Interleukin-2 after autologous stem-cell transplantation for adult patients with acute myeloid leukemia in first complete remission.

PURPOSE: To determine the disease-free survival (DFS) and toxicity of administering interleukin-2 (IL-2) immunotherapy early after autologous stem-cell transplantation (ASCT) to simulate a graft versus leukemia effect observed in allogeneic transplantation. PATIENTS AND METHODS: Fifty-six patients with acute myeloid leukemia in first remission received a single consolidation of high-dose cytarabine-idarubicin at a median of 1.1 month postremission with the intent to proceed to ASCT and IL-2 9 x 10(6) U/m(2)/24 h for 4 days, followed by 10 days of IL-2 1.6 x 10(6) U/m(2)/24 h on hematologic recovery. RESULTS: Eighty-four percent of patients received the intended ASCT, and 68% of patients received IL-2 treatment. With a median follow-up of 39.4 months (range, 1.2 to 76.3 months), the 2-year cumulative probability of DFS for all 56 patients is 68% (95% confidence interval [CI], 55% to 80%) and 74% (95% CI, 57% to 85%) for the 39 patients undergoing IL-2 treatment after ASCT. The 2-year cumulative probability of DFS for favorable, intermediate, and unfavorable cytogenetics is 88% (95% CI, 59% to 97%), 48% (95% CI, 26% to 67%), and 70% (95% CI, 23% to 93%), respectively. Toxicities from IL-2 were mainly thrombocytopenia, leukopenia, fever, and fluid retention. Two septic deaths occurred during neutropenia, which includes one during consolidation and one during transplant, for an overall 4% mortality rate. CONCLUSION: These results suggest that a moderate dose of IL-2 after high-dose cytarabine-idarubicin-mobilized ASCT is associated with a low regimen-related toxicity and may improve DFS. A phase III study of IL-2 is now warranted.     

Autologous peripheral blood progenitor cell transplantation mobilized with high-dose cytarabine in acute myeloid leukemia in first complete remission

Background: The aim of this study was to increase disease-free survival (DFS) in AML in CR1 using a high-dose cytarabine consolidation plus G-CSF as in vivo purging and mobilization of CD34+ cells before ablative therapy and peripheral blood autograft.Patients and methods: Fifty-six consecutive AML patients (pts) (including 11 children <15 years), with a median age of 32 years, were analyzed. After achievement of CR with cytarabine-mitoxantrone (7 + 3) in adults and a BFM-like protocol in children, pts were intensified with cytarabine 2 g/m² × six doses plus mitoxantrone for adults, or, 3 g/m² × six doses plus etoposide for children, followed by G-CSF 5 µg/kg SC daily. The ablative regimens used were busulfan and cyclophosphamide (Bu/Cy) in standard-risk pts plus etoposide (2400 mg/m²) for high-risk pts.Results: For the 54 pts who underwent autologous transplant, the median time to reach >1.0 × 10⁹/l neutrophils was 13 days (8–48), and to reach platelets >25 × 10⁹/l 32 days (8–364), and the median numbers of red blood cell and platelet units transfused were 3 and 5, respectively. Six pts had treatment-related deaths (11%). The disease-free survival and overall survival at 30 months (mos) for the 56 eligible pts were 61% and 62%, respectively. Only two relapses were observed after 21 mos, while there were 12 relapses within 12 mos.Conclusions: The above treatment results in a similar DFS rate as does rescue with bone marrow cells, with faster neutrophil and platelet recovery.     

Duration of second complete remission compared with first complete remission in patients with acute myeloid leukemia. Eastern Cooperative Oncology Group.

The prognosis for patients with acute myeloid leukemia in first relapse is generally poor. The ability to induce a second complete remission (CR) with the same chemotherapy used in initial induction therapy is limited. Remission inversion rate, defined as achieving a longer second CR than the first CR in response to standard chemotherapy for relapse, is important in assessing studies of novel chemotherapy or immunologic treatment strategies for patients with relapsed disease. One hundred and twenty-four patients entered on two Eastern Cooperative Oncology Group (ECOG) studies for patients with relapsed AML were analyzed to determine the remission inversion rate. Twenty-two of the 124 patients (18%; 95% confidence interval 12-26%) experienced a longer second CR duration than the first CR duration by at least 2 months. Inversion of CR duration is thus not a rare event. The inversion frequency reported here establishes a baseline upon which future studies in relapsed disease need to be defined.     

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.     

Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: no difference in related compared with unrelated transplant in first complete remission.

