To the editor,
Acute Lymphoblastic leukemia (ALL) of the central nervous system (CNS)
often presents asymptomatically; however, CNS disease has also been
noted to present with focal neurological defects or
seizures.1 Here, we present an unusual case of overt
CNS ALL presenting with rapid weight gain which was completely reversed
by administration of CNS-directed leukemia therapy.
A seven-year-old female with history of multiply relapsed pre-B acute
lymphoblastic leukemia (ALL) and autism spectrum disorder was admitted
with increased fatigue, weight gain, increased appetite, and shortness
of breath. Her ALL history started when she was two years old in her
native country and was initially treated per BFM ALL-IC 2009. She
emigrated to the United States during maintenance therapy and finished
per COG protocol AALL0932, Average Risk arm. Since that time, she has
relapsed three times. The first occurred six months following her
initial therapy, consisted of bone marrow and CNS relapse, and was
treated with reinduction therapy followed by myeloablative matched
unrelated donor (MUD) bone marrow transplant (BMT). The second relapse
occurred in eleven months later, consisted of isolated bone marrow
disease, and treated with anti-CD19 CAR-T cell therapy (brexucabtagene
autoleucel) followed by a reduced intensity MUD BMT. Ten months after
her second relapse, she had her third relapse, again consisted of
isolated bone marrow disease, and was treated with blinatumomab and
inotuzumab over a seven-month period.
One year later and one month prior to presentation, the patient was
noted to be having increasing weight and fatigue. This progressed to the
point where she was also noted to have dyspnea. She was also noted to
have hyperphagia during this time. On the day of presentation, she
developed acute abdominal pain prompting evaluation in the emergency
department. She had vital sign irregularities, both tachycardia and
tachypnea, although no visible distress. She also had a Cushingoid
appearance. CBC was unremarkable, with WBC 8.9K/µL (5.5K-15.5K/µL),
absolute neutrophil count (ANC) of 5450/µL (1500-8000/µL), and platelet
count 378K (150K-350K/µL). She was mildly anemic, with hemoglobin 11.5
g/dL (11.7-13.8 g/dL), although at her baseline. She had mild elevation
in her liver function tests, with AST and ALT 92 U/L (0-31 U/L) and 155
U/L (0-31 U/L), respectively. TSH was mildly elevated at 6.91 IU/mL
(0.5-4.5 IU/mL), but Free T4 was normal at 0.8 ng/dL 0.8-1.8 ng/dL). Her
chest radiograph was unremarkable. During her admission, she had
additional labs to assess her CRH-ACTH-cortisol axis. Her morning
cortisol was 26.2 µg/dL with adequate suppression to 1.2 µg/dL with
dexamethasone. Her ACTH level was also normal at 34 pg/mL (9-57 pg/mL).
She had a CT angiogram to assess for pulmonary embolus which was
unremarkable. Lastly, to rule out leukemic involvement of her
hypothalamic-pituitary axis or a secondary neoplasm given previous
radiation treatment during BMT, a brain MRI was obtained which was
unremarkable.
She was discharged after normalization of her vital signs, resolution of
abdominal pain, and otherwise unremarkable evaluation. Ultimately, it
was decided to send flow cytometry from her peripheral blood and bone
marrow aspirate as well as the CSF. Peripheral blood flow cytometry and
bone marrow aspirate flow cytometry showed 0.2% and 9.1% abnormal
phenotypic cells consistent with a fourth relapse of precursor B-cell
ALL. Cerebrospinal fluid analysis also demonstrated 3,114 WBCs/µL with
flow cytometry, designating 99% as lymphoblasts. She was started on
therapy as detailed in Figure 1A. Upon initiation of intrathecal
therapy, she experienced a rapid reduction in CNS leukemia burden and
weight (Figure 1A, 1B). She also received intermittent systemic
chemotherapy (IV vincristine, oral dexamethasone, oral
6-mercaptopurine), but this was limited given toxicity (sluggishness)
and need to preserve peripheral lymphocytes to allow T cell collection.
She ultimately proceeded to anti-CD19 CAR-T cell therapy
(tisagenleleucel) and achieved remission. She continues to demonstrate
no evidence of disease two years later, with continued B-cell aplasia
suggesting persistence of CAR T cells, and appropriate weight gain.
We surmise that this patient’s rapid weight gain was caused by CNS
leukemia, which corrected after administration of CNS-directed leukemia
therapy. There have been other rare cases of leukemia presenting with
weight gain reported in the literature, each associated with CNS
disease.2-5 We presume that this patient was
experiencing hypothalamic obesity because of ALL in the CNS. It is well
known that disruptions of the hypothalamus, including oncologic causes,
can cause obesity associated with hyperphagia, also known as
hypothalamic obesity. Damage to the hypothalamus by tumors infiltrating
the hypothalamus (craniopharyngioma, glioma, etc.), surgery, or
radiation are more familiar to oncologists as the cause of this
syndrome.6 Although we did not see a mass on brain MRI
or any other imaging signs suggestive of CNS leukemia, it is possible
that there was leukemia infiltrate in that region causing a hypothalamic
disruption. With the large number of leukemic blasts in the CNS, it is
likely that she had diffuse brain parenchymal involvement leading to the
clinical manifestations seen here, including rapid weight gain with
associated hyperphagia (hypothalamic obesity) and some degree of
autonomic dysfunction (tachycardia and tachypnea).
This case highlights the causative association between rapid weight gain
and increased appetite with CNS ALL. While most children will remain
asymptomatic with CNS involvement, the diagnosis of ALL should be
considered with these unique presentations to expedite timely diagnosis
and treatment.
Conflicts of Interest: The authors declare no conflict of interest.
Acknowledgments: CH is supported by the National Institutes of Health
(T32 CA060441).