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© 1999 American Society for Clinical Oncology Allogeneic Bone Marrow Transplantation Versus Chemotherapy for the Treatment of Childhood Acute Lymphoblastic Leukemia in Second Remission: A Single-Institution StudyFrom the Department of Pediatrics, Bone Marrow Transplantation Service, and Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Farid Boulad, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; Email bouladf{at}mskcc.org
PURPOSE: A retrospective analysis of the treatment of childhood acute lymphoblastic leukemia (ALL) in second remission (CR2) was undertaken at our institution to compare the outcome and prognostic factors of patients treated with chemotherapy or allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: Seventy-five children who suffered a medullary relapse and achieved a second remission were treated with either an unmodified allogeneic HLA-matched sibling BMT after hyperfractionated total body irradiation (TBI) and cyclophosphamide (n = 38) or chemotherapy according to institutional chemotherapy protocols (n = 37). To avoid the bias of survival from the attainment of second remission in favor of BMT, the final comparative statistical analysis used the landmark approach and comprised 37 and 29 patients from the BMT and chemotherapy groups, respectively RESULTS: The disease-free survival (DFS) rate was 62% and 26% at 5 years, respectively, for the BMT and the chemotherapy groups (P = .03), with relapse rates of 19% and 67%, respectively, for these two groups (P = .01). There was an overall advantage for the BMT therapeutic approach, as compared with chemotherapy, for patients with ALL in CR2 (1) for patients with a WBC count (at diagnosis) of 20 x 109/L or higher (DFS, 40% v 0%) and those with a WBC count of less than 20 x 109/L (DFS, 73% v 35%), (2) for patients whose duration of CR1 was less than 24 months (DFS 48% v 9%) and for patients whose duration of CR1 was 24 months or longer (DFS, 81% v 37%) and (3) for patients who were initially treated with intensive regimens incorporating more than five chemotherapy agents (DFS, 57% v 20%) and for patients treated with five agents or fewer (DFS, 72% v 32%). CONCLUSION: In our single-institution series, unmodified HLA-matched allogeneic sibling transplants using hyperfractionated TBI and cyclophosphamide for patients with ALL in CR2 have resulted in superior outcome with a significantly improved probability of DFS and a lower relapse rate, as compared with those for patients treated with chemotherapy, regardless of the duration of first remission, the disease characteristics at diagnosis, or the intensity of prior treatment during first remission.
MORE THAN 70% OF patients with acute lymphoblastic leukemia (ALL) can achieve a sustained first remission with long-term disease-free survival (DFS) after treatment with chemotherapy.1-9 Unfortunately, approximately 25% of these patients will relapse. Over 80% of patients who relapse will be able to achieve a second remission (CR2) with chemotherapy.10-22 However, after the achievement of CR2, there is controversy concerning the most effective subsequent treatment: chemotherapy or allogeneic bone marrow transplantation (BMT) when an HLA-matched sibling donor is identified.23-30 Recently, Barrett et al31 published the results of a large multi-institutional comparative study that showed an overall advantage in DFS for patients treated with allogeneic HLA-matched BMT, as compared with those treated with continued chemotherapy. We report a single-institution retrospective analysis of a consecutive series of children with ALL who were treated at Memorial Sloan-Kettering Cancer Center (MSKCC) in CR2. A comparison of the two therapeutic approaches is done according to risk factors at diagnosis, duration of first remission, as well as intensity of treatment in first remission.
