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Ibrutinib in Waldenström's Macroglobulinemia

Insights From:Jennifer R. Brown, MD, PhD, Harvard Medical School; Richard R. Furman, MD, Weill Cornell Medical College; Brad S. Kahl, MD, UW Carbone Cancer Cente
Published: Friday, Sep 18, 2015

 
The BTK inhibitor ibrutinib was approved for patients with Waldenström’s macroglobulinemia (WM) in January 2015, representing the first agent specifically indicated for patients with this disease, states Jennifer Brown, MD, PhD. The FDA decision was based on findings from a phase II study, which demonstrated that patients who received ibrutinib experienced dramatic improvements in hemoglobin and immunoglobulin M (IgM) levels, thrombocytopenia, and anemia, says Richard Furman, MD. Additionally, ibrutinib induced a clear restoration of hematopoiesis and reduction in splenomegaly and lymphadenopathy.

In the pivotal phase II study of 63 patients who received 420 mg of ibrutinib once daily, the overall response rate was 90.5%, and the major response rate was 73%. The median serum IgM level decreased from 3520 mg per deciliter to 880 mg per deciliter. The median hemoglobin levels increased from 10.5 g per deciliter to 13.8 g per deciliter and bone marrow involvement decreased from 60% to 25%. The estimated 2-year progression-free survival rate was 69.1% and the 2-year overall survival rate was 95.2%.

Approximately 90% of patients with MW will respond to ibrutinib therapy, says Furman. Clinicians are able to prospectively identify patients who will not respond, as almost all patients who did not respond to ibrutinib were shown to express a mutation in CXCR4. Additionally, MYD88 status also impacted the efficacy of ibrutinib. 
 
Ibrutinib therapy may be associated with thrombocytopenia, although this usually resolves, adds Brown. The most commonly observed grade >2 treatment-related adverse events were neutropenia (22%) and thrombocytopenia (14%). These events occurred most frequently in heavily pretreated patients. 

At this point, ibrutinib has been approved as a treatment for patients with WM, mantle cell lymphoma, and chronic lymphocytic leukemia. Each of these indications is for ibrutinib as a single agent. The approval of idelalisib in relapsed CLL and indolent non-Hodgkin lymphoma was in combination with rituximab. 

Idelalisib is quite active in CLL and rivals ibrutinib in terms of efficacy, but is associated with toxicities, notes Brown. Idelalisib is associated with transaminitis, pneumonitis, and diarrhea with colitis. Median time to onset of diarrhea is approximately 6 to 7 months into therapy, long after clinicians are used to seeing a drug-related event, comments Brown.

Ibrutinib and idelalisib take time to induce a response, and holding either drug may hinder their ability to induce a response. Initial studies have suggested that these medications can cause myelotoxicity, but this usually occurs in individuals who were heavily pretreated, says Brown. When the drugs are used upfront in untreated patients, cytopenias are minimal, notes Brown.
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The BTK inhibitor ibrutinib was approved for patients with Waldenström’s macroglobulinemia (WM) in January 2015, representing the first agent specifically indicated for patients with this disease, states Jennifer Brown, MD, PhD. The FDA decision was based on findings from a phase II study, which demonstrated that patients who received ibrutinib experienced dramatic improvements in hemoglobin and immunoglobulin M (IgM) levels, thrombocytopenia, and anemia, says Richard Furman, MD. Additionally, ibrutinib induced a clear restoration of hematopoiesis and reduction in splenomegaly and lymphadenopathy.

In the pivotal phase II study of 63 patients who received 420 mg of ibrutinib once daily, the overall response rate was 90.5%, and the major response rate was 73%. The median serum IgM level decreased from 3520 mg per deciliter to 880 mg per deciliter. The median hemoglobin levels increased from 10.5 g per deciliter to 13.8 g per deciliter and bone marrow involvement decreased from 60% to 25%. The estimated 2-year progression-free survival rate was 69.1% and the 2-year overall survival rate was 95.2%.

Approximately 90% of patients with MW will respond to ibrutinib therapy, says Furman. Clinicians are able to prospectively identify patients who will not respond, as almost all patients who did not respond to ibrutinib were shown to express a mutation in CXCR4. Additionally, MYD88 status also impacted the efficacy of ibrutinib. 
 
Ibrutinib therapy may be associated with thrombocytopenia, although this usually resolves, adds Brown. The most commonly observed grade >2 treatment-related adverse events were neutropenia (22%) and thrombocytopenia (14%). These events occurred most frequently in heavily pretreated patients. 

At this point, ibrutinib has been approved as a treatment for patients with WM, mantle cell lymphoma, and chronic lymphocytic leukemia. Each of these indications is for ibrutinib as a single agent. The approval of idelalisib in relapsed CLL and indolent non-Hodgkin lymphoma was in combination with rituximab. 

Idelalisib is quite active in CLL and rivals ibrutinib in terms of efficacy, but is associated with toxicities, notes Brown. Idelalisib is associated with transaminitis, pneumonitis, and diarrhea with colitis. Median time to onset of diarrhea is approximately 6 to 7 months into therapy, long after clinicians are used to seeing a drug-related event, comments Brown.

Ibrutinib and idelalisib take time to induce a response, and holding either drug may hinder their ability to induce a response. Initial studies have suggested that these medications can cause myelotoxicity, but this usually occurs in individuals who were heavily pretreated, says Brown. When the drugs are used upfront in untreated patients, cytopenias are minimal, notes Brown.
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