Unexpected Severe Anemia in a Young Patient With Diffuse Large B-Cell Lymphoma After Autologous Hematopoietic Cell Transplant

A 26-year-old man was initially diagnosed with stage IVa diffuse large B-cell lymphoma (DLBCL) in 2009, when he presented with persistent symptoms of redness, itching, and double vision in the left eye. Paranasal computed tomography (CT) revealed a mass in the left frontal and ethmoid sinuses. Endoscopic biopsy and bone marrow (BM) biopsy confirmed DLBCL with BM involvement. He was treated with four cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), resulting in a complete remission. In 2017, the patient experienced difficulty swallowing, with a positron emission tomography (PET)-CT scan revealing a hypermetabolic mass in the right tonsil. Biopsy confirmed relapsed DLBCL, and the patient underwent four cycles of R-CHOP and two cycles of R-CEOP (rituximab, cyclophosphamide, etoposide, vincristine, and prednisone), achieving a complete remission again. The patient did not routinely attend follow-up appointments.

In 2022, the patient was hospitalized with a femur fracture, which led to the detection of disease relapse upon biopsy. PET-CT showed widespread lymphoma involvement. He was treated with one cycle of R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin). The patient declined to proceed with further chemotherapy and autologous hematopoietic cell transplantation (HCT) at that time. In 2023, the patient presented to the hospital with altered mental status characterized by nonsensical speech and was subsequently diagnosed with central nervous system (CNS) relapse of his DLBCL. A ventriculoperitoneal shunt was placed to manage increased intracranial pressure, with high-dose methotrexate administered for secondary CNS lymphoma. Following four cycles of high-dose MATRix (methotrexate, cytarabine, thiotepa, and rituximab), the patient underwent autologous HCT with CBV (cyclophosphamide, carmustine, and etoposide) conditioning in November 2023. Following successful engraftment, the patient was discharged from the BM transplant unit without any complications.

Seven months post-transplant, the patient developed severe anemia with reticulocytopenia (hemoglobin: 5.8 g/dL; hematocrit: 16.1%; mean corpuscular volume: 95.4 fL; mean corpuscular hemoglobin: 30.4 pg; reticulocyte count: 0.2%). Blood smear confirmed normochromic-normocytic anemia without additional abnormalities, prompting further investigation.

Table. Differential diagnosis of anemia in hematopoietic cell transplant recipients

Etiology	Evaluation
Reticulocytopenia
Nutritional deficiency	Iron, B12, folate measurement
Pure red cell aplasia	Parvovirus B19 DNA PCR, isohemaglutinin titer (*major ABO mismatch allogeneic transplant)
Graft failure/disease relapse/therapy-related myelodysplastic syndromes or acute myeloid leukemia	Bone marrow biopsy, cytogenetics/molecular assessment, peripheral blood or bone marrow chimerism (*allogeneic only)
Graft-versus-host diseas	Clinical suspicion and biopsy of involved organ (*allogeneic only)
Infectious agents	Parvovirus DNA, CMV DNA, EBV PCR, nasal swab, blood and urine culture, chest X-ray or CT (to identify a bacterial or fungal infection)
Endocrine causes	Check TSH and T4 level, ACTH and cortisol level (if clinical suspicion for hypothyroidism and adrenal insufficiency)
Drug-induced bone marrow suppression	If other causes are excluded, suspend suspected medication
Reticulocytosis
Transplant-associated thrombotic microangiopathy	Blood smear, LDH, haptoglobin, DAT, urine protein/creatinine ratio, sC5b-9, ADAMTS13 in selected cases
ABO mismatch	LDH, haptoglobin, DAT, isohemaglutinin titer (*early period of allogeneic transplant)
Autoimmune hemolytic anemia	Blood smear, LDH, haptoglobin, DAT
Drug-induced hemolytic anemia	Blood smear, LDH, haptoglobin, DAT

ACTH, adrenocorticotropic hormone; CMA, cytomegalovirus; CT, computed tomography; DAT, direct antiglobulin test; DNA, deoxyribonucleic acid; EBV, Epstein-Barr virus; LDH, lactate dehydrogenase; PCR, polymerase chain reaction; sC5b-9, soluble C5b-9; TSH, thyroid-stimulating hormone; T4, thyroxine.

