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Low hypodiploidy defines a rare subtype of B-cell acute lymphoblastic leukemia (B-ALL) with a dismal outcome. To investigate the genomic basis of low-hypodiploid ALL (LH-ALL) in adults, we analyzed copy-number aberrations, loss of heterozygosity, mutations, and cytogenetics data in a prospective cohort of Philadelphia (Ph)-negative B-ALL patients (n = 591, ages 18–84 years), allowing us to identify 80 LH-ALL cases (14%). Genomic analysis was critical for evidencing low hypodiploidy in many cases missed by cytogenetics. The proportion of LH-ALL within Ph-negative B-ALL dramatically increased with age, from 3% in the youngest patients (under 40 years old) to 32% in the oldest (over 55 years old). Somatic TP53 biallelic inactivation was the hallmark of adult LH-ALL, present in virtually all cases (98%). Strikingly, we detected TP53 mutations in posttreatment remission samples in 34% of patients. Single-cell proteogenomics of diagnosis and remission bone marrow samples evidenced a preleukemic, multilineage, TP53-mutant clone, reminiscent of age-related clonal hematopoiesis.Significance:We show that low-hypodiploid ALL is a frequent entity within B-ALL in older adults, relying on somatic TP53 biallelic alteration. Our study unveils a link between aging and low-hypodiploid ALL, with TP53-mutant clonal hematopoiesis representing a preleukemic reservoir that can give rise to aneuploidy and B-ALL.See related commentary by Saiki and Ogawa, p. 102.This article is highlighted in the In This Issue feature, p. 101

Supplementary figure 1. Sequencing-based analysis of CNA and LOH in adult LH-ALL. Supplementary figure 2. Representation of mutations in the frequent targeted genes in adult LH-ALL. Supplementary figure 3. Longitudinal assessment of TP53-mutant cell fraction as determined by ddPCR along with clonal IG/TR-based MRD quantification in three patients with undetectable TP53 mutation at remission. Supplementary figure 4. Merged single-cell analysis of cell-surface markers by ADT-sequencing of remission samples from three LH-ALL patients. Supplementary figure 5. Individual single-cell analyses of cell-surface markers by ADT-sequencing of remission samples from three LH-ALL patients. Supplementary figure 6. Individual analyses of single-cell immunophenotyping and genotyping of remission samples from three LH-ALL patients. Supplementary figure 7. Evaluation of allelic dropout rate on heterozygous single nucleotide polymorphism (SNPs) in remission samples. Supplementary figure 8. Individual single-cell analysis of cell-surface markers by ADT-sequencing of diagnosis samples from three LH-ALL patients. Supplementary figure 9. Single-cell genotyping of heterozygous SNPs allowing LOH assessment in diagnosis samples from three LH-ALL patients. Supplementary Figure 10. Distribution of single-cell genotypes of two LH-ALL patients with persistent TP53 and JAK2 (EI_046) or DNMT3A (EI_035) mutations in remission samples.

Supplementary Table 1. Karyotypes of LH-ALL patients at diagnosis. Supplementary Table 2. Somatic variants detected in LH-ALL patients at diagnosis. Supplementary Table 3. ARCH related variants detected in LH-ALL patients at remission. Supplementary Table 4. Minimal residual disease values of remission samples used for mutation analysis. Supplementary Table 5. Somatic alterations in cell populations from diagnostic samples (BMMC) based on single-cell analyses. Supplementary Table 6. Somatic alterations in FACS-sorted cell populations from diagnostic samples. Supplementary Table 7. Panel of genes for targeted sequencing. Supplementary Table 8. Single cell DNA amplicons for genotyping and LOH analyses. Supplementary Table 9. Single cell DNA amplicons for B-ALL clono-specific IG/TR detection. Supplementary Table 10. ADT-seq panel and spike-in antibodies. Supplementary Table 11. Single cell sequencing metrics.

Low hypodiploidy defines a rare subtype of B-cell acute lymphoblastic leukemia (B-ALL) with a dismal outcome. To investigate the genomic basis of low-hypodiploid ALL (LH-ALL) in adults, we analyzed copy-number aberrations, loss of heterozygosity, mutations, and cytogenetics data in a prospective cohort of Philadelphia (Ph)-negative B-ALL patients (n = 591, ages 18–84 years), allowing us to identify 80 LH-ALL cases (14%). Genomic analysis was critical for evidencing low hypodiploidy in many cases missed by cytogenetics. The proportion of LH-ALL within Ph-negative B-ALL dramatically increased with age, from 3% in the youngest patients (under 40 years old) to 32% in the oldest (over 55 years old). Somatic TP53 biallelic inactivation was the hallmark of adult LH-ALL, present in virtually all cases (98%). Strikingly, we detected TP53 mutations in posttreatment remission samples in 34% of patients. Single-cell proteogenomics of diagnosis and remission bone marrow samples evidenced a preleukemic, multilineage, TP53-mutant clone, reminiscent of age-related clonal hematopoiesis.Significance:We show that low-hypodiploid ALL is a frequent entity within B-ALL in older adults, relying on somatic TP53 biallelic alteration. Our study unveils a link between aging and low-hypodiploid ALL, with TP53-mutant clonal hematopoiesis representing a preleukemic reservoir that can give rise to aneuploidy and B-ALL.See related commentary by Saiki and Ogawa, p. 102.This article is highlighted in the In This Issue feature, p. 101

Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA sequencing and whole-genome analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of 2 genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTF::ATXN7L3 fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cis from the deletion. Using 4C-sequencing and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3 enhancer hijacking. CDX2/UBTF ALL (n = 26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4 activating mutations. Within adult patients with Ph− B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n = 17/723, 2.4%) were young (median age, 31 years) and dramatically enriched in females (male/female ratio, 0.2, P = .002). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% vs 3%, P = .017) and higher post-induction minimal residual disease (MRD) levels (MRD ≥ 10−4, 93% vs 46%, P < .001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% vs 32.4%, P = .004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTF::ATXN7L3 fusion, representing a high-risk disease in young adults.

The OPAL study is a French multicenter observational retrospective analysis of adults with relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia treated in a real-life setting by ponatinib. Twenty-nine patients were included since 2012. Median age was 55 years. The initial dose of ponatinib, combined to chemotherapy in half of the patients, was 45 mg/day in most instances. The remission rate was 90% and seven patients received allogeneic stem cell transplantation. Median disease-free and overall survival were only 3.5 and 9.9 months respectively. The outcome of patients with

Introduction: Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) with high-risk genetics and/or measurable residual disease (MRD) are at high-risk of disease recurrence. In the previous GRAALL-2005 study, we identified KMT2A rearrangements (KMT2A-r), IKZF1 intragenic deletion (IKZF1del) and post-induction (TP1, week 6) MRD ≥ 0.01% as independent factors to predict relapse in Ph-negative B-cell precursor (BCP) ALL (Beldjord K, Blood 2014). In the GRAALL-2014 trial, high-risk (HR) patients were thus defined by the presence of at least one of these three factors. Among them, only those with higher MRD levels defined as TP1-MRD ≥ 0.1% and/or week 12 (TP2) MRD ≥ 0.01% were considered at very high risk (VHR) and proposed allogeneic hematopoietic stem cell transplant (alloSCT) in first remission (Dhedin et al., Blood 2015). Since October 2018, all these patients were eligible to be included in the GRAALL-2014-QUEST phase 2 study to receive blinatumomab as part of consolidation and maintenance phases or as a bridge to transplant. Methods: From October 2018 to December 2020, 95 patients with high-risk Ph-negative BCP-ALL without central nervous system involvement at diagnosis and in continuous complete remission after induction and consolidation 1, were prospectively included to start blinatumomab at week 12. One patient was excluded because of T-ALL phenotype (with CD19 aberrant expression). Patients with alloSCT indication and a stem cell source received blinatumomab 28 microg/d administered by continuous intravenous infusion (cIV) until transplant. A minimum of 4 weeks blinatumomab was recommended before proceeding to transplantation. All other patients received 5 cycles of blinatumomab 28 microg/day cIV (for 28 days), during consolidation 2 and 3 and at months 1/3/5 of the maintenance phase respectively. The primary objective was disease-free survival (DFS). Secondary objectives included post-blinatumomab MRD response at TP3 (after consolidation 2 or before alloSCT), overall survival (OS), and safety. Early results are reported here. Results: Median age was 35 years old (range, 18-60). Median white blood cell count (WBC) at diagnosis was 12 G/L (range, 1-449). Oncogenetic analyses allowed classifying ALL as Ph-like (18%), KMT2A-r (17%), DUX4/ERGdel (13%), ZNF384-r (11%), low hypodiploidy/near triploidy (7%), B-other (26%) or unknown (9%). An IKZF1del was found in 37/93 (40%). A TP1-MRD ≥ 0.01% was found in 46/94 patients (49%). Final risk group was HR for 45 patients and VHR for 49 patients. Last pre-blinatumomab MRD was Conclusion. In patients wih high-risk BCP-ALL, blinatumomab added to consolidation is safe and gives promising results. A comparison to similar patients treated in the same GRAALL-2014 study before October 2018 is planned with a longer follow-up. Figure 1 Figure 1. Disclosures Boissel: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; SANOFI: Honoraria; Servier: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; CELGENE: Honoraria; JAZZ Pharma: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Delabesse: Astellas: Consultancy; Novartis: Consultancy. Dombret: Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; NOVARTIS: Research Funding; pfizer: Honoraria, Research Funding; servier: Research Funding; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. OffLabel Disclosure: Blinatumomab in frontline high-risk acute lymphoblastic leukemia

