Refractory Pure Red Cell Aplasia Research Articles

ALENTUZUMAB AS THIRD LINE TREATMENT IN PURE RED SERIE APLASIA - A SUCCESSFUL CASE REPORT

Pure red cell aplasia (PRCA) is a rare hematologic disorder characterized by reticulocytopenic, normocytic anemia with absence of red cell precursors in bone marrow, normal granulopoiesis, and megakaryopoiesis. The disease may be associated with viral infections, large granular lymphocytic leukemia, chronic lymphocytic leukemia, or thymoma, but the most common form is idiopathic. Refractory PRCA may respond to more profound immunosuppression with anti-CD52. To describe a refractory PRCA patient treated with anti-CD52 humanized monoclonal antibody, alemtuzumab, with good response. A 52-year-old male patient with hemophilia A, previously treated with cryoprecipitate and currently using prophylactic Factor VIII, presents to healthcare with severe asthenia, no bleeding episodes during the period. Laboratory evaluation: Hb 3.4 g/dL; Ht 10.6% VCM 95; WBC 6.490 × 10 9 /L; Platelets 196 × 10 9 /L, intense reticulocytopenia (25 × 10 9 /L). He had normal renal function, liver function, LDH, vitamin B12, folic acid, iron profile; serology with positive anti-HCV. Bone marrow evaluation showed 50-60% cellularity with intense hypoplasia of the erythroid series, granulocytic series with no changes in morphology or maturation pattern, and normal megakaryocytes with no signs of dysplasia. After investigation with immunoglobulin dosing, chest CT, flow cytometry for LGL, and serology for parvovirus, all normal, the diagnosis of constitutional APSV was confirmed. Treatment with cyclosporine (CSA) at a dose of 6mg/kg was initiated, with no reticulocyte response. In addition, he evolved with progressively increasing bilirubin levels (BT 7.4 BD 5.6) concomitant with a significant increase in Hepatitis C viral load (380,667 IU/mL Log: 5.58). Immunosuppression was discontinued, treatment with sofosbuvir and simeprevir was initiated, with good viral response. However, he required red blood cell transfusions every 2-3 weeks; new therapy was restarted with CSA and prednisone. The patient did not tolerate this treatment and developed severe thrombocytopenia and no improvement in hemoglobin levels. Considering the high risk of bleeding, CSA was discontinued. Platelet count normalized but he continued to require mensal RBC transfusion. At this point, second-line therapy with IV Alentuzumab, 3 mg dose followed by 6 weekly 15 mg doses (total 96 mg), coupled with infectious prophylaxis, has been proposed. Response occurred as early as the third infusion, as documented by a rapid increase in reticulocyte count. Within seven weeks the patient had a complete response (Hb 12.4 g/dL, Vg 35.3% and reticulocytes 170 × 10 9 /L). He had no toxicity-related intercurrences and remained with a complete response after six months of treatment. Unfortunately, a further progressive drop in hemoglobin after nine months from the end of the first treatment was observed. We opted to restart Alentuzumab at a dose of 15 mg/month, and follow with this maintenance dose. After the third application, the patient again showed a complete response (Hb 14.3 g/dL and VG 40.5%). Currently, the patient continues to use the medication every 45 days with a maintained hemoglobin level. Small case series cite Alentuzumab for refractory APSV as a treatment possibility with 63% overall response. We suggest use in refractory cases, followed by maintenance dosing to avoid relapse in long-term follow-up.

Successful Treatment of Pure Red Cell Aplasia and Chronic GVH with Rituximab after ABO Mismatched HSCT

Background: Pure Red Cell Aplasia (PRCA) is a rare complication of ABO mismatched hematopoietic stem cell transplantation; there isn’t no standard of care, here we report a case of successful treatment by Rituximab in a refractory PRCA and chronic graft versus host disease. Case Presentation: A 26-year-old woman with PRCA following ABOmismatched allogeneic HSCT for chronic myeloid leukemia, associated with steroid refractory chronic hepatic graft versus host disease, treated with 4 doses of Rituximab 375mg/m² weekly, with an increase in her hemoglobin level and improvement of her liver’s enzymes. Conclusion: The interest of this case is to report the important therapeutic result of Rituximab, widely used in literature, especially if chronic Graft Versus host disease is associated.

