Pure Red Cell Aplasia and Other Haematological Diseases Associated With Thymoma: A Case Series and Systematic Review

Background: Thymoma-associated haematological diseases (HDs), such as pure red cell aplasia (PRCA) and Good's syndrome, are extremely rare, and due to the paucity of large-scale studies, the characteristics, remission after thymectomy, and long-term evaluation remain undetermined.Methods: We retrospectively assessed patients with thymoma and associated HDs from Jan 2005 to Dec 2020. All patients received thymectomy and/or additional treatments for HDs. A comparison with thymoma-associated myasthenic gravis (MG), and a systematic review from PubMed/MEDLINE and Embase were conducted.Results: In the median follow-up of 56 months, 130 patients were enrolled. Patients with thymoma-associated MG (n = 46) and HDs [n = 8; PRCA (n = 5), PRCA and Good's syndrome (n = 2) and autoimmune haemolytic anaemia (n = 1)] were evaluated. Patients with MG had a significantly higher remission rate after thymectomy (50 vs. 17%; p = 0.0378) as compared to those with other autoimmune diseases. Two of seven patients with PRCA experienced remission with thymectomy alone, and an additional two patients achieved remission with thymectomy plus immunosuppressive therapy (IST). In the systematic review, 60 studies (case reports, n = 46; case series including the present study, n = 14) were evaluated. Forty-four percent of patients were diagnosed with PRCA after thymoma, and 61% achieved remission with thymectomy plus IST; however, Good's syndrome was unaffected.Conclusions: Our study indicates that patients with thymoma-associated autoimmune diseases other than MG have a lower remission rate than those with MG. Remission of thymoma-associated PRCA can be achieved by thymectomy and IST. This study provides insight into extremely rare but puzzling autoimmune manifestations.

Pure red cell aplasia secondary to rheumatoid arthritis: a case report

Background Rheumatoid arthritis is a common autoimmune disease with many extra-articular manifestations. Pure red cell aplasia is a rare manifestation of rheumatoid arthritis and is sparsely documented in the literature, with a variable clinical outcome following immunosuppressive therapy. Case presentation A 63-year-old Sinhalese female presented with transfusion-dependent anemia associated with deforming inflammatory arthritis. She also had leukopenia, right subclavian venous thrombosis, and generalized lymphadenopathy. The diagnosis of rheumatoid arthritis following initial clinical workup and additional blood and bone marrow investigations revealed pure red cell aplasia as a secondary manifestation of rheumatoid arthritis after excluding other secondary causes, such as infections, thymoma, thrombophilic conditions, and hematological malignancy. She responded well to oral prednisolone, cyclosporine A, and hydroxychloroquine, and she attained complete recovery in 2 months. Conclusion Pure red cell aplasia is a disabling illness that may lead to transfusion-dependent anemia, which may occur due to rare extrapulmonary manifestation of rheumatoid arthritis. The diagnosis of pure red cell aplasia secondary to rheumatoid arthritis may be challenging where hematological investigations, including bone marrow biopsy, will aid in the diagnosis, and early diagnosis and treatment will bring about a better outcome.

Parvovirus B19 Infection due to over Immunosuppression in Kidney Transplant Recipients: Case Reports and Literature Review

Parvovirus B19 (PB19) is a single-stranded DNA virus that belongs to the Erythrovirus genus within the Parvoviridae family. Clinical presentations associated with PB19 infection vary greatly, depending on the infected individual’s age and hematologic and immunologic status. The limited data available regarding consensus on screening algorithms and indications in donors and recipients prior to kidney transplantation makes diagnosis and management challenging. We presented 3 cases of pure red cell aplasia due to parvovirus B19 after kidney transplant. These patients were diagnosed with severe normocytic, normochromic anemia (hemoglobin below 60 g/L) in the 1st 6 months posttransplant. A complete anemia work-up revealed low reticulocyte count and was otherwise inconclusive. All patients were diagnosed with pure red cell aplasia due to parvovirus B19. Two patients improved after receiving intravenous immunoglobulin 2 gm/kg given over 4 doses. Unfortunately, they relapse after few weeks and required additional doses of intravenous immunoglobulin in conjugation with reduction of their immunosuppressive medication. The third patient improved after holding mycophenolate mofetil (MMF) and did not require intravenous immunoglobulin. Whereas PB19 infection is typically self-limiting and associated with positive IgM serology in immunocompetent hosts, these cases highlight the importance of considering PB19 infection in the differential diagnosis of persistent anemia in immunocompromised patients and the challenges in confirming the diagnosis. Intravenous immunoglobulin (IVIG) can be an effective treatment in immunocompromised patients with primary or relapsed PB19 infection in conjunction with minimizing immunosuppressive medication. Further research and consideration are required to determine appropriate and targeted screening in donors and recipients in the peritransplantation period.