Patient Selection The criteria for patient selection were as follows: (1) that patients with ALL were less than 18 years of age at diagnosis and had achieved but failed to sustain a first remission; (2) that these same patients had suffered a leukemic relapse between January 1979 and October 1992; and (3) that all patients analyzed were induced successfully into CR2 with chemotherapy either at MSKCC or at a referring institution, with subsequent treatment administered at our center. All patients in the BMT group received unmodified marrow transplants after total body irradiation (TBI) and cyclophosphamide therapy. The distribution of patients in this series is shown in Fig 1. Of 54 patients with ALL in CR2 after treatment at MSKCC, six patients with HLA-matched siblings proceeded to treatment with BMT; 48 patients, including two patients with HLA-matched siblings continued to receive chemotherapy. An additional 33 patients with ALL in CR2 with HLA-matched siblings were referred from outside institutions for allogeneic BMT, bringing the total number of patients transplanted to 39. A potential area of bias that we are unable to estimate is the proportion of patients who might have been referred from outside institutions with an HLA-matched sibling for transplant but who either relapsed early in CR2 or had severe organ dysfunction that rendered them unable to receive a BMT.
In the transplant group, 38 of 39 patients had a first relapse in the bone marrow (BM). In this group, four patients presented with a combined BM and CNS relapse. Only one transplant group patient had an isolated testicular relapse. In the chemotherapy group, 37 of 48 patients had a BM relapse, including six with a combined BM and CNS relapse and one patient with BM and testicular relapse. Ten chemotherapy patients had an isolated CNS relapse, and one had an isolated testicular relapse. Because patients in CR2 after an isolated CNS or testicular relapse have a better outcome than do those who relapse with marrow disease,32-36 these patients were excluded from the final comparative analysis of the chemotherapy and BMT groups. The final two groups included 38 patients treated with BMT and 37 patients treated with chemotherapy (Fig 1). Notably, two of the 37 patients treated with chemotherapy had HLA-matched siblings but elected to continue treatment with chemotherapy. Both patients had a prolonged duration of first remission. Two other patients had siblings but did not have HLA-typing done because of financial reasons that precluded them from BMT treatment. For comparison of the chemotherapy and BMT groups, we invoked the landmark approach (see Statistical Analysis) to reduce the potential inherent advantage of the BMT group associated with survival to time of transplant, and, in the chemotherapy group, we specifically analyzed those patients who were surviving disease-free at least 3 months from the attainment of CR2. This resulted in a BMT group and a chemotherapy group that comprised 37 and 29 patients, respectively.
Patient Characteristics
Treatment Characteristics Thirty-seven patients who had an initial medullary relapse achieved a CR2 and were retreated on or according to institutional chemotherapy protocols or modified versions of these protocols. There were 28 patients who received intensive chemotherapy protocols as previously described,10,38-39 including the New York I (n = 10), New York 2 (n = 13), CNS retrieval (n = 1), Berlin-Frankfurt-Munster (n = 3), and LSA2-L2 (n = 1) protocols, and six patients who received miscellaneous intensive protocols. Three patients were treated with a standard-intensity regimen (three-drug induction, one-drug consolidation, and three- to four-drug maintenance). The median follow-up period for the chemotherapy group is shorter than that of BMT patients, with 65 months (range, 20 to 126 months).
Statistical Analysis Since some patients in the study were referred to our institution for a marrow transplant, treatment assignment was confounded by factors that occurred prior to their having entered CR2. There were four potential confounding factors considered in this analysis: (1) WBC count at diagnosis; (2) age at diagnosis; (3) administration of intensive chemotherapy in first remission; and (4) duration of the first remission. After the confounding factors were determined, an adjusted treatment comparison was made using the Cox proportional hazards model. In addition to an adjusted treatment comparison for all significant confounding factors, we used a stratified log-rank test to compare the treatments for each specific factor. Confounding risk factors at diagnosis included WBC counts of less than 20 x 109/L versus 20 x 109/L or higher. In addition, patients belonging to the high-risk group were compared with patients in the low- or average-risk groups, using the CCG criteria. The durations of first remission, using 18-month or 24-month time periods, were compared. The 36-month time period could not be evaluated because too few patients had a duration of first remission that was greater than 36 months. The intensity of the treatment received in first remission was also analyzed by two methods. Patients who received five drugs or fewer in their initial treatment in first remission were compared with patients who received more than five drugs. In addition, patients who received anthracycline and/or alkylating drugs during their initial remission induction/consolidation were compared with those who did not.
