Bone Marrow Necrosis Research Articles

Bone marrow necrosis and fat embolism syndrome in sickle cell disease during COVID-19 infection treated successfully with sequential red cell and plasma exchange.

Fat embolism syndrome (FES) is a rare life-threatening condition that is particularly seen in milder forms of sickle cell disease (SCD). Widespread systemic fat emboli are generated in the context of extensive bone marrow necrosis. Multi-organ failure with a high morbidity and mortality may quickly develop. Infection with Parvovirus B19 is a common precipitant. Here, the authors report the case of a 35-year-old Afro-Caribbean man with HbSC disease who presented with FES having tested positive for SARS-COV-2. He rapidly became critically ill and required admission to the intensive care unit for organ support. He was treated with red cell exchange and plasma exchange and made a good recovery to leave hospital at week 7.

Fat Embolization Syndrome Secondary to Steroid Treatment for Intractable Migraine

Sickle vaso-occlusive crises secondary to steroid therapy are well reported in the medical literature. Fat embolization syndrome (FES) is an uncommon yet serious complication that occurs due to bone marrow necrosis and is usually associated with increased mortality or damaging neurologic sequelae to the surviving patient. We report a case of FES secondary to steroid therapy administered for an unrelated condition. Our patient was initially admitted for intractable migraine. The initial work up for other intracranial emergencies was negative and she was administered steroids for intractable migraine. Within 24 hours of initiating steroid therapy, she developed pain in her neck and shoulders progressing to her chest and lower extremities. The initial signs of FES following steroid therapy in this patient included altered mental status and hypoxic respiratory failure. Cerebral imaging showed diffuse bilateral cerebral/cerebellar and brainstem micro-hemorrhages. Lung imaging showed bilateral diffuse lung infiltrates confirming acute chest syndrome. The patient was transferred to the intensive care unit for further management of her hypoxic respiratory failure secondary to acute chest syndrome (ACS). In addition to ACS, she had acute kidney and hepatocellular injury in keeping with multi-organ failure. Steroid therapy was discontinued and she was treated with red cell exchange transfusion for multi-organ failure. The patient had an almost complete resolution of multiple organ damage except for hypoesthesia of her lower jaw and lower lip- the "numb chin syndrome". This case report highlights the importance of recognizing potentially fatal multi-organ failure secondary to steroid therapy and for hematologists to consider concurrent red cell transfusions to attenuate the risk of such complications from steroid therapy.

Newly Diagnosed Sickle Cell Disease Complicated by AKI With Bone Marrow Necrosis and Fat Embolism Syndrome Successfully Treated With Plasma Exchange

Newly Diagnosed Sickle Cell Disease Complicated by AKI With Bone Marrow Necrosis and Fat Embolism Syndrome Successfully Treated With Plasma Exchange

Pathogenesis of Bohle iridovirus infection in Krefft's freshwater turtle hatchlings (Emydura macquarii krefftii).

Ranaviruses have been detected in over 12 families of reptiles including many genera of turtles, tortoises, and terrapins, but the pathogenesis of these infections is still poorly understood. Krefft's river turtle hatchlings (N = 36; Emydura macquarii krefftii) were inoculated intramuscularly with Bohle iridovirus (BIV, Ranavirus, isolate) or saline, and euthanized at 9 timepoints (3 infected and 1 control per timepoint) over a 24-day period. Samples of lung, liver, kidney, and spleen were collected for quantitative polymerase chain reaction (PCR); internal organs, skin, and oral cavity samples were fixed for histopathological examination. The earliest lesions, at 8 days postinoculation (dpi), were lymphocytic inflammation of the skin and fibrinoid necrosis of regional vessels at the site of inoculation, and mild ulcerative necrosis with lymphocytic and heterophilic inflammation in the oral, nasal, and tongue mucosae. Fibrinonecrotic foci with heterophilic inflammation were detected in spleen and gonads at 16 dpi. Multifocal hepatic necrosis, heterophilic inflammation, and occasional basophilic intracytoplasmic inclusion bodies were observed at 20 dpi, along with ulcerative lymphocytic and heterophilic tracheitis and bronchitis. Tracheitis, bronchitis, and rare bone marrow necrosis were present at 24 dpi. Of the viscera tested for ranaviral DNA by PCR, the liver and spleen had the highest viral loads throughout infection, and thus appeared to be major targets of viral replication. Testing of whole blood by qPCR was the most-effective ante-mortem method for detecting ranaviral infection compared with oral swabs. This study represents the first time-dependent pathogenesis study of a ranaviral infection in turtles.

Adenoviral infection in 5 red-tailed hawks and a broad-winged hawk.

Adenoviral infections among raptors are best described in falcons and are characterized most commonly by necrotizing hepatitis and splenitis; only one case has been reported in a hawk. Five red-tailed hawks (Buteo jamaicensis) and a broad-winged hawk (Buteo platypterus) had an adenoviral infection based on history, histopathology, negative-stain electron microscopy, and PCR. All birds had acute onset of illness resulting in death; 3 had evidence of a concurrent bacterial infection. Microscopically, all 6 birds had solitary, pale eosinophilic-to-amphophilic, intranuclear inclusion bodies within presumed hematopoietic cells in bone marrow and macrophages in spleen. Five of the 6 birds had similar inclusions within hepatocytes and Kupffer cells. All but one bird had severe bone marrow necrosis. There was moderate splenic necrosis (3 of 6) and mild-to-marked hepatic necrosis (4 of 6). Negative-stain electron microscopy demonstrated adenoviral particles in bone marrow (5 of 6), liver (1 of 5), and/or spleen (1 of 5). PCR was positive for adenovirus in bone marrow (3 of 5), liver (1 of 3), spleen (4 of 6), and/or intestinal contents (2 of 3). Viral DNA polymerase gene sequences clustered within the Siadenovirus genus. There was 99% nucleotide identity to one another and 90% nucleotide identity with the closest related adenovirus (Harris hawk, EU715130). Our case series expands on the limited knowledge of adenoviral infections in hawks. The splenic and hepatic necrosis, and particularly the hitherto unreported bone marrow necrosis, suggest that adenoviral infection is clinically relevant and potentially fatal in hawks.

Renin-Angiotensin Blockade Reduces Readmission for Acute Chest Syndrome in Sickle Cell Disease.

RationaleAcute chest syndrome (ACS) is a life-threatening complication of sickle cell disease (SCD). Current treatment is supportive-supplemental oxygen, transfusions, and antibiotics. Prevention of ACS may reduce morbidity and mortality in patients with SCD.Acute chest syndrome appears similar to pulmonary fat embolism (PFE), a complication of severe skeletal trauma or orthopedic procedures from pulmonary micro-vessel blockage by bone marrow fat. Vascular obstruction and bone marrow necrosis occur in PFE and ACS. Pulmonary fat embolism rat models have shown that angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) mitigate damage in PFE. These medications could work similarly in ACS. We hypothesize that time to readmission after one hospitalization for ACS will be reduced in patients taking ACEI or ARB compared to patients who are not.MethodsThis is a retrospective cohort study. Inclusion criteria are adults (18 to 100 years) with sickle cell anaemia (HbSS), hemoglobin SC (HbSC) disease, sickle cell thalassemia (HbSβThal), hospitalized with ACS over 16 years (January 1, 2000, to March 31, 2016); patients who take and don’t take ACEI or ARB. Children (<18 years old), elderly adults (>100 years old), pregnant patients, and patients with sickle cell trait were excluded.Data was collected from the Health Facts database, which contains de-identified information from the electronic medical records of hospitals in which Cerner© has a data use agreement.Kaplan-Meier estimates explored a time-to-event model of ACS readmission. Multivariable analysis (age, gender, smoking history) was conducted using Cox proportional hazards regression. Results were reported around a 95% confidence interval.ResultsThere were 6972 patients in total. Of which, 9.6% (n = 667) reported taking ACEI or ARB. Results for the covariates were: average age of 38 years old; 63% female (n = 4366/6969); 16% smokers (n = 1132).Readmission rates were higher for patients not taking ACEI/ARB than those who did: 0.44 (95% CI 0.43, 0.46) versus 0.28 (95% CI 0.24, 0.31) at one year, and 0.56 (95% CI 0.55, 0.58) versus 0.33 (95% CI 0.29, 0.37) at two years. Age had the strongest effect on readmission rates for patients taking ACEI/ARB (adjusted hazards ratio 0.78 [95% CI 0.68, 0.91]).ConclusionPatients with SCD who reported taking ACEI or ARB had lower readmission rates for ACS; age was the strongest covariate. Our results may have a significant impact on the prevention of ACS. Prospective studies comparing ACEI or ARB therapy versus placebo are needed to confirm this preventative effect.

