CRLF2 rearrangement in Ph-like acute lymphoblastic leukemia predicts relative glucocorticoid resistance that is overcome with MEK or Akt inhibition.

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a genetically heterogeneous subtype of B-cell ALL characterized by chromosomal rearrangements and mutations that result in aberrant cytokine receptor and kinase signaling. In particular, chromosomal rearrangements resulting in the overexpression of cytokine receptor-like factor 2 (CRLF2) occur in 50% of Ph-like ALL cases. CRLF2 overexpression is associated with particularly poor clinical outcomes, though the molecular basis for this is currently unknown. Glucocorticoids (GCs) are integral to the treatment of ALL and GC resistance at diagnosis is an important negative prognostic factor. Given the importance of GCs in ALL therapy and the poor outcomes for patients with CRLF2 overexpression, we hypothesized that the aberrant signal transduction associated with CRLF2 overexpression might mediate intrinsic GC insensitivity. To test this hypothesis, we exposed Ph-like ALL cells from patient-derived xenografts to GCs and found that CRLF2 rearranged (CRLF2R) leukemias uniformly demonstrated reduced GC sensitivity in vitro. Furthermore, targeted inhibition of signal transduction with the MEK inhibitor trametinib and the Akt inhibitor MK2206, but not the JAK inhibitor ruxolitinib, was sufficient to augment GC sensitivity. These data suggest that suboptimal GC responses may in part underlie the poor clinical outcomes for patients with CRLF2 overexpression and provide rationale for combination therapy involving GCs and signal transduction inhibitors as a means of enhancing GC efficacy

JAK/STAT pathway inhibition overcomes IL7-induced glucocorticoid resistance in a subset of human T-cell acute lymphoblastic leukemias

While outcomes for children with T-cell acute lymphoblastic leukemia (T-ALL) have improved dramatically, survival rates for patients with relapsed/refractory disease remain dismal. Prior studies indicate that glucocorticoid (GC) resistance is more common than resistance to other chemotherapies at relapse. In addition, failure to clear peripheral blasts during a prednisone prophase correlates with an elevated risk of relapse in newly diagnosed patients. Here we show that intrinsic GC resistance is present at diagnosis in early thymic precursor (ETP) T-ALLs as well as in a subset of non-ETP T-ALLs. GC-resistant non-ETP T-ALLs are characterized by strong induction of JAK/STAT signaling in response to interleukin-7 (IL7) stimulation. Removing IL7 or inhibiting JAK/STAT signaling sensitizes these T-ALLs, and a subset of ETP T-ALLs, to GCs. The combination of the GC dexamethasone and the JAK1/2 inhibitor ruxolitinib altered the balance between pro- and anti-apoptotic factors in samples with IL7-dependent GC resistance, but not in samples with IL7-independent GC resistance. Together, these data suggest that the addition of ruxolitinib or other inhibitors of IL7 receptor/JAK/STAT signaling may enhance the efficacy of GCs in a biologically defined subset of T-ALL

Three-year results from phase I of ZUMA-4: KTE-X19 in pediatric relapsed/refractory acute lymphoblastic leukemia

Here we present the 3-year results of ZUMA-4, a phase I/II multicenter study evaluating the safety and efficacy of KTEX19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in pediatric/adolescent patients with relapsed/refractory B-cell acute lymphoblastic leukemia. Phase I explored two dose levels and formulations. The primary endpoint was the incidence of dose-limiting toxicities. Thirty-one patients were enrolled; KTE-X19 was administered to 24 patients (median age 13.5 years, range 3-20; median follow-up 36.1 months). No dose-limiting toxicities were observed. All treated patients had grade ≥3 adverse events, commonly hypotension (50%) and anemia (42%). Grade 3 cytokine release syndrome rates were 33% in all treated patients, 75% in patients given the dose of 2×106 CAR T cells/kg, 27% in patients given the dose of 1×106 cells/kg in the 68 mL formulation, and 22% in patients given the dose of 1×106 cells/kg in the 40 mL formulation; the percentages of patients experiencing grade ≥3 neurologic events were 21%, 25%, 27%, and 11% respectively. Overall complete remission rates (including complete remission with incomplete hematologic recovery) were 67% in all treated patients, 75% in patients given 2×106 CAR T cells/kg, 64% in patients given 1×106 cells/kg in the 68 mL formulation, and 67% in patients given 1×106 cells/kg in the 40 mL formulation. Overall minimal residual diseasenegativity rates were 100% among responders; 88% of responders underwent subsequent allogeneic stem-cell transplantation. In the 1×106 (40 mL) group (recommended phase II dose), the median duration of remission censored at allogeneic stem-cell transplantation and median overall survival were not reached. Pediatric/adolescent patients with relapsed/refractory B-cell acute lymphoblastic leukemia achieved high minimal residual disease-negative remission rates with a manageable safety profile after a single dose of KTE-X19. Phase II of the study is ongoing at the dose of 1×106 CAR T cells/kg in the 40 mL formulation. ClinicalTrials.gov: NCT02625480

