The n e w e ng l a n d j o u r na l of m e dic i n e
program specifies new timelines (effective Octo-
ber 1, 2014) for the review of applications for
generic drugs in exchange for user fees; by 2017,
regulatory action will be required on 90% of new
applications for generic drugs within 10 months
after submission. The Office of Generic Drugs
also expedites applications for generic drugs that
are critical to public health or have the potential
to mitigate drug shortages.3
The FDA has a long track record of success-
fully meeting the requirements of user-fee pro-
grams for the review of drugs, and we are well
on our way to meeting the GDUFA commitments.
Although no provision exists in the GDUFA for
waiving user fees for the review of generic drugs
even for drugs of which there are shortages
having firm timelines in place will allow mar-
kets to adjust more quickly to pricing anomalies.
Kathleen Uhl, M.D.
John R. Peters, M.D.
Keith Flanagan, J.D.
Food and Drug Administration
Silver Spring, MD
kathleen.uhl@fda.hhs.gov
No potential conflict of interest relevant to this letter was re-
ported.
1. Alpern JD, Stauffer WM, Kesselheim AS. High-cost generic
drugs implications for patients and policymakers. N Engl J
Med 2014;371:1859-62.
2. Generic Drug User Fee Amendments of 2012 (GDUFA). Silver
Spring, MD: Food and Drug Administration (http://www.fda.gov/
ForIndustry/UserFees/GenericDrugUserFees/default.htm).
3. Manual of policy and procedures: MAPP 5240.3 Rev. 1: pri-
oritization of the Review of Original ANDAs, Amendments,
and Supplements, revised 8/1/2104. Silver Spring, MD: Food
and Drug Administration (http://www.fda.gov/downloads/
aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/
manualofpoliciesprocedures/ucm407849.pdf).
DOI: 10.1056/NEJMc1415471
The Authors Reply: When prices of generic
drugs are high because fewer manufacturers
make these products, appropriate policy solu-
tions can facilitate the reestablishment of strong,
Sweets Syndrome in Patients with MDS and MEFV Mutations
To the Editor: We report the finding of MEFV
mutations in two Japanese patients with the mye-
lodysplastic syndrome (MDS) and skin lesions
that are consistent with Sweets syndrome (acute
febrile neutrophilic dermatosis). Both patients had
heterozygous mutations in MEFV, which are
known to cause familial Mediterranean fever.1,2
686 n engl j med 372;7nejm.orgfebruary 12, 2015
The New England Journal of Medicine
Downloaded from nejm.org on May 28, 2015. For personal use only. No other uses without permission.
Copyright 2015 Massachusetts Medical Society. All rights reserved.
competitive markets. The FDAs move to reduce
review times for applications is one such policy.
It could also help for Congress to authorize fee
waivers for entrants into generic-drug markets in
which there are shortages of raw materials or
similar factors contributing to exits from the
market or price increases, although the current
user fee for applications for generic drugs
($58,730) is small as compared with those for
new drugs ($2,335,200) or high-risk medical
devices ($250,895). However, exorbitant generic-
drug prices can have other causes (e.g., demand
may fluctuate or improper business practices
may reduce competition artificially).1 In response,
the federal government could offer long-term
purchasing contracts for some generic drugs, as
it does for childhood vaccines, and policymakers
should enhance the ability of state and federal
government payers to respond to high prices.2,3
An array of interventions may be needed to en-
sure that essential generic medications will con-
tinue to be available to and affordable for the
patients who need them.
Aaron S. Kesselheim, M.D., J.D.
Brigham and Womens Hospital
Boston, MA
Jonathan D. Alpern, M.D.
William M. Stauffer, M.D., M.S.P.H.
University of Minnesota
Minneapolis, MN
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
1. Silverman E. Justice Department probes generic companies
after price hike reports. Wall Street Journal Pharmalot. Novem-
ber 10, 2014 (http://blogs.wsj.com/pharmalot/2014/11/10/justice
-department-probes-generic-competition-after-price-hike-reports).
2. Kesselheim AS. Why are some generic drugs skyrocketing in
price? Testimony before the Senate Committee on Health, Edu-
cation, Labor & Pensions, November 20, 2014 (http://www.help
.senate.gov/imo/media/doc/Kesselheim.pdf).
3. GovTrack.us. Text of the Medicaid Generic Drug Price Fair-
ness Act (S. 2948) (https://www.govtrack.us/congress/bills/113/
s2948/text).
DOI: 10.1056/NEJMc1415471
Patient 1, a 63-year-old man with an 8-month
history of MDS, was admitted with high fever
(temperature, 39.2C), leukocytosis, and trans-
fusion-dependent anemia. Patient 2, a 63-year-
old woman with a 3-month history of MDS, had
general malaise on admission, along with ane-
mia and thrombocytopenia. Patient 1 had an
 correspondence

