January-February 2017, Volume 14, Issue 1
Tectonic Shifts in the 2016 Treatment Landscapes for Acute Lymphocytic Leukemia
Published on: January 01, 2017
The most promising treatment advances for both children and adults with acute lymphocytic leukemia (ALL) throughout the past year have resulted from immunotherapeutic approaches. Results from trials investigating the antibody–drug conjugate inotuzumab as a single-agent salvage therapy for relapsed or refractory ALL, as well as rituximab in combination with conventional chemotherapy in the frontline, have demonstrated clinical benefits of these monoclonal antibodies in adults with B-lineage ALL (B-ALL). Likewise, harnessing the T-cell repertoire continues to yield promising results. The T-cell engager blinatumomab continues to show significant activity in both children and adults with relapsed or refractory B-ALL. Finally, there has also been continued progress in CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy in relapsed or refractory B-ALL; results of a global registration trial in pediatric patients were presented at the 2016 ASH Annual Meeting.
The cure rate for adults with newly diagnosed ALL with intensive multiagent chemotherapy is 40 to 50 percent, and among patients who relapse, only about 20 to 30 percent will achieve a complete remission (CR). Monoclonal antibodies (MoABs) targeting leukemic blast surface antigens offers the promise of unique mechanisms of action, distinct from traditional cytotoxics, and a reduction in off-target adverse effects. Inotuzumab is a CD22-directed humanized monoclonal antibody conjugated to calicheamicin, a cytotoxic antibiotic. In the pivotal INO-VATE randomized phase III trial in adult patients with relapsed or refractory B-ALL undergoing first or second salvage therapy, a striking improvement in remission rates was observed with inotuzumab as a single agent.1 Patients were randomized to inotuzumab delivered in fractionated cycles versus best available therapy with one of three conventional cytotoxic regimens. The response rate (complete remission or complete remission with incomplete hematologic recovery) for inotuzumab was 80.7 percent, compared with 29.4 percent (p<0.001) with conventional chemotherapy. Among the responders, rates of minimal residual disease (MRD) negativity were approximately three-fold higher in the inotuzumab group compared with the conventional chemotherapy group. Progression-free and median overall survival were also longer in the inotuzumab group. Based on this highly promising activity, the Children’s Oncology Group will be opening a phase II single-agent trial (COG AALL1621) investigating inotuzumab in children and young adults with relapsed or refractory B-ALL in early 2017, and plans to continue to incorporate inotuzumab into frontline and salvage ALL treatment regimens in both children and adults are underway.
A beneficial effect for the addition of rituximab, a chimeric moAB targeting CD20, to standard chemotherapy has also been reported throughout the past year in adults with Philadelphia chromosome (Ph) -negative B-ALL with CD20 expression in more than 20 percent of leukemia cells. The Group for Research on Adult Acute Lymphoblastic Leukemia 2005/R (GRAALL-2005/R) trial compared rituximab added to chemotherapy versus conventional chemotherapy alone in frontline B-ALL.2 Patients randomized to rituximab plus chemotherapy had a reduction in relapse rates and longer event-free survival (EFS) than those assigned to the control group (estimated two-year EFS: 65% vs. 52%, respectively; p=0.04). Rituximab was also well tolerated in combination with chemotherapy, with no significant differences in remission deaths between the randomized regimens. While the benefit in EFS in the rituximab group did not translate into significantly longer overall survival at four years (61% vs. 50%, respectively; p=0.10), studies are underway to continue to optimize the incorporation of rituximab into ALL treatment regimens.
