Successful treatment pure red cell aplasia after ABO major mismatched allogeneic hematopoietic stem cell transplantation with avatrombopag and low dose rituximab.

BACKGROUND: Pure red cell aplasia (PRCA) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) with ABO major incompatibility is characterized by transfusion dependent anemia. No standard treatment existed for PRCA following allo-HSCT yet. STUDY DESIGN AND METHODS: We conducted a retrospective study, and reported our experience with the use of avatrombopag and lower dose rituximab to treat five patients with PRCA subsequent to major ABO-incompatible allo-HSCT. RESULTS: Five cases of PRCA were identified from 72 patients who underwent allo-HSCT with major or bidirectional ABO mismatch. Cumulative incidence at Day +60 was 6.9% (5/72) at our center. All donor and recipient blood groups were A+  and O+ , respectively. In the first three cases we reported, patients received erythropoietin, plasma exchange, and donor lymphocyte infusion, but none of them had any effect. After 4 weeks of treatment with low dose rituximab (100 mg/week) combined with avatrombopag (40 mg/day), favorable outcomes were obtained. According to the aforementioned experience, Cases 4 and 5 were administered low-dose rituximab and avatrombopag in 3 months after transplantation, and erythroid response was observed on 3 weeks after treatment. Our patients tolerated low-dose rituximab and avatrombopag well and experienced rapid efficacy, with a median duration of 3 weeks. Furthermore, no severe infection or thrombocytosis necessitated a dose adjustment. CONCLUSION: Low-dose rituximab and avatrombopag may be an effective treatment for patients with PRCA after major ABO-incompatible allo-HSCT. The patients should be treated at least 90 days post transplantation if conventional erythropoietin therapy fails.

A nomogram model for predicting the efficacy of cyclosporine in patients with pure red cell aplasia.

Pure red cell aplasia (PRCA) is a rare bone marrow disorder characterized by a severe reduction or absence of erythroid precursor cells, without affecting granulocytes and megakaryocytes. Immunosuppressive therapies, particularly cyclosporine, have demonstrated efficacy as a primary treatment. This study aims to develop a predictive model for assessing the efficacy of cyclosporine in acquired PRCA (aPRCA). This retrospective study encompasses newly treated aPRCA patients at the General Hospital of Tianjin Medical University. Diagnosis criteria include severe anemia, and absolute reticulocyte count below 10 × 109/L, with normal white blood cell and platelet counts, and a severe reduction in bone marrow erythroblasts. Cyclosporine therapy was administered, with dose adjustments based on blood concentration. Response to cyclosporine was evaluated according to established criteria. Statistical analysis involved logistic multi-factor regression, generating a predictive model. The study included 112 aPRCA patients with a median age of 63.5 years. Patients presented with severe anemia (median Hb, 56 g/L) and reduced reticulocyte levels. Eighty-six patients had no bone marrow nucleated erythroblasts. Primary PRCA accounted for 62 cases (55.4%), and secondary PRCA accounted for 50 cases (44.6%). Univariate analysis revealed that ferritin, platelet to lymphocyte ratio (PLR), and CD4/CD8 ratio influenced treatment response. Multivariate analysis further supported the predictive value of these factors. A prediction model was constructed using ferritin, PLR, and CD4/CD8 ratio, demonstrating high sensitivity and specificity. The ferritin, PLR, and CD4/CD8-based nomogram showed good predictive ability for aPRCA response to cyclosporine. This model has potential clinical value for individualized diagnosis and treatment of aPRCA patients.

Niraparib-induced pure red cell aplasia.

