RESUMO
ABO-incompatible hematopoietic stem cell transplantations (HSCTs) are widely practiced; however, the delay in erythrocyte engraftment can be problematic. While erythrocyte engraftment is usually indicated by an increase in reticulocyte levels without the need for erythrocyte transfusions, the disappearance of recipient-derived anti-A/B isoagglutinin and detection of donor-derived A/B antigens can also be used as other parameters. We conducted a retrospective analysis of 68 ABO-incompatible HSCTs, focusing on major and bidirectional mismatch. We analyzed known clinical risk factors associated with delayed erythrocyte engraftment using the three parameters (disappearance of anti-A/B isoagglutinin in recipient, detection of donor-derived A/B antigen, and reticulocyte levels >1%). Although the three parameters were well correlated, the results showed heterogeneity when analyzing the associated risk factors for delayed erythrocyte engraftment. In the analysis of all cases, the requirement for an HLA-matched platelet transfusion was a common risk factor. Furthermore, erythrocyte engraftment was slower in adults than in children. In adults, cytomegalovirus antigenemia was a risk factor for two parameters; however, in children, underlying disease was a common risk factor for all parameters. There is a complex relationship between erythrocyte engraftment and various factors related to HSCTs. Our results suggest that greater accuracy is possible by using analysis methods other than the measurement of reticulocyte levels.
Assuntos
Incompatibilidade de Grupos Sanguíneos , Transplante de Células-Tronco Hematopoéticas , Sistema ABO de Grupos Sanguíneos , Adulto , Criança , Eritrócitos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Retrospectivos , Fatores de RiscoRESUMO
Tuberculosis, caused by Mycobacterium tuberculosis complex, is a leading cause of mortality in the world, and 15% of the patients may present with extrapulmonary diseases, including splenic lesion. However, isolated splenic infection with M. tuberculosis complex is very rare. A 19-year-old otherwise healthy woman presented with left flank pain, revealing FDG-avid nodules in the spleen. She did not have pulmonary lesions. Histopathology of splenectomized sample showed granuloma, and subsequent PCR revealed amplification of IS6110, a genetic sequence exclusively detected in M. tuberculosis complex. A wide range of differential diagnosis of isolated splenic lesion should include M. tuberculosis infection regardless of pulmonary involvement. An elective splenectomy may be mandatory in timely manner.
Assuntos
Mycobacterium tuberculosis , Esplenopatias , Tuberculose , Adulto , Feminino , Fluordesoxiglucose F18 , Humanos , Mycobacterium tuberculosis/genética , Tomografia por Emissão de Pósitrons , Tuberculose/diagnóstico por imagem , Adulto JovemRESUMO
Fluconazole (FLCZ) is an azole antifungal agent and it has shown excellent clinical activities in suppressing fungemia with Candida albicans after hematopoietic stem cell transplantation. Increased administration of prophylactic FLCZ seems to have given rise to the relatively higher incidence of more resistant Candida non-albicans infection. We present a case with a rare breakthrough fungemia with C. guilliermondii after cord blood transplantation for Extranodal NK cell Lymphoma, nasal type (ENKL), during antifungal prophylaxis with FLCZ. High level of caution is needed for the breakthrough, especially after long-term azole administration.
Assuntos
Antibioticoprofilaxia/efeitos adversos , Antifúngicos/uso terapêutico , Candida/fisiologia , Candidemia/tratamento farmacológico , Candidíase Invasiva/tratamento farmacológico , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Linfoma Extranodal de Células T-NK/cirurgia , Complicações Infecciosas na Gravidez/tratamento farmacológico , Adulto , Candida/efeitos dos fármacos , Candida/isolamento & purificação , Candidemia/complicações , Candidemia/microbiologia , Candidemia/prevenção & controle , Candidíase Invasiva/complicações , Candidíase Invasiva/microbiologia , Candidíase Invasiva/prevenção & controle , Farmacorresistência Fúngica Múltipla/efeitos dos fármacos , Feminino , Fluconazol/efeitos adversos , Humanos , Testes de Sensibilidade Microbiana , Gravidez , Complicações Infecciosas na Gravidez/microbiologia , Complicações Infecciosas na Gravidez/prevenção & controle , Natimorto , Adulto JovemRESUMO
A 45-year-old man presented with fatigue and pain in the finger joints. Despite having a history of suspected sideroblastic anemia since the age of 18 years, he had not been followed up for years. Upon presentation, laboratory data revealed microcytic anemia and elevated serum ferritin levels. In addition, ringed sideroblasts were increased in the bone marrow. A liver biopsy revealed hemochromatosis and cirrhosis. Furthermore, genetic analysis revealed that he harbored the ALAS2 R452H mutation, leading to the diagnosis of X-linked sideroblastic anemia (XLSA). Accordingly, oral folate or vitamin (Vit) B12 was administered, but his anemia did not respond. However, his hemoglobin level increased from 7 to 11 g/dl with an additional prescription of oral VitB6, which facilitated the patient to undergo phlebotomy to ameliorate organ dysfunctions caused by iron overload. Previous research has revealed that ALAS2 R452 mutations confer poor responses to VitB6 therapy. Hence, accrual of patients with an unexpectedly better response, which was observed in our case, may help elucidate the pathogenesis of and therapies for XLSA.
