppressor genes predominate over inhibitory cytokines. A hyperproliferative state results, similar to AML. At this stage, without treatment, it is a fait accompli that MDS will transform to AML, or that patients will die from cytopenic complications of the disease. Activating mutations of ras proto-oncogenes are involved in promoting signal transduction and survival signals, while mutations or methylation silencing of tumor-suppressor genes, p53 and p15INK4b, cause their inactivation or silencing.27
Treatment Options Hematopoietic Stem Cell Transplantation Hematopoietic stem cell transplantation (HSCT) is currently the only treatment for MDS that is potentially curative. SevTable 2 Mediator Activity in Indolent and Aggressive MDS2
Early Disease Proapoptotic Factors (indolent disease) Tumor necrosis factor-alpha (TNF-␣) Interleukin 6 (IL-6) Interleukin 1 beta (IL-1) Transforming growth factor-beta (TGF-) Fas ligand Vascular endothelial growth factor (VEGF)
Late Disease Proproliferative Factors (aggressive disease) Ras mutations p53 mutations
M. Sekeres and A. List
S34 eral series report long-term disease-free survival ranging from 30% to 50% with allogeneic transplants from human leukocyte antigen (HLA)-identical sibling donors. Treatment-related mortality with this approach ranges from 30% to 50%.5,33,35 Because of the excessive procedure-related risks, HSCT is reserved for younger individuals with higherrisk MDS. Factors that are related to better HSCT outcome include younger patient age, lower percentage of blasts, and a shorter time from diagnosis to treatment.13,38 As most MDS patients are of advanced age, only about 5% to 10% of MDS patients are candidates for HSCT. Although outcomes of HSCT are better in earlier stage disease, the optimum time to perform the procedure favors later stage disease. Using a Markov decision model, one study examined three options for timing of HSCT.12 These included HSCT performed immediately at the time of diagnosis; HSCT delayed until some fixed time after diagnosis—2, 4, 6, or 8 years, but prior to transformation to AML; and HSCT performed at the time of AML transformation. The model indicated that immediate transplantation at the time of diagnosis was associated with the largest extension of life expectancy for IPSS INT-2 and high-risk patients. For lowrisk and INT-1 patients, the benefit of transplant was greatest when transplant was delayed for a fixed time, as long as it was performed before progression to AML. In an attempt to make HSCT an option for a larger number of MDS patients, nonmyeloablative regimens designed to ameliorate immediate toxicity have been studied. A retrospective analysis compared outcomes for 273 patients with AML or MDS who underwent myeloablative HSCT with 37 patients who had a nonmyeloablative procedure.3 The relapse rate for patients in the nonmyeloablative group was 57%, versus 31% in the myeloablative group. However, the treatment-related mortality was higher, 20%, in the latter group compared to 8% for the nonablative treatment. At 1 year, the overall survival was 46% for both groups, and at 2 years, the overall survival was 30% and 34% for the nonmyeloablative group and the myeloablative group, respectively. In addition to the high mortality associated with allogeneic transplant, access to this treatment may be limited by the lack of a donor relative. Analyses of observational databases (National Marrow Donor Program [NMDP], European Group for Bone Marrow Transplantation [EBMT]) indicate that HSCTs for MDS that were performed using matched unrelated donors produced 2- and 3-year disease-free survival rates of 29% and 25%, respectively.6,10 Autologous stem cell transplants have also been performed for patients for whom no suitable donor exists. The 2-year disease-free survival for 79 EBMT patients who underwent autologous transplant was 34%.14 Poor stem cell harvest and the possibility of graft contamination are obstacles that may limit the utility of this approach.
Supportive Care MDS patients with symptomatic anemia secondary to ineffective erythropoiesis and thrombocytopenia can be managed supportively with transfusions of red blood cells and
platelets as needed. Repeated transfusions of red blood cells (at least 30 units) may saturate iron stores and cause secondary hemochromatosis to ensue, necessitating treatment with iron chelation therapy. The goal of chelation therapy is to maintain a serum ferritin level below 800 ng/dL. Subcutaneous administration of desferrioxamine is standard treatment for iron overload.21 Oral agents are currently being studied in clinical trials in Europe and in the United States. Supportive therapy with recombinant erythropoietin and myeloid colony-stimulating factors is a cornerstone of MDS management. Levels of endogenous erythropoietin less than 100 U/L are predictive of a better chance of response to treatment with recombinant erythropoietin. In vitro studies have demonstrated that the combinaton of erythropoietin and granulocyte colony-stimulating factors is synergistic,4,8 and in clinical trials the combination has improved response rates from approximately 15% with erythropoietin alone to 30% to 40% with the combination.19,20,29 A longer-acting form of erythropoietin, darbepoetin, has shown promising activity in MDS in preliminary studies; however, its use in this setting remains investigational.28
Antiangiogenic Agents Thalidomide has multiple mechanisms of action that contribute to its activity in hematologic neoplasms, including multiple myeloma and MDS. In addition to its antiangiogenic properties, thalidomide suppresses TNF-␣ elaboration and other cytokines. Four phase II studies evaluated thalidomide as a single agent in MDS. The largest of these evaluated escalating oral doses of thalidomide in 83 MDS patients.31 All FAB subtypes and all IPSS risk categories were represented, receiving doses of thalidomide ranging from 100 mg to 400 mg daily. The tolerability of this treatment was poor, with only 34 of the patients reaching the 400 mg daily dose level and only eight patients able to continue at this dose level for 8 weeks of treatment. Only 51 patients completed 12 weeks of treatment, and the majority of patients who continued therapy received doses between 150 and 200 mg daily. Of the 32 patients who discontinued therapy early, more than 50% were in IPSS high-risk or INT-2 groups, and only eight patients in these IPSS groups were able to finish the course of treatment. The most common adverse events were fatigue, constipation, shortness of breath, fluid retention, dizziness, rash, paresthesias, headache, fever, and nausea. Hematologic responses were reported using the criteria established by the International Working Group11 and are summarized in Table 3. There were no complete responses; however, hematologic improvement was observed in 16 patients (19%), 10 of whom experienced a reduction in transfusion requirements, one who had at least a 2 g/dL increase in hemoglobin, and four who had a minor erythroid response. There was a minor platelet response in one patient. Responses occurred preferentially in patients with low-risk disease. In 11 of the 15 erythroid responders, the response occurred within 16 weeks of thalidomide initiation, and the median duration of response was 306 days. Lenalidomide is an analogue of thalidomide that is a potent