INTRODUCTION: Niraparib, a strong poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, contributed significantly to progression-free survival as a maintenance therapy in the platinum-sensitive period in both first-line and recurrent ovarian cancer, regardless of the BRCA mutation. Grade 3-4 anemia, which has a manageable side effect profile, especially hematological, is seen in almost 1 out of every 4 patients. To the best of our knowledge, there has been no reported case of pure red cell aplasia (PRCA) induced by niraparib treatment. CASE REPORT: A 65-year-old woman diagnosed with stage 3 serous carcinoma of the tuba received niraparib front-line maintenance treatment had grade 4 anemia after 3 months of niraparib treatment. She underwent bone marrow aspiration and biopsy because of refractory anemia, which needs red blood cell (RBC) transfusions despite interruption of treatment. MANAGEMENT AND OUTCOME: The patient was treated with 1 mg/kg methyl prednisolone, after histopathological assessment was consistent with PRCA. The hemoglobin count returned to the normal range with steroid treatment. DISCUSSION: In daily practice, it should be kept in mind that in the case of refractory anemia induced by niraparib, the underlying cause might be PRCA and can be improved with steroid administration.

A late relapse thymoma and pure red cell aplasia case with an over 5 years of clinical response under everolimus.

Although several agents showed some clinical activity in patients with recurrent thymoma, there is no standard treatment option. Here, we report a late relapse thymoma and pure red cell aplasia case, responsive to everolimus with over 5 years of clinical benefit following multiple lines of treatment. Everolimus controlled the rapidly progressive disease in our patient without significant toxicity.

Secondary Pure Red Cell Aplasia During Daratumumab/ Hyaluronidase Therapy for Multiple Myeloma.

Predominantly autoimmune in origin, severe normochromic, normocytic anemia with reticulocytopenia in the setting of the normal production of leukocytes and megakaryocytic lineages is known as pure red cell aplasia (PRCA), which is unlike aplastic anemia in which all lineages are affected due to a stem cell defect. PRCA can be primary (such as autoimmune) or acquired, which can be an acute self-limited illness or a chronic disease that may be induced by medications, including immunotherapy such as monoclonal antibodies (mAbs). Daratumumab is a mAb directed against CD38 used for the treatment of multiple myeloma and systemic amyloid light-chain amyloidosis. The intravenous formulation of daratumumab received initial FDA approval, and later approval was received for the subcutaneous formulation daratumumab and hyaluronidase-fihj. The subcutaneous version increases patient convenience and has become the preferred route of administration since its approval. We herein present the case of a patient with multiple myeloma who developed acquired DNMT3A-positive PRCA while transitioning to daratumumab/hyaluronidase after initial treatment with daratumumab.

Exacerbation of autoimmune hemolytic anemia associated with pure red cell aplasia after COVID-19: A case report.

Autoimmune hemolytic anemia (AIHA) and pure red cell aplasia (PRCA) are rare complications of coronavirus disease 2019 (COVID-19). Herein, we report the case of a 28-year-old Japanese man who showed severe AIHA exacerbation associated with PRCA after COVID-19. AIHA was diagnosed and maintained for 5 years. Approximately 4 weeks after COVID-19, the patient developed severe anemia (hemoglobin level, 3.4 g/dL). Laboratory test results confirmed hemolytic exacerbation of IgG-mediated warm-type AIHA. Despite the hemolysis phase, the bone marrow revealed extreme hypoplasia of erythroblasts with a decreased reticulocyte count, similar to that observed in patients with PRCA. During oral prednisolone treatment, the patient recovered from anemia and showed increased reticulocyte count and reduced hypoplasia of marrow erythroblasts. Exacerbation of AIHA and PRCA was triggered by COVID-19 because other causes were ruled out. Although this case report highlights that COVID-19 could lead to hematological complications such as AIHA and PRCA, the exact mechanisms remain unclear.

Pure red cell aplasia occurring during ibrutinib therapy for chronic lymphocytic leukemia.