Assuntos
Anemia Sideroblástica/terapia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Vitamina B 6/uso terapêutico , 5-Aminolevulinato Sintetase/genética , Anemia Sideroblástica/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Masculino , Pessoa de Meia-Idade , MutaçãoAssuntos
Leucemia Linfocítica Granular Grande/diagnóstico , Leucemia Linfocítica Granular Grande/genética , Mutação , Proteínas de Neoplasias/genética , Receptores de Antígenos de Linfócitos T gama-delta/genética , Fator de Transcrição STAT3/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Large granular lymphocyte leukemia (LGL L) has been morphologically characterized as a group of lymphoproliferative diseases that include T-cell large granular lymphocytic leukemia (T-LGL L) and chronic lymphoproliferative disorders of natural killer cells (CLPD-NK). We investigated mutations in the Src homology 2 (SH2) domain of the signal transducer and activator of transcription 3 (STAT3) gene in Asian cohorts of T-LGL L and CLPD-NK (n = 42 and 11, respectively). Two mutations, Y640F and D661Y, were identified using direct sequencing or allele-specific (AS) PCR. Y640F and D661Y mutations were found in seven and 18 patients, respectively. Two patients were positive for both mutations. Frequencies of STAT3 mutations in T-LGL L and CLPD-NK were 47.6% and 27.2%, respectively. Pure red cell aplasia (PRCA) was associated with the mutations (P = 0.005). The mutations were persistently found at stable levels in some patients after more than 5 years using AS-quantitative PCR. The results of the present study indicate that the SH2 domain of the STAT3 gene is frequently mutated in Asian T-LGL L and CLPD-NK, and that PRCA is closely correlated with the mutations.
Assuntos
Leucemia Linfocítica Granular Grande/genética , Aplasia Pura de Série Vermelha/genética , Fator de Transcrição STAT3/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Adulto JovemAssuntos
Linfócitos T CD4-Positivos , Leucemia Linfocítica Granular Grande/genética , Mutação , Proteínas de Neoplasias/genética , Fator de Transcrição STAT5/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Leucemia Linfocítica Granular Grande/epidemiologia , Leucemia Linfocítica Granular Grande/metabolismo , Leucemia Linfocítica Granular Grande/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Fator de Transcrição STAT5/metabolismoRESUMO
Leukemia may rarely develop in a woman during pregnancy, posing clinical challenges to the patient, fetus, family, and medical staff managing malignancy and pregnancy. We retrospectively analyzed cases of pregnancy-associated leukemia consecutively diagnosed and treated at a local tertiary-care hospital in Nagano, Japan, over the past 20 years. Five cases were identified among 377,000 pregnancies in the area (one in every 75,000 pregnancies), all involving acute leukemia (three acute myelogenous leukemia [AML] and two acute lymphoblastic leukemia [ALL]). The cases were diagnosed in the first trimester (n = 1), second trimester (n = 3), or third trimester (n = 1). There were no apparent pregnancy-associated delays in diagnosing and treating the cases. Three patients underwent induction chemotherapy during pregnancy, two of whom eventually delivered healthy babies. One of the five patients chose abortion before chemotherapy initiation. Two cases showing high-risk features at the diagnosis (AML with an FLT3-ITD mutation [n = 1] and relapsed ALL [n = 1]) eventually died despite consolidative allogeneic hematopoietic stem cell transplantation. Our results suggested that patients with pregnancy-associated acute leukemia can be treated similarly to nonpregnant patients, although pregnancy imposes particular clinical challenges that should be resolved with multidisciplinary care.
