Asim Ajaz

Delong Liu

Guoqing Wei

Gustavo Cadavid

Karen Seiter

Uzoma Nwakuche

PubMed

Springer - Publisher Connector

LETTER TO THE EDITOR Open Access
Large granular lymphocytosis with severe
neutropenia following ipilimumab therapy
for metastatic melanoma
Guoqing Wei1,2†, Uzoma Nwakuche1†, Gustavo Cadavid1, Asim Ajaz, Karen Seiter and Delong Liu1*
To the editor
Cytotoxic T-lymphocyte antigen-4 (CTLA-4), a mole-
cule present on activated T cells, is a homologue of
CD28 that inhibits B7 co-stimulatory molecules
expressed on mature antigen presenting cells. Ipilimu-
mab is a fully humanized monoclonal antibody against
CTLA-4 [1]. Ipilimumab is FDA approved in the United
States for treatment of unresectable or metastatic mela-
noma [1,2]. We report the first case of large granular
lymphocytosis with severe neutropenia following ipili-
mumab therapy.
A 74 year old female presented with relapsed mela-
noma in the left lower extremity in Sept 2009. She was
treated with temozolomide. In July 2010, she developed
metastatic melanoma. She was enrolled onto a clinical
trial and treated with ipilimumab on Sept 16, 2010 and
October 7, 2010 at 3 mg/kg (232 mg per treatment)
q3wks. Her baseline CBC was normal. At the start of
the third dose, there was a significant decline in the
patient ’s WBC count. Therefore ipilimumab was
stopped. The patient was admitted on November 2,
2010 with fever, malaise and generalized weakness. She
was noted to have Hgb 6.2 G/dL, WBC 1.3 × 106 /L
with no neutrophils, and platelet count of 158 × 106
/L. The patient had a bone marrow evaluation which
showed mildly hypercellular cellular marrow with
marked myeloid hypoplasia/aplasia, relative erythroid
hyperplasia and mild megakaryocytic atypia. Karyotype
analysis demonstrated 46 XX, but FISH analysis
showed a 5q31 deletion with EGR1 gene deletion in
14% of the cells. Flow cytometry study showed 46%
T-cells with 20% large granular lymphocytes and 12%
NK cells. A T-cell receptor gene study by Genzyme
showed clonal T-cell receptor gamma gene rearrange-
ment. These findings were consistent with myelodys-
plasia and large granular lymphocytosis with severe
neutropenia. In addition to broad-spectrum antibiotics
and G-CSF, the patient was given IVIG without signifi-
cant response. The CBC on Nov 17 was WBC 0.8, Hgb
8.9, and Platelets 271. CT scans revealed bilateral locu-
lated pleural effusion for which she had thoracentesis.
The patient was started on treatment on Nov 18, 2010
with IV methylprednisolone 1 mg/kg q12h, and equine
ATG at 15 mg/kg daily × 4 days, as well as cyclospor-
ine 2.5 mg/kg twice daily. G-CSF and antibiotics were
continued. The WBC rose to 2.6 the day after ATG
was completed (Table 1). Two days later, her WBC
was 15.3. G-CSF was stopped. Her general condition
improved gradually. She was discharged 11 days later.
She remained on cyclosporine and low dose predni-
sone. Three months later, she remained only on low
dose prednisone. Her CBC showed WBC 12.1, Hgb
11.9, and Platelets 259 at last follow-up visit on Feb
23, 2011.
The most common adverse events associated with
ipilimumab are immune-related, including enterocoli-
tis, hepatitis, dermatitis and hypophysitis. Severe hema-
tological toxicity is rare. One case of severe
autoimmune-related neutropenia was reported and the
patient responded rapidly to IVIG infusion, but not to
steroids [3]. This case of large granular lymphocytosis
with severe neutropenia did not respond to IVIG and
steroids, but had a rapid response to ATG, steroids,
and cyclosporine immunosuppressive therapy. It is
unclear whether the myelodysplasia findings on the