Alternative treatments for MDS
S35
Table 3 Selected International Working Group Response Criteria11 Response Category Complete response
Partial response
Cytogenetic response Hematologic improvement
Response Characteristics Bone marrow: <5% blasts on repeat evaluation Peripheral blood: hemoglobin >11 g/dL; neutrophils >1,500/L; platelets >100,000/L; blasts 0%; no dysplasia* Bone marrow: >50% decrease in blasts versus baseline or less advanced FAB classification than baseline Peripheral blood: hemoglobin >11 g/dL; neutrophils >1,500/L; platelets >100,000/L; blasts 0% Major: no detectable abnormality, if pre-exising abnormality was present Minor: 50% or more reduction in abnormal metaphases Erythroid response (HI-E) Major: >2 g/dL increase in hemoglobin if baseline was <11 g/dL or transfusion independence if dependent at baseline Minor: 1–2 g/dL increase in hemoglobin if baseline was <11 g/dL or 50% decrease in transfusion requirements Platelet response (HI-P) Major: increase of 30,000/L if baseline was <100,000/L or stabilization of platelet count and transfusion independence if transfusion-dependent at baseline Minor: >50% increase with a net increase >10,000/L but <30,000/L if baseline was <100,000/L Neutrophil response (HI-N) Major: 100% increase or absolute increase of 500/L whichever is greater, if absolute neutrophil count (ANC) <1,500/L at baseline Minor: ANC increase of at least 100% but absolute increase <500/L if ANC < 1,500/L at baseline
NOTE. For a designated response (CR, PR, HI) all relevant response criteria must be noted on at least two successive determinations at least 1 week apart after an appropriate period following therapy (eg, 1 month or longer) *The presence of mild megaloblastoid changes may be permitted if they are thought to be consistent with treatment effect. However, persistence of pretreatment abnormalities (eg, pseudo Pelger-Hüet cells, ringed sideroblasts, dysplastic megakaryocytes) are not consistent with CR. Adapted with permission from: Cheson B, et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 2000;96:3671-4. Copyright American Society of Hematology, used with permission.
modulator of ligand-induced biological effects such as angiogenesis, inflammation, cell adhesion, erythropoietin receptor signaling, and immune response. An open-label study used three dose schedules of lenalidomide, 25 mg daily, 10 mg daily, and 10 mg daily for 21 days every 28 days, in 43 patients with symptomatic anemia and MDS that was refractory to erythropoietic growth factors.24 The major adverse events in this trial were dose-dependent neutropenia and thrombocytopenia. As seen with thalidomide, responses were more frequent in patients in lower risk IPSS than those in higher risk categories. The overall response rate was 56%, including 20 of 32 transfusion-dependent patients achieving transfusion independence. Perhaps the most promising aspect of the study was the high frequency of cytogenetic response in patients with chromosome del 5q (5q31.1). Of 12 such patients enrolled on this study, 10 (83%) had a ⱖ50% decrease in abnormal metaphases, and nine (75%) achieved a cytogenetic complete remission. Cytogenetic responses correlated with hematologic improvement. Phase II studies of arsenic trioxide (ATO) monotherapy at a dose of 0.25 mg/kg for 5 days per week for 2 weeks followed by a 2-week rest period for four cycles26 and in combination
(0.25 mg/kg/d for 2 weeks followed by a 2-week rest) with 100 mg daily dose of thalidomide for six cycles,32 indicated that this agent is capable of producing hematologic responses in both higher risk and lower risk patients. Hematologic improvements were not limited to the erythroid lineage. ATO has pro-apoptotic properties and exerts direct cytotoxicity to neovascular endothelial cells to produce its antiangiogenic effects. A French multicenter phase II study enrolled 115 patients with various FAB subtypes treated with a loading dose of 0.30 mg/kg/d ATO for 5 days followed by 0.25 mg/kg twice per week for 15 weeks.40 Mild to moderate neutropenia was the predominant adverse event and all other adverse events were mild to moderate in severity. Overall, 27% of patients responded with hematologic improvement (including one complete response), and responses were reported in all hematologic lineages. Of the 31 patients who achieved a hematologic response, 16 achieved transfusion independence.
Farnesyl Transferase Inhibitors Ras proteins are important regulatory elements in the mitogen-activated protein kinase pathway that controls survival
M. Sekeres and A. List
S36 signals involved in receptor activation, oncogenes, angiogenic response, proliferation, and apoptosis. The farnesyl protein transferase enzyme plays a critical role in activation of ras proteins. Farnesyl transferase inhibitors (FTIs), as a consequence of inhibiting the farnesyl transferase enzyme, interfere with ras membrane localization, which interrupts the ras signaling pathway.15 The most extensively studied FTIs to date are tipifarnib (R115777) and lonafarnib (SCH66336), both of which are administered orally. A phase I study of escalating doses of R115777 administered twice daily for 3 weeks every 4 weeks was conducted in 21 patients with all subtypes of MDS.22 The initial dose was 300 mg twice daily, which was increased by 100 mg/d in subsequent cohorts. The highest dose level evaluated was 900 mg/d. The maximum tolerated dose was 800 mg/d in two divided doses (400 mg twice daily). Although myelosuppression was frequent, occurring in 19 of 21 patients, it was not considered dose-limiting as myelosuppression may be considered an important indicator of activity. The dose-limiting toxicities were grade 3 fatigue, confusion, and myalgias. Responses were observed in six of the 20 patients who could be evaluated for response. There was one complete response, one partial response, and three responses in the International Working Group category of hematologic improvement, occurring at all dose levels studied. A follow-up phase II study evaluated R115777 at a dose of 600 mg twice daily for 4 weeks followed by a 2-week rest period.23 This schedule was derived from a phase I study in patients with relapsed or refractory leukemia. Although the treatment was poorly tolerated, resulting in dose reduction or treatment discontinuation in 67% of patients, there were three responses (two complete responses and one partial response) among the 27 patients evaluated. All three responding patients had advanced forms of MDS—two responders had RAEB and one had RAEB-t. The maximum tolerated dose of lonafarnib was 200 mg twice daily in a trial that enrolled 67 patients with advanced (RAEB, RAEB-t, CMML) MDS.16 Treatment was discontinued in 17 patients (67%) because of toxicity, including six patients who experienced intractable diarrhea. The most common grade 3 or 4 toxicities were diarrhea (26%), fatigue (17%), anorexia (12%), and nausea (9%). There were 12 responses among the 42 patients who could be evaluated, representing an overall response rate of 29%, and a 5% complete response rate. Of the 37 patients who had more than 5% blasts at study entry, 16 experienced a 50% reduction in blasts. Multilineage hematologic improvement was observed in 10 patients.
