Allogeneic bone marrow transplantation possibly induces a localized type of porokeratosis

A 15-year-old girl underwent allogenic bone marrow transplantation for neuroblastoma. A few years later, she noticed a round lesion on her left buttock. Since the lesion had been asymptomatic and never grown, more than 20 years had passed before she saw a local doctor to consult about it. Although the lesion was suspected to be tinea corporis, no fungi were found on microscopic examination. Subsequently, administered topical corticosteroids were not effective. She was referred to our hospital for further evaluation, and a skin biopsy confirmed the diagnosis of porokeratosis. There was a possibility that chemotherapy, total body radiation, or immunosuppressive therapy associated with allogeneic bone marrow transplantation was involved in the development of porokeratosis. Numerous cases of acquired porokeratosis in immunocompromised status have been observed; as for those after allogenic bone marrow transplantation, 12 cases have been reported in the English literature, 4 of which had only one or a few lesions on a limited area of body surface. Our case was relatively uncommon in that the lesion was solitary and comparatively large. In a localized type of porokeratosis, it was suggested that a malignant skin tumor developed earlier than in other types. Careful follow-up for malignant transformation is especially required.

Isolated CNS Hemophagocytic Lymphohistiocytosis in Children:What We Know, What We Don't Know ?

The presence of central nervous system involvement has a profound impact on the prognosis, treatment, and clinical outcome of the primary hemophagocytic lymphohistiocytosis (pHLH). However, isolated CNS-HLH is a challenging disease with a high mortality and morbidity , possibly resulting from a spsecific neuroinflammation that leads to isolated disease only without systemic activation under some additional genetic modifiers. In this study, we retrospectively reviewed our isolated CNS-HLH cases and there were 73 patients (36 male, 37 female) with a median age of 20 months (range, 1- 226 months) diagnosed as primary hemophagocytic lymphohistiocytosis at Hacettepe University Faculty of Medicine, between January 2005 and June 2021. Among these, 39 (53%) patients had central nervous system involvement either on admission or during the recurrence. On admission, the number of patients who had both CNS and sytemic involvement was 19 (49%), moreover 2 had CNS infiltration both initially and during the course of relapse. 8 patient did show CNS involvement only during the relapse. Ten (25%) patients (5 male, 5 female) with isolated CNS involvement are the main subject of this study and none of them had infectious trigger. What we know is they were presented with mostly unexplained neurological findings and /or cranial nerve paralysis. In this group median age at presentation was 101 months ( range 6 - 180 months). They all had primary HLH associated patogenic mutation and in some of them diagnosed was also confirmed by brain biopsy. Neither family history and /or consanguinity nor HLH criteria are fullfilling in this devastating disorder. Cranial MRI gives many clues during admission in experienced hands. Two of our published cases were initially diagnosed as lymphomatoid granulomatosis and acute disseminated encephalomyelitis ; they were diagnosed as hemophagocytic lymphohistiocytosis after developing systemic symptoms 3 and 12 months later. Interestingly 6 of 10 patients in this group never developed systemic symptomps, 7 patients underwent allogeneic bone marrow transplantation. Spinal cord involvement was determined in 8 patients(20%), including 4 at diagnosis and 4 during follow up ; including one previously published case, 4 out of 8 had isolated cases did show spinal involvement as well. Even though few number of cases with isolated CNS-HLH has been reported in the recent years, we believe that the number of such cases is not limited to those who have been reported because it is rather difficult to diagnose patients with isolated CNS symptoms, which leads to misdiagnosis and/or mistreatment. What we don't know is how to specifically treat patients with CNS directed therapy, and exactly which mutations are associated with isolated CNS-HLH or whether there is a known tendency in this group and perhaps unknown mutations ? Does it have a facilitating effect ? Disclosures No relevant conflicts of interest to declare.

Modulating Endothelial Cells with EGFL7 to Diminish aGVHD after Allogeneic Bone Marrow Transplantation in Mice

Acute graft versus host (aGVHD) is the second cause of death after allogeneic-hematopoietic stem cell transplant (allo-HSCT) underscoring the need for novel therapies. Based on previous work that endothelial cell dysfunction is present in aGVHD and that epidermal growth factor-like domain 7 (EGFL7) plays a significant role in decreasing inflammation by repressing endothelial cell activation and T cell migration, we hypothesized that increasing EGFL7 levels after allo-HSCT will diminish the severity of aGVHD. Here, we show that treatment with recombinant EGFL7 (rEGFL7) decreases aGVHD severity and improves survival in recipient mice after allogeneic transplantation with respect to controls without affecting graft versus leukemia effect. Histopathology analysis revealed higher amount of leukocyte infiltration in both large intestine and liver of PBS group compared to rEGFL7-treated mice. Furthermore, damage to the gut was reduced in EGFL7 treated mice. Finally, we showed that rEGFL7 treatment results in higher thymocytes, T, B and dendritic cells in recipient mice after allo-HSCT. This study constitutes a proof of concept of the ability of rEGFL7 therapy to reduce GHVD severity and mortality after allo-HSCT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Ph-Negative Acute Lymphoblastic Leukemia (ALL) in Adolescents and Young Adults (AYA) Treated with Pediatric Argentine BFM-like Protocol: Real-Word Data on Prognostic Factors and Treatment

