Group For Research On Adult Acute Lymphoblastic Leukemia Research Articles

Efficacy and Tolerance of Brexucabtagene Autoleucel in Adults with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia : A Graall Study from the Descar-T Registry

Background : Brexucabtagene autoleucel (brexu-cel) was recently approved for adult patients with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) based on the results of the ZUMA-3 phase 2 study. After a median follow-up of 39 months, brexu-cel showed a complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate of 71% and a median overall survival of 26 months (Shah B, et al. ASCO 2023). In the present study, we aimed at investigating the efficacy and safety of brexu-cel in a real-life cohort of adult BCP-ALL patients included in the French early access program. Methods : In this Group for Research on Adult Acute Lymphoblastic leukemia (GRAALL) study, we performed an analysis of the DESCAR-T registry which collects real-life data of patients treated with CAR T-cells since July 2018 in France. All patients who underwent a leukapheresis with an intent to manufacture brexu-cel were included (N=80). Efficacy and safety analyses were performed in the 64/66 infused patients with available response assessment after infusion. The data cut-off was June 2023. The present study reports on best overall response, overall survival (OS), relapse-free survival (RFS), as well as immune effector cell-associated neurotoxicity syndrome (ICANS), and cytokine release syndrome (CRS) incidence and grading (according to ASTCT Consensus). Results : Between May 2019 and February 2023, 80 adults with R/R BCP-ALL from 22 French centers had a leukapheresis for brexu-cel. Among them, 14 patients (18%) were not infused because of death (8 pts), progression (1 pt), manufacturing failure (2 pts), or other causes (3 pts). Among the 64 infused patients with available response assessment, median age was 43.5 yrs (range, 22-69). A Philadelphia(Ph)-chromosome was found in 20/64 (31%). Patients had received a median of 3 (range, 1-6) prior lines of treatment including blinatumomab, inotuzumab ozogamicin and allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 67%, 19% and 70% of patients respectively. Twelve patients (19%) had an active CNS disease (CNS2/3) prior to apheresis and 18/40 (45%) had bone marrow blasts ≥ 25% before lymphodepletion (LD). ECOG before infusion was ≥2 in 6/64 (9%) patients. All patients received fludarabine and cyclophosphamide as LD. Median time from apheresis to infusion was 40 days (range, 27-99). CRS and ICANS occurred in 48/64 (77%, grade 3+ in 6%) and 28/64 (45%, grade 3+ in 8%) of patients respectively and were reversible. A CR was achieved in 49/64 patients (77%) of whom 23/25 (92%) were MRD-negative. An older age, a prior allo-HSCT, and the occurrence of CRS were associated with significantly higher CR rates. The median follow-up was 13 months. Three patients were bridged to an allo-HSCT in continuous complete remission (second allo-HSCT for 2 of them). The median RFS and OS were 12.9 months and 15.6 months respectively (Figure). In patients who achieved a CR, median OS was 25.8 months (Figure). Patients with CNS involvement before leukapheresis had a significantly shorter RFS (HR 5.4, 95%CI 1.9-15.8, p=0.002) and OS (HR 3.3, 95%CI 1.4-8.2, p=0.008). Number of prior treatment lines, prior inotuzumab, prior blinatumomab, or pre-LD BM blast% were not associated with outcome. A better OS was observed in patients with prior allo-HSCT (HR .4, 95%CI 0.2-0.9, p=0.04). Conclusion : This multicenter real-life study confirms the efficacy and acceptable safety profile of brexu-cel in adult patients with R/R BCP-ALL. It also suggests that patients with CNS involvement, that were not eligible to ZUMA-3 study, have a limited benefit of brexu-cel when compared to other patients.