TO THE EDITOR: B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a rare aggressive malignancy in adults. BCP-ALL is frequently characterized by recurrent chromosomal translocations that deregulate proto-oncogenes or result in fusion genes encoding chimeric oncoproteins.[1][1] Gene

T-cell acute lymphoblastic leukemia (T-ALL) is a group of aggressive hematological cancers with dismal outcomes that are in need of new therapeutic options. Polycomb repressor complex 2 (PRC2) loss-of-function alterations were reported in pediatric T-ALL, yet their clinical relevance and functional consequences remain elusive. Here, we extensively analyzed PRC2 alterations in a large series of 218 adult T-ALL patients. We found that PRC2 genetic lesions are frequent events in T-ALL and are not restricted to early thymic precursor ALL. PRC2 loss of function associates with activating mutations of the IL7R/JAK/STAT pathway. PRC2-altered T-ALL patients respond poorly to prednisone and have low bone marrow blast clearance and persistent minimal residual disease. Furthermore, we identified that PRC2 loss of function profoundly reshapes the genetic and epigenetic landscapes, leading to the reactivation of stem cell programs that cooperate with bromodomain and extraterminal (BET) proteins to sustain T-ALL. This study identifies BET proteins as key mediators of the PRC2 loss of function-induced remodeling. Our data have uncovered a targetable vulnerability to BET inhibition that can be exploited to treat PRC2-altered T-ALL patients.

International audience; The prognostic value of IL7-receptor pathway (IL7Rp) mutations in T-cell acute lymphoblastic leukemia (T-ALL) remains unclear. We performed a comprehensive study of 200 adult patients with TALL included in the GRAALL2003/2005 protocols to address the clinical significance of IL7Rp mutations. Next-generation sequencing of the IL7Rp (IL7R/JAK1/ JAK3/STAT5B) revealed that IL7Rp mutations were frequent in adult TALL (28%) particularly in immature/early T-cell progenitor (ETP)-ALL. They were associated with mutations of NOTCH-pathway, PHF6, and PRC2 components but not with K/NRAS. IL7Rp mutated (IL7Rp mut) TALL were slow-responders, with a high rate of M2/M3 day-8 marrow compared with IL7Rp non-mutated (IL7Rp WT) TALL (p = 0.002) and minimal residual disease positivity at 6-weeks (MRD1) (p = 0.008) but no difference in MRD2 positivity at 12-weeks. Despite this, no adverse prognosis was evidenced when censored for allogeneic hematopoietic stem cell transplantation (HSCT). In time-dependent analysis, HSCT did not benefit IL7Rp mut patients whereas it was of marked benefit to IL7Rp WT cases. IL7Rp-mutations identify a subgroup of slow-responder T-ALLs which benefit from post-induction chemotherapy regimens but not from HSCT. Our data suggest that prior knowledge of the mutation status of IL7Rp may influence HSCT decision and help to guide therapy reduction.

International audience; Patients undergoing treatment for acute lymphoblastic leukemia (ALL) are at risk for thrombosis, in part due to the use of L-asparaginase (L-ASP). Antithrombin (AT) replacement has been suggested to prevent VTE and thus might increase exposure to ASP. We report herein the results of the prophylactic replacement strategy in the pediatric-inspired prospective GRAALL-2005 study. Between 2006 and 2014, 784 adult patients with newly diagnosed Philadelphia-negative ALL were included. The incidence rate of VTE was 16% with 69% of them occurring during induction therapy. Most patients received AT supplementation (87%). After excluding patients who did not receive L-ASP or developed thrombosis before L-ASP, AT supplementation did not have a significant impact on VTE (8% versus 14%, OR: 0.6, p=0.1). Fibrinogen concentrates administration was associated with an increased risk of VTE (17% versus 9%, OR 2.2, p=0.02) whereas transfusion of fresh-frozen plasma had no effect. Heparin prophylaxis was associated with an increased risk of VTE (13% versus 7%, OR 1.9, p=0.04). Prophylactic measures were not associated with an increased risk of grade 3-4 bleeding complications. The rate of VTE recurrence after L-ASP reintroduction was 3% (1/34). In ALL patients receiving L-ASP therapy, the use of fibrinogen concentrates may increase the risk of thrombosis and should be restricted to rare patients with hypofibrinogenemia-induced hemorrhage. Patients developed VTE despite extensive AT supplementation which advocates for additional prophylactic measures. While this large descriptive study was not powered to demonstrate the efficacy of these prophylactic measures, it provides important insight to guide future trial design. NCT00327678.

On behalf of the GRAALL group. Introduction. Tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of patients diagnosed with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). In a previous randomized trial (GRAAPH-2005; Chalandon Y., Blood 2015), our group demonstrated that anthracycline and cyclophosphamide could be safely omitted during the first Hyper-CVAD chemotherapy cycle when combined to imatinib. In the present GRAAPH-2014 trial, we investigated whether the use of nilotinib, a 2 nd generation TKI, would allow further decreasing chemotherapy intensity through the omission of high-dose cytarabine (HD-AraC) during consolidation cycles 2 and 4. Methods. From March 2016, patients aged 18-60 years old were randomized frontline to receive 4 cycles (1=3, 2=4) of chemotherapy combined with continuous nilotinib 400 mg bid. Cycle 1 and 3 were similar in both arms, identical to the less-intensive first cycle of the previous GRAAPH-2005 trial with weekly vincristine and dexamethasone and nilotinib instead of imatinib. Cycle 2 and 4 differed between control arm A (MTX 1 g/sqm over 24h, HD-AraC 3 g/sqm/12h for 2 days) and experimental arm B (MTX 1 g/sqm over 24h only). Marrow minimal residual disease (MRD) was assessed by both BCR-ABL1 and IG-TCR qPCR after each cycle (MRD1-4). Patients in complete remission (CR) after cycle 4 were eligible to receive allogeneic stem cell transplant (alloSCT). Non allografted patients had the option to receive autologous SCT (autoSCT) if a major molecular response (MMolR) (MRD4 BCR-ABL1 40y) and BCR-ABL1 breakpoint region (M/m-bcr). MMolR rate at MRD4 was the primary endpoint of this non-inferiority study, with a margin set at 0.15. In February 2019, the study DSMB decided to stop the randomizations after an unplanned analysis demonstrating a significant excess of relapse in arm B (without HD-AraC). An intention-to-treat analysis is provided. All patients gave informed consent. The study is registered at EudraCT under the number: 2014-002146-44. Results. A total of 156 patients were randomized (77 in arm A, and 79 in arm B). Median age was 47.1 years old (range 18.1-59.9). One-hundred and ten patients had the m-bcr (70.5%) and 46 (29.5%) the M-bcr. An IKZF1 intragenic deletion was found in 87/153 (56.9%). Median follow-up was 2.8 years (95%CI 2.6-3.1). All evaluable patients reached CR after a maximum of two cycles. Three patients died during cycle 1 (2 in arm A, 1 in arm B), and 2 during cycle 2 (1 per arm). Most patients received the 4 scheduled cycles (n=143, 91,7%). AlloSCT was performed in 91 patients (58.3%), whereas 41 patients received an autoSCT (26.3%) with no difference in allo/autoSCT rates between arms. A non-inferiority in late MRD response (MRD4) between the two arms was observed (primary endpoint). MMolR was reached in 55/75 (73.3%) and 61/78 (78.2%) of CR patients in arm A and B, respectively, with an estimated 95% CI of difference of -11% to +16% (-9.2% to +20.8% in the ITT analysis treating missing data as failures). At 3 years, overall survival (OS) was 86.0% in arm A versus 74.2% in arm B (p=.08, Figure A). Progression-free survival (PFS) was 79.6% in arm A versus 57.2% in arm B (p=.008, Figure B). Thirty-one patients experienced hematological relapse (8 in arm A and 23 in arm B). Twenty-height out of 31 relapsed patients were tested for the acquisition of BCR-ABL1 mutations, 20/28 (71%) had at least one mutation and 10/28 (36%) had a T315I mutation. At 3 years, the cumulative incidence of relapse (CIR) was 21.3%, significantly higher in arm B than in arm A (30.8% vs 10.6%, p=.007). When analyzing the CIR considering alloSCT as a competing event for relapse, a significant higher CIR was still observed in arm B as compared to arm A (Figure C). Conclusion. Four cycles of the combined administration of nilotinib and chemotherapy is very efficient for bridging younger adults with Ph-positive ALL to SCT. However, omitting HD-AraC is associated with a higher relapse incidence despite non-inferior levels of BCR-ABL1 MRD4. Figure 1 Figure 1. Disclosures Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Vincent: Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Raffoux: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ASTELLAS: Consultancy; ABBVIE: Consultancy. Boissel: Amgen: Consultancy, Honoraria, Research Funding; CELGENE: Honoraria; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. OffLabel Disclosure: Nilotinib as a therapy for PH-positive acute lymphoblastic leukemia

