Hairy Cell Leukemia - Information Website: CMECE

CME Information Must be read prior to engaging in activity CREDITS

Physicians

0.25 AMA PRA Category 1 Credit(s) ™

Family Physicians

0.25 Elective credits

Release Date:

Apr. 13, 2011

Expiration Date:

Apr. 13, 2012

Estimated time for completion 15.00 minutes

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1. Discuss the results of this study

2. Review the relevance and significance of the study in the broader context of clinical care

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Projects In Knowledge®, Inc. designates this enduring material for a maximum, of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Credit for Family Physicians

MedPage Today "News-Based CME" has been reviewed and is acceptable for up to 2098 Elective credits by the American Academy of Family Physicians. AAFP accreditation begins January 1, 2011. Term of approval is for one year from this date. Each article is approved for 0.25 Elective credits. Credit may be claimed for one year from the date of each article.

By John Gever, Senior Editor, MedPage Today

Published: April 13, 2011

Reviewed by Michael J. Olek, DO; Director, Newport Doctors Multiple Sclerosis Clinic and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
Note that this report discussed a preliminary single case of a patient with hairy cell leukemia treated with cladribine developing progressive multifocal leukoencephalopathy.

HONOLULU -- A patient treated with cladribine for hairy cell leukemia went on to develop progressive multifocal leukoencephalopathy (PML), suggesting that the drug may pose a similar risk when used in multiple sclerosis (MS), French researchers reported here.

Cladribine, which suppresses lymphocyte proliferation and activity, is sometimes used off label in MS. Its manufacturer, German drug firm Merck KGaA, has been seeking regulatory approval to market the drug for the condition -- so far unsuccessfully, as both the FDA and its European counterpart have turned it down.

Marc Aletti, MD, and colleagues at the St. Anne French Military Hospital in Toulon, France, reported the leukemia patient's PML case here at the American Academy of Neurology's annual meeting.

The patient was about 81 when diagnosed with PML. He had initially presented with hairy cell leukemia in 2006 with moderate neutropenia and thrombocytopenia.

Both then and in 2007, he received courses of cladribine treatment at 0.12 mg/kg/day for five days. In 2009, he also received pentostatin at 4 mg/m2 for 15 days.

Symptoms of PML developed in May of 2010, including sleepiness and memory problems. These worsened rapidly over a three-week period, leading to the diagnosis. JC virus genetic matter was identified in his cerebrospinal fluid, helping to confirm the diagnosis.

Extremely low CD4- and CD8-positive cell counts -- 67 and 28 per mm3, respectively -- were found in his peripheral blood, along with moderate neutropenia and thrombocytopenia. There were no circulating tricholeukocytes and no evidence of HIV infection.

The man eventually recovered following eight months of cidofovir treatment, Aletti and colleagues reported.

PML is well known to occur with leukemias that depress normal leukocyte counts severely, but has been rare in association with hairy cell leukemia, Aletti and colleagues noted.

As a result, the researchers suspected that cladribine may have contributed to development of PML in this case.

"Cladribine may cause deep and prolonged lymphopenia, similar to an AIDS-like immune state, which potentially increases the risk of PML," according to their poster presentation.

They emphasized that the patient in this case did not have MS and that PML has not been reported in patients treated with cladribine for MS.

But Aletti and colleagues argued that "the risk for opportunistic infections in this situation" warrants clinicians' attention.

On the other hand, Robert Fox, MD, a neurologist at the Cleveland Clinic, told MedPage Today that he wasn't especially concerned about the report.

"Leukemia patients get PML," he said, pointing out that the rate is the important issue. He noted that rituximab (Rituxan) has been linked to PML in rheumatoid arthritis patients, but at a far smaller rate than has been seen with natalizumab (Tysabri) in MS patients.

The study had no external funding.

Study authors reported that they had no relevant financial interests.

Fox reported consulting or speaker fees from Biogen Idec, Genentech, and Teva, and research funding from Biogen Idec and Genentech.

Primary source: Neurology
Source reference:
Aletti M, et al "Progressive multifocal leukoencephalopathy after cladribine treatment for hairy cell leukemia" Neurology 2011; 76:A28.

