Outcomes of Patients with B-ALL with Concomitant BCR::ABL1 and CRLF2 Rearrangements

Background: Outcomes of patients with Philadelphia chromosome positive (Ph+) ALL have improved significantly with the introduction of tyrosine kinase inhibitors (TKI). Ph-like ALL is a high-risk subtype of B-ALL with gene expression profile similar to Ph+ ALL, but without the BCR-ABL translocation. About 50% of the patients with Ph-like ALL have CRLF2 rearrangement (CRLF2-R) and are associated with poor outcomes with conventional chemoimmunotherapy. The co-occurrence of both Ph+ and CRLF2-R is rare (Jain, Haematologica 2017) and long-term outcomes unknown.

Methods: We retrospectively analyzed the Leukemia and Pathology databases for patients who presented to the MD Anderson Cancer Center (MDACC) and were noted to have concomitant Ph+ and CRLF2-R. Ph+ was assessed by conventional cytogenetics / FISH / PCR for BCR-ABL1. CRLF2-R was assessed by flow cytometry / FISH. Outcomes assessed were best response (complete remission (CR), relapse, minimal residual disease (MRD), event-free survival (EFS) and overall survival (OS).

Results: We identified 8 patients (5 newly diagnosed and 3 R/R B-ALL) who had concurrent Ph+ and CRLF2-R rearrangement (Table 1). The median age was 29 (range, 14-57), 6 (75%) were of Hispanic ethnicity, and 6 (75%) were men. The median clone size of CRLF2-R and Ph+ were 73% (56-92%) and 52% (4-96%), respectively. The most frequent mutated gene was JAK2 in 3/8 (38%) patients.

All patients were treated with chemoimmunotherapy or immunotherapy + TKI (ponatinib, n=7; dasatinib, n=1). The median follow-up was 23 months. The best response achieved was CR in 6/8 (75%). The median EFS was 8.6 months; 12-month OS was 75% (Figure 1). A total of 3/6 (50%) responders had a subsequent relapse with 2/3 relapses occurring in the extramedullary compartment (one in central nervous system and one intraperitoneal); both with CRLF2-R clone without Ph+.

Of the 5 patients who presented to MDACC as newly diagnosed B-ALL, two were treated with frontline with Hyper-CVAD + ponatinib/dasatinib, two with blinatumomab + ponatinib and the one with a pediatric regimen + dasatinib. Best response was CR with negative MRD in 5/5 (100%). All 5 patients cleared both rearrangements (Ph+ and CRLF2) at the time of remission; 2/5 patients showed CRLF2-R during relapse (without the Ph+). The 12-month OS and EFS were 80% and 60%, respectively.

Three patients presented to MDACC with R/R B-ALL. They received HCVAD + ponatinib/dasatinib +/-ruxolitinib. Best response was CR in 1/3 (33%) patients. All 3 patients cleared Ph+, but CRLF2-R persisted in 2 patients.

Conclusions: Patients who harbor concomitant Ph+ and CRLF2-R represent a rare but high-risk subgroup of B-ALL. High rate of relapse was noted despite treatment with chemotherapy + TKI +/- ruxolitinib; several patients cleared the Ph+ clone, but CRLF2-R clone persisted suggesting novel interventions against CRLF2-R B-ALL are warranted.

Jabbour:Genentech: Other: Advisory Role, Research Funding; Pfizer: Other: Advisory Role, Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; Amgen: Other: Advisory Role, Research Funding; AbbVie: Other: Advisory Role, Research Funding; Spectrum: Research Funding; Takeda: Other: Advisory Role, Research Funding. Konopleva:Reata Pharmaceuticals, Novartis and Eli Lilly: Patents & Royalties; Forty-Seven; F. Hoffman LaRoche: Honoraria; AbbVie, Genentech, F. Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, Astra Zeneca; Rafael Pharmaceutical; Sanofi, Forty-Seven: Research Funding; Stocks, Reata Pharmaceuticals: Current equity holder in publicly-traded company; AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, Kisoji; Janssen: Consultancy; Stemline Therapeutics, F. Hoffman La-Roche; Janssen: Membership on an entity's Board of Directors or advisory committees. Short:Amgen: Consultancy, Honoraria; AstraZeneca: Consultancy; Stemline Therapeutics: Research Funding; Novartis: Consultancy; Pfizer: Consultancy; Takeda Oncology: Consultancy, Research Funding; Astellas: Research Funding. Pemmaraju:abbvie: Consultancy; stemline: Consultancy; immunogen: Consultancy; mustangbio: Research Funding; incyte: Consultancy; novartis: Research Funding; pacylex: Consultancy, Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; cellectis: Research Funding; cellularity: Research Funding. Kantarjian:NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Research Funding; ImmunoGen: Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Takeda: Honoraria. Jain:Pfizer: Research Funding; Incyte Corporation: Research Funding; ADC Therapeutics: Research Funding; Cellectis: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novalgen: Research Funding; TransThera Sciences: Research Funding; Takeda: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Aprea Therapeutics: Research Funding; TG Therapeutics: Honoraria; MEI Pharma: Honoraria; Ipsen: Honoraria; CareDx: Honoraria; Pharmacyclics, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; Loxo Oncology: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Mingsight: Research Funding; Beigene: Honoraria; Medisix: Research Funding; Newave: Research Funding; Dialectic Therapeutics: Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding; Servier Pharmaceuticals LLC: Research Funding; Fate Therapeutics: Research Funding; Cellectis: Honoraria, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support; Genentech, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding.