Intensive Immunosuppressive Therapy Research Articles

Epstein-Barr Virus-Encoded RNA-Positive Lymphocytes in Bone Marrow and Lymph Nodes in an Autopsy Case of TAFRO Syndrome.

A 55-year-old man was admitted to the hospital with vomiting, diarrhoea, and chest pain. Upon examination, he exhibited signs of increased inflammatory response, acute kidney injury, and thrombocytopenia, leading to a diagnosis of TAFRO syndrome, which was supported by the clinical evidence of generalized lymphadenopathy, pleural effusion, and hepatosplenomegaly. Despite receiving intensive multimodal immunosuppressive therapy, including glucocorticoid pulse therapy (methylprednisolone 1,000 mg/day), tocilizumab, and cyclosporine in the intensive care unit, the patient showed minimal response and succumbed to the disease on the seventh day of hospitalization. Histopathological analysis of the lymph nodes revealed idiopathic multicentric Castleman disease (iMCD)-like features, and Epstein-Barr virus-encoded RNA (EBER) in situ hybridization identified multiple EBER-positive cells. These findings highlight the elusive pathogenic mechanism of TAFRO syndrome and the potential resistance of some patients to standard treatments such as tocilizumab. The presence of EBER-positive cells in lymph nodes or bone marrow may serve as an indicator of disease severity and treatment resistance. Therefore, histopathological detection of EBER-positive cells may help predict responsiveness to conventional treatments, disease severity, and prognosis in patients with TAFRO syndrome.

Lupus-like manifestations after allogenic hematopoietic stem cell transplantation: a rarecase of chronic graft-versus-host disease.

Chronic graft-versus-host disease (GvHD) is the leading cause of late death in allogenic hematopoietic stem cell transplantation recipients, of which the kidney is a potential target. In this article, we report an extremely rare case of chronic GvHD, characterized by immune complex-mediated diffuse proliferative glomerulonephritis and various autoantibodies detected in the serum; it is the first case of lupus-like chronic GvHD reported to date. The patient responded well to intensive immunosuppressive therapy and reached complete remission. Mycophenolate mofetil was more effective than tacrolimus in this case, suggesting that treatment of kidney diseases associated with chronic GvHD should be based on pathogenesis and pathological patterns.

Widespread form of Majocchi's granuloma in a kidney transplant recipient.

Kidney transplantation is the encouraged kidney replacement therapy due to providing more prolonged survival with a better quality of life. Unfortunately, kidney transplant recipients are susceptible to infections because of long-term utilization of immunosuppression. Despite dermatophyte infections are generally not life-threatening, the clinical significance has been recently enhanced by an increasing number of immunocompromised patients. We have presented a rare dermatophytosis course, Majocchi's granuloma, that spreads to all extremities during the early post-transplant period. A young kidney transplant recipient was exposed to intensive immunosuppression therapy due to acute rejection in the early period of post-transplantation. After four months, numerous nodular skin lesions were raised on various body parts. An invasive fungal infection was identified in the skin biopsy. Also, Trichophyton rubrum was isolated in the tissue cultures. Consequently, the patient was diagnosed with Majocchi's granuloma. An effectual treatment was attained with an oral terbinafine tablet. Majocchi's granuloma is a distinct form of dermatophytosis characterized by the spreading of infection into the dermis. In this unexpected case, we alerted physicians to opportunistic infections in the kidney transplant recipient.

Lupus nephritis and associated thrombotic microangiopathy

Lupus nephritis represents the most common manifestation of lupus of the solid organs and is associated with an increased risk of chronic kidney disease. The co-occurrence of lupus nephritis and thrombotic microangiopathy is described to be rare but implies the risk of fatal organ dysfunction. We report three patients in whom these two disease entities occurred in parallel, necessitating intensive immunosuppressive therapy, including complement blockade.

Early Initiation of Plasma Exchange Therapy for Anti-MDA5+Dermatomyositis with Refractory Rapidly Progressive Interstitial Lung Disease.

