Pure red cell aplasia: Review of treatment and proposal for a treatment strategy

Summary The management of pure red cell aplasia (PRCA) continues to challenge clinical investigators because the pathophysiology is heterogeneous and poorly understood. There are five treatment regimens that have established efficacy for patients with chronic PRCA. In patients with congenital hypoplastic anemia the best results have been reported using corticosteroids. Cyclosporine A is recommended as the treatment of choice in acquired PRCA. High-dose intravenous immunoglobulin therapy is highly effective in PRCA associated with parvovirus B19 infections and impaired IgG-antibody response. Treatment failures may be successfully managed with horse anti-human thymocyte globulin or cyclophosphamide plus corticosteroids. The potential of hematopoietic growth factors in the treatment of PRCA awaits further studies.     

Moderate-dose cyclophosphamide in the treatment of relapsed/refractory T-cell large granular lymphocytic leukemia-associated pure red cell aplasia

Background: T-cell large granular lymphocyte leukemia (T-LGLL) is a rare disorder characterized by clonal proliferation of large granular lymphocytes (commonly CD3+/CD8+/CD57+). However, the available data regarding the optimal treatment for relapsed/refractory T-LGLL patients are limited.

Methods: We retrospectively reviewed 10 patients treated with immunosuppressive therapy consisting of intravenous moderate-dose cyclophosphamide (MD-CTX) together with oral cyclosporine A for relapsed/refractory T-LGLL in our hospital between July 2006 and March 2013.

Results: The overall response rate to MD-CTX was 60% (6/10; hematologic complete remission rate, 50%; hematologic partial remission rate, 10%). The median time to response was 28.5 days (range, 20–118 days). The relapse rate of MD-CTX was 50% (3/6); two of these three patients achieved hematologic complete remission after receiving a second course of MD-CTX. Neutropenia was the major adverse event of the MD-CTX regimen. The median time to neutropenia was 5.5 days (range, 1–10 days) and the median neutropenia duration was 5 days (range, 3–15 days). None of the patients developed severe infection.

Conclusions: The MD-CTX regimen appears efficacious and safe in the treatment of relapsed/refractory T-LGLL patients.     

A case of pure red cell aplasia complicated by Evans syndrome

A 33-year-old woman complaining of severe anemia was admitted to our hospital for polyclonal hyperglobulinemia. She was diagnosed with pure red cell aplasia (PRCA) associated with Evans syndrome. Initially, the presence of human parvovirus B19 (HPV B19) IgM appeared to indicate that the cause of PRCA was HPV B19 infection. Evans syndrome improved with steroid therapy, but PRCA was refractory. Cyclosporine was administered; consequently, the patient markedly recovered from PRCA and was discharged. PRCA complicated by Evans syndrome occurred during the course of polyclonal hyperglobulinemia. The most direct etiology for the onset of PRCA was unclear; however, immunological disorders such as polyclonal hyperglobulinemia, in addition to HPV B19 infection, may have been partly responsible for the etiology of PRCA.     

Pure red cell aplasia: further evidence of T cell clonal disorder

Summary. We report a patient with pure red cell aplasia and type I autoimmune polyglandular syndrome who also had an expansion of suppressor T lymphocytes in the peripheral blood. Southern blotting of DNA from these cells suggested T cell receptor (TCR) γ gene rearrangement. We confirmed true clonality of this by amplification of the gene rearrangement using the polymerase chain reaction and subsequent analysis of the product by gene cloning and DNA sequencing.     

Pure red cell aplasia. Stable complete remission following antilymphocyte globulin administration

A 25-yr-old woman with idiopathic pure red cell aplasia achieved complete remission following a single 5-day course of antilymphocyte globulin at a dose of 50 mg/kg daily by intravenous injection as initial and sole therapy. Apart from transient arthralgia and asymptomatic thrombocytopenia there were no side effects. At 2 yr, the patient has normal peripheral blood, bone marrow and in vitro culture studies. This approach offers an alternative to conventional immunosuppressive therapy where there is evidence of an underlying immune disorder.     

Multicentric Castleman's disease associated with renal amyloidosis and pure red cell aplasia

 A 50-year-old man was admitted suffering from severe anemia and renal dysfunction. He had been admitted for the first time at the age of 49, and was diagnosed with multicentric Castleman's disease (MCD) and secondary amyloidosis. At that time, marked erythroid hypoplasia was demonstrated by both aspiration and biopsy of bone marrow. A diagnosis of pure red-cell aplasia (PRCA) was made. Immunosuppressive agents improved his symptoms and laboratory data. We report here a very rare case of PRCA following MCD and amyloidosis, and with reference to the literature, we discuss the relation between MCD and related diseases. Received: February 12, 1998 / Accepted: June 17, 1998     

Mesenchymal stem cells for the treatment of refractory pure red cell aplasia after major ABO-incompatible hematopoietic stem cell transplantation

Pure red cell aplasia (PRCA) is a well-known, although infrequent, hematological complication after allogeneic hematopoietic stem cell transplantation (HSCT). PRCA occurs in cases of major ABO mismatch between donor and recipient and is believed to be due to inhibition of donor erythroid progenitors by residual host isohemagglutinins. The purpose of our study was to further evaluate the efficacy of human adipose tissue-derived mesenchymal stem cells (AMSC) as the salvage therapy for refractory PRCA after major ABO-incompatible HSCT. Two patients with refractory pure red cell aplasia received intravenous infusions of AMSC at a dose of 1.5 × 10⁶/kg of the patients’ weight, and rapid recovery from PRCA without any side effects was observed. We conclude that AMSC seems to be a promising therapeutic option in patients with PRCA after ABO-mismatched HSCT, in whom conventional treatment fails.     