Overall Results The results and analyses are presented on the basis of the 37 patients in the BMT group and 29 patients in the chemotherapy group with follow-up periods greater than the 3-month landmark time point after their first relapse. The Kaplan-Meier estimate of the probability of DFS for the two groups of patients treated with BMT or chemotherapy is shown in Fig 2A. There was an overall advantage for the transplant group, with a DFS rate of 62% (SE = 8%) versus 26% (SE = 9%) for the chemotherapy group at 5 years (P = .03). Fig 2B represents the cause-specific probability of relapse among these two patient groups. The risk of relapse was significantly lower for the BMT group (19% v 67% for the chemotherapy group; P = .01).
Adjusted Treatment Comparison
When the two treatments were compared, the hazard ratio for chemotherapy versus BMT in this study was 2.84 (95% confidence interval, 1.78 to 3.91). The analysis compared DFS rates from CR2 for BMT versus chemotherapy, controlling for WBC count at diagnosis and the duration of first remission. The results indicate almost a threefold increase in the risk of relapse or death for the chemotherapy treatment (P < .01). A detailed comparison of the two groups follows.
Comparison of the Results of Marrow Transplantation Versus Chemotherapy for Individual Risk Factors
Patients were also classified as having low-, average-, or high-risk leukemia at diagnosis according to CCG criteria, which include age and hematologic indices at diagnosis. Results similar to those in the comparison of WBC counts were observed, with an advantage for the BMT group versus the chemotherapy patients (P = .05). Patients in the high-risk category who received a marrow transplant had a DFS rate of 47% (SE = 13%) versus 14% (SE = 11%) for high-risk patients treated with chemotherapy. For patients with low- or average-risk ALL treated with BMT or chemotherapy, the DFS rates were 73% (SE = 10%) and 37% (SE = 14%), respectively (Kaplan-Meier plots not shown). Duration of first remission. The Kaplan-Meier plots shown in Fig 4 compare the DFS rates of patients with a duration of first remission of less than 24 months versus those with durations of 24 months or longer in the two treatment groups. There was an overall advantage for the transplant patient group, as compared with the chemotherapy group, regardless of the duration of first remission (P < .01), with a DFS rate of 48% (SE = 11%) at 5 years for the BMT cohort and 9% (SE = 9%) for the chemotherapy cohort for the patients with a shorter duration of first remission and 81% (SE = 10%) and 37% (SE = 13%) for the patients with a longer duration of first remission, respectively. Similarly, significant differences were also found when we compared patients with a duration of first remission of less than 18 months to those with durations of 18 months or greater (data not shown).
Treatment intensity. We analyzed our results, comparing the intensity of treatment administered from diagnosis and initiation of first-induction therapy until first relapse. First we compared patients treated with more than five chemotherapy agents versus those who were treated with five chemotherapy agents or fewer. These agents represented the number of unique drugs used throughout treatment in first remission, regardless of the type of agent. As seen in Fig 5, for patients treated with more than five agents, the 5-year DFS rate was 57% (SE = 12%) for the BMT patients and 20% (SE = 11%) for the chemotherapy patients. These DFS rates were 72% (SE = 11%) and 32% (SE = 14%), respectively, for patients treated with five agents or fewer. The advantage of BMT versus chemotherapy was significant in both patient groups (P = .01).
Similar results were observed when we compared patients who received an alkylating drug, an anthracycline drug, or both agents during initial-induction and consolidation therapy with those who did not receive any of these drugs (P = .02). For patients who received anthracycline and/or alkylating drugs during treatment, the DFS rate was 55% (SE = 15%) for the BMT group and 24% (SE = 14%) for the chemotherapy group at 5 years. For the patients who did not receive anthracycline or alkylating drugs, the DFS rate for the BMT group was 75% (SE = 11%) versus 30% (SE = 12%) for the patients treated with chemotherapy (Kaplan-Meier plots not shown).