Objectives Dermatomyositis (DM) is often associated with fatal anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive rapidly progressive interstitial lung disease (RP-ILD). RP-ILD often fails to respond to intensive treatment and has a poor prognosis. We examined the effectiveness of early plasma exchange therapy plus intensive treatment with high-dose corticosteroids and multiple immunosuppressants. Methods Autoantibodies were identified by an immunoprecipitation assay and enzyme-linked immunosorbent assay. All clinical and immunological data were collected retrospectively from medical charts. We divided patients into two groups based on treatment regimen: intensive immunosuppressive therapy alone as initial treatment (IS group) and early initiation of plasma exchange (PE) plus intensive immunosuppressive therapy (ePE group). Early PE therapy was designated if PE therapy was initiated within two weeks of starting treatment. Comparisons of the treatment response and prognosis between groups were performed. Patients Anti-MDA5-positive DM with RP-ILD was screened. Results Forty-four RP-ILD and DM patients had anti-MDA5 antibodies. Four patients were excluded because they died before receiving sufficient combined immunosuppressive therapy or before the evaluation of the immunosuppressive treatment effectiveness (IS, n=31; ePE, n=9). All 9 patients in the ePE group had improved respiratory symptoms and were alive, whereas 12 of 31 patients in the IS group died (100 vs. 61%, p=0.037). Of the 8 patients who had 2 values for a poor prognosis, indicating the highest risk for death using the MCK model, 3 of 3 patients in the ePE group and 2 of 5 in the IS group were alive (100 vs. 40%, p=0.20). Conclusion The early initiation of ePE therapy plus intensive immunosuppressive therapy was effective for patients with DM and refractory RP-ILD.

Cardiovascular Manifestations in Behçet's Disease.

Cardiovascular involvement in Behçet's disease (BD) is considerably related to morbidity and mortality. However, the cardiovascular manifestation is sometimes difficult to distinguish from those of other causes. The suspicion of BD and proper treatment is pivotal in the management of BD. Histology demonstrates perivasculitis. Neutrophil seems to play an important role in the inflammation of BD. It is thought that inflammation causes venous thrombosis and arterial aneurysm. Characteristically, BD involves both arteries and veins of variable size in any region. Venous thrombosis needs immunosuppression, and inferior vena cava thrombosis and Budd-Chiari syndrome require intensive immunosuppressive therapy. Arterial involvement causes aneurysm which usually is treated by surgical or endovascular intervention with immunosuppression. Pulmonary artery aneurysm and cardiac involvement require multimodal managements.

Porcine antilymphocyte globulin versus rabbit antithymocyte globulin for intensive immunosuppressive therapy of acquired aplastic anemia: A meta-analysis and systematic review.

Several studies have reported that porcine antilymphocyte globulin (pALG) has a significant effect on aplastic anemia (AA), but their conclusions are inconsistent. To objectively evaluate its efficacy and safety, a meta-analysis was conducted. We systematically searched the relevant literature on pALG vs. rabbit antithymocyte globulin (rATG) as the first-line treatment in AA patients until August 31, 2022, in electronic databases: PubMed, Cochrane Library, Web of Science, etc. Two researchers independently extracted data and evaluated the quality of the study. Stata 14.0 was used for statistical analysis. 50 studies were included in the analysis. The overall responses at 3, 6, and 12 months between the pALG group and rATG group were equivalent. We analyzed early mortality, total mortality, relapse rates, and 5-year survival after the administration of pALG or rATG, and there was no significant difference between the pALG and rATG groups. In our study, the incidence of infection in the pALG group was better than that in the rATG group, OR=0.63, 95% CI (0.44-0.88), p=0.008, which showed a statistically significant difference. The efficacy of pALG in AA patients is equivalent to that of rATG. rATG was associated with a significantly higher incidence rate of infection than pALG.

Cytomegalovirus-Specific T Cells in Pediatric Liver Transplant Recipients.

