Allogeneic bone marrow transplantation for children with acute lymphoblastic leukemia in first remission: a cooperative study of the Groupe d'Etude de la Greffe de Moelle Osseuse

Thirty-two children ranging in age from 1.5 to 16 years with poor-prognosis acute lymphoblastic leukemia (ALL) were treated with myeloablative immunosuppressive therapy consisting of cyclophosphamide (CPM) and total body irradiation (TBI) followed by allogeneic bone marrow transplantation (BMT) while in first complete remission (CR). The main reasons for assignment to BMT were WBC count greater than 100,000/microL, structural chromosomal abnormalities, and resistance to initial induction therapy. All children were transplanted with marrow from histocompatible siblings. Twenty-seven patients are alive in first CR for 7 to 82 months post-transplantation (median, 30 months). The actuarial disease-free survival rate is 84.4% (confidence interval, 7.2% to 29%) and the actuarial relapse rate is 3.5% (confidence interval, 0.9% to 13%). Four patients died of transplant-related complications, 16 developed low-grade acute graft-v-host disease (GVHD), and six developed chronic GVHD. The very low incidence of relapse (one of 28 long-term survivors) precluded the determination of the prognostic significance of the different poor-outcome features. Moreover, two infants treated with busulfan, CPM, and cytarabine (Ara-C) relapsed promptly in the marrow. In summary, as a means of providing long-term disease-free survival and possible cure, BMT should be considered for children with ALL presenting poor-prognostic features, particularly certain chromosomal translocations [t(4;11), t(9;22)], very high WBC counts, notably if associated with a non-T immunophenotype, and, perhaps, a poor response to initial therapy with corticosteroids (CS), or infants less than 6 months of age.     

Autologous bone marrow transplantation in acute myeloid leukemia in first remission: results of a Dutch prospective study

Recent investigations have suggested a role for marrow ablative chemotherapy and radiotherapy given with autologous bone marrow transplantation (auto-BMT) in the treatment of acute myeloid leukemia (AML), but prospective studies have not been reported. We assessed the comparative values of auto-BMT and allogeneic marrow transplantation (allo-BMT) in 117 15- to 60-year-old consecutive patients (median, 43 years) with AML following remission-induction therapy. In 32 cases of the 90 (77%) complete responders, auto-BMT (nonpurged) was undertaken at a median of 3.8 months and in 23 eligible cases human leukocyte antigen (HLA)-matched allo-BMT occurred at 3.0 months after attainment of remission. Thus, nearly 60% of complete responders had access to transplantation, the others being withdrawn because of relapse, refusal, or other causes. Median time of regeneration to neutrophils 0.5 x 10(9)/L and platelets 20 x 10(9)/L were 39 and 63 days following auto-BMT versus 21 and 19 days after allo-BMT, respectively. AML relapse was the predominant cause of failure after auto-BMT (17 of 32) and procedure-related death was seen in three of 32 patients. The actuarial rates of relapse at 3 years are 60% (auto-BMT) and 34% (allo-BMT) (log-rank, P = .03). Patients treated with auto-BMT and allo-BMT have an overall survival of 37% and 66% at 3 years posttransplant, respectively (P = .05). Relapse-free 3-year survival rates are 35% and 51%, respectively (P = .12). Survival of the nongrafted complete responders is less than 10%. This study shows that allo-BMT in adult patients with AML in first complete remission (CR) results in more rapid hematopoietic reconstitution, is followed by fewer recurrences, and provides better survival than auto-BMT.     

Relevance of bone marrow cell dose on allogeneic transplantation outcomes for patients with acute myeloid leukemia in first complete remission: results of a European survey.

