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PI3-Kinase Inhibitors in Chronic Lymphocytic Leukemia

  • Chronic Leukemias (S O'Brien, Section Editor)
  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway is being explored as a target of inhibition for B-cell lymphoproliferative disorders, with agents specific for inhibition of the PI3K-δ subunit showing significant clinical activity in chronic lymphocytic leukemia (CLL). Idelalisib (CAL-101, GS-1101) and IPI-145 (INK-1147) are novel oral PI3K-δ inhibitors in development, with rates of objective response of 40-60 % and nodal responses exceeding 70 % in relapsed and refractory CLL. High rates of response have been seen in high-risk CLL (i.e., 17p and 11q deletions), and may allow for more effective therapy in inherently chemotherapy-resistant disease. Combination chemotherapy regimens with idelalisib have similarly demonstrated favorable tolerability and activity. Like other agents that target the B-cell receptor pathway, peripheral lymphocytosis, due to drug-induced changes in lymphocyte trafficking, is common. Noteworthy toxicities include transaminitis and pneumonia/pneumonitis. Multiple studies are evaluating PI3K-δ inhibitor combination regimens, and the rationale for these ongoing and planned studies is reviewed.

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Abbreviations

CLL:

Chronic lymphocytic leukemia

CR:

Complete response

DLT:

Dose limiting toxicity

DOR:

Duration of response

IB:

Idelalisib + bendamustine

IBR:

Idelalisib + bendamustine + rituximab

IR:

Idelalisib + rituximab

IWG:

International Working Group

NHL:

Non-Hodgkin lymphoma

ORR:

Overall response rate

OS:

Overall survival

PFS:

Progression-free survival

PI3K:

Phosphatidylinositol 3-kinase

PR:

Partial response

R/R:

Relapsed and refractory

SLL:

Small lymphocytic lymphoma

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Conflict of Interest

Julie E. Chang has received research support from Celgene and Genentech.

Brad S. Kahl has received research support from and served as a consultant for Genentech/Roche, Millennium, Infinity, and Gilead.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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  1. University of Wisconsin School of Medicine and Public Health, 1111 Highland Ave., 4007 Wisconsin Institute for Medical Research, Madison, WI, 53705, USA

    Julie E. Chang

  2. University of Wisconsin School of Medicine and Public Health, 1111 Highland Ave., 4059 Wisconsin Institute for Medical Research, Madison, WI, 53705, USA

    Brad S. Kahl

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Correspondence to Julie E. Chang.

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Chang, J.E., Kahl, B.S. PI3-Kinase Inhibitors in Chronic Lymphocytic Leukemia. Curr Hematol Malig Rep 9, 33–43 (2014). https://doi.org/10.1007/s11899-013-0189-7

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