Bone marrow necrosis caused by Acute Leukemia: a case report

Bone marrow necrosis (BMN) is an entity resulting from an infarction of the bone marrow stroma without involvement of the cortical bone. It is a serious complication which is associated with malignant neoplasia(among other diseases), with acute leukemia being the most described cause. From these cases, about 18% are acute lymphoblastic leukemia (ALL), affecting less than 0.5% of patients with this pathology. Its histopathology is marked by the depletion of fat cells in an eosinophilic medium with the presence of amorphous material in at least 50% of the sample. The presence of BMNs in acute leukemia suggests a worse prognosis and lower remission rates. This observational study describes a case report of BMN caused by acute leukemia, with the databeing obtained from the electronic medical record in the UNIVASF University Hospital System (UH).

Bone marrow necrosis induced by massive Staphylococcus aureus infiltration.

Bone marrow necrosis induced by massive Staphylococcus aureus infiltration.

Novel susceptibility loci for steroid-associated osteonecrosis of the femoral head in systemic lupus erythematosus.

Osteonecrosis of the femoral head (ONFH) involves necrosis of bone and bone marrow of the femoral head caused by ischemia with unknown etiology. Previous genetic studies on ONFH failed to produce consistent results, presumably because ONFH has various causes with different genetic backgrounds and the underlying diseases confounded the associations. Steroid-associated ONFH (S-ONFH) accounts for one-half of all ONFH, and systemic lupus erythematosus (SLE) is a representative disease underlying S-ONFH. We performed a genome-wide association study (GWAS) to identify genetic risk factors for S-ONFH in patients with SLE. We conducted a two-staged GWAS on 636 SLE patients with S-ONFH and 95 588 non-SLE controls. Among the novel loci identified, we determined S-ONFH-specific loci by comparing allele frequencies between SLE patients without S-ONFH and non-SLE controls. We also used Korean datasets comprising 148S-ONFH cases and 37 015 controls to assess overall significance. We evaluated the functional annotations of significant variants by in silico analyses. The Japanese GWAS identified 4 significant loci together with 12 known SLE susceptibility loci. The four significant variants showed comparable effect sizes on S-ONFH compared with SLE controls and non-SLE controls. Three of the four loci, MIR4293/MIR1265 [odds ratio (OR) = 1.99, P-value = 1.1 × 10-9)], TRIM49/NAALAD2 (OR = 1.65, P-value = 4.8 × 10-8) and MYO16 (OR = 3.91, P-value = 4.9 × 10-10), showed significant associations in the meta-analysis with Korean datasets. Bioinformatics analyses identified MIR4293, NAALAD2 and MYO16 as candidate causal genes. MIR4293 regulates a PPARG-related adipogenesis pathway relevant to S-ONFH. We identified three novel susceptibility loci for S-ONFH in SLE.

BONE MARROW NECROSIS IN ACUTE LYMPHOBLASTIC LEUKEMIA: A CASE REPORT

Bone marrow necrosis (BMN) is an entity that necrotic cells are seen on amorphous eosinophilic ground with medullary infarctus but withouth cortical bone involvement. BMN is a postmortem diagnosis in most of the reports. Bone marrow biopsy and aspiration is essential for the diagnosis. The case we report here is a patient who is diagnosed BMN and ALL at the same time with the first bone marrow biopsy, which is showed extensive necrosis. A 42-year-old man applied to our E.R. with lumbal pain. The initial blood count showed leukocyte:5.13 × 109/l, neutrophil:2.68 × 109/l, Hgb:10.7 g/dl, Hct: %31.5, thrombocyte:127 × 109/l, LDH:539 u/l (N:0-250), ALP:185 u/l (N:40-150), Total Bilirubin:0.81 mg/dl, CRP:337mg/l (N&lt;5) ), ESH: 94mm/h, folic acide: 2.8ng/ml (N&gt;5.4), Vitamin B12:398 pg/ml (N:210-900), ferritin: 5607 ug/l (N:22-320), fibrinogen:1304 mg/dl (N:200-400), D-Dimer:646 ug/l (N&lt;243) and a normal range for PZ, aPTZ, INR. Peripheral smear showed %38 PMN, %56 lymphocyte, %6 monocyte, normoblasts, rare tear drop cells and rare thrombocytes. Pathological evaluation revealed hypercellular bone marrow (%95), extensive necrosis, CD3(-) CD5(-) CD20(+), CD38(-), CD10 diffuse(+), BCL2(+) MPO(-) CD117(-), CD34(+) CD79a, Pax5 and TdT suboptimal (+). Flow cytometry showed no significant result because of the deficiency of material. PCR revealed no BCR-ABL transcript. The patient diagnosed B precursor ALL. With the BFM IA protocol complete remission obtained. At the control BMB CD3, CD20, CD79a, Pax5, TdT, MPO, CD34 was applied but there was no neoplastic involvement. After the BFM IB protocol, complete remission has been pursued. The patient is currently receiving the BFM IC protocol. BMN is an uncommon pathology with poor prognosis. Primary etiology is malignancies, especially hematologic malignancies, at %90 of the cases. As we see at this case, while the clinical and laboratory findings are insignificant; when a patient shows fever with unknown origin, bone pain, newly developed cytopenias, we must keep in mind the diagnosis of BMN and if a patient is diagnosed BMN, necessary scaning must be done immediately for malignancies as the primary cause.

