Document zdn7EedzE94KK5nyEXbzX7qv3

1 Chemotherapy and Bone Marrow Transplantation for Myelodysplastic Syndromes Bruce D, Cheson THE MYELODYSPLASTIC syndromes (MDS) are a heterogeneous group of disorders that form a spectrum that ranges from diseases that are relatively indolent (refractory anemia with [RARS] or without [RA] ringed sideroblasts) to those that are more aggressive (refractory anemia with excess blasts [RAEB] and RAEB in transformation [RAFiB-t]. Indeed, the line separating RAEB-t and acute myeloid leukemia (AML) is somewhat arbitrary, being primarily based on histopathologic features (30% blasts or the presence of Auer rods), and not clinical features.'.' Variability in bone marrow sampling or counting of bone marrow cells can even shift a patient between the diagnosis of MDS to AML. Moreover, some patients who present with MDS can develop a clinical picture with rapidly increasing numbers of blasts, consistent with AML although not yet demonstrating the requisite number of bone marrow blasts to be called AML. Although the French, American and British (FAB) subtypes vary in their duration of survival and frequency of progression to AML, MDS are uniformly fatal disorders. Even those cases of MDS that do not progress to AML have a poor prognosis as the result of complications from infection and bleeding? Chemotherapy has often been used to treat MDS patients because of the similarities to AML, and the lack of effective alternative treatments (eg, retinoids, androgens, vitamin D,): The chemotherapeutic approaches have ranged from single cytotoxic agents, to attenuated doses of multi-agent regimens, to standard therapy for AML. SINGLE AGENTS Most of the chemotherapy drugs that have been evaluated in MDS were selected because of their activity in AML. It is, therefore, no coincidence that cytarabine (Ara-C) has been the agent that has been most extensivelyused to treat patients with MDS. In contrast to the use of Ara-C in AML, however, this agent has been most often administered af 10% to 20% of standard dose Ara-C (LoDAC). This approach is based on in vitro data suggesting that lowdose Ara-C is a potent inducer of human leukemia cell differentiation? In 1968, Ellison and her Cancer and Leukemia Group B coworkers6first reported results in patients with AML using various doses of the new antileukemic agent, Ara-C. Although complete responses (CR) were observed at dose levels as low as 10 mg/m' per day, more myelosuppression was observed at 50 to 100 mg/m*;therefore, lower doses were abandoned. A decade later, Baccarani and Tura' described a previously untreated patient with AML treated with 0.7 mg/kg of Ara-C by a 24-hour continuous infusion for 7 days. A partial remission was achieved and maintained for 6 months. They interpreted an increase in the number of bone marrow myelocytes and neutrophils in the setting of persistent, although milder, dyserythropoiesisto indicate that differentiation had occurred. The same investigators subsequently reported their additional experience with "subacute myeloid leukemia" and MDS using 20 to 30 mg/m2per day of Ara-C for 7 to 10 days.' A partial response (normal blood counts, but a slight increase in bone marrow blasts) was achieved in 1of 11patients with MDS. Transient increases in a single cell line were noted in 3 additional patients (hemoglobin in 1, neutrophils in 2). Wisch et a19also reported responses to LoDAC in 8 patients with MDS. Despite the large number of publications that followed, there is a limited role for LoDAC in the treatment of MDS. In a review of over 250 published cases of MDS treated with LoDAC, the CR rate was only 17%, with an additional 19% qualifying as partial remissions (PR).'"" Response was not influenced by age, FAB subtype, prior therapy From the Medicine Section, Clinical InvestigationsBranch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD. Address reprint requests to Bruce D. Cheson, MD, National Cancer Institute, Executive Plaza N, Rm 741, Bethesda, MD 20892. This is a government work There are no restrictions on its use. 0093-7754/92/1901-oO09$00.00/0 Seminarsin Oncology, Vol 19, No 1 (February), 1992: pp 85-94 85 86 BRUCE D. CHESON for MDS, or schedule of administration (subcu- MDS that had transformed into AML. Of the taneous v continuous infusion). The median 11 with MDS, 3 patients all with RAEB-t (1 survival was 15 months, which does not support AML) achieved a CR lasting 2 months, 2 an impact of therapy on survival. Despite the months, and 11months. The use of oral idarubi- low dose of Ara-C, myelosuppression was re- cin has been reported in 14 patients with RAEB ported in 88% of cases, with more than 15% (n = 8) or RAEB-t (n = 6), with 1 CR in each toxic deaths. Based on clinical features and subtype.I6 laboratory correlative studies, the data support 5-Azacytidine is an antimetabolite that has LoDAC as a cytotoxic agent, without clinical activity in AML. The drug also induces in vitro differentiating activity.A large number of subse- cellular differentiation in association with hy- quent reports has served only to confirm these pomethylation of DNA. Cancer and Leukemia