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BRAF inhibitors in HCL
Thorsten Zenz, MD
Dept. of Translational Oncology, National Center for Tumor Diseases (NCT) /
German Cancer Research Center (DKFZ), Heidelberg
Dept. of Haematology / Oncology / Rheumatic Disease, University Hospital Heidelberg
[email protected]
Hairy Cell Leukemia
• BRAFV600E disease defining lesion
• Vemurafenib (B-raf inhibitor) transforming
treatment landscape in melanoma
• High incidence thyroid cancer, colon cancer,…
Light chain 
CD103
CD25
CD11c
D
c.T1799A, p.V600E
CD20
Tiacci et al, NEJM 2011
BRAF V600E
Incidence and clonal composition suggests that BRAF V600E
could be an ideal therapeutic target
Blood Counts
Dietrich et al, NEJM in pressDietrich, Glimm et al, NEJM 2012
Vemurafenib (mg)
d0
d 17
d 36
d 70
d0
d 17
d 36
d 70
20x
32%
<0.02%
1.04%
<0.02%
CD103+
Immunophenotyping
peripheral blood
Bone marrow
infiltration (CD20)
BRAF inhibition in HCL
CD20+
d 17
d 36
Melanoma dose
d 70
1920
1440
960
480
0
0
20
40
60
80
Days
Dietrich, Glimm et al, NEJM 2012
Response to BRAF inhibition in HCL
(blood counts)
Dietrich et al, JCO
Treatment of hairy cell leukemia by BRAF-inhibition
Dietrich Sascha, Andreas Pircher, Mindaugas Andrulis, Elena Ellert, Weichert, Frédéric Peyrade,
Clemens-Martin Wendtner, Anita Gaehler, George A Follows, Martin JS Dyer, Thomas Elter,
Robert Zeiser, Michael Herrmann, Michael Herold, Claire Dearden, Thorsten Haferlach,
Martina Seiffert, Michael Hallek, Anthony D Ho, Michael Steurer and Thorsten Zenz,
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University of Heidelberg, Department of Medicine V, Heidelberg, Germany;
Medical University Innsbruck, Innsbruck, Austria;
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany;
Centre Antoine Lacassagne, Nice, France;
Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine, Hospital MunichSchwabing, Munich, Germany;
Kantonsspital Luzern, Luzern, Switzerland;
Department of Haematology, Addenbrookes Hospital, Cambridge, United Kingdom;
Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom;
Department of Internal Medicine I, Center of Integrated Oncology (CIO), CECAD, University of Cologne, Cologne, Germany;
Department of Haematology/Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany;
Department of Hematology and Oncology, Helios Kliniken Erfurt, Erfurt, Germany;
The Royal Marsden Hospital, London, United Kingdom;
MLL Münchner Leukämielabor, München, Germany
DKFZ, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany;
Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center (dkfz),
Heidelberg, Germany;
Response
• Eight patients achieved a CR (38%)
• 12 PR (57%)
• 1 patient a minor response (5%)
Clincal studies exploring BRAFi
• A Phase II Study of the BRAF Inhibitor, Vemurafenib, in
Patients With Relapsed or Refractory Hairy Cell Leukemia
(NCT01711632)
• A Phase II, Open-label, Study in Subjects With BRAF V600EMutated Rare Cancers With Several Histologies to Investigate
the Clinical Efficacy and Safety of the Combination Therapy
of Dabrafenib and Trametinib (NCT02034110)
• A phase II, multi-center, open label study of the clinical
activity and safety of the BRAF-V600 inhibitor vemurafenib
(PLX-4032) in previously treated patients with hairy cell
leukemia (HCL) carrying the BRAF-V600E mutation (2011005487-13)
Phase II clinical trial of vemurafenib in Hairy
Cell Leukemia (HCL)
• For patients with relapsed or refractory HCL with one of the following:
– intolerance to purine analogs
– refractory to initial purine analog-based therapy
– 1st relapse within 2 years of purine analog-based therapy
– ≥2 relapses.
• PI’s: Jae Park, Marty Tallman (Memorial Sloan Kettering Cancer); Open at
Ohio State, Scripps, Northwestern, Dana Farber Cancer Center
MRD
assessment
Daily vemurafenib x 3 months
0
3 months
Jae Park, Martin Tallman
Monitor for
disease
recurrence
If MRD+ continue
3 months more
6 months
Phase II clinical trial of vemurafenib for R/R HCL
• 26 patients enrolled
• 24 patients are evaluable for toxicity with ≥ 1
month of study drug administration
• 24 patients are evaluable for response with ≥ 3
months of follow-up
– Median follow up: 12 months (5.6 – 22.1 months)
– Data cutoff date: 11/19/2014
Jae Park, Martin Tallman
Phase II clinical trial of vemurafenib for R/R HCL
Number of Patients, N=24
Overall Response Rate (CR + PR)
24/24 (100%)
Complete Response
8/24 (33.3%)*
Partial Response¶
16/24 (66.7%)§
* 2 patients achieved MRD negative CR (25%).
¶ All patients with PR achieved complete hematologic recovery.
§ Median % hairy cells in PR patients was 12.5% (range, 2-40%).
• 11 patients completed > 3 months of treatments (4-6 months).
• 2 patient experienced improvement of response.
Jae Park, Martin Tallman
Summary
• BRAF inhibitors open up targeted treatment opportunities in HCL
• Integration into clinical care to be developed
• Trials currently open for vemurafenib / Trametinib+Dabrafenib
• Developments in other disease likely to influence HCL