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Allogeneic Bone Marrow Transplantation for Therapy-Related Myelodysplastic Syndrome and Acute Myeloid Leukemia: A Long-Term Study of 70 Patients—Report of the French Society of Bone Marrow Transplantation

From the Service d’Hématologie Clinique et Greffe de Moelle Osseuse and Département de Biostatistique et Informatique Médicale, Hôpital Saint-Louis, Paris, France.

Address reprint requests to E. Gluckman, MD, Service d’Hématologie Clinique et Greffe de Moelle, Hôpital Saint Louis, 1 Avenue Claude Vellefaux, F-75475 Paris Cedex 10, France; email eliane.gluckman{at}sls.ap-hp-paris.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To identify predictive factors of survival, relapse, and transplantation-related mortality (TRM) among patients with therapy-related myelodysplastic syndrome (t-MDS) or acute leukemia (t-AML) who underwent allogeneic bone marrow transplantation (BMT).

PATIENTS AND METHODS: From 1980 to 1998, 70 patients underwent allogeneic BMT for t-MDS (n = 31) or t-AML (n = 39) after prior cytotoxic exposure. Thirty-three patients had received induction-type chemotherapy before BMT. At the time of transplantation, there were 24 patients in complete remission (CR) and 46 with active disease.

RESULTS: With a median follow-up of 7.9 years (range, 1.1 to 18.8 years) after BMT, 16 patients are alive, whereas 19 died of relapse, 34 of TRM, and one of relapse of the primary disease. The estimated 2-year overall survival, event-free survival, relapse, and TRM rates were 30% (95% confidence interval [CI], 19% to 40%), 28% (95% CI, 18% to 39%), 42% (95% CI, 26% to 57%), and 49% (95% CI, 36% to 62%), respectively. In multivariable analysis, age greater than 37 years, male sex, positive recipient cytomegalovirus (CMV) serology, absence of CR at BMT, and intensive schedules used for conditioning were associated with poor outcome.

CONCLUSION: BMT is an effective treatment for patients with t-MDS or t-AML who have responsive disease and, in particular, who have no poor-risk cytogenetic features. The poor results of the other patients, especially those with active disease at BMT, emphasize the need to delineate indications and perform prospective protocols.