Sars-Cov-2 Infection Associated with Aplastic Anemia and Pure Red Cell Aplasia

Introduction: Aplastic anemia (AA) is a life-threatening disorder characterized by pancytopenia and a hypocellular bone marrow. Pure red cell aplasia (PRCA) is a similar disorder with primary reduction in the red blood cell population and virtual absence of erythroid precursors in the bone marrow. While the etiology of immune mediated marrow failure is multifactorial, preceding viral infections have been associated with the disease; these include parvovirus B19, cytomegalovirus, and Epstein-Barr virus. We present four cases of immune mediated marrow failure with either preceding or simultaneous SARS-CoV-2 infection. Methods: The medical records of patients treated for AA or PRCA at the University of Texas Southwestern Medical Center, Parkland Hospital, and the National Institutes of Health (NIH) were reviewed for SARS-CoV-2 infection. Four patients without prior hematological diseases were identified who had SARS-CoV-2 infection prior to or with simultaneous the diagnosis of AA or PRCA. Results: Patient #1 was a 22-year-old white female who was diagnosed with asymptomatic COVID-19 10 days prior to her pancytopenia and AA diagnosis was confirmed by bone marrow biopsy (5% cellularity; Table 1). Her extensive work-up including HIV, hepatitis panel, immunoglobulins, B12 and folate was negative, and she underwent HLA-matched family donor hematopoietic stem cell transplant. Patient #2 was a 69-year-old Asian female who presented to her primary care physician with symptoms of fatigue and was found to be pancytopenic. CBC from a few months prior was completely normal. Further work-up was positive for COVID-19 and negative for HIV, nutritional deficiency, or hemolysis. She did not have respiratory symptoms, was eventually diagnosed with pRBC and platelet transfusion-dependent severe AA (5-10% cellularity on bone marrow), and underwent treatment with cyclosporine, equine antithymocyte globulin, and eltrombopag. She has had a partial response to this therapy. Both patients had bone marrow specimens stained for SARS-CoV-2 by immunohistochemistry that were negative. Patient #3 was a 76-year-old white male who was diagnosed with COVID-19 4 months prior to presenting with a non-ST segment myocardial infarction and found to be profoundly anemic, requiring pRBC transfusion. He re-presented with chest pain one week later and was found to be anemic again, and required transfusion. A trial of darbepoetin alfa was unsuccessful. Extensive work-up for malignancy, infection, and autoimmune etiologies were negative. He was diagnosed with PRCA based on the bone marrow biopsy and initiated treatment with cyclosporine. Patient # 4 was diagnosed with severe AA (presenting as pancytopenia) and COVID-19 infection. He had fatigue for one month and fever, chills and sore throat one-week prior seeking medical care. Testing for hepatitis, HIV, EBV, and CMV was negative. He was treated on a clinical trial (NCT04304820) at NIH with cyclosporine and eltrombopag until SARS-CoV-2 PCR was negative then received equine anti-thymocyte globulin. He has achieved a complete hematologic response at 6 months and remains well at last follow-up. Conclusion: The four patients described had minimal respiratory COVID-19 symptoms, but they presented with cytopenia and were eventually diagnosed with bone marrow failure. It is possible that this is co-incidental due to the high prevalence of SARS-CoV-2. However, there is emerging evidence that COVID-19 pneumonia is a hyperinflammatory and immune dysregulated state improved by dexamethasone therapy. Other immune mediated hematologic conditions, such as autoimmune hemolytic anemia and immune thrombocytopenia, have been reported. The onset from infection to cytopenia appears rapid, although patients often presented with symptoms for many days prior to diagnosis and thus testing may have been delayed from the onset of infection. This case series does not provide a mechanistic link between SARS-CoV-2 infection and bone marrow failure, but it raises the possibility that SARS-CoV-2 may mediate an immunologic response that contributes to marrow failure. Patients appear to respond well to standard immunosuppressive treatment. Further cases and studies are needed to determine if this is directly linked to SARS-CoV-2 and whether the natural history and response to standard therapy is different than idiopathic cases. Figure 1 Figure 1. Disclosures Young: Novartis: Research Funding.