Cytomegalovirus (CMV) infection is a major opportunistic infection after liver transplantation (LT) that necessitates monitoring. Because of the lack of studies in children, we aimed to investigate CMV-specific T cell immune reconstitution among pediatric LT recipients. The recipients were monitored for CMV infection and CMV-specific T cells from the start of immunosuppressive therapy until 48 weeks after LT. Clinically significant CMV viremia (csCMV) requiring preemptive therapy was defined as a CMV load of >2000 IU/mL. Peripheral blood CMV-specific T cells were analyzed by flow cytometry based on IFNγ secretion upon stimulation with CMV antigens including immediate early protein 1 (IE1) Ag, phosphoprotein 65 (pp65) Ag, and whole CMV lysate (wCMV). Of the 41 patients who underwent LT, 20 (48.8%) had csCMV. Most (17/20 patients) were asymptomatic and characterized as experiencing CMV reactivation. The onset of csCMV occurred approximately 7 weeks after LT (interquartile range: 4-12.9); csCMV rarely recurred after preemptive therapy. Lower pp65-specific CD8+ T cell response was associated with the occurrence of csCMV (p = 0.01) and correlated with increased viral load at the time of csCMV diagnosis (ρ = -0.553, p = 0.02). Moreover, those with csCMV had lower percentages of IE1-specific CD4+ and wCMV-reactive CD4+ T cells at 12 weeks after LT (p = 0.03 and p = 0.01, respectively). Despite intense immunosuppressive therapy, CMV-specific T cell immune reconstitution occurred in pediatric patients post-LT, which could confer protection against CMV reactivation.

The Efficacy of Hetrombopag Combined with Cyclosporine a in Patients with Transfusion-Dependent Non-Severe Aplastic Anemia

Objective: Thetherapeutic approach for transfusion-dependent non-severe aplastic anemia (TD-NSAA) is undetermined. Though the British guideline recommended intensive immunosuppressive therapy (IST) as front-line therapy for TD-NSAA ( Killick SB, et al. British Journal of Haematology. 2016; 172(2): 187-207), the cost and risk were relatively high. Hetrombopag is a thrombopoietin receptor agonist approved for IST-refractory severe aplastic anemia (SAA) by the China Food and Drug Administration in 2021 ( Peng G, et al. Ther Adv Hematol. 2022; 13: 20406207221085197). This study aimed to evaluate the efficacy of hetrombopag plus cyclosporine A (CsA) for TD-NSAA. Methods: 24 eligible patients receiving hetrombopag plus CsA from September 2021 to July 2023 were collected by prospective registration (ChiCTR2100045895) in the Chinese Eastern Collaboration Group of Anemia (CECGA). A historical cohort (n=79) receiving CsA alone from December 2013 to January 2017 in the CECGA was used as a comparator (Table 1). Primary endpoint was overall response at 24 weeks, defined as hematologic response in ≥ 1 lineage. Secondary endpoints were overall response at 12 and 48 weeks, complete response at 48 weeks, overall survival, transformation to SAA and treatment-related adverse events. Results: At 24 weeks, the overall response rate was 74% in hetrombopag plus CsA cohort and 16% in CsA cohort (odds ratio [OR]: 14.7; 95% confidence interval [CI]: 4.1 ~ 52.4; p＜0.001). The overall response rates at 12 and 48 weeks were also significantly higher in hetrombopag plus CsA cohort than those in CsA cohort (43% vs 8%, OR: 9.1, 95% CI: 2.7 ~ 31.1, p＜0.001; 85% vs 30%, OR: 13.0, 95% CI: 2.5 ~ 66.2, p = 0.001, respectively). At 48 weeks, the complete response rate was 23% in hetrombopag plus CsA cohort and 2% in CsA cohort (OR: 13.8; 95% CI: 1.3 ~ 146.8; p = 0.029). The median time to initial response was 11.6 [95% CI: 2.9~20.3] weeks in hetrombopag plus CsA cohort, significantly shorter than that in CsA cohort (hazard ratio: 5.0; 95% CI: 2.1 ~ 12.1; p＜0.0001) (Figure 1). The median time to erythroid, platelet and neutrophil responses in hetrombopag plus CsA cohort were 20.6 [95% CI: 9.1 ~ 32.0], 16.4 [95% CI: 3.0 ~ 29.9] and 23.0 [95% CI: 10.6 ~ 35.4] weeks, respectively. The 1-year survival rates in hetrombopag plus CsA cohort and in CsA cohort were similar (90% vs 94%; hazard ratio: 1.9; 95% CI: 0.2 ~ 15; p = 0.5). The percentage of patients transforming to SAA was 8% in hetrombopag plus CsA cohort and 34% in CsA cohort (OR: 0.2; 95% CI: 0.0 ~ 0.8; p = 0.018). Treatment-related hepatic or renal injury occurred in 7 patients (29%) in hetrombopag plus CsA cohort with only one ≥ Grade 3; all gained remission after dose reduction or discontinuation. Multivariate analysis of clinical parameters of all patients from both cohorts revealed that adding hetrombopag to therapy was strongly correlated with response (OR: 43; 95% CI: 4 ~ 528; p = 0.003), as was lower lymphocyte count (OR: 0.5; 95% CI: 0.3 ~ 0.8; p = 0.011). Conclusion: The combination of hetrombopag with CsA improved the rate, rapidity, and strength of hematologic response among patients with TD-NSAA, and lowered their risks of transforming to SAA. Disclosure: This study is supported by National Natural Science Foundation of China (81900109). The authors declare that there is no conflict of interest.