	INTRODUCTION

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THERAPY-RELATED myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) are defined as clonal malignant hematopoietic disorders that follow cytotoxic exposure. This designation does not apply to individuals who are genetically predisposed to the development of hematologic disorders or to those with de novo disorders, even in transformation. These diseases have emerged in the last few decades as a significant problem, probably because of the prolongation of the period at risk, which is a result of the successful treatment of cancers.^1,2 Many of the clinical and biologic features of t-MDS and t-AML are similar to those of de novo disorders.^3,4 However, patients with t-MDS or t-AML often have a rapidly progressive disease with fatal outcome, and their neoplastic clones usually have distinct chromosome abnormalities.^5-8 Treatment of t-MDS and t-AML remains disappointing; variable success in the correction of cytopenia has been obtained with the use of differentiating agents such as retinoids, vitamin D, interferons, and hematopoietic growth factors. These treatments, though, do not seem to have any effect on disease progression and survival.^9-12 Intensive chemotherapy in t-MDS and t-AML yields lower complete remission (CR) rates and CR duration than in de novo disorders.^3,13 This is probably a result of the high frequency of poor prognostic factors, including unfavorable cytogenetic abnormalities, that characterize secondary disorders.⁶ As for primary disorders, allogeneic bone marrow transplantation (BMT) seems to be a potential curative treatment in t-MDS and t-AML. Few studies, however, have addressed the effect of such treatment in these disorders.^14-18 In addition, interpretation of the data is confounded by the inclusion of both primary and secondary MDS and AML.^19,20 Furthermore, studies of secondary leukemia frequently involve the analysis of patients with prior hematologic disorders such as primary MDS or myeloproliferative syndromes rather than those with therapy related-AML.²¹ With the purpose of identifying predictive factors of survival, relapse, and transplantation-related mortality (TRM), we report on a study of 70 patients with t-MDS or t-AML who underwent allogeneic BMT.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Between June 1980 and February 1998, 70 patients underwent allogeneic BMT for treatment of t-MDS or t-AML as defined above. Patients who had de novo MDS or acute leukemia (AL) that progressed from MDS were excluded from the study; patients with t-MDS or t-AML after de novo AL were included only if they had phenotypes with specific cytogenetic abnormalities that were different from those observed at diagnosis of the primary AL. Patients with therapy-related acute lymphoblastic leukemia were excluded from the study, as were patients with environmentally related MDS or AML. Participating centers were asked to verify the data referred to the French Bone Marrow Transplantation Registry and to provide additional information on each patient. Initial patient characteristics, including prior cytotoxic exposures, are described in Table 1. Four patients were treated for non-Hodgkin’s lymphoma, 30 for Hodgkin’s disease, 16 for breast cancer, 12 for other cancers, four for AL, and three for autoimmune disorders. One patient with hemoglobinopathy received irradiation (four injections of radioactive phosphorus-32) because of an erroneous diagnosis of Vaquez’ disease. All but one patient with Hodgkin’s disease and one with endometrial carcinoma were in remission of their primary malignancies at the time of BMT. According to the French-American-British (FAB) classification,^22,23 nine patients had refractory anemia (RA) at diagnosis, two of whom had progressed to refractory anemia with excess blasts (RAEB) before BMT. One of these two patients progressed to RAEB in transformation (RAEB-T), and the other progressed to AML. Seventeen patients had RAEB at diagnosis, of whom, before BMT, three had progressed to RAEB-T and three to AML. Four patients had RAEB-T, one had chronic myelomonocytic leukemia, and 39 had AML. The median time from primary to secondary disease was 3.8 years (range, 0.9 to 15.3 years). Thirty-three patients (one with RA, one with RAEB who had progressed to AML, one with RAEB, and 30 with AML) received induction-type chemotherapy before BMT. At the time of BMT, 24 patients (34%) were in CR of their secondary disease, whereas 46 (66%) were with active disease. Among the latter group, there were six patients with refractory disease, three in relapse, and 37 with untreated disease. The median time from diagnosis of the secondary malignancy to BMT was 5.7 months (range, 1.3 to 75.1 months).

Transplantation Modalities
Three patients received peripheral-blood stem cell grafts, and 66 received marrow grafts. One patient underwent transplantation with unrelated cord blood. Donors were identical siblings (n = 57), identical twins (n = 2), HLA-matched unrelated (n = 5), HLA-mismatched related (n = 3), and HLA-mismatched unrelated (n = 3).

The conditioning regimens used were total-body irradiation (TBI) plus cyclophosphamide (CPM) (n = 11), busulfan plus CPM (n = 26), CPM plus melphalan (n = 4), and two other drug combinations without TBI (n = 4). The remaining 25 patients received other high-dose drug schedules, which were combined with TBI in 13 of these 25 patients. Graft-versus-host disease (GVHD) prophylaxis was based on ongoing protocols at the time of BMT in each center. Six patients received cyclosporine with or without steroids, seven received methotrexate with or without steroids, 53 received cyclosporine plus methotrexate (one of whom additionally received monoclonal antibody), and two received monoclonal antibody alone. Marrow was infused with T-cell depletion in six of 68 patients. The two patients who underwent syngeneic BMT received no GVHD prophylaxis. To prevent graft rejection, five patients received antithymocyte globulin. Clinical criteria were used for diagnosis of veno-occlusive disease of the liver.^25,26 Acute and chronic GVHD were scored according to standard criteria.²⁷

Statistical Analysis
The analysis was performed on the reference date of April 15, 1999. Overall survival was defined as the time elapsed from BMT to death, whatever the cause of death. Relapse of the secondary malignancy was defined as the presence of more than 5% marrow blasts and/or reappearance of major myelodysplastic features associated with evidence of autologous reconstitution when chimerism was available. TRM was defined as death resulting from the graft procedure without evidence of relapse. Event-free survival (EFS) was defined as survival with no evidence of relapse. All censored criteria were calculated from the time of transplantation. Distributions over time were estimated by the Kaplan-Meier product limit method.²⁸ Estimated 2-year event rates were reported because the number of events beyond 2 years was insufficient for accurate estimates. The log-rank statistic²⁹ was used to test the prognostic value of patient characteristics at BMT for the occurrence of the event, and hazard ratios (HR) with 95% confidence intervals (CIs) were obtained by use of univariable Cox models.³⁰ Multivariable Cox models were used to determine the variables that provided the most prognostic information (P < .10) and to estimate adjusted hazard ratios. Main initial characteristics were considered for multivariable analysis, namely age ( 37 or > 37 years), sex, prior induction chemotherapy, disease morphology at BMT (t-MDS, t-AML, or CR), cytopenia at BMT, percentage of marrow blasts ( 10% or >10%), sex mismatch, recipient CMV serology, and conditioning (intensive schedules v others). Cytogenetic analysis was not considered because data was missing for 24% of patients. Two-sided tests were computed, and P .05 was considered statistically significant. SAS software (SAS Institute, Cary, NC) was used.

