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© 2001 American Society for Clinical Oncology Hematopoietic Stem-Cell Transplantation for Treatment-Related Leukemia or MyelodysplasiaFrom the Clinical Research Division of the Fred Hutchinson Cancer Research Center, and Department of Medicine, University of Washington School of Medicine, Seattle, WA. Address reprints requests to Robert P. Witherspoon, MD, Fred Hutchinson Cancer Research Center, Clinical Research Division, 1100 Fairview Ave North, FM-804, Seattle, WA 98109-1024; email: rwithers{at}fhcrc.org
PURPOSE: This report describes results of related or unrelated hematopoietic stem-cell transplants in 111 patients with treatment-related leukemia or myelodysplasia performed consecutively at the Fred Hutchinson Cancer Research Center between December 1971 and June 1998, and identifies patient and treatment characteristics associated with survival and relapse. PATIENTS AND METHODS: At transplantation, 56 patients had treatment-related secondary acute myeloid leukemia (AML), 15 had refractory anemia with excess blasts in transition (RAEB-T), 23 had refractory anemia with excess blasts (RAEB), 15 had refractory anemia (RA), and two had refractory anemia with ringed sideroblasts (RARS). Conditioning regimens were total-body irradiation (TBI) and chemotherapy for 60 patients, busulfan (BU) 14 to 16 mg/kg and cyclophosphamide (CY) 120 mg/kg (BUCY) for 27 patients, BU targeted to 600 to 900 ng/mL plasma steady-state concentration with 120 mg/kg CY (BUCY-t) for 22 patients, and miscellaneous chemotherapy for two patients. The donors were HLA-identical or partially identical family members for 69 patients and unrelated donors for 42 patients. RESULTS: The 5-year disease-free survival was 8% for TBI, 19% for BUCY, and 30% for BUCY-t (P = .006). The 5-year cumulative incidence of relapse was 40% for secondary AML, 40% for RAEB-T, 26% for RAEB, and 0% for RA or RARS (P = .0009). The 5-year cumulative incidence of nonrelapse mortality after TBI was 58%; after BUCY, 52%; and after BUCY-t, 42% (P = .02). CONCLUSION: Patients at risk for treatment-related leukemia or myelodysplasia should be followed closely and be considered for stem-cell transplantation early in the course of myelodysplasia using conditioning regimens such as BUCY-t designed to reduce nonrelapse mortality.
TREATMENT-RELATED secondary acute myeloid leukemia (AML) and secondary myelodysplasia (MDS) are becoming more common problems as successful treatment for cancer and other diseases produces more long-term survivors. Unfortunately, the prognoses for treatment-related AML and MDS are poor. Chemotherapy to induce a remission has been complicated by prolonged leukopenia, infection, and a low likelihood of achieving a complete remission. Once achieved, the remissions are of short duration.1,2 Combination chemotherapy with cytarabine and fludarabine, or treatment with topotecan, shows promise to increase the remission rate.3,4 However, long-term survival is not likely for patients with treatment-related AML and MDS. Hematopoietic stem-cell transplantation (HSCT) from a suitably matched family member or unrelated donor offers the possibility of cure, but such cures are achieved in less than one third of patients because of high relapse rates and significant nonrelapse mortality.5,6 The timing of transplantation is controversial.7 Although transplantation after successful remission induction appears to improve long-term disease-free survival for patients with de novo acute leukemia, the lower remission rates in patients with treatment-related disease mean that many patients may never recover sufficiently to be able to receive transplant therapy. On the other hand, transplantation in untreated relapse is associated with a high relapse rate. We previously reported a nonrandomized study showing no statistically significant difference in outcome whether patients with secondary AML were transplanted as initial therapy or after induction chemotherapy.5 We undertook this review with the aim of identifying pre- and posttransplant patient and treatment characteristics that may be associated with better long-term disease-free survival for treatment-related AML or MDS.
