The management of relapsed/refractory acute lymphoblastic leukemia (ALL) is a vexing problem and requires extensive, aggressive supportive care throughout the course of therapy, explained Joseph C. Alvarnas, MD, City of Hope Comprehensive Cancer Center, Duarte, California, in a presentation at the National Comprehensive Cancer Network (NCCN) 7th Annual Congress on Hematologic Malignancies.1
The NCCN guidelines for ALL reveal a dichotomy between Philadelphia-positive (PH+) and Philadelphia-negative (PH-) relapsed/refractory ALL.
In PH+ ALL, gene mutation testing is important. Patients with PH+ disease who relapse following cessation of tyrosine kinase inhibitors (TKIs) can restart TKI-based therapy. For those who are refractory or relapse on TKI-based therapy, perform mutational analysis. If the T315I mutation is present, consider hematopoietic cell transplant (HCT) or clinical trial; for V299L, T315A, F317L/V/CI/C, consider nilotinib rather than dasatinib. For Y253H, E255K/V, or F359 V/C/I, consider dasatinib rather than nilotinib. For any other mutation, consider high-dose imatinib, dasatinib, or nilotinib.
PH- ALL is far more difficult to treat. Most regimens are front-loaded with the best therapeutic agents, leaving few options for second-line treatment at relapse. Patients with PH- ALL should be considered for clinical trial or allogeneic hematopoietic stem cell transplant if in remission or on chemotherapy.
Several challenges exist for salvage therapy for adults with relapsed/refractory ALL, Alvarnas continued. It may be difficult to identify a non‒cross-resistant regimen for reinduction. L-asparaginase–containing regimens may be difficult to administer to older patients. Even very intensive regimens may achieve response rates <30%. Comorbidities may limit therapeutic choices. Allogeneic HCT represents the only potentially curative option for adolescents/young adults (AYAs) and adults with ALL. Patients with significant residual disease are not candidates for allogeneic HCT.
“The lessons from our experience with relapsed/refractory ALL are twofold. First, we would like to avoid relapse, and we recommend strong risk stratification at the time of diagnosis. Second, move to transplant after first complete response is achieved,” he stated. Five-year overall survival was 62% at City of Hope when adults with ALL were transplanted in first remission.
“Unrelated donor transplant produces similar outcomes as related donor transplant. Don’t let the lack of sibling donor keep you from moving on to transplant,” he told listeners.
Alvarnas commented that transplant outcomes have not improved appreciably over the past 3 decades. “We have a long way to go,” he said. “At the same time, intensification of the transplant regimen is not feasible.”
Experience with transplant raises the importance of timely transplantation and the need for better drugs that might improve outcomes, he said.
Alvarnas discussed several new agents that may be useful in relapsed/refractory ALL. Two agents that have shown promising results in small phase 2 trials are nelarabine, a prodrug of ara-G, and clofarabine, a second-generation purine nucleoside analog. Both drugs have distinct side-effect profiles, with different toxicities. Neurologic toxicity is the key dose-limiting toxicity with nelarabine. Other significant toxicities include cytopenia, gastrointestinal effects, and pyrexia. Toxicities of clofarabine include elevations of liver enzymes, febrile neutropenia, skin rash, and cytomegalovirus reactivation.
“The use of novel therapeutics in relapsed/refractory ALL is exciting to me. We would like to identify a parallel drug to rituximab in lymphoma. We are still early on in this process. Two drugs might be interesting in this regard [blinatumomab and inotuzumab ozogamicin]. These antibodies are impressively tolerable in heavily pretreated patients, compared with chemotherapy,” Alvarnas said.
Supportive Care for ALL
Patients being treated for ALL require aggressive coordinated supportive care throughout the entire course of therapy.
Alvarnas highlighted several supportive care needs:
- Preemptive management of tumor lysis syndrome
- Disseminated intravascular coagulation and L-asparaginase coagulopathies
- Management of therapy-related cytopenia
- Management of febrile neutropenia/opportunistic infection
- Antiemetic therapy
- Alvarnas JC. New approaches to the management of relapsed/refractory acute lymphoblastic leukemia. Presented at: National Comprehensive Cancer Network (NCCN) 7th Annual Congress on Hematologic Malignancies; September 14, 2012; New York, NY.