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Allogeneic hematopoietic cell transplantation is equally effective in secondary acute lymphoblastic leukemia (ALL) compared to de-novo ALL-a report from the EBMT registry
Sadowska-Klasa, A., Zaucha, J. M., Labopin, M., Bourhis, J. H., Blaise, D., Yakoub-Agha, I., Salmenniemi, U., Passweg, J., Fegueux, N., Schroeder, T., et al
Bone marrow transplantation. 2024
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Editor's Choice
Abstract
Secondary acute lymphoblastic leukemia (s-ALL) comprises up to 10% of ALL patients. However, data regarding s-ALL outcomes is limited. To answer what is the role of allogeneic hematopoietic cell transplantation (HCT) in s-ALL, a matched-pair analysis in a 1:2 ratio was conducted to compare outcomes between s-ALL and de novo ALL (dn-ALL) patients reported between 2000-2021 to the European Society for Blood and Marrow Transplantation registry. Among 9720 ALL patients, 351 (3.6%) were s-ALL, of which 80 were in first complete remission (CR1) with a known precedent primary diagnosis 58.8% solid tumor (ST), 41.2% hematological diseases (HD). The estimated 2-year relapse incidence (RI) was 19.1% (95%CI: 11-28.9), leukemia-free survival (LFS) 52.1% (95%CI: 39.6-63.2), non-relapse mortality (NRM) 28.8% (95%CI: 18.4-40), GvHD-free, relapse-free survival (GRFS) 39.4% (95%CI: 27.8-50.7), and overall survival (OS) 60.8% (95%CI: 47.9-71.4), and did not differ between ST and HD patients. In a matched-pair analysis, there was no difference in RI, GRFS, NRM, LFS, or OS between s-ALL and dn-ALL except for a higher incidence of chronic GvHD (51.9% vs. 31.4%) in s-ALL. To conclude, patients with s-ALL who received HCT in CR1 have comparable outcomes to patients with dn-ALL.
PICO Summary
Population
Adults with acute lymphoblastic leukaemia, reported to the EBMT registry (n=9720)
Intervention
A detailed analysis cohort who were transplanted for secondary acute lymphoblastic leukaemia (s-ALL, n=80)
Comparison
Matched controls who were transplanted for de novo ALL (dn-ALL, n=80)
Outcome
The estimated 2-year relapse incidence (RI) was 19.1% (95%CI: 11-28.9), leukemia-free survival (LFS) 52.1% (95%CI: 39.6-63.2), non-relapse mortality (NRM) 28.8% (95%CI: 18.4-40), GvHD-free, relapse-free survival (GRFS) 39.4% (95%CI: 27.8-50.7), and overall survival (OS) 60.8% (95%CI: 47.9-71.4), and did not differ between solid tumour and haematological disease patients. In a matched-pair analysis, there was no difference in RI, GRFS, NRM, LFS, or OS between s-ALL and dn-ALL except for a higher incidence of chronic GvHD (51.9% vs. 31.4%) in s-ALL.
