Hyper-CVAD With Blinatumomab and Inotuzumab Shows High Efficacy in Ph-Negative B-Cell ALL

Nicholas J. Short, MD

In the frontline setting of Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic lymphoma (ALL), hyper-CVAD with sequential blinatumomab (Blincyto) plus inotuzumab (Besponsa) was highly effective at achieving minimal residual disease (MRD0 negativity and prolonging overall survival (OS), according to results from a phase 1/2 study (NCT01371630).

In a poster presented by Nicholas J. Short, MD of the University of Texas MD Anderson Cancer Center during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, hyper-CVAD with sequential blinatumomab and inotuzumab achieved a 95% MRD negativity rate and a 3-year OS rate of 85%.

Typical outcomes with standard therapy for ALL include a long-term OS rate between 40% and 50% and a complete response (CR) rate between 80% and 90%. In comparison with chemotherapy, investigators know that blinatumomab plus inotuzumab has higher rates of MRD eradication, and by adding the combination to hyper-CVAD, it was hypothesized that patients would experience higher efficacy and rates of remission with less myelosuppression.

Fifty-eight patients with newly-diagnosed Ph-negative B-cell ALL aged 14-59 years of age were enrolled in the study. The protocol allowed for prior treatment with no more than 1 cycle of induction chemotherapy. Patients were required to be eligible for intensive chemotherapy, have an ECOG performance status of ≤ 3, adequate organ function defined as bilirubin ≤ 2 mg/dL, and creatinine ≤ 2 mg/dL. Patients were not permitted to have significant central nervous system pathology.

At baseline, the population had a median age of 34 years (range, 17-59), and the majority (81%) had an ECOG performance score of 0 or 1. The median baseline white blood cell count was 4.1 x 109/L (range, 0.5-553). CNS involvement at the time of diagnosis was observed in 10% of the study population. Fifty-five percent of patients had a CD20 ≥ 20% and 98% had a CD 19 ≥50%.

In terms of karyotype, diploid was most commonly identified (31%), followed by low hypodiploidy/near triploidy (14%), KMT2A rearrangement (9%) complex (7%), and high hyperdiploidy (7%). Thirty-three percent of patients had other karyotypes.

According to cytometry, 19% of patients in the study were CRLF2-positive. Also, 26% of patients tested positive for a TP53 mutation and 8% were positive for a JAK2 mutation.

Treatment in the intensive phase lasted for 4 weeks of therapy. Patients were treated with ofatumumab (Kesimpta) or rituximab (Rituxan) twice per week with hyper-CVAD, methotrexate plus 8 doses of cytarabine. Following the intensive phase, patients received blinatumomab on weeks 2 and 4. In the maintenance phase, patients received 6 doses of mercaptopurine plus vincristine, methotrexate, and prednisone (POMP) on days 1-3, 5-7, 9-11, and 13-15. Additionally, patients were treated with blinatumomab on days 4, 8, and 12 during the maintenance phase, and inotuzumab was administered at 0.3 mg/m2 on days 1 and 8.

After induction, CRs were observed in 80% of patients overall. The CR rate in patients treated with hyper-CVAD plus blinatumomab was 81% compared with 77% among patients treated with hyper-CVAD with sequential blinatumomab plus inotuzumab. MRD negativity after induction was observed in 76% of patients overall. The hyper-CVAD plus blinatumomab arm has a CR rate of 85% after induction vs 63% in the hyper-CVAD with sequential blinatumomab plus inotuzumab group.

The CR at any time was 100% in the overall population as well as in each treatment arm. MRD negativity at any time was 95% overall and 97% for the hyper-CVAD plus blinatumomab compared with 63% in the other treatment arm.

The 30-day mortality was 3% in the overall population, with all deaths occurring in the hyper-CVAD plus blinatumomab arm.

Median follow-up was 34 months (range, 16-61) in the hyper-CVAD plus blinatumomab arm. Of the 38 patients who achieved a CR in the hyper-CVAD plus blinatumomab arm, 5 patients relapsed, 3 died, 13 went on to transplant, and 18 had ongoing CRs at the time of data cutoff.

Among patients treated with hyper-CVAD plus blinatumomab and inotuzumab, the median follow-up was 6 months (range, 3-14). Among the 20 patients who achieved a CR with the regimen, 5 went on to transplant and 15 had ongoing CRs at the time of data cutoff.

The probability of survival and CR durability at 3 years was 85% and 84%, respectively. Investigators also estimate a 1-year OS rate of 100% in the hyper-CVAD plus blinatumomab and inotuzumab arm vs 87% in the hyper-CVAD plus blinatumomab arm.

Further, the efficacy findings show no relapses among patients without baseline high-risk features, and no relapses were observed beyond 2 years.

Only 1 patient in the study discontinued treatment with blinatumomab as a result of recurrent grade 2 neurotoxicity. There were no patients who discontinued inotuzumab due to adverse events, and no cases of hepatic veno-occlusive disease were observed.

_REFERENCE:

_{Short NJ, Kantarjian H, Ravandi F, et al. A phase II study of hyper-CVAD with sequential blinatumomab (Blina), with or without inotuzumab ozogamicin (INO), in adults with newly diagnosed B-cell acute lymphoblastic leukemia (ALL). J Clin Oncol. 2022; 40(suppl 16; abstr 7034). doi: 10.1200/JCO.2022.40.16_suppl.7034}