PURPOSE: The role of unrelated allogeneic stem-cell transplantation in acute lymphoblastic leukemia (ALL) patients is still not clear, and only limited data are available from the literature. We analyzed factors affecting clinical outcome of ALL patients receiving a related or unrelated stem-cell graft from matched donors. PATIENTS AND METHODS: The total study population was 264 adult patients receiving a myeloablative allogeneic stem-cell transplant for ALL at nine bone marrow transplantation centers between 1990 and 2002. Of these, 221 patients receiving a matched related or unrelated graft were analyzed. One hundred forty-eight patients received transplantation in complete remission; 62 patients were in relapse; and 11 patients were refractory to chemotherapy before transplant. Fifty percent of patients received bone marrow, and 50% received peripheral blood stem cell from a human leukocyte antigen-identical related (n = 103), or matched unrelated (n = 118) donor. RESULTS: Disease-free survival (DFS) at 5 years was 28%, with 76 patients (34%) still alive (2.2 to 103 months post-transplantation), and 145 deceased (65 relapses, transplant-related mortality, 45%). We observed an advantage regarding DFS in favor of patients receiving transplantation during their first complete remission (CR) in comparison with patients receiving transplantation in or after second CR (P =.014) or who relapsed (P <.001). We observed a clear trend toward improved survival in favor of B-lineage ALL patients compared with T-lineage ALL patients (P =.052), and Philadelphia chromosome-positive patients had no poorer outcome than Philadelphia chromosome-negative patients. Total-body irradiation-based conditioning improved DFS in comparison with busulfan (P =.041). CONCLUSION: Myeloablative matched related or matched unrelated allogeneic hematopoietic stem-cell transplantation in ALL patients should be performed in first CR.     

Early allogeneic stem-cell transplantation for young adults with acute myeloblastic leukemia in first complete remission: an intent-to-treat long-term analysis of the BGMT experience.

PURPOSE: We analyzed the impact of allogeneic stem-cell transplantation (alloSCT) as an early consolidation for young patients with acute myeloblastic leukemia in first complete remission (CR1) through four successive protocols. PATIENTS AND METHODS: Of the 472 patients who achieved CR1, 182 (38%) had an HLA-identical sibling (donor group), and alloSCT was performed in 171 patients (94%). Of the 290 patients without donor (no-donor group), 62% received an autologous SCT. RESULTS: In an intent-to-treat analysis based on donor availability, the overall 10-year survival probability was 51% v 43% (P = .11) for the donor and no-donor groups, respectively. A Cox analysis determined that four factors had independent prognostic significance for survival (initial WBC count, French-American-British subtypes, cytogenetic risk, and number of induction courses). This permitted constitution of a simple index that reclassified 21% of the patients compared with usual cytogenetic classification and identified three subpopulations with different outcome and different impact of alloSCT. CONCLUSION: AlloSCT was associated with a survival advantage for an intermediate-risk group. In other groups, numbers are limited for definitive conclusion. However, early performed alloSCT does not seem to be the optimal treatment of high-risk patients or offer any advantage over intensive chemotherapy in low-risk patients.     

Autologous stem cell transplantation for patients with acute promyelocytic leukemia in second molecular remission

Relapse still occurs in approximately 20-30% of patients with acute promyelocytic leukemia (APL) and, after achievement of second complete remission (CR), the optimal strategy is still controversial. We describe therapeutic results from a series of 13 patients autografted in second molecular remission (MR) by a molecular negative apheresis product. In all patients, the disease was confirmed at the molecular level and all had received the GIMEMA/AIDA protocol, achieving molecular remission at the end of consolidation. Relapse was hematological in 12 cases and molecular in one. After consolidation with chemotherapy, all patients achieved MR and received a further course plus granulocyte-colony stimulating factor as mobilizing therapy. A median of 7.6×10(6) (range 2.7-10) CD34-positive cells/kg were collected. In all cases, molecular evaluation of the apheresis product was negative for the promyelocytic leukemia/retinoic acid receptor alpha gene. No case of transplant-related mortality was recorded. No maintenance or consolidation therapy after autologous stem cell transplantation (ASCT) was given to any patient. After a median follow-up of 25 months from ASCT, 10 patients are alive in sustained MR, while two relapsed after ASCT and died in the setting of refractory disease; one patient achieved a third CR and is waiting for allogeneic SCT. These results suggest that ASCT performed with a molecularly negative graft in APL patients in second MR offers a valid chance for achieving a cure. Such an approach should also be considered in relapsed patients with an HLA-compatible donor, namely in those with a first CR lasting more than one year or in unfit or elderly individuals.     

Autologous hematopoietic stem-cell transplantation for relapsed or refractory Hodgkin's disease in children and adolescents.

