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The Oncologist, Vol. 2, No. 1, 28-39, February 1997
© 1997 AlphaMed Press

The Myelodysplastic Syndromes

Bruce D. Cheson

Medicine Section, Clinical Investigations Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland, USA

Correspondence: Bruce D. Cheson, M.D., National Cancer Institute, Executive Plaza North, Room 741, Bethesda, Maryland 20892-7436, USA.. Telephone: 301-496-2522; Fax: 301-402-0557.


   ABSTRACT
Top
 Abstract
Introduction
 Therapy of MDS
 Hormone Therapy
 Chemotherapy
 Combination Chemotherapy
 Bone Marrow Transplantation
 Biological Approaches
 Biological Therapies
 Conclusions
 References
 
The myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by peripheral blood cytopenias with a hypercellular bone marrow exhibiting dyspoiesis. The MDS range from those with a relatively indolent course (e.g., refractory anemia with or without ringed sideroblasts) to more aggressive disorders (e.g., refractory anemia with excess blasts [RAEB], and RAEB in transformation [RAEB-T]), which may exhibit a clinical course indistinguishable from acute myeloid leukemia (AML). Supportive care is the standard treatment for most patients, particularly those who are elderly, with the judicious use of blood components and antibiotics. For younger patients with RAEB and RAEB-T, antileukemic therapy might be considered, since the outcome is similar to that of patients with AML. Promising new chemotherapy agents currently in clinical trials include the topoisomerase I inhibitor, topotecan. The only curative treatment for MDS is allogeneic bone marrow transplantation, with long-term survival in approximately 40%, but with treatment-related deaths in 25%-40%. Factors predicting outcome include age, cytogenetics, number of blasts, and others. Myeloid growth factors (e.g., G-CSF, GM-CSF), increase the granulocyte count in most patients and may be useful in the setting of an active infection, although the prophylactic use of these agents does not improve survival. Erythropoietin increases the hematocrit in about 20% of patients. Growth factors being evaluated for their role in enhancing platelet counts include interleukin 11, stem cell factor, and megakaryocyte growth and development factor (thrombopoietin). Newer strategies to improve the outcome of patients with MDS should be based on an increased understanding of the biology of these disorders.

Key Words. MDS • Myelodysplastic syndrome • AML • Growth factor • CMML • Bone marrow transplantation


   INTRODUCTION
Top
 Abstract
 Introduction
Therapy of MDS
 Hormone Therapy
 Chemotherapy
 Combination Chemotherapy
 Bone Marrow Transplantation
 Biological Approaches
 Biological Therapies
 Conclusions
 References
 
The myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders characterized in most patients by peripheral blood cytopenias with a hypercellular bone marrow, although the bone marrow is hypocellular in about one-quarter of patients [1]. The incidence of MDS is difficult to estimate because the diagnosis is not a separate category within most registries. Older patients are most often affected; therefore, institutions with a higher proportion of elderly patients tend to encounter a greater number of cases. When patients are routinely screened [2], the frequency of MDS may occur at a sixfold higher frequency than in acute myeloid leukemia (AML), which is reported to be 2.2/100,000 population in the U.S. [3]. In 80%-90% of patients, the etiology of MDS is unknown. In the remaining 10%-15%, MDS may occur secondary to exposure to toxins or chemotherapy.

Over the years, the MDS have been referred to by a number of terms, including oligoblastic leukemia, refractory anemia, smoldering acute leukemia, or preleukemia. The most commonly used classification scheme was published in 1982 by the French-American-British (FAB) group, and revised in 1985 [4, 5] (Table 1Go). The FAB classification includes five categories which range from those which are relatively indolent (i.e., refractory anemia with [RARS] or without [RA] ringed sideroblasts), to those with a more aggressive clinical course (i.e., refractory anemia with excess blasts [RAEB] and RAEB in transformation [RAEB-T]). The distinction between RAEB-T and AML is somewhat arbitrary, based primarily on histopathology, rather than clinical features. As a result, patients with MDS may experience a clinical course consistent with AML with rapidly increasing numbers of blasts, but without a sufficient percentage to fulfill the criteria for AML [6]. Chronic myeloid monocytic leukemia (CMML), the most variable of the MDS, often does not have an associated pancytopenia and more closely resembles a myeloproliferative disorder [7, 8]. The rate of transformation from MDS to AML varies by FAB subtype [9–12], approximately 10%-20% for RA or RARS, 20%-30% for CMML, 40%-50% for RAEB, and 60%-75% for RAEB-T (Table 2Go). Even without progression to AML, the MDS are uniformly fatal as a consequence of infections and bleeding [13, 14].


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  		Table 1. Morphologic features of MDS
 

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  		Table 2. Prognosis of the myelodysplastic syndromes
 
Factors predicting shorter survival include older age, anemia, neutropenia, thrombocytopenia, high percentage of bone marrow blasts, extensive dyspoiesis, abnormal central clustering of immature precursors within the bone marrow (ALIP score), increased numbers of circulating CD34 cells [7–9, 11, 14–20], abnormal cytogenetics (particularly involving chromosomes 5 and 7) [21], secondary MDS, expression of the mdr-1 phenotype [22], and RAS oncogene mutations or activation [23–26]. The relevance of p53 mutations is under study [27].


   THERAPY OF MDS
Top
 Abstract
 Introduction
 Therapy of MDS
Hormone Therapy
 Chemotherapy
 Combination Chemotherapy
 Bone Marrow Transplantation
 Biological Approaches
 Biological Therapies
 Conclusions
 References
 
A variety of therapeutic options have been used in MDS (Table 3Go). Supportive care remains standard treatment, with judicious use of red blood cell and platelet transfusions, antibiotics, and growth factors.


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  		Table 3. Therapeutic options for the myelodysplastic syndromes
 

   HORMONE THERAPY
Top
 Abstract
 Introduction
 Therapy of MDS
 Hormone Therapy
Chemotherapy
 Combination Chemotherapy
 Bone Marrow Transplantation
 Biological Approaches
 Biological Therapies
 Conclusions
 References
 
Corticosteroids not only achieve partial responses in fewer than 10% of patients with MDS [28, 29], but they also further increase the susceptibility to infections in these patients and are therefore contraindicated. Androgens also do not appear to be of consistent benefit [30, 31]. Clinical activity for danazol, a semisynthetic attenuated androgen, appears to be limited to a small subset of patients with an associated immune-mediated cytopenia [32, 33].


   CHEMOTHERAPY
Top
 Abstract
 Introduction
 Therapy of MDS
 Hormone Therapy
 Chemotherapy
Combination Chemotherapy
 Bone Marrow Transplantation
 Biological Approaches
 Biological Therapies
 Conclusions
 References
 
Single Agents
The chemotherapy drugs tested in MDS have generally been those which are active in AML. Following the initial reports of activity for cytarabine in AML, even at doses as low as 10 mg/m2/d [34], anecdotal reports and small series appeared in the literature suggesting that low doses administered s.c. or by a continuous i.v. infusion every 12 h for 14 to 21 days might be effective in MDS by inducing cellular differentiation [35–49]. However, the complete remission rate with low-dose cytarabine is only 17%, with 19% partial remissions, a median survival of 15 months, and no apparent prolongation of survival compared with the natural history of the disease [50, 51]. Myelosuppression was reported in 88% of cases, with 15% treatment-related deaths [31, 50–52].