Background IG/TR-based minimal residual disease (MRD) is a faithful marker of response to therapy and the strongest predictor of relapse in acute lymphoblastic leukemia (ALL). In adults with Philadelphia chromosome-positive (Ph+) ALL, MRD is commonly monitored by BCR-ABL1 transcript quantification, although its prognostic significance has not been compared to IG/TR MRD to date. Recently, it has been shown that BCR-ABL1 rearrangement may be found and persist in non-lymphoblastic cells in some patients. In the prospective GRAAPH-2014 trial, using a dual IG/TR and BCR-ABL1 MRD monitoring, we aimed to study the biological and clinical significance of persistent BCR-ABL1 clonal hematopoiesis (CH) in adults with de novo Ph+ ALL. Patients and Methods The study comprised 156 adults with de novo Ph+ ALL randomized in the GRAAPH-2014 trial. Bone marrow (BM) and peripheral blood (PB) follow-up (FU) samples were collected after each treatment cycle and before hematopoietic stem cell transplantation (HSCT). MRD monitoring was performed by quantification of both BCR-ABL1 transcripts and IG/TCR clonal rearrangements on all available samples and MRD quantification of genomic BCR-ABL1 breakpoint fusion was also performed for 37 patients. MRD results were considered discordant if more than one log10 difference or positivity/negativity discordance on the same FU sample was evidenced. Cell fractions from 14 peripheral blood mononuclear cells (PBMC) samples (T-cells, B-cells and monocytes) were FACS-sorted and evaluated for BCR-ABL1 expression. Achievement of major molecular response (MMR) defined as Results Quantification of BCR-ABL1 transcripts and IG/TR MRD levels on 876 samples from 156 patients (456 BM and 542 PB) identified 54 out of 142 (38%) evaluable patients with consistently discordant MRD results in at least 3 different timepoints, suggesting the persistence of non-lymphoblastic BCR-ABL1-positive cells in these patients and BCR-ABL1 CH. Possible bias related to variable BCR-ABL1 expression was ruled out by genomic BCR-ABL1 quantification on 263 FU samples (r s=0.89, p We then evaluated the clinical significance of BCR-ABL1 CH. Unexpectedly, CH+ patients had a significant lower cumulative incidence of relapse (CIR) (panel A, hazard ratio (HR) 0.37, 95% CI [0.15-0.90], p=0.03). However, this lower CIR did not translate into longer disease-free survival (DFS) (panel B, HR=0.85, 95% CI [0.44-1.63], p=0.63). Since an imbalance in alloSCT was observed between CH+ and CH- patients, we tested if the observed difference in CIR may be related to different alloSCT outcomes. When censoring patients at alloSCT, the difference in CIR was indeed no longer significant (subhazard ratio (SHR) 0.48, 95% CI [0.16-1.43], p=0.19). More interestingly, the benefit of alloSCT was restricted to CH- patients. Using alloSCT as a time-dependent variable, DFS was indeed improved by alloSCT in CH- (SHR 0.40, 95% CI [0.17-0.91], p=0.03, panel C) but not in CH+ patients (SHR 1.12, 95%CI [0.32-3.87], p=0.86, panel D) despite a non-significant interaction between CH status and alloSCT. Conclusion More than one third of adults with de novo Ph+ ALL displays persistent measurable BCR-ABL1 signal during therapy, likely related to BCR-ABL1 CH. Strikingly, this condition is not associated with a higher risk of relapse nor with poorer overall outcomes in the GRAAPH-2014 trial. Moreover, our results suggest that patients with BCR-ABL1 CH may not be good candidates for alloSCT. By contrast, IG/TR MRD may allow to identify patients with the higher risk of relapse. These results highlight the need for implementation of IG/TR MRD in adult Ph+ ALL to guide therapeutic decisions. Figure 1 Figure 1. Disclosures Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Straetmans: Alexion: Membership on an entity's Board of Directors or advisory committees. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Boissel: SANOFI: Honoraria; CELGENE: Honoraria; Servier: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; PFIZER: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding.

The prognostic implications of DNMT3A genotype in T-cell acute lymphoblastic leukemia are incompletely understood. We performed comprehensive genetic and clinico-biological analyses of T-cell acute lymphoblastic leukemia patients with DNMT3A mutations treated during the GRAALL-2003 and -2005 studies. Eighteen of 198 cases (9.1%) had DNMT3A alterations. Two patients also had DNMT3A mutations in non-leukemic cell DNA, providing the first potential evidence of age-related clonal hematopoiesis in T-cell acute lymphoblastic leukemia. DNMT3A mutation was associated with older age (median 43.9 years vs. 29.4 years, P

International audience; no abstract

Purpose To evaluate randomly the role of hyperfractionated cyclophosphamide (hyper-C) dose intensification in adults with newly diagnosed Philadelphia chromosome–negative acute lymphoblastic leukemia treated with a pediatric-inspired protocol and to determine the upper age limit for treatment tolerability in this context. Patients and Methods A total of 787 evaluable patients (B/T lineage, 525 and 262, respectively; median age, 36.1 years) were randomly assigned to receive a standard dose of cyclophosphamide or hyper-C during first induction and late intensification. Compliance with chemotherapy was assessed by median doses actually received during each treatment phase by patients potentially exposed to the full planned doses. Results Overall complete remission (CR) rate was 91.9%. With a median follow-up of 5.2 years, the 5-year rate of event-free survival (EFS) and overall survival (OS) was 52.2% (95% CI, 48.5% to 55.7%) and 58.5% (95% CI, 54.8% to 61.9%), respectively. Randomization to the hyper-C arm did not increase the CR rate or prolong EFS or OS. As a result of worse treatment tolerance, advanced age continuously affected CR rate, EFS, and OS, with 55 years as the best age cutoff. At 5 years, EFS was 55.7% (95% CI, 51.8% to 59.4%) for patients younger than 55 years of age versus 25.8% (95% CI, 19.9% to 35.6%) in older patients (hazard ratio, 2.16; P < .001). Patients ≥ 55 years of age, in whom a lower compliance to the whole planned chemotherapy was observed, benefited significantly from hyper-C, whereas younger patients did not. Conclusion No significant benefit was associated with the introduction of a hyper-C sequence into a frontline pediatric-like adult acute lymphoblastic leukemia therapy. Overall, tolerability of an intensive pediatric-derived treatment was poor in patients ≥ 55 years of age.

Central nervous system (CNS) thrombotic events are a well-known complication of acute lymphoblastic leukemia (ALL) induction therapy, especially with treatments including l-asparaginase (l-ASP). Data on risk factors and clinical evolution is still lacking in adult patients. We report on the clinical evolution of 22 CNS venous thrombosis cases occurring in 708 adults treated for ALL or lymphoblastic lymphoma (LL) with the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-induction protocol, which included eight L-ASP (6,000 IU/m2) infusions. The prevalence of CNS thrombosis was 3.1%. CNS thrombosis occurred after a median of 18 days (range: 11–31) when patients had received a median of three l-ASP injections (range: 2–7). Patients with CNS thrombosis exhibited a median antithrombin (AT) nadir of 47.5% (range: 36–67%) at Day 17 (range: D3–D28), and 95% of them exhibited AT levels lower than 60%. There were no evident increase in hereditary thrombotic risk factors prevalence, and thrombosis occurred despite heparin prophylaxis which was performed in 90% of patients. Acquired AT deficiency was frequently detected in patients with l-ASP-based therapy, and patients with CNS thrombosis received AT prophylaxis (45%) less frequently than patients without CNS thrombosis (83%), P = 0.0002). CNS thrombosis was lethal in 5% of patients, while 20% had persistent sequelae. One patient received all planned l-ASP infusions without recurrence of CNS thrombotic whereas l-ASP injections were discontinued in 20 patients during the management of thrombosis without a significant impact on overall survival (P = 0.4). Am. J. Hematol. 90:986–991, 2015. © 2015 Wiley Periodicals, Inc

International audience; Little data have been published concerning invasive fungal infections during treatment of acute lymphoblastic leukemia (ALL). Patients included between May 2006 and October 2012 in the multicenter phase III trial for newly diagnosed ALL (GRAALL-2005) were retrospectively reviewed for the occurrence of IFI using the EORTC modified criteria. These patients did not routinely receive antifungal prophylaxis. Among 969 patients included (median age 47 years), 65 (6.7%) developed IFI during induction chemotherapy: 26 (3.3%) invasive aspergillosis (IA), 33 (3.4%) invasive candidiasis (IC) and six other IFI. For IA, the median time between induction therapy and IA diagnosis was 20 days. Diagnosis was probable in 22 cases and proven in four. Aspergillus antigen in serum was tested in all cases and positive in 24. Overall 12-week mortality after diagnosis of IA was 5/26 and attributable mortality related to the infection was 4/26 (15.4%). For IC, the median time between induction therapy and diagnosis was 19 days. Diagnosis was proven in 29 episodes. Candida albicans was the major pathogen in yeast infections (16/27). Overall 12-week mortality after diagnosis of IC was 8/33 (24.2%) and attributable mortality related to the infection was 7/33. The median delay between induction chemotherapy initiation and attributable death related to IC was 15 days. These findings may help to optimize the future management of ALL patients, and as in AML advocate systematic monitoring and the development of prophylactic or preemptive antifungal treatments.