Oncogenetic-Driven Targeted Therapy for Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia : A French ALL-Target Observatory Report

Introduction T-cell acute lymphoblastic leukemia (T-ALL) is an orphan disease diagnosed mostly in adolescent and young adults. In adult population, 5-10% of T-ALL patients (pts) will be primary refractory and 30-40% will relapse. In relapse/refractory (R/R) patients, standard of care treatments, including nelarabine, yield response rate of about 20-40% and responses are of short duration. On behalf of the GRAALL (Group for Research on Adult Acute Lymphoblastic Leukemia), we launched the ALL-TARGET project combining a precision medicine platform dedicated to R/R T-ALL and T-cell lymphoblastic lymphoma (T-LL), and an observatory to evaluate therapeutic proposals based on mutational profile and intracellular signaling pathways alterations. Objectives and methods Leukemic samples from pts with R/R T-ALL/LL were shipped to the GRAALL T-ALL central laboratory in France (V. Asnafi, Hôpital Necker). Biological characterization comprised oncogenetic, phenotypic and in some cases functional analysis. Clinical data from R/R T-ALL/LL pts were collected in a real-life observatory (NCT05832125). Adults pts were eligible if an oncogenetic characterization was available at diagnosis or relapse, and if they received a salvage, either with conventional therapy or with a targeted therapeutic option (TTO). For example, TTOs included Tofacitinib and Venetoclax (Tofa/Ven) in case of IL7R (CD127) expression or IL7R-pathway alterations (IL7R ALT), 5-azacytidine and Venetoclax (Aza/Ven) in case of T-ALL/LL with epigenetic regulators alterations (DNMT3A, ASXL1, PHF6, TET2, PRC2, IDH1/2, SRSF2...) or Temsirolimus, Erwinase and Venetoclax (Tem/Erw/Ven) in case of PI3K signaling pathway alterations (PI3K ALT). The ALL-TARGET Observatory primary endpoint was overall response rate (ORR) including complete remission (CR), CR with incomplete hematological recovery and partial response. We report here the results of the first pts included, with a focus on those who received TTOs as salvage therapy. Results Eighty-nine were analyzed, including 80 T-ALL and 9 T-LL. Sex ratio was 3 and median age at diagnosis was 37.5y, and 51y at the time of the first TTO. Seventy-one pts were in relapse (79.7%) and 18 primary refractory (20.2%). Relapses occurred after a median first CR duration of 16.6 months (range: 2.5-92), with 62.8% in bone marrow, 30% in CNS and 30.3% in other extramedullary sites. Phenotype at diagnosis was available for 68 pts, including 36 Early T-cell Precursor (ETP or near-ETP) (52.9%), 6 immature non-ETP (8.8%), 20 cortical (29.4%) and 6 mature phenotype (8.8%). IL7R-expression was available for 53 pts, of whom 40 were IL7R+ (75.5%) and 13 IL7R- (24.5%). Out of 50 samples with available BCL2-expression, 47 were BCL2+ (94%) and 3 BCL2- (6%). IL7R ALT were evidenced in 41 pts (48.2%), PI3K ALT in 21 pts (24.7%), RAS pathway alterations (RAS ALT) in 19 pts (22.4%) and epigenetic dysregulation in 42 pts (49.4%). Ten pts harbored TP53/ATM mutations (11.7%) . These different alterations could coexist. At relapse, 33 phenotypes were reported, showing 22 ETP (66.6%), 2 immature non-ETP (6%) and 9 cortical (27.3%). IL7R-expression was available for 26 pts, among which 21 were IL7R+ (63.6%) and 5 IL7R- (19.2%). NGS was performed in 24 patients, revealing IL7R ALT in 9 pts (37.5%), PI3K ALT in 6 pts (25%), RAS ALT in 5 pts (20.8%) and epigenetic dysregulation in 15 pts (62.5%). Nine patients had TP53 mutations (37.5%). Twenty-five patients received a TTO, including 14 Aza/Ven (56%), 8 Tofa/Ven (32%), 2 Tem/Erw/Ven (8%) and 1 Trametinib/Ven (4%). Among these, 8 were in first salvage (32%), 10 in 2 nd (40%), and 6 in 3 rd/4 th salvage (28%). Of note, 14 patients received Ven associated with chemotherapy, including 4 Nelarabine-Ven, and 3 Ven in monotherapy. By 3 months, the cumulative incidence of response under the chosen TTO was 70.7% (95%CI:51-88) (Figure). Ten of 14 patients were in response after Aza/Ven (ORR 71.4%), 4 of 8 patients after Tofa/Ven (50%) and 2 of 2 patients treated with Tem/Erw/Ven (100%). Five patients were bridged to allogeneic stem cell transplantation. Conclusion Our results demonstrate the feasibility of the ALL-TARGET project. A better knowledge of the oncogenetic landscape of T-ALL, and a close collaboration between clinicians and biologists, resulted in individualized treatment strategies. With a 3 months cumulative incidence of response of 70%, TTOs appear to be a promising approach in R/R T-ALL.