The bone marrow microenvironment as a mediator of chemoresistance in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a malignancy of immature lymphoid cells that arises due to clonal expansion of cells that undergo developmental arrest and acquisition of pathogenic mutations. With the introduction of intensive multi-agent chemotherapeutic regimens, survival rates for ALL have improved dramatically over the past several decades, though survival rates for adult ALL continue to lag behind those of pediatric ALL. Resistance to chemotherapy remains a significant obstacle in the treatment of ALL, and chemoresistance due to molecular alterations within ALL cells have been described. In addition to these cell-intrinsic factors, the bone marrow microenvironment has more recently been appreciated as a cell-extrinsic mediator of chemoresistance, and it is now known that stromal cells within the bone marrow microenvironment, through direct cell-cell interactions and through the release of lymphoid-acting soluble factors, contribute to ALL pathogenesis and chemoresistance. This review discusses mechanisms of chemoresistance mediated by factors within the bone marrow microenvironment and highlights novel therapeutic strategies that have been investigated to overcome chemoresistance in this context

The epigenome in pediatric acute lymphoblastic leukemia: drug resistance and therapeutic opportunities.

Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. The genomic landscape of pediatric ALL has been extensively characterized, allowing for the identification of distinct molecular subtypes of this disease. This in turn has facilitated improvements in risk stratification and tailoring of therapy, resulting in dramatic improvements in survival rates over the past several decades. However, despite these improvements, outcomes remain dismal for the ten percent of patients who continue to fail therapy and relapse. Although the genetic landscape of pediatric ALL is well-understood, increasing evidence suggests that genetic alterations alone are insufficient to promote leukemogenesis and the acquisition of chemoresistance that leads to disease relapse. Instead, cooperating epigenetic alterations are now recognized as important contributors to the aberrant gene expression profiles that are characteristic of the molecular subtypes of ALL, and changes in the epigenetic landscape are now thought to underlie the development of chemoresistance and ultimately disease relapse. This review article focuses on the expanding knowledge of the role of the epigenome in ALL pathogenesis, progression, and response to therapy, and highlights preclinical and clinical efforts to target the epigenome as a means of overcoming chemoresistance and improving outcomes for children with ALL

The epigenome in pediatric acute lymphoblastic leukemia: drug resistance and therapeutic opportunities

Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. The genomic landscape of pediatric ALL has been extensively characterized, allowing for the identification of distinct molecular subtypes of this disease. This in turn has facilitated improvements in risk stratification and tailoring of therapy, resulting in dramatic improvements in survival rates over the past several decades. However, despite these improvements, outcomes remain dismal for the ten percent of patients who continue to fail therapy and relapse. Although the genetic landscape of pediatric ALL is well-understood, increasing evidence suggests that genetic alterations alone are insufficient to promote leukemogenesis and the acquisition of chemoresistance that leads to disease relapse. Instead, cooperating epigenetic alterations are now recognized as important contributors to the aberrant gene expression profiles that are characteristic of the molecular subtypes of ALL, and changes in the epigenetic landscape are now thought to underlie the development of chemoresistance and ultimately disease relapse. This review article focuses on the expanding knowledge of the role of the epigenome in ALL pathogenesis, progression, and response to therapy, and highlights preclinical and clinical efforts to target the epigenome as a means of overcoming chemoresistance and improving outcomes for children with ALL

The bone marrow microenvironment as a mediator of chemoresistance in acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is a malignancy of immature lymphoid cells that arises due to clonal expansion of cells that undergo developmental arrest and acquisition of pathogenic mutations. With the introduction of intensive multi-agent chemotherapeutic regimens, survival rates for ALL have improved dramatically over the past several decades, though survival rates for adult ALL continue to lag behind those of pediatric ALL. Resistance to chemotherapy remains a significant obstacle in the treatment of ALL, and chemoresistance due to molecular alterations within ALL cells have been described. In addition to these cell-intrinsic factors, the bone marrow microenvironment has more recently been appreciated as a cell-extrinsic mediator of chemoresistance, and it is now known that stromal cells within the bone marrow microenvironment, through direct cell-cell interactions and through the release of lymphoid-acting soluble factors, contribute to ALL pathogenesis and chemoresistance. This review discusses mechanisms of chemoresistance mediated by factors within the bone marrow microenvironment and highlights novel therapeutic strategies that have been investigated to overcome chemoresistance in this context

CD45, CD148, and Lyp/Pep: critical phosphatases regulating Src family kinase signaling networks in immune cells

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