A high proportion of Ph-positive Acute Lymphoblastic Leukemia (Ph+ ALL) patients still undergo relapses despite the use of Tyrosine Kinase Inhibitors (TKIs) in addition to chemotherapy as frontline therapy. In this leukemia subtype, the role of BCR-ABL1 kinase domain (KD) mutations as a driver of resistance to TKIs has already been documented by previous studies and such mutations have been reported in up to 80% of the patients at relapse. Next-generation sequencing (NGS) has been proposed to characterize these mutations with a higher sensitivity than Sanger. We report here a prospective study aiming at detecting potentially resistant cell populations by NGS in Ph+ ALL patients enrolled in the GRAAPH 2014-trial. Between March 2016 and February 2019, 156 patients aged 18 to 59 years with newly diagnosed Ph+ and/or BCR-ABL1 positive ALL have been included in the GRAAPH 2014 trial (NCT02619630). BCR-ABL1 isoforms were E1A2 69%, B2A2/B3A2 29%, atypical 2%. After a prephase of steroid, treatment consisted of 4 blocks of chemotherapy + nilotinib. 118 patients (76%) underwent allogeneic or autologous stem cell transplantation (SCT). 22 medullary relapses were recorded within a median time of 9 months (range, 2 - 35). Blood and marrow samples harvested at diagnosis, after each treatment block, before and 3 months after SCT, and at relapse, were sequenced if BCR-ABL1/ABL1 ratio were above 0.001. Mutated BCR-ABL1 transcripts were detected by sequencing the KD of BCR-ABL1 transcripts by NGS with a limit of detection (LOD) of 0.03. T315I allele specific oligonucleotide (ASO) droplet digital RT-PCR (ddRT-PCR) with a LOD of 0.0005 was also performed at diagnosis on a subset of 63 patients, including 5 who have subsequently developed a T315I clone. NGS. At diagnosis, no KD mutation was found by NGS in pretreatment samples of 137 patients. During follow-up (FU), only 12 mutations were found by NGS in 7 out of the 88 patients tested (81, 45, 30, 20, 19, 9 after block 1, 2, 3, 4, before and 3 months after SCT, respectively). Mutations were T315I (N=6), Y253H (N=1), E255K (N=2), E255V (N=1), Q252H (N=1), Y253F (N=1). At relapse, 16 mutations were identified by NGS in 12 patients out of the 17 tested (71%). Mutations were T315I (N=7), Y253H (N=n=3), F359V (N=2), E255K (N=1), E255V (N=1), Q252H (N=1), Y253F (N=1). More than 1 mutated clone were present in 2 patients (E255V+T315I+F359V and Y253H+F359V), and a compound mutation was found in 1 patient (Q252H/Y253F). Out of the 7 patients found mutated during FU, 5 have relapsed with a rapid expansion (1 to 3 months) of the mutated clone. One patient harboring a sub-clonal (10%) E255K at MRD1 has relapsed 9 months later without any detectable mutation. One patient identified with 3 mutated clones (E255K 10%, E255V 10%, T315I 80%) underwent SCT and has not relapsed so far. We failed to anticipate expansion of any mutated clone in the 7 remaining patients found mutated at relapse. T315I ASO ddRT-PCR on diagnostic samples. Low-level T315I mutated BCR-ABL1 transcripts (0.00051 to 0.0013) were detected in 14 out of 63 patients (24%) tested. Only one has expanded a T315I clone later on. In the context of the GRAAPH 2014 trial, 71% of the 17 relapses tested so far were associated with BCR-ABL1 KD mutations. Expansion of the mutated clone could have been characterized before the onset of hematological relapses in only 5 out of 12 patients (42%). Unfortunately in these cases, lags between first detection and relapse were very short (1 to 3 months). On the contrary, occurrences of relapses associated with expansion of KD-mutated clones could not have been anticipated in 58%. All mutations identified, including T315I, F359V, E255K/V and Y253F/H, Q252H/Y253F are known for conferring resistance to nilotinib. NGS is a valuable method for KD mutation detection in Ph+ ALL. It allows a quantitative characterization of KD mutations at relapse. However in our hands and in the context of an intensive therapy combining chemotherapy, nilotinib and SCT, its enhanced sensitivity as compared to Sanger (3% vs 20%) does not translate into the capacity of anticipating expansion of KD-mutated clones. Moreover, in this study, NGS did not detect any mutation in pre-therapeutic samples while T315I mutated BCR-ABL1 transcripts were found at low-level in 24% of these samples by ddRT-PCR. However it should be emphasized that when detected, low-level T315I mutated sub-clones present at diagnosis failed to expand in most instances. Disclosures Cayuela: Incyte: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Chalandon:Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Incyte Biosciences: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Rousselot:Pfizer: Research Funding. Thomas:PFIZER: Honoraria; ABBVIE: Honoraria; INCYTE: Honoraria; DAICHI: Honoraria. Huguet:Amgen: Honoraria; Servier: Honoraria; Jazz Pharmaceuticals: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Incyte Biosciences: Honoraria; Novartis: Honoraria. Chevallier:Incyte: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria. Boissel:NOVARTIS: Consultancy. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. Berthon:PFIZER: Other: DISCLOSURE BOARD; JAZZPHARMACEUTICAL: Other: DISCLOSURE BOARD; CELGEN: Other: DISCLOSURE BOARD.

The outcome of adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph− ALL) relapsing after pediatric-inspired front-line therapy is ill known. Here 229 relapsing Ph− ALL younger adults (18–63 years) treated within the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/-2005 trials were considered. Salvage regimens consisted of potentially curative therapies in 194 cases, low-intensity therapies in 21, allogeneic stem cell transplant (allo-SCT) in 6 and best supportive care in 8. Overall, 77 patients received allo-SCT after relapse. The median follow-up was 3.1 years. A second complete remission (CR2) was achieved in 121 patients (53%). In multivariate analysis, only younger age P=0.008) and CR1 duration ⩾18 months (P=0.009) predicted CR2. Overall survival (OS) at 2 and 5 years was 19.3% (14–24%) and 13.3% (8–18%), respectively. In CR2 patients, disease-free survival (DFS) at 2 and 5 years was 29.0% (21–38%) and 25% (17–33%). In multivariate analysis, CR1 duration ⩾18 months and allo-SCT after relapse were associated with longer DFS (PP=0.004, respectively) and longer OS (P=0.004 and P

International audience; Treatment with rituximab has improved the outcome for patients with non-Hodgkin's lymphoma. Patients with B-lineage acute lymphoblastic leukemia (ALL) may also have the CD20 antigen, which is targeted by rituximab. Although single-group studies suggest that adding rituximab to chemotherapy could improve the outcome in such patients, this hypothesis has not been tested in a randomized trial. We randomly assigned adults (18 to 59 years of age) with CD20-positive, Philadelphia chromosome (Ph)-negative ALL to receive chemotherapy with or without rituximab, with event-free survival as the primary end point. Rituximab was given during all treatment phases, for a total of 16 to 18 infusions. From May 2006 through April 2014, a total of 209 patients were enrolled: 105 in the rituximab group and 104 in the control group. After a median follow-up of 30 months, event-free survival was longer in the rituximab group than in the control group (hazard ratio, 0.66; 95% confidence interval [CI], 0.45 to 0.98; P=0.04); the estimated 2-year event-free survival rates were 65% (95% CI, 56 to 75) and 52% (95% CI, 43 to 63), respectively. Treatment with rituximab remained associated with longer event-free survival in a multivariate analysis. The overall incidence rate of severe adverse events did not differ significantly between the two groups, but fewer allergic reactions to asparaginase were observed in the rituximab group. Adding rituximab to the ALL chemotherapy protocol improved the outcome for younger adults with CD20-positive, Ph-negative ALL. (Funded by the Regional Clinical Research Office, Paris, and others; ClinicalTrials.gov number, NCT00327678 .)

