Targeting Mutation in Relapsed or Refractory Hairy-Cell Leukemia

Sara Griffin, Mercer University College of Pharmacy

According to National Cancer Institute (NIH), hairy-cell leukemia (HCL) is a type of cancer which involves the over-production of lymphocytes. Leukemia cells appear “hairy” when viewed under a microscope, hence the name hairy-cell leukemia. The signs and symptoms noted to be associated with this type of cancer include pain below the ribs, tiredness, and infections; however, these signs and symptoms could be caused by other conditions and should be assessed by a physician. The cause of this type of leukemia is unknown and occurs more often in older men.1

The British Journal of Haematology (BJH) states that a watch-and-wait policy is reasonable if a patient is asymptomatic and cytopenias are minimal. The risk for opportunistic infections in patients with monocytopenia, with or without neutropenia, is high and asymptomatic patients may be considered for early treatment. Symptomatic cytopenias and painful splenomegaly are the main indications for treatment.2

According to the Leukemia and Lymphoma Society (LLS), cladribine (Leustatin®) administered intravenously (IV) is the initial medication used in the treatment of HCL. Most patients with HCL have BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations according to recent data. Vemurafenib (Zelboraf ®), an oral BRAF inhibitor, has been approved by the Food and Drug Administration (FDA) as a treatment for melanoma and is now being used in clinical trials for patients with relapsed and refractory HCL.3

Title: Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia 4
Design Two phase 2, single-group, multicenter studies; N= 28 in Italian trial and N= 26 in United States (U.S.) trial
Objective To investigate the efficacy and safety of an oral BRAF (B-Raf proto-oncogene, serine/threonine kinase) inhibitor, vemurafenib, in patients with relapsed or refractory hairy cell leukemia (HCL).
Study Groups Italian trial- All patients received treatment with oral vemurafenib
U.S. trial- All patients received treatment with oral vemurafenib
Methods Italian trial- Oral vemurafenib was given to patients at a dose of 960 mg twice daily for a minimum of 8 weeks. If a patient did not have a complete response, vemurafenib was given for a maximum of 16 weeks; however, the first three patients received vemurafenib for 20 weeks. Assessments of response (blood counts, spleen size, bone marrow biopsy, and aspirate) were conducted monthly during treatment, together with a dermatologic examination, and every 3 months during follow-up (except the bone marrow evaluation, which was performed every 6 months). Doses could be reduced in the event of toxic effects (720 mg, 480 mg, or 240 mg twice daily).
U.S. trial- Oral vemurafenib was given to patients at a dose of 960 mg twice daily continuously in cycles of 4 weeks.   Bone marrow assessments were performed after first and third cycles, and at the end of treatment. Patients who had splenomegaly at enrollment had a computed tomography of the abdomen at baseline and at 3 months. All patients received dermatologic examinations at baseline, after first and third cycles, and every 3 months thereafter until at least 1 year after discontinuation of the drug. Doses could be reduced in the event of toxic effects (720 mg, 480 mg, or 240 mg twice daily).
Duration Italian trial- 11 months (May 20, 2012 through April 23, 2013)
U.S. trial- Ongoing (October 2012 through Present; estimated study completion: October 2016)
Primary Outcome Measure Italian trial- Rate of complete response
U.S. trial- Overall response rate after 12 weeks of treatment with vemurafenib
Baseline Characteristics Italian trial- Median age, year: 57 (range: 27 to 84); Median number (no.) of previous therapies: 3 (range 1 to 12); Disease refractory to immediate prior therapy- no./total no.: 15/27 (56%); Prior splenectomy: 29%; Hairy-cell involvement in bone marrow*: 82.5% (range 4 – 95)
U.S. trial- Median age, year: 62 (range: 44 to 80); Median no. of previous therapies: 3 (range: 1 to 8); Disease refractory to immediate prior therapy-no./total no.: 9/22 (41%); Prior splenectomy: 19%; Hairy-cell involvement in bone marrow*: 80% (range 25 – 100)
Results Italian trial- Two of the 28 patients discontinued treatment at or before 1 week; one deemed by the investigator as unrelated to study drug and the other due to withdrawal of consent after a drug-related event. Fifteen patients (58%) required dose reductions for at least 3 weeks due to adverse events. Nine patients received 720 mg twice daily, three patients received 480 mg twice daily, and three patients received 240 mg twice daily. Overall response rates were 96% in the 25 patients who could be evaluated. After a median of 8 weeks, 35% of the patients (9 of 26) had a complete response and 62% (16 of 26) had a partial response.
U.S. trial- Two of the 26 patients did not complete the study; one due to death deemed by the investigator as unrelated to the study drug and the other due to withdrawal of consent after a drug-related event. Thirteen patients (50%) required dose reductions due to adverse events. Two patients received 720 mg twice daily, ten patients received 480 mg twice daily, and one patient received 240 mg twice daily. Overall response rates were 100% in the 24 patients who could be evaluated.
Adverse Events Common Adverse Events:

Italian trial- Arthralgia or arthritis (43%), rash or erythema (46%)

U.S. trial- Arthralgia or arthritis (31%), rash or erythema (62%)

Serious Adverse Events:

Italian trial- Acute pancreatitis, reversible (3.6%), pancreatitis, reversible (7%)

U.S. trial- None reported

Percentage that Discontinued due to Adverse Events:

Italian trial- Reversible pancreatitis (3.6%)

U.S. trial- Reversible photosensitivity (3.8%)

Study Author Conclusions A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy-cell leukemia.

*The percentage of hairy-cell involvement in bone marrow was determined with the use of immunohistochemical testing.

Although vemurafenib is administered for an indefinite duration for patients with metastatic melanoma, this study limited the treatment to a few months due to concerns about drug inducing secondary tumors. This may have led to a reduction in the type or duration of response. The authors of the study noted that BRAF inhibitors could be combined with anti-CD 20 monoclonal antibodies in the hopes of eradicating BRAF inhibitor-resistant HCL cells; however, this study only evaluated monotherapy with vemurafenib. The combination of a BRAF inhibitor with an anti-CD 20 monoclonal antibody in the treatment of relapsed or refractory HCL may be seen in future studies. This study found that vemurafenib is an active targeted drug for patients with relapsed or refractory HCL and could potentially be approved by the FDA for this indication.

References

  1. General information about hairy cell leukemia. National Cancer Institute. http://www.cancer.gov/types/leukemia/patient/hairy-cell-treatment-pdq#link/stoc_h2_0. Revised November 11, 2014. Accessed September 16, 2015.
  2. Jones G, Parry-jones N, Wilkins B, Else M, Catovsky D. Revised guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant*. Br J Haematol. 2012;156(2):186-95.
  3. Hairy cell leukemia facts. Leukemia and Lymphoma Society. https://www.lls.org/sites/default/files/file_assets/hairycellleukemia.pdf. Revised October 2013. Accessed September 16, 2015.
  4. Tiacci E, Park JH, De carolis L, et al. Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia [published online September 9, 2015]. N Engl J Med. 2015; doi: 10.1056/NEJMoa1506583.
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