Outcomes in adults with acute lymphoblastic leukemia (ALL) are almost rivaling those in pediatric ALL, thanks to the benefits achieved by incorporating blinatumomab and inotuzumab into chemotherapy regimens. New ways of administering the chemotherapy component are also increasing tolerability and improving outcomes, according to Hagop M. Kantarjian, MD, FASCO, Professor and Chair of the Department of Leukemia and the Samsung Distinguished Leukemia Chair in Cancer Medicine at The University of Texas MD Anderson Cancer Center, who has spearheaded much of the research.
“We will have to learn how to incorporate CD19/20/22-targeting antibodies and CAR T-cell therapies into chemotherapy—and to use less chemotherapy.”— Hagop M. Kantarjian, MD, FASCO
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Dr. Kantarjian described the treatment of ALL in adult/older patients at MD Anderson—with a look to the future—at the 2021 Debates and Didactics in Hematology and Oncology conference, sponsored by the Emory University Winship Cancer Institute.1
The novel treatments now incorporate the CD19/CD3-bispecific T-cell engager (BiTE) blinatumomab and the CD22 antibody drug conjugate inotuzumab ozogamicin. These agents, he said, “are more effective than chemotherapy,” even in refractory Philadelphia chromosome–positive (Ph+) ALL, where they increase response rates and improve survival compared to intensive chemotherapy. He expects outcomes of adult ALL to further improve with later-generation chimeric antigen receptor (CAR) T-cell therapies, which should be more effective than their first-generation counterparts, he said.
“We will have to learn how to incorporate CD19/20/22-targeting antibodies and CAR T-cell therapies into chemotherapy—and to use less chemotherapy. These new approaches are not mutually exclusive. We’ll have antibody cocktails targeting CD19, CD20, and CD22, and we will incorporate them early and in a dose-dense fashion. Also, new treatments are not one-vs-the-other. They’re complementary,” Dr. Kantarjian noted. He predicted these evolving therapies will render conventional approaches “obsolete in 3 to 4 years.”
Tyrosine Kinase Inhibitors and Antibodies in Ph+ ALL
The tyrosine kinase inhibitor ponatinib has been a major contributor to improving outcomes in Ph+ ALL, but the addition of blinatumomab to this treatment can give a further boost. In a recent MD Anderson study of 28 adults with Ph+ ALL, complete responses were seen in 100% of newly diagnosed patients and 88% of relapsed patients; a complete molecular response was achieved by 87% and 86%, respectively, and estimated 1-year overall survival was 100% and 88%.2
“Half the patients became PCR [polymerase chain reaction]-negative at the end of induction, which is something I’ve never seen before,” Dr. Kantarjian reported. “So far, the 1-year overall survival is good, and we have not sent any newly diagnosed patients to allogeneic transplant.”
Blinatumomab for MRD-Positive ALL
“We also know the importance of measurable residual disease (MRD). When patients have evidence of residual disease, we can implement effective therapies, such as blinatumomab or inotuzumab, and then consider the possibility of allogeneic transplant,” he said.
Historically, patients with MRD-positive disease had cure rates < 20%. Today, with blinatumomab, 80% can become MRD-negative and 40% to 50% can potentially be cured, according to a German study of 110 patients.3 In that study, median overall survival was 36.5 months and 4-year overall survival was 45%, rising to 52% in MRD-negative patients. About 40% of patients remained in continuous complete remission posttransplant, as did 33% without transplant. “I think we can do even better than this,” he commented.
Blinatumomab With Chemotherapy
Both blinatumomab and inotuzumab are more effective than intensive chemotherapy. Therefore, their best use is probably not in the salvage setting but in the front-line setting and most likely in combination, according to Dr. Kantarjian.
The hypothesis is that early incorporation of blinatumomab in treatment for patients with newly diagnosed Ph-negative precursor B-cell ALL would decrease the need for intensive chemotherapy, lead to deeper and more durable responses, and improve survival. In one of the first studies to examine this hypothesis, investigators gave 38 newly diagnosed patients four (instead of eight) cycles of hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), alternating high-dose methotrexate and cytarabine. This was followed by four courses of blinatumomab at standard doses and 1 year of maintenance (instead of 2 years) using blinatumomab with alternating blocks of POMP (mercaptopurine, vincristine, methotrexate, prednisone).4 Patients also received eight cycles of prophylactic intrathecal methotrexate/cytarabine and, if CD20-positive, eight doses of ofatumumab or rituximab.
“When patients have evidence of residual disease, we can implement effective therapies, such as blinatumomab or inotuzumab, and then consider the possibility of allogeneic transplant.”— Hagop M. Kantarjian, MD, FASCO
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All study patients achieved complete remission, and 97% became MRD-negative (most after one cycle). There were no early deaths, and the 60-day mortality rate was 0%. These findings are “as close as it gets to results in pediatric leukemia, … and this is before inotuzumab and BiTEs targeting CD20 were added,” he commented.
Considering a 3-year overall survival of around 83% with hyper-CVAD/blinatumomab and ofatumumab or rituximab and a historical comparison of 66% reported for hyper-CVAD plus ofatumumab, the potential for cure is rising by 15% to 20%. “If this continues to be the case, this would truly be a revolution in the treatment of ALL,” Dr. Kantarjian suggested.
Dose-Dense Mini-CVD-Inotuzumab-Blinatumomab
Hyper-CVAD is a complex regimen that many patients cannot tolerate. Dr. Kantarjian and his team have rendered it simpler and easier in a regimen they labeled “dose-dense mini-CVD.”