Background: Patients undergoing treatment for acute lymphoblastic leukemia (ALL) are at risk for thrombosis, in part due to the use of L-asparaginase (L-ASP) and subsequent antithrombine (AT) deficiency. Previous reports showed that patients with venous thrombotic events (VTE) have a lower event-free survival that may be due to early discontinuation of L-ASP. It has been suggested that AT replacement could decrease the rate of thrombosis and prevent L-ASP discontinuation. We report herein the results of the prophylactic replacement strategy in the pediatric-inspired prospective GRAALL-2005 study. Methods: All patients received a 5-drug induction therapy with 8 native E. Coli-ASP intravenous injections (6,000 UI/m2/injection). Patients in complete remission (CR) received two consolidation courses each containing two L-ASP intravenous injections (10000 UI/m2/injection). All patients in persistent CR for whom allogeneic stem cell transplantation was not indicated in first CR received a late intensification with the same drugs as in the induction course, followed by the repetition of one consolidation course. Platelet transfusion support was recommended for platelets below 20 x 109/L, fresh frozen plasma (FFP) or fibrinogen concentrates were recommended if fibrinogen levels fell below 0.5 g/L, and AT concentrate substitution therapy was recommended in order to maintain AT levels above 60%. Prophylactic heparin was recommended during induction and late intensification. All cases of VTE were identified prospectively by clinical signs and confirmed by radiological imaging based on institutional guidelines. Results: Between 2006 and 2014, 787 adult patients with newly diagnosed Philadelphia-negative ALL were included. The incidence rate of VTE was 14.4% (113 VTEs in 110 patients). VTEs included 72 (64%) deep vein thromboses (DVT), with one third in the lower limb and two thirds in the upper limb, 32 (28%) cerebral venous thrombosis (CVT), and 13 (12%) pulmonary embolism (PE). No disease characteristic was associated with a higher risk of thrombosis. Patients with DVT and/or PE were older (median age of 40 versus 38 for those with CVT versus 35 for those without VTE, p=0.04), had a higher BMI (median BMI of 26 versus 23 for those with CVT and 24 for those without VTE, p=0.01), and had a higher platelet count at diagnosis (median platelet count of 100 G/l versus 84 G/l for those with CVT versus 68 G/l for those without VTE, p=0.06) whereas patients with CVT had higher hemoglobin levels (median hemoglobin level of 11.7 g/dl versus 10.1 g/dl for those with DVT/PE versus 10.2 g/dl for those without VTE, p=0.03). Sixty-seven percent of VTEs occurred during induction therapy. Other VTEs occurred as follows: 17 (15%) during consolidation phase 1 (688 patients), 4 (4%) during consolidation phase 2 (537 patients), 9 (8%) during late intensification (356 patients), and 7 (6%) in 335 during consolidation phase 3 (335 patients). The type of thrombosis was different according to treatment phase as most CVT occurred during induction therapy (29 versus 3 CVTs during subsequent phases of treatment, p=0.003). During induction therapy, patients with VTE were more likely to have received heparin prophylaxis (82% versus 60% for those without VTE, odds ratio (OR) 1.8, p=0.06) and fibrinogen prophylaxis (14% versus 8% for those without VTE, OR 2, p=0.05) whereas they received less AT prophylaxis (82% versus 88% for those without VTE, OR 0.5, p=0.05). Patients with VTE received less L-ASP infusions during induction therapy (median number of 7 versus 8 injections for those without VTE, p Conclusion: In ALL patients receiving L-ASP therapy, appropriate AT prophylaxis was associated with less VTE and should be used extensively. Maintaining higher AT levels in patients at increased risk for VTE should be evaluated. L-ASP can be reintroduced in patients who experienced VTE during induction as none had thrombotic recurrence. Fibrinogen concentrates may increase the risk of thrombosis and should be restricted to patients with hemorrhage. Disclosures Dombret: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Outcome of adult acute lymphoblastic leukemia (ALL) with central nervous system (CNS) involvement is not clearly defined. We studied 104 patients presenting with CNS involvement at diagnosis among 1493 patients (7%) included into the LALA trials, and 109 patients presenting CNS disease at the time of first relapse among the 709 relapsing patients (15%). Eighty-seven patients (84%) with CNS leukemia at diagnosis achieved complete remission (CR). Fifty-three patients underwent stem cell transplantation (SCT): 25 allogeneic SCT, 28 autologous SCT, while 34 continued with chemotherapy alone. Seven-year overall survival (OS) and disease-free survival (DFS) were 34% and 35%, respectively. There were no significant differences in terms of CR, OS and DFS among patients with CNS involvement at diagnosis and those without CNS disease. There were also no differences among the two groups regarding T lineage ALL, B lineage ALL, and among those who underwent SCT. After a first relapse, 38 patients with CNS recurrence (35%) achieved a second CR. The median OS was 6.3 months. Outcome was similar to that of relapsing patients without CNS disease. CNS leukemia in adult ALL is uncommon at diagnosis as well as at the time of first relapse. With intensification therapy, patients with CNS leukemia at diagnosis have a similar outcome than those who did not present with CNS involvement. CNS leukemia at first relapse remains of similar poor prognosis than all other adult ALL in first relapse.

BACKGROUND. Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). Although treatment intensity and outcome were not comparable, with improvements in survival it is important to evaluate the rate and the type of second neoplasms in adults with ALL. METHODS. The data from the GET-LALA group were analyzed. A cohort of 1494 patients, aged 15 to 60 years and enrolled in 2 successive multicenter protocols between 1987 and 2002, was observed to determine the incidence of second neoplasms and associated risk factors. The median follow-up from diagnosis was 6 years. RESULTS. By February 2005 secondary or concomitant neoplasms were documented in 23 patients, including 9 acute myeloid leukemias (AML) or myelodysplasias (MDS), 4 non-Hodgkin lymphomas (NHL), 5 skin tumors, and 5 other solid tumors (1 lung cancer, 1 tongue carcinoma, 1 thymoma, 1 condrosarcoma, 1 histiocytosis). Neoplasms developed 0.5 to 13.8 years (median, 4.5 years) after the diagnosis of ALL. There were 22 patients in first remission and 1 was in second remission. The overall cumulative risk of secondary neoplasms was 2.1% at 5 years, 4.9% at 10 years, and 9.4% at 15 years. The cumulative risk of developing a second hematologic malignancy was 1.8% at 5 years, 2.2% at 10 years, 3.3% at 18 years; that of developing a solid tumor was 0.2% at 5 years, 2.8% at 10 years, 6.2% at 15 years. The development of secondary neoplasm was not associated with the use of any specific cytotoxic agent. However, the risk of skin tumor increased with radiation dose and transplantation (P = .01). Overall survival (OS) after the diagnosis of a second malignant neoplasm was 55% at 10 years. However, the median OS in patients developing AML/MDS was 5.7 months. CONCLUSIONS. The data document that adult ALL survivors are at an increased risk of later malignancy. The risk of secondary or concomitant neoplasm appeared higher than that of childhood ALL previously reported in the literature. Considering the low survival rate of this large unselected adult ALL cohort (32% at 10 years) as compared with that observed in childhood ALL, the risk of second malignancy remains underestimated. Larger series with long-term follow-up are necessary, as well as methods of screening and identification of patients at increased risk. Cancer 2007. © 2007 American Cancer Society.

Acute lymphoblastic leukemia ( ALL) in the elderly is characterized by its ominous prognosis. On the other hand, imatinib has demonstrated remarkable, although transient, activity in relapsed and refractory Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL), which prompted us to assess the use of imatinib in previously untreated elderly patients. ALL patients aged 55 years or older were given steroids during 1 week. Ph+ve cases were then offered a chemotherapy-based induction followed by a consolidation phase with imatinib and steroids during 2 months. Patients in complete response (CR) after consolidation were given 10 maintenance blocks of alternating chemotherapy, including two additional 2-month blocks of imatinib. Thirty patients were included in this study and are compared with 21 historical controls. Out of 29 assessable patients, 21 (72%, confidence interval (CI): 53 - 87%) were in CR after induction chemotherapy vs 6/21 (29%, CI: 11 - 52%) in controls (P = 0.003). Five additional CRs were obtained after salvage with imatinib and four after salvage with additional chemotherapy in the control group. Overall survival ( OS) is 66% at 1 year vs 43% in the control group ( P = 0.005). The 1-year relapse-free survival is 58 vs 11% ( P = 0.0003). The use of imatinib in elderly patients with Ph+ ALL is very likely to improve outcome, including OS.

To evaluate the results of autologous stem cell transplantation (ASCT) in a large population of adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR), we performed an individual data-based overview of the last three trials from the LALA group. Overall, 349 patients with ALL prospectively randomized in the consecutive LALA-85, -87, and -94 trials to receive either ASCT or chemotherapy as post-CR treatment were analyzed. Eligibility criteria were 15-50-year-old patients without sibling donors in both LALA-85/87 trials and 15-55-year-old patients with high-risk ALL and no sibling donors in the LALA-94 trial. Intent-to-treat analysis, which compared 175 patients from the ASCT arm to 174 patients from the chemotherapy arm, showed that ASCT was associated with a lower cumulative incidence of relapse (66 vs 78% at 10 years; P=0.05), without significant gain in disease-free or overall survival. Despite a possible lack of statistical power, a nested case-control analysis performed in 85 patient pairs adjusted for time to transplant and prognostic covariates confirmed these intent-to-treat results in patients actually transplanted. Of interest, the reduced relapse risk after ASCT translated in better disease-free survival in the 300 rapid responders who reached CR after the first induction course.

Purpose We analyzed the benefits of a risk-adapted postremission strategy in adult lymphoblastic leukemia (ALL), and re-evaluated stem-cell transplantation (SCT) for high-risk ALL. Patients and Methods A total of 922 adult patients entered onto the trial according to risk groups: standard-risk ALL (group 1), high-risk ALL (group 2), Philadelphia chromosome-positive ALL (group 3), and CNS-positive ALL (group 4). All received a standard four-drug/4-week induction course. Patients from group 1 who achieved a complete remission (CR) after one course of induction therapy were randomly assigned between intensive and less intensive postremission chemotherapy, whereas those who achieved CR after salvage therapy were then included in group 2. Patients in groups 2, 3, and 4 with an HLA-identical sibling were assigned to allogeneic SCT. In groups 3 and 4, autologous SCT was offered to all other patients, whereas in group 2 they were randomly assigned between chemotherapy and autologous SCT. Results Overall, 771 patients achieved CR (84%). Median disease-free survival (DFS) was 17.5 months, with 3-year DFS at 37%. In group 1, the 3-year DFS rate was 41%, with no difference between arms of postremission randomization. In groups 2 and 4, the 3-year DFS rates were 38% and 44%, respectively. In group 2, autologous SCT and chemotherapy resulted in comparable median DFS. Patients with an HLA-matched sibling (groups 2 and 4) had improved DFS. Three-year DFS was 24% in group 3. Conclusion Allogeneic SCT improved DFS in high-risk ALL in the first CR. Autologous SCT did not confer a significant benefit over chemotherapy for high-risk ALL.

Summary. Biphenotypic acute leukaemia with T-lymphoid and myeloid markers is rare and poorly documented. In the Leucemie Aigue Lymphoblastique de l'Adulte (LALA) prospective trial (LALA 94) of treatment for adult acute lymphoblastic leukaemia (ALL), seven patients (0·86%) had T-biphenotypic forms. The clinical and biological characteristics and outcome of these seven patients are reported here. The patients’ median age was 35 years. At diagnosis, all had a tumoural syndrome and five had a mediastinal mass. In all the cases, leukaemic cells expressed myeloid and lymphoid markers. Two patients (28%) entered complete remission (CR) after induction chemotherapy. Four of the five remaining and assessable patients entered CR after designed salvage chemotherapy with mitoxantrone and high-dose cytosine arabinoside. Three patients are currently in CR. Three patients died, from treatment toxicity in two cases and progressive disease in one case. One patient relapsed 6 months after allogeneic bone marrow transplantation and is still alive. Thus, biphenotypic T-acute leukaemia is clinically frequently associated with mediastinal involvement and the response to conventional chemotherapy used in ALL is poor. However, sustained CR can be acheived by salvage chemotherapy combining an intercalating agent with high-dose cytosine arabinoside, as used in acute myeloid leukaemia.