Analysis of the Impact of Prognostic Variables Within Each Treatment Group Similarly, a short duration of remission was associated with an inferior outcome within each treatment group. For patients treated with chemotherapy, this difference (DFS rate, 37% for the long duration of CR1 v 9% for the short duration of CR1) was due to an increased relapse rate among patients with a short first remission, whereas for the patients in the BMT group, a short first remission placed the patients at higher risk of nonleukemic mortality after BMT, with a consequent inferior DFS (81% for the long duration of CR1 v 9% for the short duration of CR1; P = .07). For transplant recipients, the relapse rates, 31% in patients with a short initial remission versus 14% for those with a longer first remission, were not significantly different. The effect of treatment intensity on the outcome of patients treated with either chemotherapy or transplantation was also examined. For the BMT patients, there was no significant difference in outcome whether patients were heavily pretreated or not (DFS rate for patients treated with five drugs or fewer v those treated with more than five drugs, 72% and 57%, respectively; DFS rate for patients who received no anthracycline or alkylating drugs v patients who received either type of drug, 75% and 55%, respectively; P = .75). For the patients treated with chemotherapy, the proportion of patients initially treated with intensive chemotherapy who relapsed after the induction of CR2 was marginally higher than that observed in patients initially treated with less intensive regimens (83% v 67%, respectively).
A long-standing controversy has focused on the place of BMT in the treatment of patients with childhood ALL in CR2 after BM relapse. Published studies evaluating different chemotherapy regimens have demonstrated a probability of achieving a CR2 of 74% to 100%. However, the long-term prognosis for such patients has been variable, with DFS rates of 3% to 42%.11-23 Most studies of chemotherapy regimens applied to the treatment of children with ALL in CR2 have differentiated patients who experienced early relapses (usually during treatment or within 18 to 36 months from diagnosis), for whom DFS probabilities of 0% to 19% have been achieved,16-19 from patients who suffered late relapses after completing therapy, for whom DFS rates of 13% to 42% have been reported.18-23 Studies involving BMT for the treatment of ALL in CR2 have recorded overall higher probabilities of DFS of 38% to 64%.41-47 However, few studies have evaluated the results of BMT in comparison with chemotherapy for patients who relapse early versus those who relapse late after initial treatment. In 1981, Johnson et al24 reported a prospective study of 45 children with ALL who achieved a CR2, of whom 21 received an HLA-matched BM graft and 24 received chemotherapy. The DFS rate reported for the transplant group was 38%, which was significantly better than the 5% DFS rate recorded for children treated with chemotherapy. Since that initial report, several additional prospective and retrospective single- and multicenter trials have examined the role of transplant versus chemotherapy in the treatment of these patients. The results of these trials are summarized in Table 3. In each of the studies, the overall rate of DFS for the transplant group exceeded that of the chemotherapy group. Differences were significant in five of six studies in which the DFS rate was examined. Five of the studies specifically evaluated the relative benefits of transplantation or chemotherapy in patients who had had a short versus long initial remission. In each of these studies, a significant advantage was identified in children with short initial remissions who subsequently received a transplant. In contrast, for patients who relapsed after a prolonged initial remission, a significant advantage for the patients who received transplants was reported in only one of the five studies in which this was examined. However, this latter retrospective study reported by Barrett et al31 evaluated very large patient groups (n = 916) with pairs of patients matched for disease features at diagnosis, including age, WBC count, leukemic immunophenotype, and initial duration of initial remission. In this study, transplanted patients whose initial remission duration was greater than 36 months achieved a 53% rate of DFS at 5 years, which was significantly better than the 32% DFS rate at 5 years observed for the chemotherapy group.
