Approval Summary: Nelarabine for the Treatment of T-Cell Lymphoblastic Leukemia/Lymphoma

Abstract

Purpose: To describe the clinical studies, chemistry manufacturing and controls, and clinical pharmacology and toxicology that led to Food and Drug Administration approval of nelarabine (Arranon) for the treatment of T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma. Experimental Design: Two phase 2 trials, one conducted in pediatric patients and the other in adult patients, were reviewed. The i.v. dose and schedule of nelarabine in the pediatric and adult studies was 650 mg/m 2 /d daily for 5 days and 1,500 mg/m 2 on days 1, 3, and 5, respectively. Treatments were repeated every 21days. Study end points were the rates of complete response (CR) and CR with incomplete hematologic or bone marrow recovery (CR*). Results: The pediatric efficacy population consisted of 39 patients who had relapsed or had been refractory to two or more induction regimens. CR to nelarabine treatment was observed in 5 (13%) patients and CR+CR* was observed in 9 (23%) patients. The adult efficacy population consisted of 28 patients. CR to nelarabine treatment was observed in 5 (18 %) patients and CR+CR* was observed in 6 (21%) patients. Neurologic toxicity was dose limiting for both pediatric and adult patients. Other severe toxicities included laboratory abnormalities in pediatric patients and gastrointestinal and pulmonary toxicities in adults. Conclusions: On October 28, 2005, the Food and Drug Administration granted accelerated approval for nelarabine for treatment of patients with relapsed or refractoryT-cell acute lymphoblastic leukemia/lymphoblastic lymphoma after at least two prior regimens. This use is based on the induction of CRs. The applicant will conduct postmarketing clinical trials to show clinical benefit (e.g., survival prolongation).

A new high-performance liquid chromatography method determines low production of 9-β-D-arabinofuranosylguanine triphosphate, an active metabolite of nelarabine, in adult T-cell leukemia cells

“…Thus, we evaluated the potential of ara-G for ATL cells in vitro. The intracellular accumulation of ara-GTP was greatest in cells of T-lymphoid lineage compared with other cell types, thereby conferring ara-G cytoreductive effects specifically on T-cell malignancies (1)(2)(3)(6)(7)(8). Clinical response to nelarabine in hematologic malignancies was associated with higher intracellular ara-GTP concentrations (4,5).…”

“…Pharmacokinetic evaluation of ara-GTP will provide crucial information to optimize ara-G therapy (3)(4)(5). Clinical data have already confirmed that response to nelarabine is associated with higher intracellular ara-GTP concentrations in both acute and indolent leukemias (4,5).…”

“…The 9-ß-D-arabinofuranosylguanine (ara-G), an active compound of nelarabine, 2-Amino-9-ß-D-arabinofuranosyl-6-methoxy-9H-purine, is a purine nucleoside analog that has demonstrated potent cytotoxic effects specifically on T-cell malignancies in vitro (1)(2)(3). Nelarabine has been clinically evaluated for its efficacy against hematological malignancies including T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoma, and chronic lymphocytic leukemia (4,5).…”

Allogeneic transplantation for ALL in adults

“…Relapsed ALL in an adult is not curable, but remissions are sometimes achieved with re-induction with either a standard vincristine, prednisone and anthracycline or with a cytarabine-based regimen, particularly high-dose Ara-C combined with an anthracycline or clofarabine. [31][32][33] Available data from the IBMTR show that patients transplanted from an HLA-identical sibling for ALL in second CR (CR2) have approximately a 35-40% chance of long-term DFS, while those transplanted with disease not in remission have a DFS of only 10-20%. 34 Figure 4 shows the overall DFS for patients with ALL, depending on their remission status, who underwent allogeneic transplantation.…”

Clinical Characteristics and Treatment Results of Pediatric Relapsed/Refractory Non-Hodgkin’s Lymphomas

“…Следует отметить, что результаты лечения не зависели от варианта ТГСК и были одинаковыми при алло-и аутоТГСК [24]. В другом исследовании было показано, что несмотря на одинаковые показатели ОВ при проведении аллоТГСК и аутоТГСК (36 и 39 % соответственно) частота повторных рецидивов ЛБЛ при проведении аллоТГСК существенно ниже [25][26][27]. Данный факт, вероятно, объясняется эффектом «трансплантат про-тив опухоли», который реализуется в случаях алло-ТГСК.…”