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Risk factors and outcomes in children with high-risk B-cell precursor and T-cell relapsed acute lymphoblastic leukaemia: combined analysis of ALLR3 and ALL-REZ BFM 2002 clinical trials
Eckert, C., Parker, C., Moorman, A. V., Irving, J. A., Kirschner-Schwabe, R., Groeneveld-Krentz, S., Révész, T., Hoogerbrugge, P., Hancock, J., Sutton, R., et al
European journal of cancer (Oxford, England : 1990). 2021;151:175-189
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Editor's Choice
Abstract
AIM: Outcomes of children with high-risk (HR) relapsed acute lymphoblastic leukaemia (ALL) (N = 393), recruited to ALLR3 and ALL-REZ BFM 2002 trials, were analysed. Minimal residual disease (MRD) was assessed after induction and at predetermined time points until haematopoietic stem cell transplantation (SCT). METHODS Genetic analyses included karyotype, copy-number alterations and mutation analyses. Ten-year survivals were analysed using Kaplan-Meier and Cox models for multivariable analyses. RESULTS Outcomes of patients were comparable in ALLR3 and ALL-REZ BFM 2002. The event-free survival of B-cell precursor (BCP) and T-cell ALL (T-ALL) was 22.6% and 26.2% (P = 0.94), respectively, and the overall survival (OS) was 32.6% and 28.2% (P = 0.11), respectively. Induction failures (38%) were associated with deletions of NR3C1 (P = 0.002) and BTG1 (P = 0.03) in BCP-ALL. The disease-free survival (DFS) and OS in patients with good vs poor MRD responses were 57.4% vs 22.6% (P < 0.0001) and 57.8% vs 32.0% (P = 0.0004), respectively. For BCP- and T-ALL, the post-SCT DFS and OS were 42.1% and 56.8% (P = 0.26) and 51.6% and 55.4% (P = 0.67), respectively. The cumulative incidences of post-SCT relapse for BCP- and T-ALL were 36.9% and 17.8% (P = 0.012) and of death were 10.7% and 25.5% (P = 0.013), respectively. Determinants of outcomes after SCT were acute graft versus host disease, pre-SCT MRD (=10(-3)), HR cytogenetics and TP53 alterations in BCP-ALL. CONCLUSION Improvements in outcomes for HR ALL relapses require novel compounds in induction therapy to improve remission rates and immune targeted therapy after induction to maintain remission after SCT. TRIAL REGISTRATION ALLR3: NCT00967057; ALL REZ-BFM 2002: NCT00114348.
PICO Summary
Population
Children with high risk acute lymphoblastic leukaemia (n=393)
Intervention
Children enrolled in ALLR3, randomised to either mitoxantrone or idarubicin in induction (n=136)
Comparison
Children enrolled in ALL-REZ BFM 2002 randomised to either R-courses or Protocol II-Idarubicin as post-induction therapy (n=257)
Outcome
Outcomes of patients were comparable in ALLR3 and ALL-REZ BFM 2002. The event-free survival of B-cell precursor (BCP) and T-cell ALL (T-ALL) was 22.6% and 26.2%, respectively, and the overall survival (OS) was 32.6% and 28.2% , respectively. Induction failures (38%) were associated with deletions of NR3C1 and BTG1 in BCP-ALL. The disease-free survival (DFS) and OS in patients with good vs poor MRD responses were 57.4% vs 22.6% and 57.8% vs 32.0%, respectively. For BCP- and T-ALL, the post-SCT DFS and OS were 42.1% and 56.8% and 51.6% and 55.4%, respectively. The cumulative incidences of post-SCT relapse for BCP- and T-ALL were 36.9% and 17.8% and of death were 10.7% and 25.5%, respectively. Determinants of outcomes after SCT were acute graft versus host disease, pre-SCT MRD, HR cytogenetics and TP53 alterations in BCP-ALL.
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A decision analysis for unrelated bone marrow transplantation or immediate cord blood transplantation for patients with Philadelphia chromosome-negative acute lymphoblastic leukemia in first complete remission: Unrelated BMT or immediate CBT for Ph-negative ALL
Kako, S., Hayakawa, F., Miyamura, K., Tanaka, J., Imai, K., Kanda, J., Morishima, S., Uchida, N., Doki, N., Ikegame, K., et al
Transplantation and cellular therapy. 2021
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Editor's Choice
Abstract
