A rare presentation of immune thrombocytopenic purpura

Immune thrombocytopenic purpura (ITP) is defined as a hematologic disorder, characterized by isolated thrombocytopenia without any apparent cause. Some patients may be diagnosed during routine blood investigations or may present with bleeding diathesis. Treatment required for moderate to severe thrombocytopenia or those with bleeding manifestations. We present a case of 43 year old male, sputum positive pulmonary tuberculosis on isoniazid (H), rifampin (R), pyrazinamide (Z), and ethambutol (E) (HRZE) with persistent thrombocytopenia. He developed hepatitis hence isoniazid (INH) and rifampicin were stopped. He had fever, rash, purpura, hematuria and blood tinged sputum with platelet count of 10,000. 4 random donor platelets (RDPs) given. He suffered from mild COVID-19 infection and recovered in 2 weeks but platelets remained low. Bone marrow examination was suggestive of ITP. Inspite of steroid therapy no improvement was seen. Later was treated with injection romiplostim, and started on systemic lupus erythematosus (SLE) regimen for tuberculosis and discharged with regular follow up. Last platelet count being 1,20000/dl, liver function tests normal and now restarted on HRZE.

Treatment patterns and outcomes of 2310 patients with secondary acute myeloid leukemia: a PETHEMA registry study

Secondary acute myeloid leukemia (sAML) comprises a heterogeneous group of patients, and is associated with poor overall survival (OS). We analyze the characteristics, treatment patterns and outcomes of sAML adult patients of the Programa Español de Tratamientos en Hematología (PETHEMA) registry. Overall, 6211 (72.9%) were de novo and 2310 (27.1%) sAML, divided into myelodysplastic syndrome (MDS-AML, 44%), MDS/myeloproliferative (MDS/MPN-AML, 10%), MPN-AML (11%), therapy-related (t-AML, 25%), and antecedent neoplasia without prior chemotherapy/radiotherapy (neo-AML, 9%). Compared to de novo, sAML were older (median age 69 years old), had more ECOG ≥2 (35%) or high-risk cytogenetics (40%), less FLT3-ITD (11%) and NPM1 mutations (21%), and received less intensive chemotherapy regimens (38%) (all P<0.001). Median OS was higher in de novo than in sAML (10.9 vs 5.6 months, P<0.001); and shorter in sAML after hematologic disorder (MDS, MDS/MPN or MPN) as compared to t-AML and neo-AML (5.3 vs 6.1 vs 5.7 months, respectively, P=0.04). After intensive chemotherapy, median OS was better among de novo and neo-AML patients (17.2 and 14.6 months). No OS differences were observed after hypomethylating agents according to type of AML. sAML was as an independent adverse prognostic factor for OS. We confirm high prevalence and adverse features of sAML and we establish its independent adverse prognostic value. This study was registered at www.clinicaltrials.gov as #NCT02607059.

The need for area under the curve measurements in the field of ganciclovir therapeutic drug monitoring in children: a case report

Background Ganciclovir pharmacokinetics is characterized by a high variability in drug exposure. Usually, monitoring of ganciclovir exposure is performed by measuring trough concentration. However, due to the specificity of pediatric pharmacokinetics, trough concentration measurements may not be a relevant surrogate of ganciclovir exposure. Area under the curve of concentration (AUC) may be a more appropriate biomarker. Case presentation We report the case of 3.6-year-old boy with Emberger syndrome with a cytomegalovirus reactivation occurring after allogenic hematopoietic stem cell transplantation. After a few days of treatment with intravenous ganciclovir, sub-therapeutic trough ganciclovir concentrations were measured (< 0.5 µg/mL) and viral load still increased. Ganciclovir dosage was increased by two-fold to deal with this treatment failure. Trough concentrations remained sub-therapeutic. The patient had hematologic disorder therefore it was decided to estimate ganciclovir AUC to assess more accurately drug exposure before any further dosage modification. AUC0–12 h was measured at 51 μg h/mL, which was within the therapeutic range (40–60 μg h/mL). Afterward, viral load decreased and became undetectable. Conclusions This case report highlights that monitoring ganciclovir exposure based on AUC should be performed to tailor drug dosage in order to improve treatment efficacy and safety in pediatric patients.