PURPOSE: Many attempts have been made to improve the results of allogeneic bone marrow transplantation (alloBMT) for patients with acute myeloid leukemia (AML) in first complete remission (CR1). Bone marrow cell dose has been reported to be an important factor in alloBMT; however, its true impact on relapse incidence (RI), leukemia-free survival (LFS), and nonrelapse mortality (NRM) in a large cohort of patients is unknown. PATIENTS AND METHODS: From January 1992 to December 1999, 572 bone marrow transplantation recipients reported to the European Blood and Marrow Transplantation (EBMT) registry underwent allografting from an HLA-identical sibling donor with an unmanipulated bone marrow for AML in CR1. RESULTS: The median number of nucleated cells (NCs) infused was 2.6 x 10(8)/kg. Estimated 5-year NRM, LFS, and RI for patients receiving more or less than 2.6 x 10(8) NCs/kg were, respectively, 18% +/- 5% v 30% +/- 5% (P =.001), 68% +/- 3% v 46% +/- 3% (P <.00001), and 14% +/- 4% v 24% +/- 5% (P =.004). The association of cell dose with the above outcomes was confirmed in multivariate analyses for NRM (relative risk [RR], 0.53; P =.0007), for LFS (RR, 0.53; P =.00008), and for RI (RR, 0.57; P =.02). The cell dose was also an important factor for neutrophil (RR, 0.76; P =.009) and platelet (RR, 0.77; P =.03) recoveries; however, it did not statistically influence the incidence of acute graft-versus-host disease. CONCLUSION: This study shows that marrow cell dose is one of the most important factors influencing relapse, NRM, and LFS after alloBMT for patients with AML in CR1. Therefore, increasing the marrow cell dose should substantially improve the survival of these patients.     

Early myelodysplastic syndrome after allogeneic bone marrow transplantation for acute myeloid leukemia

A 19-year-old male with de novo acute myeloid leukemia (AML) in complete remission received a bone marrow transplant from a HLA-matched donor. Because of major incompatibility for ABO blood type, bone marrow mononuclear cells of the donor were infused after conditioning including total body irradiation (TBI). Engraftment was confirmed on day +23. On day +91, recipient ABO blood genotype was detected in burst forming-unit erythroid (BFU-E) using polymerase chain reaction. Thereafter, myelodysplastic syndrome (MDS) of recipient origin rapidly developed and progressed into a chronic myelomonocytic leukemia-like disorder. An association between MDS and TBI is suggested.     

Meta-analysis of autologous bone marrow transplantation versus chemotherapy in adult patients with acute myeloid leukemia in first remission

In the present study, we have conducted a meta-analysis comparing autologous bone marrow transplantation (ABMT) and intensive chemotherapy in adult acute myeloid leukemia (AML) patients in first remission. Combined results of the six appropriate randomised controlled studies indicate that ABMT had no advantage over chemotherapy or no further treatment concerning death rate (overall rate ratio (RR)-0.95, 95% CI, 0.81-1.11), while was superior to chemotherapy concerning event rate (overall RR--0.82, 95% CI, 0.71-0.94). In conclusion, ABMT did not improve survival but it improved event-free survival (EFS) when compared with chemotherapy or no further treatment in patients with AML in first complete remission.     

Comparison of two total body irradiation regimens in allogeneic bone marrow transplantation for acute non-lymphoblastic leukemia in first remission

Between November 1976 and December 1987, 84 patients with newly diagnosed acute non-lymphoblastic leukemia who had achieved complete remission underwent non T-cell depleted allogeneic bone marrow transplantation from Human Leukocyte Antigen-Mixed Lymphocyte Culture (HLA-MLC) matched sibling donors. The first 36 patients (November 1976-June 1983) were prepared with cyclophosphamide, 60 mg/kg/day, IV for 2 days and single fraction total body irradiation with 750 cGy at a dose rate of 26 cGy/minute (Group I). The next 48 patients (July 1983-December 1987) were prepared with similar chemotherapy, but received hyperfractionated total body irradiation with total 1320 cGy, 165 cGy twice a day at a dose rate of 10 cGy/minute (Group II). Patient characteristics between these two groups are similar except for the significantly older age distribution in Group II. Median follow-up of Groups I and II are 8 years and 11 months and 2 years and 3 months, respectively. The Kaplan-Meier relapse-free survival, survival, and relapse rates at 3 years are 56, 58, and 19% in Group I and 69 (p = 0.22), 77 (p = 0.07), and 10% (p = 0.37) in Group II. There is no difference in the incidence of interstitial pneumonitis, viral or idiopathic, engraftment rate, or incidence of graft versus host disease (GVHD) between these two groups. The fractionated total body irradiation treated group had significantly less nausea and vomiting. Multivariate analysis shows that total body irradiation regimen is not a significant factor in regard to relapse rate, relapse-free survival, and survival.     

