BioDiscovery : Case Study
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Corresponding author: Wenhan Cheng (tonymark8341@gmail.com), Bryan Jackson (bryan189j@tcmc.edu)
Academic editor: Nikolai Zhelev
Received: 12 Jun 2019 | Accepted: 19 Aug 2019 | Published: 26 Aug 2019
© 2019 Wenhan Cheng, Bryan Jackson
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation: Cheng W, Jackson B (2019) Aplastic Anemia induced by Nivolumab before a Treatment of Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia. BioDiscovery 22: e37211. https://doi.org/10.3897/biodiscovery.22.e37211
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As an Immune checkpoint blockade therapy (ICB), nivolumab has demonstrated efficacy in Acute Myeloid Leukemia (AML) and various other malignancies. Nivolumab is used as an anti-programmed cell death 1 (PD-1) agent. The toxicities are observed in more than 10% of patients, because of its ability, anti-PD-1 will upregulate the activity of T-cells. Over-activated T-cells will cause immune-related adverse events such as Aplastic Anemia (AA). Here, we present a case of an over 60-years old male patient with AML, and the possibility for him to receive an allogeneic hematopoietic stem cell transplantation (allo-HSCT). The patient was treated with nivolumab and subsequently developed AA. As an additional consideration, we will also discuss whether allo-HSCT is transplantable when AA is performed during the treatment of AML.
Acute Myeloid Leukemia, Nivolumab, Aplastic Anemia, Allogeneic hematopoietic stem cell transplantation, Cytarabine, Idarubicin, Methylprednisolone.
AML is a type of blood cancer with excess immature white blood cells in bone marrow. AML- associated regulatory T-cells (Tregs) will downregulate the function of adoptively transferred cytotoxic T-cells in vivo, and Tregs depletion followed by PD-1 inhibitor such as nivolumab will result in a superior anti-AML ability (
A 61-year-old Caucasian male was diagnosed with AML and detected mutations of DNA (cytosine-5)-methyltransferase 3 alpha (DNMT3A) by next-generation sequencing. The bone marrow biopsy was performed 3 months before presentation and found no evidence of AA; the patient had no personal or family history of AA. Laboratory investigations revealed white blood cell count (WBC) 44×109/L with 86% blasts, hemoglobin 8.1 g/dL and a platelet count of 37×109/L. After obtaining an informed consent, the patient was treated with an induction chemotherapy with IA regimen (cytarabine 1.5 g/m2 by vein daily on days 1-3, with idarubicin 12 mg/m2 by vein daily on days 1-3). After the first week of treatment, the patient’s WBC count fell to 36×109/L with a significant decrease in blast cell count. The patient had diarrhea, dizziness and headache which was most likely caused by chemotherapy, according to the comprehensive review of systems. It reveals the patient reported no other adverse reaction besides common side effects of IA regimen from the chemotherapy.On day 8, the first dose of nivolumab (1 mg/kg by vein) was started without induction chemotherapy and continued every two weeks for 10 cycles. No adverse reactions developed nor was there any disease progression. On day 138, the 11th dose of nivolumab was administered, and patient’s platelet count was 53×109/L. However, immediately after the 11th dose, there was a sudden decrease in platelet count to 32×109/L. As the following 12th dose of nivolumab was served, the patient’s platelet counts gradually dropped to 5×109/L. This result may reveal bone marrow damage, and it was possibly attributed to the nivolumab treatment. The patient’s bone marrow biopsy and aspirate was conducted. The images illustrated lacking of trilineage marrow elements, and a hypocellular marrow with global trilineage hypoplasia, (Figs
The patient characteristics .
The patient characteristics in with AA induced by nivolumab therapy |
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Gender/age |
Male/61 |
Hematology-Oncology |
Acute Myeloid Leukemia with DNMT3A mutation. |
Baseline CBC Hb (g/dL) Plt (×109/L) WBC (×109/L) |
8.1 37 44 |
ICB agent/dose |
Nivolumab (1mg/kg/two weeks) |
Presentation of AA |
151 days post 12th cycles of Nivolumab. |
AA presentation Hb (g/dL) Plt (×109/L) WBC (×109/L) |
6.1 5 12 |
BM biopsy |
The biopsy of BM reveals the bio-sample lack of hematopoietic elements and hypocellular marrow. |
Treatment of AA |
Methylprednisolone ×21 days. |
AA response |
Rapid recovery in hemoglobin and neutropenia on day 177. |
Patient outcome |
The patient has reached complete remission, no other adverse reaction is developing and further HSCT should be considered. |
BM aspirate demonstrated a spicules composed of stromal components, but lacking trilineage marrow elements.
Efficacy of chemotherapy, nivolumab and methylprednisolone in patient.
After one week DA regimen chemotherapy, patient was stared nivolumab therapy without continuing chemotherapy. After the 12th dose of nivolumab was administered an AA was detected. These graph provide last 229 days clinical dates of patient’s platelet, hemoglobin, WBC and blast cell count.
Organge Box: 1st nivolumab was administered.
Grey diamond: Aplastic anemia was detected.
Addition of nivolumab to IA regimen is safe in older AML patients; although, it may cause immune-related adverse events such as AA. Patients with AA receive a destruction of hematopoietic cells by over-activated immune system leads to pancytopenia. Somatic mutations, DNMT3A-mutated genes, were detected in some of the AML or AA patients (
Supported by Geisinger Cancer Institute Oncology Research Program.
Funding opportunity announcement number: RFA-CA-13-013, Reissued as: RFA-CA-18-016
Project Number: 5UG1CA189847-05 Former Number: 1UM1CA189847-01
Hematology Oncology Cancer Center GWV, 1000 E Mountain Blvd, Wilkes-Barre, PA 18711.
This clinical research and patient recruitment is following the ethics and regulations, which includes: Nuremberg Code (1947), Declaration of Helsinki (2000), Belmont Report (1979), CIOMS (2002), U.S. Common Rule (1991).
Reviewed by Institutional Review Board
NAME: Geisinger Institutional Review Board
IRB REGISTRATION #: 00008345
INSTITUTION: Geisinger Clinic.
FWA ASSURANCE: FWA00000063
ACCREDITATION: Geisinger Health System is accredited by the Association for the Accreditation of Human Protection Programs, Inc. (AAHRPP).
ADDRESS: Geisinger Institutional Review Board, 100 North Academy Avenue. Danville, PA 17822-3069.
The patients and author declares that they have no potential conflicts of interest.