With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by immunoglobulin/T-cell receptor minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome-negative ALL in first remission (265 B-cell precursor [BCP] and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as the primary end point. In addition to conventional risk factors, the most frequent currently available genetic alterations were included in the analysis. A higher specific hazard of relapse was independently associated with postinduction MRD level ≥10(-4) and unfavorable genetic characteristics (ie, MLL gene rearrangement or focal IKZF1 gene deletion in BCP-ALL and no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN gene alteration in T-cell ALL). These 2 factors allowed definition of a new risk classification that is strongly associated with higher CIR and shorter relapse-free and overall survival. These results indicate that genetic abnormalities are important predictors of outcome in adult ALL not fully recapitulated by early response to therapy. Patients included in this study were treated in the multicenter GRAALL-2003 and GRAALL-2005 trials. Both trials were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.

PURPOSE: To analyze the impact of pre- and posttransplantation factors on the outcome of allogeneic transplantation after nonmyeloablative conditioning regimens. PATIENTS AND METHODS: Ninety-two allogeneic transplantations after nonmyeloablative preparative regimens were reported to the Société Française de Greffe de Moelle Registry registry. Initial diagnoses were lymphoid diseases (n = 22), myeloma (n = 14), acute leukemia and myelodysplasia (n = 41), chronic myelogenous leukemia (n = 12), and solid tumors (n = 3). Forty-six patients had previously received a transplant, and 49 had progressive disease before transplantation. Three types of conditioning regimens were used with fludarabine or antithymocyte globulins. Eighty-nine patients underwent transplantation, 60 from peripheral-blood progenitor cells. Eighty-six patients received graft-versus-host disease (GHVD) prophylaxis for a median duration of 53 days. RESULTS: Seventy-nine patients engrafted, with 40 complete and 21 mixed chimerisms. The acute GHVD rate at 3 months was 50% ± 11%. Fifty-two patients achieved complete remission and 12, partial remission. At 18 months after transplantation, the overall survival (OS) and the transplant-related mortality (TRM) were 32% ± 12% and 38% ± 14%, respectively. Initial diagnosis and disease status before transplantation significantly influenced survival. Age and GHVD prophylaxis type significantly influenced TRM. We also showed an impact of GHVD prophylaxis duration on OS and TRM. In multivariate analysis, three factors remained of prognostic value on OS: initial diagnosis, disease status at transplantation, and GHVD prophylaxis duration. CONCLUSION: This series shows encouraging results from nonmyeloablative conditioning regimens before allotransplantation and demonstrates the impact of some pre- and posttransplantation factors on outcome after transplantation.

Data on all patients with acute lymphoblastic leukemia (ALL) aged 60 or older, referred to our institution over a 18-year period, were studied to determine the incidence and range of clinical and biological subtypes, and the outcome of different therapeutic approaches. Sixty-nine ALL cases (median age: 68 years) were diagnosed between 1980 and 1998 (18% of all adult ALL seen during this period). Ten of them (14%) had a past history of previous malignancy. Karyotypic analysis was performed successfully in 42 cases. Ten patients were diagnosed as Philadelphia chromosome positive (Ph(+)) ALL. Immunophenotyping was performed in 63 cases. Fifty-six patients had B-cell lineage ALL. T lymphoid markers were observed only in 5 cases. Co-expression of myeloid markers was observed in 19% of tested cases. Five patients died before any chemotherapy could be given. All other patients received "curative" treatment according to different protocols used during the period of study. Overall complete remission (CR) rate of these patients was 62% (95% confidence interval (CI): 50-74%). Thirty-nine patients achieved CR after one course of chemotherapy and 4 patients after salvage therapy. Median disease-free survival (DFS) of the entire cohort was 8.3 months (95% CI: 5-12.8 months) and median overall survival was 7 months (95% CI: 6-10 months). In multivariate analysis, the presence of hemorrhage (P = 0.02) was a poor prognostic for CR achievement. Higher WHO performance status (P = 0.003) and the presence of hemorrhage (P = 0.01) at diagnosis were poor prognostics for overall survival. When patients were stratified into three groups according to the time of admission, survival appeared significantly longer for patients admitted between July 1992 and December 1998 (median overall survival at 10 months) than for patients admitted before July 1992 (P = 0.04). "Age-adapted" therapy appeared superior to "young adult-like" therapy in terms of CR rate (96% versus 60%; P = 0.007). However, "age-adapted" therapy did not show any advantage in terms of DFS or overall survival, making the difference in CR rates questionable. We conclude that the pejorative overall outcome in elderly ALL points to the need for new therapeutic trials taking into account the specific characteristics of ALL in this age group.

Purpose The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse. Patients and Methods In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion). Results N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001). Conclusion These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.

Background: Treatment of younger adults with Ph-negative ALL has markedly evolved since the early 2000s. Survivals have substantially improved using pediatric or pediatric-inspired protocols with higher doses of steroids, vincristine (VCR), methotrexate (MTX) and L-asparaginase (L-Aspa), as was done in the GRAALL-2003 trial (Huguet et al. JCO 2009). However, the upper age limit for a pediatric-like strategy remained undetermined. In the GRAALL-2005 study (NCT00327678), we aimed to address this age issue in a larger trial and to randomly evaluate a reinforced hyper-fractionated (hyperC) vs standard (standardC) dose of cyclophosphamide (CPM) during induction and late intensification. Patients with CD20-positive B-cell precursor (BCP) ALL were also randomized in the rituximab GRAALL-2005/R study, as specifically reported last year (Maury et al. ASH 2015). Patients and Methods: Patients aged 18-59 years old with newly-diagnosed Ph-negative ALL were eligible. Chemotherapy comprised a steroid prephase, a 5-drug induction, two 3-block dose-dense consolidation phases, a late intensification, a third consolidation phase, CNS irradiation, and a 2-year maintenance (Beldjord et al. Blood 2014). Allogeneic transplantation was offered in first complete remission (CR) to patients with conventional high-risk factors (Dhédin et al. Blood 2015). During induction and late intensification, CPM was given at 750 mg/m2 on day 1 followed by 750 mg/m2 on day 15 (standardC) or 300 mg/m2/12h on day 15 to 17 (hyperC), according to randomization arm. The primary endpoint was event-free survival (EFS). Secondary endpoints were cumulative incidences of failure (CIF, including primary refractoriness and relapse) and CI of non-refractoriness/relapse mortality (CINRM, including toxic death during induction and death in first CR), overall survival (OS), compliance and safety. Compliance was assessed by comparing the median doses of specific drugs actually received by patients who completed specific treatment phases. Results: Between 2006 and 2014, 787 evaluable patients were randomized (398 standardC, 389 hyperC; 525 BCP-ALL, 262 T-ALL). Median age was 36y, with 200, 172, 171, 151 and 93 patients in the 18-24y, 25-34y, 35-44y, 45-54y and 55y+ age subgroups, respectively. Overall CR rate was 91.9% and 278 patients were transplanted in first CR. With a median follow-up of 5.2 years, 5y-EFS and OS were 52% (48-56) and 58% (55-62), respectively, confirming previous GRAALL-2003 results. No difference in outcome was observed in T- vs BCP-ALL patients. At 5 years, EFS was 60%, 58%, 54%, 50% and 26% in the youngest to the oldest age subgroup, respectively (HR, 2.2 [1.7-2.8]; p Conclusions: Taken together, these results indicate that 55 years is likely to be the upper age limit for a pediatric-like strategy in younger adults with ALL, because of excessive toxicity and worse treatment compliance observed above this age. Older adults could probably benefit from alternative front-line approaches such as hyper-fractionated CPM or new agents such asinotuzumabozogamicin. Disclosures Rousselot: BMS: Research Funding; Ariad: Research Funding; Pfizer: Research Funding.