To clarify the role of low-dose cytarabine in MDS, the Eastern Cooperative Oncology Group and the Southwest Oncology Group randomized 125 eligible patients to either low-dose cytarabine or supportive care [53]. Only 23% of patients responded to cytarabine, 11% with complete remissions and 21% with partial remissions. Responses were somewhat more common in RAEB-T (17% complete remissions and 25% partial remissions). However, the median duration of response was less than eight months, and infections were more frequent in the treated group, with no difference in the frequency of transformation to AML and no improvement in survival. Therefore, low-dose cytarabine has little role in the treatment of MDS.

High doses of cytarabine (e.g., 1-3 g/m2 every 12 h for 6 days) have resulted in a variable percentage of brief responses [54–58].

Anthracyclines and related drugs have been tested to a limited extent as single agents in MDS [59, 60]. Anecdotal activity has been noted with azathioprine [61], carboplatin, and other cisplatin analogs [62–64]. Other agents, including oral 6-thioguanine (6-TG), have not shown promise [65].

Activity has been suggested for etoposide, particularly in patients with CMML [66, 67]. In a recent randomized study [68], hydroxyurea was compared with etoposide in patients with CMML. The response rate favored hydroxyurea (60% versus 36%); however, in the 52 patients who received hydroxyurea, there was a single clinical remission, 15% partial remissions, and the rest were "good" and "minor" responses, which are generally not included in the definition of response. Although response duration was longer with hydroxyurea (24 months versus 9 months), as was survival (20 months versus 9 months), neither agent is sufficiently active to merit further study.

Based on the activity of the topoisomerase I inhibiting agent, topotecan, in refractory AML [69, 70], Beran et al. [71] treated 22 patients with MDS, and 25 with CMML. Topotecan was delivered at a dose of 2 mg/m2 by continuous i.v. infusion over 24 h for 5 days; there were 28% complete remissions (CR) and an additional 13% experienced major hematologic improvement. Combinations of topotecan with other agents are in development.


   COMBINATION CHEMOTHERAPY
Top
 Abstract
 Introduction
 Therapy of MDS
 Hormone Therapy
 Chemotherapy
 Combination Chemotherapy
Bone Marrow Transplantation
 Biological Approaches
 Biological Therapies
 Conclusions
 References
 
Since patients with MDS tend to be elderly and commonly die from marrow hypoplasia following intensive treatment, attenuated-dose chemotherapy has been attempted. The few responses have been brief [72, 73].

Response rates with aggressive AML regimens are generally lower in patients with MDS than with AML, and with more pronounced myelotoxicity (Table 4Go). Indeed, Armitage et al. [74] suggested that survival of patients treated with combination regimens might be inferior to that of patients receiving supportive care alone. More encouraging results were recently published from the Cancer and Leukemia Group B (CALGB) [75], in which 907 patients were treated on a series of AML protocols between 1984 and 1992, using standard agents. Upon central pathology review, 33 were felt to have MDS. Their CR rate, duration of response and survival were similar to the AML patients, with a surprisingly low treatment-related death rate (6%). Better results were achieved in younger patients with increased blasts.


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  		Table 4. Intensive chemotherapy regimens for MDS
 
Treatment of secondary AML or MDS has generally been associated with lower response rates, higher mortality, and shorter survival than de novo AML [58, 76, 79–83] (Table 5Go). Keating et al. [79] used rubidazone, vincristine, cytarabine, and prednisone (ROAP) in 91 patients with AML, a third of whom had a prior hematologic disorder, mostly MDS. The CR rate for the primary and secondary groups were 63% and 22%, respectively. Kantarjian et al. [14] described 112 patients who developed MDS or AML following chemotherapy or radiation therapy for a prior malignancy. The CR rate was 15% for patients with MDS and 37% for those with AML. The median survival was 21 weeks for patients with AML compared with 45 weeks for those with MDS. Martiat et al. [84] treated 25 patients with MDS that had transformed into AML with no prior toxin exposure, using daunomycin and cytarabine. A CR was achieved in 24% of patients, while 44% died of treatment-induced myelosuppression, with a median survival of five months. Gajewski et al. [82] treated 44 patients with AML following a prior hematologic disorder and 111 patients with primary AML, with complete remission rates of 41% and 73%, respectively, and more delayed bone marrow recovery in the post-MDS patients. Aul and Schneider [52] treated 16 patients with MDS and noted 56% CR and 13% partial remissions; all five RAEB-T patients achieved CR compared with 4 of 11 AML patients with prior MDS; however, the median duration of remissions was five months. The Medical Research Council’s 9th AML trial [81] used an induction regimen of daunorubicin, cytarabine, and 6-thioguanine with a post-remission randomization to either MAZE (amsacrine, 5-azacytidine, etoposide) or COAP (cyclophosphamide, vincristine, cytarabine, prednisolone); the CR rate for the 688 patients with primary AML was 66%, compared with 25% and 42% for the 20 post-cytotoxic therapy and 36 prior MDS patients, respectively. The median survival for the post-cytotoxic therapy group was only 58.5 days compared with 125.5 days in the post-MDS group. Nonetheless, neither the duration of remission nor the overall survival were different when the groups were stratified for age.


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  		Table 5. Chemotherapy for AML following MDS
 
Fludarabine (FA), G-CSF, or GM-CSF prior to cytarabine markedly augments incorporation of arabinosylcytosine 5'-triphosphate (ara-CTP) into DNA [85–87] and may also increase their sensitivity to subsequent cytarabine [88]. Estey et al. [78] combined FA (30 mg/m2 daily for 5 days) and cytarabine (2 gm/m2 over 4 h beginning three and one-half hours after completion of FA), or FA plus G-CSF (FLAG). Of 43 patients with MDS (mostly RAEB and RAEB-T) with adverse cytogenetic abnormalities or an antecedent hematologic abnormality, the CR rate was 55%, and 60% with FA and FLAG, respectively.

Many patients with MDS die as a consequence of treatment-related bone marrow hypoplasia, while a smaller number exhibit clinical drug resistance. Of note is that the gene that codes for the p-glycoprotein is localized to the long arm of chromosome 7 [89], which is commonly involved in MDS and secondary leukemias. The clinical relevance of the expression of multidrug resistance (MDR) in almost half the cases is unclear [22, 90], but studies of MDR reversal agents in MDS are being performed.


