Blinatumomab for Acute Lymphoblastic Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation.

Patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) following allogeneic hematopoietic stem cell transplantation (alloHSCT) have a poor prognosis, and alternative therapies are needed for this patient population. Blinatumomab, a bispecific T cell engager immunotherapy, was evaluated in an open-label, single-arm, phase II study of adults with R/R Philadelphia chromosome-negative B cell precursor ALL and resulted in a rate of complete remission (CR) or CR with partial hematologic recovery of peripheral blood counts (CRh) of 43% within 2 treatment cycles. We conducted an exploratory analysis to determine the efficacy and safety of blinatumomab in 64 patients who had relapsed following alloHSCT before enrollment in the phase II study. Forty-five percent of the patients (29 of 64) achieved a CR/CRh within the first 2 cycles of treatment, 22 of whom had a minimal residual disease (MRD) response (including 19 with a complete MRD response). After 1 year and 3 years of follow-up, the median relapse-free survival was 7.4 months for patients who achieved CR/CRh in the first 2 cycles, and the median overall survival was 8.5 months; overall survival rate (Kaplan-Meier estimate) was 36% at 1 year and 18% at 3 years. Grade 3 and 4 adverse events were reported in 20 patients (31%) and 28 patients (44%), respectively, with grade 3 and 4 neurologic events in 8 and 2 patients, respectively, and grade 3 cytokine release syndrome in 2 patients. Eight patients had fatal adverse events, including 5 due to infections. Seven patients had grade ≤ 3 graft-versus-host disease during the study, none of which resulted in the discontinuation of blinatumomab or hospitalization. Our data suggest that blinatumomab is an effective salvage therapy in this patient population.

Inotuzumab: from preclinical development to success in B-cell acute lymphoblastic leukemia.

Inotuzumab ozogamicin (InO) is a recently US Food and Drug Administration-approved antibody-drug conjugate for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). InO consists of a CD22-targeting immunoglobulin G4 humanized monoclonal antibody conjugated to calicheamicin. Although initially developed for the treatment of non-Hodgkin lymphoma (NHL) because of activity in preclinical models and high response rates in indolent lymphomas, a phase 3 trial was negative and further development focused on CD22+ ALL. Although results in NHL were disappointing, parallel testing in early-phase trials of CD22+ ALL demonstrated feasibility and efficacy. Subsequently, the randomized phase 3 Study Of Inotuzumab Ozogamicin Versus Investigator's Choice Of Chemotherapy In Patients With Relapsed Or Refractory Acute Lymphoblastic Leukemia trial showed that InO was superior to standard of care regimens with a significantly improved complete remission (CR) rate in patients with relapsed/refractory disease (80.7% vs 29.4%, P < .001). Patients achieving CR with InO also had a significantly higher rate of undetectable minimal residual disease compared with chemotherapy (78.4% vs 28.1%, P < .001). InO-specific side effects, including veno-occlusive disease, have been an ongoing area of concern, and consensus guidelines for minimizing toxicities are now available. Ongoing trials are investigating the combination of InO with other agents in the relapse setting and the addition of InO to frontline therapy. This review details the preclinical and clinical development of InO, focusing on how best to use it and future directions for further development.

Cost comparison by treatment arm and center-level variations in cost and inpatient days on the phase III high-risk B acute lymphoblastic leukemia trial AALL0232.

The Children's Oncology Group (COG) develops and implements multi-institutional clinical trials with the primary goal of assessing the efficacy and safety profile of treatment regimens for various pediatric cancers. However, the monetary costs of treatment regimens are not measured. AALL0232 was a COG randomized phase III trial for children with acute lymphoblastic leukemia that found that dexamethasone (DEX) was a more effective glucocorticoid than prednisone (PRED) in patients younger than 10 years, but PRED was equally effective and less toxic in older patients. In addition, high-dose methotrexate (HD-MTX) led to better survival than escalating doses of methotrexate (C-MTX). Cost data from the Pediatric Health Information System database were merged with clinical data from the COG AALL0232 trial. Total and component costs were compared between treatment arms and across hospitals. Inpatient costs were higher in the HD-MTX and DEX arms when compared to the C-MTX and PRED arms at the end of therapy. There was no difference in cost between these arms at last follow-up. Considerable variation in total costs existed across centers to deliver the same therapy that was driven by differences in inpatient days and pharmacy costs. The more effective regimens were found to be more expensive during therapy but were ultimately cost-neutral in longer term follow-up. The variations in cost across centers suggest an opportunity to standardize resource utilization for patients receiving similar therapies, which could translate into reduced healthcare expenditures.

Inotuzumab ozogamicin in relapsed B-cell acute lymphoblastic leukemia.

Despite an improved understanding of disease biology and the use of multi-agent chemotherapy, the long-term survival of adults with B-cell acute lymphoblastic leukemia (B-ALL) ranges from 35% to 50%. Management of patients with relapsed B-ALL, a group characterized by dismal outcomes, poses a clinical challenge. To address this unmet need, novel therapeutics are being investigated in the setting of relapsed B-ALL with encouraging results. CD22 is an important B-cell antigen expressed in 80-90% of B-ALL cases. CD22 undergoes constitutive endocytosis with antibody ligation, making it an attractive biologic target for immunoconjugates. Inotuzumab ozogamicin (IO), a CD22-targeted antibody-drug conjugate demonstrated impressive single agent activity even among heavily pretreated relapsed B-ALL patients. A recent randomized phase III clinical trial demonstrates superiority of IO over standard of care chemotherapy as first- or second-line salvage therapy for relapsed B-ALL. In this review, we summarize the preclinical and clinical data available to date using IO in relapsed B-ALL.

Blinatumomab for the Treatment of Philadelphia Chromosome-Negative, Precursor B-cell Acute Lymphoblastic Leukemia.