DNA Methyltransferase Inhibitors Neoplastic cells almost universally exhibit increased DNA methyltransferase activity. The methyltransferase enzyme is integral to silencing tumor-suppressor genes, such as p15INK4B in MDS, thereby supporting the proliferation and longevity of malignant cells.37,39 In low doses, the nucleoside analogues 5-azacitidine and decitabine act as methyltrans-
ferase inhibitors, thus allowing transcription of tumor-suppressor genes that had been silenced by hypermethylation. These drugs have been compared to supportive care in two phase III randomized trials.34,36 Decitabine was administered at a dose of 15 mg/m2 every 8 hours for 3 consecutive days every 6 weeks, while azacitidine was given at a dose of 75 mg/m2/d for 7 days every 28 days. In the decitabine trial, the overall response rate for decitabine-treated patients, using the IWG criteria,11 was 17% (9% complete responses, 8% partial responses), whereas there were no responses in the supportive care treatment group. The median age of patients in this trial was 70 years. In the azacitidine study, patients in the control group had a response rate of 0%, compared to 23% for azacitidine-treated patients (7% complete resposnes, 16% partial responses), using Cancer and Leukemia Group B (CALGB) response criteria, but 16% for azacitidine-treated patients (6% compelte responses, 10% partial responses) using more strict criteria upon submission to the US Food and Drug Administration. Both studies demonstrated decreased transfusion requirements and a quality of life benefit with the experimental agent.
Immunosuppressive Agents A subtype of MDS, often referred to as hypoplastic MDS, is diagnosed in 5% to 10% of MDS patients. More than other subtypes of MDS, this entity is thought to represent an immunemediated disese, often difficult to distinguish from aplastic anemia, other than through the identification of cytogenetic abnormalities in the former. As such, it is treated with immunosuppressive medications similar to those given to treat aplastic anemia. These include steroids (includng anabolic steroids), cyclosporine, and anti-thymocyte globulin.
Summary MDS is a spectrum of disorders requiring a variety of treatment approaches depending on the patient’s age, prognostic features, and comorbid conditions. The IPSS facilitates treatment selection by providing a standard method of assigning risk of progression to AML and overall survival from diseaserelated complications. Allogeneic stem cell transplantion, while curative, is not appropriate treatment for the large majority of MDS patients, and efforts are ongoing to expand the number of patients who can benefit from this type of treatment, or modified versions of it. In addition, understanding the varied biological processes that are operative in MDS has encouraged the development of novel therapies and could be beneficial to patients who are currently managed conservatively with supportive care.
References 1. Albitar M, Manshouri T, Shen Y, et al: Myelodysplastic syndrome is not merely “preleukemia.” Blood 100:791-798, 2002 2. Allampallam K, Shetty V, Mundle S, et al: Biological significance of proliferation, apoptosis, cytokines and monocyte/macrophage cells in bone marrow biopsies of 145 patients with myelodysplastic syndrome. Int J Hematol 75:289-297, 2002 3. Alyea E, Kim H, Cutler C, et al: AML and MDS treated with myeloablative stem cell transplantation: Overall and progression free survival
Alternative treatments for MDS
4.
5.
6.
7. 8. 9.
10.
11.
12.
13.
14.
15. 16.
17.
18.
19.
20.
21.
comparable to myeloablative transplantation. Blood 102:79, 2003 (abstr) Amano Y, Koike K, Nakahata T: Stem cell factor enhances growth of primitive erythroid progenitors to a greater extent than interleukin 3 in patients with aplastic anemia. Br J Haematol 85:663-669, 1993 Anderson J, Appelbaum F, Storb R: An update on allogeneic marrow transplantation for myelodysplastic syndrome. Leuk Lymphoma 17: 95-99, 1995 Arnold R, de Witte T, Van Biezen A, et al: Unrelated bone marrow transplantation in patients with myelodysplastic syndromes and secondary acute myeloid leukemia: An EBMT survey. Bone Marrow Transplant 21:1213-1216, 1998 Aul C, Bowen D, Yoshida Y: Pathogenesis, etiology and epidemiology of myelodysplastic syndromes. Haematologica 83:71-78, 1998 Backx B, Broeders L, Löwenberg B: Kit ligand improves in vitro erythropoiesis in myelodysplastic syndromes. Blood 80:1213-1217, 1992 Bennett J, Catovsky D, Daniel M, et al: The French-American-British (FAB) Group: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:188-189, 1982 Castro-Malaspina H, Harris R, Gajewski J, et al: Unrelated donor marrow transplantation for myelodysplastic syndromes: Outcome analysis in 510 transplants facilitated by the National Marrow Donor Program. Blood 99:1943-1951, 2002 Cheson B, Bennett J, Kantarjian H, et al: Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 96:3671-3674, 2000 Cutler C, Lee S, Greenberg P, et al: A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: Delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 104:579-585, 2004 de Witte T, van Biezen A, Hermans J, et al: Autologous bone marrow transplantation for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia following MDS. Chronic and Acute Leukemia Working Parties of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 110:620-630, 2000 de Witte T, van Biezen A, Hermans J, et al: Autologous bone marrow transplantation for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia following MDS. Blood 90:3583-3857, 1997 Estey E: Modulation of angiogenesis in patients with myelodysplastic syndrome. Best Pract Res Clin Hematol 17:623-639, 2004 Feldman E, Cortes J, Holyoake T, et al: Continuous oral lonafarnib (Sarasar) for the treatment of patients with myelodysplastic syndrome. Blood 102:421, 2003 (abstr) Greenberg P, Cox C, LeBeau M, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:20792088, 1997 Harris N, Jaffe E, Diebold J, et al: The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, VA, November, 1997. Ann Oncol 10:1419-1432, 1999 Hellström-Lindberg E: Efficacy of erythropoietin in the myelodysplastic syndromes. An analysis of 205 patients in 17 studies. Br J Haematol 89:67-71, 1995 Hellström-Lindberg E, Birgegård G, Carlsson M, et al: A combination of granulocyte-colony-stimulating factor and erythropoietin may synergistically improve the anaemia in patients with myelodysplastic syndromes. Leuk Lymphoma 11:221-228, 1993 Jensen P, Heickendorff L, Pedersen B, et al: The effect of iron chelation
S37
22.
