BRAF Inhibition in Refractory Hairy-Cell Leukemia

The
n e w e ng l a n d j o u r na l
of
m e dic i n e
BRAF Inhibition in Refractory Hairy-Cell Leukemia
To the Editor: Hairy-cell leukemia (HCL) is a treated with purine analogues.1 Virtually all pamature B-cell lymphoid cancer that is commonly tients with HCL carry the BRAF V600E mutation,
A
5000
Cells/µl
4000
3000
Leukocytes
2000
1000
0
Neutrophils
2009
2010
2011
2012
2009
2010
2011
2012
2009
2010
2011
2012
Hemoglobin (g/dl)
16
14
12
10
0
250,000
Platelets/µl
200,000
150,000
100,000
50,000
0
Cladribine
Pentostatin Pentostatin
Cladribine plus
Rituximab
Vemurafenib
B
BRAF V600E–
Specific Antibody
Sanger Sequencing
c.T1799A, p.V600E
A
C
A
G T/A G
A
Bone Marrow Infiltration (CD20)
Day 0
A
A
T
Day 36
C
Immunophenotyping of Peripheral Blood
Day 0
CD103
105
2038
104
32%
Day 17
105
104
1.04%
Day 70
Day 36
105
104
<0.02%
105
104
103
103
103
103
102
0
102
0
102
0
102
0
0 102 103 104 105
0 102 103 104 105
CD20
CD20
0 102 103 104 105
CD20
<0.02%
0 102 103 104 105
CD20
n engl j med 366;21 nejm.org may 24, 2012
The New England Journal of Medicine
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Copyright © 2012 Massachusetts Medical Society. All rights reserved.
correspondence
which constitutively activates the MEK–ERK pathway and which can be inhibited in vitro by the
mutation-specific BRAF inhibitor PLX-4720.2
BRAF mutations have been identified in melanoma but are found across cancers.3 An inhibitor
of mutated BRAF (vemurafenib) has transformed
the treatment of melanoma. It is unclear whether
this clinical efficacy can be extrapolated to other
cancers.4,5 We used vemurafenib in a patient with
refractory HCL and a pressing need for treatment
(platelet count, 27,000 per cubic millimeter; neutrophil count, 314 per cubic millimeter). The 51year-old male patient received a diagnosis of classical HCL in 2009. He did not have a response to
conventional treatments (Fig. 1A). After the provision of counseling and the demonstration of BRAF
V600E in the leukemic cells (Fig. 1B), the patient
provided consent for vemurafenib treatment.
The rate of bone marrow infiltration was 70%,
and massive splenomegaly (24.8 cm by 8.3 cm) and
severe cytopenia (Fig. 1A) were present. Treatment was begun at a dose of 240 mg twice
daily, followed by a slow escalation of the dose.
Figure 1 (facing page). Effect of Low-Dose Vemurafenib
on Blood Counts, Bone Marrow Infiltration, and the
Hairy-Cell Leukemia Clone in a Patient with Hairy-Cell
Leukemia.
The patient’s peripheral-blood counts (granulocytes,
platelets, and hemoglobin) declined while he received
conventional treatment over a period of 3 years (Panel A).
The patient received cladribine at a dose of 0.14 mg per
square meter of body-surface area for 5 consecutive days
in February 2009, pentostatin at a dose of 4 mg per
square meter every 2 weeks from December 2010 through
January 2011 and March through April 2011 (seven doses),
cladribine at a dose of 0.14 mg per square meter for 5 consecutive days in May 2011, and rituximab at a dose of
375 mg per square meter every 2 weeks from May through
September 2011 (eight infusions). Before the start of
vemurafenib treatment in November 2011, the platelet
count was 27,000 per cubic millimeter, the neutrophil
count 314 per cubic millimeter, and the hemoglobin count
9.8 mg per deciliter. With vemurafenib treatment, the
peripheral-blood counts normalized rapidly (treatment
was begun at a dose of 240 mg twice daily [loading dose,
960 mg], followed by a slow escalation of the dose). Before treatment with vemurafenib, the presence of BRAF
V600E was confirmed by means of Sanger sequencing
and immunohistochemical analysis (BRAF V600E–specific
antibody) (top of Panel B). Bone marrow infiltration, as
determined by immunohistochemical staining for CD20
(top of Panel B), was 70% before vemurafenib treatment
and cleared with treatment. The size of the hairy-cell
leukemia clone in the peripheral blood, as assessed by
immunophenotyping (CD20 and CD103) (bottom of
Panel B), decreased rapidly with vemurafenib treatment.
Within days, the spleen softened and decreased
in size (to 18.8 cm by 6.9 cm on day 6 and 14.0 cm
by 5.0 cm on day 17). Platelet, hemoglobin, and
granulocyte counts rose to levels not observed
since diagnosis (Fig. 1A). Complete-remission
criteria were met on day 43, and treatment was
terminated on day 56. At this point, there was no
evidence of disease persistence on the basis of
immunophenotyping of the peripheral blood
and trephine-biopsy findings, but a small HCL
clone was detectable by immunophenotyping of
the bone marrow sample (<0.1% of cells).
