Hyper-CVAD Plus Ofatumumab Demonstrates Activity in Ph-Negative, CD20-Positive B-Cell ALL

Hyper-CVAD in combination with ofatumumab (Arzerra) appeared to be safe and active as frontline treatment of adult patients with Philadelphia chromosome (Ph)-negative CD20-positive B-cell acute lymphoblastic leukemia (ALL), according to results from a phase 2 clinical trial.

“In this single-arm, phase 2 study, the combination of ofatumumab with the hyper-CVAD regimen resulted in a high proportion of adult patients with Ph-negative CD20- positive B-cell ALL having durable remission and long-term survival…,” the study authors, led by Elias Jabbour, MD, wrote. “Additionally, the toxicity profile of hyper-CVAD plus ofatumumab was similar to the combination of hyper-CVAD with or without rituximab [Rituxan], with myelosuppression and infections being the most frequent complications.”

Of the 72 patients who were screened, 69 patients were enrolled and treated in the study. Overall, 67 patients (97%) had B-cell ALL and 2 (3%) had B-cell lymphoblastic lymphoma. The median age of patients was 41 years (range, 32-50), and 33 patients (48%) were considered adolescents or young adults. The majority of patients were male (40%) and had an ECOG performance status of 0 or 1 (90%).

At a median follow-up of 44 months (interquartile range [IQR], 26-53), 46 patients (67%) were alive, and 37 patients (54%) were alive and in their first complete remission (CR). One patient (1%) died during induction therapy, 10 (14%) died in CR, and 21 (30%) had a morphological relapse. Additionally, 12 patients (17%) died of progressive disease, and 9 (13%) were still living following relapse.

The median time from CR to relapse was 15 months (IQR, 10-25), and the median event-free survival (EFS) was 51 months (95% CI, 44-not reached [NR]). The estimated 4-year EFS rate was 59% (95% CI, 48%-73%). The median overall survival (OS) had not been reached (95% CI, 65-NR), but the 4-year OS rate was 68% (95% CI, 58%-81%).

Bone marrow specimens from a subset of 43 patients with were used for a post-hoc exploratory molecular analysis, in which copy number alterations were analyzed on 40 diagnostic specimens, and RNA sequencing or Archer FusionPlex ALL analysis was done on a subset of 33 patient samples.

In the RNA sequencing analysis, 9 patients (27%) had gene expression profiling consistent with Ph-like lymphoblastic leukemia, and among those patients, 6 had fusions including 2 with P2RY8– CRLF2 and 1 each with IGH–CRLF2, BCR–FGFR1, ZCCHC7–PAX5, and ATF71P-PDGFRB. Thirty-seven patients had genomic alterations, and the most frequent alterations included deletions in CDKN2A or CDKN2B (49%), VPREB1 (35%), and IKZF1 (30%), alterations of PAX5 (23%), point mutations in TP53 (14%), and JAK2 mutations (9%). IKZF1 deletions, exon 4-7 deletion, which are commonly known to have a dominant negative effect, were identified in 7 patients (16%).

The 4-year EFS in the post-hoc subgroup analysis was 69% (95% CI, 54%-87%) for adolescents and young adults versus 51% (95% CI, 37%-71%) for patients aged 40 years or older (P =.32). The 4-year OS in the younger group was 74% (95% CI, 60%-91%) versus 63% in the older group (95% CI, 49%-81%; P =.41). Patients of 55 years of age or older had a 4-year EFS of 38% (95% CI, 16%-87%), and the 4-year OS was 56% (95% CI, 32%-100%).

For patients with Ph-like lymphoblastic leukemia, the 4-year EFS was 56% (95% CI, 31%-100%) versus 58% (95% CI, 42%-82%) among patients without Ph-like expression (P =.61), and the 4-year OS was 40% (95% CI, 17%-94%) versus 69% (95% CI, 53%-91%; P =.12), respectively. EFS and OS appeared similar among patients with CD20 expression of 1% to 19% compared with 20% and more (P =.89 for EFS; P =.31 for OS).

OS for patients with early minimal residual disease (MRD) negativity after 1 course of chemotherapy was 77% (95% CI, 65%-91%) compared with 51% (95% CI, 33%-77%) for patients with MRD positivity after the first course of chemotherapy (P =.06). The only molecular abnormality that was associated with both poorer EFS and OS was the JAK2 mutation, which had a hazard ratio (HR) of 4.71 for EFS (95% CI, 1.50-14.82; P =.0081) and a HR of 8.06 for OS (95% CI, 2.23-29.16; P =.0014). There was not a significant association in patients with IKZF1 deletion exon 4-7 for EFS (HR, 1.48; 95% CI, 0.58-3.75; P =.41) and OS (HR, 2.59; 95% CI, 0.96-6.94; P =.059).