RESUMO
Acquired chronic pure red cell aplasia (PRCA) develops idiopathically or in association with other medical conditions, including T cell large granular lymphocytic leukemia (T-LGLL) and thymoma. T cell dysregulation is considered a cardinal pathogenesis of PRCA, but genetic-phenotypic associations in T cell abnormalities are largely unclear. We evaluated an extended cohort of 90 patients with acquired PRCA, including 26 with idiopathic, 36 with T-LGLL-associated and 15 with thymoma-associated PRCA, for their T cell immuno-phenotypes, clonalities and STAT3 mutations. TCR repertoire skewing of CD8+ T cells was detected in 37.5% of idiopathic, 66.7% of T-LGLL-associated and 25% of thymoma-associated PRCA patients, and restriction to Vß1 was most prominent (41%). Clonalities of TCRß or γ chain and STAT3 mutational status were statistically associated (P = 0.0398), and they were detected in all three subtypes. The overall response rate to cyclosporin A was 73.9%, without significant difference by subtypes nor STAT3 mutational status. The T cell dysregulations, such as TCR repertoire skewing with predominant Vß1 usage, clonality and STAT3 mutations, were frequently found across the subtypes, and the close associations between them suggest that these T cell derangements reflect a common pathophysiological mechanism among these PRCA subtypes.
Assuntos
Leucemia Linfocítica Granular Grande , Aplasia Pura de Série Vermelha , Fator de Transcrição STAT3 , Timoma , Neoplasias do Timo , Linfócitos T CD8-Positivos/patologia , Humanos , Leucemia Linfocítica Granular Grande/genética , Leucemia Linfocítica Granular Grande/imunologia , Leucemia Linfocítica Granular Grande/patologia , Mutação , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Aplasia Pura de Série Vermelha/genética , Aplasia Pura de Série Vermelha/imunologia , Aplasia Pura de Série Vermelha/patologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Timoma/genética , Timoma/imunologia , Neoplasias do Timo/imunologiaRESUMO
Vaccination against SARS-COV-2 is considered the most promising approach to curbing the pandemic. Patients with an immunocompromised state, such as those with hematological malignancies and organ transplantation recipients, are considered more susceptible to infection, but these at-risk patients were underrepresented in early clinical trials for vaccination. Although a growing body of studies suggests that the humoral response to COVID-19 vaccination in each of these at-risk groups of patients may be suboptimal in comparison to healthy controls, a clinical and strategic information for the further comparative analysis among these groups is not fully described. The humoral responses after two doses of BNT162b2 vaccination were evaluated in a total of 187 patients either with allogeneic hematopoietic transplantation, with renal transplantation, with anti-CD20 antibody therapy, or with anti-CD38 antibody therapy, and in 66 healthy controls. The early response at one to three months after vaccination was significantly inferior among patients with renal transplantation, patients with anti-CD20 antibody therapy, and patients with anti-CD38 antibody therapy in comparison to healthy control. But the patients with allogeneic hematopoietic transplantation showed early humoral response comparable to healthy control. The late response at 6 months after vaccination was still suboptimal among patients with renal transplantation and patients with anti-CD20 therapy. Among our patient group, renal transplant recipients had the lowest antibody titers after vaccination regardless of timing of vaccination. Patients who had received allogeneic hematopoietic transplantation attained a comparable serological response to the control group especially if they are vaccinated >300 days after transplantation, but the response was suboptimal if the vaccination was within 300 days after transplantation. Our results may provide policy makers with critical information for the further stratification of at-risk groups, helping contribute to a better allocation of resources, including additional booster vaccination.
Assuntos
COVID-19 , Vacinas contra Influenza , Transplante de Órgãos , Humanos , Vacina BNT162 , Vacinas contra COVID-19/uso terapêutico , Anticorpos Antivirais , SARS-CoV-2 , COVID-19/prevenção & controle , TransplantadosRESUMO
GATA2 is a zinc-finger transcription factor regulating early hematopoiesis and developmental processes. Heterozygous germline mutations in GATA2 underlie a pleiotropic autosomal dominant disorder, GATA2 deficiency syndrome. The wide spectrum of its clinical features involves familial predisposition to myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) and multiorgan dysfunction, including congenital sensorineural hearing loss (CSHL). We herein report a pedigree with a novel germline frameshift mutation presenting as CSHL and familial MDS. The proband was a 46-year-old man, and his daughter also presented with an identical set of clinical syndromes. Target DNA sequencing identified a novel eight-nucleotide duplicative insertion at exon 5 (NM_032638.4:c.1126_1133dup:p.Lys378Asnfs*12)ãof the GATA2 gene. RT-PCR and subcloning analysis showed that the frameshift might result in a truncated mutation with an early stop codon without interfering with the predicted splice site. The predicted mutant protein had 388 amino acids and in silico analysis showed the variant was considered deleterious. This mutation was not detected in unaffected family members. Its deleterious effect is highly likely to have portended the familial MDS and CSHL in this pedigree. Genetic testing among suspected individuals may be warranted for adequate management, including timely transplantation.
Assuntos
Códon sem Sentido , Fator de Transcrição GATA2/genética , Mutação em Linhagem Germinativa , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Biomarcadores , Biópsia , Medula Óssea/patologia , Análise Mutacional de DNA , Fator de Transcrição GATA2/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
We evaluated the cerebrospinal fluid (CSF) levels of the B-cell activating factor of the tumor necrosis factor family (BAFF) and A proliferation-inducing ligand (APRIL) in two cases of primary central nervous system B-cell lymphoma (PCNSBL) before and after treatment. One patient achieved clinical remission, and demonstrated decrease in the CSF levels of both BAFF and APRIL after treatment. Meanwhile, the other patient with insufficient therapeutic response showed increase in the BAFF levels despite decrease in APRIL levels. This report suggests that the combination of BAFF and APRIL levels could be useful in estimating the therapeutic efficacy in treating PCNSBL as reliable CSF markers.
Assuntos
Fator Ativador de Células B/líquido cefalorraquidiano , Biomarcadores Tumorais/líquido cefalorraquidiano , Neoplasias Encefálicas/líquido cefalorraquidiano , Linfoma de Células B/líquido cefalorraquidiano , Neoplasias da Coluna Vertebral/líquido cefalorraquidiano , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/líquido cefalorraquidiano , Idoso , Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Cauda Equina/diagnóstico por imagem , Feminino , Humanos , Masculino , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/tratamento farmacológico , Resultado do TratamentoRESUMO
Primary adrenal lymphoma (PAL) is rare and known to have a predilection for central nervous system (CNS) relapse. A 70-year-old man with a 2-year history of primary aldosteronism presented because of a fever. He was hypotensive, and his adrenal glands were unequivocally enlarged. PAL was diagnosed. Despite showing an initial response to immunochemotherapy, progressive paralysis ensued. Magnetic resonance imaging findings were negative, and rituximab was ineffective. His debilitated condition hindered further chemotherapy. A postmortem examination revealed lymphoma relapse in the systemic peripheral nerves. The sequential presentation of two rare lymphomas implies that PAL might have a predilection for not only the CNS but also peripheral nerves.
Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neurolinfomatose/diagnóstico , Neurolinfomatose/tratamento farmacológico , Rituximab/uso terapêutico , Idoso , Evolução Fatal , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/tratamento farmacológicoRESUMO
Chronic lymphoproliferative disorder of natural killer (NK) cells (CLPD-NK) is a rare disease with an indolent clinical course, which is characterized by persistent increase in large granular lymphocytes of NK-cell type. A somatic mutation in signal transducer and activator transcription 3 (STAT3) has been reported in patients with CLPD-NK; however, the details of the mutational profiles and their clinical significance remain unclear. We performed mutation analyses of the STAT3, STAT5B, and TNF-alpha-induced protein 3 (TNFAIP3) genes for mononuclear cell-derived DNA in 17 CLPD-NK patients using allele-specific polymerase chain reaction and amplicon sequencing. Mutations in STAT3 and TNFAIP3 were found in 29% (5/17) and 6% (1/17) of cases, respectively. All patients were negative for STAT5B mutations. In all three STAT3-mutation (+) patients studied, STAT3 mutations were restricted to sorted NK cells. STAT3 mutation (+) patients had a lower hemoglobin level (6.6 g/dL vs. 13.9 g/dL, P = 0.0044) and showed a trend toward reduced neutrophil counts (1.22 × 109/L vs. 3.10 × 109/L, P = 0.070) compared with the STAT3 mutation (-) patients. No mutations in these genes were found in patients with neuropathy. These results suggest that heterogeneity of CLPD-NK and STAT3-mutated NK cells may play a significant role in cytopenia in CLPD-NK patients.
Assuntos
Anemia/genética , Células Matadoras Naturais , Transtornos Linfoproliferativos/genética , Neutropenia/genética , Fator de Transcrição STAT3/genética , Idoso , Idoso de 80 Anos ou mais , Anemia/patologia , Doença Crônica , Feminino , Humanos , Transtornos Linfoproliferativos/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/patologiaRESUMO
Asplenia may yield an increased risk of fulminant sepsis with various pathogens. Human infection with Campylobacter fetus is rare, but it often presents with non-gastrointestinal tract infection among immunocompromised individuals. A 55-year-old abattoir worker presented with a fever. He had had splenectomy for follicular lymphoma and rituximab maintenance therapy by four months before the presentation. Blood cultures yielded C. fetus, and the administration of meropenem dissolved the bacteremia. Further maintenance therapy was withheld, and no recurrence of infection has been observed for seven years. Asplenia, occupational exposure, and/or rituximab maintenance therapy might have been precipitating factors of this rare infection.
