Correspondence
by cold or exercise) for which we found the
strongest genetic effect in our study.
As noted by Leow, several authors, including
Tews et al.,3 argue that the FTO locus acts on
obesity through the m6A epitranscriptomic func-
tion of the FTO protein. However, only IRX3 and
IRX5 showed a significant difference in their
levels of adipocyte expression between risk-allele
carriers and nonrisk allele carriers. Moreover,
several manipulations described by Tews et al.
may have altered IRX3 and IRX5 expression levels
(which were not reported), possibly explaining
the resulting phenotypes. Last, patients who have
homozygous loss-of-function mutations affect-
ing the FTO protein have severe growth retarda-
tion and multiple malformations but no effect of
obesity,4 indicating the FTO protein is unlikely
to be a primary phenotypic mediator, irrespec-
tive of the tissue of action.
As suggested by ORahilly et al., we also use
analysis of covariance (ANCOVA) to compare the
energy expenditure of Irx3 dominant-negative
(aP2-Irx3DN) and control mice, with adjustment
for lean body mass with the use of ANCOVA. We
continue to find significant differences in energy
expenditure (Fig. 1), which support our initial
conclusions. Last, we agree that additional stud-
ies are needed to continue the process of eluci-
Chimeric Antigen Receptor T Cells in Myeloma
To the Editor: Garfall et al. (Sept. 10 issue)1
describe an interesting case of a patient with
multiple myeloma who was successfully treated
with autologous stem-cell transplantation fol-
lowed by infusion of anti-CD19 chimeric antigen
receptortransduced CTL019 cells. The vast ma-
jority (99.95%) of the patients myeloma cells did
not express CD19; this indicates that the effects
of CTL019 could not be attributed to direct cyto-
toxicity against the predominant malignant clone
itself.
The authors hypothesize that the therapeutic
activity of CTL019 is due to targeting of rare
CD19-expressing myeloma precursors. However,
an alternative explanation for the antimyeloma
effect of CTL019 therapy could be that CTL019
results in depletion of nonmalignant CD19-pos-
itive B cells. Studies have shown that B cells can
promote cancer by providing growth and survival
n engl j med 374;2nejm.org January 14, 2016
The New England Journal of Medicine
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Copyright 2016 Massachusetts Medical Society. All rights reserved.
dating the ways in which genetic variants in the
FTO locus affect obesity beyond the ARID5B
rs1421085IRX3/IRX5browning axis elucidated
in our study.
Melina Claussnitzer, Ph.D.
Harvard Medical School
Boston, MA
melina@broadinstitute.org
ChiChung Hui, Ph.D.
Hospital for Sick Children
Toronto, ON, Canada
Manolis Kellis, Ph.D.
Massachusetts Institute of Technology
Cambridge, MA
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
1. Hakanen M, Raitakari OT, Lehtimki T, et al. FTO genotype
is associated with body mass index after the age of seven years
but not with energy intake or leisure-time physical activity. J Clin
Endocrinol Metab 2009;94:1281-7.
2. Speakman JR. The fat mass and obesity related (FTO) gene:
mechanisms of impact on obesity and energy balance. Curr Obe-
sity Reports 2015;4:73-91.
3. Tews D, Fischer-Posovszky P, Fromme T, et al. FTO defi-
ciency induces UCP-1 expression and mitochondrial uncoupling
in adipocytes. Endocrinology 2013;154:3141-51.
4. Boissel S, Reish O, Proulx K, et al. Loss-of-function muta-
tion in the dioxygenase-encoding FTO gene causes severe
growth retardation and multiple malformations. Am J Hum
Genet 2009;85:106-11.
DOI: 10.1056/NEJMc1513316
factors for the tumor and by suppressing antitu-
mor immunity.2-4 Of note, patients with multiple
myeloma frequently have altered B-cell homeo-
stasis with a characteristic expansion of a dis-
tinct population of memory B cells.5 Thus,
CTL019-mediated depletion of a pro-myeloma
B-cell population could contribute to the clinical
benefit of CTL019.
Alexander ShimabukuroVornhagen, M.D.
HansA. Schloesser, M.D.
MichaelS. vonBergweltBaildon, M.D., Ph.D.
University Hospital of Cologne
Cologne, Germany
shima@uk-koeln.de
No potential conflict of interest relevant to this letter was re-
ported.
1. Garfall AL, Maus MV, Hwang W-T, et al. Chimeric antigen
receptor T cells against CD19 for multiple myeloma. N Engl J
Med 2015;373:1040-7.
2. de Visser KE, Korets LV, Coussens LM. De novo carcinogen-
193
 The n e w e ng l a n d j o u r na l of m e dic i n e