PHF6-altered T-ALL Harbor Epigenetic Repressive Switch at Bivalent Promoters and Respond to 5-Azacitidine and Venetoclax.

To assess the impact of PHF6 alterations on clinical outcome and therapeutical actionability in T-cell acute lymphoblastic leukemia (T-ALL). We described PHF6 alterations in an adult cohort of T-ALL from the French trial Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/2005 and retrospectively analyzed clinical outcomes between PHF6-altered (PHF6ALT) and wild-type patients. We also used EPIC and chromatin immunoprecipitation sequencing data of patient samples to analyze the epigenetic landscape of PHF6ALT T-ALLs. We consecutively evaluated 5-azacitidine efficacy, alone or combined with venetoclax, in PHF6ALT T-ALL. We show that PHF6 alterations account for 47% of cases in our cohort and demonstrate that PHF6ALT T-ALL presented significantly better clinical outcomes. Integrative analysis of DNA methylation and histone marks shows that PHF6ALT are characterized by DNA hypermethylation and H3K27me3 loss at promoters physiologically bivalent in thymocytes. Using patient-derived xenografts, we show that PHF6ALT T-ALL respond to the 5-azacytidine alone. Finally, synergism with the BCL2-inhibitor venetoclax was demonstrated in refractory/relapsing (R/R) PHF6ALT T-ALL using fresh samples. Importantly, we report three cases of R/R PHF6ALT patients who were successfully treated with this combination. Overall, our study supports the use of PHF6 alterations as a biomarker of sensitivity to 5-azacytidine and venetoclax combination in R/R T-ALL.

Genetic alterations and MRD refine risk assessment for KMT2A-rearranged B-cell precursor ALL in adults: a GRAALL study

AbstractKMT2A-rearranged (KMT2A-r) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is widely recognized as a high-risk leukemia in both children and adults. However, there is a paucity of data on adults treated in recent protocols, and the optimal treatment strategy for these patients is still a matter of debate. In this study, we set out to refine the prognosis of adult KMT2A-r BCP-ALL treated with modern chemotherapy regimen and investigate the prognostic impact of comutations and minimal residual disease (MRD). Of 1091 adult patients with Philadelphia-negative BCP-ALL enrolled in 3 consecutive trials from the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL), 141 (12.9%) had KMT2A-r, with 5-year cumulative incidence of relapse (CIR) and overall survival (OS) rates of 40.7% and 53.3%, respectively. Molecular profiling highlighted a low mutational burden in this subtype, reminiscent of infant BCP-ALL. However, the presence of TP53 and/or IKZF1 alterations defined a subset of patients with significantly poorer CIR (69.3% vs 36.2%; P = .001) and OS (28.1% vs 60.7%; P = .006) rates. Next, we analyzed the prognostic implication of MRD measured after induction and first consolidation, using both immunoglobulin (IG) or T-cell receptor (TR) gene rearrangements and KMT2A genomic fusion as markers. In approximately one-third of patients, IG/TR rearrangements were absent or displayed clonal evolution during the disease course, compromising MRD monitoring. In contrast, KMT2A-based MRD was highly reliable and strongly associated with outcome, with early good responders having an excellent outcome (3-year CIR, 7.1%; OS, 92.9%). Altogether, our study reveals striking heterogeneity in outcomes within adults with KMT2A-r BCP-ALL and provides new biomarkers to guide risk-based therapeutic stratification.