Background : Bacterial infections (BI) are a major cause of morbidity and mortality in patients treated for hematological malignancies, especially those with acute myeloblastic leukemia or receiving allogeneic hematopoietic stem cell transplantation. Despite severe neutropenia and prolonged treatment with corticosteroids, there are little published data on BI during induction chemotherapy in adults with acute lymphoblastic leukemia (ALL). Between 2006 and 2014, 787 adult patients were included in the GRAALL-2005 study, a prospective, randomized and multicenter phase III trial for patients newly diagnosed patients with Philadelphia chromosome-negative B-cell precursor (BCP) or T-cell ALL. We retrospectively reviewed the occurrence of BI during induction treatment in these patients. Patients and Methods: The GRAALL-2005 study evaluated the value of hyperfractionated cyclophosphamide in the whole study population and of rituximab in patients with CD20+ BCP-ALL. All patients received a 5-drug induction therapy with corticosteroids (prednisone) for 21 days, associated with vincristine, daunorubicin, cyclophosphamide and L-asparaginase. A broad-spectrum antibiotic treatment effective on Gram-negative and positive germs was recommended when the neutrophil count was less than 0.5 G/L. Pneumocystis prophylaxis was made by trimethoprim/sulfamethoxazole or pentamidine. Results: During induction chemotherapy, 270 of the 787 patients (34.3%) experienced a total of 376 BI episodes (1.4 BI episodes per patient). The BI incidence rate was higher in the subgroup of patients combining hyperfractionated cyclophosphamide and rituximab as compared to those who received standard-dose cyclophosphamide and no rituximab (40.7% versus 29.5%; p=0.098). The median time from the first day of induction therapy to BI diagnosis was 10 days (range, 7-14). The infection was considered as serious in 58 patients, with a diagnosis of septic shocks in 57. Forty-one patients were transferred in intensive care unit. At 50 days after induction initiation, 22 patients had died from BI: 8.1% of patients with BI and 2.8% of all patients. Bloodstream was the most common site (82.7%), followed by gastrointestinal tract (6.5%) and lungs (6.5%). In less than 2% of cases, skin and soft tissues, central venous catheter, or urinary tract was concerned. Infections with Gram-positive cocci predominated as the etiology of microbiologically documented infections (46.9%), more specifically coagulase-negative Staphylococci. E. coli and Pseudomonas species were the most common Gram-negative organisms (40.5%). The patients received a median number of 3 antibiotics. The first-line was a monotherapy in 57% of cases, with the predominant use of betalactam. In one-third of the cases, it was betalactam in combination with aminoglycoside or glycopeptide. More than 2 antibiotics were prescribed in 12% of cases. Conclusion: Induction chemotherapy in adults with ALL is associated with a high incidence of bacterial infections and a significant related mortality. To our knowledge, this report is the only large adult ALL study dealing with bacterial infectious complications during induction chemotherapy. Despite an intensely myelosuppressive chemotherapy regimen, the infection-related mortality seems to be lower than that reported during induction in acute myeloid leukemia. Predictive risk factors for bacterial infections have to be analyzed, as well as prophylactic/empirical antibiotic strategies in order to improve care for this subset of patients. Disclosures No relevant conflicts of interest to declare.

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Purpose Retrospective comparisons have suggested that adolescents or teenagers with acute lymphoblastic leukemia (ALL) benefit from pediatric rather than adult chemotherapy regimens. Thus, the aim of the present phase II study was to test a pediatric-inspired treatment, including intensified doses of nonmyelotoxic drugs, such as prednisone, vincristine, or l-asparaginase, in adult patients with ALL up to the age of 60 years. Patients and Methods Between 2003 and 2005, 225 adult patients (median age, 31 years; range, 15 to 60 years) with Philadelphia chromosome–negative ALL were enrolled onto the Group for Research on Adult Acute Lymphoblastic Leukemia 2003 protocol, which included several pediatric options. Some adult options, such as allogeneic stem-cell transplantation for patients with high-risk ALL, were nevertheless retained. Results were retrospectively compared with the historical France-Belgium Group for Lymphoblastic Acute Leukemia in Adults 94 (LALA-94) trial experience in 712 patients age 15 to 55 years. Results Complete remission rate was 93.5%. At 42 months, event-free survival (EFS) and overall survival (OS) rates were 55% (95% CI, 48% to 52%) and 60% (95% CI, 53% to 66%), respectively. Age remained an important bad prognostic factor, with 45 years of age as best cutoff. In older versus younger patients, there was a higher cumulative incidence of chemotherapy-related deaths (23% v 5%, respectively; P < .001) and deaths in first CR (22% v 5%, respectively; P < .001), whereas the incidence of relapse remained stable (30% v 32%, respectively). Complete remission rate (P = .02), EFS (P < .001), and OS (P < .001) compared favorably with the previous LALA-94 experience. Conclusion These results suggest that pediatric-inspired therapy markedly improves the outcome of adult patients with ALL, at least until the age of 45 years.

Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). Although treatment intensity and outcome were not comparable, with improvements in survival it is important to evaluate the rate and the type of second neoplasms in adults with ALL.The data from the GET-LALA group were analyzed. A cohort of 1494 patients, aged 15 to 60 years and enrolled in 2 successive multicenter protocols between 1987 and 2002, was observed to determine the incidence of second neoplasms and associated risk factors. The median follow-up from diagnosis was 6 years.By February 2005 secondary or concomitant neoplasms were documented in 23 patients, including 9 acute myeloid leukemias (AML) or myelodysplasias (MDS), 4 non-Hodgkin lymphomas (NHL), 5 skin tumors, and 5 other solid tumors (1 lung cancer, 1 tongue carcinoma, 1 thymoma, 1 condrosarcoma, 1 histiocytosis). Neoplasms developed 0.5 to 13.8 years (median, 4.5 years) after the diagnosis of ALL. There were 22 patients in first remission and 1 was in second remission. The overall cumulative risk of secondary neoplasms was 2.1% at 5 years, 4.9% at 10 years, and 9.4% at 15 years. The cumulative risk of developing a second hematologic malignancy was 1.8% at 5 years, 2.2% at 10 years, 3.3% at 18 years; that of developing a solid tumor was 0.2% at 5 years, 2.8% at 10 years, 6.2% at 15 years. The development of secondary neoplasm was not associated with the use of any specific cytotoxic agent. However, the risk of skin tumor increased with radiation dose and transplantation (P = .01). Overall survival (OS) after the diagnosis of a second malignant neoplasm was 55% at 10 years. However, the median OS in patients developing AML/MDS was 5.7 months.The data document that adult ALL survivors are at an increased risk of later malignancy. The risk of secondary or concomitant neoplasm appeared higher than that of childhood ALL previously reported in the literature. Considering the low survival rate of this large unselected adult ALL cohort (32% at 10 years) as compared with that observed in childhood ALL, the risk of second malignancy remains underestimated. Larger series with long-term follow-up are necessary, as well as methods of screening and identification of patients at increased risk.

Fifty-four percent of adults with acute lymphoblastic leukemia (ALL) who entered the LALA-94 trial experienced a first relapse. We examined the outcome of these 421 adult patients. One hundred and eighty-seven patients (44%) achieved a second complete remission (CR). The median disease-free survival (DFS) was 5.2 months with a 5-year DFS at 12%. Factors predicting a better outcome after relapse were any transplant performed in second CR (P0.0001), a first CR duration1 year (P=0.04) and platelet level100 x 10(9)/l at relapse (P=0.04). Risk groups defined at diagnosis and treatment received in first CR did not influence the outcome after relapse. The best results were obtained in a subset of patients who were eligible for allogeneic stem cell transplantation (SCT). Geno-identical allogeneic SCT was performed in 55 patients, and 3 patients received donor lymphocyte infusions. Forty-four transplantations were performed from an unrelated donor (of which four were cord blood). We conclude that most adult patients with recurring ALL could not be rescued using current available therapies, although allogeneic SCT remains the best therapeutic option.

The combination of imatinib with chemotherapy has been recently reported as very promising in patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). During 2004 and 2005, 45 patients with newly diagnosed Ph+ ALL were treated in the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAAPH) 2003 study, in which imatinib was started with HAM (mitoxantrone with intermediate-dose cytarabine) consolidation in good early responders (corticosensitive and chemosensitive ALL) or earlier during the induction course in combination with dexamethasone and vincristine in poor early responders (corticoresistant and/or chemoresistant ALL). Imatinib was then continuously administered until stem cell transplantation (SCT). Overall, complete remission (CR) and BCR-ABL real-time quantitative polymerase chain reaction (RQ-PCR) negativity rates were 96% and 29%, respectively. All of the 22 CR patients (100%) with a donor actually received allogeneic SCT in first CR. At 18 months, the estimated cumulative incidence of relapse, disease-free survival, and overall survival were 30%, 51%, and 65%, respectively. These 3 end points compared very favorably with results obtained in the pre-imatinib LALA-94 trial. This study confirms the value of the combined approach and encourages prospective trials to define the optimal chemotherapy that has to be combined with imatinib and to carefully reevaluate the place of allogeneic SCT in this new context.

Purpose: The use of rituximab, a chimeric monoclonal antibody to CD20, has led to significant improvement in the treatment of B-cell non-Hodgkin's lymphoma and mature B-cell ALL. CD20 is expressed in 30 to 50% of adult BCP-ALL patients. Although some single arm studies suggested that adding rituximab to chemotherapy could improve the outcome of these patients, no randomized study has been reported so far. Methods: To evaluate the potential benefit of adding rituximab, we conducted a multicenter randomized trial comparing the pediatric-inspired GRAALL protocol to the same regimen plus rituximab, in patients aged 18-59 years old with newly diagnosed CD20-positive Ph-negative BCP-ALL enrolled in the GRAALL 2005 trial. CD20 positivity was defined as expression of CD20 in more than 20% of leukemia blasts. Rituximab (375 mg/m2) was given during induction (day 1 and 7), salvage reinduction when needed (day 1 and 7), consolidation blocks (6 infusions), late intensification (day 1 and 7) and first year of maintenance (6 infusions) for a total of 16 to 18 infusions. Allogeneic stem cell transplantation (SCT) was offered in first complete remission (CR) to patients with one or more conventional high-risk criteria and a donor. The primary study objective was event-free survival (EFS). A study sample size of 220 patients was estimated in order to detect a 20% gain in EFS at 2 years (two-sided test, power 85%, type 1 error 5%). A sensitivity analysis was performed after censoring patients allografted in first CR at transplant time. This trial was registered at http://www.clinicaltrials.gov as #NCT00327678. Results: From 2005 to 2014, 220 patients from 56 centers were randomized. Eleven patients had non-eligibility criteria (n=5 Ph+ ALL; n=3 CD20-negative ALL; n=1 HIV infection) or withdrew their consent (n=2) and were accordingly excluded from this modified ITT analysis that dealt with 209 patients (105 in the rituximab arm and 104 in the control arm). Median age was 40 years. Both randomization arms were well balanced for pretreatment characteristics including age, ECOG status, WBC, and central nervous system (CNS) involvement (6% of the whole cohort). After induction ± salvage reinduction, CR rate was 92% and 91% in rituximab and control arm, respectively. In patients who reached CR after first induction and were evaluated for Ig/TCR minimal residual disease level (MRD), the rates of patients with MRD Conclusions: In adults with CD20-positive, Ph-negative, BCP-ALL, the addition of rituximab to the pediatric-inspired GRAALL protocol improves EFS; it also prolongs OS when ignoring patient's outcome after transplantation in first CR. Disclosures Off Label Use: Rituximab is not currently approved for this indication.. Chalandon:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Prospective multicentric molecular study for poor prognosis fusion transcripts at diagnosis in adult B-lineage ALL patients: the LALA 94 experience