	RESULTS

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Engraftment and Transplantation Toxicity
Ten patients did not experience neutrophil engraftment: nine died and one underwent autologous BMT 80 days after allogeneic BMT (he was alive in CR 20 months after the second BMT). The estimated median time to reach the neutrophil count of 0.5 x 10⁹ cells/L was 20 days after BMT (95% CI, 19 to 24 days). Five patients rejected the grafts after sustained engraftment. Twenty-six patients (37%) developed acute (grades II) GVHD, including 13 who had grade III or IV disease. Thirteen (28%) of the 46 assessable patients developed chronic GVHD, including two with extensive grades. Twelve patients (17%) developed veno-occlusive disease between day 1 and day 87 after transplantation, and twelve developed interstitial pneumonia between day 2 and day 125 after transplantation. The patient who developed interstitial pneumonia at day 2 also had staphylococcal septicemia.

Patient Outcome
One patient was lost to follow-up 11.6 years after transplantation, at which time he was alive and in CR. On the reference date of April 15, 1999, median follow-up from BMT was 7.9 years (range, 1.1 to 18.8 years), and 16 patients were alive and in CR. Estimated median survival time was 197 days (95% CI, 117 to 314 days). Twenty patients relapsed: 19 died and one returned in CR after a second allogeneic BMT and remained alive in CR 6 years after the second transplantation. Overall, 54 patients died, 19 of relapse, 34 of TRM, and one of relapse of the primary disease. Causes of death according to disease status at BMT are presented in Table 2. Patients not in CR at BMT died more often of relapse (44%) than did patients in CR at BMT (8%; P = .02, Fisher’s exact test). According to the disease status and morphology at BMT, five of five patients with RA died (three of relapse), 11 of 13 with RAEB (five of relapse), eight of eight with RAEB-T (five of relapse), 16 of 19 with AML (five of relapse), and 13 of 24 in CR (one of relapse). Of the nine patients in whom prior induction chemotherapy failed, seven (78%) died 38 to 432 days after BMT. The remaining two patients (22%) were still alive in CR 634+ and 1,576+ days, respectively, after BMT. Of the 37 patients allografted with untreated disease, 34 (92%) died between day 6 and day 3,761 after BMT; the remaining three patients (8%) were still alive in CR 3,232+, 3,950+, and 6,009+ days after BMT. However, the difference in death rates between patients in whom prior induction chemotherapy failed and those with untreated disease was not significant (P = .25, Fisher’s exact test).

View larger version (13K): [in this window] [in a new window]   Fig 1. Kaplan-Meier estimates of overall survival, EFS, relapse, and TRM in the 70 patients.

View larger version (22K): [in this window] [in a new window]   Fig 2. Kaplan-Meier estimates of overall survival, EFS, relapse, and TRM in the 70 patients, according to the disease status at BMT.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

As reported by others,^20,31 younger age, negative recipient CMV serology, and female sex were associated with better outcome.³² The last parameter might be explained by the adverse influence of the sex-mismatched donors on TRM in our population.

