Advances in Hematologic Malignancies
Issue 17, Winter 2023
— Marlise Luskin, MD, MSCE
Acute lymphoblastic leukemia (ALL) is a rare disease that affects both children and adults. Fortunately, in 2022, most children (≥90%) diagnosed with ALL will be cured. However, outcomes for adults diagnosed
with ALL, particularly those ≥60 years or with other health conditions, remain very poor, with fewer than 1 in 5 cured.1 Older adults are more commonly diagnosed with aggressive disease sub-types that possess genetic and non-genetic biologic
features associated with chemotherapy resistance. Additionally, older adults tolerate conventional chemotherapy (steroids, L-asparaginase, vincristine, anthracyclines, and alkylating agents) poorly, often experiencing severe complications early in
treatment leading to death or inability to continue therapy. It is common for older adults to not be offered treatment at all, or to have their treatment reduced, delayed, or discontinued prematurely. Older adults with ALL who do receive treatment
less frequently achieve complete remission and more commonly relapse.
Approximately half of older adults are diagnosed with Philadelphia-chromosome (Ph) positive ALL, where outcomes have improved dramatically because of the development of tyrosine kinase inhibitors (TKIs).2 Older adults with Ph+ ALL can achieve
remission with chemotherapy-free regimens including TKI plus corticosteroids, and those remissions can be maintained with TKI plus low-intensity chemotherapy and/or reduced-intensity allogeneic stem cell transplantation. Several groups are also investigating
the addition of blinatumomab, a bi-specific CD19-CD3 T-cell engager, to Ph+ ALL treatment regimens as way to achieve deeper and more durable remissions, without added toxicity.
Progress for the older adults diagnosed with ALL without the Philadelphia-chromosome (Ph-negative ALL) has been more difficult to achieve.2 Approaches developed for younger patients, including adopting pediatric-style regimens in adults
<40 years, have been too toxic for older adults, even with modifications of dose and schedule of chemotherapy. Fortunately, the development of more effective and less toxic drugs for ALL is providing the tools needed to improve outcomes for older patients.
Treatment regimens including these promising novel agents may have improved efficacy with less toxicity, as novel agents permit conventional chemotherapy to be reduced or omitted.
Assisted by pre-clinical and clinical work by Anthony Letai, MD, PhD, a leukemia laboratory scientist, and others at Dana-Farber Cancer Institute, venetoclax, a BCL2 inhibitor, has recently been approved
for the more common acute leukemia in adults, acute myeloid leukemia, as well as in chronic lymphocytic leukemia. Pre-clinical data suggests that ALL cells (lymphoblasts) are also highly sensitive to this compound3 which prompted
clinical investigators at Dana-Farber (Daniel J. DeAngelo, MD, PhD, Chief of the Division of Leukemia, and Marlise R. Luskin, MD MSCE, Associate
Program Director, Dana-Farber/Mass General Brigham Hematology/Oncology Fellowship and Education Director, Adult Leukemia
Program) to collaborate with colleagues at the University of Texas MD Anderson Cancer Institute, to test a new regimen of venetoclax plus reduced intensity chemotherapy (mini-hyper-CVD).
In a phase Ib study of venetoclax plus mini-hyper-CVD, 10 of 11 newly diagnosed patients achieved deep (measurable residual disease negative) remissions.4 Of those 10 patients, 9 were able to receive allogeneic stem cell transplants.
The regimen was also well tolerated in both newly diagnosed and relapsed patients. Based on these promising early results, the Dana-Farber and MD Anderson investigators launched a phase II study,
which is currently enrolling. Drs. Luskin, DeAngelo, and Letai are particularly excited about this regimen given its promising efficacy, tolerability, and broad application — patients with both B- and T-cell ALL can receive this regimen, which
is not the case with other novel approaches which target B-cell antigens.
An older adult diagnosed with ALL in 2022 has dramatically improved outcomes compared to just five years ago. Given the rapidly changing therapeutic landscape, and the availability of clinical trials, Dr. Luskin, DeAngelo, and their colleagues
in the Dana-Farber Adult Leukemia Program welcome the chance to consult with patients and referring physicians and consider eligibility for the venetoclax plus mini-hyper-CVD and others.