23.
24. 25. 26.
27. 28.
29.
30.
31.
32.
33.
34.
35.
36.
37. 38.
39.
40.
on haemopoiesis in MDS patients with transfusional iron overload. Br J Haematol 94:288-299, 1996 Kurzrock R, Kantarjian H, Cortes J, et al: Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: Clinical and biological activities in the pahse I setting. Blood 102:4527-4534, 2003 Kurzrock R, Albitar M, Cortes J, et al: Phase II study of R115777, a farnesyl transferase inhibitor, in myelodysplastic syndrome. J Clin Oncol 22:1287-1292, 2004 List A, Kurtin S, Rose D, et al: Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 352:549-557, 2005 List A, Vardiman J, Issa J-P, et al: Myelodysplastic syndromes. Hematology (Am Soc Hematol Educ Program) 297-317, 2004 List A, Schiller G, Mason J, et al: Trisenox (arsenic trioxide, ATO) in patients (pts) with myelodysplastic syndromes (MDS): Preliminary findings in a phase II clinical study. Blood 100:790, 2002 (abstr) List A: New approaches to the treatment of myelodysplasia. Oncologist 7:39-49, 2002 (suppl 1) Mannone L, Gardin C, Quarre M, et al: High response rate to darbopoetin alfa in “low risk” MDS: Results of a phase II study. Blood 104:24, 2004 (abstr) Negrin R, Stein R, Doherty K, et al: Treatment of the anaemia of myelodysplastic syndromes using human granulocyte-CSF in combination with erythropoietin. Blood 82:737-743, 1993 Nosslinger T, Reisner R, Koller E, et al: Myelodysplastic syndromes from French-American-British to World Health Organization: Comparison of classifications on 431 unselected patients from a single institution. Blood 98:2935-2941, 2001 Raza A, Meyer P, Dutt D, et al: Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood 98:958-965, 2001 Raza A, Lisak L, Tahir S, et al: Trilineage responses to arsenic trioxide (Trisenox) and thalidomide in patients with myelodysplastic syndromes (MDS), particularly those with inv(3)(q21q26.2). Blood 100: 795, 2002 (abstr) Runde V, de Witte T, Arnold C, et al: Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: Early transplantation is associated with improved outcome. Bone Marrow Transplant 21:255-260, 1998 Saba H, Rosenfeld C, Issa J, et al: First report of the phase III North American trial of decitabine in advanced myelodysplastic syndrome (MDS). Blood 104:23, 2004 (abstr) Sierra J, Pérez W, Rozman C, et al: Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood 100: 1997-2004, 2002 Silverman L, Demakos E, Peterson B, et al: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the cancer and leukemia group B. J Clin Oncol 20:2429-2440, 2002 Singal R, Ginder G: DNA methylation. Blood 93:4059-4070, 1999 Sutton L, Chastang C, Ribaud P, et al: Factors influencing outcome in de-novo myelodysplastic syndromes treated by allogeneic bone marrow transplantation: A long-term study of 71 patients. Blood 88:358365, 1996 Uchida T, Kinoshita T, Nagal H, et al: Hypermethylation of the p15INK4B gene in myelodysplastic syndromes. Blood 90:1403-1409, 1997 Vey N, Dreyfus F, Guerci A, et al: Trisenox (arsenic trioxide) in patients with myelodysplastic syndromes (MDS): Preliminary results of a phase I/II study. Blood 104:401, 2004 (abstr)
T
he myelodysplastic syndromes (MDS) are a collection of stem cell malignancies that share features of cytologic dysplasia in myeloid, erythroid, or megakaryocytic cells, which result in ineffective hematopoiesis and peripheral blood cytopenias.7 At one time, MDS was thought to be a precursor to leukemic transformation. It is now clear that only a percentage of MDS progresses to acute myeloid leukemia (AML) and that MDS can be divided into several prognostically distinct categories on the basis of cytogenetic characteristics, bone marrow morphology, blast percentages, and number of cytopenias present.1 More than leukemic transformation, the greater morbidity and mortality concerns for patients with MDS are anemia, hemorrhage, and infection.25 The two morphologic classification systems that are most commonly used to describe the varied types of MDS are the French-American-British (FAB)9 and the World Health Organization (WHO).18 Both rely on morphologic characteristics and the presence of myeloblasts in specific threshold
aDepartment
of Hematology and Medical Oncology, The Cleveland Clinic Foundation, Cleveland, OH. bDivision of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, and Department of Medicine, University of South Florida, Tampa, FL. Address correspondence to Mikkael Sekeres, MD, MS, Assistant Professor of Medicine, Department of Hematology and Medical Oncology, The Cleveland Clinic Foundation, 9500 Euclid Ave, Desk R 35, Cleveland, OH 44195. E-mail: [email protected]
S32
0037-1963/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.seminhematol.2005.05.008
percentages to delineate the different subtypes of MDS. The five categories into which MDS is divided under the FAB system are: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-t), and chronic myelomonocytic leukemia (CMML). The principal differences between the FAB and WHO classifications are the elimination of the RAEB-t classification from the WHO classification, where patients with ⱖ20% myeloblasts are now considered to have AML; the subdivision of the FAB RAEB group into RAEB-1 and RAEB-2 in the WHO system, using a blast threshold of less than or greater than 10%; the addition of two new categories, refractory cytopenia with multilineage dysplasia (RCMD), which acknowledges the importance of dysplasia in non-erythroid lineages, and RCMD with ringed sideroblasts (RCMD/RS); and the recognition of the importance of cytogenetics in identifying 5q⫺ syndrome as a distinct subgroup.30 Even though the FAB and WHO nomenclatures can distinguish among the diverse diseases that comprise MDS, these classification systems provide little insight into prognosis or potential response to therapy for the various morphologic types. To develop a system that provides greater prognostic discrimination, the International MDS Risk Analysis Workshop performed an analysis of more than 800 patients with primary MDS to identify those disease characteristics predictive of AML transformation and survival. The analysis singled out
Alternative treatments for MDS
S33
Table 1 International Prognostic Scoring System17 Characteristic Karyotype* Good Intermediate Poor Cytopenia 0/1 2/3 % Bone marrow blasts <5 5–10 11–20 21–30 Risk group Low Intermediate 1 (INT-1) Intermediate 2 (INT-2) High
Pathobiology of MDS
Point Value 0 0.5 1.0 0 0.5 0 0.5 1.5 2.0 Total points 0 0.5-1.0 1.5-2.0 >2.5
*Good-risk cytogenetics include normal, del (5q) only, del (20q) only, ⴚY. Intermediate-risk cytogenetics include ⴙ8, single miscellaneous, double abnormalities. Poor-risk cytogenetics include complex (ie, >3 anomalies) or chromosome 7 abnormalities.