Therapy for childhood acute myeloid leukemia: Role of allogeneic bone marrow transplantation

Acute myeloid leukemia (AML) has one of the lowest survival rates of childhood cancers. The first significant improvement in AML therapy started with the introduction of the now standard regimen of 3 days of anthracyclines and 7 days of cytarabine (Ara-C), the so-called 3+7 combinations. Several different therapeutic approaches have been taken in attempts to improve the outcome, including intensification of therapy both for remission induction and in the postremission phase. Intensification of postremission therapy included multiple courses of high-dose chemotherapy and/or myeloablative therapy followed by stem-cell rescue from either allogeneic or autologous sources. Furthermore, risk-tailored therapy is now possible, by cytogenetic risk stratification, promptness of remission induction, and identification of distinct clinical subgroups such as children with Down syndrome. This approach is rapidly changing potential therapeutic strategies for children with AML. It is in this changing mileu that we address the proper role of stem-cell transplantation, a modality that is changing (like chemotherapy) with expanding stem-cell sources and approaches to decrease transplant-related toxicity.     

Allogeneic marrow transplantation during untreated first relapse of acute myeloid leukemia.

PURPOSE: The purpose of this report was to review the Seattle experience in bone marrow transplantation (BMT) for acute myeloid leukemia (AML) during untreated first relapse. PATIENTS AND METHODS: Through 1990, 126 patients were transplanted during untreated first relapse of AML. Several preparative regimens were used, two of which involved more than 20 patients. Regimen 1 (29 patients) consisted of cyclophosphamide (CY) 120 mg/kg and 15.75 Gy of fractionated total-body irradiation (TBI) with methotrexate (MTX) given intermittently during a 102-day period to prevent graft-versus-host disease (GVHD). Regimen 2 (22 patients) consisted of the same CY and TBI treatment and a combination of MTX and cyclosporine (CSP) for GVHD prophylaxis. The remaining 75 patients were treated with 17 other transplant regimens. Outcome was compared for patients who were treated with regimen 1, regimen 2, and any other regimen. RESULTS: The 5-year probabilities of relapse-free survival (RFS), relapse, and nonrelapse mortality for 126 patients were .23, .57, and .44, respectively. With regimen 1, relapse (.26) was significantly less than for regimen 2 (.70; P = .004) or any other regimen (.76; P = .004). Regimen 1 patients developed more acute GVHD (.67) than regimen 2 patients (.26; P = .02) or patients on other regimens (.41; P = .02), and had increased nonrelapse mortality. Nevertheless, regimen 1 patients had a significantly higher 3-year RFS (.38) than those treated with regimen 2 (.18; P = .04) or any other regimen (.20; P = .05). CONCLUSIONS: For patients who received 120 mg/kg CY and 15.75 Gy TBI, relapse incidence was less and survival was better after GVHD prophylaxis with MTX alone than after a combination of MTX and CSP, despite a significantly higher incidence of acute GVHD. The results of treatment with regimen 1 justify future studies of the optimal timing of allogeneic BMT in the treatment of patients with AML.     

Modern trends in bone marrow transplantation for acute myeloid and acute lymphoblastic leukemia.

