Diagnosis and Management of Philadelphia-Like Acute Lymphoblastic Leukemia in Adults.

A Multicenter Analysis of Allogeneic Transplant Outcomes in Patients with Philadelphia-like (Ph-like) Acute Lymphoblastic Leukemia (ALL)

Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults

Purpose Philadelphia chromosome (Ph) -like acute lymphoblastic leukemia (ALL) is a high-risk subtype of childhood ALL characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. We sought to define the prevalence and genomic landscape of Ph-like ALL in adults and assess response to conventional chemotherapy. Patients and Methods The frequency of Ph-like ALL was assessed by gene expression profiling of 798 patients with B-cell ALL age 21 to 86 years. Event-free survival and overall survival were determined for Ph-like ALL versus non-Ph-like ALL patients. Detailed genomic analysis was performed on 180 of 194 patients with Ph-like ALL. Results Patients with Ph-like ALL accounted for more than 20% of adults with ALL, including 27.9% of young adults (age 21 to 39 years), 20.4% of adults (age 40 to 59 years), and 24.0% of older adults (age 60 to 86 years). Overall, patients with Ph-like ALL had an inferior 5-year event-free survival compared with patients with non-Ph-like ALL (22.5% [95% CI, 14.9% to 29.3%; n = 155] v 49.3% [95% CI, 42.8% to 56.2%; n = 247], respectively; P < .001). We identified kinase-activating alterations in 88% of patients with Ph-like ALL, including CRLF2 rearrangements (51%), ABL class fusions (9.8%), JAK2 or EPOR rearrangements (12.4%), other JAK-STAT sequence mutations (7.2%), other kinase alterations (4.1%), and Ras pathway mutations (3.6%). Eleven new kinase rearrangements were identified, including four involving new kinase or cytokine receptor genes and seven involving new partners for previously identified genes. Conclusion Ph-like ALL is a highly prevalent subtype of ALL in adults and is associated with poor outcome. The diverse range of kinase-activating alterations in Ph-like ALL has important therapeutic implications. Trials comparing the addition of tyrosine kinase inhibitors to conventional therapy are required to evaluate the clinical utility of these agents in the treatment of Ph-like ALL.

GATA3 rs3824662A allele in B-cell acute lymphoblastic leukemia in adults, adolescents and young adults: association with CRLF2 rearrangement and poor prognosis.

High-Risk Subtype of Ph-like Acute Lymphoblastic Leukemia (ALL) in Adults: Dismal Outcomes of CRLF2+ ALL Patients Treated with Intensive Chemotherapy

BCR-ABL1-like Acute Lymphoblastic Leukemia Is Associated with IKZF1 and JAK2 Alterations and inferior Outcome in Adults

The Role of Cytotoxic Therapy with Hematopoietic Stem Cell Transplantation in the Treatment of Adult Acute Lymphoblastic Leukemia: Update of the 2006 Evidence-Based Review

Acute Lymphoblastic Leukemia

Despite the success of current therapies for pediatric acute lymphoblastic leukemia (ALL) more effective treatments are required for the management of high-risk subtypes. Ph-like ALL is a high-risk subtype defined by a gene expression signature similar to that of BCR-ABL1-positive ALL despite the absence of the BCR-ABL1 translocation. Approximately 50% of Ph-like pediatric ALLs harbor mutations in Janus kinases (JAKs). Birinapant is a small molecule SMAC (second mitochondria-derived activator of caspase) mimetic that potently and specifically antagonizes inhibitors of apoptosis proteins (IAPs), resulting in IAP degradation, inactivation of NF-κB survival signaling and tumor necrosis factor (TNF)-dependent apoptosis. The combination of birinapant plus azacitidine is being evaluated in a Phase 2 clinical trial for the treatment of high-risk myeloid dysplastic syndrome. The aim of this study was to evaluate the efficacy of birinapant against patient-derived xenografts (PDXs) of pediatric ALL subtypes. Birinapant (30 mg/kg IP Q3 days × 5) significantly delayed the progression of 17/19 PDXs derived from Ph-like ALL (n = 7), B-cell precursor ALL (BCP-ALL, n = 8), and infant MLL¬-rearranged ALL (MLL-ALL, n = 4) by between 2 and 80 days compared with vehicle-treated controls. Using stringent objective response criteria modeled after the clinical setting, birinapant induced objective responses in 12/19 PDXs, including 7/7 Ph-like ALL (5 complete responses, CRs; 2 maintained CRs, MCRs), which was significantly better than BCP-ALL (4/8; 2 partial responses, PRs; 1 CR; 1 MCR) or infant MLL-ALL (1/4; 1 CR) PDXs (P&amp;lt;0.05). Birinapant induced a CR in a Ph-like PDX at a dose 1/8th (3.8 mg/kg) of its maximum tolerated dose (30 mg/kg). Analysis at 14 days following treatment initiation revealed &amp;gt;98% clearance of human leukemia cells from the bone marrow, spleen and peripheral blood of mice treated with birinapant doses that achieve drug levels attainable in humans. In vitro apoptosis assays confirmed the greater sensitivity of the Ph-like ALL PDX panel. Moreover, the cIAP1 protein was rapidly degraded in PDXs upon birinapant treatment both in vitro and in vivo, regardless of their relative sensitivity. Microarray analysis of gene expression revealed a significant correlation between baseline TNFα expression and in vivo birinapant sensitivity across 19 PDXs (P = 0.002; R2 = 0.46). While exogenously-added TNFα did not potentiate apoptosis induced by birinapant, a TNFα blocking antibody partially reversed apoptosis in 3/4 Ph-like PDXs. These results show that birinapant exerts profound single-agent in vivo efficacy against Ph-like pediatric ALL PDXs, indicate a role for endogenous TNFα in the birinapant mechanism of action against this high-risk pediatric ALL subtype, and support further evaluation of birinapant in the treatment of Ph-like ALL. Supported by NCI NO1CM42216. Citation Format: Jennifer Richmond, Kathryn Evans, Alissa Robbins, Raushan T. Kurmasheva, Peter J. Houghton, Malcolm A. Smith, Richard B. Lock. In vivo and in vitro efficacy of birinapant in preclinical models of Ph-like pediatric acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1620. doi:10.1158/1538-7445.AM2015-1620

Early Achievement of Deep Measurable Residual Disease (MRD) Negativity Identifies Patients with B-Cell Acute Lymphoblastic Leukemia (ALL) Who Have Excellent Long-Term Outcomes and Do Not Benefit from Allogeneic Stem Cell Transplant, Irrespective of Baseline High-Risk Cytomolecular Features

Adults with Philadelphia Chromosome–Like Acute Lymphoblastic Leukemia: Considerations for Allogeneic Hematopoietic Cell Transplantation in First Complete Remission

Clinical, Cytogenetic and Immunophenotype Distribution of Adult Acute Lymphoblastic Leukemia Among Latinos — a Report from a Large Single Institution Cohort in Southern California

Have any strategies in Ph-like ALL been shown to be effective?

Novel Targets Identified By in Vitro Screening of Patient Samples with Adult Acute Lymphoblastic Leukemia

“Dose-Dense” Mini-Hyper-CVD, Inotuzumab Ozogamicin and Blinatumomab Achieves High Rates of Rapid MRD-Negativity in Patients with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia: A Retrospective Analysis