A B C
Patient 1 Patient 2
G304R R202Q

T C G G T C A C C R G G T C C R G C T G C
Patient

T C G G T C A C C G G G T C C G G C T G C

E F
Control

Figure 1. MEFV Mutations and Clinical and Pathological Findings in Two Patients with the Myelodysplastic Syndrome and Lesions Consistent
with Sweets Syndrome.
Panel A shows sequence analysis of MEFV in Patient 1 and Patient 2. The upper row shows the MEFV sequences from the two patients,
and the lower row shows two sequences without the mutations. The arrows indicate the heterozygous mutations. In Patient 2, Sweets
syndrome was manifested as a lesion in the left preauricular area (Panel B) and in bilateral intramuscular liquefactive necrosis and ab-
scess formation in the lower legs with perforation to the skin (Panel C). A computed tomographic image shows multiple bilateral intra-
muscular areas of necrosis in the thighs (Panel D). Pathological examination of samples obtained from the left preauricular area and
right lower leg showed neutrophil-based inflammatory-cell infiltration from the deep dermis to the subcutaneous adipose tissue associat-
ed with Sweets syndrome (Panels E and F, hematoxylin and eosin).

MDS subtype that included refractory anemia
with excess blasts, which was classified as very
high risk, according to the revised International
Prognostic Scoring System (IPSS). Patient 2 had
an MDS subtype that included refractory cytope-
nia with trilineage dysplasia, which was classi-
fied as high risk, according to the revised IPSS
(Table S1 in the Supplementary Appendix, avail-
able with the full text of this letter at NEJM.org).
Both patients had a history of periodic flares
of inflammatory symptoms, including antibiotic-
resistant high fever with marked neutrophilia,
systemic arthralgia, pericarditis, and enterocoli-
tis, symptoms that resembled those of familial
Mediterranean fever. Such symptoms were not
observed when the MDS was controlled with the
use of azacitidine or azacitidine plus lenalido-
mide (Fig. S1 in the Supplementary Appendix).
Sequence analyses of MEFV revealed hetero-
zygous mutations that have been identified as
causes of familial Mediterranean fever (G304R in
Patient 1 and R202Q in Patient 2, both in exon 2)
(Fig. 1A). Colchicine was then administered with
no effect in either patient. In Patient 1, skin
lesions that included facial erythema, genital
ulcers, and bilateral orbital cellulitis were ob-
served sporadically. It was suspected that the
lesions were caused by Sweets syndrome, but
the diagnosis was not confirmed on skin bi-
opsy. In Patient 2, a lesion developed on the face

