Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the USA to treat adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (R/R ...B-ALL) based on ZUMA-3 study results. We report updated ZUMA-3 outcomes with longer follow-up and an extended data set along with contextualization of outcomes to historical standard of care.
Adults with R/R B-ALL received a single infusion of KTE-X19 (1 × 10
CAR T cells/kg). Long-term post hoc subgroup assessments of ZUMA-3 were conducted. Outcomes from matched patients between historical clinical trials and ZUMA-3 patients were assessed in the retrospective historical control study SCHOLAR-3.
After 26.8-months median follow-up, the overall complete remission (CR) rate (CR + CR with incomplete hematological recovery) among treated patients (N = 55) in phase 2 was 71% (56% CR rate); medians for duration of remission and overall survival (OS) were 14.6 and 25.4 months, respectively. Most patients responded to KTE-X19 regardless of age or baseline bone marrow blast percentage, but less so in patients with > 75% blasts. No new safety signals were observed. Similar outcomes were observed in a pooled analysis of phase 1 and 2 patients (N = 78). In SCHOLAR-3, the median OS for treated patients from ZUMA-3 (N = 49) and matched historical controls (N = 40) was 25.4 and 5.5 months, respectively.
These data, representing the longest follow-up of CAR T-cell therapy in a multicenter study of adult R/R B-ALL, suggest that KTE-X19 provides a clinically meaningful survival benefit with manageable toxicity in this population.
NCT02614066.
CAR-T Cells have opened new doors for cellular immunotherapies and provides new therapeutic options for patients with refractory B-cell malignancies, B-cell acute lymphoblastic leukemia and diffuse ...large B-cel lymphoma. CAR-T Cells have benefited from an accelerated approval procedure in many countries. Indeed, The French health authorities have approved the specialties Tisacel ® and Axicel ®, but additional data including the use of CAR-T Cells in real life were also mandatory. In regard to the scientific interest of the project, LYSA-LYSARC committed itself to prospectively and retrospectively collect information on patients eligible for CAR-T Cells as required by French health authorities. Other academic cooperating groups (GRAALL, IFM, SFCE, FILO and the scientific society SFGM-TC) were associated to this initiative which aims to build a nationwide CAR-T Cells devoted registry, so-called DESCART (Dispositif d'Enregistrement et Suivi des patients traités par CAR-T cells). DESCAR-T is a real-life multicentric registry set up in French sites qualified for CAR-T Cells treatment. DESCAR-T objective is to describe the use of CAR-T Cells in real life. All paediatric and adult patients with hematological malignancy fulfilling CAR-T Cells approval criteria and for whom a CAR-T Cells therapy has been discussed are included from 1 July 2018. Clinical data are directly collected from medical records and patients are treated according to the centers' routine practices. One of the distinctive features of DESCAR-T is its link with HTA for CAR-T Cells s reimbursement by the French public health system. DESCAR-T is the first national registry promoted by an academic group allowing centralized data collection for both academic and HTA/health authorities' purposes.
The 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.
•SET-NUP214 is a recurrent (6%) γδ lineage-specific fusion transcript in adult T-ALL.•SET-NUP214 is strongly associated with corticosteroid and chemotherapy resistance but does not negatively influence clinical outcome.
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 BCR-ABL mutation was similar to that of unmutated patients. With a median duration of exposure to ponatinib of 4 months, only 3 cardio-vascular events were recorded despite a high incidence of risk factors, and overall safety was acceptable. These results underline the place of ponatinib to induce early response in advanced disease and the need of new combinations to improve long-term outcome.
The treatment of older patients with acute myeloid leukemia that is secondary to previous myelodysplastic syndrome, myeloproliferative neoplasm, or prior cytotoxic exposure remains unsatisfactory. We ...compared 92 and 107 patients treated, respectively, with intensive chemotherapy or azacitidine within two centres. Diagnoses were 37.5% post-myelodysplastic syndrome, 17.4% post-myeloproliferative neoplasia, and 45.1% therapy-related acute myeloid leukemia. Patients treated by chemotherapy had less adverse cytogenetics, higher white blood-cell counts, and were younger: the latter two being independent factors entered into the multivariate analyses. Median overall-survival times with chemotherapy and azacitidine were 9.6 (IQR: 3.6-22.8) and 10.8 months (IQR: 4.8-26.4), respectively (
= 0.899). Adjusted time-dependent analyses showed that, before 1.6 years post-treatment, there were no differences in survival times between chemotherapy and azacitidine treatments whereas, after this time-point, patients that received chemotherapy had a lower risk of death compared to those that received azacitidine (adjusted HR 0.61, 95%CI: 0.38-0.99 at 1.6 years). There were no interactions between treatment arms and secondary acute myeloid leukemia subtypes in all multivariate analyses, indicating that the treatments had similar effects in all three subtypes. Although a comparison between chemotherapy and azacitidine remains challenging, azacitidine represents a valuable alternative to chemotherapy in older patients that have secondary acute myeloid leukemia because it provides similar midterm outcomes with less toxicity.