Severe gastrointestinal cytomegalovirus infection with underlying common variable immunodeficiency in a middle aged lady

Cytomegalovirus is a common herpes virus infection found worldwide and by adulthood majority become seropositive. In immunosuppressed state it may reactivate to cause tissue invasive disease in gastro intestinal tract, liver, lungs, brain and retina with or without viremia. It is commonly seen in bone marrow transplant, organ transplant, AIDS and autoimmune disease requiring intense immunosuppressive therapy. Common variable immunodeficiency is a condition that affects both arms of the immune system and can lead to opportunistic infections. Chance is more when CD4 counts falls below 50 cells/microlt.

Squamous cell carcinoma of the skin after cardiac transplantation: a clinical case

Background. Solid organ transplantation recipients have a high risk of non-melanoma skin tumors. Patients after heart transplantation are prone to a higher incidence of malignant skin tumors due to intensive immunosuppressive therapy. The most common histological type is squamous cell carcinoma, followed by basal cell carcinoma. These tumors have a more aggressive clinical course, including the frequency of recurrence and metastasis, and a tendency to multifocal lesions.
 Materials and methods. We present a clinical case of primary multiple squamous cell carcinoma with metastatic lesions of regional lymph nodes in a patient after heart transplantation.
 Results. A 67-year-old patient underwent an orthotopic heart transplant in September 2018 for ischemic cardiomyopathy. Subsequently, triple immunosuppressive therapy was administered, including tacrolimus combined with mycophenolate mofetil and prednisolone. In May 2022, a solid tumor with ulceration occurred on the skin of the right scapular region. After some time, similar tumors appeared on the skin of the temporal region on the left, the posterior surface of the auricle and the parietal region on the left. The patient later found a solid, painless tumor on the left jaw angle. As a part of the examination in the oncology dispensary, a biopsy of the scapular skin tumor, scrapings from tumors, and aspiration biopsy of the submandibular lymph nodes were performed. Histological and cytological studies of all neoplasms showed squamous cell keratinizing cancer with metastases to the submandibular lymph nodes. Additional examination methods showed no signs of progression. The diagnosis was made: primary multiple synchronous skin cancer: right scapular area, stage III, cT3N0M0; left parietal area, stage II, cT2N0M0; occipital area, stage I, cT1N0M0; left auricle, stage IV, cT1N2M0. Considering the localization of tumors, surgical treatment was performed, including of excision of tumors in the scapular and parietal regions. Radiation therapy was performed on lymph nodes with metastases. After 6 months, a tumor recurrence was detected in the irradiation area.
 Conclusion. After heart transplantation, squamous cell carcinoma of the skin is common. Usually, it affects the scalp and neck with metastases to the regional lymph nodes and is prone to recurrence. The primary treatment method is surgical and radiation therapy.