BACKGROUND A human leucocyte antigen (HLA)-matched relative is the first-choice donor for patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1). The most promising alternative donor is thought to be an HLA-matched unrelated donor (MUD) in patients who do not have an HLA-matched related donor. Cord blood transplantation (CBT) is one of alternative options. Higher rates of engraftment failure and non-relapse mortality are big problems, but the ready availability of cord blood can be an advantage because patients can immediately undergo transplantation before progression. OBJECTIVE To determine an appropriate alternative donor in patients with Ph-negative ALL in CR1, who do not have HLA-matched relatives. STUDY DESIGN Decision analyses using a Markov model were performed to compare immediate CBT, in which CBT was performed at 1 month after the achievement of CR1, with elective unrelated bone marrow transplantation (uBMT) from 8/8 MUD (8/8 uBMT) or uBMT from 7/8 MUD (7/8 uBMT), in which uBMT was performed at 4 months, in patients aged 16-55 years with Ph-negative ALL in CR1 who did not have HLA-matched relatives. We constructed a decision tree as described in Figure 1. The cycle length was set at 3 months, and analyses were performed for 19 cycles for uBMT and 20 cycles for CBT, which resulted in evaluation of the 5-year life expectancy after both decisions. Transition probabilities and utilities were estimated from prospective and retrospective Japanese studies and the registry database of Japan as summarized in Table 1. Subgroup analyses were performed according to risk stratification on the basis of the white blood cell count and cytogenetics at the diagnosis, and according to age stratification with a cutoff of 25 years. One-way sensitivity analyses for TPs and utilities were also performed. RESULTS The baseline analyses showed that the decision to perform 8/8 uBMT or 7/8 uBMT gave superior results, with quality-adjusted life years (QALYs) of 2.86, 2.84, and 2.75 in 8/8 uBMT, 7/8 uBMT, and CBT, respectively. One-way sensitivity analyses showed that the results of the baseline analyses were reversed if the probabilities of non-relapse mortality (NRM) in CBT improved. Subgroup analyses showed the similar results in lower-aged, higher-aged, and high-risk patients. However, QALY in 8/8 uBMT was worse than that in CBT in standard-risk patients. In one-way sensitivity analyses, the probabilities of NRM in uBMT and CBT affected the baseline results in all analyses except for comparisons between 8/8 uBMT and CBT in lower-aged and high-risk patients. In these 2 populations, the superiority of 8/8 uBMT was consistently demonstrated throughout the entire one-way sensitivity analyses. CONCLUSION For patients with Ph-negative ALL in CR1 who decide to undergo transplantation from an alternative donor, elective uBMT from either 8/8 MUD or 7/8 MUD is expected to give a better outcome than immediate CBT. However, CBT is a viable option, and improvements to reduce the probabilities of NRM in CBT may change these results.
PICO Summary
Population
Outcomes of patients identified from the Japan Transplant Registry Unified Management Program (TRUMP) database with Philadelphia chromosome-negative acute lymphoblastic leukaemia (Ph-negative ALL) age 16 to 55 years who underwent a first unrelated bone marrow transplantation (uBMT) in Japan (n= 327)
Intervention
Decision tree analysis using a Markov model comparing unrelated bone marrow transplantation (uBMT) to upfront cord blood transplantation, as follows:
Comparison
Comparison of 8/8 matched unrelated donor (MUD) transplant (n=163), 7/8 MUD (n=98) or Cord blood transplantation (CBT) with a single unit (n=66)
Outcome
The baseline analyses showed that the decision to perform 8/8 uBMT or 7/8 uBMT gave superior results, with quality-adjusted life years (QALYs) of 2.86, 2.84, and 2.75 in 8/8 uBMT, 7/8 uBMT, and CBT, respectively. One-way sensitivity analyses showed that the results of the baseline analyses were reversed if the probabilities of non-relapse mortality (NRM) in CBT improved. Subgroup analyses showed the similar results in lower-aged, higher-aged, and high-risk patients. However, QALY in 8/8 uBMT was worse than that in CBT in standard-risk patients. In one-way sensitivity analyses, the probabilities of NRM in uBMT and CBT affected the baseline results in all analyses except for comparisons between 8/8 uBMT and CBT in lower-aged and high-risk patients. In these 2 populations, the superiority of 8/8 uBMT was consistently demonstrated throughout the entire one-way sensitivity analyses.