Because of the poor results of patients with active disease at BMT (2 of 27 and 3 of 19 patients with t-MDS and t-AML, respectively, were long-term survivors), initial subgroup FAB classification had no significant influence on outcome. However, the presence of fewer than two cytopenias and marrow blasts involvement 10% at BMT, which is probably a result of the good outcome of patients in CR at BMT in our study, seemed to be strongly associated with better EFS. Cytogenetic features are currently an important factor that influences prognosis of MDS and AML before BMT. Recently, three cytogenetic prognosis subgroups were defined in the IPSS²⁴ for untreated patients with primary MDS. In a series of 60 allografted patients with primary MDS, Nevill et al³³ observed EFS rates of 50%, 40%, and 6% for good-, intermediate-, and poor-risk IPSS cytogenetic subgroups respectively. Appelbaum and Anderson³⁴ observed a significant correlation between outcome of BMT for MDS patients and IPSS risk groups in terms of cytogenetic features, marrow blasts, and cytopenias, among other things. Our results confirm these observations and suggest that cytogenetic abnormalities are predictive of outcome even after BMT. Thus, the lower frequency of poor-risk karyotypes in CR patients probably contributed to the better outcome of these patients.

The value of cytoreductive chemotherapy for advanced MDS remains to be determined. Forty-seven percent of our patients had received induction-type chemotherapy before the graft, and 71% of them were in CR at BMT. This CR rate seems to be higher than the CR rates obtained after intensive chemotherapy that are reported in the literature.^1,3,18,35 This result could be explained, in part, by the preselection of patients proposed for the graft in our population. However, Fenaux et al³⁶ reported that CR was significantly more frequent in patients with de novo MDS treated by intensive chemotherapy when marrow blasts were more than 20%. In our study, 31 of 33 patients who had received prior induction chemotherapy had more than 20% marrow blasts. In univariable analysis, induction chemotherapy before BMT had a beneficial effect on the outcome of BMT; in multivariable analysis, however, this parameter had low prognostic value and was not entered in the final Cox model. The beneficial effects of prior induction chemotherapy might be explained, in part, by the adverse effects of the intensive conditioning regimen that is usually used for patients with active disease (often untreated) at transplantation. On the other hand, patients who achieved a previous remission with chemotherapy might have a less severe disease than did others who did not respond and did not undergo transplantation. In a series of 71 patients allografted for de novo MDS or AML after MDS, Sutton et al³² observed, as did we, that intensifying the conditioning regimen worsens outcome without reducing the risk of relapse; unlike us, however, they observed in a small number of patients (17 of 71) that prior intensive chemotherapy had no significant influence on outcome. Sargur et al¹⁴ treated seven patients with therapy-related leukemia, six of whom had active disease. None of the seven patients were alive at 1 year after treatment. In contrast, Geller et al¹⁵ reported the outcome of five patients with t-AML who underwent transplantation after achieving CR: two patients died from GVHD and three remained alive in CR for more than 1 year after BMT. In another study, Longmore et al¹⁶ reported on 11 patients who underwent transplantation with active t-MDS or t-AML. Only three of them survived disease-free 3, 5, and 9 years after BMT. In 30 patients who underwent transplantation for secondary leukemia, de Witte et al²¹ found that pretreated patients who achieved CR before BMT had better outcome than did those who failed to enter CR, based on either therapy-related MDS or progression from MDS. Based on our studies and these, it seems that the best candidates for achieving good outcome are patients who have responsive disease. However, it is difficult to recommend that induction chemotherapy should be routinely used before BMT in patients with t-MDS and t-AML, because we do not know the number of patients who were not referred for transplantation as a result of complications from prior induction chemotherapy. Nevertheless, an attempt to obtain CR before BMT could be proposed in young patients with advanced t-MDS or t-AML, especially in those without poor-risk cytogenetic features.

One of the limitations of BMT is donor availability. We observed no significant difference in outcome between patients who underwent transplantation with related donors and those with unrelated donors, but the latter group was small. In agreement with our results and those reported by others,^19,37,38 we believe that alternative donors can be proposed for young patients who do not have appropriate family donors.

The most appropriate conditioning regimen remains to be clearly established. We did not find any significant influence of classical regimens on outcome even when TBI was used. However, we do not recommend, as do others,^32,39,40 intensive schedules that seem to increase toxicity without reducing the risk of relapse after BMT.

This study shows that allogeneic BMT provides a substantial chance of long-term survival and cure, especially in patients with t-MDS or t-AML who respond to chemotherapy before BMT. New approaches that are evaluated in prospective trials might further improve results in other patients.

	REFERENCES

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Submitted August 2, 1999; accepted October 19, 1999.

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