A greater understanding of the underlying mechanisms of hematopoiesis and leukemogenesis in the clinical management of acute myeloid and lymphoblastic leukemia has led to an improvement in survival from what were invariably fatal diseases. Bone marrow transplantation is increasingly becoming an accepted form of therapy for acute myeloid leukemia and acute lymphoblastic leukemia in certain situations. This review seeks to address some of the recent advances and controversies including whether bone marrow transplantation is more efficacious than modern intensive chemotherapy, the role of autologous bone marrow transplantation and matched-unrelated donor transplants, the graft-versus-leukemia effect, and the role of purging in autologous bone marrow transplantation. Furthermore, advances in supportive therapy including the introduction of hematopoietic growth factors is critically evaluated. Finally, the appropriate timing and role of bone marrow transplantation is discussed in the context of previous ongoing and future clinical trials.     

Autologous hematopoietic stem-cell transplantation for children with acute myeloid leukemia in first or second complete remission: a prognostic factor analysis.

PURPOSE: To determine prognostic factors correlated with outcomes after autologous hematopoietic stem-cell transplantation (HSCT) in children with acute myeloid leukemia (AML). PATIENTS AND METHODS: We studied 219 children who received autologous HSCT for AML in first complete remission (CR) and 73 children in second CR and who were reported to the Autologous Blood and Marrow Transplant Registry. Among 29 of 73 patients who underwent transplantation in second CR, duration of first CR was > or = 12 months. RESULTS: Three-year cumulative incidences of relapse were 37% (95% CI, 31% to 44%), 60% (95% CI, 41% to 74%), and 36% (95% CI, 20% to 53%) for children in first CR, second CR after a short (< 12 months) first CR, and second CR after a long (> or = 12 months) first CR, respectively. Corresponding 3-year probabilities of leukemia-free survival were 54% (95% CI, 47% to 60%), 23% (95% CI, 10% to 39%), and 60% (95% CI, 42% to 75%). In multivariate analyses, risks of relapse, mortality, and treatment failure (relapse or death, inverse of leukemia-free survival) were higher for patients in second CR after a short first CR than for the other two groups. Transplant-related mortality, treatment failure, and overall mortality rates were higher in older (> 10 years) children. CONCLUSION: Duration of first CR seems to be the most important determinant of outcome. Results in children who experience treatment failure with conventional chemotherapy support the use of autologous transplantation as salvage therapy if such patients achieve a subsequent CR.     

Allogeneic bone marrow transplantation in adults with Burkitt's lymphoma or acute lymphoblastic leukemia in first complete remission

The prognosis of adults with Burkitt's lymphoma is very poor and depends on initial CNS and/or bone marrow involvement. We report results in nine adult patients with CNS (n = 9) and/or bone marrow involvement (n = 7) treated in first complete remission (CR) with allogeneic bone marrow transplantation (BMT). CNS treatment before the conditioning regimen consisted of cranial irradiation at 15 Gy (n = 8) and intrathecal chemotherapy (n = 9). The conditioning regimen included cyclophosphamide and total body irradiation (TBI) in a single dose. No postgraft CNS prophylaxis was administered. At the present time, seven patients are alive and disease-free at 18, 23, 44, 47, 54, 54, and 59 months. Two patients died at 14 and 7 months from transfusion-related acquired immune deficiency syndrome and bacterial septicemia and were disease-free at the time of their death. These preliminary results should encourage the use of BMT. A prospective randomized trial is warranted to further specify and investigate the advantages of allogeneic BMT versus conventional chemotherapy.     

Allogeneic bone marrow transplantation in a program of intensive sequential chemotherapy for children and young adults with acute nonlymphocytic leukemia in first remission

