Nivolumab-associated bone marrow necrosis

Nivolumab-associated bone marrow necrosis Bone marrow necrosis (BMN) is an uncommon pathologic entity of unknown etiology. It is highly associated with metastatic tumor or hematolymphoid malignancies, typically in the setting of chemotherapy [1]. Common symptoms include bone pain and fever. The majority of patients have pancytopenia, as well as elevated lactate dehydrogenase (LDH) and alkaline phosphatase levels [2]. We describe a patient with diffuse large B cell lymphoma who was treated with nivolumab and developed BMN while on treatment. This is the first case in the literature reporting this potential adverse event. A 52-year-old man with a history of high-grade non-Hodgkin’s lymphoma diagnosed in January 2014 was treated with rituximab, cyclophosphamide, doxorobucin, vincristine, and prednisone for six cycles and achieved a complete response. He had evidence of disease relapse in the mediastinum in April 2015 on surveillance imaging. He was treated with rituximab, ifosfamide, carboplatin, and etoposide for three cycles. His bone marrow evaluation in June 2015 showed a normocellular marrow with no lymphoma, and he was able to undergo an uneventful stem cell harvest and autologous stem cell transplant. His disease relapsed again in March 2016 with evidence of mediastinal and retroperitoneal lymphadenopathy; he received salvage chemotherapy with rituximab, etoposide, methylprednisolone, cytarabine, and cisplatin for two cycles and had an inadequate response on positron emission tomography scan in June 2016. He received rituximab, gemcitabine, oxaliplatin for two cycles and again had an inadequate response with a hypermetabolic mass in the abdomen and progressive lymphadenopathy. At that point, his bone marrow evaluation again was normocellular marrow with no evidence of lymphoma or other malignancy (Figure 1A). Figure 1. View largeDownload slide (A) Bone marrow core biopsy showing a normocellular marrow without evidence of lymphoid aggregates (H&E 100×). (B) Bone marrow core biopsy showing extensive necrosis with sheets of necrotic ghost cells (H&E 200×). Figure 1. View largeDownload slide (A) Bone marrow core biopsy showing a normocellular marrow without evidence of lymphoid aggregates (H&E 100×). (B) Bone marrow core biopsy showing extensive necrosis with sheets of necrotic ghost cells (H&E 200×). The patient was started on nivolumab in an attempt to achieve a response that would make him a candidate for an allogeneic stem cell transplant. He received 300 mg every 2 weeks for five cycles. Repeat imaging showed a complete response with no evidence of hypermetabolic disease. A repeat bone marrow biopsy in December 2016 showed extensive necrosis and regenerative-type fibrosis replacing 90% of the core biopsy (Figure 1B). No viable lymphoma was identified. His blood counts showed a hemoglobin level of 12 g/dl, platelet count of 171k/μl, WBC of 6 × 10(9)/l. Serum chemistries including liver enzymes were normal. LDH was 190 U/l. The patient went on to receive four more cycles of nivolumab and an allogeneic SCT in March 2017. He remains in remission as of July 2017 with evidence of chronic graft-versus-host disease of the skin. Although the cause of BMN is poorly understood, analyzing the molecular mechanisms underlying BMN in acute lymphoblastic leukemia showed significant overexpression of Fas-ligand and macrophage-eliciting TNF-α in patients with BMN. Furthermore, perforin and granzyme B appear to be overexpressed [3]. Both these findings indicate that cell death seen with BMN may be induced by the extrinsic pathway and the perforin/granzyme B pathway of apoptosis [4]. Nivolumab, an immune checkpoint inhibitor, increases T-cell-mediated immune responses thereby turning the immune system against the tumor. However, immune-related adverse events are a major source of morbidity [5]. We hypothesize that T-cell activation and cytokine (TNF-α) production induced by immune checkpoint inhibitors may induce cell apoptosis via both the extrinsic and perforin/granzyme pathway. BMN should be considered in patients who develop cytopenias while receiving immunotherapy. Funding None declared. Disclosure The authors have declared no conflicts of interest. References 1 Wool GD, Deucher A. Bone marrow necrosis: ten-year retrospective review of bone marrow biopsy specimens. Am J Clin Pathol  2015; 143( 2): 201– 213; quiz 306. Google Scholar CrossRef Search ADS PubMed  2 Paydas S, Ergin M, Baslamisli F et al.   Bone marrow necrosis: clinicopathologic analysis of 20 cases and review of the literature. Am J Hematol  2002; 70( 4): 300– 305. Google Scholar CrossRef Search ADS PubMed  3 Moritake H, Obara M, Sameshima N et al.   Analysis of the molecular mechanism underlying bone marrow necrosis with acute lymphoblastic leukemia [Clinical Trial Multicenter Study]. Int J Hematol  2015; 102( 3): 349– 356. Google Scholar CrossRef Search ADS PubMed  4 Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol  2007; 35( 4): 495– 516. Google Scholar CrossRef Search ADS PubMed  5 Naidoo J, Page DB, Li BT et al.   Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol  2015; 26( 12): 2375– 2391. Google Scholar PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Oncology Oxford University Press