Abstract 1122‐000037: LVO in the Setting of TTP

Introduction : Thrombotic Thrombocytopenic Purpura (TTP) is a disorder of coagulation caused by a deficiency of ADAMTS13 due to either hereditary mutations or acquired autoimmune inhibitors. Low levels of ADAMTS13 metalloprotease leads to Von Willebrand Factor (VWF)‐platelet aggregation and microvascular thrombosis when patients with TTP are exposed to high shear stress in the microcirculation. [1] Hematologic disorder or coagulopathies are the major cause of 1–4% of all ischemic strokes. [2] TTP patients usually present with small vessel strokes or sometimes very distal branches of large arteries. The gold standard treatment for acute stroke in these patients is plasma exchange, however in patients presenting with LVO strokes, recanalization therapies should be considered. [3] Here we present a case of large vessel occlusion stroke in the setting of TTP. Methods : 31‐year‐old African American female with TTP and Strokes admitted to with right sided hemiparesis, and expressive aphasia within 2h of symptom onset. National Institute of Health Stroke Scale (NIHSS) of 16. Laboratory work up significant for Platelets 114k, Hemoglobin 12, PTT 24 seconds, Serum glucose 107, ADAMTS‐13 <1 IU/dL and negative COVID‐19 PCR. CTH showing ASPECTS of 9 (Picture A), CTA head and neck revealing a left MCA occlusion and intracranial vessel irregularities in the left Anterior Cerebral Artery (ACA) and bilateral Posterior Cerebral Arteries (PCA) (Picture B). CTP with 24cc core and 132 cc mismatch (Picture C). Patient was taken to the Angiogram Suite for urgent thrombectomy with a final TICI score of 3 achieved after one pass (Picture D/E). Results : Post procedure NIHSS was 1 for mild expressive aphasia. Brain MRI revealed Left MCA and right parietal territories infarct (Picture F). Transesophageal Echocardiogram was unremarkable. She underwent urgent Plasma Exchange (PLEX) for TTP flair in light of undetectable ADAMTS‐13, significant drop in platelet count and thrombotic event. After 5 PLEX sessions platelets remained stable with counts greater than 150.000. Immunotherapy with Prednisone, Caplacizumab, Atovaquone and Mycophenolate Mofetil was continued and she was discharged home on day 7 from admission. Conclusions : Our patient had severe and refractory disease presenting with LVO and underwent an unusual therapeutic approach considering the etiology of her disease. IV thrombolysis and arterial thrombectomy are well established therapies for acute strokes in the general population, but are rarely performed in patients affected by Thrombotic Microangiopathy (TMA) such as TTP. Safety and efficacy of these procedures have not been studied in this population and it is usually selected by extrapolating data from studies that used individuals without TMA. We aim to illustrate this uncommon case of LVO stroke in the setting of TTP and potentially stimulate the elaboration of studies that include these patients.

Bilineal evolution of a U2AF1-mutated clone associated with acquisition of distinct secondary mutations

Rare hematologic malignancies display evidence of both myeloid and lymphoid differentiation. Here, we describe such a novel bilineal event discovered in an adult woman with B-lymphoblastic leukemia (BLL). At the time of BLL diagnosis, the patient had a normal karyotype and a bulk sequencing panel identified pathogenic variants in BCOR, EZH2, RUNX1, and U2AF1, a genotype more typical of myeloid neoplasia. Additionally, the patient was noted to have 3-year history of cytopenias, and morphologic dyspoiesis was noted on post-treatment samples, raising the possibility of an antecedent hematologic disorder. To investigate the clonal architecture of her disease, we performed targeted sequencing on fractionated samples enriched for either B-lymphoblasts or circulating granulocytes. These studies revealed a truncal founder mutation in the spliceosome gene U2AF1 in both fractions, while distinct secondary mutations were present only in B-lymphoblasts (BCOR, NRAS) or myeloid cells (ASXL1, EZH2, RUNX1). These results indicate that both processes evolved from a common U2AF1-mutated precursor, which then acquired additional mutations during a process of divergent evolution and bilineal differentiation. Our findings highlight novel mechanisms in BLL leukemogenesis and expand the spectrum of observed bilineal neoplasms.

Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease

Idiopathic multicentric Castleman disease (iMCD) is a poorly understood hematologic disorder involving cytokine-induced polyclonal lymphoproliferation, systemic inflammation, and potentially fatal multiorgan failure. Although the etiology of iMCD is unknown, interleukin-6 (IL-6) is an established disease driver in approximately one-third of patients. Anti–IL-6 therapy, siltuximab, is the only US Food and Drug Administration–approved treatment. Few options exist for siltuximab nonresponders, and no validated tests are available to predict likelihood of response. We procured and analyzed the largest-to-date cohort of iMCD samples, which enabled classification of iMCD into disease categories, discovery of siltuximab response biomarkers, and identification of therapeutic targets for siltuximab nonresponders. Proteomic quantification of 1178 analytes was performed on serum of 88 iMCD patients, 60 patients with clinico-pathologically overlapping diseases (human herpesvirus-8–associated MCD, N = 20; Hodgkin lymphoma, N = 20; rheumatoid arthritis, N = 20), and 42 healthy controls. Unsupervised clustering revealed iMCD patients have heterogeneous serum proteomes that did not cluster with clinico-pathologically overlapping diseases. Clustering of iMCD patients identified a novel subgroup with superior response to siltuximab, which was validated using a 7-analyte panel (apolipoprotein E, amphiregulin, serum amyloid P-component, inactivated complement C3b, immunoglobulin E, IL-6, erythropoietin) in an independent cohort. Enrichment analyses and immunohistochemistry identified Janus kinase (JAK)/signal transducer and activator of transcription 3 signaling as a candidate therapeutic target that could potentially be targeted with JAK inhibitors in siltuximab nonresponders. Our discoveries demonstrate the potential for accelerating discoveries for rare diseases through multistakeholder collaboration.

