The addition of the monoclonal antibody blinatumomab to hyper-CVAD could represent a potential option for extending remission times in patients with Philadelphia chromosome–negative B-cell acute lymphoblastic leukemia.
Data presented from a phase 2 trial of patients with Philadelphia chromosome (Ph)–negative B-cell acute lymphoblastic leukemia (ALL) indicated that the addition of the monoclonal antibody blinatumomab (Blincyto) to standard chemotherapy in the frontline setting enhanced survival as well as rates of minimal residual disease (MRD) negativity.
These data—reported in December 2020 at the American Society of Hematology (ASH) Annual Meeting & Exposition by Nicholas J. Short, MD, of The University of Texas MD Anderson Cancer Center—introduced a potential treatment alternative in a population of patients with a high rate of treatment failure.
“Multiple studies, including a large meta-analysis, have consistently shown that the achievement of MRD-negativity is the most important prognostic factor in ALL and is associated with more durable remissions and higher rates of cure,” Short said. “Thus, the ability to achieve a high rate of MRD negativity is a key end point when evaluating new and emerging ALL therapies.”
Blinatumomab is a bi-specific CD3/CD19 T-cell–engaging antibody that has been shown in the relapsed/refractory setting to be superior to chemotherapy and is highly effective at eradicating MRD in patients with residual detectable disease after initial chemotherapy.
The trial was designed to administer the hyper-CVAD regimen—or hyperfractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone—with sequential blinatumomab in the first line to patients with Ph-negative B-cell ALL in hopes of achieving higher MRD rates and more durable remissions versus conventional chemotherapy alone. The investigators also hoped that incorporation of the agent would lead to needing less chemotherapy, shorter treatment duration, and lower morbidity and mortality.
The primary end point was relapse-free survival (RFS) with secondary outcome measures of overall response rate, MRD negativity rate, overall survival (OS), and safety.
Out of 32 response-evaluable patients, 81% achieved a complete remission (CR) after induction therapy with all patients reaching this end point at some point during therapy. The MRD-negativity rate by flow cytometry was 71% in 34 evaluable patients after induction and rose to 97% when these patients were examined over the total course of therapy. The only patient not achieving negative MRD had 11q23 translocation and relapsed prior to receiving blinatumomab. All patients who were MRD positive after induction converted to undetectable MRD after 1 cycle of blinatumomab. The 30-day mortality rate was 0%.
At a median follow-up of 24 months, the 1- and 2-year RFS rates are 80% and 71%, respectively. Two patients with a t(4;11) translocation, 2 with a TP53 mutation, and 1 with a white blood cell count greater than 30 × 109/L relapsed. Twelve patients underwent subsequent hematopoietic stem cell transplantation with 2 later relapsing. In total, 21 patients are in ongoing response without transplant.
The OS rate at 1 year was 85%; at 2 years, that rate was 80%. When Short compared these results against data from a trial in which patients were treated with hyper-CVAD and ofatumumab (Kesimpta), the Kaplan-Meier curves showed a plateau of survival in the blinatumomab data that’s not seen in the comparator data, despite similar rates at 2 years.
Therapy was well tolerated with expected adverse events (AEs) associated with hyper-CVAD and blinatumomab. Infusions reactions accounted for the most common all-grade events at 47%. The most frequent grade 3/4 AEs were elevated liver enzymes (24%). Notably, cytokine-release syndrome occurred in 13% of patients, mostly as a grade 1/2 event, and blinatumomab-related neurologic events were seen in 45% of patients with 13% of these being grade 3/4.
Patients were eligible for the trial if they had newly diagnosed disease, were at least 14 years of age, could receive intensive chemotherapy, had an ECOG performance status of 3 or less, and had adequate organ function. Patients could not have significant central nervous system (CNS) pathology, excluding CNS leukemia. Treated patients had a median age of 37 years (range, 17-59) and a majority had an ECOG performance status of 1 or 0 (79%).
In the original study design, patients were administered 4 cycles of hyper-CVAD followed by 4 cycles of blinatumomab; but after 2 patients with high-risk features experienced early relapse prior to blinatumomab exposure, the trial protocol was amended so that those patients could receive the agent after just 2 chemotherapy cycles. Patients who were considered high risk included those with persistent MRD positivity, a TP53 mutation, and complex karyotype among others. Ofatumumab or rituximab (Rituxan) was given to all patients with CD20-positive disease. Maintenance therapy included alternating cycles of blinatumomab and POMP, defined as daily mercaptopurine, monthly vincristine, weekly methotrexate, and monthly pulses of prednisone.
“Hyper-CVAD with sequential blinatumomab was highly effective with an overall MRD-negatively rate of 97% and a 2-year overall survival rate of 80%,” concluded Short. “Notable, no relapses have occurred in patients without a high-risk disease feature nor in any patients beyond 2 years from the start of therapy suggesting long-term durability of these responses.”
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. Blood. 2020;136(suppl 1):9-11. Abstract 464. doi: 10.1182/blood-2020-138565