Impact of cytogenetic abnormalities in adults with Ph-negative B-cell precursor acute lymphoblastic leukemia

AbstractMultiple cytogenetic subgroups have been described in adult Philadelphia chromosome (Ph)-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL), often comprising small numbers of patients. In this study, we aimed to reassess the prognostic value of cytogenetic abnormalities in a large series of 617 adult patients with Ph-negative BCP-ALL (median age, 38 years), treated in the intensified Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/2005 trials. Combined data from karyotype, DNA index, fluorescence in situ hybridization, and polymerase chain reaction screening for relevant abnormalities were centrally reviewed and were informative in 542 cases (88%), allowing classification in 10 exclusive primary cytogenetic subgroups and in secondary subgroups, including complex and monosomal karyotypes. Prognostic analyses focused on cumulative incidence of failure (including primary refractoriness and relapse), event-free survival, and overall survival. Only 2 subgroups, namely t(4;11)/KMT2A-AFF1 and 14q32/IGH translocations, displayed a significantly worse outcome in this context, still observed after adjustment for age and after censoring patients who received allogeneic stem cell transplantation (SCT) in first remission at SCT time. A worse outcome was also observed in patients with low hypodiploidy/near triploidy, but this was likely related to their higher age and worse tolerance to therapy. The other cytogenetic abnormalities, including complex and monosomal karyotypes, had no prognostic value in these intensive protocols designed for adult patients up to the age of 60 years.

An Early Thymic Precursor Phenotype Predicts Outcome Exclusively in HOXA-Overexpressing Adult T-ALL: A GRAALL Study

▪Introduction: Gene expression studies have consistently identified a HOXA positive (HOXAPos) subgroup of T-cell acute lymphoblastic leukemia (T-ALL) (Ferrando et al, Cancer Cell 2002, Soulier et al, Blood 2005, Homminga et al, Cancer Cell 2011). It is however unclear if HOXAPos T-ALL constitutes a distinct and homogeneous clinical entity, and the biological consequences of HOXA over-expression have not been systematically examined.Methods: We identified and characterized the biological characteristics and clinical outcome of 55 HOXAPos cases among a cohort of 209 adult T-ALL patients who were uniformly treated as part of the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003 and -2005 studies.Results: HOXAPos patients had higher rates of an early thymic precursor (ETP)-like immunophenotype (38% v 13.9%, p = 0.0008), early bone marrow chemoresistance (59.3% v 40.8%, p = 0.026) and positive minimal residual disease (MRD, 51.5% v 23.5%, p = 0.01) than the HOXANeg group. These differences were due to a particularly high frequency of chemoresistant ETP-ALL among HOXAPos cases harboring leukemic fusion proteins that trans-activate the HOXA locus (e.g. PICALM-MLLT10, SET-NUP214).Strikingly, the presence of an ETP-like immunophenotype conferred marked differences in outcome within the HOXAPos group (5 year event-free survival (EFS) 25% for HOXAPos ETP v 52.2% for HOXAPos non-ETP, p = 0.02), which were mirrored by corresponding increases in cumulative incidence of relapse (CIR, 57.1% v 25%, p = 0.01, Figure 1). In contrast, these survival differences were not seen in the HOXANeg patients, where ETP and non-ETP cases had similar 5 year EFS (54.9% v 50%, p = 0.73) and CIR (34.5% v 41.2%, p = 0.57).Multivariate analysis revealed that early bone marrow chemosensitivity was the clinico-biological covariate that had the strongest prognostic interaction with HOXA status. HOXA positivity conferred significant decreases in both the EFS and CIR of chemoresistant patients (p = 0.053 and 0.039 respectively), that was independent of white blood cell count (WCC), stem cell transplant (SCT), ETP phenotype, EGIL classification, and our recently reported risk classifier that integrates the prognostic effects of mutations of NOTCH1, FBXW7, RAS and PTEN (Trinquand et al, J Clin Oncol 2013). There were corresponding marked survival differences within the HOXAPos cohort between chemoresistant and chemosensitive cases. These disparities were not seen in the HOXANeg group, indicating that the prognostic value of chemosensitivity in adult T-ALL is specific to HOXAPos patients.Discussion: Our data show that clinico-biological phenotype is intimately linked to the underlying mechanism of HOXA locus deregulation, and we identify HOXA overexpression as a novel prognostic variable in ETP-ALL. Multivariate analysis suggests that this poor outcome is strongly related to intrinsic treatment resistance, and that this effect is exclusive to the HOXAPos cohort. Patients in the GRAALL-2003 and -2005 studies received enhanced induction and/ or salvage therapy in the event of poor early treatment response. Our results suggest that pediatric regimen-based intensification provides significant survival benefits for HOXANeg chemoresistant cases. In contrast, these modifications are inadequate for therapeutic rescue of the majority of HOXAPos chemoresistant ETP-ALL. The dramatically inferior prognosis of this group mandates consideration for alternative treatments in future clinical trials. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia

AbstractBecause 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.

Value of Cytogenetic Abnormalities in Adult Patients with Philadelphia Chromosome (Ph)-Negative Acute Lymphoblastic Leukemia (ALL) Treated in the Pediatric-Inspired Trials from the Group for Research on Adult ALL (GRAALL)

Background: Numerous recurrent chromosomal abnormalities have been described in adult Ph-negative ALL, often observed in small patient cohorts. In the largest MRC/ECOG study (Moorman, Blood 2007), t(4;11)(q21;q23), 14q32 involvement, complex karyotype (≥5 abnormalities), and low hypodiploidy/near triploidy (Ho-Tr) were associated with shorter event-free survival (EFS), while patients with high hyperdiploidy or del(9p) had a better outcome. We aimed to confirm these observations in 955 adult patients (15-60y; median, 35y) with Ph-negative ALL treated in the pediatric-inspired GRAALL-2003/2005 trials.Patients and Methods: Overall, a karyotype was performed for 946 (611 BCP-ALL, and 335 T-ALL), successful for 811 (523 BCP-ALL and 288 T-ALL) and abnormal in 590 patients (387 BCP-ALL and 203 T-ALL). FISH and/or PCR screening for relevant abnormalities and DNA index were also performed, finally allowing for the identification of cytogenetic abnormalities in 677/955 patients (71%). All were centrally reviewed. Ultimately, 857/955 patients (90%; 542 BCP-ALL and 315 T-ALL) could be classified in 18 exclusive primary cytogenetic subsets as detailed below. Endpoints were cumulative incidence of failure (CIF, including primary refractoriness and relapse) and EFS. With a median follow-up of 4 years, 5-year CIF and EFS were estimated in these patients at 31% and 51%, respectively. As some abnormalities, including MLL rearrangements, Ho/Tr, t(1;19)(q23;p13)/TCF3 and complex karyotypes were used to stratify allogeneic stem cell transplantation (SCT) in GRAALL trials, some comparisons were repeated after censoring patients transplanted in first CR at SCT time.Results: The 542 informative BCP-ALL patients were classified as: t(4;11)(q21;q23)/MLL-AFF1 (n=72; 13%); other MLL+ 11q23 abnormalities (n=11; 2%); t(1;19)(q23;p13)/TCF3-PBX1 (#28; 5%); Ho/Tr (n=33; 6%); high hyperdiploidy (n=36; 7%); abnormal 14q32/IGH translocation (n=27; 5%); t(12;21)(p13;q22)/ETV6-RUNX1 (n=2; 0.4%); iAMP21 (n=3; 0.6%); other abnormalities (n=210; 39%); and no abnormality (n=120; 22%). The 315 informative T-ALL patients were classified as: t(10;14)(q24;q11)/TLX1 (n=64; 20%); other 14q11 or 7q34/TCR (n=31; 10%); t(5;14)(q35;q32)/TLX3 (n=29; 9%); t(10;11)(p12;q14)/PICALM-MLLT10 (n=14; 4%); deletion 1p32/SIL-TAL (n=18; 6%); MLL+ 11q23 abnormalities (n=6; 2%); other abnormalities (n=93; 30%); and no abnormalities (n=60; 19%). A complex karyotype was observed in 27/527 (5%) BCP-ALL and 21/298 (7%) T-ALL patients and a monosomal karyotype (as per Breems, JCO 2008) in 82/518 (16%) BCP-ALL and 26/286 (9%) T-ALL patients. In BCP-ALL, trends towards higher CIF and shorter EFS were observed in t(4;11) patients, with or without SCT censoring (HRs, 1.34 to 1.64; p values <0.10). Shorter EFS was observed in 3 subsets: 14q32 (HR, 2.10; p=0.002), Ho/Tr (HR, 1.45; p=0.10), and monosomal karyotype (HR, 1.42; p=0.029), but CIF were not different. This might be related to the older age of patients in these subsets (medians, 43y, 53y and 44y; p=0.029, <0.001 and <0.001, respectively) and worse treatment tolerance. For instance, higher incidences of non ALL-related deaths were observed in patients with 14q32 abnormalities or monosomal karyotype (p=0.031 and 0.067, respectively). Patients with high hyperdiploidy only tended to have lower CIF and longer EFS. Complex karyotype did not impact CIF and EFS, even after SCT censoring. Conversely, in T-ALL, complex karyotypes were associated with shorter EFS (HR, 2.20; p=0.004), even if the difference in CIF did not reach significance. A worse outcome was also observed in patients with t(10;11)(p12;q14)/PICALM-MLLT10 (HR, 2.45 and 2.14; p=0.016 and 0.021, for CIF and EFS respectively). A longer EFS was observed in patients with t(10;14)(q24;q11)/TLX1 (HR, 0.55; p=0.014), with a trend for lower CIF (HR, 0.59; p=0.070), while no inferior outcome was observed in t(5;14)(q35;q32)/TLX3 patients.Conclusion: These results show that, in the context of an intensified pediatric-inspired protocol designed for adult Ph-negative ALL patients, few cytogenetic subsets remained reliably predictive of response to therapy. Differences observed in EFS might partly be due to treatment-related mortality. Combining cytogenetics, molecular genetics and minimal residual disease monitoring could allow for better individual risk assessment (Beldjord, Blood 2014). DisclosuresNo relevant conflicts of interest to declare.

