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Segunda-feira, 27.07.15

New Drug Approvals Bring Hope, Challenges in the Treatment of Chronic Leukemia

New Drug Approvals Bring Hope, Challenges in the Treatment of Chronic Leukemia

The approvals of obinutuzumab, ibrutinib, and idelalisib provide clinicians with new treatment options for patients with CLL.

The paradigm of the treatment of chronic lymphocytic leukemia (CLL) has shifted, with the recent addition of obinutuzumab, idelalisib, and ibrutinib to the armamentarium.

 “These agents underscore our advancement in the understanding of the biology of CLL and will improve outcomes for many patients with CLL,” wrote David S. Sanford, MD, of The University of Texas MD Anderson Cancer Center in Houston, TX, and colleagues in Clinical Lymphoma, Myeloma, and Leukemia.1


Approved by the U.S. Food and Drug Administration (FDA) in November 2013 in combination with chlorambucil for treatment-naïve patients with CLL, obinutuzumab is a humanized type II immunoglobulin G1 antibody that targets CD20. Its cytotoxic effect is likely a result of antibody-dependent cell-mediated toxicity.2

The front-line efficacy was demonstrated in the randomized, open-label, phase 3 CLL11 trial, in which obinutuzumab plus chlorambucil resulted in greater complete (20.7% vs. 7.0%) and molecular response rates compared with rituximab plus chlorambucil.3

In addition, treatment with chlorambucil resulted in a prolonged median progression-free survival (PFS) of 26.7 months compared with 16.3 months in the rituximab plus chlorambucil arm (hazard ratio [HR], 0.44; 95% CI, 0.34 to 0.57; P<0.001) and 11.1 months in the chlorambucil monotherapy arm (HR, 0.18; 95% CI, 0.13 to 0.24; P<0.001).

In addition, overall survival (OS) was significantly greater in the obinutuzumab arm compared with chlorambucil monotherapy (HR, 0.41; 95% CI, 0.23 to 0.74; P=0.002), but was not significant compared with the rituximab arm (HR, 0.66; 95% CI, 0.41 to 1.06; P=0.08).

Median OS has not yet been reached. However, the improved efficacy with obinutuzumab did not carry over to patients with 17p deletion.

The addition of obinutuzumab did result in greater rates of adverse events (AEs) including grade 3 to 4 neutropenia and thrombocytopenia, but rates of infection were similar compared with the addition of rituximab.3

In addition, 20% of patients experienced infusion-site reactions during their first infusion of obinutuzumab, compared with 4% of patients who received rituximab.

Furthermore, patients in the obinutuzumab arm were more likely to discontinue therapy compared with the rituximab or chlorambucil monotherapy arms.


Ibrutinib was approved by the FDA in February 2014 for the treatment of patients with CLL whose disease did not respond to at least one prior therapy.

Ibrutinib is an irreversible Bruton tyrosine kinase (BTK) inhibitor, leading to the decreased activity of downstream signaling events and, ultimately, the proliferation of leukemic cells.4,5

Furthermore, ibrutinib has been shown to suppress the expression adhesion proteins in the bone marrow microenvironment, impairing B-cell homing.6

The efficacy of ibrutinib in relapsed and heavily pretreated patients with CLL was demonstrated in a multicenter, nonrandomized, open-label, phase 1b/2 trial.7

In this trial, the overall response rate was 71% in both the 420-mg and 840-mg arms. Importantly, the response rate among patients with a 17p deletion was similar at 68%; however, patients with a mutated immunoglobulin variable-region heavy-chain (IGHV) gene had a significantly lower response rate (P=0.005).

The PFS and OS rates were 75% and 83%, respectively, at 26 months. In addition, among patients with the 17p deletion, the 26-month PFS rate was 57% and OS rate was 70%.

The most common AEs included diarrhea, upper respiratory tract infection, and fatigue. Pneumonia, dehydration, and neutropenia were the most common grade 3 or higher AEs.

The phase 2 RESONATE-17 trial further demonstrated ibrutinib's efficacy in patients with a 17p deletion.8 In this nonrandomized trial, patients with relapsed CLL or small lymphocytic leukemia (SLL) with a 17p deletion received ibrutinib monotherapy for a median follow-up of 13 months. The 12-month PFS rate was 79.3%, and the median duration of response had not yet been reached.