   BONE MARROW TRANSPLANTATION
Top
 Abstract
 Introduction
 Therapy of MDS
 Hormone Therapy
 Chemotherapy
 Combination Chemotherapy
 Bone Marrow Transplantation
Biological Approaches
 Biological Therapies
 Conclusions
 References
 
Allogeneic bone marrow transplantation (BMT) is the only curative therapy for patients with MDS [57, 91–105] (Table 6Go). Unfortunately, most patients with MDS are elderly and, therefore, only a small fraction of them would be suitable candidates for BMT. Anderson et al. [91] described 93 patients with a median age of 29 (range 4-54 years). The actuarial probability of relapse was 23%; relapses occurred only in patients with RAEB and RAEB-T. As of the report, 28 patients were free of disease 12-215 months after transplant. However, 39% died from transplant-related complications. O’Donnell et al. [100] treated 20 patients (age 4-48, median 36); 45% died of transplant-related complications, and three relapsed at 67, 462, and 2,922 days following BMT and one underwent a second, successful transplant. Eight patients remained alive and well from 108+ to 3,359+ days post-transplant. The European BMT Group published a retrospective analysis of 78 patients with MDS or secondary AML [95]. Patients transplanted while in complete remission had a 60% two-year disease-free survival compared with 18% for those who only partially responded to prior intensive chemotherapy. The disease-free survival at two years for previously untreated patients was 58% for RA or RARS, 74% for RAEB, 50% for RAEB-T, and 18% for secondary AML. Thirty-five of the 78 patients were disease-free at 2-91 months, 18 relapsed, and 32% died of transplant-related complications, mainly interstitial pneumonitis and graft-versus-host-disease (GVHD). O’Donnell et al. [103] transplanted 38 patients, with 37% in remission 18 to 60 months post-BMT, for an overall survival rate at two years of 43%, but with 29% treatment-related deaths. Sutton et al. [105] reported 71 patients with de novo MDS, 17 of whom had received cytoreductive therapy prior to BMT. Only 23 patients were alive at a median follow-up of six years; 24 died of relapse and 24 of treatment-related complications. The estimated event-free survival at seven years was 32%. Anderson et al. [104] evaluated a preparative regimen of busulfan, cyclophosphamide, and total body irradiation (TBI) in 31 patients with a median age of 41 years, and compared the outcome with 44 historical controls who had received cyclophosphamide and TBI. The three-year disease-free survival was similar at 23% versus 30%, there were fewer relapses (28% versus 54%), but a higher treatment-related mortality (68% versus 36%). Overall, treatment-related deaths occur in approximately 40% of patients with MDS. Whether hematopoietic growth factors and donor peripheral blood stem cells will reduce treatment-related morbidity and mortality remains to be demonstrated.


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  		Table 6. Bone marrow transplantation for MDS
 
Factors predicting outcome following transplantation vary among series. Poor features include age greater than 40 years, chemotherapy-resistant disease, longer disease duration, the presence of excess blasts, cytogenetic abnormalities, the use of cytoreduction prior to BMT, and the preparative regimen [91, 95, 103–105]. The impact of extensive bone marrow fibrosis is controversial.

Sources of stem cells other than HLA-identical siblings have also been used, including matched unrelated donors and partially matched family members [91, 94, 96, 107]. The National Marrow Donor program reported 32 patients with MDS, with a median age of 24 years, and a median time to transplantation from diagnosis of less than a year. The probability of survival at two years was 24%; however, the probability of disease-free survival was only 18%. A matched unrelated transplant is a therapeutic option to be considered for a younger patient (under 40 years) without a suitable family donor, who is experiencing progressive disease.

Autologous bone marrow or peripheral blood stem cell transplantation has been used in a few patients with MDS, or AML and a preexisting MDS, with disappointing results [108, 109].


   BIOLOGICAL APPROACHES
Top
 Abstract
 Introduction
 Therapy of MDS
 Hormone Therapy
 Chemotherapy
 Combination Chemotherapy
 Bone Marrow Transplantation
 Biological Approaches
Biological Therapies
 Conclusions
 References
 
Differentiating Agents
A variety of drugs capable of differentiating AML and MDS cells in vitro can be safely given to patients and have been evaluated in clinical studies in MDS. Other than low-dose cytarabine, as mentioned above, retinoids have been most widely used, with response rates from 0% to approximately 20% with 13-cis-retinoic acid or isoretinoin in MDS [49, 110–117], and two randomized trials failed to demonstrate any activity or a survival advantage associated with 13-cis-retinoic acid therapy [118–120]. Although all-trans retinoic acid exhibits major activity in patients with acute promyelocytic leukemia [121–123], its activity in MDS has been minimal [124–126]. Retinoids may actually accelerate transformation to acute leukemia [127, 128].

5-azacytidine is a pyrimidine analogue with activity in AML, but at doses complicated by substantial toxicity [129–133]. This drug induces in vitro cellular differentiation in association with hypomethylation of DNA. Using a variety of doses, schedules, and routes of administration, results to date are no better than with low-dose cytarabine [134–136]. A randomized comparison between 5-azacytidine and supportive care is undergoing analysis.

Disappointing results have also been noted with vitamin D3 [137, 138] and combinations of low-dose cytarabine with other putative differentiating agents or chemotherapy drugs [49, 83, 118, 139, 140].

Recent in vitro data suggest that amifostine may stimulate the production of normal colonies from MDS bone marrow. Clinical studies are under way [141].


   BIOLOGICAL THERAPIES
Top
 Abstract
 Introduction
 Therapy of MDS
 Hormone Therapy
 Chemotherapy
 Combination Chemotherapy
 Bone Marrow Transplantation
 Biological Approaches
 Biological Therapies
Conclusions
 References
 
Interferons
Clinical efficacy of alpha or gamma interferons has been minimal, with substantial treatment-related toxicity [142–149].

Hematopoietic Colony-Stimulating Factors
Myeloid growth factors have been extensively evaluated in patients with MDS, both to decrease the morbidity and mortality associated with prolonged neutropenia, and, perhaps, to induce in vivo cellular differentiation [150–163]. Neutrophil counts improve in about 85% of patients. Platelet counts improve in 10% of patients; however, drug-induced thrombocytopenia has been reported with clinical bleeding [164, 165]. The increased reticulocyte count in almost 40% has rarely been accompanied by either an elevation in hemoglobin or a decreased transfusion requirement.

A number of newer growth factors has entered clinical trials. Results with IL-3, IL-6, and PIXY-321 have been disappointing [151, 155, 158, 166, 167]. Other cytokines which have potential beneficial effects on platelet counts include IL-11 [168] and thrombopoietin [169–172]. No data are yet available in MDS.

Since neutrophil counts generally return to baseline within days to weeks of discontinuation of growth factor therapy, continuous administration has been studied. Negrin et al. [173] administered G-CSF to 11 patients with MDS for periods of 3-16 months; maintaining the neutrophil count above 1500/µl reduced the frequency of severe infections and, perhaps, also transfusion requirements in a rare patient. However, this expensive approach remains a research issue and not standard care.

In more than a quarter of cases of MDS, growth factor therapy has been associated with a significant increase in the percent of bone marrow blasts. The rapid onset of AML has occurred in a similar number and has generally not been reversible when growth factor therapy was discontinued. No prognostic factors consistently predict patients most likely to either respond or transform [154]. Some data suggest that transformation to AML more likely reflects the natural history of the disease [174]. Nevertheless, these agents are not recommended in patients with an increased number of blasts.

The optimal use of hematopoietic growth factors has not been defined. The current recommendation is to reserve the use of myeloid growth factors for patients who are experiencing an infection in the setting of neutropenia [175].