Clinical Characteristics, Prognostic Factors and Misdiagnosis of Bone Marrow Necrosis Patients

To analyze the clinical characteristics, diagnosis and prognostic factors of bone marrow necrosis (BMN) patients, aim to avoid misdiagnosis, missed diagnosis or delayed treatment. The clinical data of 51 BMN patients treated in the Affiliated Hospital of Xuzhou Medical University from January 2010 to December 2017 were retrospectively analyzed. The types of primary disease, etiology, clinical manifestations, laboratory tests, radiological findings, treatment outcomes and prognostic factors were summrized, and the reasons for misdiagnosis were analyzed. Among 51 BMN patients, the hematologic tumor was detected out in 32 patients; solid tumors caused- BMN was detected out in 14 patients, benign lesions for 5 patients. The time of interval from the appearance of symptoms to the confirmation of BMN was 7 days to 6 months, with a median of 35 days. Misdiagnosis and missed diagnosis occurred in 25.5% of the BMN patients. Anemia was found in all of the 51 BMN patients, fever accounted for 58.8%, systemic bone pain for 52.9%, bleeding for 29.4%, lymphadenectasis for 37.3%, and hepatosplenomegaly for 19.6%. Leukoerythroblastic anemia accounted for 84.3%, bicytopenia for 51.0%, pancytopenia for 25.5%, and monocytopenia for 23.5%. The serologic test revealed no specific results. The first bone marrow aspiration were 38 patients and multi-site puncture were 7 patients. The diagnostic coincidence rate of bone marrow smear was 88.2%. Among 51 BMN patients, 41 patients received bone marrow biopsy, and the diagnostic coincidence rate of bone marrow biopsy was 75.6%. The abnormal signals were found in multiple vertebral bodies by spinal/pelvic MRI scan in 13 BMN patients; PET-CT scan revealed a diffuse pattern of low FDG uptake in the bone marrow in 16 patients, with a local increase in FDG uptake accompanied by bone marrow involvement. For 46 patients with BMN combined with malignancies, among which 35 patients died (76.1%) and the median survival time was 25 days. Among the 32 patients with hematologic tumors, early death occurred in 12 patients, BMN disappeared in 11 out of 20 patients received active chemotherapy for the primary disease, 9 patients died within 1 week to 3 months. Fourteen patients combined with bone marrow metastatic carcinoma died within 2 weeks to 3 months. Focal necrosis disappeared in 4 out of 5 BMN patients secondary to non-malignant diseases after symptomatic supportive treatment and still alived. Multiple logistic regression was performed to analyze factors affecting the prognosis of BMN patients, the result showed that the prognosis of BMN was closely related to the factors of primary disease (benign and malignant). The reasons for misdiagnosis and missed diagnosis were as follows: hidden onset of the primary disease, nonspecific symptoms, insufficient understanding and alertness of the physicians regarding the primary clinical characteristics and hematological abnormalities, and failure to receive multiple sites bone marrow punctures or bone marrow biopsies. BMN usually occurs concomitantly to hematologic tumors and bone marrow metastases from solid tumors. Its prognosis is closely related to the nature and severity of the primary disease and its own severity. In the clinic, BMN should be suspected in patients with severe bone pain, fever, hepatosplenomegaly, hemocytopenia, lymphadenectasis and leukoerythroblastic anemia. Bone marrow puncture at multiple positions and bone marrow biopsy can compensate for each other in the diagnosis of BMN. The combined use of the two methods can improve the diagnostic coincidence rate of BMN, and the positive rate of the etiological diagnosis of BMN.

