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Chimeric antigen receptor-associated hemophagocytic lymphohistiocytosis (HLH)-like toxicities (LTs) involving hyperferritinemia, multiorgan dysfunction, coagulopathy, and/or hemophagocytosis are described as occurring in a subset of patients with cytokine release syndrome (CRS). Case series report poor outcomes for those with B-cell acute lymphoblastic leukemia (B-ALL) who develop HLH-LTs, although larger outcomes analyses of children and young adults (CAYAs) with B-ALL who develop these toxicities after the administration of commercially available tisagenlecleucel are not described. Using a multi-institutional database of 185 CAYAs with B-ALL, we conducted a retrospective cohort study including groups that developed HLH-LTs, high-grade (HG) CRS without HLH-LTs, or no to low-grade (NLG) CRS without HLH-LTs. Primary objectives included characterizing the incidence, outcomes, and preinfusion factors associated with HLH-LTs. Among 185 CAYAs infused with tisagenlecleucel, 26 (14.1%) met the criteria for HLH-LTs. One-year overall survival and relapse-free survival were 25.7% and 4.7%, respectively, in those with HLH-LTs compared with 80.1% and 57.6%, respectively, in those without. In multivariable analysis for death, meeting criteria for HLH-LTs carried a hazard ratio of 4.61 (95% confidence interval, 2.41-8.83), controlling for disease burden, age, and sex. Patients who developed HLH-LTs had higher pretisagenlecleucel disease burden, ferritin, and C-reactive protein levels and lower platelet and absolute neutrophil counts than patients with HG- or NLG-CRS without HLH-LTs. Overall, CAYAs with B-ALL who developed HLH-LTs after tisagenlecleucel experienced high rates of relapse and nonrelapse mortality, indicating the urgent need for further investigations into prevention and optimal management of patients who develop HLH-LTs after tisagenlecleucel.

Lymphoid interstitial pneumonia (LIP) is a rare disease characterized by benign reactive polyclonal proliferation of bronchus-associated lymphoid tissue after exposure to inhaled or circulating antigen(s), leading to a disease symptomatology similar to idiopathic interstitial pneumonia. Its association with diseases that are caused due to immune dysregulation (autoimmune diseases, congenital/acquired immunodeficiency, and allogeneic bone marrow transplant) and response to immunomodulatory/suppressive medications suggests an immunologic pathophysiology. Although LIP has been reported in association with lymphoproliferative diseases like Castleman disease, it has never been described in patients with leukemia. We report the first case of LIP in a patient with juvenile myelomonocytic leukemia (JMML) who was found to have a novel germline mutation of unknown significance in additional sex combs-like-1 (ASXL1) gene and a pathogenic somatic mutation of protein tyrosine phosphatase, nonreceptor type 11 (PTPN11) gene at diagnosis. The patient underwent a matched unrelated bone marrow transplant for JMML with complete resolution of JMML and LIP with no recurrence to date. We also emphasize the importance of considering LIP in differential diagnosis of pulmonary lesions seen in conjunction with hematologic malignancies and distinguishing it from malignant infiltration of the lung.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, inherited bone marrow failure syndrome. Hematopoietic stem cell transplantation (HSCT) is considered a curative treatment option, but existing descriptions of patient and transplant characteristics and outcomes after related and unrelated donor HSCT are sparse. We describe outcomes after HSCT for congenital amegakaryocytic thrombocytopenia (CAMT; n = 86) from 2000 to 2018. We conducted an analysis of data collected by the Center for International Blood and Marrow Transplant Research on patients with CAMT receiving therapeutic allogeneic HSCT. The predominant donor type was HLA-matched or mismatched unrelated donors (n = 58, 67%). The remaining included HLA-matched sibling (n = 23, 27%) and HLA-mismatched relative (n = 5, 6%). The predominant graft types were bone marrow (n = 53, 62%) and cord blood (n = 25, 29%). The median age at transplantation was 3 years, with 82 of 86 patients being transplanted aged ≤10 years. The 5-year graft failure-free and overall survival were 83% (95% confidence interval [CI], 74-90) and 86% (95% CI, 78-93), respectively. An examination for risk factors confirmed mortality was higher after HLA-mismatched relative and mismatched unrelated donor HSCT compared to HLA-matched sibling and matched unrelated donor HSCT (hazard ratio 3.52, P = .04; 75% versus 93%). The 1-year incidence of graft failure was 19% after HLA-mismatched HSCT (n = 32) compared to 7% after HLA-matched HSCT (n = 54, P = .15). Day-100 grade II-IV acute graft-versus-host disease was 13%, 26%, and 30% after HLA-matched sibling, HLA-matched and mismatched unrelated donor HSCT. The 5-year incidence of chronic graft-versus-host disease was 33% with 24 of 28 patients having received grafts from HLA-matched (n = 13) and mismatched unrelated (n = 11) donors. Although HLA-matched donors are preferred, HLA-mismatched donors also extend survival for CAMT.