percentage of bone marrow blasts, cytogenetic abnormalities, and number of cell linages affected by cytopenias as factors that are signficantly predictive for AML evolution in a multivariate analysis. As shown in Table 1, the International Prognostic Scoring System (IPSS) assigns weighted values to these features in accordance with the corresponding prognostic power. The IPSS divides MDS patients, regardless of morphologic type, into discrete risk groups, as shown in Table 1, based on their total point score.17 An aggregate IPSS ⱕ1.0 places a patient in one of the two lower risk groups (Low and INT-1), whereas an aggregate IPSS of 1.5 or higher would indicate placement in one of two higher risk groups (INT-2 and High). The IPSS provides more reliable patient stratification by incorporating relevant and easily obtainable prognostic variables, without relying on bone marrow blast percentage alone as do the FAB and WHO pathologic classifications schemas. The more accurate assessment of risk provided by the IPSS permits therapeutic decisions within a framework of cohesive goals commensurate with the level of risk for leukemic transformation and expected survival, and establishes a context for standardizing the evaluation of clinical trials for this heterogeneous disease.11 Treatment options for patients with MDS range from supportive care and low-intensity treatments for those with low and INT-1 IPSS, to aggressive chemotherapy or even stem cell transplantation with curative intent for eligible patients at the highest risk (INT-2 and high risk), whose age and performance status do not earmark them as poor candidates for treatment. Although MDS remains a challenging disorder to manage, encouraging developments are emerging directed by the delineation of pathobiologic features underlying the disease.
Like its clinical presentation, the pathobiology of MDS varies depending on the risks posed by the disease. Although the precise biological mechanisms have not been described with unequivocal precision, several lines of evidence provide a basis for developing new therapeutic interventions. Some of the effectors that have been implicated in the disease process are catalogued in Table 2. A number of the genes involved in regulation of hematopoiesis are located on the long arm of chromosome 5, and clonal abnormalities on chromosomes 5 and 7 are common findings in MDS. The clonal basis for the development of MDS lends credence to the view that MDS is, in fact, a cancer, and is considered by many to be a subtype of leukemia. The events culminating in MDS are initiated by abnormalities in the genome of pluripotent stem cells in the bone marrow. Excessive apoptosis is predominant in low-risk or early MDS, where there is a hypercellular marrow in the presence of peripheral blood cytopenias. Under these circumstances, an inhospitable milieu in the bone marrow microenvironment is maintained by the presence of angiogenic factors, such as vascular endothelial growth factor, and proapoptotic, inflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣), interleukin (IL)-1, IL-6, transforming growth factor-, and soluble fas ligand.2 In advanced stages of MDS where there is a preponderance of blasts, activation of oncogenes and the inactivation of tumor-suppressor genes predominate over inhibitory cytokines. A hyperproliferative state results, similar to AML. At this stage, without treatment, it is a fait accompli that MDS will transform to AML, or that patients will die from cytopenic complications of the disease. Activating mutations of ras proto-oncogenes are involved in promoting signal transduction and survival signals, while mutations or methylation silencing of tumor-suppressor genes, p53 and p15INK4b, cause their inactivation or silencing.27
Treatment Options Hematopoietic Stem Cell Transplantation Hematopoietic stem cell transplantation (HSCT) is currently the only treatment for MDS that is potentially curative. SevTable 2 Mediator Activity in Indolent and Aggressive MDS2
Early Disease Proapoptotic Factors (indolent disease) Tumor necrosis factor-alpha (TNF-␣) Interleukin 6 (IL-6) Interleukin 1 beta (IL-1) Transforming growth factor-beta (TGF-) Fas ligand Vascular endothelial growth factor (VEGF)
Late Disease Proproliferative Factors (aggressive disease) Ras mutations p53 mutations
M. Sekeres and A. List
S34 eral series report long-term disease-free survival ranging from 30% to 50% with allogeneic transplants from human leukocyte antigen (HLA)-identical sibling donors. Treatment-related mortality with this approach ranges from 30% to 50%.5,33,35 Because of the excessive procedure-related risks, HSCT is reserved for younger individuals with higherrisk MDS. Factors that are related to better HSCT outcome include younger patient age, lower percentage of blasts, and a shorter time from diagnosis to treatment.13,38 As most MDS patients are of advanced age, only about 5% to 10% of MDS patients are candidates for HSCT. Although outcomes of HSCT are better in earlier stage disease, the optimum time to perform the procedure favors later stage disease. Using a Markov decision model, one study examined three options for timing of HSCT.12 These included HSCT performed immediately at the time of diagnosis; HSCT delayed until some fixed time after diagnosis—2, 4, 6, or 8 years, but prior to transformation to AML; and HSCT performed at the time of AML transformation. The model indicated that immediate transplantation at the time of diagnosis was associated with the largest extension of life expectancy for IPSS INT-2 and high-risk patients. For lowrisk and INT-1 patients, the benefit of transplant was greatest when transplant was delayed for a fixed time, as long as it was performed before progression to AML. In an attempt to make HSCT an option for a larger number of MDS patients, nonmyeloablative regimens designed to ameliorate immediate toxicity have been studied. A retrospective analysis compared outcomes for 273 patients with AML or MDS who underwent myeloablative HSCT with 37 patients who had a nonmyeloablative procedure.3 The relapse rate for patients in the nonmyeloablative group was 57%, versus 31% in the myeloablative group. However, the treatment-related mortality was higher, 20%, in the latter group compared to 8% for the nonablative treatment. At 1 year, the overall survival was 46% for both groups, and at 2 years, the overall survival was 30% and 34% for the nonmyeloablative group and the myeloablative group, respectively. In addition to the high mortality associated with allogeneic transplant, access to this treatment may be limited by the lack of a donor relative. Analyses of observational databases (National Marrow Donor Program [NMDP], European Group for Bone Marrow Transplantation [EBMT]) indicate that HSCTs for MDS that were performed using matched unrelated donors produced 2- and 3-year disease-free survival rates of 29% and 25%, respectively.6,10 Autologous stem cell transplants have also been performed for patients for whom no suitable donor exists. The 2-year disease-free survival for 79 EBMT patients who underwent autologous transplant was 34%.14 Poor stem cell harvest and the possibility of graft contamination are obstacles that may limit the utility of this approach.
