Because a pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol yielded a markedly improved outcome in adults with Philadelphia chromosome–negative ALL, we ...aimed to reassess the role of allogeneic stem cell transplantation (SCT) in patients treated in the GRAALL-2003 and GRAALL-2005 trials. In all, 522 patients age 15 to 55 years old and presenting with at least 1 conventional high-risk factor were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission. At 3 years, posttransplant cumulative incidences of relapse, nonrelapse mortality, and relapse-free survival (RFS) were estimated at 19.5%, 15.5%, and 64.7%, respectively. Time-dependent analysis did not reveal a significant difference in RFS between SCT and no-SCT cohorts. However, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) ≥10−3 (hazard ratio, 0.40) but not in good MRD responders. In B-cell precursor ALL, SCT also benefitted patients with focal IKZF1 gene deletion (hazard ratio, 0.42). This article shows that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patients who may benefit from allogeneic SCT in the context of intensified adult ALL therapy. Trial GRAALL-2003 was registered at www.clinicaltrials.gov as #NCT00222027; GRAALL-2005 was registered as #NCT00327678.
•SCT in first complete remission is associated with 69.5% 3-year overall survival in high-risk ALL adult patients treated with intensified pediatric-like protocol.•Poor early MRD response is a powerful tool to select patients who may benefit from SCT in first complete remission.
Transferring a patient undergoing an allogeneic stem cell transplantation to the intensive care unit (ICU) is always a challenging situation on a medical and psychological point of view for the ...patient and his relatives as well as for the medical staff. Despite the progress in hematology and intensive care during the last decade, the prognosis of these patients admitted to the ICU remains poor and mortality is around 50 %. The harmonization working party of the SFGM-TC assembled hematologists and intensive care specialist in order to improve conditions and modalities of the transfer of a patient after allogeneic stem cell transplantation to the ICU. We propose a structured medical form comprising all essential information necessary for optimal medical care on ICU.
Background: The treatment of Acute Myeloid Leukemia (AML) in elderly patients remains unsatisfactory, with an expected survival time of about 1 year post diagnosis. In an attempt to improve outcome ...for these patients, the prospective open-label phase 3 LAMSA-2007 trial (Clinicaltrial.gov ID, NCT00590837) repeated, at decreasing doses in consolidation and reinduction courses, a standard induction regimen with cytarabine and idarubicin (IC), with or without the randomized addition of lomustine (ICL). This alkylating agent with significant anti-leukemic activity is widely used in France for AML therapy. This study was performed as a confirmatory trial, following our previous report of the French experience in which this compound stood out as a favorable factor of improved outcome for patients with non-unfavorable cytogenetics (Pigneux, JCO 2010).
Methods: Eligible patients were adults 60 years old or more, with previously untreated AML, fit to receive intensive chemotherapy (ECOG and SORROR <3), with non-unfavorable cytogenetics. Secondary AML to MDS and MPS were excluded, but not AML secondary to chemotherapy or radiotherapy. As induction therapy, the patients received idarubicin 8 mg/m2/d iv on days 1-5, cytarabine 100 mg/m2/d iv on days 1-7 ± lomustine, 200 mg\m2 orally at day 1. Patients achieving complete response (CR) or CRi received then a first consolidation with idarubicin 8 mg/m2/d iv on days 1-3 and cytarabine 100 mg/m2/d s/cut on days 1-5 ± lomustine, 80 mg orally at day 1, then 6 courses of reduced doses consolidation with idarubicin 8 mg/m2/d iv on day 1 and cytarabine100 mg/m2/d s/cut on days 1-5 ± lomustine, 40 mg orally at day 1. This was followed by 6 months maintenance therapy with alternating courses of purinethol and methotrexate. The primary objective of the study was overall survival (OS); secondary objectives were response rate, cumulative incidence of relapse (CIR), event-free (EFS) survival, as well as safety.
Results: From February 2008 to December 2011, 459 patients were enrolled and 424 were evaluable. The median age of analyzed patients was 68 yo (60-81), 58% were male. Cytogenetics was favorable (5.2%), intermediate (90.3%) or failure (4.5%). Overall, 26% of the patients had a favorable genotype based on NPM, CEBPa and FLT3 ITD mutational status. The two arms were comparable for pre-treatment characteristics. There were 3.7% induction deaths in the IC arm and 7.7% in the ICL arm (p=0.11). The rate of primary resistant AML was 21.4% after IC versus 7.7% after ICL (p<10-4). CR or CRi was achieved in 74.9% of IC patients versus 84.7% in ICL patients (p= 0.01). At two years, OS was much better than expected for such a population, and improved in the ICL arm at 56% versus 48% in the IC arm. As expected at this age, a significant number of events occurred after two years, resulting in the absence of statistical significant difference for OS over the whole period of follow-up. At two years, EFS was improved in the ICL arm at 41% versus 26% in the IC arm (p=0.01). The CIR at two years was 41.2% in the ICL arm versus 60.9% in the IC arm (p=0.003). Grade 3 and 4 toxicities were significantly different between treatment arms after induction and after the first consolidation. Neutropenia <0.5 G/L was prolonged of 2 days in the ICL arm (23 versus 21 for the IC arm, p=0.0001) after induction and of 4 days (11 versus 7 for the IC arm, p<0.0001) after first consolidation. Thrombopenia < 20G/L was prolonged of 5 days in the ICL arm (19 versus 14 for the IC arm, p<0.001) after induction and of 7 days (11 versus 4 for the IC arm, p<0.001) after first consolidation.