Patients The records of 111 patients with treatment-related secondary leukemia or myelodysplasia transplanted consecutively at the Fred Hutchinson Cancer Research Center between December 1971 and June 1998 were reviewed with follow-up to June 11, 1999. The patient characteristics are listed in Table 1 . Information on treatment of secondary AML or MDS before transplantation was available on 69 patients, 58 of whom had transfusions and supportive care, and 11 had hydroxyurea, low-dose cytarabine, or induction chemotherapy that had no effect on the disease. Conditioning for grafting consisted of 9.6 to 15.75 Gy total-body irradiation (TBI) and cyclophosphamide (CY) 120 mg/kg,8,9 busulfan (BU) 14 to 16 mg/kg and CY 120 mg/kg (BUCY),10,11 BU given to target the concentration in the plasma at steady-state to between 600 and 900 ng/mL with 120 mg/kg CY (BUCY-t),12,13 and miscellaneous regimens.14-17 Busulfan dosing was targeted by measuring the BU plasma level at predose, 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, and 6 hours after the first dose; and at predose, 1 hour, 2 hours, 4 hours, and 6 hours after doses five and nine of the 16-dose regimen. Doses three through six, seven through 10, and 11 through 16 were adjusted on the basis of the concentrations calculated from the area under the curve.12,13 One patient each received 200 mg/kg CY,18 or BCNU, CY, and etoposide.19 The donors were HLA-identical or partially identical family members for 69 patients, and HLA-identical or partially identical unrelated donors for 41 patients; one patient was transplanted with unrelated umbilical cord blood. The prophylactic treatment for acute graft-versus-host disease (GVHD) used various regimens of methotrexate,20 cyclosporine,21 FK506,22 or combinations of these23,24 over the 28 years of cases reviewed. Treatment of acute GVHD consisted of cyclosporine, corticosteroids, or antithymocyte globulin.25,26
Statistical Methods The overall probabilities of survival and disease-free survival were calculated using the method of Kaplan and Meier.27 Because 32 of the 34 patents who relapsed died of their disease, the overall survival and the disease-free survival are very similar. Therefore, only the disease-free survival will be presented. The incidences of relapse and nonrelapse mortality were estimated from the cumulative incidence curves at 1 and 5 years. Cox regression analysis was used to estimate hazard ratios relative to a reference group. Multivariate analyses of the various predictors were performed using a forward selection procedure with the Cox regression model. For purposes of this analysis, the cytogenetic abnormality risk categories included the group of patients whose chromosomal status was unknown.
The median time to achieve a granulocyte count more than 0.5 x 103/µL for at least 3 days was 19 (range, eight to 29) days, and platelets to more than 20 x 103/µL for at least 7 days without transfusion was 21 (range, seven to 80) days. The median time and probability to develop grade 2 or greater acute GVHD was 20 days and 65%, respectively. Overall, 22 patients were alive at the date of last contact, 15 of whom had chronic GVHD and seven of whom did not. Two of these have relapsed but are still alive. Eighty-nine patients died. The causes of death are listed in Table 2. Although acute GVHD was the primary cause of death in five patents, it was a coexisting condition contributing to mortality in four of the patients with Aspergillus infection, two patients with bacterial infection, one patient with hepatic veno-occlusive disease, two patients with multiorgan failure, and one patient with cardiomyopathy (data not shown).
Multivariate Analyses Table 3 lists the results of the multivariate analyses. The factor most significantly affecting disease-free survival was the preparative regimen (P = .006). Patients receiving BUCY-t had the best disease-free survival ( Fig 1). Stage of disease was not significant for disease-free survival (P = .5). The incidence of relapse was strongly affected by the stage of disease at transplant (P = .0009). None of the patients with refractory anemia (RA) or RA with ringed sideroblasts (RARS) stage relapsed ( Fig 2). A marginal effect on relapse was seen with longer disease duration from diagnosis to transplantation (P = .03) and with low cytogenetic risk abnormalities at time of transplantation (P = .07) ( Fig 3). The nonrelapse mortality was marginally significantly affected by the preparative regimen (P = .09) and the year of transplantation (P = .08). Patients conditioned with BUCY-t had the lowest nonrelapse mortality ( Fig 4). Because there were more nonrelapse deaths than relapses, the conditioning regimen became the strongest predictor of disease-free survival.
Univariate Analysis Table 4 lists the univariate analyses of the probability of disease-free survival, cumulative incidences of relapse, and nonrelapse mortality at 1 and 5 years after transplantation for the entire group with respect to the stage of MDS at transplant, conditioning regimen, cytogenetic risk group, duration of disease from diagnosis to transplant, and transplant year. The hazard ratios are shown.