Serum erythropoietin (EPO) levels are generally elevated in patients with MDS and do not correlate with erythropoiesis [176, 177]. Indeed, the overall response to EPO is 10%-20%, and patients may develop progressive anemia despite continued use of this agent [178–181]. Preliminary data suggest that combinations of EPO with a myeloid growth factor may improve these results [182, 183].


   CONCLUSIONS
Top
 Abstract
 Introduction
 Therapy of MDS
 Hormone Therapy
 Chemotherapy
 Combination Chemotherapy
 Bone Marrow Transplantation
 Biological Approaches
 Biological Therapies
 Conclusions
References
 
Supportive care remains the standard for MDS. Current chemotherapy agents achieve meaningful responses in a minority of patients with MDS and are associated with considerable morbidity and mortality. Red cell and platelet transfusions should be used conservatively to minimize the risk of alloimmunization and antibiotics when indicated (Fig. 1Go). Iron chelation therapy may be required to prevent complications in heavily transfused patients and may even be associated with a rise in hemoglobin, white blood cell count, and platelet count [184]. Although EPO, G-CSF, and GM-CSF are commercially available, and clinical trials are ongoing using IL-11, stem cell factor, thrombopoietin, and others, they are useful only as supportive care for specific indications in select patients. Rational development of combinations of these agents may prove to be more effective [183].



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  		Figure 1. The therapeutic approach to the patient with MDS depends on whether the disease is indolent or aggressive. Patients can often be followed with supportive measures, such as red blood cell or platelet transfusions, antibiotics, or hematopoietic growth factors, until there is evidence of clinical or hematologic deterioration. In the setting of progressive disease, therapy should be delivered, if possible, in the context of a clinical trial. For patients with more favorable MDS, studies evaluating new biological therapies are appropriate. For those with more unfavorable characteristics, such as complex cytogenetic abnormalities or RAEB or RAEB-T histologies, more aggressive treatment programs may be more suitable. The option of allogeneic BMT should be offered to all patients under the age of 55 years with an HLA-identical sibling.

 
New treatment approaches are critically needed. However, results of published studies in MDS are often difficult to interpret because of difficulties in establishing an accurate diagnosis, clinical heterogeneity within MDS subtypes, and the lack of standardized response definitions [6]. Progress toward improving the outcome of patients with MDS requires the rapid completion of carefully designed and conducted clinical trials addressing important biologic and therapeutic questions.


   REFERENCES
Top
 Abstract
 Introduction
 Therapy of MDS
 Hormone Therapy
 Chemotherapy
 Combination Chemotherapy
 Bone Marrow Transplantation
 Biological Approaches
 Biological Therapies
 Conclusions
 References
 