impressions.Moreover, combining LoDAC with Group B investigatorsconducted a phase I1 trial other putative differentiating agents has not of continuous infusion ti-azacytidine in 48 pa- improved on these results." tients with MDS and noted l l % CRs and 25% I In a recent intergroup study conducted by the PRs." The major toxicity was nausea and vomit- Eastern Cooperative Oncology Group and the Southwest Oncology Group, 140 patients were randomized to either LoDAC or supportive care.I3 Central pathology review excluded 25 cases on the basis of an incorrect diagnosis, 20 of which were reclassified as AML. The overall response rate to LoDAC was 23%,of which 8% were CRs. These results are consistent with the summarized published data." The highest response rate was seen in RAEB-t, with 17% CRs and 25% PRs. The median duration of response was less than 8 months. More infections were noted in the LoDAC arm. The frequency of transformation to AML was similar in the two arms. Most important, there was no difference in survival (8.7 months for LoDAC v 6.9 months for supportivecare). This study provides convinc- ing with one patient dying from neutropenic sepsis. Studies to determine if the effect were the result of cytotoxicity or differentiation were not presented. A subsequent study using a more convenient subcutaneous schedule is being pursued. Any enthusiasm for these results should be tempered by the fact that the response rate is similar to the results achievable with LoDAC, although substantial palliative benefit was observed, primarily a reduction in transfusion requirements. Moreover, interpretation of these results is further confounded by the lack of a randomized trial. The analogue 5-aza-2'deoxycytidine has been administered as an intermittent intravenous infusion to eight patients with MDS; one patient with CMML achieved a CR ing data that LoDAC should not be considered and another a PR, whereas two patients with standard therapy for MDS. RAEB-t achieved PRs." Based on alterations in At the other end of the dose intensity range is blast cell immunophenotype and a decrease in the use of high-dose Ara-C (HiDAC) in MDS. c-myc expression in responders, the authors Preisler et all4treated 15 patients with 3 g/m2(2 speculated that the responses were the result of gm/m2for patients older than 70years of age) of cellular differentiation. However, the lack of Ara-C every 12 hours for 6 days. Complete two-channel flow cytometry makes this conclu- remissionswere achieved in only 2 cases (13%). sion difficult to support. Moreover, grade 4 Peripheral blood counts normalized in 2 other neutropenia was encountered in almost half of patients, but extensive bone marrow fibrosis the responders, and grade 4 thrombocytopenia precluded CR status. The treatment-related in over 70% of patients. death rate exceeded 40%, and the median Homoharringtonine is a cephalotaxine ester duration of survival was only 43 days. with activity in AML and chronic myelogenous Despite the activity of daunomycin in AML, leukemia (CML)." Feldman et alm treated 11 there has been only limited testing of other patients with MDS or AML that had trans- anthracycline analogues or related drugs in formed from MDS using a 9-day continuous MDS. Shibuya et all5 used low doses (3 to 14 infusion. There were two CRs and one PR mg/m2 daily for 7 to 10 days for 2 courses) of (response by histology was not provided). Other aclarubicin to treat 15 patients with MDS or drugs, including oral 6-thioguanine or etopo- CHEMOTHERAPY AND BMT FOR MDS 87 side, have not demonstrated sufficient promise to pursue in large-scale clinical trials.21Y Table 2. Chemotherapyfor Acute Myeloid Leukemia Following MDS Carboplatin is an analogue of cisplatin that Author PTS Regimen CR (%) Toxic DeathsI%) i differs from the parent drug primarily in its Mertle~mann'~ 16 AT f D 31 NR toxicity spectrum; carboplatin is less neurotoxic De Wine" 22 D or Ad/A 62 15 and nephrotoxic, but is more myelotoxic. Several recent reports have demonstrated that this Fenaux" Gajewskij' Keating3' 9 RIA;HiDAC 44 DAT 32 ROAP 44 41 22 44 21 53 agent is active and well tolerated in relapsed MartiaP 25 DNRIA 24 44 AMLU*"and it merits evaluation in MDS. Preisle?' 11 HiDAC 18 64 Hoyle" 36 DAT 42 25 COMBINATION CHEMOTHERAPY Abbreviations: A, cytarabine; T. 6-thioguanine: D. daunomy- Combination chemotherapy for MDS has cin; HiDAC, high-dose cytarabine; R, rubidazone; Ad, Adriamy- primarily includedtraditional regimensfor Ah4L cin; 0,vincristine. (Table 1). Mertlesmann et alz conducted a retrospective analysis of 263 cases of AML treated between 1970 and 1978 with Ara-C, daunomycin, and 6-thioguanine.When the blood and bone marrow samples were subsequently reclassified blindly according to the FAB system, 45 cases were believed to be more consistent with the diagnosis of MDS. The CR rate was 48% in this subset of patients, compared with 59% for the AML patients whose leukemia cells exhibited some degree of differentiation, and the survival duration was similar. Armitage et a P treated 20 patients with MDS using daunorubicin and Ara-C. They observed only three CRs (15%), all in previously