The 5-year disease-free survival for the entire group was 16% and by conditioning regimen was 8% for a regimen containing TBI, 19% for BUCY, and 30% for BUCY-t (P = .006) (Fig 1 and Table 4). By stage of MDS the 5-year disease-free survival was 9% for secondary AML, 18% for RA with excess blasts in transition (RAEB-T), 17% for RA with excess blasts (RAEB), and 42% for RA and RARS (P = .08). By stage of MDS, the 5-year cumulative incidence of relapse for the entire group was 32%, 40% for secondary AML, 40% for RAEB-T, and 26% for RAEB; no patient with RA or RARS relapsed (P = .0009) (Fig 2 and Table 4). By cytogenetic risk level at time of transplantation, the cumulative incidence of relapse at 5 years was 7% for patients with low risk, 33% for intermediate risk, and 40% for high risk (Fig 3 and Table 4) (P = .02). The cumulative incidence of relapse at 5 years by disease duration between diagnosis of MDS and transplantation was 36% for 0 to 6 months, 40% for 7 to 12 months, and 13% for 13 to 24 months; no patient with disease duration of more than 24 months relapsed (P = .03). The cumulative incidence of nonrelapse mortality at 5 years for the entire group was 53%, and by conditioning regimen for those containing TBI was 58%; BUCY, 52%; and BUCY-t, 42% (Fig 4 and Table 4)(P = .02). The cumulative incidence of nonrelapse mortality at 5 years by stage of disease was 51% for secondary AML, 42% for RAEB-T, 57% for RAEB, and 58% for RA or RARS (P = .90). Among nonrelapse mortality there was a suggestion for less organ failure–related mortality or infection-related mortality with BUCY-t than with TBI-containing conditioning regimens (data not shown). A similar sparing effect on nonrelapse mortality was seen in the period more than 1995 when BUCY-t was used (P = .02) (Table 4). There were no significant differences by age of recipient, related or unrelated donor (Table 4 and Figs 5, 6, and 7), primary diagnosis (Hodgkin’s disease, non-Hodgkin’s lymphoma, breast carcinoma, or other diagnosis), or treatment of the primary disease (chemotherapy, radiotherapy, chemoradiotherapy, autologous transplant, or other treatment) for disease-free survival, relapse, or nonrelapse mortality.
This study was undertaken to identify patient and treatment characteristics that lead to better disease-free survival among patients given family member or unrelated donor HSCT for treatment-related AML or MDS. Previous reports of results of HSCT for secondary MDS from this and other centers suggest a worse prognosis for secondary AML or MDS compared with results in patients with primary disease.5,6,10,28,29 We have focused this report on treatment-related AML and MDS because its prevalence is increasing and, therefore, it is increasingly important to identify ways to improve the treatment. Given the retrospective nature of this analysis, there are a number of factors that could contribute to bias in our results. Nevertheless, the relatively large number of patients included in the study and their treatment at a single center argue that the results may be useful at least for designing hypotheses that can then be further tested. The most important observations on disease-free survival from this study are that transplantation earlier in the disease course appeared to reduce the risk of relapse, and that use of targeted BU in the regimen improved outcome by reducing nonrelapse mortality. Relapse was associated with several factors. Relapse correlated strongly with stage of disease at transplant (P = .0009). Similar results associating stage of disease with posttransplant relapse rates have been seen in primary MDS patients.10,28,30 Duration of disease from diagnosis to HSCT was also significantly linked to relapse rates. Somewhat surprisingly, those with longer delay to HSCT had lower relapse rates (multivariate P = .03). The most likely explanation for this association is that most patients with long delays from diagnosis to transplant had less aggressive subtypes of secondary MDS. The International Prognostic Scoring System (IPSS) was developed to evaluate primary MDS, and treatment-related MDS or AML cases were specifically excluded in development of the IPSS.31 We did not attempt an assessment by IPSS criteria because the data at the time of diagnosis of secondary MDS or AML were not consistently available on the patients referred to this center over the time period of the study. However, the cytogenetic risk levels used in the IPSS, but determined at the time of transplant, showed a trend for a lower relapse rate after transplant in patients with low-risk cytogenetic abnormalities (multivariate P = .07). Because the RA and RARS stages so strongly influenced relapse after transplantation, we performed the analysis of risk to relapse with and without the inclusion of these patients. When RA and RARS patients were excluded, the remaining RAEB, RAEB-t, and secondary AML patients with low-risk cytogenetic abnormalities had lower