Supportive Care MDS patients with symptomatic anemia secondary to ineffective erythropoiesis and thrombocytopenia can be managed supportively with transfusions of red blood cells and
platelets as needed. Repeated transfusions of red blood cells (at least 30 units) may saturate iron stores and cause secondary hemochromatosis to ensue, necessitating treatment with iron chelation therapy. The goal of chelation therapy is to maintain a serum ferritin level below 800 ng/dL. Subcutaneous administration of desferrioxamine is standard treatment for iron overload.21 Oral agents are currently being studied in clinical trials in Europe and in the United States. Supportive therapy with recombinant erythropoietin and myeloid colony-stimulating factors is a cornerstone of MDS management. Levels of endogenous erythropoietin less than 100 U/L are predictive of a better chance of response to treatment with recombinant erythropoietin. In vitro studies have demonstrated that the combinaton of erythropoietin and granulocyte colony-stimulating factors is synergistic,4,8 and in clinical trials the combination has improved response rates from approximately 15% with erythropoietin alone to 30% to 40% with the combination.19,20,29 A longer-acting form of erythropoietin, darbepoetin, has shown promising activity in MDS in preliminary studies; however, its use in this setting remains investigational.28
Antiangiogenic Agents Thalidomide has multiple mechanisms of action that contribute to its activity in hematologic neoplasms, including multiple myeloma and MDS. In addition to its antiangiogenic properties, thalidomide suppresses TNF-␣ elaboration and other cytokines. Four phase II studies evaluated thalidomide as a single agent in MDS. The largest of these evaluated escalating oral doses of thalidomide in 83 MDS patients.31 All FAB subtypes and all IPSS risk categories were represented, receiving doses of thalidomide ranging from 100 mg to 400 mg daily. The tolerability of this treatment was poor, with only 34 of the patients reaching the 400 mg daily dose level and only eight patients able to continue at this dose level for 8 weeks of treatment. Only 51 patients completed 12 weeks of treatment, and the majority of patients who continued therapy received doses between 150 and 200 mg daily. Of the 32 patients who discontinued therapy early, more than 50% were in IPSS high-risk or INT-2 groups, and only eight patients in these IPSS groups were able to finish the course of treatment. The most common adverse events were fatigue, constipation, shortness of breath, fluid retention, dizziness, rash, paresthesias, headache, fever, and nausea. Hematologic responses were reported using the criteria established by the International Working Group11 and are summarized in Table 3. There were no complete responses; however, hematologic improvement was observed in 16 patients (19%), 10 of whom experienced a reduction in transfusion requirements, one who had at least a 2 g/dL increase in hemoglobin, and four who had a minor erythroid response. There was a minor platelet response in one patient. Responses occurred preferentially in patients with low-risk disease. In 11 of the 15 erythroid responders, the response occurred within 16 weeks of thalidomide initiation, and the median duration of response was 306 days. Lenalidomide is an analogue of thalidomide that is a potent
Alternative treatments for MDS
S35
Table 3 Selected International Working Group Response Criteria11 Response Category Complete response
Partial response
Cytogenetic response Hematologic improvement
Response Characteristics Bone marrow: <5% blasts on repeat evaluation Peripheral blood: hemoglobin >11 g/dL; neutrophils >1,500/L; platelets >100,000/L; blasts 0%; no dysplasia* Bone marrow: >50% decrease in blasts versus baseline or less advanced FAB classification than baseline Peripheral blood: hemoglobin >11 g/dL; neutrophils >1,500/L; platelets >100,000/L; blasts 0% Major: no detectable abnormality, if pre-exising abnormality was present Minor: 50% or more reduction in abnormal metaphases Erythroid response (HI-E) Major: >2 g/dL increase in hemoglobin if baseline was <11 g/dL or transfusion independence if dependent at baseline Minor: 1–2 g/dL increase in hemoglobin if baseline was <11 g/dL or 50% decrease in transfusion requirements Platelet response (HI-P) Major: increase of 30,000/L if baseline was <100,000/L or stabilization of platelet count and transfusion independence if transfusion-dependent at baseline Minor: >50% increase with a net increase >10,000/L but <30,000/L if baseline was <100,000/L Neutrophil response (HI-N) Major: 100% increase or absolute increase of 500/L whichever is greater, if absolute neutrophil count (ANC) <1,500/L at baseline Minor: ANC increase of at least 100% but absolute increase <500/L if ANC < 1,500/L at baseline
NOTE. For a designated response (CR, PR, HI) all relevant response criteria must be noted on at least two successive determinations at least 1 week apart after an appropriate period following therapy (eg, 1 month or longer) *The presence of mild megaloblastoid changes may be permitted if they are thought to be consistent with treatment effect. However, persistence of pretreatment abnormalities (eg, pseudo Pelger-Hüet cells, ringed sideroblasts, dysplastic megakaryocytes) are not consistent with CR. Adapted with permission from: Cheson B, et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 2000;96:3671-4. Copyright American Society of Hematology, used with permission.
modulator of ligand-induced biological effects such as angiogenesis, inflammation, cell adhesion, erythropoietin receptor signaling, and immune response. An open-label study used three dose schedules of lenalidomide, 25 mg daily, 10 mg daily, and 10 mg daily for 21 days every 28 days, in 43 patients with symptomatic anemia and MDS that was refractory to erythropoietic growth factors.24 The major adverse events in this trial were dose-dependent neutropenia and thrombocytopenia. As seen with thalidomide, responses were more frequent in patients in lower risk IPSS than those in higher risk categories. The overall response rate was 56%, including 20 of 32 transfusion-dependent patients achieving transfusion independence. Perhaps the most promising aspect of the study was the high frequency of cytogenetic response in patients with chromosome del 5q (5q31.1). Of 12 such patients enrolled on this study, 10 (83%) had a ⱖ50% decrease in abnormal metaphases, and nine (75%) achieved a cytogenetic complete remission. Cytogenetic responses correlated with hematologic improvement. Phase II studies of arsenic trioxide (ATO) monotherapy at a dose of 0.25 mg/kg for 5 days per week for 2 weeks followed by a 2-week rest period for four cycles26 and in combination
(0.25 mg/kg/d for 2 weeks followed by a 2-week rest) with 100 mg daily dose of thalidomide for six cycles,32 indicated that this agent is capable of producing hematologic responses in both higher risk and lower risk patients. Hematologic improvements were not limited to the erythroid lineage. ATO has pro-apoptotic properties and exerts direct cytotoxicity to neovascular endothelial cells to produce its antiangiogenic effects. A French multicenter phase II study enrolled 115 patients with various FAB subtypes treated with a loading dose of 0.30 mg/kg/d ATO for 5 days followed by 0.25 mg/kg twice per week for 15 weeks.40 Mild to moderate neutropenia was the predominant adverse event and all other adverse events were mild to moderate in severity. Overall, 27% of patients responded with hematologic improvement (including one complete response), and responses were reported in all hematologic lineages. Of the 31 patients who achieved a hematologic response, 16 achieved transfusion independence.