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More precisely defining risk peri-HCT in pediatric ALL: pre- vs post-MRD measures, serial positivity, and risk modeling
Bader, P., Salzmann-Manrique, E., Balduzzi, A., Dalle, J. H., Woolfrey, A. E., Bar, M., Verneris, M. R., Borowitz, M. J., Shah, N. N., Gossai, N., et al
Blood advances. 2019;3(21):3393-3405
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Editor's Choice
Abstract
Detection of minimal residual disease (MRD) pre- and post-hematopoietic cell transplantation (HCT) for pediatric acute lymphoblastic leukemia (ALL) has been associated with relapse and poor survival. Published studies have had insufficient numbers to: (1) compare the prognostic value of pre-HCT and post-HCT MRD; (2) determine clinical factors post-HCT associated with better outcomes in MRD+ patients; and (3) use MRD and other clinical factors to develop and validate a prognostic model for relapse in pediatric patients with ALL who undergo allogeneic HCT. To address these issues, we assembled an international database including sibling (n = 191), unrelated (n = 259), mismatched (n = 56), and cord blood (n = 110) grafts given after myeloablative conditioning. Although high and very high MRD pre-HCT were significant predictors in univariate analysis, with bivariate analysis using MRD pre-HCT and post-HCT, MRD pre-HCT at any level was less predictive than even low-level MRD post-HCT. Patients with MRD pre-HCT must become MRD low/negative at 1 to 2 months and negative within 3 to 6 months after HCT for successful therapy. Factors associated with improved outcome of patients with detectable MRD post-HCT included acute graft-versus-host disease. We derived a risk score with an MRD cohort from Europe, North America, and Australia using negative predictive characteristics (late disease status, non-total body irradiation regimen, and MRD [high, very high]) defining good, intermediate, and poor risk groups with 2-year cumulative incidences of relapse of 21%, 38%, and 47%, respectively. We validated the score in a second, more contemporaneous cohort and noted 2-year cumulative incidences of relapse of 13%, 26%, and 47% (P < .001) for the defined risk groups.
PICO Summary
Population
Paediatric patients (age 1-21 years) with acute lymphoblastic leukaemia (n=616)
Intervention
An international database of patients in complete remission following myeloablative allogeneic transplant, with at least one minimal residual disease (MRD) measurement prior to transplant
Comparison
None
Outcome
Although high and very high MRD pre-HCT were significant predictors in univariate analysis, with bivariate analysis using MRD pre-HCT and post-HCT, MRD pre-HCT at any level was less predictive than even low-level MRD post-HCT. Patients with MRD pre-HCT must become MRD low/negative at 1 to 2 months and negative within 3 to 6 months after HCT for successful therapy. Factors associated with improved outcome of patients with detectable MRD post-HCT included acute graft-versus-host disease.
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Impact of cytogenetic abnormalities on outcomes of adult Philadelphia-negative acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation: a study by the Acute Leukemia Working Committee of the Center for International Blood and Marrow Transplant Research
Lazaryan, A., Dolan, M., Zhang, M. J., Wang, H. L., Kharfan-Dabaja, M. A., Marks, D. I., Bejanyan, N., Copelan, E., Maijhail, N., Waller, E. K., et al
Haematologica. 2019
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Editor's Choice
Abstract
Cytogenetic risk stratification at diagnosis has long been one of the most useful tools to assess prognosis in acute lymphoblastic leukemia. To examine the prognostic impact of cytogenetic abnormalities on outcomes after allogeneic hematopoietic cell transplantation, we studied 1731 adults with Philadelphia-negative acute lymphoblastic leukemia in complete remission who underwent myeloablative or reduced intensity/non-myeloablative conditioning transplant from unrelated or matched sibling donors reported to Center for International Blood and Marrow Transplant Research. A total of 632 patients had abnormal conventional metaphase cytogenetics. Patients with abnormal cytogenetics had 40% leukemia-free survival and 42% overall survival at 5-years post-transplant, which was similar to those with normal karyotype. Of the previously established cytogenetic risk classifications, modified Medical Research Council-Eastern Cooperative Oncology Group score was the only independent prognosticator of leukemia-free survival (p=0.03). In the multivariable analysis, monosomy 7 predicted post-transplant relapse (hazard ratio=2.11; 95% confidence interval, 1.04-4.27) and treatment failure (hazard ratio=1.97; 1.20-3.24). Complex karyotype was prognostic for relapse (hazard ratio=1.69; 1.06-2.69), whereas t(8;14) predicted treatment failure (hazard ratio=2.85; 1.35-6.02) and overall mortality (hazard ratio=3.03; 1.44-6.41). This large study suggested a novel transplant-specific cytogenetic scheme with adverse (monosomy 7, complex karyotype, del(7q), t(8;14), t(11;19), del(11q), tetraploidy/near triploidy), intermediate (normal karyotype and all other abnormalities), and favorable (high hyperdiploidy) risks to prognosticate leukemia-free survival (p=0.02). Although some previously established high-risk Philadelphia-negative cytogenetic abnormalities of acute lymphoblastic leukemia can be overcome by transplant, monosomy 7, complex karyotype, and t(8;14) continue to pose significant risks and yield inferior outcomes.