Nivolumab-associated bone marrow necrosis

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Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
ISSN
0923-7534
eISSN
1569-8041
D.O.I.
10.1093/annonc/mdx643
Publisher site
See Article on Publisher Site

Abstract

Bone marrow necrosis (BMN) is an uncommon pathologic entity of unknown etiology. It is highly associated with metastatic tumor or hematolymphoid malignancies, typically in the setting of chemotherapy [1]. Common symptoms include bone pain and fever. The majority of patients have pancytopenia, as well as elevated lactate dehydrogenase (LDH) and alkaline phosphatase levels [2]. We describe a patient with diffuse large B cell lymphoma who was treated with nivolumab and developed BMN while on treatment. This is the first case in the literature reporting this potential adverse event. A 52-year-old man with a history of high-grade non-Hodgkin’s lymphoma diagnosed in January 2014 was treated with rituximab, cyclophosphamide, doxorobucin, vincristine, and prednisone for six cycles and achieved a complete response. He had evidence of disease relapse in the mediastinum in April 2015 on surveillance imaging. He was treated with rituximab, ifosfamide, carboplatin, and etoposide for three cycles. His bone marrow evaluation in June 2015 showed a normocellular marrow with no lymphoma, and he was able to undergo an uneventful stem cell harvest and autologous stem cell transplant. His disease relapsed again in March 2016 with evidence of mediastinal and retroperitoneal lymphadenopathy; he received salvage chemotherapy with rituximab, etoposide, methylprednisolone, cytarabine, and cisplatin for two cycles and had an inadequate response on positron emission tomography scan in June 2016. He received rituximab, gemcitabine, oxaliplatin for two cycles and again had an inadequate response with a hypermetabolic mass in the abdomen and progressive lymphadenopathy. At that point, his bone marrow evaluation again was normocellular marrow with no evidence of lymphoma or other malignancy (Figure 1A). Figure 1. View largeDownload slide (A) Bone marrow core biopsy showing a normocellular marrow without evidence of lymphoid aggregates (H&E 100×). (B) Bone marrow core biopsy showing extensive necrosis with sheets of necrotic ghost cells (H&E 200×). Figure 1. View largeDownload slide (A) Bone marrow core biopsy showing a normocellular marrow without evidence of lymphoid aggregates (H&E 100×). (B) Bone marrow core biopsy showing extensive necrosis with sheets of necrotic ghost cells (H&E 200×). The patient was started on nivolumab in an attempt to achieve a response that would make him a candidate for an allogeneic stem cell transplant. He received 300 mg every 2 weeks for five cycles. Repeat imaging showed a complete response with no evidence of hypermetabolic disease. A repeat bone marrow biopsy in December 2016 showed extensive necrosis and regenerative-type fibrosis replacing 90% of the core biopsy (Figure 1B). No viable lymphoma was identified. His blood counts showed a hemoglobin level of 12 g/dl, platelet count of 171k/μl, WBC of 6 × 10(9)/l. Serum chemistries including liver enzymes were normal. LDH was 190 U/l. The patient went on to receive four more cycles of nivolumab and an allogeneic SCT in March 2017. He remains in remission as of July 2017 with evidence of chronic graft-versus-host disease of the skin. Although the cause of BMN is poorly understood, analyzing the molecular mechanisms underlying BMN in acute lymphoblastic leukemia showed significant overexpression of Fas-ligand and macrophage-eliciting TNF-α in patients with BMN. Furthermore, perforin and granzyme B appear to be overexpressed [3]. Both these findings indicate that cell death seen with BMN may be induced by the extrinsic pathway and the perforin/granzyme B pathway of apoptosis [4]. Nivolumab, an immune checkpoint inhibitor, increases T-cell-mediated immune responses thereby turning the immune system against the tumor. However, immune-related adverse events are a major source of morbidity [5]. We hypothesize that T-cell activation and cytokine (TNF-α) production induced by immune checkpoint inhibitors may induce cell apoptosis via both the extrinsic and perforin/granzyme pathway. BMN should be considered in patients who develop cytopenias while receiving immunotherapy. Funding None declared. Disclosure The authors have declared no conflicts of interest. References 1 Wool GD, Deucher A. Bone marrow necrosis: ten-year retrospective review of bone marrow biopsy specimens. Am J Clin Pathol  2015; 143( 2): 201– 213; quiz 306. Google Scholar CrossRef Search ADS PubMed  2 Paydas S, Ergin M, Baslamisli F et al.   Bone marrow necrosis: clinicopathologic analysis of 20 cases and review of the literature. Am J Hematol  2002; 70( 4): 300– 305. Google Scholar CrossRef Search ADS PubMed  3 Moritake H, Obara M, Sameshima N et al.   Analysis of the molecular mechanism underlying bone marrow necrosis with acute lymphoblastic leukemia [Clinical Trial Multicenter Study]. Int J Hematol  2015; 102( 3): 349– 356. Google Scholar CrossRef Search ADS PubMed  4 Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol  2007; 35( 4): 495– 516. Google Scholar CrossRef Search ADS PubMed  5 Naidoo J, Page DB, Li BT et al.   Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol  2015; 26( 12): 2375– 2391. Google Scholar PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Annals of OncologyOxford University Press

Published: Feb 1, 2018

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