Background: ALL in adults is considered a heterogeneous disease with poor prognosis. However, adolescents and young adults (AYA) display intermediate characteristics as compared with children. Risk groups and response predictors are essential to guide the treatment. Aims: The aim of this report was to evaluate the experience of Ph-negative ALL in AYA patients (pts) treated with the pediatric Argentine type-BFM protocol, assessing predictors of response in terms of overall survival (OS) and event-free survival (EFS). Methods: We performed a retrospective multicenter analysis of AYA pts diagnosed between 2013 to 2021, from 16 Argentine institutions who were treated following the pediatric Argentine type-BFM protocol. Response to prednisone (PR) at day(d) 8 (<1.0 and ≥1.0 x10 -9 blasts) in peripheral blood (PB) and complete remission (morphological remission -MCR- together with negative minimal residual disease -MRD- by flow cytometry) were evaluated. Events were defined as relapse, refractoriness or death. Chi2/Fisher's exact test, Kaplan-Meier / log rank test and Cox regression were used for statistical analysis. Results: One hundred and seventy-three patients similarly distributed among private and public institutions were analyzed. The median (Md) age was 22 years (15-40) with a male predominance (66%). At diagnosis, 23% presented central nervous system (CNS) involvement, 79.5% B and 20.5% T immunophenotype, 29% CD20 positive, 16% adverse cytogenetic/molecular findings and 29% no data. Ph-like screening was not routinely performed assessed only in 13% revealing two CRLF2 and one PDGFRB rearrangements. Twenty-one (12%) of pts underwent allogeneic bone marrow transplantation (Allo-HSCT) at 1 st line, 20 with MRD negative and 1 MRD positive at the time of the procedure.Of 171 pts, 155 (91%) achieved MCR, 12 (7%) were refractory, 3 (2%) died prior/during induction and 1 (0.6%) patient dropped out of treatment; 144 (84%) achieved negative MRD, 22 (13%) positive MRD and 5 (3%) were not evaluated. The Md to reach CR and MRD (-) was 33d (IQR 31-42) and 35d (IQR 32-73), respectively. With a Md follow-up of 16 months (1-79), 52 pts (30%) relapsed and 68 pts (39%) died. Early deaths at 3 months occurred in 8 (5%) pts, 5 related to treatment and 3 to disease. The Md OS and EFS were 58 and 34 months, respectively. Prognostic predictors analyzed were sex, white blood counts (WBC) at diagnosis (limit of 30 x10 -9/L), age (limit of 30 years), CNS involvement, cytogenetic/molecular findings, PR at d8, MRD in bone marrow (BM) at d15, 33 and 78. In the univariate analysis, response at d8, MRD at d15, 33 and 78 were useful to predict both OS and EFS, adding age and WBC in terms of OS. Similar results were obtained when patients who underwent Allo-HSCT were censored at the time of the procedure. (Table). In the multivariate analysis, positive MRD at d33 and d78 (and WBC in OS) maintained their independent adverse prognostic impact in relation to OS and EFS. Allo-HSCT showed benefits in pts with MRD >0.1% at d33 and >0.01% at d78 in terms of OS (d33: NR vs. 11 m, p =0.048, HR 0.3, 95%CI [0.1-0.9]; d78: NR vs. 8 m, p =0.009, HR 0.4, 95%CI [0.2-0.8]) and EFS (d33: NR vs. 6 m, p =0.022, HR 0.2, 95%CI [0.1-0.8]; d78: NR vs. 5 m, p =0.003, 0.1 HR, 95%CI [0.02-0.5]). The adverse risk of positive MRD at day 33 and 78 in terms of OS and EFS was overcome when pts were transplanted. Summary/Conclusion: The results show that positive MRD at d33 and 78 independently impacted on OS and EFS in our series and that Allo-HSCT overcame their adverse risk. Our data confirms the relevance of using pediatric protocols in AYA. On the other hand, the importance of prognostic tools in order to improve the outcome of AYA patients, reinforcing their inclusion in current guidelines. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Chronic active Epstein–Barr virus-associated secondary hemophagocytic lymphohistiocytosis in pregnancy: a case report