Eighty-seven consecutive children and young adults with acute nonlymphocytic leukemia (ANLL) were treated uniformly with induction chemotherapy based on daunorubicin and cytarabine (ara-C), with the addition of etoposide (VP-16) and azacytidine (5-Az) for refractory patients. Of the 65 patients who entered complete remission, 42 were eligible for assessment of response to intensive chemotherapy consisting of four pairs of drugs administered in sequential fashion. Nineteen others with available histocompatibility locus antigen (HLA)-compatible donors were assigned to receive allogeneic bone marrow transplants within 16 weeks from their dates of complete remission. Durations of continuous complete remission (CCR) in the two groups were not significantly different at a median follow-up time of 6 years (P = .30 by log-rank analysis). Kaplan-Meier estimates of CCR probabilities (+/- SE) at 6 years were 43% +/- 13% (transplantation) and 31% +/- 7% (sequential chemotherapy). Postremission failures in the sequential chemotherapy group resulted from bone marrow relapse in 23 of 29 patients (79%), whereas in the transplantation group, failures were equally divided between marrow relapse and transplantation-related complications of graft-versus-host disease (GVHD) or infection due to the immunosuppressive effects of ablative chemotherapy. Comparison of hematologic remission curves indicated a significant advantage for marrow transplantation in terms of systemic leukemia control (P = .06). Thus, in programs of intensive chemotherapy of the type described here, allogeneic marrow transplantation should be seriously considered as alternative therapy for patients in first remission who have an HLA-matched sibling donor, provided that effective methods for control of transplant-related complications are available.     

Radiation-free preparation for allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia.

PURPOSE: The study was undertaken to investigate the effectiveness of allogeneic bone marrow transplantation from HLA-identical siblings after preparation with busulfan and cyclophosphamide in adults with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Thirty-nine patients aged 15 to 42 years underwent transplantation at three different centers from November 1984 through November 1990. All patients received 16 mg/kg busulfan and 120 mg/kg cyclophosphamide as preparative therapy. Cyclosporine plus methotrexate or cyclosporine plus corticosteroids with or without methotrexate were given for prevention of graft-versus-host disease (GVHD). RESULTS: Twelve patients died of treatment-related complications, 12 patients relapsed, and 15 patients are leukemia-free survivors. For 27 patients in group 1 (first remission, second remission, first relapse), the estimated leukemia-free survival (LFS) rate is 42.3% (95% confidence interval [CI], 22.9% to 71.7%) at 3 years. For 12 patients with more advanced disease (group 2), the 1-year LFS rate is 13.5% (95% CI, 0% to 37.1%). Chronic GVHD occurred at an estimated incidence of 63.3% and developed significantly more frequently among patients who received corticosteroids for prevention of acute GVHD. Chronic GVHD was associated with a significantly lower incidence of relapse and with improved LFS rates. CONCLUSION: LFS rate in this study is comparable to that obtained with radiation-containing regimens; however, the effectiveness of this preparative regimen in ALL requires further study.     

Successful treatment of acute myeloid leukemia beyond first remission with autologous bone marrow transplantation using busulfan/cyclophosphamide and unpurged marrow: the British autograft group experience

The results in 34 adult patients with acute myeloid leukemia (AML) who have undergone autologous bone marrow transplantation (ABMT) using busulfan and cyclophosphamide (Bu/Cy) in 12 United Kingdom (UK) centers have been analyzed. There were 19 females and 15 males; median age was 40 years (range, 21 to 62 years). Nine patients were in first relapse; 25 were in second remission. The median time of first remission for the whole group was 11.5 months (range, 1 to 56 months). All the patients in first relapse and six patients in second remission received first remission marrow. The leukemia-free survival (LFS) for the patients in first relapse was 33%, with a median follow-up of 20 months. The LFS for the patients in second remission was 48% with a median follow-up of 26 months. The length of second remission exceeds the length of first remission in 14 patients. Considerable toxicity with hemorrhagic cystitis (four patients; none fatal), venoocclusive disease (four patients; one fatal), pneumonitis (four patients; one fatal), intracranial hemorrhage (two patients; two fatal) has occurred. There have been four procedure-related deaths (12%). Hematologic recovery was satisfactory for neutrophils (median time to 0.5 x 10(9)/L, 22 days [range, 11 to 101 days]), but very slow for platelets (median time to 50 x 10(9)/L, 62 days [range, 15 to 1,080 days]). This study suggests that the use of Bu/Cy with ABMT for patients beyond first remission in AML compares favorably with chemotherapy, and although the procedure-related mortality is acceptable, it is associated with protracted platelet recovery.     