INTRODUCTION: Chronic lymphocytic leukemia (CLL) has long been known for its complications related to immune deregulation, of which autoimmune cytopenias (AIC) were frequently reported. Ibrutinib has dramatically changed the overall prognosis of patients with CLL. However, whether ibrutinib can induce or aggravate AIC in CLL patients is still disputable. Here we report a CLL patient with pure red cell aplasia (PRCA) occurring during ibrutinib treatment and review available data to discuss the possible role of ibrutinib in developing AIC. CASE REPORT: A 70-year-old female was diagnosed with CLL with indications to initiate ibrutinib treatment given progressive bulky disease. She was admitted for advanced fatigue on the 14th day of ibrutinib monotherapy. A complete blood count revealed severe anemia of hemoglobin (Hb) 37 g/L and a meager reticulocyte count. After excluding other conditions that could cause anemia, PRCA was diagnosed as a complication of CLL. MANAGEMENT AND OUTCOME: Ibrutinib was discontinued on the day of admission. At the same time, the patient received prednisone and intravenous immunoglobulin (IVIg). Five days later, the Hb did not improve. Cyclosporine A (CsA) was added; IVIg was discontinued, and prednisone was tapered. Ten days later, the Hb had risen to 92 g/L with a high reticulocyte count of 0.279 × 1012/L. The CLL treatment restarted with Zanbrutinib in combination with a low dose of prednisone and CsA. Her CLL was in partial remission by the latest follow-up with an average Hb count. DISCUSSION: Our case demonstrates a need to evaluate the risk of developing AIC before initiating ibrutinib. For patients with high-risk factors for AIC episodes, the transient addition of other immunosuppressive therapies should be taken into consideration.

Immune reconstitution and survival of patients with parvovirus B19 related pure red cell aplasia after haplo-PBSCT.

Parvovirus B19 (PvB19) infection and PvB19 related pure red cell aplasia (PRCA) in recipients with allogeneic hematopoietic stem cell transplantation have been reported sporadically. However, clinical studies with large sample sizes are lacking, especially in patients undergoing HLA-haploidentical peripheral blood stem cell transplantation (haplo-PBSCT). In addition, clinical features, immune reconstitution, and outcomes of these patients are not clear. We conducted a retrospective analysis of 164 patients who received haplo-PBSCT with low-dose anti-thymocyte globulin (ATG) plus low-dose posttransplant cyclophosphamide (PTCy)-based regimen as graft-versus-host disease (GVHD) prophylaxis. We analyzed the incidence of PvB19 related PRCA and compared the clinical characteristics, immune reconstitution, incidence of GVHD, relapse rate, and survival between patients with and without PvB19 related PRCA. A total of 14 (8.5%) recipients developed PvB19 related PRCA after a median of 5.3 months after haplo-PBSCT. These patients with PvB19 related PRCA had slower immune reconstitution, but similar incidences of GVHD, relapse rate, and overall survival compared with recipients without PvB19 related PRCA. PvB19 related PRCA indicated relative delayed and poor immune reconstitution of the recipients early after haplo-PBSCT. PvB19 related PRCA had no effects on GVHD, relapse, and survival.

Pure red cell aplasia accompanied by COVID-19 successfully treated using cyclosporine.

A 67-year-old Japanese man was admitted to our hospital with severe coronavirus disease 2019 (COVID-19) in March 2020. Mechanical ventilation was initiated 8 days after admission, due to severe respiratory failure. Multiple severe complications such as liver dysfunction, arrhythmia, brain infarction, and venous thromboembolism were also observed. We initially diagnosed Coombs test-positive warm autoimmune hemolytic anemia. Corticosteroids proved ineffective and anemia worsened with severe erythroid hypoplasia (0.5% erythroblasts in bone marrow), so we diagnosed pure red cell aplasia (PRCA). We also identified massive infiltration of cytotoxic T-lymphocytes expressing CD8, granzyme B, and perforin in bone marrow. Systemic cyclosporine was started, with full resolution of anemia and no need for blood transfusions after 4 weeks. We believe that this represents the first report of COVID-19-associated PRCA successfully treated using cyclosporine.

Roxadustat Improves Erythropoietin Antibody-Mediated Pure Red Cell Aplasia in a Patient with Hemodialysis.