PURPOSE: To determine the treatment outcome and clinical factors that are of prognostic significance for children and adolescents with relapsed or refractory Hodgkin's disease (HD) who received treatment with high-dose chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT). PATIENTS AND METHODS: Fifty-three consecutive children and adolescents 21 years of age or younger with relapsed or refractory HD underwent HSCT. RESULTS: At day 100 after transplantation, 29 patients (55%) were in a complete remission or maintained a continuous complete response, six (11%) had a partial response, and 11 (21%) failed to respond or had progressive disease. The failure-free survival (FFS) at 5 years was 31%, and overall survival was 43%. Twenty-one patients died of progressive HD, and nine died secondary to transplantation-related complications, including two secondary leukemias. Prognostic factors important for FFS were normal pretransplantation lactate dehydrogenase levels (5-year FFS = 42%), compared with patients with elevated LDH levels (5-year FFS = 0%) (P < .001), and disease sensitivity at the time of HSCT with FFS in untreated relapse, sensitive disease, and resistant disease 44%, 35%, and 9%, respectively (P = .06). There was no statistically significant difference in FFS or overall survival between age subgroups that were analyzed (< 13, 13 to 18, 19 to 21) or in comparison with an adult cohort. CONCLUSION: HSCT is an effective treatment modality that can result in long-term cures and should be considered for children and adolescents with relapsed HD.     

Potential cure of acute myeloid leukemia : analysis of 1069 consecutive patients in first complete remission

BACKGROUND: Potential cure of acute myeloid leukemia (AML) is now a widely accepted idea, but it is uncertain whether there is heterogeneity in the failure rate in patients once they have been in complete remission (CR) for various periods of time. METHODS: The long-term outcomes were analyzed in 1069 consecutive AML patients in first CR who were diagnosed and treated at the University of Texas M. D. Anderson Cancer Center between 1991 and 2003. RESULTS.: The failure rates as yearly risk of treatment failure were 69.1 in the first year, 37.7 in the second year, 17.0 in the third year, 7.6 in the fourth year, and 6.6 in the fifth year, suggesting that 3 years from the CR date is a convenient time to consider patients potentially cured. The effect of cytogenetics on relapse-free survival (RFS) remained constant throughout the first 3 years, whereas the effect of age increased with time. The probability of RFS for patients alive without disease recurrence at 3 years was 84.0% at 6 years. When the interaction between age and cytogenetics was examined for these patients, the outcomes of those with favorable cytogenetics were found to be excellent regardless of age. However, in the intermediate cytogenetic group, although patients aged <60 years had excellent outcomes, those aged > or =60 years were found to be at a substantial risk of disease recurrence even after 3 years of CR, with a 6-year RFS rate of 56.5%. There were only 6 patients with adverse cytogenetics in this cohort. CONCLUSIONS: The results of the current study demonstrate that the risk of treatment failure differs over time according to a combination of cytogenetics and age.     

Pre-transplant consolidation chemotherapy may not improve outcomes after reduced intensity conditioning hematopoietic stem cell transplantation for acute myeloid leukemia in first complete remission

The role consolidation chemotherapy prior to reduced-intensity (RIC) HCT is unclear. We reviewed 60 consecutive patients with AML in CR1 undergoing RIC HCT at the University of Minnesota and evaluated outcomes based on exposure to pre-transplant consolidation chemotherapy. The two year incidence of relapse and the probability of overall survival were similar between those who did and did not receive consolidation chemotherapy. The 2 year incidence of transplant-related mortality was slightly higher in those who did not receive consolidation and correlated with a higher HCT comorbidity index (HCT-CI) in that cohort. Our data suggest that exposure to consolidation chemotherapy prior to RIC HCT may not improve post-transplant outcomes for patients with AML in CR1.     

Chemotherapy for patients with acute myeloid leukemia in first remission

Although the majority of patients with acute myeloid leukemia (AML) achieve a complete remission with induction chemotherapy, most will ultimately relapse. Therefore, the optimal postremission therapy for AML remains to be defined, and further improvements in treatment strategies are required. Clinical trials have demonstrated that early intensive consolidation therapy with high-dose cytarabine can produce prolonged responses in up to 40% of patients in remission after standard induction therapy. Equally, however, it has been shown that high-dose cytarabine used in induction therapy can deliver equivalent long-term results. Autologous and allogeneic stem cell transplantation in first remission are also valid alternatives, but the value of low-dose maintenance treatment seems confined to acute promyelocytic leukemia. Further improvement in the treatment of AML is likely to depend on the development of new strategies, such as molecularly targeted or immune therapies.     

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.     

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.     