Conclusion: Thisschedule using the same drugs at decreasing doses during induction, consolidation and reinductions provided unusually good results in the IC arm, further improved in the ICL arm by the addition of lomustine, in fit elderly AML patients without unfavorable cytogenetics, with acceptable toxicity. The higher rate of CR, reduced relapse incidence and improved EFS in the ICL arm support the anti-leukemic effect of lomustine in elderly AML patients, even if it does not translate in a significantly prolonged long term overall survival. New strategies for maintenance therapy remain to be improved in this setting to sustain this positive effect.
Vey:Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria.
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The pediatric-inspired intensified GRAALL protocol yielded a marked improvement in the outcome of adults with Ph-negative acute lymphoblastic leukemia (ALL) (Huguet et al,JCO 2009), raising the ...issue of the place of allogeneic HSCT in this new context. We report here the results associated with HSCT in first complete remission (CR) in younger adults treated in the GRAALL-2003/2005 trials.
In these trials, HSCT was offered in first CR to patients aged 15-55 years with ALL at higher risk of relapse. High-risk factors included white blood count >30 x 109/L for B-lineage ALL, central nervous system (CNS) involvement, t(4;11)/MLL anomalies, t(1;19), low hypodiploidy/near triploidy, complex karyotype, early resistance to the steroid prephase (CsR), early resistance to chemotherapy (ChR) as assessed by poor bone marrow blast clearance at day 8, and late CR. Per protocol, HSC donor should be a matched sibling or an unrelated donor (10/10 or eventually 9/10 HLA matched) and conditioning regimen should include single fraction 10-Gy or fractionated 12-Gy total body irradiation (TBI) and high-dose cyclophosphamide. The role of HSCT was evaluated by HSCT versus no-HSCT cohort comparison (Mantel-Byar time-dependent analysis).
Among the 522 high-risk patients eligible, 283 (54%) actually received HSCT in first CR (185 B-lineage and 98 T-lineage ALL; median age, 31 years). There were no significant differences in baseline characteristics and early response between HSCT and no-HSCT cohorts, except more HSCT patients with t(4;11)/MLL anomalies. Among the 283 HSCT patients, 46 had t(4;11)/MLL anomalies, 13 had CNS disease, 116 had CsR and 176 had ChR ALL. Origin of HSC was 140 sibling and 143 unrelated donors, including 47 unrelated donors with 1 HLA mismatch. The following HSCT protocol violations were observed: a) conditioning did not include TBI in 17 patients; b) 10 patients received reduced-intensity conditioning (RIC); and c) 13 patients received cord blood HSCT. These patients remained in the HSCT cohort for the analysis. With a median post-transplant follow-up of 3.5 years, post-HSCT cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and relapse-free survival (RFS) were estimated respectively at 19% (95% CI, 15-25), 16% (95% CI, 12-21) and 64% (95% CI, 58-70) at 3 years, without any RFS difference between sibling and unrelated donors. A marked trend for a higher NRM was observed in patients aged 45 years or more (26% versus 13% at 3 years; HR, 1.6; p=0.059), while post-transplant CIR was similar in older and younger patients. Mantel-Byar RFS estimations showed no significant difference between both HSCT and no-HSCT cohorts (HR, 0.80; p=0.13), meaning that the risk factors used in these protocols failed to identify patients who could significantly benefit from HSCT in first CR. As minimal residual disease (MRD) had a major prognostic impact, we retrospectively analyzed the effect of HSCT in the 278/522 patients evaluated for 6-week Ig/TCR MRD level (154 HSCT and 124 no-HSCT patients, including 92 and 62 patients with MRD >=10-4, respectively). Mantel-Byar RFS estimations showed that HSCT did not benefit to patients with MRD <10-4 (HR, 1.2; p=0.67) as opposed to those with MRD >=10-4 (HR, 0.6; p=0.02), with a positive HSCT-by-MRD interaction (p=0.04) (Figure 1).
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In adult patients with high-risk ALL in first CR treated in the GRAALL-2003/2005 trials, myeloablative allogeneic HSCT from sibling and unrelated donors was associated with a 64% RFS at 3 years. The 26% NRM observed at 3 years in patients aged 45 years or more suggests considering RIC-HSCT in these patients. MRD response appears to be a powerful tool to select patients who might benefit from HSCT. This selection tool will be prospectively evaluated in the next GRAALL-2013 trial.
ND and AH contributed equally to the work.
No relevant conflicts of interest to declare.
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