B-ALL With t(5;14)(q31;q32); IGH-IL3 Rearrangement and Eosinophilia: A Comprehensive Analysis of a Peculiar IGH-Rearranged B-ALL

International audienceBackground: B-cell acute lymphoblastic leukemia associated with t(5;14)(q31;q32); IGH-IL3 is an exceptional cause of eosinophilia. The IGH enhancer on 14q32 is juxtaposed to the IL3 gene on 5q31, leading to interleukin-3 overproduction and release of mature eosinophils in the blood. Clinical, biological and outcome data are extremely scarce in the literature. Except for eosinophilia, no relevant common feature has been highlighted in these patients. However, it has been classified as a distinct entity in the World Health Organization classification. Cases Presentation: Eight patients with t(5;14)(q31;q32) treated by French or Austrian protocols were retrospectively enrolled. Array comparative genomic hybridization, multiplex ligation-dependent probe amplification or genomic PCR search for IKZF1 deletion were performed in 7. Sixteen patients found through an exhaustive search in the literature were also analyzed. For those 24 patients, median age at diagnosis is 14.3 years with a male predominance (male to female ratio = 5). Eosinophilia-related symptoms are common (neurologic in 26%, thromboembolic in 26% or pulmonary in 50%). Median white blood cells count is high (72 x 10(9)/L) and linked to eosinophilia (median: 32 x 10(9)/L). Peripheral blasts are present at a low level or absent (median: 0 x 10(9)/L; range: 0-37 x 10(9)/L). Bone marrow morphology is marked by a low blast infiltration (median: 42%). We found an IKZF1 deletion in 5 out of 7 analyzable patients Outcome data are available for 14 patients (median follow-up: 28 months): 8 died and 6 are alive in complete remission. Some of these features are concordant with those seen in patients with other IGH-rearranged B-cell acute lymphoblastic leukemias: young age at onset, male sex, low blast count, high incidence of IKZF1 deletion and intermediate prognosis. Conclusion: Based on shared epidemiological and biological features, B-cell acute lymphoblastic leukemia with t(5;14)(q31;q32) is a peculiar subset of IGH-rearranged B-cell acute lymphoblastic leukemia with an intermediate prognosis and particular clinical features related to eosinophilia

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

International audienceIntroduction 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