Pure red cell aplasia developing into myeloproliferation with myelodysplasia and subsequent leukemia after cyclosporin A therapy

We describe a very rare case of a patient who presented with red cell aplasia that later developed into myeloproliferation with myelodysplasia and eventually leukemia. A 63-year-old man presented with anemia and reticulocytopenia in May 1997. A bone marrow examination revealed erythroid aplasia with normal production of myeloid cells and megakaryocytes with a normal karyotype. After the diagnosis of pure red cell aplasia was made, the patient was treated with prednisolone and then with cyclosporin A (CyA). Two weeks after the initiation of CyA treatment, the peripheral reticulocyte count began to increase with a regrowth of erythroid cells in the bone marrow. Meanwhile, the peripheral white blood cell and platelet counts also increased to more than 10,000/microL and 1,000,000/microL, respectively. Examination of a bone marrow aspirate in December 1997 revealed myelodysplastic changes with trisomy 8. Despite the discontinuation of CyA and the administration of 1-beta-D-arabinofuranosylcytosine stearyl monophosphate, leukemia developed in August 1998. In September 1998, the patient died of sepsis during a neutropenic period that followed remission-induction therapy. In the mechanism of pathogenesis, CyA may induce upon pure red cell aplasia a secondary myeloproliferative disorder with myelodysplasia and leukemia. An alternative possibility is that CyA reduces autoimmune-mediated suppression of the underlying stem cell disorder and that the result of this reduction is the manifestation of myeloproliferation and leukemia.     

Azathioprine-associated pure red cell aplasia

Abstract. Azathioprine-associated pure red cell aplasia in patients with a renal allograft is a rare complication. Although immunological inhibition of erythroid progenitor cell has been suggested, the cause of this phenomenon remains unclear. The patient we describe showed a decrease in the number of erythroid progenitor cells and no evidence for the presence of a serum inhibitor of these precursor cells. Discontinuation of azathioprine was associated with a complete recovery from anaemia as well, with an increase in the number of erythroid progenitor cells.     

Spontaneous IL-2 production in vitro in two patients with pure red cell aplasia

Summary We investigated spontaneous cytokine production in two patients with pure red cell aplasia (PRCA). The peripheral blood mononuclear cells (PBMNC) from two patients produced IL-2. Cyclosporin A (CyA) suppressed in vitro IL-2 production in one patient, but not in the other. Spontaneous IL-2 production disappeared in one patient 10 months after the start of CyA therapy. The patient for whom CyA therapy was stopped after the disappearance of spontaneous IL-2 production has remained in continuous remission for 1 year. The present case suggests that spontaneous IL-2 production in PBMNC might be an indicator of disease activity.     

Successful treatment of pure red cell aplasia with high-dose dexamethasone after ABO-incompatible allogeneic hematopoietic stem cell transplantation

The literature reports an incidence of Pure Red Cell Aplasia (PRCA) ranging from 6-30% of all cases of ABO-incompatible HSCT. Although most patients resolve spontaneously after withdrawal immunosuppression, some of them require more aggressive treatment to manage this condition.     

Cytotoxic immunosuppressive drug treatment strategy in pure red cell aplasia

Remissions occurred in 2 of 5 consecutive cases of acquired pure red cell aplasia (PRCA) during an initial course of treatment with either azathioprine and prednisolone, or cyclophosphamide and prednisolone. Crossover to therapy with the alternative cytotoxic immunosuppressive agent in conjunction with continued administration of prednisolone in 3 unresponsive cases resulted in remission induction. Crossover to azathioprine was effective in 2 cases initially unresponsive to cyclophosphamide, and crossover to cyclophosphamide in 1 initially unresponsive to azathioprine. This emphasises that lack of cross-resistance to these drugs can occur in PRCA, and that crossover to treatment with the alternative agent in refractory cases is a useful strategy which has been underutilised in reported approaches to management. Administration of the effective regimen was continued for a mean of 15 months, and this more extended period of treatment was associated with a longer mean duration of remission than reported in previous studies.     

Pure red cell aplasia associated with thymoma: clinical insights from a 50-year single-institution experience

Acquired pure red cell aplasia (PRCA) is a rare disorder of erythropoiesis that can develop in association with a thymoma. Optimal management of this subgroup is unclear, and there have been few series reporting long-term clinical outcomes. Here, we report features of 13 patients treated for PRCA associated with thymoma over 50 years at our institution. Surgical resection of the thymoma was insufficient for normalisation of erythropoiesis in all cases. T-cell gene rearrangement studies did not routinely demonstrate a clonal process, and ciclosporin and anti-thymocyte globulin were effective adjuvant treatments. However, treatment-related morbidity was high, with frequent infectious complications.     