In this single-institution study, we analyzed 75 consecutive pediatric patients with ALL in CR2 treated at our center and compared the outcome of 38 patients treated with an allogeneic BMT from an HLA-matched sibling to that of 37 patients treated with chemotherapy in order to gauge the relative merits of allogeneic BM grafts when applied to patients grouped by disease features at presentation, the intensity of initial chemotherapy, and the duration of initial remission. Because our center is a referring institution for the treatment of leukemia for both therapeutic modalities, these patients were not all treated at this institution during their first remission; rather, a number of patients were referred for treatment after having relapsed, and a proportion of patients were referred after they had achieved a CR2 at other institutions. Potential areas of bias include the fact that patients might have been referred for BMT from outside institutions but were not able to achieve a CR2 or achieved a CR2 of short duration and were in relapse by the time they were ready for BMT. This issue was addressed by using an adjusted landmark approach for the statistical analysis of these results, taking into account the time from CR2 to treatment with chemotherapy or BMT. Our analysis revealed, overall, a significantly superior outcome for patients treated with BMT, with a DFS rate of 62% and a low relapse rate of 19%, as compared with a DFS rate of 26% and a relapse rate of 67% for patients treated with chemotherapy. Because risk factors at diagnosis, duration of first remission, and treatment intensity in first remission all preceded the treatment modalities chronologically, these confounding factors were studied in a Cox proportional hazards model. In this model, the age of the patients at diagnosis did not significantly influence overall outcome. However, the WBC count at diagnosis did represent an important prognostic factor. The DFS rates for patients treated with BMT or chemotherapy were 40% and 0%, respectively, for patients with WBC counts greater than or equal to 20 x 109/L at diagnosis and 73% versus 35% at 5 years, respectively, for patients with WBC counts less than 20 x 109/L. We could not study the influence of T-cell phenotype or cytogenetic abnormalities because the number of patients in groups segregated according to these features was too small for analysis. The duration of first remission was also found to be a significant factor affecting the DFS rates of patients treated with either BMT or chemotherapy. The 5-year probability of DFS for patients with a duration of first remission of less than 24 months was 48% after BMT, as compared with 9% for patients treated with chemotherapy. For patients with late relapses, these outcome results were significantly superior, with DFS rates of 81% and 37%, respectively, for patients treated with BMT and chemotherapy. Similar results were found when the 18 months' mark was used for the duration of first remission. These results are similar to those achieved in the largest comparative study by Barrett et al,31 who reported DFS rates of 29% and 14% for BMT and chemotherapy in the early-relapse patients and DFS rates of 53% and 32% for BMT and chemotherapy for the late-relapse patients. Our results confirm the recommendation that the duration of first remission should not influence the therapeutic decision of BMT versus chemotherapy, although it does reflect an important prognostic factor for the overall outcome. Recently, questions have again been raised as to the utility of allogeneic BM grafts when applied to patients who have failed to sustain first remissions after treatment with the more aggressive chemotherapeutic regimens currently in use, because such patients might be expected to have more resistant disease and/or less tolerance to the treatment intensity of BMT. For our analyses of the influence of the intensity of prior treatment on the final outcome of patients treated with chemotherapy or BMT, we adopted two criteria as indicators of prior treatment intensity: the total number of chemotherapy agents used during the initial induction consolidation and maintenance (five or fewer agents v greater than five agents) and whether patients received any alkylating drugs, anthracycline drugs, or both as part of their initial treatment. Patients treated with a BM allograft who had initially received chemotherapy regimens containing more than five drugs or who received prior treatment with alkylating drugs, anthracycline drugs, or both achieved DFS rates of 57% and 55%, respectively, as compared with 20% and 24% for patients treated with chemotherapy. For patients treated less intensively with five chemotherapy agents or fewer or without the use of alkylating drugs, anthracycline drugs, or both, the