The presence of BRAF V600E in most patients
with HCL suggested that it represents a key driver
mutation in the disease.2 Our observations provide evidence to substantiate this concept and validate mutant BRAF as a therapeutic target in HCL.
The findings are reminiscent of successes with
targeted inhibition of BCR-ABL1 in chronic myeloid leukemia. The fact that heavily pretreated,
refractory disease responded to very low doses
of vemurafenib suggests that HCL represents a
single-kinase–dependent cancer that can be
treated with targeted monotherapy.
Although an appropriate dosing schedule will
be developed in clinical trials, HCL was exquisitely
sensitive to BRAF inhibition. Secondary resistance
to BRAF inhibition, which occurs invariably in
patients with BRAF-mutant melanoma, might
develop in HCL. Because patients with HCL remain in hematologic remission after therapy with
purine analogues in spite of minimal residual disease and because other effective drugs are available, resistance may be less challenging in HCL.1
Sascha Dietrich, M.D.
University Hospital Heidelberg
Heidelberg, Germany
Hanno Glimm, M.D.
German Cancer Research Center
Heidelberg, Germany
Mindaugas Andrulis, M.D.
University Hospital Heidelberg
Heidelberg, Germany
Christof von Kalle, M.D.
National Center for Tumor Diseases
Heidelberg, Germany
Anthony D. Ho, M.D.
Thorsten Zenz, M.D.
University Hospital Heidelberg
Heidelberg, Germany
[email protected]
Drs. Dietrich and Glimm contributed equally to this letter.
n engl j med 366;21 nejm.org may 24, 2012
The New England Journal of Medicine
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Copyright © 2012 Massachusetts Medical Society. All rights reserved.
2039
The
n e w e ng l a n d j o u r na l
Supported by the Helmholtz Society, Harald Huppert Stiftung,
the M.D. Anderson Cancer Center–German Cancer Research
Center (Deutsches Krebsforschungszentrum) Sister Institution
Network Fund, and German Cancer Aid.
Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
1. Grever MR. How I treat hairy cell leukemia. Blood 2010;
115:21-8.
2. Tiacci E, Trifonov V, Schiavoni G, et al. BRAF mutations in
hairy-cell leukemia. N Engl J Med 2011;364:2305-15.
3. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF
gene in human cancer. Nature 2002;417:949-54.
4. Chapman PB, Hauschild A, Robert C, et al. Improved sur-
vival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16.
5. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated,
activated BRAF in metastatic melanoma. N Engl J Med 2010;363:
809-19.
Correspondence Copyright © 2012 Massachusetts Medical Society.
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corrections
Case 13-2012: A 62-Year-Old Man with Paresthesias, Weight
Loss, Jaundice, and Anemia (April 26, 2012;366:1626-33). In
the Vitamin B12 Deficiency subsection of Differential Diagnosis
(page 1630), the third and fourth sentences of the second paragraph should have read, “The homocysteine level is elevated in
both anemia due to vitamin B12 deficiency and anemia due to
2040
of
m e dic i n e
folate deficiency. In contrast, the methylmalonic acid level is
elevated only in vitamin B12 deficiency and is normal in folate
deficiency,” rather than “The methylmalonic acid level is elevated . . . In contrast, the homocysteine level is elevated . . . .”
The Continuing Medical Education examination associated
with this Case Record is also affected by these changes. In
Question 3 of the examination, option B should have read,
“Elevated folate level,” rather than “Elevated homocysteine
level.” The explanation of the correct answer to Question 3 has
also been updated according to the changes in the Case Record.
Both the article and the examination are correct at NEJM.org.
The Road to an Effective HIV Vaccine (April 5, 2012;366:134344). In the final paragraph of the article (page 1344), the penultimate sentence, “But if properly designed and conducted,
they may play an indispensable, iterative role on the road toward the development of an effective vaccine to control the HIV
pandemic,” should have been the final sentence, and the sentence
that followed it, beginning, “If this approach works,” should not
have been included. The article is correct at NEJM.org.
Case 8-2012: A 53-Year-Old Man with Crohn’s Disease, Diarrhea,
Fever, and Bacteremia (March 15, 2012;366:1039-45). In the third
paragraph of the Presentation of Case section, in the sentence
beginning, “Medications included” (page 1040), the list of medications should not have included minocycline. The article is
correct at NEJM.org.
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n engl j med 366;21 nejm.org may 24, 2012
The New England Journal of Medicine
Downloaded from nejm.org on January 13, 2017. For personal use only. No other uses without permission.
Copyright © 2012 Massachusetts Medical Society. All rights reserved.