Transfusion-dependent non-severe aplastic anemia: characteristics and outcomes in the clinic.

Transfusion-dependent non-severe aplastic anemia (TD-NSAA) is a rare condition of bone marrow failure that can persist for a long time or develop into severe aplastic anemia (SAA). Little is known about the clinical and laboratory characteristics, and disease prognosis and outcomes in TD-NSAA patients. The clinical and laboratory data of 124 consecutive TD-NSAA patients in the Chinese Eastern Collaboration Group of Anemia from December 2013 and January 2017 were analyzed retrospectively. In 124 TD-NSAA patients, the median age was 32 years (range: 3-80) and the median disease course was 38 months (range: 3-363). Common complications were iron overload (53/101, 52.5%), liver and kidney dysfunction (42/124, 33.9%), diabetes mellitus/impaired glucose tolerance (24/124, 19.4%), and severe infection (29 cases, 23.4%). 58% of patients (57/124) developed severe aplastic anemia with a median progression time of 24 months (range: 3-216). Patients with absolute neutrophil count (ANC) <0.5×109/L, severe infection, or iron overload had a higher probability of progression to SAA (P=0.022, P=0.025, P=0.001). Patients receiving antithymocyte globulin (ATG) plus Cyclosporin A (CsA) had a higher overall response rate compared to those receiving CsA alone (56.7% vs 19.3%, P < 0.001). The addition of ATG was the favorable factor for efficacy (P=0.003). Fourteen patients developed secondary clonal hematologic disease: eleven patients with paroxysmal nocturnal hemoglobinuria, two patients with myelodysplastic syndromes, and one patient with acute myeloid leukemia, respectively. Ten patients (8.1%) died with a median follow-up of 12 months (range: 3- 36 months). Patients with TD-NSAA usually have a prolonged course of disease, and are prone to be complicated with important organ damage and disease progression to SAA. Intensive immunosuppressive therapy based on ATG might be an appropriate approach for TD-NSAA. Clinical trial registration: http://www.chictr.org.cn/edit.aspx?pid=125480&htm=4, identifier ChiCTR2100045895.

Rapidly progressive interstitial lung disease combined with pneumocystis jiroveci pneumonia in a patient with single anti-TIF-1γ antibody positive dermatomyositis in the context of an underlying tumor

BackgroundInterstitial lung disease (ILD) is a frequently observed comorbidity in autoimmune diseases such as dermatomyositis/polymyositis (DM/PM), and it is significantly associated with specific autoantibody types. One unique antibody type is the anti-transcription intermediate factor-1γ antibody (anti-TIF-1γ Ab), which has a positive rate of only 7%. It is often found in combination with malignancy and rarely with ILD, particularly rapidly progressive ILD (RPILD). In some cases, the presence of ILD in individuals with DM may indicate a paraneoplastic syndrome. Pneumocystis jiroveci pneumonia (PJP) typically occurs due to intensive immunosuppressive therapy, human immunodeficiency virus (HIV) infection, or malignancy, and rarely as an isolated condition.Case presentationA 52-year-old man with a history of rapid weight loss but non-HIV infected and not immunosuppressed who presented with fever, cough, dyspnea, weakness of the extremities, characteristic rash and mechanic's hand. Pathogenic tests suggested PJP, laboratory tests suggested a single anti-TIF-1γ Ab positive DM, imaging suggested ILD, and pathology revealed no malignancy. RPILD and acute respiratory distress syndrome (ARDS) developed after anti-infection and steroid hormone therapy. After mechanical support therapy such as Extracorporeal Membrane Oxygenation (ECMO), the patient developed late-onset cytomegalovirus pneumonia (CMVP), complicated bacterial infection, and ultimately death. Additionally, we discuss the potential causes of rapid weight loss, the mechanisms by which anti-TIF-1γ Ab may lead to ILD, and the possible connection between anti-TIF-1γ Ab positivity, rapid weight loss, immune abnormalities, and opportunistic infections.ConclusionsThis case emphasizes the importance of early recognition of malignant tumors and pulmonary lesions, assessment of the body's immune status, prompt initiation of immunosuppressive treatment, and prevention of opportunistic infections in individuals with single anti-TIF-1γ Ab positive DM presenting with rapid weight loss.