Successful treatment of refractory pure red cell aplasia with eltrombopag after ABO-incompatible allogeneic hematopoietic stem cell transplantation

Pure red cell aplasia (PRCA) is a well-recognized complication of ABO major mismatched allogeneic hematopoietic stem cell transplantation (allo-HSCT), with a reported incidence of 10%-20% (Zhidong et al., 2012; Busca et al., 2018). It is clinically characterized by anemia, reticulocytopenia, and the absence of erythroblasts in a normal-appearing bone marrow biopsy (Shahan and Hildebrandt, 2015). The mechanism for PRCA has been presumed to be persistence of recipient isoagglutinins, produced by residual host B lymphocytes or plasma cells, which can interfere with the engraftment of donor erythroid cells (Zhidong et al., 2012). Several risk factors of PRCA at presentation are known, such as presence of anti-A isoagglutinins before transplantation, reduced intensity conditioning, absence of acute graft-versus-host disease (GVHD), sibling donors, and cyclosporin A (CsA) as GVHD prophylaxis (Hirokawa et al., 2013). PRCA is not considered to be a barrier to HSCT, as some patients can recover spontaneously or benefit from various approaches including high-dose steroids, erythropoietin (EPO), plasma exchange, immunoadsorption, donor lymphocyte infusion (DLI), treatment with rituximab, bortezomib, or daratumumab, and tapering or discontinuation of immunosuppression (Hirokawa et al., 2013; Bathini et al., 2019). However, there are still some patients who fail to respond even to aggressive treatment; they become red cell transfusion-dependent and iron-overloaded, and their life quality is impaired.

Low‐dose ibrutinib in the treatment of refractory pure red cell aplasia in chronic lymphocytic leukaemia

Low‐dose ibrutinib in the treatment of refractory pure red cell aplasia in chronic lymphocytic leukaemia

Response to cyclosporine A and corticosteroids in adult patients with acquired pure red cell aplasia: serial experience at a single center.

To assess response to cyclosporine A, and/or corticosteroids, and possible factors influencing the response in adult patients with acquired pure red cell aplasia (PRCA). Clinical data from 42 cases were retrospectively analyzed. These patients received cyclosporine A (CsA), and/or corticosteroids (CS), or other immunosuppressive agents on becoming refractory and relapse. Thirty-nine patients were evaluated. Remission induction therapy included CsA (n = 16), CS (n = 13), CsA in combination with CS (n = 6), or other immunosuppressive agents (n = 4). Initial response rates were 75.0, 46.2, 66.7 and 75.0%, respectively (P = 0.456). Cumulative response rates in patients who received CsA, CS, CsA in combination with CS, or other immunosuppressive agents were 69.6% (16/23), 50.0% (7/14), 71.4% (5/7), 42.9% (6/14), respectively (P = 0.376). Cumulative rates of CR were 26.1% (6/23), 28.6% (4/14), 57.1% (4/7), 14.3% (2/14), respectively (P = 0.284). In 27 refractory and relapsed PRCA patients, 11 of 17 patients (64.7%) achieved remission by CsA and/or CS regimen, while three of ten patients (30.0%) responded to other immunosuppressive agents (P = 0.120). CsA and/or CS were effective in treating PRCA. For patients with relapse or refractory PRCA, there were no satisfactory treatments if CsA and/or CS failed or were not administered.

Adenosine Deaminase 2 Deficiency As a Cause of Pure Red Cell Aplasia Mimicking Diamond Blackfan Anemia

Diamond Blackfan anemia (DBA) is an inherited pure red cell aplasia. Most cases present in the first year of life with elevation in erythrocyte adenosine deaminase (eADA) and frequently with increased mean corpuscular volume (MCV) and hemoglobin F (hgb F). Approximately 70 percent of cases are due to a mutation in one of several ribosomal protein (RP) genes or in GATA1, whereas the remaining cases are genetically uncharacterized. Here we report a child born with severe anemia and diagnosed with DBA at 2 months of age. His bone marrow was normocellular with a paucity of erythroid progenitors and scattered lymphocytes. An eADA level was not obtained prior to the first red cell transfusion. He was red cell transfusion dependent and his anemia did not respond to a steroid trial. His 4 year old sister, who had normal hemoglobin, MCV, hgb F, and eADA measurements, served as his HLA identical donor for hematopoietic stem cell transplantation (HSCT). HSCT resulted in 100% donor chimerism, but red cell engraftment was not achieved. He subsequently underwent a mismatched unrelated HSCT with trilineage engraftment.Ten years later, at the age of 14 years, the sister presented with profound hypoproductive normocytic anemia. The bone marrow showed absence of erythroid precursors and presence of lymphoid aggregates. Findings of immunodeficiency included numerous cutaneous warts, recurrent aphthous ulcers, Epstein Barr virus (EBV) reactivation, low IgM, and low numbers and percentages of CD19+ and CD3-56+16+ lymphocytes. The anemia and reticulocytopenia persisted despite resolution of EBV reactivation. Upon her presentation, levels of iron, ferritin, transferrin saturation, and liver transaminases were elevated. A liver biopsy obtained after transfusion of a total of 60 ml/kg packed red blood cells demonstrated 4.8 mg Fe/g dry liver weight with stage 2 portal fibrosis.Targeted DNA sequencing studies performed on the affected sister were negative for single nucleotide variants in any of 12 RP genes previously implicated in DBA and a genome wide chromosome microarray was normal. Whole exome analysis of her and her parents demonstrated that she carried compound heterozygous variants in CECR1 (cat eye syndrome chromosome region, candidate 1). The variant p.R169Q had been previously reported as pathogenic, while the p.G358R variant was of uncertain significance. These variants are present at frequencies of 4.9X10-4 and 2.6X10-5 in the Exome Aggregation Consortium database, respectively. Analysis of buccal swab DNA of the proband showed the same biallelic variants. An unaffected 16-year-old sibling had a normal genotype. CECR1 encodes adenosine deaminase 2 (ADA2) and ADA2 levels in the plasma of the affected sister were markedly low, consistent with a deficiency state.CECR1 is highly expressed in cells of myeloid origin and ADA2 is a secreted protein implicated in macrophage differentiation and proliferation. Deficiency of ADA2 (DADA2) results in aberrant monocyte differentiation favoring M1 over M2 macrophages, thereby resulting in a proinflammatory state. Recent descriptions of patients with DADA2 due to CECR1 mutations reported a spectrum of phenotypes including intermittent fevers, lacunar stroke in childhood, livedoid rash, polyarteritis nodosa, and immunodeficiency with B lymphopenia and low IgM levels. Our cases are similar to the report of one of two brothers, homozygous for CECR1 p.R169Q, described by van Montfrans, et al,. (NEJM, 2014). The eldest was given a diagnosis of atypical DBA (refractory pure red cell aplasia) in infancy and underwent a HSCT from his asymptomatic, HLA identical brother. This HSCT resulted in non-engraftment, necessitating a subsequent unrelated donor HSCT. The younger sibling donor later developed hepatosplenomegaly, profound lymphopenia, and evidence of an inflammatory state.Together, these three cases support pure red cell aplasia as a presentation of DADA2 and that this may be confused with DBA, particularly when manifest in infancy. We propose DADA2 should be considered in patients with genetically uncharacterized DBA. Differentiating features to suggest DADA2 may include normal eADA, MCV, and hgb F levels and findings of associated immunodeficiency. Additionally, the macrophage activation due to DADA2 may have played a role in the iron overload observed in our second patient prior to any red cell transfusion. DisclosuresNo relevant conflicts of interest to declare.