bone marrow biopsy were related to the ipilimumab* Correspondence: DELONG_LIU@NYMC.EDU
† Contributed equally
1Division of Hematology and Oncology, New York Medical College and
Westchester Medical Center, Valhalla, NY 10595, USA
Full list of author information is available at the end of the article
Wei et al. Experimental Hematology & Oncology 2012, 1:3
http://www.ehoonline.org/content/1/1/3 Experimental 
Hematology & Oncology
© 2012 Wei et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
therapy or to previous chemotherapy with
temozolomide.
Acknowledgements
This study was supported in part by NYMC Blood Disease Fund (DL).
Author details
1Division of Hematology and Oncology, New York Medical College and
Westchester Medical Center, Valhalla, NY 10595, USA. 2Bone Marrow
Transplantation Center, the First Affiliated Hospital, Zhejiang University
School of Medicine, Hangzhou 310003, China.
Authors’ contributions
GW and UN contributed equally to the study. All authors participated in
concept design, data collection and analysis, drafting and critically revising
the manuscript. All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 13 February 2012 Accepted: 26 March 2012
Published: 26 March 2012
References
1. Lee B, Mukhi N, Liu D: Current management and novel agents for
malignant melanoma. J Hematol Oncol 2012, 5:3.
2. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB,
Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al: Improved survival
with ipilimumab in patients with metastatic melanoma. N Engl J Med
2010, 363(8):711-723.
3. Akhtari M, Waller EK, Jaye DL, Lawson DH, Ibrahim R, Papadopoulos NE,
Arellano ML: Neutropenia in a patient treated with ipilimumab (anti-
CTLA-4 antibody). J Immunother 2009, 32(3):322-324.
doi:10.1186/2162-3619-1-3
Cite this article as: Wei et al.: Large granular lymphocytosis with severe
neutropenia following ipilimumab therapy for metastatic melanoma.
Experimental Hematology & Oncology 2012 1:3.
Submit your next manuscript to BioMed Central
and take full advantage of: 
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at 
www.biomedcentral.com/submit
Table 1 Complete Blood Counts of the Patient
Date WBC
(×109)/L)
ANC
(×109)/L)
Hgb
(×g/L)
Plt
(×109)/L)
11/17/2010 0.8 8.9 271
11/18/2010 0.9 9.0 280
11/19/2010 0.1 8.3 142
11/20/2010 0.3 8.1 90
11/21/2010 0.7 8.8 92
11/22/2010 2.6 1.2 8.5 60
11/23/2010 15.3 6.7 8.7 70
11/24/2010 30.3 19.4 8.2 73
11/25/2010 35.9 7.8 55
11/27/2010 28.4 25.8 9.7 43
11/28/2010 23.6 20.5 10.1 41
11/30/2010 15.0 13.8 8.5 77
12/1/2010 12.4 8.8 82
12/2/2010 8.8 7.2 7.9 61
12/17/2010 2.7 1.6 9.8 59
12/21/2010 7.0 5.3 10.8 157
2/17/2011 6.5 5.6 10.1 194
2/23/2011 12.1 10.3 11.9 259
Abbreviations: WBC: white blood cell; ANC: absolute neutrophils count; Hgb:
hemoglobin; Plt: platelet.
Wei et al. Experimental Hematology & Oncology 2012, 1:3
http://www.ehoonline.org/content/1/1/3
Page 2 of 2


Large granular lymphocytosis with severe neutropenia following ipilimumab therapy for metastatic melanoma

1:3. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color ﬁgure charges

al: Improved survival with ipilimumab in patients with metastatic melanoma.

Arellano ML: Neutropenia in a patient treated with ipilimumab (antiCTLA-4 antibody).

Current management and novel agents for malignant melanoma. J Hematol Oncol

file:///data/core-remote/dit/data/Springer-OA/pdf/38e/aHR0cDovL2xpbmsuc3ByaW5nZXIuY29tLzEwLjExODYvMjE2Mi0zNjE5LTEtMy5wZGY=.pdf

Large granular lymphocytosis with severe neutropenia following ipilimumab therapy for metastatic melanoma

Abstract

Similar works

Full text

Available Versions

Springer - Publisher Connector