Anemia is a common complication of chronic kidney disease (CKD). Recombinant human erythropoietin (rHu-EPO) is used extensively in patients with CKD. However, anti-erythropoietin (anti-EPO) antibody has been reported during rHu-EPO treatment, which causes pure red cell aplasia (PRCA). We presented a case of 75-year-old man, who underwent hemodialysis for 2 years. He developed PRCA during rHu-EPO treatment. The rHu-EPO was immediately discontinued, and the patient was given roxadustat treatment. After 6 months of roxadustat treatment, the anti-EPO antibody was disappeared, and hemoglobin recovered normal range. The results suggest that roxadustat can be used to treat patients with anti-EPO antibody-mediated PRCA without immunosuppressive therapy.

[The efficacy of alemtuzumab for pure red cell aplasia associated with autoimmune polyendocrine syndrome type 1].

We present a case of a 41-year-old woman who was diagnosed with autoimmune polyendocrine syndrome type 1 (APS-1) at the age of 2. She developed severe anemia and was diagnosed with pure red cell aplasia (PRCA) and T-cell large granular lymphocyte leukemia at the age of 34. The pathogenesis of APS-1 is based on the presence of an inactive mutation in the autoimmune regulator gene on thymic medullary epithelial cells. It is thought that the autoimmune T cells generated by impaired negative selection in the thymus induce PRCA. The patient was treated with immunosuppressive therapy (ciclosporin, antithymocyte globulin, prednisolone, and cyclophosphamide) for a long time by her previous doctor. After a long period of remission and exacerbation, she became dependent on blood transfusion approximately at the age of 40 and was transferred to our hospital. At our hospital, alemtuzumab treatment resulted in the disappearance of large granular lymphocytes and improvement of anemia. We report this case as a valuable demonstration of the efficacy of alemtuzumab for treating PRCA associated with APS-1.

Daratumumab for Delayed Red-Cell Engraftment after Allogeneic Transplantation.

Daratumumab, a human IgG1κ monoclonal antibody targeting CD38, is used to treat multiple myeloma. We describe successful treatment with daratumumab in a case of treatment-refractory pure red-cell aplasia after ABO-mismatched allogeneic stem-cell transplantation. The patient was a 72-year-old man with the myelodysplastic syndrome who received a transplant from an HLA-matched, unrelated donor with a major ABO incompatibility (blood group A in the donor and blood group O in the recipient). The patient had persistent circulating anti-A antibodies and no red-cell recovery 200 days after transplantation. Standard treatments had no effect. Within 1 week after the initiation of treatment with daratumumab, he no longer required transfusions.

Good treatment-free survival of monoclonal gammopathy of undetermined significance associated pure red cell aplasia after bortezomib plus dexamethasone.

Pure red cell aplasia (PRCA) is a rare syndrome characterized by severe anemia and absence of erythroid precursors. PRCA associated to monoclonal gammopathy of undetermined significance (MGUS) is a scarce condition with less than five cases reported so far. There is no agreement on the treatment of MGUS associated PRCA and treatment- free survival (TFS) is an unmet clinical need. In this report, for the first time, we demonstrated two patients with MGUS associated PRCA obtained rapid remission and maintained TFS after accepting intensive short-term bortezomib plus dexamethasone. The first case was refractory to cyclosporine and prednisone, but achieved complete remission after ten doses of bortezomib. Moreover, he has kept TFS for 12 months. The other case initiated bortezomib plus dexamethasone as soon as making a definite diagnosis. She obtained complete remission after twelve doses of bortezomib and she has maintained a normal level of haemoglobin for 8 months.

Daratumumab for pure red cell aplasia post ABO incompatible allogeneic hematopoietic stem cell transplant for aplastic anemia.

Pure red cell aplasia is a known complication after ABO incompatible stem cell transplant. Due to rarity of disease, no established treatment guidelines are available for PRCA. Daratumumab is a monoclonal antibody against CD38 expressed by plasma cells. In this report we present our experience of successfully managing a patient of post-transplant PRCA with daratumumab. Our patient had failed multiple lines of therapy prior to receiving daratumumab. Response was seen after the 3rd weekly dose of daratumumab.

