CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: March 21, 2023
Expiration: March 20, 2024
Eunice Wang, MD:
The next group of abstracts will discuss updates in ALL for the adult population. The ongoing phase III ECOG-ACRIN E1910 study was designed to determine if patients with B-ALL who become MRD negative after induction and intensification chemotherapy can have improved outcomes by adding blinatumomab to chemotherapy consolidation. In this study, patients with BCR::ABL1–negative B-ALL received induction with a Berlin-Frankfurt-Münster‒type chemotherapy regimen. Those who achieved a CR/CRi received intensification with high-dose methotrexate and pegaspargase followed by MRD assessment, then randomization to consolidation therapy with either blinatumomab plus chemotherapy or chemotherapy alone.
Following completion of consolidation chemotherapy, patients received 2.5 years of maintenance therapy with prednisone, mercaptopurine, methotrexate, and vincristine. The primary endpoint was OS in MRD-negative patients. At ASH 2022, Litzow and colleagues16 presented OS and safety results from E1910.
Eunice Wang, MD:
In this analysis of E1910 (N = 488), the postinduction CR/CRi rate was 81%, with 78% of these patients achieving MRD negativity after intensification. At this third interim analysis, 80% of patients assigned to the experimental arm had received ≥2 cycles of consolidation blinatumomab. The patients’ baseline characteristics were well balanced in both arms of the study, with a median age of 51 years.
Eunice Wang, MD:
At the third interim efficacy analysis of this trial, the data and safety monitoring board recommended releasing the results because of the pronounced benefit demonstrated with blinatumomab in MRD-negative disease. Median OS in the blinatumomab/chemotherapy arm was not reached vs 71 months in the chemotherapy-only consolidation arm (HR: 0.42; 95% CI: 0.24-0.75; P = .003). At 3.6 years, 83% of patients in the blinatumomab/chemotherapy arm remained alive vs 65% with chemotherapy alone.
Eunice Wang, MD:
The median OS in MRD-positive disease was not reached with blinatumomab/chemotherapy vs 22.4 months in the chemotherapy-only arm. There was a nonsignificant trend toward improvement with the addition of blinatumomab in this setting (HR: 0.39; 95% CI: 0.14-1.10).
Eunice Wang, MD:
These data from E1910 have the potential to change standard-of-care intensive frontline chemotherapy regimens for fit patients with Ph-negative B-ALL, regardless of MRD status. The finding of substantial OS benefit from the addition of blinatumomab to chemotherapy is potentially practice changing. In centers that give intensive chemotherapy for this patient population, there is already discussion about using this bispecific antibody in coming weeks or months.
Amir Fathi, MD:
I agree that this study is practice changing. There are many different approaches to upfront therapy of ALL, and a robust controversy exists regarding how to best treat adults (younger or older) with B-ALL. So, now the question is how in incorporate blinatumomab into hyper-CVAD or regimens for adolescents and young adults. These data clearly indicate that incorporating these novel immune-based therapies into upfront treatment improves outcomes.
Amir Fathi, MD:
GRAALL-2014/B was a large, prospective, observational study that enrolled approximately 500 adults with Ph-negative ALL and treated them with pediatric-inspired chemotherapy regimens. Patients in this study were designated as high risk by molecular profile (KMT2A rearrangement, IKZF1 deletion) and/or MRD1 >10-4.
QUEST is a nested substudy cohort in GRAALL-2014/B that added blinatumomab in consolidation for high-risk patients. At ASH 2022, Boissel and colleagues17 presented results from the QUEST substudy cohort (n = 94), with comparison to an internal control cohort (n = 104) of patients who did not receive blinatumomab in GRAALL-2014/B.
In this analysis, high-risk patients with Ph-negative ALL received blinatumomab 28 µg/day as a continuous IV infusion for 4 weeks. Patients received a total of 5 courses of blinatumomab: 1 each in consolidation cycles 2 and 3, and 3 cycles during maintenance. Those patients who were eligible for alloHSCT received blinatumomab continuously for ≥4 weeks prior to transplant.