The pharmacokinetic analysis of cyclosporine is essential for the management of refractory pure red cell aplasia

The pharmacokinetic analysis of cyclosporine is essential for the management of refractory pure red cell aplasia

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 x 10(6)/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 complicating B cell small lymphocytic lymphoma: a case report

Pure red cell aplasia (PRCA) is characterized by severe normocytic, normochromic anemia, reticulocytopenia and absence of erythroblasts from an otherwise normal bone marrow [1]. According to PRCA classification, secondary forms are associated with thymoma, hematologic malignancies, solid tumors, systemic autoimmune diseases, drugs, viruses and chronic renal failure [2]. The association of B cell small lymphocytic non-Hodgkin lymphoma with PRCA is considered to be extremely rare [1]. In this case report, we present a patient with PRCA and B cell lymphocytic lymphoma. A 70-year-old male patient, undergoing trans-urethral prostatectomy for benign prostate hyperplasia, was found with leukocytosis (WBC = 27,000/lL), lymphocytosis (65%) and normocytic, normochromic anemia (Hb = 7 g/ L), during pre-operative investigation. After successful operation, he was referred to our department for further investigation. Previous medical history was unremarkable. Physical examination revealed hepato-splenomegaly and peripheral lymphadenopathy. Extensive screening for viruses (HBV, HCV, HIV, PARVO B19, etc.) proved negative; no immunological abnormalities suggesting an underlying systemic autoimmune disease were detected. Reticulocyte count was\0.5%. Bone marrow aspiration revealed diffuse infiltration by lymphocytes with complete absence of erythroblasts (\3%) and normal megacaryocytes. Peripheral blood immunophenotype and lymph node biopsy led to the diagnosis of CD20 (?) B cell small lymphocytic lymphoma. Additionally, peripheral blood immunophenotyping revealed FMC7 (?) and CD5(-). The patient was administered combined therapy with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) in 21-day intervals; prednisolone was administered uninterruptedly. Unfortunately, he suffered an acute allergic reaction to rituximab and the drug was discontinued. After three cycles of CHOP, lymphadenopathy and leukocytosis were markedly improved; however, anemia was refractory and maintained by frequent blood transfusions (approximately 3–4 units of packed RBCs every 2 weeks). Cyclosporine A (dose 5 mg/ kg) was added to the therapeutic regimen; after 1 month, the patient needed no further transfusions and he managed to complete eight cycles of CHOP. After 18 months of follow up, the patient remains in remission, regarding both PRCA and B cell lymphoma. Treatment with low-dose cyclosporine A (5 mg/kg) was continued with no further need for RBC transfusions and no adverse effects. Diagnosis of PRCA relies mainly on the absence of erythroblasts from the bone marrow combined with reticulocytopenia. A defined upper cut-off value of erythroblasts required for diagnosis is still controversial; different studies advocate values ranging from 0.5 to 5% [3]. In this patient, there was almost complete absence of erythroblasts, as well as low reticulocyte count. The pathogenetic basis of PRCA remains to be elucidated; nevertheless, evidence support involvement of immune mechanisms, such as marrow infiltration by CD8? T cells and cell-mediated cytotoxicity [4]. Latest reports on the favorable outcome of refractory PRCA with rituximab suggests B cell involvement [5, 6]. It is possible, though, that multiple factors contribute to disease pathophysiology E. Vlachaki (&) K. Tselios S. Charalambidou E. Ioannidou I. Klonizakis Hematology Unit, 2nd Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Konstantinoupoleos St. 49, 54642 Thessaloniki, Greece e-mail: efivlachaki@yahoo.gr

Retreatment with Fludarabine and Cyclosporine for One Case of Refractory Pure Red Cell Aplasia

Retreatment with Fludarabine and Cyclosporine for One Case of Refractory Pure Red Cell Aplasia

Refractory idiopathic pure red cell aplasia complicated by immune thrombocytopenia successfully treated with subcutaneous alemtuzumab

Refractory idiopathic pure red cell aplasia complicated by immune thrombocytopenia successfully treated with subcutaneous alemtuzumab