Farnesyl Transferase Inhibitors Ras proteins are important regulatory elements in the mitogen-activated protein kinase pathway that controls survival
M. Sekeres and A. List
S36 signals involved in receptor activation, oncogenes, angiogenic response, proliferation, and apoptosis. The farnesyl protein transferase enzyme plays a critical role in activation of ras proteins. Farnesyl transferase inhibitors (FTIs), as a consequence of inhibiting the farnesyl transferase enzyme, interfere with ras membrane localization, which interrupts the ras signaling pathway.15 The most extensively studied FTIs to date are tipifarnib (R115777) and lonafarnib (SCH66336), both of which are administered orally. A phase I study of escalating doses of R115777 administered twice daily for 3 weeks every 4 weeks was conducted in 21 patients with all subtypes of MDS.22 The initial dose was 300 mg twice daily, which was increased by 100 mg/d in subsequent cohorts. The highest dose level evaluated was 900 mg/d. The maximum tolerated dose was 800 mg/d in two divided doses (400 mg twice daily). Although myelosuppression was frequent, occurring in 19 of 21 patients, it was not considered dose-limiting as myelosuppression may be considered an important indicator of activity. The dose-limiting toxicities were grade 3 fatigue, confusion, and myalgias. Responses were observed in six of the 20 patients who could be evaluated for response. There was one complete response, one partial response, and three responses in the International Working Group category of hematologic improvement, occurring at all dose levels studied. A follow-up phase II study evaluated R115777 at a dose of 600 mg twice daily for 4 weeks followed by a 2-week rest period.23 This schedule was derived from a phase I study in patients with relapsed or refractory leukemia. Although the treatment was poorly tolerated, resulting in dose reduction or treatment discontinuation in 67% of patients, there were three responses (two complete responses and one partial response) among the 27 patients evaluated. All three responding patients had advanced forms of MDS—two responders had RAEB and one had RAEB-t. The maximum tolerated dose of lonafarnib was 200 mg twice daily in a trial that enrolled 67 patients with advanced (RAEB, RAEB-t, CMML) MDS.16 Treatment was discontinued in 17 patients (67%) because of toxicity, including six patients who experienced intractable diarrhea. The most common grade 3 or 4 toxicities were diarrhea (26%), fatigue (17%), anorexia (12%), and nausea (9%). There were 12 responses among the 42 patients who could be evaluated, representing an overall response rate of 29%, and a 5% complete response rate. Of the 37 patients who had more than 5% blasts at study entry, 16 experienced a 50% reduction in blasts. Multilineage hematologic improvement was observed in 10 patients.
DNA Methyltransferase Inhibitors Neoplastic cells almost universally exhibit increased DNA methyltransferase activity. The methyltransferase enzyme is integral to silencing tumor-suppressor genes, such as p15INK4B in MDS, thereby supporting the proliferation and longevity of malignant cells.37,39 In low doses, the nucleoside analogues 5-azacitidine and decitabine act as methyltrans-
ferase inhibitors, thus allowing transcription of tumor-suppressor genes that had been silenced by hypermethylation. These drugs have been compared to supportive care in two phase III randomized trials.34,36 Decitabine was administered at a dose of 15 mg/m2 every 8 hours for 3 consecutive days every 6 weeks, while azacitidine was given at a dose of 75 mg/m2/d for 7 days every 28 days. In the decitabine trial, the overall response rate for decitabine-treated patients, using the IWG criteria,11 was 17% (9% complete responses, 8% partial responses), whereas there were no responses in the supportive care treatment group. The median age of patients in this trial was 70 years. In the azacitidine study, patients in the control group had a response rate of 0%, compared to 23% for azacitidine-treated patients (7% complete resposnes, 16% partial responses), using Cancer and Leukemia Group B (CALGB) response criteria, but 16% for azacitidine-treated patients (6% compelte responses, 10% partial responses) using more strict criteria upon submission to the US Food and Drug Administration. Both studies demonstrated decreased transfusion requirements and a quality of life benefit with the experimental agent.
Immunosuppressive Agents A subtype of MDS, often referred to as hypoplastic MDS, is diagnosed in 5% to 10% of MDS patients. More than other subtypes of MDS, this entity is thought to represent an immunemediated disese, often difficult to distinguish from aplastic anemia, other than through the identification of cytogenetic abnormalities in the former. As such, it is treated with immunosuppressive medications similar to those given to treat aplastic anemia. These include steroids (includng anabolic steroids), cyclosporine, and anti-thymocyte globulin.
Summary MDS is a spectrum of disorders requiring a variety of treatment approaches depending on the patient’s age, prognostic features, and comorbid conditions. The IPSS facilitates treatment selection by providing a standard method of assigning risk of progression to AML and overall survival from diseaserelated complications. Allogeneic stem cell transplantion, while curative, is not appropriate treatment for the large majority of MDS patients, and efforts are ongoing to expand the number of patients who can benefit from this type of treatment, or modified versions of it. In addition, understanding the varied biological processes that are operative in MDS has encouraged the development of novel therapies and could be beneficial to patients who are currently managed conservatively with supportive care.
References 1. Albitar M, Manshouri T, Shen Y, et al: Myelodysplastic syndrome is not merely “preleukemia.” Blood 100:791-798, 2002 2. Allampallam K, Shetty V, Mundle S, et al: Biological significance of proliferation, apoptosis, cytokines and monocyte/macrophage cells in bone marrow biopsies of 145 patients with myelodysplastic syndrome. Int J Hematol 75:289-297, 2002 3. Alyea E, Kim H, Cutler C, et al: AML and MDS treated with myeloablative stem cell transplantation: Overall and progression free survival
Alternative treatments for MDS
4.
5.
6.
7. 8. 9.
10.
11.
12.
13.