Baseline characteristics were well matched between the treatment and control cohorts, with no significant difference in rates of high-risk genetic features (ie, KMT2A rearrangement, IKZF1 deletion).
Amir Fathi, MD:
It is exciting to see that incorporating blinatumomab was associated with a higher rate of MRD3 negativity; 72% of patients in the QUEST cohort were MRD3 undetectable. Although median follow-up was shorter in the blinatumomab group (2.3 months vs 4.3 months in the control group), slightly more patients went on to transplant (47% vs 37% in the control group). At 2.5 years, rates of cumulative incidence of relapse and disease-free survival were significantly better in patients who received blinatumomab (both P <.05). However, no OS advantage has been seen to date.
The benefit of blinatumomab seemed to be greater in patients with a good MRD response prior to blinatumomab administration. In other words, it mattered whether patients had achieved MRD negativity.
Amir Fathi, MD:
The absence of complete MRD response after blinatumomab conferred an unfavorable prognosis similar to detectable MRD after chemotherapy.
Amir Fathi, MD:
In summary, incorporating blinatumomab into frontline treatment and as a bridge to transplant seems to improve outcomes in patients with B-ALL. Of importance, these are retrospective data, but they do support results of prospective cooperative group studies of blinatumomab. Together, these results will help health care professionals become increasingly comfortable incorporating blinatumomab into upfront therapy.
Amir Fathi, MD:
GMALL-INITIAL1 is an exciting ongoing study looking at incorporating the CD22-targeted antibody–drug conjugate inotuzumab ozogamicin into upfront treatment of ALL.
At ASH 2022, Stelljes and colleagues18 presented results from this single-arm, open-label phase II study in 45 patients older than 55 years of age with previously untreated CD22-positive, Ph-negative B-ALL.
In this trial, patients received up to 3 cycles of weekly induction with inotuzumab ozogamicin at 0.5 mg/m2. This was followed by consolidation with conventional chemotherapy and maintenance with 6-mercaptopurine plus methotrexate. The primary endpoint was the 12-month EFS rate, with secondary endpoints including CR rate, MRD, 2-year RFS, 2-year OS, and safety. Patients had a median age of 64 years.
Amir Fathi, MD:
It is notable that after 2 induction cycles with inotuzumab ozogamicin, all 43 evaluable patients achieved CR, and 42 went on to receive 3 cycles of inotuzumab. The rate of MRD negativity was promising at 53% after 2 cycles and 74% after 3 cycles. The median time between cycles was not too prolonged at 21-30 days.
With the caveat that this is a small study, the 2-year OS and EFS with inotuzumab were both striking at 81% and 73%, respectively.
Amir Fathi, MD:
General safety concerns about antibody–drug conjugates, particularly those that incorporate calicheamicin, include liver toxicity and veno-occlusive disease.19 However, in this study, only 1 patient had grade 3 or higher veno-occlusive disease.18
Most of the grade 3/4 AEs occurred during cycle 1, with few patients continuing to experience high-grade events by cycle 3. The most common grade 3/4 events in cycle 1 were leukocytopenia (74%), thrombocytopenia (49%), and anemia (37%), and all had decreased to 2% or less by cycle 3.
Amir Fathi, MD:
All of the patients receiving inotuzumab ozogamicin achieved CR/CRi by 2 cycles of induction treatment, and 74% achieved MRD-negative status by cycle 3. The EFS and OS also were very impressive, with 81% remaining alive at 2 years. Although these are phase II data from a relatively small number of patients, these results are pretty exciting. Randomized studies are underway evaluating whether inotuzumab ozogamicin may have a role in frontline treatment of B-ALL (NCT03959085).
Eunice Wang, MD:
Earlier, you made the very important point that treatment of B-ALL is evolving toward less-intensive approaches with less chemotherapy in favor of more targeted immunotherapies. This study, which generated a 2-year OS rate of 81%, provides a good example of an induction regimen with no conventional chemotherapy in very sick, older, or unfit patients. This is the future of treatment. As both blinatumomab and inotuzumab ozogamicin move into the upfront setting, it should be possible to reduce the amount of chemotherapy in older, frail patients without compromising—and potentially enhancing—long-term survival.
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