SET-NUP214 is a recurrent γδ lineage-specific fusion transcript associated with corticosteroid/chemotherapy resistance in adult T-ALL

AbstractThe SET-NUP214 (TAF1/CAN) fusion gene is a rare genetic event in T-cell acute lymphoblastic leukemia (T-ALL). Eleven (6%) of 196 T-ALL patients enrolled in the French Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) 2003 and 2005 trials harbored a SET-NUP214 transcript. SET-NUP214–positive patients were predominantly (10 [91%] of 11) T-cell receptor (TCR)–negative and strikingly associated with TCRγδ lineage T-ALLs, as defined by expression of TCRγδ, TCRδ and/or TCRγ rearrangements but no complete TCRβ variable diversity joining rearrangement in surface CD3/TCR-negative cases. When compared with SET-NUP214–negative patients, SET-NUP214–positive patients showed a significantly higher rate of corticosteroid resistance (91% vs 44%; P = .003) and chemotherapy resistance (100% vs 44%; P = .0001). All SET-NUP214–positive patients but one achieved complete remission, and 9 were allografted. Despite the poor early-treatment sensitivity, the outcome of SET-NUP214–positive patients was similar to that of SET-NUP214-negative patients.

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) In Adults With Philadelphia Chromosome (Ph)-Negative Acute Lymphoblastic Leukemia (ALL): Results From The Group For Research On Adult ALL (GRAALL)

▪ PurposeThe 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. Patients and methodsIn 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). ResultsAmong 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). [Display omitted] ConclusionIn 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. Disclosures:No relevant conflicts of interest to declare.