Pure red cell aplasia due to parvovirus following treatment with CHOP and rituximab for B-cell lymphoma

A 26-year-old woman, diagnosed with diffuse large B-cell lymphoma, was treated with CHOP (cyclophosphamide, hydroxydaunomycin, oncovin, prednisone), rituximab and radiotherapy. She developed transfusion-dependant anaemia, which persisted following chemotherapy. Bone marrow aspirate and biopsy were consistent with pure red cell aplasia and parvovirus infection. Serology was negative for previous or acute infection but parvovirus DNA was detected by polymerase chain reaction. Administration of intravenous immunoglobulin (1 g/kg) resulted in reticulocytosis and recovery of her haemoglobin. We hypothesize that rituximab caused depletion of her normal B cells, resulting in an inability to mount a primary immune response to parvovirus infection.     

Serum erythropoietic inhibitors in patients with pure red cell aplasia

Summary Inhibitory mechanisms of erythropoiesis in 20 patients with pure red cell aplasia (PRCA) were investigated using the technique of in vitro hematopoiesis and an assay for human parvovirus. Complement-dependent serum inhibitors against late erythroid progenitors (CFU-E) were demonstrated in seven of 19 patients examined, and complement-dependent inhibitors against early erythroid progenitors (BFU-E) were demonstrated in three of these seven patients. Nonspecific and complement-independent inhibitors against CFU-E were thought to be associated with the etiology of PRCA in one patient. Human parvovirus-mediated erythropoietic suppression was demonstrated in a patient with complete remission of acute lymphoblastic leukemia complicated with marrow erythroid aplasia, whose serum showed a perfect inhibition against erythroid progenitor cells. T-cell-mediated erythroid suppression was not demonstrated in the patients examined. These findings reveal that erythroid aplasia is associated with complement-dependent serum erythropoietic inhibitor in some patients (36.8% in the present study) with PRCA, but it is difficult to identify the mechanism of erythroid aplasia in more than half of the patients with PRCA. In addition, our present study discovered the presence of parvovirus-mediated marrow pure red cell aplasia in one adult patient with acute lymphoblastic leukemia.     

Lack of clinical efficacy of rituximab in the treatment of autoimmune neutropenia and pure red cell aplasia: implications for their pathophysiology

We describe 11 patients with severe refractory autoimmune cytopenias treated with the anti-CD20 monoclonal antibody rituximab. Six patients had autoimmune neutropenia (AIN), two had pure red cell aplasia (PRCA), one had AIN and autoimmune haemolytic anaemia, one had AIN and immune thrombocytopaenia purpura (ITP) and one had PRCA and ITP. Rituximab was administered at a dose of 375 mg/m² as an intravenous infusion weekly for 4 weeks. Six of eight patients with AIN and all three patients with PRCA did not respond. Two patients died: one with resistant AIN and autoimmune haemolytic anaemia died of pneumocytis pneumonia infection, and one with PRCA and ITP died of an acute exacerbation of bronchiectasis. Rituximab in AIN and PRCA appears to be less effective than Campath-1H when compared to historical data from our group. This supports the hypothesis that T cells may be important in the pathophysiology of AIN and PRCA.     

Pure red cell aplasia due to parvovirus B19 infection after liver transplantation： A case report and review of the literature

Pure red cell aplasia （PRCA） due to parvovirus B19 （PVB19） infectiori after solid organ transplantation has been rarely reported and most of the cases were renal transplant recipients, Few have been described after liver transplantation. Moreover, little information on the management of this easily recurring disease is available at present. We describe the first case of a Chinese liver transplant recipient with PVB19-induced PRCA during immunosuppressive therapy. The patient suffered from progressive anemia with the lowest hemoglobin level of 21 g/L. Bone marrow biopsy showed selectively inhibited erythropoiesis with giant pronormoblasts. Detection of PVB19-DNA in serum with quantitative polymerase chain reaction （PCR） revealed a high level of viral load. After 2 courses of intravenous immunoglobulin （IVIG） therapy, bone marrow erythropoiesis recovered with his hemoglobin level increased to 123 g/L. He had a lowlevel PVB19 load for a 5-too follow-up period without recurrence of PRCA, and finally the virus was cleared. Our case indicates that clearance of PVB19 by IVIG in transplant recipients might be delayed after recovery of anemia.     

Sirolimus for the treatment of multi-resistant pure red cell aplasia

Patients with relapsed, refractory or advanced stage B non-Hodgkin lymphoma (NHL) continue to have a dismal prognosis. This review summarises current and novel cellular and immunotherapy for these high-risk populations, including haematopoietic stem cell transplant, bispecific antibodies, viral-derived cytotoxic T cells, chimeric antigen receptor (CAR) T cells, and natural killer (NK) cell therapy, as discussed at the 6th International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma on September 26th–29th 2018 in Rotterdam, the Netherlands, and explores the future of NK/CAR NK therapies.