Nelarabine in Combination with Etoposide and Cyclophosphamide Is Active in First Relapse of Childhood T-Acute Lymphocytic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LL)
Authors: Whitlock James , dalla Pozza Luciano , Goldberg John M , Silverman Lewis B. , Ziegler David S. , Attarbaschi Andishe , Brown Patrick , Gardner Rebecca A , Gaynon Paul S. , Hutchinson Raymond J. , Marcus Leigh J. , Messinger Yoav H. , Schultz Kirk R. , Vandergiessen Jeannette , Eckroth Elena , Locatelli Franco , Zwaan C Michel , Wood Brent L. , Sposto Richard , Gore Lia 
Published: October 2019

Introduction

Children with relapsed T-ALL and T-LL have a dismal prognosis, with survival of less than 25% (Goldberg et al, J Clin Oncol 2003; Reismuller et al, Brit J Haematol 2009). Fewer than a third of children with relapsed T-ALL/LL attain a second remission with standard reinduction therapies (Raetz et al, J Clin Oncol 2008). Nelarabine (NEL) is a purine nucleoside analogue prodrug of AraG, which is resistant to cleavage by endogenous purine nucleoside phosphorylase and cytotoxic to T-lymphoblasts at micromolar concentrations. NEL has substantial single-agent activity in first and multiply relapsed T-ALL (Berg et al, J Clin Oncol 2005). In an effort to improve reinduction rates for children with T-ALL and T-lymphoblastic lymphoma (T-LL) in first relapse, we evaluated the safety and preliminary efficacy of NEL in combination with cyclophosphamide (CPM) and etoposide (ETOP) in this setting.

Methods

T2008-002: A Phase I trial of NECTAR (Nelarabine, Etoposide and Cyclophosphamide in T-ALL Relapse), is an investigator-initiated collaboration between the Therapeutic Advances in Childhood Leukemia & Lymphoma consortium (TACL), the Pediatric Oncology Experimental Therapeutics Investigators' Consortium (POETIC), and the Innovative Therapies for Children with Cancer consortium (ITCC). Eligible patients had first relapse or initial induction failure of T-ALL or T-LL, no CNS-3, no prior stem cell transplantation, and adequate performance status and organ function. The studyÕs primary objective was to establish the recommended phase 2 doses (RP2D) of NEL and CPM in combination with a fixed dose of ETOP.

Subjects received a single course of NEL (325-650 mg/m2) and CPM (330-440 mg/m2) at 1 of 3 assigned dose levels in combination with a fixed ETOP dose (100 mg/m2), each for 5 consecutive days. Intrathecal therapy was administered no less than 7 days prior to or 21 days following the start of a course. Responding patients without dose-limiting toxicity (DLT) were eligible for a second course. The primary study endpoint was the occurrence of dose-limiting toxicity (DLT) during course 1. Secondary endpoints included rates of CR2, complete remission without platelet recovery (CRp), or partial response (PR), and minimal residual disease (MRD) levels at the end of each course.

Results

Of 19 children enrolled on T2008-002, 6 were enrolled at Dose Level (DL) 1 (NEL 325 mg/m2, CPM 330 mg/m2), 7 at DL2 (NEL 650 mg/m2, CPM 330 mg/m2), and 6 at DL3 (NEL 650 mg/m2, CPM 440 mg/m2). Two potential DLTs led to subject removal during course 1, but were later reversed upon committee review and those subjects replaced. 17 patients were evaluable for DLT and response. Confirmed DLTs occurred in 2 patients: 1 at DL2 (grade 2 (Gr2) motor neuropathy and Gr3 sensory neuropathy) and 1 at DL3 (Gr3 sensory neuropathy). Other ³ Gr3 non-hematologic adverse events are listed in the Table. Of 9 T-ALL patients evaluable for response, there were 2 CRs,1 CRp and 1 CR in the bone marrow/PR in an extramedullary site, with responses at all dose levels, for a response rate of 44% in the T-ALL cohort; at the RP2D, 2/4 evaluable T-ALL patients had a response. Of 8 T-LL patients evaluable for response, there were 2 CRs (1 each at DL1 and DL2), for an overall T-LL response rate of 25%. Eight patients received a second course of NECTAR; 9 subsequently underwent HSCT. MRD levels were available for 2 responding T-ALL patients, with 0.027% and 0.07% blasts after Course 1 and 0.07% and <0.001% blasts after Course 2.TableGrade ³3 Non-Hematologic Adverse Events Occurring in >5% of SubjectsToxicity (CTC3.0)Grade ³ 3 Anorexia3 (16%)Aspartate aminotransferase increased2 (11%)Diarrhoea NOS2 (11%)Febrile neutropenia6 (32%)Hyperkalemia2 (11%)Hypoalbuminaemia3 (16%)Hypocalcaemia4 (21%)Hypokalemia8 (42%)Hypotension NOS2 (11%)Nausea3 (16%)Pleural effusion3 (16%)Vomiting NOS2 (11%)Pain-Other2 (11%)

Conclusions

The recommended phase 2 doses (RP2D) for NECTAR are NEL 650 mg/m2, CPM 440 mg/m2 and ETOP 100 mg/m2, each given daily for 5 days. The activity and toxicity seen in this phase I dose escalation cohort compare favorably with established reinduction regimens in relapsed T-ALL/LL. An ongoing cohort expansion at the RP2D will better define the activity of NECTAR in first relapse of T-ALL and T-LL.

Acknowledgments: Glaxo-Smith-Kline; Higgins Family Foundation; Women's Auxiliary Millennium Chair in Haematology/Oncology

Disclosures

Whitlock: Glaxo-Smith-Kline: Research Funding. Off Label Use: Nelarabine, cyclophosphamide and etoposide for relapsed T-ALL/T-LL are off-label drug uses.. Zwaan:GSK: Research Funding. Gore:GSK: Research Funding.