  1. Nand S, Godwin JE. Hypoplastic myelodysplastic syndrome. Cancer 1988;62:958–964.[Medline]
  2. Hamblin TJ, Oscier DG. The myelodysplastic syndrome— a practical guide. Hematol Oncol 1987;5:19–34.[Medline]
  3. Miller BA, Linet MS, Cheson BD. Leukemias. In: Miller BA, Gloeckler Ries LA, Hankey BF, eds. SEER Cancer Statistics Review: 1973-1990. Bethesda, MD: National Cancer Institute, 1993;XIII:1-23.
  4. Bennett JM, Catovsky D, Daniel M-T et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51:189–199.[Medline]
  5. Bennett JM, Catovsky D, Daniel MT et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British group. Ann Intern Med 1985;103:626–629.
  6. Cheson BD, Cassileth PA, Head DR et al. Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 1990;8:813–819.[Abstract]
  7. Fenaux P, Beuscart R, Lai JL et al. Prognostic factors in adult chronic myelomonocytic leukemia: an analysis of 107 cases. J Clin Oncol 1988;6:1417–1424.[Abstract/Free Full Text]
  8. Tefferi A, Hoagland HC, Therneau TM et al. Chronic myelomonocytic leukemia: natural history and prognostic determinants. Mayo Clin Proc 1989;64:1246–1254.[Medline]
  9. Tricot G, Vlietinck R, Boogaerts MA et al. Prognostic factors in the myelodysplastic syndromes: importance of initial data on peripheral blood counts, bone marrow cytology, trephine biopsy and chromosome analysis. Br J Haematol 1985;60:19–32.[Medline]
  10. Todd WM, Pierre RV. Preleukaemia: a long-term prospective study of 326 patients. Scand J Haematol 1986;36(suppl 45):114–120.
  11. Vallespí T, Torrabadella M, Julia A et al. Myelodysplastic syndromes: a study of 101 cases according to the FAB classification. Br J Haematol 1985;61:81–92.
  12. Kerkhofs H, Hermans J, Maak HL et al. Utility of the FAB classification for myelodysplastic syndromes: investigation of prognostic factors in 237 cases. Br J Haematol 1987;65:83–92.[Medline]
  13. Weisdorf DJ, Oken MM, Johnson GJ et al. Chronic myelodysplastic syndrome: short survival with or without evolution to acute leukaemia. Br J Haematol 1983;55:691–700.[Medline]
  14. Kantarjian HM, Keating MJ, Walters RS et al. Therapy-related leukemia and myelodysplastic syndrome: clinical, cytogenetic, and prognostic features. J Clin Oncol 1986;4:1748–1757.[Abstract]
  15. Mufti GJ, Stevens JR, Oscier DG et al. Myelodysplastic syndromes: a scoring system with prognostic significance. Br J Haematol 1985;59:425–433.[Medline]
  16. Foucar K, Langdon RM, Armitage JO et al. Myelodysplastic syndromes. A clinical and pathologic analysis. Cancer 1985;56:553–561.[Medline]
  17. Sullivan SA, Marsden KA, Lowenthal RM et al. Circulating CD34+ cells: an adverse prognostic factor in the myelodysplastic syndromes. Am J Hematol 1992;39:96–101.[Medline]
  18. Sanz GF, Sanz MA, Vallespí T et al. Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patients. Blood 1989;74:395–408.[Abstract/Free Full Text]
  19. Tricot G, De Wolf-Peeters C, Vlietinck R et al. Bone marrow histology in myelodysplastic syndromes. II. Prognostic value of abnormal localization of immature precursors. Br J Haematol 1984;58:217–225.[Medline]
  20. Varela BL, Chuang C, Woll JE et al. Modifications in the classification of primary myelodysplastic syndromes: the addition of a scoring system. Hematol Oncol 1985;3:55–63.[Medline]
  21. Pierre RV, Catovsky D, Mufti GJ et al. Clinical-cytogenetic correlations in myelodysplasia (preleukemia). Cancer Genet Cytogenet 1989;40:149–161.[Medline]
  22. List AF, Spier CM, Cline A et al. Expression of the multidrug resistance gene product (P-glycoprotein) in myelodysplasia is associated with a stem cell phenotype. Br J Haematol 1991;78:28–34.[Medline]
  23. Janssen JWG, Steenvoorden ACM, Lyons J et al. RAS gene mutations in acute and chronic myelocytic leukemias, chronic myeloproliferative disorders, and myelodysplastic syndromes. Proc Natl Acad Sci USA 1987;84:9228–9232.[Abstract/Free Full Text]
  24. Yunis JJ, Boot AJM, Mayer MG et al. Mechanisms of ras mutation in myelodysplastic syndrome. Oncogene 1989;4:609–614.[Medline]
  25. Melani C, Haliasos A, Chomel JC et al. Ras activation in myelodysplastic syndromes: clinical and molecular study of the chronic phase of the disease. Br J Haematol 1990;743:408–413.[Medline]
  26. Paquette RL, Landaw EM, Pierre RV et al. N-ras mutations are associated with poor prognosis and increased risk of leukemia in myelodysplastic syndrome. Blood 1993;82:590–599.[Abstract/Free Full Text]
  27. Sugimoto K, Hirano N, Toyoshima H et al. Mutations of the p53 gene in myelodysplastic syndrome (MDS) and MDS-derived leukemia. Blood 1993;81:3022–3026.[Abstract/Free Full Text]
  28. Bagby Jr GC, Gabourel JD, Linan JW. Glucocorticoid therapy in the preleukemic syndrome (hemopoietic dysplasia). Ann Intern Med 1980;92:55–58.
  29. Motoji T, Teramura M, Takahashi M et al. Successful treatment of refractory anemia with high-dose methylprednisolone. Am J Hematol 1990;33:8–12.[Medline]
  30. Najean Y, Pecking A. Refractory anaemia with excess of myeloblasts in the bone marrow: a clinical trial of androgens in 90 patients. Br J Haematol 1977;37:25–33.[Medline]
  31. Najean Y, Pecking A. Refractory anemia with excess of blast cells: prognostic factors and effect of treatment with androgens or cytosine arabinoside. Cancer 1979;44:1976–1982.[Medline]
  32. Cines DB, Cassileth PA, Kiss JE. Danazol therapy in myelodysplasia. Ann Intern Med 1985;103:58–60.
  33. Stadtmauer EA, Cassileth PA, Edelstein M et al. Danazol treatment of myelodysplastic syndrome. Br J Haematol 1991;77:502–508.[Medline]
  34. Ellison RR, Holland JF, Weil M et al. Arabinosyl cytosine: a useful agent in the treatment of acute leukemia in adults. Blood 1968;32:507–523.[Abstract/Free Full Text]
  35. Baccarani M, Tura S. Differentiation of myeloid leukaemic cells: new possibilities for therapy. Br J Haematol 1979;42:485–490.[Medline]
  36. Baccarani M, Zaccaria A, Bandini G et al. Low dose arabinosyl cytosine for treatment of myelodysplastic syndromes and subacute myeloid leukemia. Leuk Res 1983;7:539–545.[Medline]
  37. Griffin JD, Spriggs D, Wisch JS et al. Treatment of preleukemic syndromes with continuous intravenous infusion of low-dose cytosine arabinoside. J Clin Oncol 1985;3:982–991.[Abstract/Free Full Text]
  38. Hoelzer D, Ganser A, Schneider W et al. Low-dose cytosine arabinoside in the treatment of acute nonlymphoblastic leukemia and myelodysplastic syndromes. Sem Oncol 1985;12(suppl 3):208–211.[Medline]
  39. Inbal A, Januszewicz E, Rabinowictz M et al. A therapeutic trial with low-dose cytarabine in myelodysplastic syndromes and acute leukemia. Acta Haematol 1985;73:71–74.[Medline]
  40. Jehn U, De Bock R, Haanen C. Clinical trial of low-dose ara-C in the treatment of acute leukemia and myelodysplasia. Blut 1984;48:255–261.[Medline]
  41. Maiolo AT, Foa P, Cortellaro M et al. Low-dose cytosine arabinoside (ara-C) therapy in the myelodysplastic syndromes and acute myelogenous leukemia. Haematologica 1987;72:61–65.[Medline]
  42. Powell BL, Capizzi RL, Jackson DV et al. Low dose ara-C for patients with myelodysplastic syndromes. Leukemia 1988;2:153–156.[Medline]