Long-term follow-up of Asian patients younger than 46 years with acute myeloid leukemia in first complete remission: comparison of allogeneic vs. autologous hematopoietic stem cell transplantation

Optimal therapy for patients with acute myeloid leukemia (AML) in first complete remission (CR-1) remains the subject of debate: with the possibilities of chemotherapy alone, autologous (auto) or allogeneic (allo) hematopoietic stem cell transplantation (HSCT). We undertook a retrospective analysis of AML patients aged below 46 years and in CR-1, who had undergone auto- or allo-HSCT in our institution, to determine the factors associated with a better outcome. Between September 1985 and April 2003, 81 patients underwent autologous (n = 29) or allogeneic (n = 52) HSCT in CR-1. With a median follow-up of 10 years, the probability of 15-year overall survival (OS) was 51%[95% confidence interval (CI) = 32 - 70%] for auto-HSCT vs. 55% (95% CI = 42 - 69) for allo-HSCT, respectively (P = 0.92). The cumulative incidence of relapse at 3 years was 49% (95% CI = 30 - 67) (auto) vs. 21% (95% CI = 10 - 30) (allo), respectively. Non-relapse-related mortality at 3 years was 5% (95% CI = 0 - 14) (auto) vs. 17% (95% CI = 7 - 28) (allo), respectively. This retrospective analysis confirmed that auto- and allo-HSCT led to similar OS. The significantly lower incidence of relapse amongst allograft recipients was balanced by an increased incidence of death in CR.     

Bone marrow transplantation for children with acute myelogenous leukaemia in the first complete remission

Of 52 children aged 9 months to 16 years old with acute myelogenous leukaemia (AML) in first complete remission undergoing bone marrow transplantation at our institution, 31 received allogeneic transplants (allo-BMT) and 21 received autologous transplants (ABMT). Initial induction and consolidation chemotherapy were not uniform. BMT was performed at a median of 7 months (range: 2.5 to 22.5 months) from the diagnosis. Conditioning included chemotherapy (n=43: 4 x 4 mg/kg of busulfan and 3 x 60 to 70 mg/m(2) of melphalan) or total body irradiation (12 Gy) plus chemotherapy (n=9). Graft-versus-host disease (GVHD) prophylaxis in allo-BMT cases consisted of methotrexate +/- cyclosporin A. Unpurged marrow was used in ABMT cases. All patients showed sustained engraftment. Amongst allograft cases, acute or chronic GVHD developed in 7 patients each (23%). 8 patients (15%) died (5 with allo-BMT, 3 with ABMT), including transplant-related mortality in 3 of the allo-BMT patients. 7 patients had relapses (3 with allo-BMT, 4 with ABMT). As of June 1999, 43 patients are alive and well 13 to 160 months after BMT (median, 71), with 5-year disease-free survival rates after BMT of 84% for allo-BMT, 81% for ABMT and 83% altogether. Although the presented data are based on a retrospective evaluation, we consider BMT for childhood AML during first complete remission an effective treatment for eradicating leukaemia.     

Early blast clearance by remission induction as a prognostic factor in acute myeloid leukemia

Conclusions Day 16 blasts are an important prognostic factor in newly diagnosed AML.     

Allogeneic stem cell transplantation in acute myeloid leukemia in first or subsequent remission: weighing prognostic markers predicting relapse and risk factors for non-relapse mortality

Allogeneic hematopoietic stem cell transplantation (alloSCT) has been established as a powerful treatment modality in acute myeloid leukemia (AML) in first or subsequent remission. Although alloSCT effectively prevents relapse, non-relapse mortality (NRM) associated with the procedure may counterbalance that beneficial effect. As a result, alloSCT generally is restricted to patients with a relatively high risk of relapse and a relatively low risk for NRM. Here, we review recent studies that evaluated specific risk factors that, on the one hand, identified categories of AML patients with a higher risk of relapse and, on the other hand, identified patients with an increased risk for NRM. We discuss how these recent developments may affect our decision-making about whether and when to proceed to alloSCT.     

Syngeneic hematopoietic stem cell transplantation for acute myeloid leukemia: a propensity score-matched analysis

The present study evaluated outcomes and prognostic factors in adult patients with acute myeloid leukemia (AML) after syngeneic hematopoietic stem cell transplantation (HSCT). Among patients in first complete remission (CR1), outcomes of syngeneic HSCT (Syn) were compared with those of autologous HSCT (Auto), allogeneic HSCT from human leukocyte antigen (HLA)-matched sibling donor (MSD), or allogeneic HSCT from HLA-matched unrelated donor (MUD). Among 11,866 patients receiving first HSCT, 26 in the Syn group were analyzed. The 5-year overall survival (OS) rate, the cumulative incidence of relapse, and the cumulative incidence of non-relapse mortality (NRM) were 47.8%, 59.6%, and 4.6%, respectively. The OS was significantly better in patients in CR1 (n = 13) than in patients in non-CR1 (P = 0.012). Furthermore, 39 patients in CR1 each were assigned to the Auto, MSD, and MUD groups using propensity score matching. The 5-year OS in the Syn (68.4%) was not significantly different from those in the Auto (55.9%, P = 0.265), MSD (62.4%, P = 0.419), or MUD (63.7%, P = 0.409) groups. A higher relapse in the Syn than in the MSD and MUD groups was offset by lower NRM. In summary, syngeneic HSCT might be an alternative option for AML patients in CR1.Subject terms: Acute myeloid leukaemia, Cancer immunotherapy