Efficacy of allogeneic hematopoietic stem cell transplantation depends on cytogenetic risk for acute myeloid leukemia in first disease remission: a metaanalysis

BACKGROUND: The efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) from a human leukocyte antigen-identical sibling donor remains controversial for patients with acute myeloid leukemia (AML) in first complete disease remission (CR1). Because the karyotype identified at diagnosis is the most relevant prognostic factor for AML, it should be possible to assess the efficacy more accurately on the basis of cytogenetic risk. METHODS: The authors performed a metaanalysis of five studies, which employed both natural randomization based on donor availability and intention-to-treat analysis, with overall survival as an outcome of interest. Metaregression analysis was then performed to identify the efficacy for patients stratified into the favorable, intermediate, and poor cytogenetic risk groups. RESULTS: For the entire cohort, there was a statistically significant advantage with allo-HSCT in terms of overall survival with a summary hazard ratio of 1.15 (95% confidence interval, 1.01-1.32, P = 0.037) for the random-effect model. Metaregression analysis showed a significant coefficient of +0.24 for the poor cytogenetic risk group, and -0.25 for the favorable cytogenetic risk group, indicating that the benefit of allo-HSCT was further increased for the former, and lost for the latter. The coefficient for the intermediate cytogenetic risk group was +0.09, and was not statistically significant. CONCLUSIONS: These findings suggested that the efficacy of allo-HSCT for patients with AML in CR1 depended on cytogenetic risk. The beneficial effect of allo-HSCT was yielded for the poor risk group, and probably for the intermediate risk groups, but was absent for the favorable risk group.     

Autologous bone marrow transplantation in acute leukemia.

Autologous bone marrow transplantation can induce long-term LFS in 20% to 40% of patients with relapsed acute leukemia and should be considered as salvage therapy for patients who lack an HLA-matched donor and for patients over 45. Adult ALL patients and children with ALL in extramedullary relapse beyond second CR should receive alloBMT if at all possible. The role of ABMT in acute leukemia patients in first CR remains unclear despite randomized trials (Table 2). Because protocol deviations, early relapse, and inappropriately high treatment-related mortality unequally affected the ABMT cohort, and because recent randomized trials have used old purging methodologies, it is not possible to conclude that ABMT is not beneficial. More recent studies show that most patients are able to proceed with the intended ABMT and that modern purging may be associated with a treatment-related mortality rate of less then 5%. Immunomodulation and graft engineering uniquely suited to autologous progenitor cells indicate that ABMT should continue to be studied in the management of acute leukemia.     

Autologous bone marrow transplantation in acute leukemia.

Twenty-one cases of relapsed acute leukemia were treated with high dose piperazindione and total body irradiation followed by infusion of autologous cryopreserved remission bone marrow. Evidence for engraftment was obtained in nineteen. Eleven patients achieved complete remission; of two to fourteen months duration (median 3+). Attempts to decrease leukemic contamination of the remission bone marrow by density separation did not influence the complete remission rate and duration.     

Long-term follow-up of 23 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with allogeneic bone marrow transplant in first complete remission.

Between 1984 and 1997, 23 consecutive patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in first complete remission were treated with allogeneic bone marrow transplants from HLA-matched siblings. All patients but one were conditioned with fractionated total body irradiation (1320 cGy) and high-dose etoposide (60 mg/kg). One patient received high-dose cyclophosphamide instead of etoposide, and another patient received both drugs. Nine patients died following BMT, two from relapsed leukemia, and seven from transplant-related causes. The 3-year probabilities of disease-free survival and relapse are 65% and 12%, respectively. For patients transplanted after 1992, these probabilities are 81% (48-95%, 95% confidence interval) and 11% (2-50%), respectively. The relatively low relapse rate in this group of patients compared to published reports may reflect the enhanced anti-leukemic activity of etoposide in combination with FTBI compared to other conditioning regimens. The enhancement in overall survival for patients transplanted after 1992 may reflect improvements in supportive care, in particular, the prophylaxis of serious fungal and viral infections.