Immunosuppressive Therapy in Large Granular Lymphocyte Leukemia-Associated Pure Red Cell Aplasia: Cyclophosphamide Responded Better Than Cyclosporine

Background Large granular lymphocyte leukemia associated pure red cell aplasia (LGLL-PRCA) accounts for a significant portion of secondary PRCA. Cyclosporine (CsA) and cyclophosphamide (CTX) are the main immunosuppressive agents used in treating LGLL-PRCA [1]. Considering the cytotoxicity of CTX, CsA may be proposed as first-line therapy [2]. However, because of the rarity of LGLL-PRCA, long-term responses and relapse rates after CsA and CTX therapy are largely unknown. Methods and results From September 2009 to December 2020, we selected 65 uniformly diagnosed LGLL-PRCA and analyzed clinical features and treatment outcomes of CsA and CTX. In the present study, 43.1% harbored neutropenia (<1.5×10 9/L) and only 1 patient had spondyloarthritis (Table 1). Besides, we found that 9.2% developed recurrent oral ulcer and 18.5% had reduced serum complemet C3 level, both of which were related to abnormal immune status. In our cohort, 44 patients received CsA therapy and 21 patients received CTX therapy. 53.8% (35/65) obtained erythroid lineage response and 26.2% (17/65) achieved complete response. CTX produced higher response rate (81.0% vs 40.9%, P=0.002) and complete response rate (47.6% vs 15.9%, P=0.007) than CsA. We further analyzed related factors influencing efficacy by Binary-Logistic multivariate regression model and found that higher response rate was mainly related to CTX therapy (P=0.02) (Table 2). We detected STAT3 and STAT5b gene in 50 cases. None of the patients had STAT5b mutation and 14 patients had STAT3 mutation. 12 of 14 mutation cases were non-elderly patients (<60 years ). For younger patients, STAT3 mutation was more frequent (85.7% vs 22.2%, P<0.01). In STAT3 mutation group, patients appeared to respond better to CTX than CsA (83.3% vs 37.5%, P=0.138). Up to the last follow-up, 11 patients treated with CsA recurred after CsA reduction or discontinuation, with a median relapse time of 10 (3~80) months after remission. Only 1 patient relpsed after the discontinuation of CTX due to neutropenia and returned to remission status after CTX retreatment. In our research, CsA had higher recurrence rate than CTX without statistical significance (25.0% vs 4.8%, P=0.104). Discussion CsA may be proposed as first-line therapy for LGLL-PRCA [2,3]. CTX also appears to be a good treatment choice, but CTX should not be used for more than 12 months since associated toxicities and the risk for developing myelodysplastic syndromes and acute myeloid leukemia. Therefore, it is necessary to compare the efficacy of CsA or CTX in the treatment of LGLL-PRCA. Deep sequencing analyses of residuals LGLL clones reveals that CTX could eradicate LGLL clones, providing durable response, low relapse rate, whereas CsA is associated with the persistence of leukemic clones, and high frequency of relapse [4]. Our results show that the response rate of CTX is higher than CsA (P=0.02), and the probability of recurrence is relatively low (25.0% vs 4.8%, P=0.104). This is consistent with the results of previous study by Rajala [4]. It was important to note that patients with STAT3 mutations are more likely to respond to MTX [5]. Our study showed that the response rate for CTX was 83.3% in patients with STAT3 mutations, which was seemingly higher than CsA (37.5%), although remained statistically insignificant (P=0.138) that might be due to small number of cases. Conclusions The results of the current study may reflect the real world experience of LGLL-PRCA in whom treated by CTX or CsA, may be limited by its retrospective nature, small cohorts. In preliminary conclusion, LGLL-PRCA could acquired better response to CTX than CsA. Besides, CTX may reduce relapse. References 1. Means RT Jr. Pure red cell aplasia. Blood, 2016, 128(21): 2504~9. 2. Moignet A, Lamy T. Latest Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia. Am Soc Clin Oncol Educ Book, 2018, 38: 616~25. 3. Go RS, Tefferi A, Li CY, et al. Lymphoproliferative disease of granular T lymphocytes presenting as aplastic anemia. Blood, 2000, 96(10):3644~6. 4. Rajala HLM, Olson T, Clemente MJ, et al. The analysis of clonal diversity and therapy responses using STAT3 mutations as a molecular marker in large granular lymphocytic leukemia. Haematologica, 2015, 100: 91~9. 5. Loughran TP, Zickl L, Olson TL, et al. Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998). Leukemia, 2015, 29(4): 886~94. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

PURE RED CELL APLASIA : A CASE REPORT

Pure cell aplasia is a rare bone marrow failure that affects erythroid lineage characterized by normocytic normochromic anemia with reticulocytopenia in the peripheral blood and absent or infrequent erythroblasts in the bone marrow. It can be congenital or acquired. Acquired can be primary when no cause is identied or secondary-due to underlying or associated pathology. Herein we report a case of a 28 year old female with Primary Acquired Pure Red cell aplasia. The patient presented with severe anemia (Hb-1.9gm%) and low reticulocyte count 0.1%. Bone marrow aspiration shows normocellular marrow with Decreased erythropoiesis with M:E ratio of 20:1..Patient was started on oral prednisolone and improvement was seen and the patient became transfusion independent.