#2649 INFECTIOUS COMPLICATIONS AFTER KIDNEY TRANSPLANTATION IN RELATION TO INDUCTION IMMUNOSUPPRESSIVE THERAPY

Abstract Background and Aims Infections are the most common non-cardiac cause of death after kidney transplantation (KT). The main goal of immunosuppressive therapy is to find a balance between the low incidence of acute rejection and infectious complications. Method We conducted a retrospective, monocentric analysis of transplant patients at the Transplant Center University Hospital Martin from 2011 to 2020 with various induction immunosuppressive therapies. We monitored the incidence of infections in terms of etiology, localization and severity at different intervals after KT. Results Our study included 39 patients on induction therapy with basiliximab to whom we paired 39 patients with induction therapy with thymoglobulin based on gender and age, in total our population consisted of 78 patients (56 men, 22 women), the mean age was 45 years. In the group of patients with induction therapy with thymoglobulin, we noted a higher proportion of fungal (P=0.0409), urogenital infections (P=0.0384), sepsis (P=0.0497) and leukopenia (0.0384) from 1st to 6th month after KTx, higher incidence of skin infections (P= 0.0218) and serious infections requiring hospitalization (P = 0.0269) from 6th-12th months to TO. On the other hand, in the basiliximab patient group, we identified a higher incidence of acute humoral and cellular rejection (P=0.0218) after 6 months of TO. From the perspective of recurrent infections, in the Thymoglobulin induction group, we noted a higher incidence of infections by localization, etiology and severity. Risk factors for recurrent bacterial infections from 1st to 6th month after KT are: history of respiratory diseases (P = 0.0108), thrombocytopenia (P = 0.0104) and infections caused by multi-resistant bacteria (P = 0.0003). Conclusion Patients on inductive immunosuppressive therapy with thymoglobulin are at a higher risk of recurrent, multidrug-resistant and severe infections after KT compared to induction with basiliximab with identical maintenance immunosuppressive therapy. On the other hand, patients on induction therapy with basiliximab have a higher risk of developing acute rejection. Therefore, it is essential to identify risk groups of patients benefiting from milder or more intensive inductive immunosuppressive therapy without a concomitant increased risk of infectious complications or acute graft rejection

Diagnostic Value of Vessel Wall Imaging to Determine the Timing of Extracranial‒Intracranial Bypass for Moyamoya Syndrome Associated with Active Sjögren's Syndrome: A Case Report.

Sjögren's syndrome is a chronic autoimmune disorder that predominantly affects exocrine organs. It is characterized by an organ-specific infiltration of lymphocytes. The involvement of the major cerebral arteries in Sjögren's syndrome has rarely been reported. A recent study reported a case of successful extracranial-intracranial (EC-IC) bypass without complications, even in the active inflammatory state, although the optimal timing of such a bypass remains unclear. We here report the case of a 43-year-old woman presenting with acute ischemic stroke due to progressive middle cerebral artery (MCA) occlusion and signs of primary Sjögren's syndrome. During intensive immunosuppressive therapy for active Sjögren's syndrome, the patient was monitored using contrast-enhanced magnetic resonance vessel wall imaging (MR-VWI). A couple of intravenous cyclophosphamide injections combined with a methylprednisolone pulse and antiplatelet therapy resulted in clear resolution of vessel wall enhancement, which suggested remission of inflammatory vasculitis. Nevertheless, she still experienced a transient ischemic attack (TIA) due to decreased regional cerebral blood flow by MCA occlusion, as demonstrated by the conventional time-of-flight MR angiography and single-photon emission computed tomography. Considering the increased risk of further stroke, the decision was made to perform an EC-IC bypass as a treatment for medically uncontrollable hemodynamic impairment. Her postoperative course was uneventful without further repeated TIAs, and continued immunosuppressive therapy for Sjögren's syndrome provided effective management. Our findings emphasize the diagnostic value of contrast-enhanced MR-VWI in monitoring the effect of immunosuppressive therapy for the major cerebral artery vasculitis and in determining the timing of EC-IC bypass as a "rescue" treatment for moyamoya syndrome associated with active Sjögren's syndrome.

