Novel targeted therapies hold the most promise for improving outcomes for patients with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). This is the conclusion published in two reports by Decision Resources. Key Opinion Leaders (KOL) and medical experts interviewed for these reports are enthusiastic about the potential of blinatumomab (Amgen/MicroMet), a first-in-class bispecific T-cell engager.

In phase II trial results published in 2012 and presented during that year’s Annual Meeting of the American Society of Clinical Oncology (ASCO) [1], treatment with blinatumomab (AMG 103) helped achieve a high-rate of complete response (CR) in 72% of adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL) treated in the study. Blinatumomab is the first of a new class of agents called bi-specific T cell engagers (BiTE?) antibodies, designed to harness the body’s cell-destroying T cells to kill cancer cells. Blinatumomab targets cells expressing CD19, a protein found on the surface of B-cell derived leukemias and lymphomas, such as ALL.

In this Phase II single-arm dose-ranging trial, 26 of the 36 patients treated with blinatumomab across all of the tested doses and schedules achieved a CR or complete response with partial hematologic recovery (CRh). All but two patients achieved a molecular response, meaning there was no evidence of leukemic cells by polymerase chain reaction.

Quizartinib: unprecedented activity
In the published reports, experts also highlighted the potential of quizartinib (AC220) in AML.Quizartinib (Ambit Biosciences/Astellas Pharma) is the first therapeutic agent targeting patients with mutations in FLT3, aspecific sub-population of approximately 34% of all patients with AML.

AML associated with an internal tandem duplication (ITD) of theFLT3 gene (FLT3-ITD mutation) has an inferior outcome that is attributed to a higher relapse rate and is associated with a more aggressive disease that is resistant to standard chemotherapy. [2][3]

“AML is amongst the most challenging hematological malignancies to treat, and patients with activating FLT3 mutations have a particularly poor prognosis and often relapse or are refractory to current treatment options,” said Jorge Cortes, M.D., Internist and Professor, Deputy Chair, Department of Leukemia, Division of Cancer Medicine, TheUniversity of Texas M.D. Anderson Cancer Center,Houston, Texas. “The findings from the Phase II ACE study with quizartinib in patients with relapsed and refractory AML are especially encouraging. In the patients with the FLT3-ITD mutation, quizartinib represents the most active single-agent we have observed with any class of investigational drugs in this challenging patient population. We look forward to further investigation of quizartinib in the expanding clinical program which includes multiple treatment strategies and subpopulations of AML patients”.

Research has shown that the oncogenic role of FLT3 mutants has been attributed to the abnormal activation of several downstream signaling pathways, such as STAT3, STAT5, ERK1/2, and AKT.

In addition to the clinical benefit observed in FLT3-ITD positive patients, there was substantial evidence of activity in FLT3-ITD negative patients, with approximately one-in-three of these patients achieving a Complete Response (CRc) and a comparable percentage receiving hematopoietic stem celltransplant (HSCT) as in the FLT3-ITD positive group.Based on these results, researchers anticipate that clinical benefit in relapsed/refractory patients that do not harbor mutations in FLT3 also suggests that uptake of the drug in a wider population is warranted.

Promising pipeline
“The late-stage acute leukemia pipeline has shown a lot of promise lately, and KOL/experts are excited at the prospect of having more targeted therapies available to add to traditional chemotherapy options,” Joanne Graham, Ph.D, a therapy leader working for Decision Resourcesnoted. “New formulations of existing chemotherapies will also play a role in the late-stage pipeline. Despite the promise of novel targeted drugs, there is no doubt that the future treatment of acute leukemia will continue to rely heavily on chemotherapies.”

The reports also show that, despite the launch of several new agents throughout the forecast period, there are still high levels of unmet need in acute leukemia, especially for treatments that provide improved efficacy outcomes for, and are less toxic to, older patients, as well as treatments tailored towards currently underserved populations, such as T-cell leukemia.

“Acute lymphoblastic leukemia is the most commonly diagnosed cancer in children but only accounts for a minority of adult leukemias,” Graham said. “The prognosis for adult patients is discouraging, with an overall adult survival rate of approximately 40%, compared with 80% in children. As this demographic grows, so does the need for treatments directed at older and adult patients whose disease is often more aggressive.”

References:

[1]Topp M, Goekbuget N, Zugmaier G, Viardot A, Stelljes M, Neumann S, Horst HA, et al. Effect of anti-CD19 BiTE blinatumomab on complete remission rate and overall survival in adult patients with relapsed/refractory B-precursor ALL. J Clin Oncol 30, 2012 (suppl; abstr 6500^)
[2]Kottaridis PD, Gale RE, Frew ME, et al.: The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 98 (6): 1752-9, 2001.[PubMed Abstract]
[3] Yanada M, Matsuo K, Suzuki T, et al.: Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia 19 (8): 1345-9, 2005.[PubMed Abstract]

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