Evolutionary course of the femoral head osteonecrosis: Histopathological - radiologic characteristics and clinical staging systems.

Osteonecrosis of the femoral head (ONFH) is a recalcitrant ischemic disorder, which could be classified into two major categories: traumatic and nontraumatic. Regardless of different risk factors, it has been testified that ONFH results from primitive vascular problems, leading to temporary or permanent loss of blood supply to bone tissue. Histopathological and microarchitectural alterations ensues, which is a gradual evolutionary process involving bone marrow and osteocyte necrosis, progressive destruction of subchondral bone, unsuccessful reparative process, and eventual articular collapse and degenerative arthritis. Based on the imaging features of ONFH, different classification systems have been developed to evaluate the severity and prognosis of the disease, which is pivotal for implementation of treatment strategy, especially the joint-preserving surgery. However, patients classified with the same severity stage, especially in the peri-collapse stage, sometimes responded differently after similar joint-preserving surgery. The unusual phenomenon may be attributed to the limitation of the current imaging classification systems, which might underestimate the disease severity, especially when referring to the early stages. In this review, we briefly summarize the etiology and pathogenesis of ONFH. The imaging features and staging classification systems of ONFH are also described. More importantly, we focus on histopathological and microstructural alterations of the femoral head, and provide an overview of their essential contribution to ONFH progression. Given the observation of discordance between imaging characteristics and histopathological alterations, a substantial amount of research on the relationship between imaging and histopathological features is required to further modify and revise the current wide-accepted classification systems.

Qualitative and quantitative magnetic resonance imaging evaluation of bone tissue vaso-occlusive events in patients with sickle cell disease

To evaluate the association between bone changes due to vaso-occlusive events in sickle cell disease (SCD) revealed by conventional MRI sequences and the fat fraction obtained using a 6-point DIXON technique (FFdix), in an attempt to use quantitative data as a biomarker for bone complications. Cross-sectional study, with 48 SCD patients, 26-homozygous (HbSS), and 22-compound heterozygous (HbSC). Forty-eight healthy individuals paired by age, weight, and sex with SCD patients. All participants underwent lumbar spine and pelvis MRI. Conventional sequences: bone complications related to vaso-occlusive events-femoral head avascular necrosis, bone infarctions, "H"-shaped vertebrae, bone marrow necrosis. Six-point DIXON technique: quantitative evaluation of the bone marrow at pre-established sites (lumbar vertebrae, sacrum, iliacs, femoral heads, greater femoral trochanters, femoral necks). Pearson's correlation, ROC curve, and binary logistic regression analysis were performed. The most frequent findings in the SCD group included femoral head avascular necrosis (75%), bone infarctions (58.3%), "H"-shaped vertebrae (58.3%), and typical imaging findings of bone marrow necrosis (8.3%). Cortical bone thickness in the proximal femoral diaphysis in patients with SCD was moderately negatively correlated with FFdix in lumbar vertebrae, iliacs, femoral necks, and first sacral vertebrae. The ROC curves and odds ratios demonstrated excellent performance of FFdix in all the evaluated anatomical sites and identified patients having bone complications. FFdix could serve as a potential biomarker in SCD because of its association with bone complications secondary to vaso-occlusive events in patients with SCD, especially in femoral heads, femoral necks, and iliacs.

Hyperhemolysis Syndrome in a Patient with Sickle Cell Disease: A Case Report.