  43. Roberts JD, Ershler WB, Tindle BH et al. Low-dose cytosine arabinoside in the myelodysplastic syndromes and acute myelogenous leukemia. Cancer 1985;56:1001–1005.[Medline]
  44. Tricot G, De Bock R, Dekker AW et al. Low dose cytosine arabinoside (ara-C) in myelodysplastic syndromes. Br J Haematol 1984;58:231–340.[Medline]
  45. Vincent PC, Buck M, Young GAR et al. Low dose cytarabine in acute non-lymphoblastic leukemia or myelodysplastic syndrome: report of six cases of review of the literature. Aust NZ J Med 1985;15:10–15.[Medline]
  46. Winter JN, Variakojis D, Gaynor ER et al. Low-dose cytosine arabinoside (ara-C) therapy in the myelodysplastic syndromes and acute leukemia. Cancer 1985;56:443–449.[Medline]
  47. Wisch JS, Griffin JD, Kufe DW. Response of preleukemic syndromes to continuous infusion of low-dose cytarabine. New Engl J Med 1983;309:1599–1602.[Abstract]
  48. Degos L, Castaigne S, Tilly H et al. Treatment of leukemia with low-dose ara-C: a study of 160 cases. Semin Oncol 1985;12:(suppl 3):196–199.[Medline]
  49. Letendre L, Levitt R, Pierre RV et al. Myelodysplastic syndrome treatment with danazol and cis-retinoic acid. Am J Hematol 1995;48:233–236.[Medline]
  50. Cheson BD, Jasperse DM, Simon R et al. A critical appraisal of low-dose cytosine arabinoside in patients with acute non-lymphocytic leukemia and myelodysplastic syndromes. J Clin Oncol 1986;4:1857–1864.[Abstract]
  51. Cheson BD, Simon R. Low-dose ara-C in acute nonlymphocytic leukemia and myelodysplastic syndromes: a review of 20 years’ experience. Semin Oncol 1987;14(suppl 1):126–133.[Medline]
  52. Aul C, Schneider W. The role of low-dose cytosine arabinoside and aggressive chemotherapy in advanced myelodysplastic syndromes. Cancer 1989;64:1812–1818.[Medline]
  53. Miller KB, Kyungmann K, Morrison FS et al. The evaluation of low-dose cytarabine in the treatment of myelodysplastic syndromes: a phase-III intergroup study. Ann Hematol 1992;65:162–168.[Medline]
  54. Preisler HD, Raza A, Barcos M et al. High-dose cytosine arabinoside in the treatment of preleukemic disorders: a Leukemia Intergroup study. Am J Hematol 1986;23:131–134.[Medline]
  55. Richard C, Iriondo A, Garijo J et al. Therapy of advanced myelodysplastic syndrome with aggressive chemotherapy. Oncology (Basel) 1989;46:6–9.[Medline]
  56. Fenaux P, Lai JL, Jouet JP et al. Aggressive chemotherapy in adult primary myelodysplastic syndromes. Blut 1988;57:297–302.[Medline]
  57. Tricot G, Boogaerts MA. The role of aggressive chemotherapy in the treatment of the myelodysplastic syndromes. Br J Haematol 1986;63:477–483.[Medline]
  58. Larson RA, Wernli M, Le Beau MM et al. Short remission durations in therapy-related leukemia despite cytogenetic complete responses to high-dose cytarabine. Blood 1988;72:1333–1339.[Abstract/Free Full Text]
  59. De Bock R, Van Hoof A, Van Hove W et al. Oral idarubicin (IDA) for RAEB, RAEBt, and acute leukemia (AL) post myelodysplastic syndrome (MDS). A phase II open study. Proc ASCO 1989;8:204 (794a).
  60. Shibuya T, Teshima T, Harada M et al. Treatment of myelodysplastic syndrome and atypical leukemia with low-dose aclarubicin. Leuk Res 1990;14:161–167.[Medline]
  61. Zervas J, Geary CG, Oleesky S. Sideroblastic anemia treated with immunosuppressive therapy. Blood 1974;44:117–123.[Abstract/Free Full Text]
  62. Martinez JA, Martin G, Sanz GF et al. A phase II clinical trial of carboplatin infusion in high-risk acute non-lymphocytic leukemia. J Clin Oncol 1991;9:39–43.[Abstract/Free Full Text]
  63. Tamura K, Makino S, Araki Y. A phase I study of a new cisplatin derivative for hematologic malignancies. Cancer 1990;66:2059–2063.[Medline]
  64. Meyers FJ, Welborn J, Lewis JP et al. Infusion carboplatin treatment of relapsed and refractory acute leukemia: evidence of efficacy with minimal extramedullary toxicity at intermediate doses. J Clin Oncol 1989;7:173–178.[Abstract]
  65. Spitzer TR, Lazarus HM, Crum ED et al. Treatment of myelodysplastic syndromes with low-dose oral 6-thioguanine. Med Ped Oncol 1988;16:17–20.[Medline]
  66. Doll D, Sun PCJ, List AF. Complete hematologic remission with oral etoposide in a patient with chronic myelomonocytic leukemia and profound dyserythropoiesis. Leuk Res 1994;18:381–384.[Medline]
  67. Oscier DG, Worsley A, Hamblin TJ et al. Treatment of chronic myelomonocytic leukaemia with low dose etoposide. Br J Haematol 1989;72:468–471.[Medline]
  68. Wattel E, Guerci A, Hecquest B et al. A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Blood 1996;88:2480–2487.[Abstract/Free Full Text]
  69. Rowinsky EK, Adjei A, Donehower RC et al. Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia. J Clin Oncol 1994;12:2193–2203.[Abstract/Free Full Text]
  70. Kantarjian HM, Beran M, Ellis A et al. Phase I study of topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia. Blood 1993;81:1146–1151.[Abstract/Free Full Text]
  71. Beran M, Kantarjian H, O’Brien S et al. Topotecan, a topoisomerase I inhibitor is active in the treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 1996;88:2473–2479.[Abstract/Free Full Text]
  72. Letendre L, Levitt R, Pierre R et al. A pilot study of VP-16/ara-C in the treatment of unfavorable myelodysplastic syndrome. Proc ASCO 1990;9:288(1119a).
  73. Owens MR, Bennett JM. Effectiveness of attenuated chemotherapy in myelodysplastic syndromes: a preliminary report. Med Ped Oncol 1988;16:107–110.[Medline]
  74. Armitage JO, Dick FR, Needleman SW et al. Effect of chemotherapy for the dysmyelopoietic syndrome. Cancer Treat Rep 1981;65:601–605.[Medline]
  75. Bernstein SH, Brunetta VL, Davey FR et al. Acute myeloid leukemia-type chemotherapy for newly diagnosed patients with antecedent cytopenias having myelodysplastic syndrome as defined by French-American-British criteria: a Cancer and Leukemia Group B study. J Clin Oncol 1996;14:2486–2494.[Abstract]
  76. Mertlesmann R, Thaler HT, To L et al. Morphological classification, response to therapy, and survival in 263 adult patients with acute nonlymphoblastic leukemia. Blood 1980;56:773–781.[Abstract/Free Full Text]
  77. De Witte T, Muus P, De Pauw B et al. Intensive chemotherapy for patients with myelodysplastic syndromes and acute myelogenous leukemia younger than 65 years. Bone Marrow Transplant 1989;4(suppl 3):33–35.
  78. Estey E, Thall P, Andreef M et al. Use of granulocyte colony-stimulating factor before, during, and after fludarabine plus cytarabine induction therapy of newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome: comparison with fludarabine plus cytarabine without granulocyte colony-stimulating factor. J Clin Oncol 1994;12:671–678.[Abstract]
  79. Keating MJ, McCredie KB, Benjamin RS et al. Treatment of patients over 50 years of age with acute myelogenous leukemia with a combination of rubidazone and cytosine arabinoside, vincristine, and prednisone (ROAP). Blood 1981;58:584–591.[Abstract/Free Full Text]
