Nelarabine for the Treatment of Patients with Relapsed or Refractory T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
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Relapsed T-cell acute lymphoblastic leukemia and lymphoma
T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) is an aggressive disease affecting a small number of adult and pediatric patients that progresses rapidly in the absence of effective therapy. There are an estimated 4300 patients diagnosed with ALL annually in the United States, approximately one third of whom are over 20 years of age1 and approximately 20% to 25% of whom have T-cell disease.2, 3 Approximately 54,000 patients are diagnosed with non-Hodgkin's lymphoma
Nelarabine
Nelarabine (compound 506U78; Arranon) is a prodrug, which is demethylated by adenosine deaminase to the deoxyguanosine analog, 9-β-d-arabinofuranosylguanine (ara-G).12 T lymphoblasts are exquisitely sensitive to the cytotoxic effects of deoxyguanosine (Fig. 1).12, 13, 14, 15, 16, 17, 18 The accumulation of deoxyguanosine triphosphate and subsequent inhibition of ribonucleotide reductase, inhibition of DNA synthesis, and resultant cell death account for nelarabine's T-cell activity.14, 15, 16, 17
Phase I trials with nelarabine
A phase I study explored the administration of nelarabine as a 1-hour intravenous infusion daily for 5 consecutive days.22 Ninety-three adult and pediatric patients with refractory hematologic malignancies were enrolled on this multi-institutional trial. The half-life of nelarabine was determined to be approximately 20 minutes due to rapid conversion of the drug to ara-G. The half-life of ara-G is approximately 3 hours, but the intracellular half-life of the active ara-GTP is more than 24 hours.
Phase II studies with nelarabine in adult patients with relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma
A phase II, open-label, multicenter, clinical trial was initiated to evaluate the efficacy and safety of single-agent nelarabine in adult subjects with refractory or relapsed T-ALL/LBL.26 Although a dose of 2.2 g/m2/day was initially chosen, the study was amended after three patients received therapy to a dose of 1.5 g/m2/day on days one, three, and five to decrease the potential risk of neurologic toxicities. Three subjects received the 2.2 g/m2 dose, and data from these subjects were included
Nelarabine before stem cell transplant
Successful engraftment after SCT was not an endpoint in the adult phase II study design,26 but data were collected and reported retrospectively. Seven subjects who were treated with nelarabine subsequently received a SCT. Only five patients who achieved a CR or a CRi and two subjects who did not respond to nelarabine underwent a SCT. Engraftment data for five of these seven patients were collected and full hematopoietic engraftment was documented on days 7, 11, and 18 post transplant in three
The use of nelarabine in pediatric patients
A total of 121 pediatric patients were enrolled on a phase II study of nelarabine.29 There were four different patient strata analyzed. Stratum 1 consisted of patients in first relapse with greater than 25% bone marrow involvement. Stratum 2 included patients in second relapse with greater than 25% bone marrow involvement. The third stratam included patients with CNS relapse, and the fourth stratum included patients with extramedullary, non-CNS relapse. Unfortunately, significant neurotoxicity
New treatment strategies
Combination therapy in young patients with newly diagnosed T-ALL is currently being tested within the Children's Oncology Group. Patients receive multiagent chemotherapy with the addition of nelarabine to assess toxicity and safety. As the trial began enrollment in January 200733, other proposals include stratification within the newly diagnosed adult patients with T-ALL to receive nelarabine during a component of consolidation chemotherapy.
The use of nelarabine in indolent non-Hodgkin's lymphoma
A large phase I trial was conducted at the MD Anderson Cancer Center in 35 patients with B-cell chronic lymphocytic leukemia and T-cell prolymphocytic leukemia (T-PLL).32 Two different schedules were used with or without the addition of fludarabine. Twenty percent of patients with CLL, 15% with T-PLL, and 63% of patients treated with a combination of nelarabine plus fludarabine achieved a response. In keeping with the treatment in patients with ALL, peripheral neuropathy was the most frequent
Summary
Nelarabine is now approved in pediatric and adult T-ALL and T-LBL patients with relapsed refractory disease after two or more prior treatment regimens. Although T-ALL and T-LBL are chemotherapy-sensitive diseases, response rates in patients with relapsed/refractory disease are low and durations are short, especially in patients with second or greater relapse. This group of patients typically proceeds toward SCT. This approach may produce prolonged remissions in a fraction of the patients who
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Cited by (38)
Synthesis and application of small molecules approved for the treatment of lymphoma
2023, European Journal of Medicinal ChemistrySynthesis and biological evaluation of aminobenzamides containing purine moiety as class I histone deacetylases inhibitors
2022, Bioorganic and Medicinal ChemistryCitation Excerpt :Purine is an important heterocyclic nucleus which exists in the chemical architecture of various bioactive compounds. Many purine derivatives, such as vidarabine, nelarabine, fludarabine, cladribine, clofarabine, are clinically widely used antitumor drugs.42–45 Our research efforts in the resent years were focused on developing purine as SRD of HDACi and have found 9-substituted purine hydroxamic acids, such as compound 7 m′(Fig.1), have favourable anti-HDACs activities (IC50 of HDACs: 15.3 nM) and puring as SRD can increased binding of target compounds with the rim of active pocket of HDAC.46
Adult Acute Lymphoblastic Leukemia
2016, Mayo Clinic ProceedingsCitation Excerpt :This mutation profile is similar to that of myeloid neoplasms, and hence, addition of myeloid-based therapies may improve ETP-ALL outcomes. Nelarabine is a T-cell–specific purine nucleoside analogue that is catabolized to arabinosylguanine triphosphate.113,114 T cells appear to accumulate arabinosylguanine triphosphate at higher levels, and once incorporated into the DNA, arabinosylguanine triphosphate leads to inhibition of DNA synthesis and eventually apoptosis.
Allogeneic hematopoietic cell transplantation in adult patients with acute lymphoblastic leukemia
2014, Hematology/Oncology Clinics of North AmericaCitation Excerpt :Cord blood and haplo-identical stem cell transplantation should be considered. Efforts are being made to improve the outcome of relapse with trials of B-cell antibodies28 and nelarabine.29 However, currently the results are poor and patients at high risk of relapse should be considered for transplantation in CR1.
MIP-1α enhances Jurkat cell transendothelial migration by up-regulating endothelial adhesion molecules VCAM-1 and ICAM-1
2014, Leukemia ResearchCitation Excerpt :It progresses rapidly and relapses in approximately 30% of patients after 2 years, and brain metastases are common in the advanced stage. The incidence of central nervous system (CNS) involvement in T-ALL is estimated to be approximately 25–81% and is associated with high mortality [6,17,25]. Despite its clinical importance, the way in which T-cells in T-ALL enter the CNS is poorly understood.
Childhood Leukemia
2014, Abeloff's Clinical Oncology: Fifth Edition