Factors able to predict overall survival in adult patients with acute lymphoblastic leukaemia were assessed according to the period since initiation of the treatment using a Cox proportional hazards model. This period covers successively an initial period during the induction treatment and a consolidation period during the postinduction treatment. From 1994 to 2002, 922 patients with acute lymphoblastic leukaemia (excluding French-American-British L3 subtype) were enrolled in a multicentre protocol and followed, with a mean follow up of 58 months. A multivariate time-segmented analysis was performed on 658 patients. Analyses of the initial (before 100 d) and the late phases were realised after stratification on the type of induction treatment and on the different treatment strategies respectively. Age was the sole factor that influenced survival during the initial phase (hazard ratio 1.48 per 10-yr increase; P

BackgroundClinical trials throughout the world must be evaluated by research ethics committees. No one has yet attempted to clearly quantify at the national level the activity of ethics committees and describe the characteristics of the protocols submitted. The objectives of this study were to describe 1) the workload and the activity of Research Ethics Committees in France, and 2) the characteristics of protocols approved on a nation-wide basis.MethodsRetrospective cohort of 976 protocols approved by a representative sample of 25/48 of French Research Ethics Committees in 1994. Protocols characteristics (design, study size, investigator), number of revisions requested by the ethics committee before approval, time to approval and number of amendments after approval were collected for each protocol by trained research assistant using the committee's files and archives.ResultsThirty-one percent of protocols were approved with no modifications requested in 16 days (95% CI: 14–17). The number of revisions requested by the committee, and amendments submitted by the investigator was on average respectively 39 (95% CI: 25–53) and 37 (95% CI: 27–46), per committee and per year. When revisions were requested, the main reasons were related to information to the patient (28%) and consent modalities (18%). Drugs were the object of research in 68% of the protocols examined. The majority of the research was national (80%) with a predominance of single-centre studies. Workload per protocol has been estimated at twelve and half hours on average for administrative support and at eleven and half hours for expertise.ConclusionThe estimated workload justifies specific and independent administrative and financial support for Research Ethics Committees.

Data on all patients diagnosed with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) aged 55 or older, seen in our institution over a 17-year period, were studied to determine the incidence and range of clinical and biological subtypes, and the outcome of different therapeutic approaches. Twenty-five Ph+ ALL cases (median age: 64 years) were diagnosed between 1986 and 2003 (28% of all B-lineage elderly ALL seen during this period). Karyotypic analysis was performed successfully in 22 cases, while 3 were only diagnosed by molecular biology analysis. All patients had B-cell lineage ALL. Co-expression of myeloid markers was observed in 20% of tested cases. One patient died before chemotherapy could be given. All other patients received "curative" treatment according to different protocols used during the period of study. Overall the complete remission (CR) rate was 76% (95% confidence interval, CI: 55-91%). Fifteen patients achieved CR after one course of chemotherapy and 4 patients after salvage therapy. Median disease-free survival (DFS) of the entire cohort was 5.6 months (95% CI: 4.5-8.4 months) and median overall survival was 10.1 months (95% CI: 7.9-13 months). In multivariate analysis, ageor=70 years was of poor prognostic value for achieving CR (p=0.05) and hyperleukocytosis at diagnosis was of poor prognostic value for overall survival (p=0.001). Overall survival duration was not significantly influenced by achieving CR. Ph+ ALL patients did not show a significant difference in terms of outcome as compared with Philadelphia-negative ALL patients. The very poor overall outcome in elderly patients with Ph+ ALL may be significantly improved by the introduction of imatinib mesylate into current treatment regimens.

Patients with T-cell acute lymphoblastic leukemias (T-ALLs) within the Leucémies Aiguës Lymphoblastiques de l'Adulte-94 (LALA-94) prospective trial were treated with a 4-drug per 4-week induction, with intermediate-dose cytarabine and mitoxantrone salvage treatment for patients not achieving complete remission (CR) in 1 course. Only the latter received allografts, if possible, thus providing an informative setting for assessing early response. Representative patients with T-ALL (91 patients) were classified into surface T-cell receptor (TCR)–expressing T-ALL patients (TCRαβ+ or TCRγδ+), pre-αβ T-ALL patients (cTCRβ+, TCR–), and immature (IM) cTCRβ–, TCR– T-ALL patients; 81 patients underwent genotyping for SIL-TAL1, CALM-AF10, HOX11, and HOX11L2. Overall, CR was obtained in 81 (89%) patients; relapse rate was 62% at 4 years and overall survival (OS) rate was 38%. CR rate was significantly lower in IM T-ALL patients after 1 course (45% vs 87%; P < .001) and after salvage (74% vs 97%; P = .002), with the latter inducing a higher rate of CR (9 [64%] of 14) than initial induction. Once CR was obtained, cumulative relapse rates were similar for IM, pre-αβ, and TCR+ T-ALL patients (P = .51), but were higher in HOX11L2 (83%) and SIL-TAL1 (82%) T-ALL patients compared with other genetic subgroups (48%; P = .05). This was associated with an inferior OS for HOX11L2 T-ALLs (13% vs 47% in HOX11L2-T-ALLs; P = .009). The majority of patients with HOX11 T-ALL underwent allografting, predominantly in second CR, but were not associated with a superior OS. Both TCR and genotypic stratification can therefore contribute to risk-adapted management of adult T-ALLs.

To reveal the relationship between hypodiploidy with 30 to 39 chromosomes and near-triploidy in acute lymphoblastic leukemia (ALL), we studied 24 patients presenting with one of these aneuploidies among 623 adults with ALL registered in the Leucemie Algue Lymphoblastique de l'Adulte (LALA) protocols. The 2 ploidy groups presented a striking similarity of their cytogenetic profiles: chromosomes 2, 3, 4, 7, 13, 15, 16, and 17, significantly monosomic in hypodiploidy 30 to 39, were also frequently disomic in near-triploidy, whereas those retained in pairs in hypo diploidy 30 to 39 were frequently tetrasomic in near-triploidy. DNA content data revealed the simultaneous presence of 2 aneuploid peaks in most tested cases (DNA indexes: 0.72-0.87/1.39-1.89) and a multiple correspondence analysis applied on cytogenetic profiles ascertained their strong relationship. We thus assumed that near-triploidy derives from the duplication of hypodiploidy with 30 to 39 chromosomes and that both aneuploid groups are 2 expressions of the same disease. These 24 patients presented with B-cell phenotype, low leukocytoses (median white blood cell count, 4.2 x 10(9)/L), and poor prognosis (complete remission, 57%; median disease-free-survival, 8 months; median survival, 10.4 months) comparable to that of Ph+ patients treated according to the same protocol. We suggest that hypodiploidy with 30 to 39 chromosomes or near-triploidy should be regarded as a new high-risk factor in the risk stratification of adult ALL protocols. (C) 2004 by The American Society of Hematology.

Purpose: To compare pediatric and adult therapeutic practices in the treatment of acute lymphoblastic leukemia (ALL) in adolescents. Patients and Methods: From June 1993 to September 1994, 77 and 100 adolescents (15 to 20 years of age) were enrolled in the pediatric FRALLE-93 and adult LALA-94 protocols, respectively. Among the different prognostic factors, we retrospectively analyzed the effect of the trial on achieving complete remission (CR) and event-free survival (EFS). Results: Patients were younger in the FRALLE-93 than in the LALA-94 protocol (median age, 15.9 v 17.9 years, respectively), but other characteristics were similar, including median WBC count (18 × 109 cells/L v 16 × 109 cells/L), B/T-lineage (54 of 23 v 72 of 28 patients), CD10-negative ALL (13% v 15%), and poor-risk cytogenetics (t(9;22), t(4;11), or hypodiploidy less than 45 chromosomes: 6% v 5%). The CR rate depended on WBC count (P = .005) and trial (94% v 83% in FRALLE-93 and LALA-94, respectively; P = .04). Univariate analysis showed that unfavorable prognostic factors for EFS were as follows: the trial (estimated 5-year EFS, 67% v 41% for FRALLE-93 and LALA-94, respectively; P < .0001), an increasing WBC count (P < .0001), poor-risk cytogenetics (P = .005), and T-lineage (P = .01). The trial and WBC count remained significant parameters for EFS in multivariate analysis (P < .0001 and P = .0004). Lineage subgroup analysis showed an advantage for the FRALLE-93 trial for CR achievement (98% v 81%; P = .002) and EFS (P = .0002) in B-lineage ALL and for EFS (P = .05) in T-lineage ALL. Age was not a significant prognostic factor in this population of adolescents. Conclusion: This study’s findings indicate that adolescents should be included in intensive pediatric protocols and that new trials should be designed, inspired by pediatric protocols, for the treatment of young adults with ALL.