  80. Preisler HD, Raza A, Barcos M et al. High-dose cytosine arabinoside as the initial treatment of poor-risk patients with acute nonlymphocytic leukemia: a Leukemia Intergroup study. J Clin Oncol 1987;5:75–82.[Abstract]
  81. Hoyle CF, De Bastos M, Wheatley K et al. AML associated with previous cytotoxic therapy, MDS or myeloproliferative disorders: results from the MRC’s 9th AML trial. Br J Haematol 1989;72:45–53.[Medline]
  82. Gajewski JL, Ho WG, Nimer SD et al. Efficacy of intensive chemotherapy for acute myelogenous leukemia associated with a preleukemic syndrome. J Clin Oncol 1989;7:1637–1645.[Abstract]
  83. Kusnierz-Glaz CR, Normann D, Weinberg R et al. Subcutaneous low dose arabinosyl-cytosine and oral idarubicin in high risk adult acute myelogenous leukemia. Hematol Oncol 1993;11:73–80.
  84. Martiat P, Ferrant A, Michaux J-L et al. Intensive chemotherapy for acute non-lymphoblastic leukemia after primary myelodysplastic syndrome. Hematol Oncol 1988;6:299–305.[Medline]
  85. Gandhi V, Nowak B, Keating MJ et al. Modulation of arabinosylcytosine metabolism by arabinosyl-2-fluoroadenine in lymphocytes from patients with chronic lymphocytic leukemia: implications for combination therapy. Blood 1989;74:2070–2075.[Abstract/Free Full Text]
  86. Gandhi V, Estey E, Keating MJ et al. Synergistic combination of fludarabine and ara-C for AML therapy. Blood 1991;78(suppl 1):52a (198a).
  87. Gandhi V, Kemena A, Keating MJ et al. Fludarabine infusion potentiates arabinosylcytosine metabolism in lymphocytes of patients with chronic lymphocytic leukemia. Cancer Res 1992;52:897–903.[Abstract/Free Full Text]
  88. Bhalla K, Birkhofer M, Arlin Z et al. Effect of recombinant GM-CSF on the metabolism of cytosine arabinoside in normal and leukemic human bone marrow cells. Leukemia 1988;2:810–813.[Medline]
  89. Bell DR, Trent JM, Willard HF et al. Chromosomal location of human P-glycoprotein gene sequence. Cancer Genet Cytogenet 1987;25:141–148.[Medline]
  90. Holmes J, Jacobs A, Cater G et al. Multidrug resistance in haemopoietic cell lines, myelodysplastic syndromes and acute myeloblastic leukaemia. Br J Haematol 1989;72:40–44.[Medline]
  91. Anderson JE, Appelbaum FR, Fisher LD et al. Allogeneic bone marrow transplantation for 93 patients with myelodysplastic syndrome. Blood 1993;82:677–681.[Abstract/Free Full Text]
  92. Bellanger R, Gyger M, Perreault C et al. Bone marrow transplantation for myelodysplastic syndromes. Br J Haematol 1988;69:29–33.[Medline]
  93. Bhaduri S, Kubanek B, Heit W et al. A case of preleukemia —reconstitution of normal marrow function after bone marrow transplantation (BMT) from identical twin. Blut 1979;38:145–149.[Medline]
  94. Bunin NJ, Casper JT, Chitambar C et al. Partially matched bone marrow transplantation in patients with myelodysplastic syndromes. J Clin Oncol 1988;6:1851–1855.[Abstract]
  95. De Witte T, Zwaan F, Hermans J et al. Allogeneic bone marrow transplantation for secondary leukemia and myelodysplastic syndrome: a survey by the Leukaemia Working Party of the European Bone Marrow Transplantation Group (EBMTG). Br J Haematol 1990;74:151–155.[Medline]
  96. Gajewski JL, Ho WG, Feig SA et al. Bone marrow transplantation using unrelated donors for patients with advanced leukemia or bone marrow failure. Transplantation 1990;50:244–249.[Medline]
  97. Guinan E, Tarbell NJ, Tantravahi R et al. Bone marrow transplantation for children with myelodysplastic syndrome. Blood 1989;73:619–622.[Abstract/Free Full Text]
  98. Kolb HJ, Holler E, Bender-Gotze C et al. Myeloablative conditioning for marrow transplantation in myelodysplastic syndromes and paroxysmal nocturnal haemoglobinuria. Bone Marrow Transplant 1989;4:29–34.[Medline]
  99. Longmore G, Guinan EC, Weinstein HJ et al. Bone marrow transplantation for myelodysplasia and secondary acute nonlymphoblastic leukemia. J Clin Oncol 1990;8:1707–1714.[Abstract]
  100. O’Donnell MR, Nademanee AP, Snyder DS et al. Bone marrow transplantation for myelodysplastic and myeloproliferative syndromes. J Clin Oncol 1987;5:1822–1826.[Abstract/Free Full Text]
  101. Uderzo C, Locasciulli A, Rajnoldi AC et al. Allogeneic bone marrow transplantation for myelodysplastic syndromes of childhood: report of three children with refractory anemia with excess blasts in transformation and review of the literature. Med Ped Oncol 1993;21:43–48.[Medline]
  102. Woods WG, Kobrinsky N, Buckley J et al. Intensively timed induction therapy followed by autologous or allogeneic bone marrow transplantation for children with acute myeloid leukemia or myelodysplastic syndrome: a Children’s Cancer Group pilot study. J Clin Oncol 1993;11:1448–1457.[Abstract/Free Full Text]
  103. O’Donnell MR, Long GD, Parker PM et al. Busulfan/cyclophosphamide as conditioning regimen for allogeneic bone marrow transplantation for myelodysplasia. J Clin Oncol 1995;13:2973–2979.[Abstract]
  104. Anderson JE, Appelbaum FR, Schoch G et al. Allogeneic marrow transplantation for myelodysplastic syndrome with advanced disease morphology: a phase II study of busulfan, cyclophosphamide, and total-body irradiation and analysis of prognostic factors. J Clin Oncol 1996;14:220–226.[Abstract]
  105. 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 1996;88:358–365.[Abstract/Free Full Text]
  106. Tricot G, Boogaerts MA, Verwilghen RL. Treatment of patients with myelodysplastic syndromes: a review. Scand J Haematol 1986;36(suppl 45):121–127.[Medline]
  107. Kernan NA, Bartsch G, Ash RC et al. Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program. New Engl J Med 1993;328:593–602.[Abstract/Free Full Text]
  108. Gribben JG, Goldstone AH, Linch DC et al. Double autologous bone marrow transplantation in acute myeloid leukemia. Bone Marrow Transplant 1989;4(suppl 1):209–211.
  109. Demuynck H, Delforge M, Verhoef GEG et al. Autologous peripheral blood progenitor cell transplantation (PBSCT) as an alternative treatment option for patients with myelodysplastic syndromes. Blood 1994;84(suppl 1):87a (336a).
  110. Leoni F, Ciolli S, Longo G et al. 13-cis-retinoic acid treatment in patients with myelodysplastic syndrome. Acta Haematol 1988;80:8–12.[Medline]
  111. Kerndrup G, Bendix-Hansen K, Pedersen B et al. 13-cis retinoic acid treatment of myelodysplastic syndromes. Leuk Res 1987;11:7–16.[Medline]
  112. Kerndrup G, Bendix-Hansen K, Pedersen B et al. Primary myelodysplastic syndrome: treatment of 6 patients with 13-cis retinoic acid. Scand J Haematol 1986;36(suppl 45):128–132.
  113. Hast R, Lauren SAL, Reizenstein P. Absent clinical effects of retinoic acid and isoretinoin treatment in the myelodysplastic syndrome. Hematol Oncol 1989;7:297–301.[Medline]
  114. Greenberg BR, Durie BGM, Barnett TC et al. Phase I-II study of 13-cis retinoic acid in myelodysplastic syndrome. Cancer Treat Rep 1985;69:1369–1374.[Medline]
  115. Gold EJ, Mertlesmann RH, Itri LM et al. Phase I clinical trial of 13-cis retinoic acid in myelodysplastic syndromes. Cancer Treat Rep 1983;67:981–986.[Medline]