The effect of donor leukocyte infusion on refractory pure red blood cell aplasia after allogeneic stem cell transplantation in a patient with myelodysplastic syndrome developing from kostmann syndrome

We describe the clinical course of a patient who experienced refractory pure red cell aplasia (PRCA) after undergoing HLA-matched allogeneic peripheral blood stem cell transplantation (allo-PBSCT) for refractory anemia with an excess of blasts in transformation that had evolved from Kostmann syndrome. The treatment for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) developing from Kostmann syndrome has not been standardized. We treated this patient with allo-PBSCT using a regimen combining high-dose cytosine arabinoside with granulocyte colony-stimulating factor, in addition to total body irradiation and cyclophosphamide without preceding intensive chemotherapy. The donor was ABO incompatible. Myeloid and platelet recoveries were achieved rapidly. Erythroid engraftment was not evident, however, and the patient was given a diagnosis of PRCA. Regimen-related toxicity and graft-versus-host disease (GVHD) were limited. The PRCA did not respond to various therapies, including the discontinuation of immunosuppressants for the induction of chronic GVHD, human recombinant erythropoietin, immunosuppressive treatment with steroids, cyclosporin A, and human anti-CD20 antibody (rituximab). The patient received transfusions 48 times until the resolution of his anemia by donor leukocyte infusion (DLI) at 25 months after PBSCT. He is now clinically well (performance status, 100%) with normal blood cell counts at 5 years after SCT. An in vitro study demonstrated that serum from the recipient blocked the differentiation of erythroid cells in the bone marrow. The results indicate that the conditioning regimen we describe seems safe and effective for those who have MDS/AML and that DLI might be a valuable approach for refractory PRCA after ABO-incompatible SCT.

Azathioprine-induced pure red cell aplasia: Case report and review

The major adverse effect of azathioprine is its myelotoxicity, with leukocytes being affected more commonly than the other bone marrow elements. Although megaloblastic change is frequent, reportedly seen in 16% to 82% of bone marrow aspirates, long-term use of azathioprine rarely causes severe anemia. We report a case of refractory pure red cell aplasia resulting from long-term use of azathioprine in a renal transplant recipient and examine the possible underlying mechanisms. There was no response to dose reduction or to erythropoietin administration. However, there was immediate recovery after complete drug withdrawal. A review of the literature revealed that only ten cases of azathioprine-induced red cell aplasia have so far been described, all in transplant recipients.

Additional Stem Cell Therapy for Graft Failure after Allogeneic Bone Marrow Transplantation

In this study we retrospectively evaluated the effect and outcome of a boost dose of donor stem cells without additional chemotherapy or total body irradiation. Between March 1983 and August 1999, 20 of 788 (2.5%) patients receiving allogeneic bone marrow transplantation (BMT) were treated with an additional boost dose of donor cells. The reasons for the use of the boost treatment were primary graft failure (early rejection; n = 7), secondary graft failure including late rejection (n = 10), refractory pure red cell aplasia caused by the remaining recipient cells producing anti-erythrocyte antibodies (n = 2), and donor lymphocyte infusion induced pancytopenia (n = 1). The patients were aged from 17 to 48 years (median age 31 years). The underlying diseases of the patients were severe aplastic anemia in 12 patients, acute myelogenous leukemia in 3, acute lymphocytic leukemia in 3, and chronic myelogenous leukemia in 2. The donors were human leukocyte antigen-identical siblings in 18 cases, 1 mismatched related donor, and 1 unrelated donor. The cell source was bone marrow in 6 cases and peripheral blood progenitor cells in 14. The median interval between BMT and the boost treatment was 7 weeks (range 1–124). No conditioning regimen was given prior to the boost treatment for 11 patients, while 4 received total nodal irradiation (TNI) plus antithymocyte globulin (ATG), 3 ATG alone, and 2 TNI plus steroid. The median infused booster mononuclear cell dose was 2.55 × 10⁸/kg (range 0.28–37.0). Fifteen (75%) patients achieved a hematological recovery. After the boost treatment, 6 of 20 (30%) patients developed acute graft-versus-host disease (GVHD) ≧ grade II, 3 of whom had had prior GVHD. Five (31.3%) of the evaluable 16 patients developed chronic GVHD. The GVHDs were easily controlled using immunosuppressive agents except in the case of 1 patient. Five patients died after the boost treatment; 2 within 30 days, 2 within 60 days, and 1 after 32 months. The causes of death were: 3 engrafment failures, 1 late rejection, and 1 infection following GVHD. With a median follow-up of 31.5 months (range 6–92), the Kaplan-Meier method estimated that the overall survival rate 1 and 3 years after the boost treatment was 80 and 71%, respectively. The survival of patients with primary graft failure was determined to be significantly lower compared to that of patients with secondary graft failure, using the log rank test (p = 0.0176). Disease category, stem cell source, conditioning prior to a boost treatment, and year of boost treatment did not have an influence on survival. We conclude that the reinfusion of donor stem cells is frequently successful in achieving engraftment with rare occurrence of fatal GVHD. Furthermore, relatively good long-term survival was demonstrated.

