Nelarabine-Based Salvage Therapy in Adult Patients with T-Cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma (T-ALL/LL) Relapsing After Allogeneic Stem Cell Transplantation: A French Experience on Behalf of the Group for Research in Adult Lymphoblastic Leukemia (GRAAL),

The prognosis of patients with T-ALL/LL has been recently re-assessed, based on monitoring of minimal residual disease (MRD) levels and new insights in pathogenesis (NOTCH1 pathway mutations). To date, allogeneic hematopoietic stem cell transplant (HSCT) in first complete remission (CR) remains the standard option in patients identified with a high risk of relapse. In this context, patients relapsing after HSCT represent a very difficult challenge to get a second CR. Nelarabine, a pro-drug of Ara-G, has been associated with a high response rate in relapsing ALL (Gökbuget N et al., Blood 2011), but very few data are available on its efficacy and safety in the post-HSCT setting. Patients: Medical records of 11 T-ALL/LL patients who received nelarabine-based salvage therapy for a relapse after HSCT were retrospectively reviewed. These patients were treated with nelarabine alone (1,5g/m²/day (D) D1, D3, D5, every 28 days) (N=5) or nelarabine associated with hyperfractionated cyclophosphamide (HyperC; N=6). Results: Ten patients had T-ALL and one had T-LL. Median age was 23 years (14–62) at time of diagnosis. Ten patients underwent HSCT in first CR (median time between diagnosis and HSCT: 141 days). HSCT conditioning regimen was myeloablative for 7 patients including Total Body Irradiation for 6 of them (reduced intensity conditioning for 4 patients). Source of stem cells was hematopoietic peripheral blood stem cells in 6 patients, bone marrow in 4 patients and unrelated cord blood in one patient. Four patients received a transplant from an HLA matched sibling donor and 7 from an unrelated donor (HLA-matched 10/10 in 3 patients). GVHD prophylaxis consisted in ciclosporine for all patients, either associated with methotrexate for 8 patients, mycophenolate for 2 patients or alone for one patient. Eight patients presented grade I-II acute GVHD (no patient had grade III-IV). Two patients developed chronic GVHD (1 extensive). Relapse occurred with a median duration of 199 days (119–2099). Six patients were still under immunosuppressive agents, because of slow tapering off or context of GVHD, which was stopped quickly. One patient presented a relapse in the context of cGVHD. Of the 11 patients treated with nelarabine-based salvage therapy, 81% achieved hematological CR within a median delay of 48 days. At one year, disease-free and overall survivals were 56% and 90%, respectively. Eight patients received additional nelarabine consolidation cycles (median, 4 cycles) and 2 CR patients received Donor Lymphocytes Infusion (1 complete molecular CR). One patient presented acute GVHD following nelarabine-based first cycle, requiring immunosuppressive treatment. Main toxicity was neurological (Grade 2 according to National Cancer Institute Common Terminology Criteria for Adverse Events), with 2 patients presenting sensitive neuropathy and cerebellar ataxia. Conclusion: In patients with T-ALL/LL relapsing after allogeneic HSCT, nelarabine-based salvage therapy was well tolerated with 2 neurological complications grade 2 and one acute GVHD. Moreover, this treatment was associated with a very high (81%) response rate with some patients experiencing prolonged remission. Post-HSCT nelarabine maintenance might thus be a valuable option to investigate in high-risk patients, possibly driven by MRD detection. Assessing immune responses in this particular setting could also be of particular interest.

Peffault de Latour:Alexion: Consultancy, Research Funding.