Background Secondary hemophagocytic lymphohistiocytosis (sHLH) is a rare and fatal disease characterized by uncontrolled immune cell activation that can lead to a cytokine storm. Unfortunately, this condition can occur even during pregnancy, threatening both maternal and fetal lives. Case presentation A 23-year-old nulliparous woman at 26 weeks of gestation presented with continuous fever, coughing, and sore throat. Upon arrival at our hospital, her temperature was >38°C and laboratory findings indicated cytopenia (neutrophil count, 779/μL; hemoglobin level, 10.2 g/dL; platelet count, 29,000/μL), elevated ferritin level (1,308 ng/mL), and elevated soluble interleukin-2 receptor level (11,200 U/mL). Computed tomography showed marked splenomegaly. Bone marrow examination revealed hemophagocytosis, and blood examination showed a plasma Epstein–Barr virus (EBV) DNA level of 8.9 × 105 copies/μg. The monoclonal proliferation of EBV-infected T cells was confirmed by Southern blotting, and the patient was diagnosed with chronic active EBV-associated sHLH and T-cell lymphoproliferative disease. Immediately after admission, the patient’s condition suddenly deteriorated. She developed shock and disseminated intravascular coagulation, requiring endotracheal intubation along with methylprednisolone pulse and etoposide therapy. Although the patient recovered, she delivered a stillborn baby. After delivery, she was treated with reduced-dose dexamethasone, etoposide, ifosfamide, and carboplatin (DeVIC) and steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapies. Five months after diagnosis, she received human leukocyte antigen-haploidentical allogeneic bone marrow transplantation from her sister. She remains in remission for 5 months from the time of transplantation to the present. Conclusions sHLH, which may cause maternal and fetal death, should be carefully considered in critically ill pregnant women, particularly those presenting with continuous fever and cytopenia.

From Biology to Clinical Practice: Iron Chelation Therapy With Deferasirox

Iron chelation therapy (ICT) has become a mainstay in heavily transfused hematological patients, with the aim to reduce iron overload (IOL) and prevent organ damage. This therapeutic approach is already widely used in thalassemic patients and in low-risk Myelodysplastic Syndrome (MDS) patients. More recently, ICT has been proposed for high-risk MDS, especially when an allogeneic bone marrow transplantation has been planned. Furthermore, other hematological and hereditary disorders, characterized by considerable transfusion support to manage anemia, could benefit from this therapy. Meanwhile, data accumulated on how iron toxicity could exacerbate anemia and other clinical comorbidities due to oxidative stress radical oxygen species (ROS) mediated by free iron species. Taking all into consideration, together with the availability of approved oral iron chelators, we envision a larger use of ICT in the near future. The aim of this review is to better identify those non-thalassemic patients who can benefit from ICT and give practical tips for management of this therapeutic strategy.

Transcriptional plasticity drives leukemia immune escape

Relapse of acute myeloid leukemia (AML) after allogeneic bone marrow transplantation (alloSCT) has been linked to immune evasion due to reduced expression of major histocompatibility complex class II (MHC-II) proteins through unknown mechanisms. We developed CORENODE, a computational algorithm for genome-wide transcription network decomposition, that identified the transcription factors (TFs) IRF8 and MEF2C as positive regulators and MYB and MEIS1 as negative regulators of MHC-II expression in AML cells. We show that reduced MHC-II expression at relapse is transcriptionally driven by combinatorial changes in the levels of these TFs, acting both independently and through the MHC-II coactivator CIITA. Beyond the MHC-II genes, MYB and IRF8 antagonistically regulate a broad genetic program responsible for cytokine signaling and T-cell stimulation that displays reduced expression at relapse. A small number of cells with altered TF levels and silenced MHC-II expression are present at the time of initial leukemia diagnosis, likely contributing to eventual relapse. Our findings reveal an adaptive transcriptional mechanism of AML evolution after allogenic transplantation whereby combinatorial fluctuations of TF levels under immune pressure result in selection of cells with a silenced T-cell stimulation program.

Aplasia medular congénita de serie roja: Anemia de Diamond Blackfan. A propósito de un caso

Pure red cell aplasia medullary is a disorder characterized by anemia with almost complete absence of red cell precursors in the bone marrow, with leukocyte count and platelets. The Diamond-Blackfan anemia is a failure syndrome characterized by bone marrow anemia, reticulocytopenia and decreased erythroid precursors in the bone marrow. the case of an infant under 2 months of age presented no family or perinatal history major, whose mother progressive skin pallor evidence mucosa associated with hyporexia; go to health center where they perform paraclinical reporting hemoglobin 1.7 g / dL. peripheral blood smear where erythroid frankly affected with normal megakaryocytic granulocytic count shown is made; It biopsied and bone marrow aspirate concluding marrow red cell aplasia; possible anemia Diamond-Blackfan in light of other clinical findings arises. It stays with glucocorticoid treatment, however insufficient response, begins erythropoietin dose progressively increasing, despite it, warrants blood transfusions on a regular basis; compatibility studies performed with first-degree resulting positive, currently a candidate for allogeneic bone marrow transplantation. It is concluded that despite being a rare syndrome should be suspected in severe anemia where there is acute blood loss, ruling out other etiologies; also timely initiation of treatment is critical to the survival of these patients.