Comparison of haploidentical-allogeneic hematopoietic stem cell transplantation and intensive immunosuppressive therapy for patients with severe aplastic anemia with an absolute neutrophil count of zero: a retrospective study.

A retrospective analysis was conducted based on the clinical data from 60 patients older than 16 years from January 2016 to January 2021. All the patients were newly diagnosed with severe aplastic anemia (SAA) with an absolute neutrophil count (ANC) of zero. We compared the hematological response and survival of haploidentical-allogeneic hematopoietic stem cell transplantation (HID-HSCT) (n = 25) and intensive immunosuppressive therapy (IST) (n = 35) treatments. At six months, the overall response rate and complete response were significantly higher in the HID-HSCT group than those in the IST group (84.0% vs. 40.0%, P = 0.001; 80.0% vs. 17.1%, P = 0.001). With a median follow-up of 18.5 months (4.3~30.8 months), patients in the HID-HSCT group had longer overall survival and event-free survival (80.0% vs. 47.9%, P = 0.0419; 79.2% vs. 33.5%, P = 0.0048). These data suggested that HID-HSCT might be an effective alternative treatment option for adult patients with SAA with an ANC of zero, which requires further validation in an additional prospective study.

Prognostic value of pre-treatment PNH clone among the patients with aplastic anemia: a meta-analysis

ABSTRACTBackgroundParoxysmal nocturnal hemoglobinuria (PNH) clone can be detected in some patients with aplastic anemia (AA) before treatment. But the prognostic value of the presence of pre-treatment PNH clone for intensive immunosuppressive therapy (IIST) is controversial and no consensus on whether the occurrence of PNH/AA-PNH syndrome is related to pre-treatment PNH clone.ObjectiveThis study aims to summarize the prognostic value of the presence of pre-treatment PNH clone treated with IIST among the AA patients and to elucidate its relationship with the development of PNH / AA-PNH syndrome.MethodsAll published studies on the prognostic value of pre-treatment PNH clone among AA patients were retrieved. Pooled odds ratio (OR) was calculated to compare the rates, along with 95% confidence intervals (CI) and p value to assess whether the results were statistically significant.ResultsThe meta-analysis consisted of 15 studies with a combined total of 1349 patients in the cohort. Pre-treatment PNH clone had a positive effect on AA patients 6-month (pooled OR = 1.49,95% Cl: 1.06-2.08, P = 0.020), 12-month (pooled OR = 3.10,95% Cl: 1.89-5.10, P = 0.000), and overall hematological response rate (pooled OR = 1.69,95% Cl: 1.07-2.68, P = 0.024) after IIST. Patients with pre-treatment PNH clone are more likely to develop PNH/AA-PNH syndrome after IIST(pooled OR = 2.78,95%Cl:1.21-6.39, P = 0.016).ConclusionPatients with positive pre-treatment PNH clone had better hematological responses to IIST than negative. And, those patients are more likely to develop PNH/AA-PNH syndrome after IIST.

A severe cerebral infarction associated with giant cell arteritis, which developed during tocilizumab therapy and was successfully treated with intravenous cyclophosphamide.

Giant cell arteritis (GCA) is a large vessel vasculitis that primarily involves aorta and its major branches. Cerebral infarction is a serious complication that can occur secondary to GCA in up to 3% of patients with a mortality rate of over 50%. Due to the rarity of this severe complication, no therapeutic strategies are currently available. Furthermore, despite the recent progress in molecular-targeted therapy for GCA, it remains unknown whether tocilizumab is effective for severe ischemic complications such as cerebral infarction. The accumulation of individual cases in which this fatal complication could be treated is apparently required to build a better management of the disease. We present our case of GCA that developed severe cerebral infarction during high-dose glucocorticoid and tocilizumab therapy, and its symptoms and image findings were improved by switching to intravenous cyclophosphamide. Our case suggests that an intensive immunosuppressive therapy, including cyclophosphamide, may be necessary to stabilise this fatal complication of GCA.

Immune Ablation and Stem Cell Rescue in Two Pediatric Patients with Progressive Severe Chronic Graft-Versus-Host Disease

Transplantation of allogeneic hematopoietic stem cells represents an established treatment for children with high-risk leukemia. However, steroid-refractory chronic graft-versus-host disease (SR-cGvHD) represents a severe life-threatening complication, for which there is no standard therapy. After failing several lines of immunosuppressive and biological treatment, we applied an immunoablative therapy with re-transplantation of purified CD34+ donor stem cells to reset the aberrant immune system. Two pediatric patients, who had been transplanted for high-risk acute lymphoblastic leukemia, underwent the procedure. Interestingly, enough stem cells could be mobilized, harvested, and purified to be used as grafts more than one year after allogeneic transplantation under intensive immunosuppressive therapy and ongoing SR-cGvHD. With a follow-up of 8 and 22 months, respectively, both patients are without immunosuppressive therapy and do not show signs of active disease. Regeneration of skin manifestations started promptly, other damaged organs did not progress and continue to show recovery from severe fibrotic transformation. Bone marrow function is robust and T cell receptor repertoires showed polyclonal immune reconstitution. In conclusion, stem cell harvest and re-transplantation of human CD34+-selected allogeneic stem cells is possible and represents a new therapeutic option in SR-cGvHD by resetting a profoundly disturbed immune network.

Hematologic responses to avatrombopag switch in TPO-RA refractory aplastic anemia

Objective: Short-term efficacy and safety of afatrombopag conversion therapy in patients with aplastic anemia (AA) who were previously ineffectively treated with intense immunosuppressive therapy (IST) combined with TPO receptor Agonist (TPO-RA) or who were unable to tolerate the side effects of TPO-RA. Methods: Analysis of patients with severe aplastic anemia (SAA) treated in Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College from January 2021 to December 2021 who received IST combined with TPO-RA (eltrombopag/hatrombopag) for at least 6 months, but was ineffective for at least 3 months or patients who cannot continue to use TPO-RA due to side effects, and switched from TPO-RA to avatrombopag (APAG) , and treated for at least 6 months. This study analyzed its short-term efficacy and evaluated its safety. Results: The median age was 54 (14-68) years old among the 16 patients with AA (8 male and eight female) . A total of ten patients (refractory group) who did not respond to IST combined with TPO-RA were converted to APAG median therapy for 6 (6-10) months. Only seven patients (70% ) obtained trilineage HR [four cases of complete treatment response (CTR) , one case of good treatment response (GPR) , and two cases of partial treatment response (PR) ], all of which began to take effect at 3 months of APAG treatment. There were six patients with TPO-RA intolerance, and APAG was treated for 6 (2 to 8) months. About four patients (67% ) received HR (three GPR cases and one PR case) , of which two patients received PR at 3 months and four patients received HR at 6 months of APAG treatment. No APAG-related grade 2 or more adverse events occurred during the APAG therapy, no thrombotic events occurred, no fibrologic tissue hyperplasia was found in the bone marrow pathology reexamination at 6 months of treatment, and none of the patients discontinued the drug due to adverse events. Conclusion: APAG may be a better switching treatment option for patients with AA who are refractory or are intolerant to TPO-RA.