Description and prognostic significance of the kinetics of minimal residual disease status in adults with acute lymphoblastic leukemia treated with HyperCVAD

Abstract

HyperCVAD is a commonly-used regimen for adults with newly-diagnosed acute lymphoblastic leukemia (ALL). However, relatively little is known about the application of minimal residual disease (MRD) detection with this treatment. To address this, we studied 142 adults with ALL treated with hyperCVAD over a 10-year period who had MRD assessed by either multi-parameter flow cytometry or (for patients with Philadelphia chromosome positive ALL) reverse transcriptase polymerase chain reaction for the BCR-ABL1 translocation. In a multivariate analysis, patients who achieved MRD negativity (MRD ) at any point had significantly better overall survival (OS; hazard ratio [HR] 0.43; P = .01) and event-free survival (EFS; HR 0.27; P < .01). Of 121 patients with MRD assessed at various points within 90 days of starting hyperCVAD, 50% (n = 61) had achieved MRD . Among those that became MRD , the median time to MRD was 68 days. Time to MRD was significantly associated with EFS (P = .009), but not OS (P = .19), implying increasingly better EFS the earlier MRD is achieved. These data add to our understanding of MRD assessment during treatment with hyperCVAD, aide clinicians with predicting relapse risk, and provide additional historical data on which future clinical trials can be designed.

Acute lymphoblastic leukemia: A population‐based study of outcome in the United States based on the surveillance, epidemiology, and end results (SEER) database, 1980–2017

“…The addition of CD20 antibodies (rituximab, ofatumumab) to chemotherapy started in 2000, but was established as a standard of care in adult patients with ALL since 2017. [11][12][13][14][42][43][44] The use of inotuzumab and blinatumomab in frontline chemotherapy regimen is too recent to influence the SEER data results. 36,37,45 The estimated survival of 73% in Ph-negative ALL could soon be significantly improved with the addition of CD20, CD19, and CD22 antibodies to the chemotherapy in adult (age 30-46 years) 45 and older ALL (age 60 + years).…”

“…This improvement was markedly observed in older patients 60+ years (5‐year OS rates of 20% and 33% in Ph‐negative and in Ph‐positive ALL, respectively) ( p = .015). The addition of CD20 antibodies (rituximab, ofatumumab) to chemotherapy started in 2000, but was established as a standard of care in adult patients with ALL since 2017 11‐14,42‐44 . The use of inotuzumab and blinatumomab in frontline chemotherapy regimen is too recent to influence the SEER data results 36,37,45 .…”

Phase I study of escalating doses of carfilzomib with HyperCVAD in patients with newly diagnosed acute lymphoblastic leukemia

“…HyperCVAD regimen appeared particularly effective for the B-ALL subpopulation with 88% of patients achieving MRD negativity, which compares favorably with HyperCVAD historical controls, 2,3 with an MRD negativity rate of 53% in Ph-negative B-ALL after 90 days in patients treated with HyperCVAD alone 2. Furthermore, 70% of the…”

“…Hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (HyperCVAD) is a multi-agent and multi-course high-intensity chemotherapy regimen that results in high complete remission (CR) rates, long-term survival in 30-40%, 1 and measurable/minimal residual disease (MRD) negativity in 50-60% adults with ALL. 2,3 As an established backbone regimen for ALL treatment, the HyperCVAD regimen has evolved to incorporate recent advances in anti-ALL therapy, and new agents continue to be tested in combination with the HyperCVAD backbone in efforts to improve outcomes. 4,5 Bortezomib, a first-generation proteasome inhibitor, has demonstrated synergism with chemotherapy, including cyclophosphamide, vincristine, cytarabine, rituximab, 6,7 and as an inhibitor of NF-κB, is hypothesized to act that results in accumulation of pro-apoptotic proteins that could sensitize ALL cells to dexamethasone and doxorubicin.…”

“…Fetal hemoglobin (HbF, α 2 γ 2 ) inhibits deoxyHbS polymerization. It is the major modulator of sickle cell disease severity 2. AI haplotype sickle cell anemia was initially believed to be a "mild" form of disease that was attributed to patients' high levels of HbF.…”