DFS rates were 72% and 75%, respectively, for the BMT group, as compared with 32% and 30%, respectively, for the chemotherapy group. Risk factors at diagnosis, duration of initial remission, and intensity of initial treatment may influence responses quite differently in patients treated with BMT, as compared with those treated with chemotherapy alone. For example, for those patients treated with chemotherapy after achieving a CR2, high initial WBC count and short duration of initial remission proved to be markers of resistant disease with a consequent increased risk of relapse. On the other hand, patients who were treated with an allogeneic BMT after achieving CR2, had low relapse rates, irrespective of the characteristics of their initial disease. Initial treatment intensity did not significantly affect the results of a BMT administered during a CR2. However, high WBC counts at presentation and short initial remission placed the patient at higher risk of peritransplant mortality. This likely reflects the fact that patients with higher initial WBC counts are at risk for shorter initial remissions. Those patients who do suffer early relapse must undergo a course of induction therapy to achieve a CR2 and thereafter undergo subsequent pretransplant cytoreduction when they have only recently recovered from the early, more intensive segments of chemotherapy administered to induce and consolidate their first remission. As a result of these intensive treatments over a relatively short time period and the added toxicity of pretransplant myeloablative therapy, the patients may be predisposed to the increased peritransplant mortality observed. Prior reports comparing the results of chemotherapy and transplantation for childhood ALL in CR2 (Table 3) have yielded DFS and relapse rates that are quite similar to those recorded in our own single-institution study for patients treated with chemotherapy who experienced either a short or long initial remission. However, in comparison with these reports, the incidence of relapse after transplant in our series is low, irrespective of the duration of first remission (overall relapse rate, 19%; relapse rate, 33% for patients with a CR1 duration of less than 24 months and 16% for patients with a CR1 duration of 24 months or greater). This low relapse rate has been achieved with a cytoreductive regimen using 1,375 to 1,500 cGy hyperfractionated TBI followed by cyclophosphamide, a regimen initially designed to increase the leukemic ablative dose of radiation while reducing toxicity to normal tissues.41,42,48 Indeed, the potential advantages of this regimen are also suggested by the overall DFS rates for our transplant group and, specifically, the DFS rates achieved by both patients whose initial remission duration was less than 24 months (45%) or was more prolonged (81%). A similarly low overall relapse rate (12%) and a sustained DFS rate of 64% have also been reported by centers at Stanford and the City of Hope when this hyperfractionated regimen of TBI was combined with high-dose etoposide rather than cyclophosphamide for preparative cytoreduction of adult patients in CR1 who received transplants for high-risk leukemia.49 We have recently used a modification of this regimen that contains hyperfractionated TBI and cyclophosphamide with thiotepa in 11 children with ALL in CR2 who were receiving transplants, using T-cell–depleted marrow from unrelated donors. This has yielded overall DFS and relapse rates of 58% and 11%, respectively.50 In conclusion, in this single-institution series, unmodified HLA-matched allogeneic sibling transplants using hyperfractionated TBI and cyclophosphamide for patients with ALL in CR2 have resulted in superior outcome with a significantly improved probability of DFS and a lower relapse rate, as compared with patients treated with chemotherapy. This advantage was consistently observed regardless of the different factors analyzed: namely, the duration of first remission and the diagnostic risk/prognostic factors. In addition, the intensity of prior treatment during first remission did not affect the superiority of outcome for patients treated with BMT.
Supported by P01 CA23766 from the National Cancer Institute and the National Institutes of Health; the Andrew Gaffney Foundation; the Lisa Bilotti Foundation; the Laura Rosenberg Foundation; and by the Vincent Astor Chair in Clinical Research to Dr. Reilly We gratefully acknowledge the expert care provided to these patients by the fellows and housestaff of Memorial Sloan-Kettering Cancer Center, as well as the nursing staff on Memorial 5 and 19.
Drs. Gillio and Brochstein are currently affiliated with Tomorrows Children's Institute, Hackensack University Medical Center, Hackensack, NJ.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
