Better Therapies Continue to Improve Remission Rates in Patients With ALL

Hagop M. Kantarjian, MD

Treatment of acute lymphoblastic leukemia (ALL) is inching away from chemotherapy and transplantation and toward therapies that are more likely to improve survival rates and get patients into remission.

Recently, BCR-ABL tyrosine kinase inhibitors (TKIs) as well as chimeric antigen receptor (CAR) T-cell therapies have offered improvement in survival and better remission rates. Such therapies include blinatumomab (Blincyto) and inotuzumab ozogamicin (Besponsa), 2 FDA approved treatments for ALL.

Most recently, it was reported that blinatumomab followed by prednisone, vincristine, 6-mercaptopurine, and methotrexate maintenance chemotherapy was effective and tolerable in older patients with ALL after 3 years of follow-up in the SWOG 1318 study (NCT02143414). The agent has also demonstrated survival benefit in patients with high-risk B-cell precursor ALL.¹

Inotuzumab, as evaluated in the phase 3 INO-VATE study (NCT01564784), correlated with higher chance of patients experiencing a complete response or complete remission with incomplete hematologic recovery and was also a successful bridge to hematopoietic stem cell transplantation compared with standard chemotherapy.²

In terms of CAR T-cell therapy in ALL, the most recent approval was that of brexucabtagene autoleucel (Tecartus), for patients with B-cell precursor disease. The approval was granted based on findings from ZUMA-3 (NCT02614066), in which brexucabtagene autoleucel lead to high CR and CRi rates.³

In an interview with Targeted Oncology™, Hagop M. Kantarjian, MD, professor and chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center, and the Samsung Distinguished Leukemia Chair in Cancer Medicine, discussed the evolution of the ALL-treatment landscape and how further changes may be soon to come.

TARGETED ONCOLOGY: What have been the most impactful innovations in ALL over the past decade?

Kantarjian: In acute lymphocytic leukemia, I think there's now a paradigm shift in the cytopathic approaches. This is because we started introducing targeted therapies like the BCR-ABL TKIs in Philadelphia-positive acute lymphocytic leukemia, as well as introducing the antibodies targeting CD19 and CD22.

So, in Philadelphia-positive acute lymphocytic leukemia, using the third-generation TKIs like ponatinib in combination with blinatumomab, which is the CD19 by specific T-cell engager, or BITE, we found that we can induce almost all patients in remission. The estimated 2-year survival is over 90%. And we are not needing to send the patients to transplant. So, we have shifted from a combination of intensive chemotherapy with first- and second-generation TKIs and relying on allogeneic transplantation to a strategy that has no chemotherapy, no need for transplant and a very high cure potential in pre-B acute lymphocytic leukemia.

We introduced both blinatumomab and inotuzumab into the frontline therapy with less chemotherapy. And we again found that almost all patients achieved a complete remission. And at 3 to 4 years, their estimated survival is over 80%, which is the first time that we've seen such survivor rates at MD Anderson. So, I'm hoping that 5 years from now, there's going to be a therapeutic revolution in ALL where instead of giving 3 years of intensive chemotherapy in the adults and older patient and hope for a cure rate of maybe 40% to 50%, we'll be able to give the newer regimens and maybe double the cure rate to levels which are maybe similar to childhood ALL.

Can you discuss the introduction of CAR T cells in ALL and their impact to date?

CAR T cells are very important, and maybe again are a cytopathic revolution in myeloma and lymphoma. In ALL, the first-generation CAR T cells have been able to produce a 2-year survival rate of maybe 50% in children. But in adults with ALL, when we use CAR T cells in active disease, very few patients are cured.

The second-generation CAR T cells are better, and they produced 2-year survivals of about 20% to 40% in adults and older patients. But there is data now that shows that they work better if they are infused in the setting of minimal residual disease (MRD) and inactive disease.

Even though the FDA approval for CAR T cells is for relapsed/refractory ALL, I think their best use and the best results will be if they are infused in the setting of MRD or inactive disease. So, the patients are covered for treatment with the CAR T cells for active disease but then they receive preparative regimens like fludarabine, cyclophosphamide and if they happen to get into a MRD status or even MRD negativity, then their 2-year survival goes to above 70%.

So, in the future, we have to think maybe using the CAR T cells after giving the patients some form of chemoimmunotherapy like chemotherapy with blinatumomab and inotuzumab and then infuse the CAR T cells in the setting of MRD in complete remission.

What clinical trial research in the ALL space looks encouraging?

I think as I mentioned, the targeted therapies with the BCR-ABL new generation. These are showing very promising results in combinations with antibodies like blinatumomab. The antibody cocktails with chemotherapy and pre-B ALL are very promising. I'm also very interested in the potential that instead of bispecific T-cell engagers, meaning that you get the CD3 cells to target CD19 or CD22, we can develop trispecific T-cell engagers. And the same applies for the CAR T cells, the CAR T cells can target also more than one cluster designation. So, they could be designed to target both CD19 and 22, or CD19 and 20.

So, I think the trispecific T cell engagers and CAR T cells having more than one leukemia target are going to be the future nuclear bombs against ALL.

_REFERENCES:

_{1. Blincyto® (Blinatumomab) demonstrated significantly prolonged event-free survival compared with consolidation chemotherapy in pediatric patients with relapsed acute lymphoblastic leukemia. News release. Amgen. March 2, 2021. Accessed April 27, 2022. https://bit.ly/382RH0c}

_{2. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019;15;125(14):2474-2487. doi: 10.1002/cncr.32116.}

_{3. FDA approves brexucabtagene autoleucel for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. News release. FDA. October 1, 2021. Accessed April 27, 2022.}