Daratumumab for delayed RBC engraftment following major ABO mismatched haploidentical bone marrow transplantation.

BACKGROUND: Recent case reports have described the efficacy of daratumumab to treat refractory pure red cell aplasia (PRCA) following major ABO mismatched allogeneic hematopoietic stem cell transplantation (HSCT). In this report, we describe the use of daratumumab as a first-line agent for treatment of delayed red blood cell (RBC) engraftment following a major ABO mismatched pediatric HSCT and provide a review of the literature. STUDY DESIGN AND MATERIALS: We report on a 14-year-old with DOCK8 deficiency who underwent a myeloablative, haploidentical bone marrow transplant from her major ABO mismatched sister (recipient O+, donor A+) for treatment of her primary immunodeficiency. Despite achieving full donor chimerism, she had delayed RBC engraftment requiring ongoing transfusions. Due to iron deposition, symptomatic anemia, and persistence of anti-A iso-hemagglutinins despite discontinuation of immunosuppression, treatment for delayed RBC engraftment with the CD38-targeted monoclonal antibody daratumumab was selected as a less immunosuppressive agent that could more selectively target iso-hemagglutinin producing plasma cells without causing broad B-cell aplasia. RESULTS: Clinical effect with daratumumab was demonstrated by reduced iso-hemagglutinin titer, increased reticulocytosis, normalization of her hemoglobin, and transfusion independence. In the 11-month follow-up period to date, no additional transfusions or immunosuppression have been necessary, despite persistence of low-level anti-A iso-hemagglutinin. CONCLUSION: Our experience suggests that daratumumab was an effective first-line therapy for delayed RBC engraftment and that earlier consideration for daratumumab in treatment of delayed RBC engraftment may be warranted.

Pure Red Cell Aplasia following ABO-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation: Resolution with Daratumumab Treatment.

Pure red cell aplasia (PRCA) can potentially occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT) if recipient and donor ABO blood groups are mismatched, with the recipient having isoagglutinins against the donor blood group. Patient plasma cells that survive transplant conditioning produce anti-ABO isoagglutinins targeting donor erythroid precursors in the bone marrow and thus causing red cell aplasia. Therapeutic options include steroids, discontinuation of immunosuppression, plasmapheresis, donor lymphocyte infusion, rituximab, and bortezomib, all with limited benefit. Daratumumab utilized in the treatment of multiple myeloma is an anti-CD38 monoclonal antibody targeting plasma cells, which makes it a potentially efficient therapy for PRCA. The current case report presents a patient with post-allo-HSCT PRCA cured with daratumumab applied after failure of other therapies. Our findings demonstrate safety and high efficiency of daratumumab, suggesting its applicability as early treatment of post-allo-HSCT PRCA.

Immunosuppressive therapy for elderly-acquired pure red cell aplasia: cyclosporine A may be more effective.

This current study retrospectively analyzed the clinical characteristics of 69 adult patients with acquired pure red cell aplasia (PRCA) including 40 elderly and 29 non-elderly patients from September 2009 to June 2019. The remission induction therapy regimens included cyclosporine A (CsA), corticosteroids (CS), or other immunosuppressive agents. The overall response rate was 55% (22/40) in the elderly group compared with 75.9% (22/29) in non-elderly patients (P = 0.075). In elderly patients, the best remission was achieved in the group treated with CsA than those treated with CS or other immunosuppressive agents (83.3% vs 26.7% vs 42.9%%, P = 0.004). However, outcomes of remission were similar among different treatment groups (P = 0.458) in non-elderly patients. CS induced a higher response rate in the non-elderly than that in the elderly (88.9% vs 26.7%, P = 0.009). By univariate and multivariate analysis, the clinical efficacy of elderly patients with acquired PRCA was closely associated with an induction regimen of CsA (P = 0.009; P = 0.017). In conclusion, CsA might produce higher response rate than CS and other drugs in elderly patients with acquired PRCA.