untreated patients with RAEB, and 5 patients died as a result of therapy. A concurrent cohort of 15 patients was managed with supportive care alone because they were believed to be a poor risk for intensive chemotherapy; those with RAEB lived a median of 14 months compared to 1month for the treated patients, suggesting that the chemotherapy was detrimental. In general, the best results with aggressivechemotherapy in MDS tend to occur in patients who are younger and have not received prior therapy for their MDS?630 The use of multi-agent antileukemia therapy for AML that has evolved from MDS has generally been less effective than for de novo patients with AML (primary AML). Complete remission rates are lower and treatment-related deaths are more frequent than with primary AML (Table 2).303B1oth of these factors contribute to the shorter overall survival. Keating et ai3' used rubidazone, vincristine, Ara-C, and prednisone (ROAP) to treat 91 patients with AML, a third of whom had an antecedent hematologic disorder, mostly MDS. The CR rate for the primary AML group was 63% compared with 22% for the secondary leukemias. Martiat et treated 25 patients with MDS that had transformed into AML, with no antecedent toxin exposure, using daunomycin and Ara-C. A CR was achieved in only 24% of patients, whereas 44% died of complications of treatment-induced myelosuppression. The median survival for this series was 5 months. Gajewski et a13' treated 196 patients with AML using daunomy- cin, Ara-C, and 6-thioguanine; CR rates for the Table 1. Intensive ChemotherapyRegimens for 44 patients with AML following a prior hemato- Myelodysplastic Syndromes logic disorder and the 111patients with primary Author PTS Regimen CR (%) Toxic Deaths ( O h ) AML were 41% and 73%, respectively. More- Preisler" 15 HiDAC Mertlesmann" 45 A T k D 13 40' 51 NR over, it took longer for bone marrow recovery for the post-MDS patients. Aul and S~hneide?~ Armitagem Tricotn De Wine" Fenauxa Aula 20 DNRlA 15 HiDAC;DNR/A 14 D or Ad/A 20 R/A:HIDAC 16 DAT 15 53 64 50 56 25 33 + 20 30 13 Abbreviations: A, cytarabine; T, 6-thioguanine; D. daunomycin; HiDAC, high-dose cytarabine; R, rubidazone; Ad, Adriamycin (doxorubicin; Adria Laboratories,Columbus, OH). treated 16patients with MDS with daunomycin, Ara-C, and thioguanine. There were 9 (56%) CRs and 2 (13%) PRs; all 5 RAEB-t patients achieved CRs compared with 4 of 11AML with a prior history of MDS. Two patients (13%) died from infection during neutropenia. They treated another cohort of 31 patients with MDS 88 BRUCE D. CHESON and 20 with MDS that had transformed into AML with LoDAC. The CR rate for the MDS patients was 16%, 20% for the secondary AML group. The induction death rate was 16% and 35%,respectively. The survivalof these patients was similar to their historical controls treated with supportive care only. They concluded that aggressive treatment is more effective than LoDAC in MDS. Larson et treated 17patients with therapyrelated MDS or AML with 1 to 3 g/m2 of HiDAC every 12 hours for 12 doses, followedby intensive consolidation with HiDAC. Death from treatment-induced marrow hypoplasia occurred in 5 patients (27%). Of 8 patients who achieved a CR, cytogenetic analysis was repeated in 7, and a previously existing abnormality was no longer detectable in 6 of these. Nevertheless, the median remission duration was only 5 months, with 7 of the 8 relapsing within 8 months. In contrast is the report by De Witte et aizBwho treated 126 patients with primary AML, 22 patients with secondaryAML, and 14 with MDS. Complete remission rates were 67%, 62%, and 64%, respectively. It is likely that the younger age of the patients (median age A M L - 4 4 years, secondary AML 47 years, MDS 42 years) was responsible, to a large extent, for the favorable results. Kantarjian et aIMdescribed 112 patients who developed AML or MDS following chemotherapy or radiation therapy for a prior malignancy. In 51% of the patients, MDS was the first presentation, although 55% of these cases subsequently progressed to AML. The CR rate for the two groups was 29%; 15% for patients with MDS and 37% for those with AML. The overall median survival was 30 weeks, and was significantly shorter for those patients with AML than MDS at presentation (21 v 45 weeks), and did not appear to be different for those patients whose MDS progressed to AML. Whether AML following MDS and AML followingcytotoxic chemotherapyor toxin exposure differ in their responsivenessto chemotherapy is controversial. Preisler et a13' treated 67 patients with poor risk AML (age >70 years, unable to receive anthracyclines, prior toxin exposure, or a hematopoietic disorder lasting longer than 3 months) with HiDAC. The CR rate for the 23 patients with prior toxin expo- sure was 61% compared to 18% for the 11 patients with an antecedent hematologic disor- der. The differencein response rate reflected an induction death rate of 22%in the former group and 64% in the latter. The Medical Research Council (MRC) 9th Acute Myeloid Leukaemia Trial3' accrued 688 patients with primary AML and 66 with AML following either cytotoxic chemotherapy (n = lo), MDS (n = 36), or a myeloproliferative disorder (n = 10). For induc- tion therapy, patients were randomized be- tween two schedules of daunomycin, Ara-C, and 6-thioguanine. Patientswere again random- ized postremission to either MAZE (amsacrine, 5-azacytidine, etoposide) or COAP (cyclophos- phamide, vincristine,Ara-C, prednisolone). The CR rate for patients with primary AML was 66% compared with 25% and 42% for the postcytotoxic therapy and prior MDS patients, respectively. This difference was explained, in part, by a high rate of resistant disease in the latter two groups. Moreover, the median sur- vival for the postcytotoxic therapy group was only 58.5 days compared with 125.5 days for the post-MDS group. However, the duration of remission was not different when stratified for age. The discrepancy between the results from Preisler et aP7and the MRC may be explained by the small sample sizes, the routine use of consolidationin the MRC trial, or other unspec- ified patient characteristics. The negative influence of age has also been observed by other The pa- tients reported by Gajewski et aI3l who had post-MDS AML and who were 264 years of age experienced a 23% CR rate, compared with 48% for the younger patients, although the differencewas not significant. However, none of their 13 patients in the older group survived beyond a year, compared with 12% of the younger patients (P < 0.01). De Witte et alB treated 22 patients with either secondary AML or poor prognosis MDS with aggressive combi- nation chemotherapy; CR rates for those who were 15 to 45 years of age were 75% and 71%, and for those older than 45 years 50% and 57%, respectively. Although patients with MDS most commonly fail to respond to therapy because of death from marrow hypoplasia, many exhibit clinical drug resistance. An interesting observation is that CHEMOTHERAPY AND BMT FOR MDS 89 the gene that codes for the p-glycoprotein has been localized to the long arm of chromosome 7 7 which is commonly involved in cytogenetic abnormalities in MDS and secondary leukemias. Holmes et a14 evaluated 19 cases of MDS for the presence of the multi-drug resistance (mdr) phenotype associatedwith the p-glycoprotein using the mdrl gene probe. Southern blot analysis failed to detect gene amplification; however, 7 patients showed an increase of mdr messenger RNA expression. List et a14' used a monoclonal antibody reactive with the surface epitope or the cytoplasmic domain of p-glycoprotein to demonstrate p-glycoprotein expression in 7 of 32 cases of primary MDS, and in 4 of 7 cases with leukemia secondary to MDS, and in 5 of 6 cases of therapy-related hematologic disorders. The clinical relevance of these observations remains to be determined. Less often, attenuated dose chemotherapy has been used for MDS. The rationale for attenuated doses is based on the generally older age of patients with MDS, and their tendency to die from marrow hypoplasia following intensive treatment. Letendre et a14' treated 18 patients (RAEB-9, RAEB-t-7,CMML-2)with 100mg/m2 of Ara-C and 60 mglm' of etoposide (VP-16) as a 1-hour infusion every 12 hours for 5 days. All patients developed severe neutropenia and thrombocytopenia. Nevertheless, there were two unspecified responses lasting 2 and 6 months, and three patients progressed to AML within a month of therapy. Owens and Bennett43treated five elderly men (median age 64 years) with RAEB or CMML with attenuated doses of DAT, which required hospitalization. Four of the patients responded with an improvement in blood counts, although with less than would be classified as a CR or PR, lasting 1.5 to 9 months. One patient experienced an early death. BONE MARROW TRANSPLANTATION Allogeneic bone marrow transplantation is a rational approach for stem cell disorders such as MDS. One of the earliest reports was published in 1979 of a successful syngeneic BMT followingcyclophosphamide and total body irradiation (TBI).# At 6 weeks there was complete hematologic and cytogenetic remission. Unfortunately, no long-term follow-up data were provided. Subsequentstudies in both adults and children demonstrating prolonged disease-free survival of greater than 10 years confirm that BMT is the only currently available curative approach for MDS (Table 3)?5-54Appelbaum et alSOrecently updated their experience with 59 patients, most of whom were treated with cyclophosphamide and TBI. The median age was 29 years (range, 4 to 54 years). At the time of the report, 28 of the 59 patients were alive and disease-free from 12 to 215 months after transplant. Disease recurred in 8 patients, between 14 days and 783 days following transplant, for an actuarial probability of relapse of 23%. The highest relapse rate was observed in patients with RAEB and RAEB-t. Twenty-three patients (39%) died from transplant-related complications, most often interstitial pneumonia and graft-versus-host disease (8 patients each). Younger age was a favorable prognostic factor by impacting on nonmalignant deaths, but not on relapse rates. The degree of marrow cellularity or fibrosis did not appear to influence outcome, consistent with the results of other invest