n engl j med 372;7nejm.orgfebruary 12, 2015 687

The New England Journal of Medicine
Downloaded from nejm.org on May 28, 2015. For personal use only. No other uses without permission.
Copyright 2015 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l
(Fig. 1B), and liquefactive necrosis and abscess
formation subsequently developed in multiple
muscles in the bilateral lower legs (Fig. 1C), as
shown on computed tomography (Fig. 1D),
with marked neutrophilia. Pathological exami-
nation showed neutrophil-based inflammatory-
cell infiltration in two samples obtained from
the left preauricular area and the right lower leg
(Fig. 1E and 1F).
Generally, Sweets syndrome presents as one
of three clinical types: classic, cancer-associated,
or drug-induced.3,4 On the basis of the clinical
courses of the two patients, the skin lesions
could not be classified as drug-induced. In a
healthy Japanese population, E148Q (exon 2) is
the most prevalent mutated allele in MEFV (pres-
ent in 23.0% of persons with this mutation),
whereas the R202Q and G304R alleles are rela-
tively rare.5 By themselves, heterozygous muta-
tions R202Q and G304R in exon 2 were not
sufficient to induce inflammatory symptoms in
either patient. Therefore, the second factor was
an unknown trigger induced by MDS, which
activates the inflammasome. Our findings raise
the possibility that MEFV mutations may be iden-
tified with some frequency in both the classic
and cancer-associated forms of Sweets syndrome.
A CALR Mutation Preceding BCR-ABL1 in an Atypical
Myeloproliferative Neoplasm
To the Editor: Myeloproliferative neoplasms
are classified into two main types according to
the presence or absence of the Philadelphia chro-
mosome with translocation t(9;22) (BCR-ABL1).1
Mutations in signaling genes are considered to
be mutually exclusive,2-4 although the coexistence
of Janus kinase 2 (JAK2) V617F and BCR-ABL1 has
been observed.5 We report on a patient with both
a mutation in the gene encoding calreticulin
(CALR) and the BCR-ABL1 fusion gene in the same
dominant clone.
A 73-year-old woman was referred to the hos-
pital in June 2006 for a 2-year history of throm-
bocytosis. At initial examination, the patient
had marked clinical splenomegaly (spleen size,
18 cm in length) with moderate anemia (hemo-
globin level, 10.9 g per deciliter), teardrop eryth-
rocytes, a leukocyte count of 25,000 per cubic
688 n engl j med 372;7nejm.orgfebruary 12, 2015
The New England Journal of Medicine
Downloaded from nejm.org on May 28, 2015. For personal use only. No other uses without permission.
Copyright 2015 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
Therefore, sequence analysis of MEFV should be
considered in patients with MDS who have
marked neutrophilia and high fever, as well as
in those with Sweets syndrome.
Tatsuro Jo, M.D., Ph.D.
Kensuke Horio, M.D.
Japanese Red Cross Nagasaki Genbaku Hospital
Nagasaki, Japan
firetj@nagasaki-med.jrc.or.jp
Kiyoshi Migita, M.D.
Nagasaki Medical Center
Omura, Japan
Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
1. The International FMF Consortium. Ancient missense muta-
tions in a new member of the RoRet gene family are likely to
cause familial Mediterranean fever. Cell 1997;90:797-807.
2. Chae JJ, Komarow HD, Cheng J, et al. Targeted disruption of
pyrin, the FMF protein, causes heightened sensitivity to endo-
toxin and a defect in macrophage apoptosis. Mol Cell 2003;11:
591-604.
3. Raza S, Kirkland RS, Patel AA, Shortridge JR, Freter C. In-
sight into Sweets syndrome and associated-malignancy: a review
of the current literature. Int J Oncol 2013;42:1516-22.
4. Sweet RD. An acute febrile neutrophilic dermatosis. Br J Der-
matol 1964;76:349-56.
5. Sugiura T, Kawaguchi Y, Fujikawa S, et al. Familial Mediter-
ranean fever in three Japanese patients, and a comparison of the
frequency of MEFV gene mutations in Japanese and Mediterra-
nean populations. Mod Rheumatol 2008;18:57-9.
DOI: 10.1056/NEJMc1412998
millimeter with myelocytosis, and thrombocy-
tosis (platelet count, 523,000 per cubic milli-
meter). A high level of BCR-ABL1 transcripts
(9;22)(q34;q11) was detected in the absence of
JAK2 V617F, MPL W515L, and MPL W515K muta-
tions. She had a good response to imatinib, with
reductions in the leukocyte count and spleen size.
However, the anemia and the thrombocytosis
worsened even though the BCR-ABL1 transcript
level markedly decreased (Fig. 1A). A bone mar-
row biopsy showed moderate myelofibrosis.
The patient received a combination of ima-
tinib and peginterferon alfa. Because of toxic
effects, the interferon was replaced with a com-
bination of hydroxyurea and erythropoietin. In
2010, the BCR-ABL1 transcript level increased, and
imatinib was replaced with dasatinib at a dose
of 100 mg per day. The BCR-ABL1 transcript level