IntroductionHyperhemolysis syndrome (HHS) is a rare complication of repeat blood transfusions in sickle cell disease (SCD). This can occur acutely or have a delayed presentation and often goes unrecognized in the emergency department (ED) due to its rapid progression and similarity to acute chest syndrome and other common complications of SCD.Case ReportWe present a case of a 20-year-old male with SCD who presented to the ED with pain and tenderness in his lower extremities one day after discharge for a crisis. Unbeknownst to the ED team, during his admission he had received a blood transfusion. On presentation he was noted to have hyperkalemia, hyperbilirubinemia, anemia, and uncontrolled pain, and was admitted for sickle cell pain crisis. Over the next 36 hours, his hemoglobin dropped precipitously from 8.9 grams per deciliter (g/dL) to 4.2 g/dL (reference range: 11.5–14.5 g/dL), reticulocyte count from 11.7 % to 3.8% (0.4–2.2%), and platelets from 318,000 per cubic centimeter (K/cm3) to 65 K/cm3 (140–350 K/cm3). He also developed a fever, hypoxia, transaminitis, a deteriorating mental status, and severe lactic acidosis. Hematology was consulted and he was treated with methylprednisolone, intravenous immunoglobulin, two units of antigen-matched red blood cells, fresh frozen plasma, and cryoprecipitate. He was transferred to an outside hospital for exchange transfusion and remained hospitalized for 26 days with acute liver failure, bone marrow necrosis, and a fever of unknown origin.ConclusionBecause of the untoward outcomes associated with delay in HHS diagnosis and the need for early initiation of steroids, it is important for emergency providers to screen patients with hemoglobinopathies for recent transfusion at ED presentation. Asking the simple question about when a patient’s last transfusion occurred can lead an emergency physician to include HHS in the differential and work-up of patients with sickle cell disease complications.

Bone marrow necrosis in pediatric malignancies: 10-Year retrospective review and review of literature.

Bone marrow necrosis (BMN) is a rare pathologic finding, but when encountered is most often associated with malignancy. In adults, its presence correlates with an inferior prognosis, however in children the prognostic implication is unclear. We performed a retrospective review of 3,760 bone marrow specimens in patients ≤18 years over a 10-year period. BMN was identified in less than 1% of specimens and only in patients with leukemia, lymphoma, or neuroblastoma. BMN contributed to a delay in diagnosis; however, advanced medical imaging may serve as a tool to localize nonnecrotic areas for bone marrow sampling, facilitating an expedited diagnosis.

Analysis and Clinical Characteristics of 23 Cases of Bone Marrow Necrosis

BackgroundBone marrow necrosis (BMN) is a rare secondary disorder of many discrepant neoplastic processes. The etiology is diverse, and malignancy is the most common background disease. Patients and MethodsBetween 2005 and 2019, a total of 23 cases of BMN were detected and analyzed at Zhujiang Hospital and Nanfang Hospital. ResultsIn our study, the 40-60-year-old age group was the one with the highest incidence of BMN (n = 12, 52.2%). The background diseases of patients with BMN varied. Eighteen (78.3%) of 23 patients were diagnosed with hematologic diseases at the same time, most of which were acute B lymphocytic leukemia (n = 8, 34.8%). The complete blood count of these 23 patients noted a decrease in hemoglobin (100%), a decrease or increase in white blood cells and neutrophils, and thrombocytopenia (78.3%). The levels of lactate dehydrogenase (> 300 U/L) and serum ferritin (> 500 μg/L) were elevated in all patients, and 16 (94.1%) of 17 patients presented with increased d-dimer levels. The 2-week cumulative survival and 2-year cumulative survival of patients with BMN were 56.5% and 47.4%, respectively. The mortality probability within 2 weeks was 43.5%, and the adjusted mortality probability was 26.7% within 2 weeks to 2 years, indicating that patients with BMN had the greatest risk of death within 2 weeks. ConclusionBMN patients with B lymphocytic leukemia as the background disease had a better prognosis than those with other background diseases. BMN of unknown etiology may have an extremely poor prognosis. Therefore, diagnosing the background disease plays an important role in the treatment of BMN.

Fat Embolism Syndrome in Sickle Cell Disease.