Micro-Abstract Therapy options are limited for adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL). In the present phase II study, 36 patients with relapsed or refractory ...ALL were treated with the anti-CD19 antibody-drug conjugate, coltuximab ravtansine. Coltuximab ravtansine was well tolerated, but the clinical response rate was low (4 of 17 patients).
Invasive fungal infections (IFIs) remain a major clinical burden due to their morbidity and mortality, particularly in patients with acute leukemias and allogeneic HSCT which represent the main risk ...factors for proven/probable IFI in hematology. We conducted a study in France which enrolled 677 patients with acute myeloid leukemia (AML) receiving intensive chemotherapy from 34 ALFA centers. This study confirmed the significant lower rate of proven/probable IFI in patients who received antifungal prophylaxis (AFP), and that IFI was associated with an increased early mortality rate.
The trial recommended laminar air flow rooms and posaconazole AFP according to the 2009 recommendations of the European Conference on Infections in Leukaemia (ECIL). IFI were graded as proven/probable or possible by local investigators. Two central review processes were performed. All study data were centrally reviewed by hematological expert according to the EORTC classification. In parallel, available CT-scans were reviewed by two independent experts (hematologist and pneumologist).
We showed three supplementary important observations: (1) Despite the ECIL recommendations, 30% of patients (203/677) did not receive any AFP, and 91 patients (13%) received another antifungal agent than the one recommended. (2) with regards to the IFI grading (Figure 1), 71 IFI were diagnosed and graded by the investigators. After review by the experts, the grade was maintained for 49/71 IFI 69%, 20 possible and 28 proven/probable IA and 1 proven/probable invasive candidiasis (IC), while 9 possible IFI (13%) (8 IA and 1 IC) were upgraded as proven/probable, and 13 proven/probable IFI (18%) (13 IA) were downgraded as possible. Twenty-five IFI were not graded by the investigators including 3 cases of IA graded by the experts (2 proven/probable and 1 possible) for whom antifungal prophylaxis was pursued, and 22 cases of other IFI graded only by the experts: 15 IC and 7 invasive mucormycosis (IM) all proven/probable, for whom AFP was modified for a curative therapy. In addition, chest imaging data of 37 patients were centrally reviewed, and 21 (57%) were reclassified. The review of imaging data was 100% consistent with the EORTC-based expert review. The experts graded more proven/probable IFI than the investigators with 9.0% (61/677) versus 6.2% (42/677). (3) Among patients without IFI, the rate of complete hematological remission was higher (513/581, 88.3%) versus those with IFI (77/96, 80.2%) (p=0.04). Among patients with IFI, the rate of posaconazole-based AFP was 45.5% (35/77) for those who achieved CR, vs. 63.2% (12/19) for those who did not achieve CR.
In conclusion, we showed in this very high-risk population, ECIL recommendations were followed only in 57% of patients. The frequent “misgrading” of the IFI (33% of IA up or downgraded and 92% of other IFI) has an impact on their appropriate management. Another important message is that haematological failure is associated with more IFI despite the AFP.
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De Botton:Pierre Fabre: Consultancy; AbbVie: Consultancy; Forma: Consultancy, Research Funding; Daiichi: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Agios: Consultancy, Research Funding; Servier: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy, Speakers Bureau; Syros: Consultancy; Astellas: Consultancy. Bertoli:Astellas: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Daiichi Sankyo: Consultancy. Castaigne:Pfizer: Consultancy. Vey:Janssen: Honoraria; Novartis: Consultancy, Honoraria. Dombret:CELGENE: Consultancy, Honoraria; AGIOS: Honoraria; Institut de Recherches Internationales Servier (IRIS): Research Funding. Thomas:DAICHI: Honoraria; ABBVIE: Honoraria; PFIZER: Honoraria; INCYTE: Honoraria.
The prognostic implications of DNMT3A genotype in T-ALL are incompletely understood. We performed comprehensive genetic and clinicobiological analyses of T-ALL 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-ALL. DNMT3A mutation was associated with older age (median 43.9 years v 29.4 years, p < 0.001), immature T-receptor genotype (53.3% v 24.4%, p = 0.016) and lower remission rates (72.2% mutated v 94.4% non-mutated, p = 0.006). DNMT3A alterations were significantly associated with worse clinical outcome, with higher cumulative incidence of relapse (CIR, HR 2.33, 95% CI 1.05-5.16, p = 0.037) and markedly poorer event-free survival (EFS, HR 3.22, 95% CI 1.81-5.72, p < 0.001) and overall survival (OS, HR 2.91, 95% CI 1.56-5.43, p = 0.001). Adjusting for age as a covariate, or restricting the analysis to patients over 40 years, who account for almost 90% of DNMT3A-mutated cases, did not modify these observations. In multivariate analysis using the risk factors that were used to stratify treatment during the GRAALL studies, DNMT3A mutation was significantly associated with shorter EFS (HR 2.33, 95% CI 1.06 - 4.04, p = 0.02). Altogether, these results identify DNMT3A genotype as a predictor of aggressive T-ALL biology. The GRAALL-2003 and -2005 studies were registered at www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.
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