In July 2015, the FDA approved the use of idelalisib in combination with rituximab in patients with relapsed CLL in whom rituximab monotherapy is considered appropriate due to the presence of comorbidities. Idelalisib specifically and reversibly binds to the p110δ isoform of PI3 kinase (PI3K), reducing the phosphorylation of downstream signaling factors such as Akt. As a result, the tumor microenvironment within the bone marrow and chemokine signaling is disrupted, thereby promoting apoptosis of leukemic cells.9,10

A randomized, double-blind, phase 3 trial demonstrated that idelalisib plus rituximab improved overall response rates compared with placebo plus rituximab.11 Median PFS was not reached in the idelalisib arm, but was 5.5 months in the placebo arm (HR, 0.15; P<0.001). In addition, the 12-month OS rate was 92% in the idelalisib arm compared with 80% in the placebo arm (HR, 0.21; P=0.02).

A second interim analysis of the trial demonstrated that the addition of idelalisib improved PFS for patients with unfavorable cytogenetics, including a 17p deletion, TP53 mutation, or ZAP70 positivity.12

Furthermore, a nonrandomized, open-label, phase 2 extension of study 101-08 of front-line idelalisib monotherapy resulted in a 90% response rate.13

Serious AEs were more common in the idelalisib arm, and the most common AEs included diarrhea, nausea, pyrexia, fatigue, and chills. Anemia, neutropenia, thrombocytopenia, and liver enzyme elevation were more common in the idelalisib arm compared with the placebo arm.

New Options for High-risk CLL

Ibrutinib and idelalisib demonstrated efficacy in patients with CLL who harbor a chromosome 17p deletion—a feature that is notorious for difficult to treat disease, as chemoimmunotherapy typically elicits low response rates compared with wild-type 17p.13

As a result, ibrutinib is recommended by the National Comprehensive Cancer Network as the preferred first-line agent for patients with a 17p deletion. Obinutuzumab plus chlorambucil may also be used as first-line therapy, and idelalisib with or without rituximab is recommended for relapsed or refractory disease.

Incorporating into Practice

The approval of obinutuzumab, ibrutinib, and idelalisib, as well as potential approvals of additional novel, targeted agents in the future provide clinicians with new and improved options for patients with CLL. However, how to best incorporate them into clinical practice remains a challenge.

For example, clinicians may be surprised at the extent of lymphocytosis that may occur in patients that receive one of these agents; however, lymphocytosis is generally asymptomatic and slowly normalizes.

“Many questions remain about their use including long-term efficacy, safety, and how and when to best incorporate these treatments into therapy,” wrote Dr. Sanford and colleagues.1



  1. Sanford DS, Wierda WG, Burger JA, et al. Three newly approved drugs for chronic lymphocytic leukemia: incorporating ibrutinib, idelalisib, and obinutuzumab into clinical practice. Clin Lymphoma Myeloma Leuk. 2015;15(7):385-391.
  2. Beers SA, Chan CH, French RR, et al. CD20 as a target for therapeutic type I and II monoclonal antibodies. Semin Hematol. 2010;47(2):107-114.
  3. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101-1110.
  4. Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA. 2010;107(29):13075-13080.
  5. Cheng S, Ma J, Guo A, et al. BTK inhibition targets in vivo CLL proliferation through its effects on B-cell receptor signaling activity. Leukemia. 2014;28(3):649-657.
  6. Chang BY, Francesco M, De Rooij MF, et al. Egress of CD19(þ)CD5(þ) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood. 2013;122(14):2412-2424.
  7. Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223.
  8. O'Brien S, Jones JA, Coutre S, et al. Efficacy and safety of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic leukemia with 17p deletion from the phase II RESONATE-17 trial. 56th ASH Annual Meeting and Exposition; San Francisco, CA. Abstract 327.
  9. Hoellenriegel J, Meadows SA, Sivina M, et al. The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 2011;118(13):3603-3612.
  10. Lannutti BJ, Meadows SA, Herman SE, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117(2):591-594.
  11. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007.
  12. Sharman JP, Coutre SE, Furman RR, et al. Second interim analysis of a phase 3 study of idelalisib (ZYDELIG) plus rituximab (R) for relapsed chronic lymphocytic leukemia (CLL): efficacy analysis of patient subpopulations with del(17p) and other adverse prognostic factors. 56th ASH Annual Meeting and Exposition; San Francisco, CA. Abstract 330.
  13. Zelenetz AD, Gordon LI, Wierda WG, et al. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin Lymphoma. Version 2.2015. 2015. Available at: Accessed July 21, 2015.

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Julho 2015