Fat embolism syndrome is a devastating complication of sickle cell disease resulting from extensive bone marrow necrosis and associated with high mortality rates, while survivors often suffer severe neurological sequelae. Despite that, the syndrome remains under-recognised and under-diagnosed. Paradoxically, it affects exclusively patients with mild forms of sickle cell disease, predominantly HbSC and HbSβ+. A significant number of cases occur in the context of human parvovirus B19 infection. We provide here a brief summary of the existing literature and describe our experience treating 8 patients in our institution. One patient had HbSS, 6 HbSC and 1 HbSβ+. All patients developed type I respiratory failure and neurological involvement either at presentation or within the first 72 h. The most striking laboratory abnormality was a 100-fold increase of the serum ferritin from baseline. Seven patients received emergency red cell exchange and 1 simple transfusion. Two patients (25%) died, 2 patients (25%) suffered severe neurological impairment and 1 (12%) mild neurological impairment on discharge, while 3 (38%) patients made a complete recovery. With long-term follow-up, 1 patient with severe neurological impairment and one patient with mild neurological impairment made dramatic improvements, making the long-term complete recovery or near complete recovery rate 63%. Immediate red cell exchange transfusion can be lifesaving and should be instituted as soon as the syndrome is suspected. However, as the outcomes remain unsatisfactory despite the increasing use of red cell exchange, we suggest additional therapeutic measures such as therapeutic plasma exchange and pre-emptive transfusion for high risk patients.

Phase I Clinical Trial of Autologous CLL1 CAR-T Therapy for Pediatric Patients with Relapsed and Refractory Acute Myeloid Leukemia

Background Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable success in treating a variety of blood cancers, such as CD19 CAR-T for B-cell malignancies and BCMA CAR-T for myeloid myeloma (MM). However, similar progress has yet to be achieved with relapsed and refractory acute myeloid leukemia (R/R AML), primarily due to the heterogeneous nature of AML, making it difficult to find an ideal CAR-T target. Previous efforts have targeted single CD33, CD123, LeY, NKG2D, or CD70 receptors, but the overall response rate is much lower compared to CD19 CAR-T. Improved clinical outcome was recently reported with a dual-receptor CAR-T (CD33 and CLL1), reaching ~80% CR for R/R AML patients. However, CD33 is also expressed in normal hematopoietic stem cells (HSC) and patients need allogeneic hematopoietic stem cell transplantation (HSCT) following CAR-T therapy. Notably, AML mainly affects the elder population, and patients more than 65 years old are usually not suitable for HSCT. To address these challenges, we aim to find an effective target for AML without the need for the HSCT. In our study, CLL1 is chosen as a promising target as it is not expressed on normal HSCs, but highly expressed on AML blasts cells and leukemia stem cells (LSCs), which is a small population that plays an important role in disease progression and relapse. Here we report the results from a Phase I clinical trial to evaluate the toxicity and efficacy of the CLL1 CAR-T in the treatment of pediatric R/R AML. Methods We have generated a 2nd generation of CLL1 CAR-T, the extracellular scFv was derived from a murine CLL1 monoclonal antibody, which was generated by hybridoma technology. Autologous CAR-T cells were manufactured in a cGMP facility. Between Oct 2019 and Mar 2020, 3 pediatric R/R AML patients were infused. CAR-T cells were given by a dose at 0.2-1x106/kg with a single dose. Results Of the 3 patients infused, cytokine release syndrome (CRS) occurred in 3 patients (2 grade Ⅰ, 1grade II), no neurotoxicity occurred. All patients suffered pancytopenia, granulocytopenia and monocytopenia. All the adverse effects were resolved after treatment. Patient 1 is a refractory AML patient with more than 95% of AML blasts being CLL1 positive. The infused CAR-T cells showed typical clonal expansion peaking at Day 8. The patient reached CR/MRD- when evaluated at Day 21 post infusion. The patient received HSCT at Day 35, and remained CR/MRD- till now (Jul 2020, 8 months post CAR-T infusion). Patient 2 is a relapsed patient after HSCT and showed severe bone marrow necrosis (BMN). Therefore, we only generated a dose 0.35-1x106/kg CAR-T cells. The patient reached CR/MRD- when evaluated at Day 14 post infusion. The patient went through a second HSCT at Day 38. However, the patient passed away due to GVHD two months after the second HSCT. Patient 3 is a refractory AML patient with about 85% of AML blasts being CLL1 positive. The patient reached CR/MRD+ (1%) when evaluated at Day 14 post infusion. However, AML blast increased to 11% when evaluated at Day 30, a majority of them were CLL1 negative. The patient received Azacitidine treatment at Day 30-34, and AML blast decreased to 2.8% at Day 45. Notably this patient was refractory to Azacitidine treatment previously, suggesting that CLL1 CAR-T could eradicate LSCs, making the left AML tumor cells sensitive to chemotherapy. This patient received HSCT at Day 75, and remained CR/MRD- till now (Jul 2020, 7 months post CAR-T infusion). Conclusion Our study suggested that CLL1 CAR-T is a therapy with high efficacy and manageable toxicity in R/R AML patients. All patients in this study could reach CR within one month and only experienced 1-2 grade CRS. For patients with CLL1 negative AML blast, the CLL1- cells may take over after CLL1 CAR-T therapy. Combination with chemotherapy like Azacitidine may help patients reach complete response. Figure Disclosures No relevant conflicts of interest to declare.