“Instead of sequencing blinatumomab, we have moved it to day 5 of every course of chemotherapy plus inotuzumab and, instead of giving four courses of chemotherapy and then four more courses, we are doing six courses—so it’s the same total days of blinatumomab as in the sequential approach,” he explained. Next-generation sequencing is used to determine whether patients are MRD-negative at a level of 1 per 1 million cells and therefore may forgo maintenance.
Dr. Kantarjian’s team is currently conducting a study that combines less chemotherapy with inotuzumab, with dose-dense blinatumomab incorporated with the lower doses of chemotherapy. Other investigators are exploring simpler approaches as well. “Parallel studies from other institutions are showing the benefit of adding the new effective antibodies into the chemotherapy regimen,” he commented.
“CAR T cells today are what allogeneic transplant was in 1980. With time, investigators will come up with CAR T cells that are much more effective.”— Hagop M. Kantarjian, MD, FASCO
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For example, Italian investigators recently reported results on 149 patients who received chemotherapy (GIMEMA LAL1913 protocol) followed by blinatumomab after the third and sixth courses.5 MRD clearance at the end of chemotherapy consolidation was achieved by 73% (similar to chemotherapy), but this rose to 96% after the first dose of blinatumomab. Of 23 MRD-positive patients, 20 (87%) became MRD-negative. One-year survival was 84%.
Modified Mini-HCVD for the Elderly
Prior to the dose-dense mini-CVD protocol, Dr. Kantarjian and his team developed “modified mini-HCVD,” which reduced the chemotherapy doses in hyper-CVAD by about 50% and the methotrexate-high dose cytarabine doses even more. The protocol involves dose-reduced hyper-CVD (no anthracycline) for four to eight courses, including:
- Inotuzumab (low-dose, fractionated) on day 3 and day 11 (first four courses)
- Rituximab on days 2 and 8 (first four courses) for CD20-positive patients
- Intrathecal chemotherapy on days 2 and 8 (first four courses)
- Blinatumomab for four courses, and three courses during maintenance.
In a study of 70 older patients (median age = 78), this approach resulted in responses in 98%, complete responses in 88%, and MRD-negativity in 96%.6 Five-year survival exceeded 50%, similar to what was historically observed in younger patients. “Again, in older patients who have almost been incurable, we are getting a potential cure rate of about 50%,” he emphasized. Other single-arm studies of this type of approach are reporting similar outcomes.
Emerging Efficacy With CAR T-Cell Therapy
Although first-generation CAR T cells have not yielded impressive results in adult ALL, the second-generation therapeutics are promising and are potentially curing about 20% of refractory patients, Dr. Kantarjian said.
“CAR T cells today are what allogeneic transplant was in 1980,” he said. “With time, investigators will come up with CAR T cells that are much more effective.”
At the European Hematology Association 2021 Congress, Chinese investigators reported excellent results in 20 children with relapsed or refractory ALL who received CAR T-cell infusions—first, of a CD19-targeted CAR T-cell product and then one targeting CD22.7 All patients achieved complete remission and MRD negativity, and 80% remained in remission at 2 years.
“I am excited about the potential for allogeneic CAR T cells…. At this MRD level, leftover disease can be eradicated with repeated allogeneic CAR T-cell infusions.”— Hagop M. Kantarjian, MD, FASCO
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“I am excited about the potential for allogeneic CAR T cells. They can target multiple cluster designations, not just one. They don’t have to expand, and they don’t have to live longer. All you have to do is give repeated infusions with a total volume equal to the volume of the residual leukemia cells. We don’t have to use these in active disease. We can use them in the setting of residual disease because there the number of leukemic cells drops to about 10 billion or less. At this MRD level, leftover disease can be eradicated with repeated allogeneic CAR T-cell infusions,” he explained.
DISCLOSURE: Dr. Kantarjian has received honoraria from AbbVie, Actinium, Agios, Amgen, Ariad, Bristol Myers Squibb, Immunogen, Orsenix, Pfizer, and Takeda; has received institutional research funding from AbbVie, Agios, Amgen, Ariad, Astex Pharmaceuticals, Bristol Myers Squibb, Cyclacel, Immunogen, Jazz Pharmaceuticals, Novartis, and Pfizer.
REFERENCES
2. Short N, Kantarjian H, Konopleva M, et al: Interim results of a phase II study of blinatumomab plus ponatinib for Philadelphia chromosome-positive acute lymphoblastic leukemia. 2020 ASH Annual Meeting and Exposition. Abstract 465. Presented December 6, 2020.
3. Goekbuget N, Dombret H, Zugmaier G, et al: Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia: Median overall survival is not reached in complete MRD responders at a median following of 53.1 months. Blood 132(suppl 1):554, 2018.
4. Short NJ, Kantarjian HM, Ravandi F, et al: Hyper-CVAD and sequential blinatumomab in adults with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia. Results from a phase II study. 2020 ASH Annual Meeting. Abstract 464. Presented December 6, 2020.
5. Bassan R, Chiaretti S, Starza ID, et al: Preliminary results of the GIMEMA LAL2317 sequential chemotherapy-blinatumomab front-line trial for newly diagnosed adult Ph-negative B-lineage ALL patients. 2021 European Hematology Association Congress. Abstract S114. Presented June 9, 2021.
6. Jabbour E, Sasaki K, Ravandi F, et al: Chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD, with or without blinatumomab, is highly effective in patients with Philadelphia chromosome-negative acute lymphoblastic leukemia in first salvage. Cancer 124:4044-4055, 2018.
7. Pan J, Tang K, Deng B, et al: Long-term follow-up of sequential CD19-22 CAR T-cell therapy in 20 children with refractory or relapsed B-ALL. 2021 European Hematology Association Congress. Abstract S119. Presented June 9, 2021.
