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Combining Chemotherapy With Immunotherapy to Treat ALL: A Novel Approach

Eunice S. Wang, MD

Professor, Oncology
Chief, Leukemia Service
Department of Medicine
Roswell Park Comprehensive Cancer Center
Buffalo, New York

Eunice S. Wang, MD, has disclosed that she has received consulting fees from AbbVie, Agios, Amgen, Astellas, Celyad, Daiichi Sankyo, Jazz, Kite, Pfizer, and Stemline and honoraria from Pfizer and Stemline.

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Released: February 25, 2020

Although pediatric acute lymphocytic leukemia (ALL) is now considered a highly curable disease, the same cannot be said for adult ALL, particularly ALL occurring in older patients aged 60 years or older. For adult patients, 5-year survival rates range from 5% to 30%. Although many adult patients still have disease that is sensitive to chemotherapy, they are often simply unable to tolerate the high doses and multiple cycles of chemotherapy lasting 2-3 years that result in high cure rates in children.

To address this unmet need, novel treatment regimens have recently been developed for the treatment of adult patients with ALL that combine immunotherapies with reduced intensity conventional chemotherapy. The rationale is 2-fold: to improve efficacy by combining therapeutic agents with different mechanisms of action and to reduce toxicity for adult patients to allow long-term administration and treatment. In this commentary, I discuss 2 recent presentations at ASH 2019 on combining mini-hyperCVD and inotuzumab ozogamicin (InO) with or without blinatumomab in patients with Philadelphia chromosome (Ph)–negative B-cell ALL to illustrate the potential of this approach.

Relapsed/Refractory Disease
Sasaki and colleagues reported the results of mini-hyperCVD combined with InO with or without subsequent blinatumomab in 62 adult patients with Ph-negative B-cell ALL at first relapse. Compared with standard hyperCVAD chemotherapy, mini-hyperCVD contains 50% less cyclophosphamide and dexamethasone, 75% less methotrexate, and no anthracycline drug. Patients were generally young with a median age of 39 years and 13% had primary refractory disease. This regimen was associated with low early mortality rates of 3% at 60 days, high ORR of 92%, and median OS of 17 months. However, development of veno-occlusive disease (VOD) in 12% of patients who did not receive blinatumomab led to further dose reduction of InO and addition of blinatumomab in subsequent patients. Among patients who received lower doses of InO and sequential blinatumomab, only 5% developed VOD.

Newly Diagnosed Disease
Based on the results in relapsed/refractory disease, the same regimen of mini-hyperCVD plus InO with or without blinatumomab was then investigated in 64 patients aged 60 years or older with newly diagnosed Ph-negative B-cell ALL. Updated results from this study reported by Short and colleagues showed an ORR of 98% with a 3-year OS rate of 54%. These outcomes compare favorably with prior trials of more intensive chemotherapy regimens in similar patients, suggesting that highly cytotoxic chemotherapy in these patients may be successfully replaced by novel immunotherapeutic agents without sacrificing efficacy.

However, additional questions remain. Despite the low early mortality rate of 3% at 60 days, patients aged 70 years or older fared worse compared with younger patients. One half of these patients died in CR, leading to a 3-year OS rate of only 42% that was significantly lower than the 63% observed in patients aged 60-69 years. Moreover, it is not clear whether blinatumomab is required to achieve the efficacy outcomes seen as they were similar in patients who received blinatumomab and in those who did not. There was also no difference in the rate of VOD whether patients received blinatumomab or not. Lastly, these results in patients with newly diagnosed disease were obtained in a phase II clinical trial setting at a single academic center and will require further validation by other centers and investigators. Nevertheless, for older patients with ALL, the advent of a novel well-tolerated combination approach incorporating less intensive chemotherapy and upfront immunotherapeutic therapies represents a highly promising approach and step forward for the treatment of ALL.

Your Thoughts?
What are your questions on combining reduced dose chemotherapy with immunotherapies for treating patients with ALL? I encourage you to answer the polling question and join the conversation in the discussion box below.

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