There has been continued progress in the treatment of ALL with blinatumomab, a bispecific T-cell engager (BiTE) antibody that redirects cytotoxic T-cells to blasts expressing CD19. Blinatumomab was granted accelerated approval by the U.S. Food and Drug Administration (FDA) in December 2014 based on phase II data demonstrating strong clinical activity in adults with relapsed or refractory B-ALL. Results from the confirmatory randomized phase III TOWER study were presented this year at the 2016 European Hematology Association Congress.3 In this open-label trial, adult patients with relapsed or refractory Ph-negative B-ALL were randomized 2:1 to blinatumomab or to one of four standard of care (SOC) chemotherapy regimens. The CR rate with blinatumomab was 39 percent compared to 19 percent with SOC (p<0.001) and a significant almost two-fold improvement in median overall survival was observed (7.7 months for blinatumomab vs. 4 months for SOC). A phase I/II study investigating blinatumomab was also completed in 93 pediatric patients with second overt relapse, and/or relapse after allogeneic hematopoietic stem cell transplantation or refractory B-ALL after salvage therapy.4 Among those patients who received the recommended dosage of blinatumomab, CR was achieved within two cycles in 39 percent of patients, with 52 percent achieving a complete MRD response. Based on these results, the FDA granted an accelerated approval to blinatumomab for pediatric and adolescent patients with relapsed/refractory Ph-negative B-ALL in September 2016. With growing clinical experience with the delivery of blinatumomab, there have also been studies evaluating health-related quality of life outcomes. At the 2016 ASH Annual Meeting, patients who received blinatumomab versus standard chemotherapy on the TOWER study were reported to have quality of life benefits — another factor for consideration when evaluating MoAB therapy.5
Table 1. Summary of Selected 2016 ALL Immunotherapy Trial ResultsAbbreviations: B-ALL, B-lineage acute lymphocytic leukemia; CR/CRi, complete remission or complete remission with incomplete hematologic recovery;
EFS, event-free survival; moAB: monoclonal antibody; Ph–, Philadelphia chromosome–negative; R/R: relapsed/refractory.
|Inotuzumab1||CD22-directed humanized moAB conjugated to calicheamicin||Adults with CD22+ R/R B-ALL||80.7% CR/CRi|
|Rituximab plus chemotherapy2||CD20-directed chimeric moAB||Adults with newly diagnosed CD20+ Ph- B-ALL||65% 2-year EFS|
|Blinatumomab3,4||Bispecific T cell receptor engager (BiTE) that redirects CD3+ T cells to CD19+ blasts||Adults with R/R Ph- B-ALL||39% CR|
|Children with R/R B-ALL||39% CR|
|CAR T-cells7||T cells transduced ex vivo with chimeric anti-CD19 receptor||Children with CD19+ R/R B-ALL||83% CR/CRi|
Finally, progress has continued in the use of CAR T cell therapy in relapsed and refractory B-ALL. In a follow-up to an initial single center trial of CD19 directed CAR T-cell therapy in pediatric patients with relapsed/refractory ALL,6 findings of the first multicenter global registration CAR T cell trial in pediatric patients were reported at the 2016 ASH Annual Meeting.7 Results from this study confirmed a high level of efficacy with CTL019 therapy and a safety prolife similar to that observed in the prior single center trial. Overall remission rates of 83 percent were achieved at the time of the data cutoff, all of which were MRD negative. Cytokine release syndrome (CRS) was uniformly managed with a protocol-specified algorithm, and no cases of refractory CRS were reported. Ongoing investigation to explore expanded integration of the full spectrum of immunotherapeutic agents into frontline and salvage treatment regimens in ALL is an area of great interest moving forward.
Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375:740-753.
Maury S, Chevret S, Thomas X, et al. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016;375:1044-1053.
Topp M, Stein A, Gökbuget N, et al. Blinatumomab improved overall survival in patients with relapsed or refractory Philadelphia negative B-cell precursor acute lymphoblastic leukemia in a randomized, open-label phase 3 study (TOWER). EHA. 2016:149.
von Stackelberg A, Locatelli F, Zugmaier G, et al. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. J Clin Oncol. 2016;34:4381-4389.
Topp MS, Zimmerman Z, Cannell P, et al. Health-related quality of life (HRQoL) of blinatumomab versus standard of care (SOC) chemotherapy in patients with relapsed or refractory Philadelphia negative B-cell precursor acute lymphoblastic leukemia in a randomized, open-label phase 3 study (TOWER). Blood. 2016;128:222.
Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507-1517.
Grupp SA, Laetsch TW, Buechner J, et al. Analysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL). Blood. 2016;128:221.
Conflict of Interests
Dr. Raetz indicated no relevant conflicts of interest.
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