Epstein-Barr virus (EBV) was the first identified human oncovirus and is also one of the most ubiquitous viral infections known with established infections in more than 90% of individuals by early adulthood. EBV establishes latency by controlling expression of the viral genome making it silent to immune surveillance. In immunocompetent individuals, up to 1% of circulating T cells are directed at maintaining control over EBV replication. In addition to being involved in oncogenesis of lymphoid and epithelial tumors in immune-competent individuals, loss of immune surveillance over EBV predisposes individuals to EBV malignancies. Lymphoid proliferations from EBV-infected B cells arise in up to 20% of recipients of solid organ transplants (SOTs). One question not answered is why, when EBV requires such active immune surveillance, EBV malignancies are not even more prevalent in severely immune-compromised individuals. A better understanding of who develops complications related to EBV and what the immunologic risks are will ultimately make it feasible to perform prophylactic trials in those at highest risk. This review summarizes our current understanding of factors in SOT recipients that predispose them to the development of an EBV malignancy and that predict response to initial therapy. We then review the current landscape of those therapies, focusing on the goal of restoring long-term EBV-directed immunity to patients at risk.

Epstein-Barr virus-associated mucocutaneous ulcer (EBV-MCU) is a recently characterized entity that falls under the spectrum of EBV-lymphoproliferative disorders. First described in 2010 by Dojcinov et al, it is an EBV-driven localized proliferation of B cells, occurring in mucocutaneous tissues including the skin, the oropharynx, and the gastrointestinal tract of immunosuppressed patients in the absence of an intact T-cell repertoire. Typically, it has been described in elderly patients with age-related immunosenescence and patients who are on immunosuppressive therapy. However, only 2 cases have been reported in pediatric, adolescent, and young adult age groups, with all these patients manifesting after solid organ transplant. To the best of our knowledge there are no case reports of EBV-MCU occurring in association with hematologic malignancy. Here, we present a case of EBV-MCU in a young adult patient with T-cell acute lymphoblastic leukemia. Our report serves to promote awareness among clinicians regarding this newly described and extremely rare clinical entity in young immunosuppressed patients. In addition, we highlight the importance of accurate diagnosis to prevent overtreatment of this indolent, often self-resolving disease that has a significant clinicopathologic overlap with other aggressive forms of EBV-lymphoproliferative disorders that require more intensive therapy.

Patients with a combined immunodeficiency characterized by normal numbers but impaired function of T and B cells had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded by TFRC. The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts. Tfrc(Y20H/Y20H) mice recapitulated the immunological defects of patients. Despite the critical role of TfR1 in erythrocyte development and function, patients had only mild anemia and only slightly increased TfR1 expression in erythroid precursors. We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia. These findings demonstrate the importance of TfR1 in adaptive immunity.

Hematopoietic stem cell transplant (HSCT) with matched sibling donor (MSD) is considered the first line of therapy for patients with severe aplastic anemia (SAA) who are

High-dose melphalan (HDM) followed by autologous hematopoietic cell transplantation (auto-HCT) remains the standard-of-care therapy for multiple myeloma (MM) even with the availability of proteasome inhibitors and immunomodulatory drugs. Gastrointestinal (GI) toxicity is the main cause of morbidity after HDM. Amifostine, a cytoprotective agent, may reduce HDM-associated GI toxicity. We conducted a case control study comparing HDM + auto-HCT with or without amifostine for MM patients. One hundred and seven patients treated at University Hospitals Cleveland Medical Center who received pre-transplant amifostine were compared to 114 patients treated at MD Anderson Cancer Center without use of this agent. Amifostine 740 mg/m

Introduction Anaphylaxis is a life threatening systemic inflammatory process that share mediators involved in the coagulation cascade. Platelet activating factor, known to increase platelet aggregation, has also been implicated as an important mediator of anaphylaxis. Although other inflammatory reactions are associated with an increased risk of thrombosis, anaphylaxis is currently not reported as one of them. Furthermore the role platelets may have in the perianaphylaxis period is not well understood. We here in present a retrospective case series of three patients that had platelet aberrations suggestive of PAF involvement and clinically significant thrombosis in close relationship with anaphylaxis. Objective To investigate platelet response before and after anaphylaxis and indirect observation evidence of platelet activating factors involvement with possible increased risk of thrombosis. Methods A retrospective investigation into medical records including medication administrations times, laboratory, and radiology results. Platelet levels pre‐ and post‐ anaphylaxis were statistically analyzed. Results Case 1, a 44 year old man had an anaphylactic reaction shortly after envenomation and subsequently suffered an acute infarction with thrombus in a cerebral artery. Case 2 is a 49 year old man with idiopathic anaphylaxis who developed a deep vein thrombosis after a protracted anaphylaxis event. Case 3 involved an 18 year old female with acute myeloid leukemia was found to have a thrombus in the celiac trunk following anaphylaxis. A paired two‐tailed Wilcoxon test on the subjects pre and post anaphylactic platelet levels resulted in a overall P

