Although pediatric patients with acute lymphoblastic leukemia (ALL) have seen a dramatic improvement in long-term survival rates over the past 40 years, from approximately 10% to over 95%, adults aged 29 and older have not experienced the same treatment benefits, with survival rates still below 50%.1,2
Aaron C. Logan, MD, PhD, MPhil
At the 2023 National Comprehensive Cancer Network (NCCN) Annual Congress: Hematologic Malignancies, Aaron C. Logan, MD, PhD, MPhil, of the University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, discussed strategies for selection of consolidation therapy in adults with ALL, highlighting the role of measurable residual disease (MRD) to appropriately guide treatment decisions.3 Dr. Logan also explored emerging treatment options for patients with Philadelphia chromosome–positive (Ph-positive) ALL.
Advancement in MRD Detection in ALL
According to Dr. Logan, the challenge of overcoming a poor prognosis in adults with relapsed or refractory ALL has led to further advancement in detection of MRD, which is characterized as a low disease burden present in patients who are in complete remission. New methodologies, including next-generation sequencing and flow cytometry, have boosted the sensitivity of MRD detection, he said, helping to identify patients with an unsatisfactory response to therapy. A complete remission with undetectable MRD using a high-sensitivity methodology translates to a high likelihood of disease-free survival, whereas the presence of residual disease is linked to a likely relapse and a poor prognosis.4
“Blinatumomab could potentially offer curative therapy for a portion of patients with a low disease burden.”— AARON C. LOGAN, MD, PhD, MPhil
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Drug development for ALL encompasses several different classes, including cytotoxic chemotherapy, targeted small-molecule inhibitors, antibodies, antibody-drug conjugates, bispecific antibodies, chimeric antigen receptor (CAR) T cells, and the complete replacement of the immune system via an allogeneic stem cell transplantation. “Astonishingly, for such a rare disease, there are FDA-approved drugs in all mentioned classes,” commented Dr. Logan, who noted these treatments are under continued evaluation in combination and in earlier lines of therapy in ongoing clinical trials.
Blinatumomab in B-Cell ALL
Blinatumomab is the only drug approved for treating MRD, based on the results of the BLAST trial.5 The study evaluated the use of blinatumomab in patients with Ph-negative B-cell ALL who had MRD greater than 10-3 after three chemotherapy cycles. Blinatumomab was then offered for up to four cycles, with some patients eligible for an allotransplant after the first cycle. A significant 67% of patients went on to allogeneic transplantation.
The results of the BLAST trial showed that blinatumomab successfully transitioned 80% of patients from higher (≥ 10-3) to lower (≤ 10-4) disease burden with one cycle when treating MRD. Blinatumomab proved more effective treating MRD in first remission than in subsequent remissions.
Long-term follow-up of the BLAST trial revealed that, in responders to MRD therapy, 50% more patients (46% vs 30%) were alive without disease if they received an allotransplant after blinatumomab vs blinatumomab alone. Importantly, though, 30% of patients who did not receive an allogeneic transplant after treatment for MRD remained alive more than 5 years after therapy.
“This is a remarkable signal and suggests that blinatumomab could potentially offer curative therapy for a portion of patients with a low disease burden, but we don’t know yet how to identify those particular patients,” said Dr. Logan, adding that he favors allogeneic transplant after blinatumomab, when given or MRD, until additional data become available. He noted that blinatumomab is listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) as preferred therapy for MRD-positive ALL.
The ECOG 1910 study examined blinatumomab as consolidative therapy in patients who had attained MRD-negative remission of ≤ 10-4. The randomized study enrolled patients who received Berlin-Frankfurt-Münster (BFM)-like therapy, comparing the outcomes of those who received blinatumomab with those who did not.6
“Just 60% of the 488 enrolled patients progressed to randomization because of a substantial drop-off, the cause of which remains unclear until the trial is fully published as a manuscript,” said Dr. Logan. “Nevertheless, the findings showed a significant improvement in overall survival and progression-free survival in patients given blinatumomab.”