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By Charles Bankhead, Staff Writer, MedPage Today

Published: June 11, 2011

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Explain that a single mutation (BRAF V600E) occurred in every patient in a cohort with hairy cell leukemia, suggesting that targeting the mutation could have major implications for treating the disease.
Note that the method used was genome-wide massively parallel sequencing of tumor and normal cells from the same patient to identify recurrent somatic mutations.

A single mutation occurred in every patient in a cohort with hairy cell leukemia, suggesting that targeting the mutation could have major implications for treating the disease, Italian investigators reported.

The same BRAF V600E mutation appeared in 47 consecutive patients with hairy cell leukemia versus none of 195 patients with other types of peripheral B-cell lymphomas and leukemias.

In vitro studies showed that incubation of BRAF-mutated primary hairy cell leukemia cells with a specific inhibitor of BRAF led to a marked decrease in levels of two known downstream targets of BRAF kinase, according to an article published online in the New England Journal of Medicine.

"The BRAF V600E mutant is a potential therapeutic target in patients with hairy cell leukemia who do not have a response (or have a suboptimal response) to initial therapy with purine analogs, as well as in patients with repeated relapses or unacceptable toxic effects," Brunangelo Falini, MD, of the University of Perugia, and co-authors wrote in conclusion.

"Notably, BRAF V600E inhibitors have shown remarkable activity in patients with BRAF-mutated metastatic melanoma. These results, along with our in vitro finding that a specific active BRAF inhibitor causes MEK and ERK dephosphorylation in primary hairy cell leukemia cells, warrant the clinical testing of active BRAF inhibitors."

The findings were reported simultaneously at the European Hematology Association meeting.

Despite advances in the diagnosis and treatment of hairy cell leukemia over the past 50 years, little progress has occurred toward elucidation of the underlying genetic alterations associated with disease.

Gene-expression profiling has failed to pinpoint any recurrent genetic alterations, nor has genome-wide single-nucleotide polymorphism genotyping, the authors wrote in the introduction to their findings.

Falini and colleagues used a more powerful approach to examining the genetic basis of cancer: genome-wide massively parallel sequencing of tumor and normal cells from the same patient. They sought to identify recurrent somatic mutations in protein-coding genes, with the goal of gaining more insight into the origin of the disease and identifying new options for diagnosis and treatment.

Investigators obtained leukemic and nonleukemic genomic DNA from a single patient with hairy cell leukemia. By use of massively parallel sequencing, candidate somatic mutations were identified. Researchers used polymerase-chain-reaction (PCR) amplification and direct DNA sequencing to validate the findings from the index patient.

Falini and colleagues performed whole-exome sequencing of genomic DNA from the index patient and identified five unique variants specific to tumor DNA, the best known of which was BRAF.

The amino acid substitution at position 600 of the BRAF protein (V600E) is associated with several solid tumors. At the recent American Society of Clinical Oncology meeting, treatment with a BRAF inhibitor led to unprecedented activity in patients with metastatic melanoma.

With the finding from the index patient, Falini and colleagues screened DNA samples for 47 additional patients with hairy cell leukemia and the 195 patients with other leukemias and lymphomas. They identified the V600E mutation in samples from all of the patients with hairy cell leukemia but none of the patients with other hematologic malignancies.

Working from the understanding that V600E constitutively activates BRAF kinase activity, Falini and colleagues evaluated the phosphorylation status of MEK and ERK. The former is the kinase target immediately downstream from BRAF and the latter is the kinase phosphorylated by MEK.

Using antibodies specific to phosphorylated MEK and ERK, the investigators confirmed the presence of the two kinases in DNA specimens from five patients with BRAF-mutated hairy cell leukemia. Introduction of the BRAF inhibitor PLX-4720 led to marked decrease in phosphorylated MEK and ERK, whereas vehicle-treated samples retained MEK and ERK phosphorylation.

Falini had no relevant disclosures. Co-author Robin Foa disclosed relationships with Roche, Bristol-Myers Squibb, GlaxoSmithKline, and Celgene.

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Hairy Cell Leukemia - Information Website

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