Blinatumomab is a CD19/CD3 bispescific antibody designed to redirect T cells toward malignant B cells and induce their lysis. It recently gained accelerated approval by the FDA for the treatment of relapsed or refractory Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (RR-ALL). In the phase II trial that served as the basis for approval, blinatumomab demonstrated significant single-agent activity and induced remission [complete remission (CR) and CR with incomplete recovery of peripheral blood counts (CRh)] in 43% of 189 adult patients with RR-ALL; the majority of responders (82%) also attained negative minimal residual disease (MRD(-)) status that did not generally translate into long-term remissions in most cases. Additional studies show that blinatumomab can induce high response rates associated with lasting remissions in patients in first remission treated for MRD positivity, suggesting a role for blinatumomab in the upfront, MRD-positive setting. Blinatumomab infusion follows a predictable immunopharmacologic profile, including early cytokine release that can be associated with a clinical syndrome, T-cell expansion, and B-cell depletion. Neurologic toxicities represent a unique toxicity that shares similarities with adverse effects of other T-cell engaging therapies. Further studies are needed to clarify the optimal disease setting and timing for blinatumomab therapy. Additional insights into the pathogenesis, risk factors, and prevention of neurologic toxicities as well as a better understanding of the clinical consequences and biologic pathways that are associated with drug resistance are needed.

Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children's Oncology Group study AALL0232.

Minimal residual disease (MRD) is highly prognostic in pediatric B-precursor acute lymphoblastic leukemia (B-ALL). In Children's Oncology Group high-risk B-ALL study AALL0232, we investigated MRD in subjects randomized in a 2 × 2 factorial design to receive either high-dose methotrexate (HD-MTX) or Capizzi methotrexate (C-MTX) during interim maintenance (IM) or prednisone or dexamethasone during induction. Subjects with end-induction MRD ≥0.1% or those with morphologic slow early response were nonrandomly assigned to receive a second IM and delayed intensification phase. MRD was measured by 6-color flow cytometry in 1 of 2 reference labs, with excellent agreement between the two. Subjects with end-induction MRD <0.01% had a 5-year event-free survival (EFS) of 87% ± 1% vs 74% ± 4% for those with MRD 0.01% to 0.1%; increasing MRD amounts was associated with progressively worse outcome. Subjects converting from MRD positive to negative by end consolidation had a relatively favorable 79% ± 5% 5-year disease-free survival vs 39% ± 7% for those with MRD ≥0.01%. Although HD-MTX was superior to C-MTX, MRD retained prognostic significance in both groups (86% ± 2% vs 58% ± 4% for MRD-negative vs positive C-MTX subjects; 88% ± 2% vs 68% ± 4% for HD-MTX subjects). Intensified therapy given to subjects with MRD >0.1% did not improve either 5-year EFS or overall survival (OS). However, these subjects showed an early relapse rate similar to that seen in MRD-negative ones, with EFS/OS curves for patients with 0.1% to 1% MRD crossing those with 0.01% to 0.1% MRD at 3 and 4 years, thus suggesting that the intensified therapy altered the disease course of MRD-positive subjects. Additional interventions targeted at the MRD-positive group may further improve outcome. This trial was registered at www.clinicaltrials.gov as #NCT00075725.

Treatment of relapsed precursor-B acute lymphoblastic leukemia with intensive chemotherapy: POG (Pediatric Oncology Group) study 9411 (SIMAL 9).

Pediatric patients who experience a bone marrow relapse of precursor-B acute lymphoblastic leukemia are cured <50% of the time. This study was designed to determine if intensification of therapies with known activity in this disease would improve the cure rates for patients with relapsed acute lymphoblastic leukemia. Patients were treated with intensive asparaginase during induction followed by repeated cycles of ifosfamide/etoposide and cytarabine/idarubicin. Patients with well-matched related donors were encouraged to undergo hematopoietic stem cell transplant as consolidation. The results of this study demonstrate no significant difference in disease-free survival in patients who received chemotherapy alone (45%) or chemotherapy followed by allogeneic stem cell transplant (50%). Furthermore, results from this study show no significant difference in event-free survival (39.9%±6.2%) or overall survival (41.6%±6.1%) at 8 years when compared with previous studies using less intensive regimens. Our results suggest that alternative therapies are needed to improve cure rates for pediatric patients with relapsed leukemia.

Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia.

CRLF2 rearrangements, JAK1/2 point mutations, and JAK2 fusion genes have been identified in Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL), a recently described subtype of pediatric high-risk B-precursor ALL (B-ALL) which exhibits a gene expression profile similar to Ph-positive ALL and has a poor prognosis. Hyperactive JAK/STAT and PI3K/mammalian target of rapamycin (mTOR) signaling is common in this high-risk subset. We, therefore, investigated the efficacy of the JAK inhibitor ruxolitinib and the mTOR inhibitor rapamycin in xenograft models of 8 pediatric B-ALL cases with and without CRLF2 and JAK genomic lesions. Ruxolitinib treatment yielded significantly lower peripheral blast counts compared with vehicle (P < .05) in 6 of 8 human leukemia xenografts and lower splenic blast counts (P < .05) in 8 of 8 samples. Enhanced responses to ruxolitinib were observed in samples harboring JAK-activating lesions and higher levels of STAT5 phosphorylation. Rapamycin controlled leukemia burden in all 8 B-ALL samples. Survival analysis of 2 representative B-ALL xenografts demonstrated prolonged survival with rapamycin treatment compared with vehicle (P < .01). These data demonstrate preclinical in vivo efficacy of ruxolitinib and rapamycin in this high-risk B-ALL subtype, for which novel treatments are urgently needed, and highlight the therapeutic potential of targeted kinase inhibition in Ph-like ALL.