i g a t o r ~ .A~n~ unexpected finding was that patients with clonal cytogenetic abnormalities Author TricorS O'Donnell" Belanger" Bunin" Appelbaumw Longmore5' DeWitte5' Kolb" GajewskP Table 3. Bone Marrow Transplantationfor MDS Regimen ARA-CITBI+ /-Cy Cy+/-AITBI VP-161TBI;BuCy Cy1TBI;BuCy CyIBuIAIMPITBI Cy+/-TBI;BuCy Cy+ I -A/TBI Variable Cy1TBI;BuCy BuCy 2 TBI PTS DFS(mos) 7 4 (5+-32+) 20 8 (3+-120+) 8 5 (9+-35+) 6 3 (8+-18+) 59 28 (12+-215+) 23 12 (6+-102+) 65 32 (6+-91+) 7 5 (6-34) 6 3 (4-5) BMT-Related Deaths( O h ) 29 45 25 33 39 22 31 29 50 90 BRUCE D. CHESON had a significantly longer disease-free and overall survivalthan those without such an abnormality. The meaning of this observation is not clear because it has not been verified by other investi-gators. O'Donnell et a1&from the City of Hope (Duarte, CA) treated 20 patients (age 4 to 48 years, median 36) with one of four preparative regimens. Nine (45%) patients died of transplant-related complications including interstitial pneumonia (n = 6), gastrointestinal bleeding (n = 2), and fungal sepsis (n = 1). Eight patients remain alive and well from 108+ to 3,359t-days posttransplant. Three patients re- lapsed at 67, 462, and 2,922 days following transplant, one of whom had a second, successful transplant. Although the number of patients in the series was small, there was no apparent correlation between outcome and FAJ3 subtype, marrow fibrosis, cytogenetic abnormalities, or preparative regimen. DeWitte et aF2recently published the retrospective experience from the European Bone Marrow Transplant Group (EBMTG) of 78 patients with MDS or secondary AML. The preparative regimens varied among the institutions, although 69 patients received TBI in addition to chemotherapy. Disease status at the time of transplant was highly predictive for survival; those patients transplanted while in CR had a 60% 2-year disease-free survival compared with 18% for those who only partially responded to prior intensive chemotherapy. The disease-free survival at 2 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 to 91 months; 25 (32%) died of transplant-related complications, mainly interstitial pneumonitis (n = 9) and GVHD (n = 7); and 18 patients relapsed. None of the 8 patients transplanted with chemotherapy-resistant disease survived; 4 died of transplant-related complications, 4 from relapse. Longmore et aI5'transplanted 23 patients with MDS and secondary AML. Of the 12 patients with MDS, 8 were alive with a median follow-up of 2 years, 7 of whom were disease-free. They suggested that T-cell depletion should be avoided in patients with marrow fibrosis because of an increased incidence of graft failure. The authors also concluded that attempts to induce remission prior to BMT were unnecessary based on their success in 10 patients with secondary MDS/AML. The contrast with the conclusions of DeWitte et alS2may reflect the small sample size, patient characteristics, or other factors that have not been identified. Sources of bone marrow other than HLAidentical sibling have also been attempted in MDS.4853-55B8u5n6in et ala described 6 patients treated with BMT using T-celldepleted bone marrow from a partiallymatched relative (n = 3) or unrelated donor (n = 3). Four patients engrafted without difficulty. One patient required a second graft because of initial graft failure. Three patients died, 1 prior to engraftment from aspergillosis, 1 at day 257 of recurrent disease, the third at day 515 of pancreatitis and respiratory failure. Three patients are diseasefree at 240, 395, and 560 days. Gajewski et alS5 transplanted six patients with MDS with bone marrow from an unrelated donor, three of whom were alive 4, 4, and 5 months after transplant. Though allogeneic BMT achieves prolonged disease-free survival in approximately 40% of patients with MDS, deaths can be attributed to the transplant in 30% to 40%. The recent availabilityof hematopoietic growth factors may abbreviate the period of neutropenia and reduce the treatment-related morbidity from infections. However, there is limited evidence currently available to support an improvement in survival. On the other hand, hematopoietic growth factors may also delay consideration of BMT until the patient has developed a more progressive disease, reducing the likelihood of a successful BMT. Although allogeneic BMT has been successful in MDS, the majority of patients with this disorder are elderly and, therefore, only a small proportion of patients would be suitable candidates for this procedure. Autologous BMT has been used in only a few patients with MDS or AML and a preexisting MDS. Gribben et aI5' reported five cases of secondary AML, all of whom relapsed within 1 year of either a single or double graft. A recent study by the Children's Cancer Study Group identified 18 cases of MDS in a series of 137 patients with MDS or AML referred for allografting or a~tografting.