“Blinatumomab is an agent for relapsed disease now and hopefully eventually for use in earlier disease settings.”— Richard M. Stone, MD
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NEW DRUGS that will improve the outcome of adult patients who develop a deadly disease such as acute leukemia are badly needed; combinations of cytotoxic chemotherapeutic drugs may have reached an upper limit of utility. Agents that eradicate leukemia by alternative mechanisms would be of particular interest.
In precursor B-cell acute lymphoblastic leukemia (pre–B-cell ALL) either rituximab plus hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone; R-HCVAD)1 or “pediatric-inspired” chemotherapy regimens2,3 lead to cures in 40% to 60% of those with Philadelphia chromosome–negative pre–B-cell ALL.
Subsets with poor outcome have adverse biologic characteristics such as chromosomal translocations involving the MLL gene on chromosome 11q234 or blasts that display a gene-expression signature termed “Philadelphia-like” ALL.5 Another group with poor outcomes (heavily weighted within those categories) are patients who fail to achieve a minimal residual disease–negative state after initial chemotherapy using techniques such as polymerase chain reaction and immunophenotype, each more sensitive than light microscopic analysis. Even allogeneic stem cell transplant may not undo the negative prognostic impact of minimal residual disease.6
Furthermore, patients who have relapsed pre–B-cell ALL can rarely be cured.7
Key Findings From TOWER Trial
IN SETTINGS OF considerable unmet need, including upfront patients with a poor prognosis, minimal residual disease–positive patients after initial chemotherapy, and those with relapsed disease, the trial reported by Kantarjian et al in The New England Journal of Medicine provides hope.8 (The study is reviewed in this issue of The ASCO Post.) The experimental arm in this trial employed blinatumomab (Blincyto), the novel bispecific monoclonal antibody that binds to CD3-positive T cells and brings them in physical proximity to the CD19-positive leukemic cells, thereby taking advantage of the immune system to kill the malignant clone.
This phase III TOWER trial randomized patients with primary refractory or relapsed pre–B-cell ALL to receive standard intensive combination chemotherapy vs blinatumomab. Blinatumomab therapy was prolonged: each cycle consisted of 4 weeks of continuous-infusion blinatumomab followed by 2 weeks off. The two groups (271 blinatumomab patients and 134 chemotherapy patients) were balanced for age, geographic region, performance status, phase of treatment (salvage or other), receipt of prior allogeneic transplant, and degree of bone marrow blast infiltration.
The median overall survival was 7.7 months in the blinatumomab group vs 4 months in the chemotherapy group, with a hazard ratio of 0.71 (P = .01). Adverse events were fairly well balanced in the two study arms. In particular, fatal adverse events considered related to study treatment were reported in 3% of blinatumomab-treated patients compared with 7% of chemotherapy-treated patients.
Protocol-specified treatment interruptions due to adverse events occurred in almost one-third of the blinatumomab patients, usually for infection, neurologic events, or cytokine-release syndrome. The remission rate was also higher in the blinatumomab group, with 34% achieving a complete remission with full hematopoietic recovery and an additional 10% achieving remission with a partial or incomplete hematologic recovery, compared with 16% and 9%, respectively, in the chemotherapy arm. The median duration of remission was 7.3 months in the blinatumomab arm and 4.6 months in the chemotherapy arm.
A New Standard of Care?
THE DIRECT IMPORTANCE of this study is the provision of a new standard of care for the treatment of relapsed pre–B-cell ALL. The goal of any patient with relapsed leukemia is to achieve disease control, ideally in the form of complete remission, and then to consolidate that remission if feasible with an allogeneic stem cell transplant.
Given the response rate was relatively higher with blinatumomab, better long-term outcomes are possible; since overall survival was better in the blinatumomab arm, patients may have been more likely to achieve long-term survival with blinatumomab followed by allogeneic stem cell transplant. Although the profile of adverse events with blinatumomab is different from that with chemotherapy—with an increased likelihood of having neurologic and/or cytokine-release events—they are manageable.
Even more important than the use of this agent in relapsed pre–B-cell ALL will be the potential incorporation of blinatumomab early in the disease course as a means to “erase” minimal residual disease. An important ongoing study, ECOG 1910, asks whether the addition of blinatumomab after induction/consolidation therapy in middle-aged and older adults with pre–B-cell ALL will be able to lower disease burden, especially in those with measurable residual disease after initial chemotherapy, and thus lead to improved overall and event-free survival.
Blinatumomab is an agent for relapsed disease now and hopefully eventually for use in earlier disease settings.
Benefit of Inotuzumab
SIMILAR TO the benefit of blinatumomab in relapsed ALL, the INNOVATE trial9 showed the anti-CD22 antibody-toxin conjugate inotuzumab is superior to chemotherapy in the relapsed setting. Differences between blinatumomab and inotuzumab, both in the relapsed and early-disease settings, need to be explored. The calicheamicin toxin attached to the CD22 humanized monoclonal antibody may lead to hepatotoxicity.
Patients with Philadelphia chromosome–positive pre–B-cell disease were excluded from the TOWER trial, but they appeared to benefit from inotuzumab in the INNOVATE trial. An Alliance-led U.S. Intergroup phase III trial will test whether the addition of inotuzumab to pediatric-inspired therapy will lead to improved event-free survival.
In conclusion, patients with pre–B-cell ALL will benefit from having blinatumomab and inotuzumab available. With anti-CD19 chimeric antigen receptor T-cell–directed therapy,10 the therapeutic outlook for ALL has brightened considerably. ■
DISCLOSURE: Dr. Stone reported no conflicts of interest.
REFERENCES
1. Thomas DA, Faderl S, O’Brien S, et al: Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer 106:1569-1580, 2006.
2. DeAngelo DJ, Stevenson KE, Dahlberg SE, et al: Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia. Leukemia 29:526-534, 2015.
3. Maury S, Chevret S, Thomas X, et al: Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med 375:1044-1053, 2016.
4. Muñoz L, Nomdedéu JF, Villamor N, et al, Spanish CETLAM Group: Acute myeloid leukemia with MLL rearrangements: Clinicobiological features, prognostic impact and value of flow cytometry in the detection of residual leukemic cells. Leukemia 17:76-82, 2003.
5. Roberts KG, Li Y, Payne-Turner D, et al: Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med 371:1005-1015, 2014.
6. Brüggemann M, Raff T, Kneba M: Has MRD monitoring superseded other prognostic factors in adult ALL? Blood 120:4470-4481, 2012.
7. Gökbuget N, Stanze D, Beck J, et al, German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia: Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood 120:2032-2041, 2012.
8. Kantarjian H, Stein A, Gökbuget N, et al: Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 376:836-847, 2017.
9. Kantarjian HM, DeAngelo DJ, Stelljes M, et al: Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 375:740-753, 2016.
10. Grupp SA, Kalos M, Barrett D, et al: Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368:1509-1518, 2013.