Treatment of refractory pure red cell aplasia with cyclosporine A: disappearance of IgG inhibitor associated with clinical response

Remissions were obtained in 6/9 evaluable patients with pure red cell asplasia (PRCA) refractory to other immunosuppressive agents who were treated with cyclosporine A (CsA). Four of these patients have remained in continuous remission off all treatment for 4-19 months. Another patient who stopped CsA abruptly relapsed, but responded to reinstitution of therapy. The sixth patient died of a cerebrovascular accident while in remission on a low dose of CsA. Acute side effects were minimal and were responsive to dose reduction. One patient developed a lymphoma while in an unmaintained remission, and one patient who did not respond to CsA was found to have a lymphoma approximately a year after stopping treatment. In vitro studies of autologous erythroid progenitors in a patient with an IgG inhibitor of erythropoiesis showed a reduction of autoantibody associated with the response to CsA. The antigen to which this inhibitor is directed was expressed only during the marrow erythroid burst-forming unit (BFU-E) period of erythroid differentiation. CsA can induce sustained remissions in cases of PRCA refractory to other multiple agents, and these remissions may be associated with a reduction in autoantibody to erythroid progenitor cells. Further studies of patients with PRCA who respond to CsA may lead to an improved understanding of this disorder.

Treatment of pure red‐cell aplasia and aplastic anaemia with Ciclosporin: Long‐term clinical effects

6 patients with pure red-cell aplasia were treated with Ciclosporin (Cyclosporine A; CS) alone or combined with prednisolone for a period of 9-46 (median 27) months. Prior to study, 5 cases had refractory disease, steroids were contraindicated in 1, and 4/6 patients, including 2 cases with congenital disease, had a disease duration exceeding 11 years. A complete haematological response was obtained in 5/6 subjects, and a partial response in 1. When the pre-treatment Hb levels (mean +/- S.D. = 64 +/- 13 g/l, range 41-80) for all 6 PRCA patients were compared with the Hb levels after 6 months of CS therapy (104 +/- 17 g/l, 80-125), a significant improvement was registered (p less than 0.005). In half of the patients, remission is maintained with CS as single drug in a dose-dependent manner. We also treated 5 patients with refractory severe aplastic anaemia with CS (1 case) or CS plus prednisolone (4 cases) for 3-27 (median 10) months. Only 1 patient responded. In this case, a complete haematological remission was induced with CS alone, and remission has been maintained for 27 months. Side effects of CS therapy were common but were dose-dependent and reversible, with the exception of persistent nephrotoxicity in 1 patient with pure red-cell aplasia. Based on our present results and a survey of the literature, we conclude that CS therapy is effective and indicated in refractory pure red-cell aplasia. In severe aplastic anaemia resistant to conventional immunosuppression, the response rate is lower, but a small proportion (around 15%) of patients may benefit from CS therapy. Longer treatment periods may, however, be needed to evaluate the role of CS in aplastic anaemia.