Tandem Allogeneic Hematopoietic Stem Cell Transplantation for Salvage Treatment of Acute Myeloid Leukemia Refractory to Induction Chemotherapy: A Case Report

BackgroundPrimary refractory acute myeloid leukemia (AML) is associated with dismal prognosis. No standard treatment options are available, and it remains an unmet clinical need. Here, we report a case of a tandem allogeneic hematopoietic stem cell transplantation (allo-HSCT) performed in a patient who did not achieve remission after 2 courses of induction chemotherapy. Methods Case reportThe treatment was approved by the Bioethical Commission of the Medical University of Warsaw and was performed in accordance with the Declaration of Helsinki. The patient gave informed consent. ResultsA 41-year-old woman was diagnosed with AML, high cytogenetic risk, with concomitant skin and central nervous system involvement, bone marrow necrosis, and hemophagocytic lymphohistiocytosis. She received “3+7” induction and HAM (cytarabine, mitoxantrone) reinduction, after which she did not achieve remission and hematopoietic recovery. Tandem allo-HSCT was performed from the same HLA-identical brother---the first after reduced intensity conditioning (cladribine, cytarabine, mitoxantrone, melphalan) and the second after myeloablative conditioning (BuCy--busulphan, cyclophosphamide). The patient obtained complete remission after the first allo-HSCT and remains disease-free after the second for 5 years ConclusionTandem allo-HSCT may be a treatment option for primary refractory AML.

Transformation gélatineuse de la moelle osseuse au cours d’une leucémie aiguë

Serous degeneration of bone marrow is a rare hematological complication, of multiple etiologies, which physiopathology is yet to be fully understood. It is described as a focal hypoplasia of the bone marrow and atrophy of its adipocytes coupled with an extracellular deposit of an eosinophilic substance that corresponds to "hyaluronic acid". The prognosis of these lesions depends on the etiological diagnosis. We report the case of a 19-year-old female patient without no notable pathological history, hospitalized in a regional hospital for mucocutaneous pallor with an impaired general condition. The biological assessment revealed a pancytopenia, and the presence of 60% blast cells on the blood smear, which was in favor of acute leukemia. As part of the etiological assessment, a bone marrow biopsy was performed, revealing a typical aspect of serous degeneration. The bone marrow cellularity was reduced, made of rare hematopoietic cells, dissociated by pale extracellular deposits that were colored by PAS and alcian blue, with no individualized blasts. Serous transformation of the hematopoietic marrow is a rare condition, described at the end of the 19th century. The most severe forms are observed in young patients with hypoplasia. It most often manifests as pancytopenia at the beginning, if not then by an isolated cytopenia, anemia or thrombocytopenia. It is interesting to underline the contribution of MRI in diagnosis. The foci of bone marrow serous degeneration are characterized in the long bones by a fluid signal with a T1hypo-signal and a T2hyper-signal with no enhancement after injection of gadolinium, unlike bone metastases. The histology of bone marrow biopsy finds focal marrow hypoplasia of the hematopoietic lines associated with a depletion of adipocytes and an eosinophilic gelatinous interstitial infiltration alcian blue and PAS positive. The histological differential diagnosis is amyloidosis due to red Congo positivity, a previous biopsy (the absence of adipose tissue or hematopoietic tissue with granulation tissue and bone formation) and interstitial edema. Bone marrow necrosis can also be observed. Serous degeneration of bone marrow can be a symptom of a chronic systemic illness. In most cases, it is found in cases of severe chronic malnutrition, such as anorexia nervosa, certain cancers (acute leukemia), systemic diseases (lupus) or severe infection. Though there is no specific treatment for this complication, the treatment of the cause most often allows for the complete regression of the peripheral and spinal anomalies. In rare cases, as is the case in our observation, the serous degeneration of bone marrow can reveal underlying solid tumors or hemopathies, knowledge of it can help guide the investigations towards these etiologies.