Successful sirolimus treatment of patients with pure red cell aplasia complicated with renal insufficiency.

For patients with pure red cell aplasia (PRCA), cyclosporine (CsA) is the first line therapy. Occasionally, some patients who suffer from renal insufficiency cannot tolerate CsA. To explore the efficacy and tolerance of sirolimus treatment for those patients, twelve PRCA patients with renal insufficiency from May 2014 to May 2018 in Peking Union Medical College Hospital were enrolled, treated with sirolimus, and followed up at the median time of 16 (10-50) months. Eleven patients (91.7%) responded to sirolimus, with 58.3% complete response (CR) and 41.7% partial response (PR). The median time to achieve the optimum effect was 4 (1-7) months. The serum creatinine level remained stable or even reduced during the treatment period for eleven patients. Seven patients (58.3%) reported adverse events during sirolimus therapy, including increased blood glucose, infection, skin rash, elevated triglyceride or total cholesterol, and elevated serum creatinine compared with baseline. No treatment-related death was noticed during the follow-up time. Three patients relapsed with an overall response rate of 75.0% at 1 year. These results suggested that sirolimus was effective and tolerable for patients with PRCA complicated with renal insufficiency.

Immunosuppression therapy is effective for both acquired tumor-associated and primary pure red cell aplasia: a match pair case-control study.

No agreement had been reached on the treatment of patients with pure red cell aplasia (PRCA) secondary to indolent malignancies. Data was collected from patients with acquired PRCA from May, 2014 to May, 2018 in Peking Union Medical College Hospital. Tumor-associated PRCA and primary PRCA patients were matched at a ratio of 1:2 with compatible baseline characteristics. All patients had been treated with CsA or sirolimus for at least 6 months with the efficacy and adverse events recorded. Twelve tumor-associated PRCA patients (3 thymoma, 8 lymphoproliferative disorders, and 1 smoldering multiple myeloma) with stable underling disease and 24 acquired primary PRCA patients were selected. 83.3% tumor-associated PRCA patients and 100% primary PRCA patients (P = 0.436) responded to immunosuppression therapy (IST) at a median of 2.5 and 3.5 months (P = 0.137), respectively. No different was found in side effects. The ORR at the end of a median of 21.5-month follow-up was 75% and 70.8% (P = 0.795), respectively. No tumor progression was reported except one secondary patient had lymphoma relapse after 2 years of IST and was given chemotherapy again. These results suggested IST had similar effect, safety on patients with tumor-associated, and primary PRCA patients when the tumors were stable.

Successful treatment of refractory red cell aplasia after allogeneic hematopoietic cell transplantation with daratumumab.

Pure red cell aplasia (PRCA) is an uncommon complication secondary to ABO mismatched allogeneic stem-cell transplantation (allo-HSCT). The best approach for PRCA after allo-HSCT remains unclear. We aim to report a single case with refractory PRCA post-ABO mismatched allo-HSCT resolved with daratumumab. A 34-year-old male diagnosed with aplastic anemia in March 2014 received a peripheral blood reduced-intensity allo-HSCT from an HLA-matched related donor in July 2016. Donor and recipient blood groups were AB positive and 0 positive, respectively, indicating a major ABO incompatibility. The patient was diagnosed with PRCA 2 months after allo-HSCT. After failing multiple standard lines of treatment, compassionate treatment with daratumumab was requested. After receiving six doses of daratumumab, the patient had a marked reticulocyte response and consecutively become transfusion independent. In conclusion, Daratumumab is a human IgG1κ monoclonal antibody targeting CD38 and is used to treat multiple myeloma. The use of anti-CD38 therapy with daratumumab to target residual host plasma cells is safe and effective, and it can be considered in refractory recipients with PRCA after allo-HSCT secondary to ABO incompatibility.