  116. Abrahm J, Besa EC, Hyzinski M et al. Disappearance of cytogenetic abnormalities and clinical remission during therapy with 13-cis-retinoic acid in a patient with myelodysplastic syndrome: inhibition of the patient’s malignant monocytoid clone. Blood 1986;67:1323–1327.[Abstract/Free Full Text]
  117. Besa EC, Abrahm JL, Bartholomew MJ et al. Treatment with 13-cis-retinoic acid in transfusion-dependent patients with myelodysplastic syndrome and decreased toxicity with addition of alpha-tocopherol. Am J Med 1990;89:739–747.[Medline]
  118. Clark RE, Ismail SAD, Jacobs A et al. A randomized trial of 13-cis retinoic acid with or without cytosine arabinoside in patients with the myelodysplastic syndrome. Br J Haematol 1987;66:77–83.[Medline]
  119. Clark RE, Jacobs A, Lush CJ et al. Effect of 13-cis retinoic acid on survival of patients with myelodysplastic syndrome. Lancet 1987;1:763–765.[Medline]
  120. Koeffler HP, Heitjan D, Mertlesmann R et al. Randomized study of 13-cis retinoic acid v placebo in the myelodysplastic disorders. Blood 1988;71:703–708.[Abstract/Free Full Text]
  121. Meng-er H, Yu-chen Y, Shu-rong C et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988;72:567–572.[Abstract/Free Full Text]
  122. Warrell Jr RP, Frankel SR, Miller WH et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). New Engl J Med 1991;324:1385–1393.[Abstract]
  123. Castaigne S, Chomienne C, Daniel MT et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood 1990;76:1704–1709.[Abstract/Free Full Text]
  124. Ohno R, Naoe T, Hirano M et al. Treatment of myelodysplastic syndromes with all-trans retinoic acid. Blood 1993;81:1152–1154.[Abstract/Free Full Text]
  125. Kurzrock R, Estey E, Talpaz M. All-trans retinoic acid: tolerance and biologic effects in myelodysplastic syndrome. J Clin Oncol 1993;11:1489–1495.[Abstract/Free Full Text]
  126. Kahn MJ, Stadtmauer EA, Edelstein M et al. Intermittent all-trans retinoic acid (ATRA) for the treatment of myelodysplasia (MDS). Blood 1994;84(suppl 1):632a (2514a).
  127. Lawrence HJ, Conner K, Kelly MA et al. cis-Retinoic acid stimulates the clonal growth of some myeloid leukemia cells in vitro. Blood 1987;69:302–307.[Abstract/Free Full Text]
  128. Garewal H, Greenberg B, List A et al. N-(4-hydroxyphenyl) retinamide (4-HPR) therapy in myelodysplastic syndromes (MDS): possible disease acceleration by retinoids. Blood 1987;70(suppl 1):228a (767a).
  129. Vogler WR, Miller DS, Keller JW. 5-Azacytidine (NSC 102816): a new drug for the treatment of myeloblastic leukemia. Blood 1976;48:331–337.[Abstract/Free Full Text]
  130. Saiki JH, McCredie KB, Vietti TJ et al. 5-Azacytidine in acute leukemia. Cancer 1978;42:2111–2114.[Medline]
  131. Saiki JH, Bodey GP, Hewlett JS et al. Effect of schedule on activity and toxicity of 5-azacytidine in acute leukemia. A Southwest Oncology Group study. Cancer 1981;47:1739–1742.[Medline]
  132. Glover AB, Leyland-Jones BR, Chun HG et al. Azacytidine: 10 years later. Cancer Treat Rep 1987;71:737–746.[Medline]
  133. Larson RA, Sweet DL, Golomb HM et al. Response to 5-azacytidine in patients with refractory acute nonlymphocytic leukemia and association with chromosome findings. Cancer 1982;49:2222–2225.[Medline]
  134. Chitambar CR, Libnoch JA, Matthaeus WG et al. Evaluation of continuous infusion low-dose 5-azacytidine in the treatment of myelodysplastic syndromes. Am J Hematol 1991;37:100–104.[Medline]
  135. Silverman LR, Davis RB, Holland JF et al. 5-Azacytidine (AZ) as a low dose continuous infusion is an effective therapy for patients with myelodysplastic syndromes (MDS). Proc ASCO 1989;8:198 (768a).
  136. Silverman LR, Holland JF, Nelson D et al. Trilineage (TLR) response of myelodysplastic syndromes (MDS) to subcutaneous (SQ) azacytidine (Aza C). Proc ASCO 1991;10:222 (747a).
  137. Koeffler HP, Hirji K, Itri L. 1,25-Dihydroxyvitamin D3: in vivo and in vitro effects on human preleukemic and leukemic cells. Cancer Treat Rep 1985;69:1399–1407.[Medline]
  138. Mehta AB, Kumaran TO, Marsh GW. Treatment of advanced myelodysplastic syndrome with alfacalcidol (Letter). Lancet 1984;2:761.
  139. Hellström E, Robert K-H, Samuelsson J et al. Treatment of myelodysplastic syndromes with retinoic acid and 1{alpha}-hydroxy-vitamin D3 in combination with low-dose ara-C is not superior to ara-C alone. Results from a randomized study. Eur J Haematol 1990;45:255–261.[Medline]
  140. Hellström E, Robert K-H, Gahrton G et al. Therapeutic effects of low-dose cytosine arabinoside, alpha-interferon, 1{alpha}-hydroxyvitamin D3 and retinoic acid in acute leukemia and myelodysplastic syndromes. Eur J Haematol 1988;40:449–459.[Medline]
  141. List AF, Heaton R, Glinsmann-Gibson B et al. Amifostine stimulates formation of multipotent progenitors and generates macroscopic colonies in normal and myelodysplastic bone marrow. Proc ASCO 1996;15:449 (1403a).
  142. Elias L, Van Epps D, Smith KJ et al. A trial of recombinant {alpha}2 interferon in the myelodysplastic syndrome: II. Characterization and response of granulocyte and platelet dysfunction. Leukemia 1987;1:111–115.[Medline]
  143. Elias L, Hoffman R, Boswell S et al. A trial of recombinant {alpha}2 interferon in the myelodysplastic syndromes: I. Clinical results. Leukemia 1987;1:105–110.[Medline]
  144. Aul C, Gattermann N, Schneider W. Treatment of advanced myelodysplastic syndromes with recombinant interferon-alpha 2b. Eur J Haematol 1991;46:11–16.[Medline]
  145. Rosti V, Carlo-Stella C, Pedrazzoli P et al. In vitro and in vivo effects of recombinant interferon gamma on the growth of hematopoietic progenitor cells from patients with myelodysplastic syndrome. Haematologica 1989;74:435–440.[Medline]
  146. Gisslinger H, Chott A, Linkesch W et al. Long-term {alpha}-interferon therapy in myelodysplastic syndromes. Leukemia 1990;4:91–94.[Medline]
  147. Beran M, Andersson B, Kantarjian H et al. Hematologic response of four patients with smoldering acute myelogenous leukemia to partially pure gamma interferon. Leukemia 1987;1:52–57.[Medline]
  148. Maiolo AT, Cortelezzi A, Calori R et al. Recombinant {gamma}-interferon as first line therapy for high risk myelodysplastic syndromes. Leukemia 1990;4:480–485.[Medline]
  149. Stone R, Spriggs D, Arthur D et al. A phase I-II trial of recombinant human interferon gamma (rIFN-gamma) for acute myelocytic leukemia (AML) and myelodysplastic syndromes (MDS). Proc ASCO 1989;8:207 (805a).
  150. Antin JH, Smith BR, Holmes W et al. Phase I/II study of recombinant human granulocyte-macrophage colony-stimulating factor in aplastic anemia and myelodysplastic syndrome. Blood 1988;72:705–713.[Abstract/Free Full Text]
  151. Brach M, Klein H, Platzer E et al. Effect of interleukin 3 on cytosine arabinoside-mediated cytotoxicity of leukemic myeloblasts. Exp Hematol 1990;18:748–753.[Medline]
  152. Estey EH, Kurzrock R, Talpaz M et al. Effects of low dose recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) in patients with myelodysplastic syndromes. Br J Haematol 1991;77:291–295.[Medline]
  153. Ganser A, Volkers B, Greher J et al. Recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes—a phase I/II trial. Onkologie 1988;11:53–55.