~P'atients received a 5-drug induction program of dexamethasone, CHEMOTHERAPY AND BMT FOR MDS 91 Ara-C, &thioguanine, etoposide and daunomycin, followed by busulfan and cyclophosphamide as a conditioning regimen. Eight of the 18 patients with MDS underwent successful autografting (W. Woods, personal communication). Long-term follow-upinformation on these cases will be of interest. CONCLUSIONS The optimal therapy for patients with MDS is not yet known. Although a substantial number of trials with cytotoxic, biologic, and differentiating agents have been reported: the results of these published studies are often difficult to interpret. One problem is whether all of the cases have been accurately diagnosed. In multiinstitutional trials in which central review of bone marrow samples is required, almost 25% of cases diagnosed locally as MDS are rendered ineligible for the protocol because of misdiagnosis; those cases have generally been reclassified as AML.I3Moreover, there is considerable clinical and biological heterogeneity even within MDS subtypes. Studies are also difficult to compare because there are no standardized response definitions for MDS. These issues will become even more problematic as more effective treatments are developed. The accepted standard therapy for MDS has been supportive care, with red cell and platelet transfusions, and antibiotics when indicated. This approach may change markedly, however, with the recent commercial availabilityof erythropoietin, G-CSF, and GM-CSF. There are at least three ways in which these agents may alter the pattern of care. First, they may be used individually or in combination with each other as primary therapy for patients with MDS. Unfortunately, as currently used, these agents are palliative; they do not induce CRs, a necessary factor in achieving cure. Whether or not the use of growth factors to reduce the cytopenias will improve survival is being addressed by ongoing trials comparing these agents with either supportive care or placebo. Nevertheless, the cross-over design in one of these trials has made survival comparisons impossible to inter~ r e t . 5H~ematopoietic growth factors may also be used to synchronize the malignant cells, making them more sensitive to chemotherapy. For example, both GM-CSF and IL3 preferentially increase the uptake of Ara-C in leukemic cells compared with normal cell^.^-^^ Third, growth factors could make intensive chemotherapy an option for a larger number of patients; these agents may ameliorate the toxicities of aggressive chemotherapy, reducing the treatment-associated death rate and, therefore, permitting a greater number of CR. Whether hematopoietic growth factors will become standard treatment for patients with MDS remains to be determined. These agents are expensive, and they are associated with some side effects.@There is also the potential for stimulating progression to AML.Another consequence of the routine use of growth factors is that there will be an increased number of patients who will not be referred for a clinical trial until they require therapy or secondary AML. It is imperative that a patient who is a suitable candidate for allogeneic bone marrow transplantation be considered for that procedure as soon as possible. The current recommended treatment strategy for newly diagnosed, asymptomatic patients with MDS involves observation for several weeks, when possible, to assess the biologic activity of the disease. Patients who are clini- cally stable can be managed with supportive care (eg, intermittent antibiotics and blood components as needed). Initiation of systemic treatment should be considered when there is evidence of clinical deterioration as manifested by repeated infections, a requirement for increasing red blood cell or platelet transfusions, or progression to a more unfavorable histologic subtype. When indicated, treatment should be dictated by clinical and laboratory factors. An occasional patient whose clinical picture is characterized by symptomatic anemia may benefit from erythropoietin, although, to date, responses to this factor have been infreq~ent.".`~ Those patients with neutropenia and recurrent infections as their primary feature may respond to G-CSF, GM-CSF, or IL3. Patients with RA or RARS or CMML with favorable prognostic features can be considered for treatment with potential differentiating agents, hematopoietic growth factors, or various combination approaches, or possibly bone marrow transplantation. Unfortunately, none of the currently avail- 92 BRUCE D. CHESON able hematopoietic growth factors is associated with a consistent improvement in thrombocytopenia, and they may even worsen thrombocytopenia in a small proportion of patients. Patients with RAEB or RAEB-t, CMML, or others with poor risk features are candidates for cytotoxic therapy, either combination chemotherapy with or without the use of growth factors, or, if eligible, allogeneic bone marrow transplantation. Whatever therapy is most appropriate for a particular patient, based on clinical and biologic characteristics, should be delivered in the context of a carefully designed and conducted clinical trial. These trials should include biologic correlates such as cytogenetics,oncogenes, and growth factor receptors so that we may increase our understanding of the biology of these disorders leading to a more rational approach to therapy. REFERENCES 1. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol51:189-199, 1982 2. 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 Oncol8:813-819, 1990 3. Weisdorf DJ, Oken MM, Johnson GJ, et al: Chronic myelodysplastic syndrome: Short survival with or without evolution to acute leukaemia. Br J Haematol 55:691-700, 1983 4. Cheson BD: The myelodysplastic syndromes: Current approaches to therapy. Ann Intern Med 112:932-941,1990 5. Lotem J, Sachs L Potential pre-screening for therapeutic agents that induce differentiation in human myeloid leukemia cells. Int J Cancer 25561-564, 1980 6. Ellison RR, Holland JF, Weil M, et al: Arabinosyl cytosine: A useful agent in the treatment of acute leukemia in adults. Blood 32507-523,1968 7. Baccarani M, Tura S: Differentiation of myeloid leukaemic cells: New possibilities for therapy. Br J Haematol 42~485-490,1979 8. Baccarani M, Zaccaria A, Bandini G, et al: Low dose arabinosyl cytosine for treatment of myelodysplastic syndromes and subacute myeloid leukemia. Leukemia Res 7539-545,1983 9. Wisch JS, Griffin JD, Kufe DW: Response of preleukemic syndromes to continuous infusion of low-dose cytarabine. N Engl J Med 309:1599-1602, 1983 10. 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 Oncol4:1857-1864,1986 11. Cheson BD, Simon R: Low-dose ara-C in acute nonlymphocytic leukemia and myelodysplastic syndromes: A review of 20 years' experience. Semin Oncol 14:126-133, 1987(suppl 1) 12. Hellstrom E, Robert K-H, Samuelsson J, et al: Treatment of myelodysplastic syndromes with retinoic acid and la-hydroxy-vitamin D3 in combination with low-dose ara-C is not superior to ara-C alone. Results from a randomized study. Eur J Haematol45:255-261,1990 13. Miller KB, Kim K, Morrison FS, et al: Evaluation of low dose ara-C versus supportive care in the treatment of myelodysplastic syndromes: An intergroup study by the Eastern Cooperative Oncology Group and the Southwest Oncology Group. Blood 72:215a, 1988 (abstr 771) (suppl 1) 14. Preisler HD, Raza A, Barcos M, et al: High-dose cytosine arabinoside in the treatment of preleukemic disorders: A Leukemia Intergroup study. Am J Hematol23:131134,1986 15. Shibuya T, Teshima T, Harada M, et al: Treatment of myelodysplastic syndrome and atypical leukemia with lowdose aclarubicin. Leuk Res 14:161-167, 1990 16. 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 I1 open study. Proc Am SOCClin Oncol8:204 (abstr 794), 1989 17. Silverman LR, Davis RB, Holland JF, et al: 5-azacyti- dine (AZ)as a low dose continuous infusion is an effective therapy for patients with myelodysplasticsyndromes (MDS). Proc h e r Soc Clin Oncol8:198,1989 (abstr 768) 18. Pinto A, Zagonel V, Attadia V, et al: 5-Aza-2'deoxycytidine as a differentiation inducer in acute myeloid leukaemias and myelodysplastic syndromes of the elderly. Bone Marrow Transpl4:28-32,1989 (suppl3) 19. Grem JL, Cheson BD, King SA. et al: Cephalotaxine esters: Antileukemia advance or therapeutic failure? J Natl Cancer Inst 80:1095-1103,1988 20. Feldman E, Sullivan P, Ahmed T, et al: Phase I1 trial of homoharringtonine (HHT) in patients with myelodysplastic syndromes (MDS). Blood 72:198a. 1988 (abstr 701) (SUPPI 1) 21. Spitzer TR, Lazarus HM, Crum ED, et al: Treatment of myelodysplastic syndromes with low-dose oral 6-thioguanine. Med Ped Oncol 16:17-20,1988 22. Oscier DG, Worsley A, Hamblin TJ: Treatment of chronic myelomonocytic leukemia with low dose etoposide. Br J Haematol72:468-471, 1989 23. 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 Oncol7:173-178, 1989 24. Martinez JA, Martin G, Sanz GF. et al: A phase I1 clinical trial of carboplatin infusion in high-risk acute nonlymphoblastic leukemia. J Clin Oncol9:39-43, 1991 25. Mertelsmann R. Thaler HT, To L. et ai: Morphological classification, response to therapy, and survival in 263 adult patients with acute nonlymphoblastic leukemia. Blood 56:773-781, 1980 26. Armitage JO, Dick FR, Needelman SW, et al: Effect of chemotherapy for the dysmyelopoietic syndrome. Cancer Treat Rep 65:601-605,1981 CHEMOTHERAPY AND EMT FOR MDS 93 27. Tricot G, Boogaerts M A The role of aggressive chemotherapy in the treatment of the myelodysplastic syndromes. Br J Haematol63:477-483,1986 28. 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 4:33-35, 1989 (suppl3) 29. Richard C, Iriondo A, Garijo J, et al: Therapy of advanced myelodysplastic syndrome with aggressive chemotherapy. Oncology (Basel) 46:6-9,1989 30. F e n a w P, Lai JL, Jouet JP, et al: Aggressive chemotherapy in adult primary myelodysplastic syndromes. Blut 57:297-302, 1988 31. Gajewski JL, Ho WG, Nimer SD, et al: Efficacy of intensive chemotherapy for acute myelogenous leukemia associated with a preleukemic syndrome. J Clin Oncol 7:1637-1645,1989 32. 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 (ROAF'). Blood 58584-591, 1981 33. Martiat P, Ferrant A, Michaux J-L, et al: Intensive chemotherapy for acute non-lymphoblastic leukemia after primary myelodysplastic syndrome. Hematol Oncol 6299305,1988 34. Aul C, Schneider W: The role of low-dose cytosine arabinoside and aggressive chemotherapy in advanced myelodysplastic syndromes. Cancer 64:1812-1818,1989 35. 