Application of Nelarabine for Refractory or Relapsed T-Lymphatic Neoplasms In Adults Before Allogeneic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (allogeneic HSCT) has found entrance into treatment of patients (patients) with poor-risk T-cell malignancies, but post-transplant relapse rates of ~30% were reported (Marks et al. Blood 2009). Improvement of the pre-transplant remission status in relapsed/refractory disease might lead to better outcomes. Nelarabine - a novel purine antimetabolite - has been approved by the FDA in 2005 as salvage approach for patients with T-cell malignancies, but data on pre-transplant use are limited (Goekbuget et al. ASH Annual Meeting 2005).

Aiming to estimate its clinical applicability and efficacy in the pre-transplant period, we evaluated its use in 8 patients (5 males, 3 females; 22–56 years) with precursor/mature T-cell neoplasms who had failed to ≥2 previous conventional/intensified chemotherapy regimens (including a history of autologous/allogeneic HSCT in 2 patients) and were consequently proceeded to allogeneic HSCT (in 6 cases the 1^st, in 2 cases the 2^nd allogeneic HSCT). Five had T-ALL (1 pre-T-, 3 cortical, 1 mature), 3 had mature T-cell lymphomas (angioimmunoblastic lymphoma, n=1; peripheral T-cell lymphoma not otherwise specified, n=2), all with bone marrow involvement. Patients entered conventional chemotherapy in 6 cases at the 1^st manifestation of disease, in 2 cases at the 1^st relapse. Following conventional chemotherapy, 5 patients developed an early relapse, while 2 patients were refractory to treatment; one patient was minimal residual disease (MRD) positive as assessed by multiparameter flow cytometry. Therefore, all 8 patients were offered an allogeneic HSCT (1^st allogeneic HSCT: n=6; 2^nd allogeneic HSCT: n=2) with pre-treatment with nelarabine. The median interval from the last chemotherapy to 1^st nelarabine administration was 8 weeks (range, 1– 252 weeks). Nelarabine (1,500 mg/m² i.v.) was administrated on days 1, 3, and 5 at a median of 11 weeks (range, 2–53 weeks) before allogeneic HSCT. Three patients received a 2^nd cycle of nelarabine after a median of 4 weeks (range, 2–9 weeks) from the 1^st. Six patients had unrelated (HLA-match, n=4; mismatch, n=2) and 2 patients matched related donors. Most patients received myeloablative conditioning (TBI, 12 Gy; cyclophosphamide 120 mg/kg; n=3; treosulfan 36 g/m²; etoposide 30 mg/kg; cyclophosphamide 120 mg/kg; n=4). In the 8^th patient who had already received 2 courses of nelarabine, a 3^rd nelarabine application was incorporated as pre-phase into reduced-intensity conditioning (nelarabine 2 × 1,500 mg/m²; fludarabine 90 mg/m²; TBI 8 Gy).

i) Pre-transplant application of nelarabine: Immediate neurotoxicity was observed in 1 patient (grand mal seizure day +3 after the last nelarabine administration). Grade II hematotoxicity was observed in 3/8 patients. There were no treatment-related deaths. Seven of 8 patients showed response to nelarabine (86%; CR, n=5; PR, n=2) after a median of 4 weeks (1 – 35 days) from the 1^st cycle. One patient had stable disease (SD). ii) Peri-/post-transplant period: there were no uncommon adverse events. After HSCT, prolonged leukocytopenia (WBC <1,000/μL >20 days) and thrombocytopenia (thrombocytes <20,000/ μL >30 days) were observed in 3 and 5 patients, respectively. At the 1^st post-transplant bone marrow control, 3 patients with residual disease (PR or SD) prior to allogeneic HSCT achieved CR, and all other patients maintained CR. Acute (grade II) and chronic GvHD developed in 2/8 (25%) and in 2/6 (33%) patients, respectively; there was no case of grade III-IV acute GvHD. At a median follow up of 9 months (range, 1–24), 3 patients had died (38%; relapse, n=1, t-AML, n=1; transplant-related toxicity, n=1). All 5 patients being alive were in CR; 4 patients required no further treatment, and one patient received donor lymphocyte infusions (DLIs) due to mixed chimerism.

Nelarabine improves pre-transplant remission in patients with relapsed/refractory T-cell neoplasms and seems to be well tolerated immediately before allogeneic HSCT even in heavily pre-treated patients. The compound might be used as pre-phase or be incorporated into conditioning for allogeneic HSCT which should be further evaluated.

No relevant conflicts of interest to declare.