Assuntos
Antibacterianos/uso terapêutico , Infecções por Campylobacter/complicações , Campylobacter fetus/isolamento & purificação , Linfoma Folicular/complicações , Sepse/complicações , Esplenectomia/efeitos adversos , Infecção da Ferida Cirúrgica/complicações , Matadouros , Infecções por Campylobacter/tratamento farmacológico , Humanos , Hospedeiro Imunocomprometido , Linfoma Folicular/diagnóstico , Masculino , Pessoa de Meia-Idade , Rituximab , Sepse/tratamento farmacológico , Sepse/microbiologia , Infecção da Ferida Cirúrgica/tratamento farmacológico , Infecção da Ferida Cirúrgica/microbiologiaRESUMO
Eculizumab is the complement inhibitor administered to ameliorate intravascular hemolysis in paroxysmal nocturnal hemoglobinuria. Whether or not the inhibitory mechanism may also increase the susceptibility to non-Neisserial infection is unclear. A 73-year old woman presented with bacteremia, cholecystitis and liver abscess with Pseudomonas aeruginosa. Although she had been neutropenic for 21 years, she had no history of severe infection before eculizumab had been administered. The infection with P. aeruginosa was successfully controlled with antibiotics, granulocyte colony-stimulating factor and cholecystectomy. The present case might be representative of less common bacterial infections than Neisseria spp. among patients treated with eculizumab.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Bacteriemia/tratamento farmacológico , Colecistectomia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Hemoglobinúria Paroxística/tratamento farmacológico , Pseudomonas aeruginosa/isolamento & purificação , Idoso , Bacteriemia/microbiologia , Feminino , Humanos , Infecções por Pseudomonas , Resultado do TratamentoRESUMO
Dysregulation of T-cell-mediated immunity is responsible for acquired pure red cell aplasia (PRCA). Although STAT3 mutations are frequently detected in patients with T-cell large granular lymphocytic leukemia (T-LGLL), which is often complicated by PRCA and which is also reported to be associated with acquired aplastic anemia (AA) and myelodysplastic syndrome (MDS), whether STAT3-mutated T cells are involved in the pathophysiology of PRCA and other types of bone marrow failure remains unknown. We performed STAT3 mutation analyses of the peripheral blood mononuclear cells from PRCA patients (n = 42), AA (n = 54), AA-paroxysmal nocturnal hemoglobinuria (AA-PNH; n = 7), and MDS (n = 21) using an allele-specific polymerase chain reaction and amplicon sequencing. STAT3 mutations were not detected in any of the 82 patients with AA/PNH/MDS but were detected in 43% of the 42 PRCA patients. In all 7 STAT3-mutation-positive patients who were studied, the STAT3 mutations were restricted to sorted CD8+ T cells. The prevalence of STAT3 mutation in idiopathic, thymoma-associated, autoimmune disorder-associated, and T-LGLL-associated PRCA was 33% (5 of 15), 29% (2 of 7), 20% (1 of 5), and 77% (10 of 13), respectively. The STAT3-mutation-positive patients were younger (median age, 63 vs 73 years; P= .026) and less responsive to cyclosporine (46% [6 of 13] vs 100% [8 of 8]; P= .0092) in comparison with STAT3-mutation-negative patients. The data suggest that STAT3-mutated CD8+ T cells may be closely involved in the selective inhibition of erythroid progenitors in PRCA patients.
Assuntos
Linfócitos T CD8-Positivos/metabolismo , Aplasia Pura de Série Vermelha/genética , Fator de Transcrição STAT3/genética , Feminino , Humanos , Masculino , Mutação , Aplasia Pura de Série Vermelha/metabolismoRESUMO
An 84-year-old woman was referred to our hospital presenting anemia. Her hemoglobin level was 5.8 g/dL, and white blood cell count was 9400/µL, consisting of 82% lymphocytes. Given the lymphocyte phenotype (CD2+, CD3-, CD16+, and CD56-) and negative whole blood EBV viral load, we made a diagnosis of chronic lymphoproliferative disorder of NK cells (CLPD-NK). We suspected hemolytic anemia because of the high levels of reticulocytes in the peripheral blood and the low haptoglobin value. Although the direct Coombs test was negative and there was no cold agglutination, we examined her red-blood-cell-bound IgG (RBC-IgG), which was elevated. She was diagnosed as having as Coombs-negative autoimmune hemolytic anemia (AIHA). We report the effectiveness of oral cyclophosphamide for Coombs-negative autoimmune hemolytic anemia in CLPD-NK.