The patient’s initial workup consisted of the following items:

Viral serologies: All infectious-related viral immunoglobulin M (IgM) markers (parvovirus, herpes simplex virus 1, cytomegalovirus, Epstein-Barr virus viral capsid antigen, anti-hemoglobin C, hepatitis C virus IgM) and human immunodeficiency virus antigen/antibody combo test were negative.
Nutritional assessment: no deficiencies in vitamin B12, folate, or iron
Normal thyroid-stimulating horome and serum thyroxine level
PET-CT and cranial magnetic resonance imaging: no evidence of relapse

BM biopsy revealed profound erythroid aplasia with giant pronormoblasts, while overall cellularity remained normal. Peripheral blood parvovirus deoxyribonucleic acid (DNA) was detected at greater than 15 million copies, confirming active parvovirus infection despite the absence of serum IgM positivity.

The patient was diagnosed with pure red cell aplasia (PRCA) due to human parvovirus B19 (HPV-B19) infection. Given the high viral load and post-transplant immunosuppression, intravenous immunoglobulin (IVIG) therapy at 400 mg/kg/d for five days was initiated.

The patient’s hemoglobin levels and viral load were monitored to assess response to IVIG, which resulted in successful recovery, with gradual improvement in hemoglobin levels and resolution of anemia (Figures 1 & 2).

Figure 1. Parvovirus DNA trend

Figure 2. Hemoglobin trend

Follow-up testing showed a significant decline in parvovirus DNA load, confirming effective viral clearance. The patient remained stable without recurrence of anemia.

PRCA is a rare disease that presents with anemia secondary to erythropoiesis failure. It is characterized by normocytic, normochromic anemia associated with reticulocytopenia in the peripheral blood and a sparse presence or absence of erythroblasts and giant pronormoblasts in the BM.¹ In hosts with chronic hemolysis or immunosuppression, PRCA may occur due to HPV-B19.² In the literature, HPV-B19-associated PRCA is seen more frequently in the early period after transplant. In immunocompromised hosts, serological tests may yield negative results. Consequently, parvovirus DNA polymerase chain reaction (PCR) analysis should be performed for an accurate diagnosis.³

The recommended treatment for HPV-B19 associated with PRCA includes dose reduction if there is ongoing immunosuppression, change of calcineurin inhibitor, and passive immunization with IVIG. According to current guidelines, standard therapy against HPV-B19 infection consists of IVIG in a total dose of 2 g/kg in five divided doses.⁴ Although antiviral medications are not considered effective treatment options for HPV-B19 infection, recent studies have demonstrated the efficacy of foscarnet in cases of relapsed or unresponsive parvovirus infection following IVIG treatment.⁵

In conclusion, it is recommended that HPV-B19 infection be considered in the differential diagnosis of anemia with reticulocytopenia in immunocompromised patients. It is acknowledged that standard HPV-B19 serological tests may not detect HPV-B19 infection. Consequently, HPV-B19 PCR testing should be performed when there is clinical suspicion.

Sawada K, Fujishima N, Hirokawa M. Acquired pure red cell aplasia: updated review of treatment. Br J Haematol. 2008;142:505-514.
Brown KE, Young NS. Parvovirus B19 infection and hematopoiesis. Blood Rev. 1995;9(3):176-182.
Ersal T, Özkalemkaş F, Özkocaman V, et al. Two cases of kidney transplant recipients with multiple relapsing pure red cell aplasia due to parvovirus B19 infection. Exp Clin Transplant. 2024;22(1):75-79.
Liefeldt L, Buhl M, Schweickert B, et al. Eradication of parvovirus B19 infection after renal transplantation requires reduction of immunosuppression and high-dose immunoglobulin therapy. Nephrol Dial Transplant. 2002;17(10):1840-1842.
Yu Y, Bao R, Lyu J, et al. Foscarnet therapy for pure red cell aplasia related to human parvovirus B19 infection in kidney transplant recipients: a preliminary exploration. Infect Drug Resist. 2021;14:2911-2923.

Disclosure Statement: Drs. Gülderen and Hunutlu indicated no relevant conflicts of interest.

Acknowledgment: This article was reviewed by Jeffrey Edwards, MD, MPH, and Pallawi Torka, MD, MBBS.