relapse rates than patients with intermediate- or high-risk cytogenetic abnormalities (multivariate P = .06, data not shown). These trends also argue for transplantation earlier in the disease evolution, if possible, when chromosomes are normal or low-risk abnormalities are present. Reduction in nonrelapse mortality was significantly associated with the conditioning regimen of BUCY-t in the univariate analysis (P = .02) (Table 4). There was lower nonrelapse mortality in the period after 1995 when the BUCY-t regimen was in use (univariate P = .02). Besides instituting use of targeted BU, use of fluconazole for fungal prophylaxis and ganciclovir for cytomegalovirus prophylaxis became routine during this period. Our data suggest that both the preparative regimen change and changes in supportive care had some influence on outcome because, in the multivariate analysis, both transplant year and preparative regimen showed trends influencing nonrelapse mortality. One of the aims of targeting BU was to reduce liver and pulmonary complications. The univariate analysis also showed a trend for reduction in organ failure–related mortality with BUCY-t. There was also a trend for reduced infection-related mortality with BUCY-t. In contrast, other causes of nonrelapse mortality such as death from acute or chronic GVHD, secondary cancer, or CNS hemorrhage were not associated with the conditioning regimen. It appears, therefore, that the strategy of adjusting BU dosing in the conditioning regimen to control toxicity had an important effect on nonrelapse mortality that translated to better disease-free survival. Similar strategies to reduce conditioning toxicity should be explored, such as targeted therapy with radioisotopes32 or reduction in side effects of irradiation possibly through protective agents such as amifostine. There was no evidence that disease-free survival, relapse, or nonrelapse mortality were affected by the characteristics of the primary diagnosis, or by the treatment of the primary disease with chemotherapy, chemoradiotherapy, radiotherapy, autologous transplantation, or other modalities. In particular, patients with aplastic anemia did not fare better, and patients with secondary MDS after a previous autologous transplant did not do worse. However, the numbers of aplastic anemia or previous autologous transplant patients in this data set are small. Of interest, there were no significant differences in disease-free survival, relapse, or nonrelapse mortality by related or unrelated donor, suggesting that the outcomes for these two groups were quite similar. The dilemma for physicians recommending therapy for treatment-related MDS lies in the risk of mortality after transplantation balanced against the projected survival when secondary MDS is initially diagnosed. Results of transplantation are better for those transplanted earlier at the RA or RARS stage, but those patients have had a high risk of nonrelapse mortality early after transplantation. Those who wait, or otherwise cannot be transplanted earlier because they present in the RAEB-t or secondary AML stages, have a high risk of mortality from both relapse and nonrelapse causes. The data presented here suggest that the conditioning regimen can affect nonrelapse mortality, and the best results are achieved by targeting BU to reduce nonrelapse mortality. Additional measures are needed. A retrospective review of pretransplant induction-type therapy for treatment-related leukemia did not show improvement in posttransplant outcome,5 and there was no effect on the disease of 11 patients in this report who had chemotherapy treatment of secondary AML or MDS before the transplant. New approaches such as low-dose conditioning regimens to establish mixed chimerism to enhance GVHD and its graft-versus-leukemia effect as currently tested in patients with chronic lymphatic leukemia, chronic myeloid leukemia, and low-grade lymphoma need to be investigated.33-35 At the present time, however, donor HSCT is the only treatment that has the potential to cure treatment-related MDS or AML. We interpret the data in this report to suggest that patients at risk to develop treatment-related MDS should be observed for the early changes of MDS. Transplantation from a suitably matched family member or an unrelated donor should at least be considered in the early stages of MDS using regimens that result in lower nonrelapse mortality, because the results of early transplantation are better than those of transplantation later in the course of the disease.
Supported in part by grant nos. HL36444 of the National Heart, Lung and Blood Institute; CA18029, CA18221, CA15704, and N01-CP51027 of the National Cancer Institute; AI33484 of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, Bethesda, MD; and the Gabrielle Rich Foundation. We thank Helen Crawford for technical skills in the preparation of this manuscript.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