L-Asparaginase-Loaded Red Blood Cells Combined with Standard EWALL Chemotherapy in Older Patients with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (Ph- ALL): First Results of the GRASPALL/GRAALL-SA2-2008 Study

Abstract 2579 Introduction:In adults with Ph- ALL, the clinical benefit of L-asparaginase is hampered by its toxicity. With its improved efficacy/tolerability potential, L-asparaginase-loaded red blood cells (GRASPA®) could be a suitable option for combining L-asparaginase with standard chemotherapy, especially in older patients with the disease. Methods:The GRASPALL/GRAALL-SA2-2008 was an open label Phase II dose escalation study conducted by the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) in patients aged >55y with newly diagnosed ALL Ph-. The aim was to determine the optimal dose of GRASPA® that could be combined with the standard EWALL chemotherapy backbone in these patients. The primary composite endpoint included tolerance and efficacy, the latter being defined as the achievement of target asparagine depletion for at least 7 days. Hematological and molecular Ig/TCR minimal residual disease (MRD) response rates, survival and anti L-asparaginase antibody titer (Abs), were secondary endpoints. Three doses of Graspa® (50, 100 and 150 IU/kg), infused at d3 and d6 of two successive induction cycles, were investigated, using a Bayesian experimental plan. After each 3-pt cohort, an independent Data Safety Monitoring Board reviewed study drug tolerance before opening the next dose. EWALL backbone consisted of dexamethasone prephase followed by induction-1 (dexamethasone 10 mg/m2 d1-2,/8-11, vincristine 1 mg d1,8, and idarubicine 10 mg d1-2/8-9) and induction-2 (cyclophosphamide 500 mg/m2 d15-17 and cytarabine 60 mg/m2 d16-19/23-26). Consolidation consisted of 6 monthly alternating cycles with methotrexate (1 g/m2 d1), E.coli asparaginase (10,000 IU/m2 d2) and high-dose cytarabine (1 g/m2/q12 hrs d1,3,5). Maintenance included mercaptopurine, methotrexate and vincristine/dexamethasone pulses for a total duration of 2 years. Dose reductions were recommended for pts aged >70y. Results:Between March 2009 and October 2010, 30 pts were recruited in 20 GRAALL centers. The 50, 100 and 150 dose levels included 3, 13 and 14 pts, respectively. Median age was 67 years (range 59–77). Twenty-six pts had B-lineage ALL and 4 had T-ALL. No differences in baseline characteristics were observed across the 3 dose level groups. Overall, 0 (0%), 2 (15%) and 5 (36%) pts presented limiting toxicities in the 50, 100 and 150 dose level, respectively. Because of insufficient efficacy, only 3 pts received the lower 50 IU/kg dose. At the higher 100 and 150 dose levels, 85% and 71% pts reached target asparagine depletion at d7, respectively. In these two 100 and 150 IU/kg groups, grade 3/4 infections were observed in 69% and 71% pts and invasive fungal infection in 23% and 43% pts, respectively. Incidences of adverse events tended to be lower in the 100 IU/kg group:Dose levels50 IU/kg n=3100 IU/kg n=13150 IU/kg n=14Pancreatic enzyme elevation1 (33%)4 (31%)4 (28%)Clinical Pancreatitis000Liver enzyme elevation2 (66%)9 (69%)9 (64%)Antithrombin III decrease2 (66%)7 (54%)12 (86%)Thrombosis1 (33%)1 (8%)2 (14%)Protein synthesis disorders2 (66%)4 (30%)7 (50%)Allergy000Anti L-asparaginase Abs were detected in 0/3, 2/13 and 1/14 pts after induction-1 and 1/2, 3/9 and 5/9 pts after induction-2, in the 50, 100 and 150 dose level group, respectively. Nevertheless, no clinical allergy was observed after the second drug infusion, but allergic reactions to native E-Coli L-asparaginase were observed in 5/19 pts after consolidation 1. Grade 3–4 infections and renal methotrexate toxicities were observed in 11% (11/99) and 10% (11/51) of consolidations courses.Responses to therapy were as follows:Dose levels50 IU/kg n=3100 IU/kg n=13150 IU/kg n=14AllInduction failure0/3 (0%)1/13 (8%)2/14 (14%)3/30 (10%)Induction death1/3 (33%)1/13 (8%)4/14 (28%)6/30 (20%)Complete remission (CR)2/3 (77%)11/13 (84%)8/14 (57%)21/30 (70%)MRD clearance1/2 (50%)4/8 (50%)1/5 (20%)6/15 (40%)Pts alive at 6 months2/3 (67%)11/13 (85%)9/14 (64%)22/30 (73%)Pts alive in CR at 6 months2/3 (67%)11/13 (85%)5/14 (36%)19/30 (63%) Conclusion:Two infusions of 100 IU/kg GRASPA® appear to be a safe and active manner to introduce L-asparaginase during initial induction chemotherapy of older pts with Ph- ALL. Larger prospective evaluations of this new L-asparaginase formulation are warranted. Disclosures:Liens:ERYTECH Pharma: Employment, Equity Ownership. Godfrin:ERYTECH Pharma: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Pediatric-inspired intensified therapy of adult T-ALL reveals the favorable outcome of NOTCH1/FBXW7 mutations, but not of low ERG/BAALC expression: a GRAALL study

