The Combination of Venetoclax and Tofacitinib Induced Hematological Responses in Patients with Relapse/ Refractory T-ALL with BCL2 Expression and Surface IL7R Expression or IL7R-Pathway Mutations (On behalf of the GRAALL)
Authors: Cabannes Aurélie , Schmidt Aline , Brissot Eolia , Balsat Marie , Maury Sébastien , Isnard Francoise , Chevallier Patrice , Cacheux Victoria , Cluzeau Thomas , Graux Carlos , Lhermitte Ludovic , Dombret Herve , Boissel Nicolas , Asnafi Vahid , Rousselot Philippe 
Published: November 2019

Background. We previously reported that IL7R-pathway genes are mutated in 29% of T-ALL and that surface IL7R is expressed in 53% of T-ALL (Rathana K et al. abstract S131, EHA 2019). In these samples, in vitro and in vivo (IL7R+PDX T-ALL) sensitivity to JAK inhibitors is determined by the expression of IL7R regardless of the IL7Rp genomic status. BCL2 inhibition has been shown to be synergistic with the IL7R pathway inhibition (Degrise S et al., Leukemia 2018;32(3):788-800). We therefore explored whether the combination of tofacitinib, a potent JAK3 inhibitor, with venetoclax may improve the hematological status of patients with relapse/refractory T-ALL.
Methods. Patients with relapse/refractory T-ALL, with surface IL7R expression or IL7R-pathway mutations and BCL2 expression were eligible if they had failed all available therapeutic options (including clofarabine and/or allogenic HSCT if eligible). Patients were offered to be treated with venetoclax, 100 mg/d day1; 200 mg/d day2; 300 mg/d day3 and 400 mg/day thereafter and for subsequent 28 days cycles combined with tofacitinib, 10mg twice a day started from day 5 cycle 1 (off-label use). Responses were assessed after cycle 1 and cycle 3. Responding patients may continue therapy until relapse, death or allogenic HSCT if eligible.
Results. Eight patients were treated including 7 ETP-ALL and 1 T-cell lymphoblastic lymphoma. Median age was 56 years (27-69) and sex ratio (M/F) was 4/4. Four patients were refractory to at least 2 lines of therapy and 4 patients relapsed, all on therapy. Relapsing patients were in failure after at least one salvage therapy. All patients expressed BCL2. A mutation of JAK3 L857P was found in 5 cases including one patient with both JAK3 and JAK1 mutations. except one with a mutation of IL7-R. Other patients expressed IL7R. A response to therapy was observed in 5 out of seven evaluable cases (71%) including 2 CR associated with a negative MRD (sensitivity 10-4) and 3 partial responses (medullar blasts less than 15%). The remaining patient has just started the first cycle of therapy. Duration of responses was 10 months and +6 months (allo HSCT planned) for the 2 patients in CR and 3 months or less for the partial responders. No serious adverse event related to therapy was observed.
Conclusion. IL7-pathway is a possible target for therapy with JAK inhibitors in patients with T-ALL in relapse or refractory to conventional therapy. A combination of venetoclax and tofacitinib may offer a potential savage for these patients with limited therapeutic options.

Disclosures
Chevallier: Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria. Dombret:Institut de Recherches Internationales Servier (IRIS): Research Funding; AGIOS: Honoraria; CELGENE: Consultancy, Honoraria. Boissel:NOVARTIS: Consultancy. Rousselot:Pfizer: Research Funding; Incyte: Research Funding.

OffLabel Disclosure:
Venetoclax in T-ALL Tofacitinib in T-ALL