Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access
Article copyright, the authors; Journal compilation copyright, J Hematol and Elmer Press Inc
Journal website http://www.thejh.org

Case Report

Volume 8, Number 2, June 2019, pages 71-78

Bone Marrow Findings of Immune-Mediated Pure Red Cell Aplasia Following Anti-Programmed Cell Death Receptor-1 Therapy: A Report of Two Cases and Review of Literature

Figures

Figure 1.
Figure 1. Patient 1. (a) Bone marrow aspirate smear demonstrating predominantly granulocytic precursors with rare pro-erythroblasts (× 50 oil objective). (b) Core biopsy showing a normocellular bone marrow with erythroid hypoplasia, granulocytic hyperplasia, and megakaryocytes with a normal appearance (× 20 objective). (c) CD3 immunohistochemical stain depicting increased scattered and occasional clusters of small lymphocytes (× 10 objective). (d) CD20 immunohistochemical stain with rare scattered small B lymphocytes (× 10 objective).
Figure 2.
Figure 2. Patient 2. (a) Bone marrow aspirate showing rare pro-erythroblasts (× 50 oil objective). (b) Trephine biopsy showing a mildly hypercellular bone marrow with erythroid hypoplasia, granulocytic hyperplasia, megakaryocytes with a normal appearance, and increased lymphocytes without atypia. (c) CD3 immunohistochemical stains demonstrating increased T cells (× 10 objective). (d) CD20 immunohistochemical stain showing rare scattered small B cells (× 10 objective).
Figure 3.
Figure 3. Patient 2. (a, b) CD4 and CD8 immunohistochemical stains, respectively (CD8 > CD4) (× 10 objective). (c) TCR bF1 staining highlighting a majority of T cells (× 10 objective). (d) T-cell intracytoplasmic antigen immunohistochemical stain highlighting many T cells (× 10 objective).
Figure 4.
Figure 4. (a) Patient 1: flow cytometry demonstrating increased CD3+/CD8+ T cells with a CD4/CD8 ratio of 0.62 and increased gamma-delta T cells. (b) Patient 2: flow cytometry showing increased CD3+/CD8+ T cells with a CD4/CD8 ratio of 0.54.

Tables

Table 1. Peripheral Blood and Bone Marrow Aspirate Differential Counts of Two Patients
 
Patient 1Patient 2
WBC: white blood cell; Hb: hemoglobin; HCT: hematocrit; MCV: mean corpuscular volume; PLTs: platelets.
Peripheral blood count
  WBCs12,560/µL5,400/µL
  Hb7.6 g/dL9.4 g/dL
  HCT22.3%27.6%
  MCV88.1 fL87.9 fL
  PLTs55,000/µL153,000/µL
Bone marrow aspirate differential (200 cells count)
  Granulocytic precursors76.5%58.50%
  Erythroid precursors1%4.50%
  Eosinophils precursors1.5%4.5%
  Lymphocytes14.5%29.0%
  Monocytes3.0%0.50%
  Plasma cells3.5%3.0%
  Blasts0.0%0.0%
  CytogeneticsNot performed46,XY[20]

 

Table 2. Characteristics and Bone Marrow Findings of Patients With Immune-Related Pure Red Cell Aplasia Following Checkpoint Inhibitor Therapy
 
Our two patients and from literature (author, year)Gender, age, diseaseCheckpoint inhibitorTime to pure red cell aplasia occurrenceBaseline Hb (g/dL)Nadir Hb (g/dL)Bone marrow findingsTreatment for pure red cell aplasia
Nivolumab and pembrolizumab: anti-PD-1 checkpoint inhibitors; ipilimumab: anti-CTLA-4 checkpoint inhibitor; Hb: hemoglobin; IVIG: intravenous immunoglobulin.
Patient 1Female, 58 years old, metastatic head and neck poorly differentiated squamous cell carcinomaPembrolizumab3 weeks9.86.7Normocellular bone marrow with marked erythroid hypoplasia with maturation arrest. Numerous T cells with rare B cellsN/A, hospice
Patient 2Male, 74 years old, liposarcoma of the leg diagnosed in 2002, metastatic angiosarcoma of the thigh in 2015Nivolumab6 months12.77.7Hypercellular bone marrow with marked erythroid hypoplasia with maturation arrest; T lymphocytosis in a diffuse and interstitial pattern of distributionGlucocorticoids stabilize Hb level
Nair et al, 2016 [17]Female, 52 years old, metastatic melanomaIpilimumab initially then switched to pembrolizumabAfter three doses of pembro-lizumab12.56.3Marked erythroid hypoplasia with maturation arrest; numerous T cells and rare B cellsExcellent response to glucocorticosteroids with pure red cell aplasia flare upon tapering; treatment with IVIG enabled tapering of glucocorticosteroids
Yuki et al, 2017 [18]Female, 70 years old, metastatic melanomaNivolumab21 monthsN/A5.7Increased megakaryocytes and decreased erythroblasts (normal morphology)Excellent response to prednisone with taper
Gordon et al, 2009 [24]Male, 55 years old, metastatic melanomaIpilimumab6 weeks14.45.4Marked erythroid hypoplasia, granulocytic hyperplasia, adequate numbers of mature-appearing megakaryocytes, CD3-positive T cells outnumber CD20-positive B cellsPoor response to steroids; rapid clinical benefits from IVIG