AbstractDespite recent progress in the understanding of acute lymphoblastic leukemia (T-ALL) oncogenesis, few markers are sufficiently frequent in large subgroups to allow their use in therapeutic stratification. Low ERG and BAALC expression (E/Blow) and NOTCH1/FBXW7 (N/F) mutations have been proposed as powerful prognostic markers in large cohorts of adult T-ALL. We therefore compared the predictive prognostic value of N/F mutations versus E/Blow in 232 adult T-ALLs enrolled in the LALA-94 and Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocols. The outcome of T-ALLs treated in the pediatric-inspired GRAALL trials was significantly superior to the LALA-94 trial. Overall, 43% and 69% of adult T-ALL patients were classified as E/Blow and N/F mutated, respectively. Strikingly, the good prognosis of N/F mutated patients was stronger in more intensively treated, pediatric-inspired GRAALL patients. The E/B expression level did not influence the prognosis in any subgroup. N/F mutation status and the GRAALL trial were the only 2 independent factors that correlated with longer overall survival by multivariate analysis. This study demonstrates that the N/F mutational status and treatment protocol are major outcome determinants for adults with T-ALL, the benefit of pediatric inspired protocols being essentially restricted to the N/F mutated subgroup.

NOTCH1/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study

AbstractMany somatic genetic abnormalities have been identified in T-cell acute lymphoblastic leukemia (T-ALL) but each individual abnormality accounts for a small proportion of cases; therapeutic stratification consequently still relies on classical clinical markers. NOTCH1 and/or FBXW7 mutations both lead to activation of the NOTCH1 pathway and are among the most frequent mutations in T-ALL. We screened 141 adult diagnostic T-ALL samples from patients treated on either the Lymphoblastic Acute Leukemia in Adults (LALA)-94 (n = 87) or the GRAALL-2003 (n = 54) trials. In 88 cases (62%) there were demonstrated NOTCH1 mutations (42% heterodimerization [HD], 10% HD+proline glutamate serine threonine [PEST], 6% PEST, 2% juxtamembrane mutations, 2% transactivation domain [TAD]) and 34 cases (24%) had FBXW7 mutations (21 cases had both NOTCH1 and FBXW7 mutations); 40 cases (28%) were wild type for both. There was no significant correlation between NOTCH1 and/or FBXW7 mutations and clinico-biologic features. Median event-free survival (EFS) and overall survival (OS) were 36 versus 17 months (P = .01) and not reached versus 32 months (P = .004) in patients with NOTCH1 and/or FBXW7 mutations versus other patients, respectively. Multivariate analysis showed that the presence of NOTCH1/FBXW7 mutations was an independent good prognostic factor for EFS and OS (P = .02 and P = .01, respectively). These data demonstrate that NOTCH1 pathway activation by either NOTCH1 or FBXW7 mutation identifies a large group of patients with a favorable outcome that could justify individual therapeutic stratification for T-ALL.