This trial shows that immunologic consolidation with blinatumomab was beneficial for patients achieving undetectable MRD with conventional chemotherapy, according to Dr. Logan. In MRD-positive patients, blinatumomab improved overall survival, mirroring expectations from the BLAST trial results.
Hyper-CVAD Plus Blinatumomab
The combination regimen of hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus blinatumomab, developed by MD Anderson Cancer Center, has also yielded favorable outcomes in a single-center phase II clinical trial.7 Patients received hyper-CVAD for up to four cycles followed by four consolidation cycles of blinatumomab and maintenance with POMP (mercaptopurine, vincristine, methotrexate, and prednisone) chemotherapy and intercalated, quarterly blinatumomab.
The trial demonstrated “similar, remarkable outcomes” to the ECOG 1910 study: 3-year overall and disease-free survival rates of between 70% and 75%. For high-risk patients (including those with MRD positivity after the second cycle of chemotherapy, TP53 abnormalities, or MLL rearrangements), survival rates were slightly lower, with more transplants needed.
On the strength of the ECOG 1910 trial and the study on hyper-CVAD plus blinatumomab, the NCCN Guidelines now recommend blinatumomab for consolidative therapy in patients with ALL, regardless of MRD status, said Dr. Logan.
Inotuzumab Ozogamicin
Inotuzumab ozogamicin is also gaining traction in the treatment of adults with ALL. A CD22-targeted antibody-drug conjugate, inotuzumab ozogamicin is approved for treating relapsed or refractory ALL, based on the results of the INO-VATE trial. The investigators of this study reported an 80% composite complete response rate and a more than doubled progression-free survival rate with this agent—but no apparent effect on overall survival.8
The ongoing INITIAL-1 study is exploring the use of inotuzumab ozogamicin as induction and initial consolidation therapy in older patients (≥ age 55) to reduce chemotherapy toxicities. Early reports have shown a 2-year overall survival rate of more than 70% and a disease-free survival rate of around 60%.9
“This innovative approach [inotuzumab ozogamicin followed by blinatumomab] could reshape induction and consolidation modules for ALL treatment.”— AARON C. LOGAN, MD, PhD, MPhil
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In addition, the MD Anderson group has studied a mini-CVD method for incorporating this antibody-drug conjugate in front-line therapy. It removes the anthracycline from cycle 1A of hyper-CVAD and combines it with low-dose inotuzumab ozogamicin through four mini-CVD cycles.10
“This combination led to a 3-year progression-free and overall survival rate of 50% in patients aged 60 and older, a significant improvement on historical outcomes with hyper-CVAD,” said Dr. Logan. The “pie-in-the-sky dream,” he added, would be to take the advantages of inotuzumab ozogamicin in the front-line setting as an induction agent and combine it with the advantages of blinatumomab as a consolidative agent.
The combination of inotuzumab ozogamicin and blinatumomab for ALL was examined in the ALLIANCE study (A041703). In this trial, patients received up to two cycles of inotuzumab ozogamicin followed by blinatumomab, with central nervous system–targeted intrathecal methotrexate as the only other chemotherapy.11
Initial results showed a high composite complete response rate, promising event-free survival, and overall survival rates. “When compared with other regimens for this specific age group, the outcomes appeared particularly favorable,” said Dr. Logan. “This innovative approach could reshape induction and consolidation modules for ALL treatment.”
Tyrosine Kinase Inhibitors for Ph-Positive ALL
Finally, Dr. Logan discussed the revolutionary impact of tyrosine kinase inhibitors on Ph-positive ALL treatments, highlighting the superior performance of hyper-CVAD with ponatinib compared with other regimens.
The MD Anderson group demonstrated this combination’s effectiveness, with long-term follow-up data showing a 3-year event-free survival rate of approximately 70%.12 “Only approximately one in five patients required allogeneic transplant,” he said, and this combination is now a standard-care approach at many centers.