14.
15. 16.
17.
18.
19.
20.
21.
comparable to myeloablative transplantation. Blood 102:79, 2003 (abstr) Amano Y, Koike K, Nakahata T: Stem cell factor enhances growth of primitive erythroid progenitors to a greater extent than interleukin 3 in patients with aplastic anemia. Br J Haematol 85:663-669, 1993 Anderson J, Appelbaum F, Storb R: An update on allogeneic marrow transplantation for myelodysplastic syndrome. Leuk Lymphoma 17: 95-99, 1995 Arnold R, de Witte T, Van Biezen A, et al: Unrelated bone marrow transplantation in patients with myelodysplastic syndromes and secondary acute myeloid leukemia: An EBMT survey. Bone Marrow Transplant 21:1213-1216, 1998 Aul C, Bowen D, Yoshida Y: Pathogenesis, etiology and epidemiology of myelodysplastic syndromes. Haematologica 83:71-78, 1998 Backx B, Broeders L, Löwenberg B: Kit ligand improves in vitro erythropoiesis in myelodysplastic syndromes. Blood 80:1213-1217, 1992 Bennett J, Catovsky D, Daniel M, et al: The French-American-British (FAB) Group: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:188-189, 1982 Castro-Malaspina H, Harris R, Gajewski J, et al: Unrelated donor marrow transplantation for myelodysplastic syndromes: Outcome analysis in 510 transplants facilitated by the National Marrow Donor Program. Blood 99:1943-1951, 2002 Cheson B, Bennett J, Kantarjian H, et al: Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 96:3671-3674, 2000 Cutler C, Lee S, Greenberg P, et al: A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: Delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 104:579-585, 2004 de Witte T, van Biezen A, Hermans J, et al: Autologous bone marrow transplantation for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia following MDS. Chronic and Acute Leukemia Working Parties of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 110:620-630, 2000 de Witte T, van Biezen A, Hermans J, et al: Autologous bone marrow transplantation for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia following MDS. Blood 90:3583-3857, 1997 Estey E: Modulation of angiogenesis in patients with myelodysplastic syndrome. Best Pract Res Clin Hematol 17:623-639, 2004 Feldman E, Cortes J, Holyoake T, et al: Continuous oral lonafarnib (Sarasar) for the treatment of patients with myelodysplastic syndrome. Blood 102:421, 2003 (abstr) Greenberg P, Cox C, LeBeau M, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:20792088, 1997 Harris N, Jaffe E, Diebold J, et al: The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, VA, November, 1997. Ann Oncol 10:1419-1432, 1999 Hellström-Lindberg E: Efficacy of erythropoietin in the myelodysplastic syndromes. An analysis of 205 patients in 17 studies. Br J Haematol 89:67-71, 1995 Hellström-Lindberg E, Birgegård G, Carlsson M, et al: A combination of granulocyte-colony-stimulating factor and erythropoietin may synergistically improve the anaemia in patients with myelodysplastic syndromes. Leuk Lymphoma 11:221-228, 1993 Jensen P, Heickendorff L, Pedersen B, et al: The effect of iron chelation
S37
22.
23.
24. 25. 26.
27. 28.
29.
30.
31.
32.
33.
34.
35.
36.
37. 38.
39.
40.
on haemopoiesis in MDS patients with transfusional iron overload. Br J Haematol 94:288-299, 1996 Kurzrock R, Kantarjian H, Cortes J, et al: Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: Clinical and biological activities in the pahse I setting. Blood 102:4527-4534, 2003 Kurzrock R, Albitar M, Cortes J, et al: Phase II study of R115777, a farnesyl transferase inhibitor, in myelodysplastic syndrome. J Clin Oncol 22:1287-1292, 2004 List A, Kurtin S, Rose D, et al: Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 352:549-557, 2005 List A, Vardiman J, Issa J-P, et al: Myelodysplastic syndromes. Hematology (Am Soc Hematol Educ Program) 297-317, 2004 List A, Schiller G, Mason J, et al: Trisenox (arsenic trioxide, ATO) in patients (pts) with myelodysplastic syndromes (MDS): Preliminary findings in a phase II clinical study. Blood 100:790, 2002 (abstr) List A: New approaches to the treatment of myelodysplasia. Oncologist 7:39-49, 2002 (suppl 1) Mannone L, Gardin C, Quarre M, et al: High response rate to darbopoetin alfa in “low risk” MDS: Results of a phase II study. Blood 104:24, 2004 (abstr) Negrin R, Stein R, Doherty K, et al: Treatment of the anaemia of myelodysplastic syndromes using human granulocyte-CSF in combination with erythropoietin. Blood 82:737-743, 1993 Nosslinger T, Reisner R, Koller E, et al: Myelodysplastic syndromes from French-American-British to World Health Organization: Comparison of classifications on 431 unselected patients from a single institution. Blood 98:2935-2941, 2001 Raza A, Meyer P, Dutt D, et al: Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood 98:958-965, 2001 Raza A, Lisak L, Tahir S, et al: Trilineage responses to arsenic trioxide (Trisenox) and thalidomide in patients with myelodysplastic syndromes (MDS), particularly those with inv(3)(q21q26.2). Blood 100: 795, 2002 (abstr) Runde V, de Witte T, Arnold C, et al: Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: Early transplantation is associated with improved outcome. Bone Marrow Transplant 21:255-260, 1998 Saba H, Rosenfeld C, Issa J, et al: First report of the phase III North American trial of decitabine in advanced myelodysplastic syndrome (MDS). Blood 104:23, 2004 (abstr) Sierra J, Pérez W, Rozman C, et al: Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood 100: 1997-2004, 2002 Silverman L, Demakos E, Peterson B, et al: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the cancer and leukemia group B. J Clin Oncol 20:2429-2440, 2002 Singal R, Ginder G: DNA methylation. Blood 93:4059-4070, 1999 Sutton L, Chastang C, Ribaud P, et al: Factors influencing outcome in de-novo myelodysplastic syndromes treated by allogeneic bone marrow transplantation: A long-term study of 71 patients. Blood 88:358365, 1996 Uchida T, Kinoshita T, Nagal H, et al: Hypermethylation of the p15INK4B gene in myelodysplastic syndromes. Blood 90:1403-1409, 1997 Vey N, Dreyfus F, Guerci A, et al: Trisenox (arsenic trioxide) in patients with myelodysplastic syndromes (MDS): Preliminary results of a phase I/II study. Blood 104:401, 2004 (abstr)