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Leukemia abstracts to watch at ASCO Annual Meeting
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Michael J. Mauro, MD, leader of the myeloproliferative neoplasms program at Memorial Sloan Kettering Cancer Center and a HemOnc Today Editorial Board Member, identified four leukemia abstracts to watch at ASCO Annual Meeting.
Below, he provides an overview of each study and explains why the results could be important for clinical practice.
1. Abstract 7004 — Moxetumomab pasudotox in heavily pretreated patients with relapsed/refractory hairy cell leukemia: Results of a pivotal international study.
This pivotal, multicenter, single-arm, international study evaluated moxetumomab pasudotox (MedImmune/AstraZeneca) for 80 patients with relapsed/refractory hairy cell leukemia.
Hairy cell leukemia is a highly treatable blood cancer, benefitting from highly effective traditional therapy using purine analogs. However, many patients inevitably require retreatment after relapse. Identification of the ubiquitous BRAF V600E mutation in classic hairy cell leukemia has further defined this disease while fostering development of targeted therapy with vemurafenib (Zelboraf, Genentech).
Additional approaches are needed for the frequent scenario of relapsed disease. Among these is immunotherapy with recombinant anti-CD-22 immunotoxin containing an Fv fragment fused to truncated Pseudomonas exotoxin, under development for many years.
This pivotal trial of relapsed/refractory hairy cell leukemia treated with moxetumomab pasudotox shows a high rate of response and remarkable ability to eradicate minimal residual disease among heavily pretreated patients with minimal hematologic and immune suppression.
With this data, I suspect treatment options for such patients will continue to expand and add immunotherapy to targeted therapy as a highly effective option for hairy cell leukemia.
2. Abstract 7000 — Ivosidenib in mutant IDH1 relapsed/refractory acute myeloid leukemia: Results of a phase 1 study.
This phase 1 study included 258 patients with relapsed/refractory AML treated with 500 mg once-daily ivosidenib (Agios).
The available options for treatment of AML thankfully have expanded in the past several years with the addition of FLT3-directed therapy with midostaurin (Rydapt, Novartis), liposomal daunorubicin and cytarabine for AML after chemotherapy/radiotherapy or arising from minimal residual disease, and discovery and development of targeted therapy for mutations in the isocitrate dehydrogenase enzyme.
Leukemia bearing the IDH2 mutation can be treated with the recently approved agent enasidenib (Idhifa; Celgene, Agios); parallel development of an inhibitor active against AML bearing mutations in IDH1 has been ongoing and is now yielding more mature results with the presentation of this phase 1 study.
In relapsed/refractory AML with an IDH1 mutation, ivosidenib (AG-120, Agios) is active in a significant minority of patients with a distinct side effect profile similar to its predecessor, namely risk of differentiation syndrome. As myeloid leukemias continue to be unraveled and such targets emerge, both molecular characterization and agents such as the IDH1/IDH2 inhibitors will allow for safer, more selective and personalized therapy. Further research is ongoing to reveal best combinations and prove their worth earlier in diagnosis.
3. Abstract 7003— Long-term treatment-free remission in patients with chronic myeloid leukemia in chronic phase after stopping second-line nilotinib: ENESTop 144-week results.
This trial examined treatment-free remission among patients with CML after stopping second-line nilotinib (Tasigna, Novartis).
The authors of this study start their abstract by saying, “Treatment-free remission is a new treatment goal” in CML, justifiably focusing on what may be considered the next chapter of the remarkable evolution of treatment for this disease.
With five available tyrosine kinase inhibitors and realization that the majority of patients secure deep and stable remission, sequential research into treatment-free remission with imatinib and now the second-generation TKIs — either used from diagnosis or, as in the case of the ENESTop study, nilotinib following imatinib in order to optimize response and secure stable remission after observation deemed good enough to consider treatment-free remission.
Results from the study, now with longer follow-up, show the success of second-line nilotinib to permit high rates of treatment-free remission, the ability of patients to regain stable deep remission if treatment-free remission is not successful, and that long-term monitoring is essential to capture information about rare late loss of treatment-free remission as well as “withdrawal syndrome” from TKIs.
With increasing awareness given to treatment-free remission, inclusion in National Comprehensive Cancer Network guidelines and FDA endorsement of treatment-free remission in the label of nilotinib, these data will expand treatment-free remission options to more patients on second-line therapy, as well as remind us to proceed carefully through this next chapter in CML therapy evolution.
4. Abstract 7010 — Durable response with venetoclax in combination with decitabine or azacitadine in elderly patients with acute myeloid leukemia.
This open-label, phase 1b, dose-escalation and expansion study included 145 elderly patients with untreated AML who were treated with venetoclax (Venclexta; AbbVie, Genentech) with decitabine or azacitadine.
The antiapoptotic protein BCL-2 has been shown to be a broadly applicable target in hematologic malignancies, being overexpressed in CLL as well as AML cells, and in AML stem cells.
The highly specific BCL-2 inhibitor venetoclax proved its value and potency in resistant and even 17p deleted CLL, a difficult population. Based on strong preclinical work, AML came next. Single-agent activity but, moreover, synergy with hypomethylating agents and cytarabine held great promise and now are proving to be powerful combinations in the clinic.
In this study, a population with more limited options — elderly patients with AML — received venetoclax at different doses combined with decitabine or azacitadine. Results reveal the target dose of venetoclax (lower dose) and the fact that the majority of patients gain remission, complete or without full count recovery, with mainly myelosuppression and febrile neutropenia by way of toxicity.
Importantly, the venetoclax/hypomethylating agent combination appears to clear minimal residual disease in a significant proportion of patients with AML.
Given the high frequency of remission, often deep, in patients with AML not eligible for traditional chemotherapy, this combination has created quite a stir and offers yet another novel, advantageous approach for a devastating disease with historically limited options. Further study of this potent BCL-2 inhibitor across diseases continues and proves that the “right drug” for the “right target” may have many worthy applications.