PICO Summary
Population
Adults with Philadelphia-negative acute lymphoblastic leukemia in complete remission who underwent myeloablative or reduced intensity/non-myeloablative conditioning transplant from unrelated or matched sibling donors reported to CIBMTR registry (n=1731)
Intervention
Patients with abnormal conventional metaphase cytogenetics (n=632)
Comparison
Patients with normal cytogenetics (n=1099)
Outcome
Of the previously established cytogenetic risk classifications, modified Medical Research Council-Eastern Cooperative Oncology Group score was the only independent prognosticator of leukemia-free survival. In the multivariable analysis, monosomy 7 predicted post-transplant relapse and treatment failure. Complex karyotype was prognostic for relapse, whereas t(8;14) predicted treatment failure and overall mortality.
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Hematopoietic Stem Cell Transplantation Does Not Improve the Poor Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia: A Report From Children's Oncology Group
McNeer, J. L., Devidas, M., Dai, Y., Carroll, A. J., Heerema, N. A., Gastier-Foster, J. M., Kahwash, S. B., Borowitz, M. J., Wood, B. L., Larsen, E., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2019;:Jco1800884
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Editor's Choice
Abstract
PURPOSE Children and young adults with hypodiploid B-lymphoblastic leukemia (B-ALL) fare poorly and hematopoietic stem cell transplantation (HSCT) is often pursued in first complete remission (CR1). We retrospectively reviewed the outcomes of children and young adults with hypodiploid B-ALL who were enrolled in recent Children's Oncology Group (COG) trials to evaluate the impact of HSCT on outcome. PATIENTS AND METHODS Cytogenetic analyses and DNA index were performed at COG-approved laboratories, and hypodiploidy was defined as modal chromosome number less than 44 and/or DNA index less than 0.81. Minimal residual disease (MRD) was determined centrally using flow cytometry at two reference laboratories. Patients with hypodiploid ALL came off protocol therapy postinduction and we retrospectively collected details on their subsequent therapy and outcomes. Event-free survival (EFS) and overall survival (OS) were estimated for the cohort. RESULTS Between 2003 and 2011, 8,522 patients with National Cancer Institute standard-risk and high-risk B-ALL were enrolled in COG AALL03B1 ( ClinicalTrials.gov identifier: NCT00482352). Hypodiploidy occurred in 1.5% of patients (n = 131), 98.3% of whom achieved CR after induction therapy. Five-year EFS and OS were 52.2% +/- 4.9% and 58.9% +/- 4.8%, respectively. Outcomes for patients undergoing CR1 HSCT were not significantly improved: 5-year EFS and OS were 57.4% +/- 7.0% and 66.2% +/- 6.6% compared with 47.8% +/- 7.5% and 53.8% +/- 7.6%, respectively ( P = .49 and .34, respectively) for those who did not undergo transplantation. Patients with MRD of 0.01% or greater at the end of induction had 5-year EFS and OS of 26.7% +/- 9.3% and 29.3% +/- 10.1%, respectively, and HSCT had no significant impact on outcomes. CONCLUSION Children and young adults with hypodiploid B-ALL continue to fare poorly and do not seem to benefit from CR1 HSCT. This is especially true for patients with MRD of 0.01% or greater at the end of induction. New treatment strategies are urgently needed for these patients.
PICO Summary
Population
Children and young adults with hypodiploid B-lymphoblastic leukemia (n=131)
Intervention
Haematopoietic stem cell transplantation in first complete remission (CR1 HSCT)
Comparison
No transplantation
Outcome
Outcomes for patients undergoing CR1 HSCT were not significantly improved