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 72:1333-1339,1988 36. Kantajian HM, Keating MJ, Walters RS. et al: Therapy-related leukemia and myelodysplastic syndrome: Clinical, cytogenetic, and prognostic features. J Clin Oncol 4~17481-757, 1986 37. 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 Oncol5:75-82,1987 38. 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 Haematol72:45-53, 1989 39. Bell DR, Trent JM, Willard HF, et al: Chromosomal location of human P-glycoprotein gene sequence. Cancer Genet Cytogenet 25:141-148,1987 40. Holmes J, Jacobs A, Carter G, et al: Multidrug resistance in haematopoietic cell lines, myelodysplastic syndromes and acute myeloblastic leukaemia. Br J Haemato1 72~4044,1989 41. 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 Haematol78:28-34,1991 42. Letendre L, Levitt R, Pierre R. et al: A pilot study of VP-16iara-C in the treatment of unfavorable myelodysplastic syndrome. Proc Am SOCClin Oncol 9:288, 1990 (abstr 1119) 43. Owens MR, Bennett JM: Effectiveness of attenuated chemotherapy in myelodysplastic syndromes: A preliminary report. Med Ped Oncol 16:107-110,1988 44. 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 38:145-149, 1979 45. Tricot G, Boogaerts MA, Verwilghen R L Treatment of patients with myelodysplastic syndromes: A review. Scand J Haematol36:121-127,1986 (suppl45) 46. O'Donnell MR, Nademanee AP,Snyder DS, et al: Bone marrow transplantation for myelodysplasticand myeloproliferative syndromes. J Clin Oncol5:1822-1826,1987 47. Belanger R, Gyger M, Perreault C, et al: Bone marrow transplantation for myelodysplastic syndromes. Br J Haematol69:29-33,1988 48. Bunin NJ, Casper JT, Chitambar C, et al: Partially matched bone marrow transplantation in patients with myelodysplastic syndromes. J Clin Oncol6:1851-1855, 1988 49. Guinan EC, Tarbell NJ, Tantravahi R, et al: Bone marrow transplantation for children with myelodysplastic syndromes. Blood 73:619-622,1989 50. Appelbaum FR, Barrall J, Storb R, et al: Bone marrow transplantation for patients with myelodysplasia. Ann Intern Med 112590-597,1990 51. Longmore G, Guinan EC, Weinstein HJ, et al: Bone marrow transplantation for myelodysplasia and secondary acute nonlymphoblastic leukemia. J Clin Oncol 8:17071714,1990 52. De Witte T, Zwaan F, Hermans J, et al: Allogeneic bone marrow transplantation for secondary leukaemia and myelodysplasic syndrome: A survey by the Leukaemia Working Party of the European Bone Marrow Transplantation Group (EBMTG). Brit J Haem 74:151-155,1990 53. Kolb HJ, Holler E, Bender-Gotze Ch, et al: Myeloablative conditioning for marrow transplantation in myelodysplastic syndromes and paroxysmal nocturnal haemoglobinuria. Bone Marrow Transpl4:29-34, 1989 54. le Maignan C, Ribaud P, Maraninchi D, et al: Bone marrow transplantation for mutagen-related leukemia or myelodysplasia. Exp Hematol 18:660, 1990 (abstr) 55. Gajewski JL, Ho WG, Feig SA, et al: Bone marrow transplantation using unrelated donors for patients with advanced leukemia or bone marrow failure. Transplantation 50:244-249, 1990 56. Phillips GL, Rybka WB, Chan KW, et ai: Allogeneic bone marrow transplantation (BMT) using unrelated donors (UD): A Canadian BMT Group pilot study. Proc Am SOCClin Oncol9:ll. 1990 (abstr 38). 57. Gribben JG, Goldstone AH, Linch DC, et al: Double autologous bone marrow transplantation in acute myeloid leukemia. Bone Marrow Transplant 4:209-211, 1989 (suppl 1) 58. Woods WG, Lange BJ, Kobrinsky N, et al: Intensively times induction therapy followed by autologous (AUTO) or allogeneic (ALLO) bone marrow transplantation (BMT) for children with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS): A CCSG pilot study. Proc Am SOCClin Oncol 10:234, 1991(abstr 795) 59. Schuster MW, Larson RA, Thompson JA, et al: Granulocyte-macrophage colony-stimulating factor (GM- 94 CSF) for myelodysplastic syndrome (MDS): Results of a multi-center randomized controlled trial. Blood 76:318a, 1990(abstr 1263) (suppl 1) 60. Miyauchi J, Kelleher CA, Wang C, et a1 Growth factors influence the sensitivity of leukemic stem cells to cytosine arabinoside in culture. Blood 73:1272-1278,1989 61. Bhalla K, Birkhofer M, Arlin Z, et ai: Effect of recombinant GM-CSF on the metabolism of cytosine arabinoside in normal and leukemic human bone marrow cells. Leukemia 2:810-813,1988 62. Cannistra SA, Groshek P, Griffin JD: Granulocytemacrophage colony stimulating factor enhances the cytotoxic effects of cytosine arabinoside in acute myeloblastic BRUCE D.CHESON leukemia and in the myeloid blast crisis phase of chronic myeloid leukemia. Leukemia 3:328-334,1989 63. Lista P, Porcu P, Avanzi GC, et al: Interleukin 3 enhances the cytotoxic activity of 1-b-D-arabinofuranosylcytosine (ara-C) on acute myeloblastic leukemia (AML) cells. Br J Haematol69:121-123,1988 64. Greenberg PL: Treatment of myelodysplastic syndromes with hemopoietic growth factors. Semin Oncol 19:96-104, 1992 65. Schouten HC, Vallenga E, van Rhenen D, et al: Recombinant human erythropoietin (rhEPO) for patients with a myelodysplastic syndrome (MDS).Blood 76:317a, 1990 (abstr 1260) (suppl 1) ,