Out of the 69 patients in the study, 65 were treatment-naïve and evaluable for overall response. Sixty-four of these patients received induction chemotherapy and went into remission; 64 patients had a CR and 1 had a CR with incomplete platelet recovery. In addition, 2 patients required 2 courses to achieve a CR. One patient died due to septic shock during induction therapy.

The rate of CR with MRD negativity was 63% after the first course of chemotherapy and 93% overall. Patients with Ph-like ALL were associated with a significantly lower occurrence of MRD negativity after induction chemotherapy compared with patients without Ph-like disease (P =.020). IKZF1 exon 4-7 deletion was the only molecular feature to predict MRD negativity, whereas none of these patients had MRD negativity after induction chemotherapy (P =.041).

In a post-hoc 6-month landmark analysis, the investigators assessed the effect of HSCT in first CR, which demonstrated no difference in EFS (HR, 0.93; 95% CI, 0.35-2.44; P =.88) or OS (HR, 1.23; 95% CI, 0.41-2.70; P =.71) according to whether or not patients had HSCT. The 4-year EFS was 46% (95% CI, 55%-84%) and 4-year OS was 68% (95% CI, 55%-84%) in those without HSCT.

Overall, this regimen appeared well tolerated, and most adverse events (AEs) were of grade 1 or 2 in severity. A median of 8 courses of intensive chemotherapy (IQR, 4.5-8) was administered in the study, and 35 patients (51%) had completed all 8 courses of therapy planned for the study. The median number of courses was 8 (IQR, 6-8) in adolescents and young adults compared with 6 (IQR, 4-8) in patients of 40 years or older.

The most frequent nonhematological AE of grade 3/4 was infection, occurring in 35 patients (54%) during induction and 53 (78%) during consolidation. Grade 3/4 infections were observed in 15 (47%) adolescents and young adults versus 20 (61%) in the older group. Grade 3/4 AEs were also more common in the older group of patients aged 40 years or older versus the younger group, particularly including hyperglycemia (72% vs. 24%), hyperbilirubinemia (31% vs. 15%), hypoalbuminemia (28% vs. 3%), and hyponatremia (28% vs. 3%), respectively.

One patient aged 52 years old died from an infectious complication during induction with a 30-day mortality of 2%. Ten patients (14%) died in CR due to sepsis, including cardiac arrest in 2 (3%), HSCT-related complications in 5 (7%), and therapy-related acute myeloid leukemia in 2 (3%). The 3 infection-related deaths all occurred in patients of 40 years or older, but no deaths were considered related to either ofatumumab or standard chemotherapy.

The open-label study was conducted at the MD Anderson Cancer Center and enrolled patients with newly diagnosed Ph-negative CD20-positive B-cell lymphoblastic leukemia or B-cell lymphoblastic lymphoma. To be eligible, patients had to be treatment-naïve or have received one course of induction chemotherapy, have an ECOG performance status of 2 or less, adequate renal and hepatic function, and adequate cardiac function. Patients were excluded from the study if they had t(9;22)(q32;q11.2) translocation, an active or co-occurring malignancy, a life expectancy of less than 12 months, an active uncontrolled infection, or active hepatic or biliary disease, although patients with Gilbert’s syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease were eligible. Patients who had a history of clinically significant cerebrovascular and disease within 6 months or ongoing event with active symptoms were also ineligible for the study.

Patients received hyper-CVAD for up to 8 induction and consolidation cycles, alternating high-dose methotrexate and cytarabine. Ofatumumab was given on days 1 and 11 during courses 1 and 3, and on days 1 and 8 during courses 2 and 4. The first ofatumumab dose was 300 mg administered intravenously, then 2000 mg for all doses thereafter.

Reference

Jabbour E, Richard-Carpentier G, Konopleva, et al. Hyper-CVAD regimen in combination with ofatumumab as frontline therapy for adults with Philadelphia chromosome- negative B-cell acute lymphoblastic leukaemia: a single-arm, phase 2 trial. Lancet Haematol. 2020; 7: e523–33.