Successful reduced intensity hematopoietic cell transplant in a patient with deficiency of adenosine deaminase 2

HLH occurring after HSCT is a relatively rare disease. Many conditions may mimic or trigger HLH in post-HSCT period (eg, cytokine release syndrome, engraftment syndrome, graft rejection/failure, acute graft-vs-host disease, infections systemic inflammatory response syndrome/sepsis, and thrombotic microangiopathy). Moreover, this period is usually marked by febrile illness, cytopenia, and a "cytokine storm" leading to elevation of inflammatory biomarkers like ferritin and sCD25. These parameters overlap with the diagnostic criteria for HLH. Such confounding factors make the management of post-HSCT HLH quite challenging. We illustrate this critical issue with case report of a patient who was diagnosed with HLH after allogeneic HSCT for tAML. He received MP and CsA for HLH but VP-16 was not administered due to fear of severe myelosuppression. Fortunately, he responded well to treatment and remains in remission to date. We recommend caution while using HLH-94/HLH-2004 guidelines for the diagnosis and management of post-HSCT HLH. In this article, we pinpoint these issues with a brief review of all the pediatric cases and clinical studies of post-HSCT HLH along with a critical evaluation of its various diagnostic criteria. Finally, based on the limitations of current diagnostic criteria, we suggest a need for formulating disease-specific diagnostic criteria for post-HSCT HLH.

Background Aplastic anemia is a bone marrow failure syndrome with high mortality affecting children and young adults. Although current treatment guidelines recommend hematopoietic stem cell transplant (HCT) for patients with matched sibling donors, outcomes with alternate donor options have been improving. Procedure We analyzed a validated multiinstitutional pediatric cohort using one of the largest pediatric and young adult database, the Pediatric Health Information System, for patients diagnosed with aplastic anemia (AA) from 2006 to 2015. Outcomes with upfront and salvage transplants were analyzed along with healthcare utilization. Results Among 2,169 patients in the study period, almost 20% underwent HCT, while others received immunosuppressive therapy. In a multivariate model, there was no significant difference in mortality with upfront or salvage transplants (odds ratio [OR] 1.24, 95% confidence interval [CI] 0.6–2.58, P = 0.567), while every platelet transfusion was associated with higher mortality (OR 1.37, 95% CI 1.12–1.67, P = 0.002). Healthcare utilization was significantly higher in salvage transplants requiring frequent hospitalization and transfusion requirements. Treatment mortality and graft failure rates were significantly reduced in the salvage transplant group in recent years (2011–2015 as compared to 2006–2010). Conclusion As outcomes with HCT continue to improve in severe AA, transplant with good alternate donors should be considered upfront in children and young adults.

A cross sectional study was carried out to assess immunisation coverage among 257 urban and 339 rural children aged 13-36 months who were vaccinated at pulse polio booths in Shimla hills. 84.37% urban children and 57.59% rural children were fully vaccinated. BCG scar was negative in a large number of children, especially from rural areas. Increasing maternal education was associated with complete immunisation. OPV I-III dropouts were 3% among urban children and 15% among rural. The corresponding dropout rates for DPT I-III were 1% and 8% respectively. The immunisation coverage in this region was higher than others. Sustained efforts are required to achieve full immunisation coverage and eradicate polio and measles.In India, where the universal immunization program launched in 1985 has dramatically reduced the incidence of preventable childhood diseases, pockets of low immunization still exist in the country's tribal and hilly areas. To obtain an accurate picture of immunization coverage in Shimla district, a cross-sectional study of 257 urban and 339 rural children 13-36 months of age from 30 urban and 30 rural clusters was conducted. Study participants were recruited at pulse polio booths in Shimla hills on a national immunization day in 1995. 286 (84.37%) urban and 148 (57.59%) rural children were fully vaccinated. The drop-out rates for oral polio vaccine were 3% among urban children and 15% among rural children; for diphtheria-pertussis-tetanus vaccine, these rates were 1% and 8%, respectively, and for measles vaccine, they were 94.1% and 81.3%, respectively. Complete immunization was positively associated with maternal education. Sustained efforts are required to achieve full immunization coverage in India.