Joseph C. Alvarnas, MD, discussed new drugs that might improve outcomes for relapsed/refractory acute lymphoblastic leukemia (ALL) at the National Comprehensive Cancer Network 7th Annual Congress on Hematologic Malignancies.1 Alvarnas is director of medical quality and clinical associate professor at City of Hope Comprehensive Cancer Center in Duarte, California.
Two new investigational drugs in relapsed ALL are nelarabine and clofarabine. Nelarabine, a prodrug of 9-beta-D-ara-G, is active in the management of relapsed/refractory ALL and is non–cross resistant with most other ALL drugs. Phase 2 trials included 39 pediatric patients and 28 adults with relapsed/refractory ALL.2 In pediatric patients, complete response (CR) rate was 5 of 39, and 9 of 39 patients achieved CR or CR with incomplete marrow recovery. In adults, 5 of 28 achieved CR, and 6 of 28 achieved CR or CR with incomplete marrow recovery.
Nelarabine has a distinct toxicity profile. Neurotoxicity is the key dose-limiting toxicity. In phase 1 and 2 trials, 64% of patients experienced headache and seizures, and 1 case of fatal status epilepticus was reported. Additional significant toxicities included cytopenia, gastrointestinal disorders, and pyrexia.
Clofarabine, a second-generation purine nucleoside analog, is active in both relapsed/refractory ALL and acute myeloid leukemia (AML). The drug can be used as monotherapy or as part of a preparative regimen for transplant in combination with additional chemotherapeutic agents, such as etoposide, cytarabine, and cyclophosphamide. It is more active in B-cell disease than T-cell disease.
“These combination regimens [with clofarabine] are not for the faint of heart. Patients can develop mucositis and cytopenia. Be prepared for a sick patient who requires inpatient hospitalization,” Alvarnas told listeners.
In a single-agent trial of 61 pediatric patients with ALL who had failed 2 or more previous regimens, response rate was 20% (7 CR and 5 CR with incomplete marrow recovery).3 “The small percentage of response is impressive in this disease,” he said.
In a trial of children with refractory AML or ALL treated with the combination of clofarabine, etoposide, and cytarabine, 19 of 24 ALL patients achieved CR or CR with incomplete recovery of bone marrow; 1 of 16 AML patients achieved CR or CR with incomplete recovery of bone marrow; 13 of 17 responders subsequently underwent allogeneic hematopoietic cell transplant; and 24-month overall survival was 25%.3
Toxicities associated with clofarabine include elevations of liver enzymes, febrile neutropenia, infections (cytomegalovirus [CMV] reactivations), and skin rash.
Alvarnas noted that the rate of CMV reactivation is not high, “but it is real, and patients can develop visceral disease."
Investigators would like to discover a drug for ALL that is parallel to rituximab in lymphoma, but they are still early in this pursuit.
“Two drugs might be interesting in this regard,” he said.
Blinatumomab (AMG 103) brings the T-cell in opposition to the tumor cell and allows destruction of the tumor cell. In a phase 2 trial of 36 patients with relapsed/refractory ALL, 26 of 36 achieved CR or CR with incomplete bone marrow recovery, and median survival was 9 months (range, 8.2-15.8 months).4 Reversible central nervous system events were reported in 6 patients.
Inotuzumab ozogamicin was the second drug he discussed. This is an anti-CD22 antibody conjugated with calicheamicin that induces double-stranded DNA breaks. In a phase 2 trial of 40 patients with relapsed/refractory ALL who received a median of 2 courses of therapy, CR was 56%; 70% of responders were alive at 6 months following therapy; and 12 patients went on to allogeneic stem cell transplant.5 Adverse events included grade 3 or 4 fever in 9 patients and grade 3 hypotension in 1 patient.
“I am excited about the use of novel agents in relapsed/refractory ALL. These antibodies are impressively tolerable in heavily pretreated patients, compared with chemotherapy,” he stated.
- Alvarnas JC. New approaches to the management of relapsed/refractory acute lymphoblastic leukemia. Presented at: National Comprehensive Cancer Network 7th Annual Congress on Hematologic Malignancies; September 14, 2012; New York, NY.
- Cohen MH, Johnson JR, Justice R, et al. FDA drug approval summary: nelarabine (Arranon) for the treatment of T-cell lymphoblastic leukemia/lymphoma. Oncologist. 2008;13(6):709-714.
- Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. 2006;24(12):1917-1923.
- Topp M, Goekbuget N, Zugmaier G, et al. Effect of anti-CD19 BiTE blinatumomab on complete remission rate and overall survival in adult patients with relapsed/refractory B-precursor ALL. Presented at: 2012 American Society of Clinical Oncology Annual Meeting; June 2012; Chicago, IL. Abstract 6500.
- Byrd JC, Furman RR, Coutre SE, et al. The Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 (P) in treatment-naive (TN) chronic lymphocytic leukemia (CLL) patients (pts): Interim results of a phase Ib/II study. Presented at: 2012 American Society of Clinical Oncology Annual Meeting; June 2012; Chicago, IL. Abstract 6507.