esis promoted by chronic inflammation is B lymphocyte depen-
dent. Cancer Cell 2005;7:411-23.
3. Ammirante M, Luo J-L, Grivennikov S, Nedospasov S, Karin
M. B-cell-derived lymphotoxin promotes castration-resistant
prostate cancer. Nature 2010;464:302-5.
4. Balkwill F, Montfort A, Capasso M. B regulatory cells in
cancer. Trends Immunol 2013;34:169-73.
5. Hansmann L, Blum L, Ju C-H, Liedtke M, Robinson WH,
Davis MM. Mass cytometry analysis shows that a novel memory
phenotype B cell is expanded in multiple myeloma. Cancer Im-
munol Res 2015;3:650-60.
DOI: 10.1056/NEJMc1512760
The authors reply: In reply to Shimabukuro-
Vornhagen and colleagues: the mechanism of ac-
tion underlying the efficacy of CTL019 in the
case of multiple myeloma we reported remains
uncertain. In our discussion, we acknowledged
the possibility that elimination of non-neoplastic
B cells by CTL019 might be at least partially re-
sponsible for its therapeutic activity, and we cited
prior studies showing the tumor-promoting ca-
pabilities of B cells and CD19-positive plasma
cells.1,2 Through this mechanism, CTL019 may
have clinical usefulness in other cancers that do
not express CD19, particularly in combination
with other immunotherapies.
AlfredL. Garfall, M.D.
EdwardA. Stadtmauer, M.D.
CarlH. June, M.D.
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
cjune@exchange.upenn.edu
Since publication of his article, Dr. Garfall reports receiving
consulting fees from Novartis. No further potential conflict of
interest relevant to this letter was reported.
1. Affara NI, Ruffell B, Medler TR, et al. B cells regulate mac-
rophage phenotype and response to chemotherapy in squamous
carcinomas. Cancer Cell 2014;25:809-21.
2. Shalapour S, Font-Burgada J, Di Caro G, et al. Immunosup-
pressive plasma cells impede T-cell-dependent immunogenic
chemotherapy. Nature 2015;521:94-8.
DOI: 10.1056/NEJMc1512760

Dependent Coverage under the ACA and Medicaid Coverage

for Childbirth
To the Editor: In the United States, rates of ment sources for childbirth among young adults
uninsurance have been historically high among (details of the methods are provided in the
young adults (19 to 26 years of age). One of the Supplementary Appendix, available with the full
first implemented provisions of the Affordable
Care Act (ACA) was a mandate that all private- Figure 1 (facing page). Time Trends in Payment Sources
insurance family policies cover dependents until for Childbirth, According to Age Group.
26 years of age. Estimates suggest that this pro- Seasonally adjusted time trends in payment sources
vision has reduced the rate of uninsurance for childbirth according to the Centers for Disease
among young adults by approximately 10%.1 Control and Prevention natality data obtained from
Childbirth, the major reason for hospitalization states that provided health insurance information are
shown.3 The payment sources were private insurance
of young adults, has received little attention in (Panels A and B), Medicaid (Panels C and D), self-pay
prior literature on the mandate. ment (Panels E and F), and other payment (Panels G
Childbirth is financed differently from other and H). Each circle in the scatter plot represents the
U.S. health care services. Before the ACA, Med- percentage of births paid for by the particular payment
type in that month for that age group. The category of
icaid covered all pregnant women earning less
other payment included the Indian Health Service,
than 133% of the federal poverty level. During the TRICARE military health system (formerly known
this time, the government covered approximate- as the Civilian Health and Medical Program of the Uni
ly half of U.S. births.2 Though 32.2% of young formed Services), other government insurance at the
adults were uninsured in 2009, for instance, only federal, state, and local levels, and all other insurance.
The time period was January 2009 through December
approximately 5% of births to these adults were
2012, except for the period from March 2010 through
uninsured; more than 60% were covered by December 2010 (the staggered implementation period).
Medicaid. 1
We used regression modeling of the individual-level
In our study, we used data from the natality data with the payment type as the outcome in order to
files of the Centers for Disease Control and Pre- calculate the monthly seasonal adjustments as coeffi
cients on monthly dummy variables. We then subtract
vention and the Nationwide Inpatient Sample
3
ed the seasonal adjustments from averages calculated
from the Agency for Healthcare Research and at the age and month levels.
Quality to consider the effect of the ACA on pay-

194 n engl j med 374;2nejm.org January 14, 2016

The New England Journal of Medicine

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