According to Dr. Logan, even better outcomes may be achieved by incorporating blinatumomab in the front-line therapy with either dasatinib or ponatinib, based on the results of the D-ALBA study and a single-arm MD Anderson study.13 The initial results look promising, he said, but further data maturation is required, along with a potential blinatumomab label modification for front-line use in Ph-positive disease.
The NCCN Guidelines currently list blinatumomab as a consolidative option for patients with Ph-positive ALL, whether they display MRD positivity or negativity. In cases of chemotherapy intolerance, Dr. Logan noted, patients are often switched from chemotherapy with ponatinib to blinatumomab with ponatinib.
DISCLOSURE: Dr. Logan has received research funding from Astellas Pharma, Pharmacyclics, Kite, a Gilead company, Kadmon/Sanofi, Amgen, Autolus, and Talaris and has received consulting fees from Actinium, Amgen, Bristol-Meyers Squibb, Pfizer, Sanofi, and Takeda.
REFERENCES
1. Hunger SP, Mullighan CG: Acute lymphoblastic leukemia in children. N Engl J Med 373:1541-1552, 2015.
2. Juliusson G, Karlsson K, Lazarevic VLJ, et al: Hematopoietic stem cell transplantation rates and long-term survival in acute myeloid and lymphoblastic leukemia: Real-world population-based data from the Swedish Acute Leukemia Registry 1997–2006. Cancer 117:4238-4246, 2011.
3. Logan AC: Adult acute lymphocytic leukemia: Strategies for selection of consolidation therapy. 2023 NCCN Annual Congress: Hematologic Malignancies. Presented September 22, 2023.
4. Berry DA, Zhou S, Higley H, et al: Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: A meta-analysis. JAMA Oncol 3:e170580, 2017.
5. Gökbuget N, Dombret H, Bonifacio M, et al: Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood 131:1522-1531, 2018.
6. Litzow MR, Sun Z, Paletta E, et al: Consolidation therapy with blinatumomab improves overall survival in newly diagnosed adult patients with B-lineage acute lymphoblastic leukemia in measurable residual disease negative remission: Results from the ECOG-ACRIN E1910 randomized phase III National Cooperative Clinical Trials Network Trial. 2022 ASH Annual Meeting & Exposition. Abstract LBA-1. Presented December 13, 2022.
7. Jabbour E, Short NJ, Jain N, et al: Hyper-CVAD and sequential blinatumomab for newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: A single-arm, single-centre, phase 2 trial. Lancet Haematol 9:e878-e885, 2022.
8. Kantarjian HM, DeAngelo DJ, Stelljes M, et al: Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 375:740-753, 2016.
9. Stelljes M, Alakel N, Wäsch R, et al: Inotuzumab ozogamicin induction followed by standard chemotherapy yields high remission rates and promising survival in older (> 55 years) patients with de novo B-lymphoblastic leukemia (GMALL-Initial1 Trial). Blood 140(suppl 1):510-512, 2022.
10. 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.
11. Wieduwilt M, Yin J, Kour O, et al: S117: Chemotherapy-free treatment with inotuzumab ozogamicin and blinatumomab for older adults with newly diagnosed, Ph-negative, CD22-positive, B-cell acute lymphoblastic leukemia: ALLIANCE A041703. HemaSphere 7(suppl):e08838b7, 2023.
12. Sasaki K, Jabbour EJ, Ravandi F, et al: Hyper-CVAD plus ponatinib versus hyper-CVAD plus dasatinib as frontline therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: A propensity score analysis. Cancer 122:3650-3656, 2016.
13. Jabbour E, Short NJ, Jain N, et al: Ponatinib and blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukaemia: A US, single-centre, single-arm, phase 2 trial. Lancet Haematol 10:e24-e34, 2023.