Successful treatment of multiple relapsed–refractory Langerhans cell histiocytosis with cyclosporine and review of the literature

Langerhans cell histiocytosis is a rare hematologic disorder and patients who fail first-line treatment have a poor prognosis, and require more intensive treatment. We present an infant diagnosed with multisystem Langerhans cell histiocytosis refractory to multimodal therapy who was successfully treated with cyclosporine. Cyclosporine might be an effective alternative drug as nonmyelosuppressive rescue therapy for multiple relapsed-refractory Langerhans cell histiocytosis that has not achieved remission with cladribine and cytarabine therapy.

Refractory vaccine-induced thrombotic thrombocytopenia (VITT) managed with delayed therapeutic plasma exchange (TPE)

Vaccine-induced thrombotic thrombocytopenia (VITT) is a newly-described hematologic disorder which presents as acute thrombocytopenia and thrombosis after administration of adenovirus-based vaccines against COVID-19. Due to positive assays for antibodies against platelet factor 4 (PF4), VITT is managed similarly to autoimmune heparin-induced thrombocytopenia (HIT) with intravenous immunoglobulin (IVIG) and non-heparinoid anticoagulation. We describe a case of VITT in a 50-year-old man with antecedent alcoholic cirrhosis who presented with platelets of 7 × 103/µL and portal vein thrombosis 21 days following administration of the Ad26.COV2.S COVID-19 vaccine. The patient developed progressive thrombosis and persistent severe thrombocytopenia despite IVIG, rituximab and high-dose steroids and had persistent anti-PF4 antibodies over 30 days after his initial presentation. As such, delayed therapeutic plasma exchange (TPE) was pursued as salvage therapy, with a rapid and sustained improvement in his platelet count. Our case serves as proof-of-concept of the efficacy of TPE in VITT.

Preliminary results of V-FAST, a phase 1b master trial to investigate CPX-351 combined with targeted agents in newly diagnosed AML.

7026 Background: CPX-351 (US: Vyxeos; EU: Vyxeos Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar drug ratio, is approved by the US FDA and EMA for adults with newly diagnosed t-AML or AML with myelodysplasia-related changes. Preclinical data suggest CPX-351 may exert synergistic activity when combined with agents such as the BCL-2 inhibitor venetoclax (VEN) or FLT3 inhibitor midostaurin (MIDO). Methods: V-FAST (Vyxeos – First Phase Assessment With Targeted Agents) is an open-label, multicenter, phase 1b master trial (NCT04075747) to evaluate safety and establish the recommended phase 2 dose (RP2D) of CPX-351 combined with targeted agents in patients (pts) aged 18-75 y with untreated AML who are fit for intensive chemotherapy. The study includes a dose-exploration phase (3+3 design) and subsequent expansion phase. Pts received CPX-351 (dose level 1 for first induction [DL1]: 100 units/m2 on Days 1, 3, and 5) plus VEN (Arm A; DL1: 400 mg on Days 1-14), MIDO (Arm B; DL1: 50 mg BID on Days 8-21), or the IDH2 inhibitor enasidenib ([ENA] Arm C; DL1: 100 mg on Days 8-28) based on mutation testing. Results: Among 21 pts with available data enrolled by 11/06/20 (24 pts enrolled total; data cut-off: 01/19/21), the median age was 54 y (range: 35, 69). In Arm A (n = 17), 11 (65%) pts had de novo AML, 5 (29%) had an antecedent hematologic disorder (2 [12%] had myelofibrosis), and 2 (12%) had t-AML; 12 (71%) had adverse-risk AML; and 6 (35%) had mutated TP53. In Arms B (n = 3) and C (n = 1), all pts had intermediate-risk de novo AML. DL1 was the RP2D in Arms A and B; the RP2D in Arm C is still under investigation. In Arm A, 1/6 pts in the dose-exploration phase had 2 dose-limiting toxicities (DLTs) of grade 4 neutropenia and thrombocytopenia that extended beyond 49 days; no DLTs have occurred for Arms B and C. The combinations exhibited manageable safety profiles (Table). Of pts with available response data, complete remission (CR) or CR with incomplete platelet or neutrophil recovery was achieved by 6/14 (43%) pts in Arm A, including 4 (29%) with CR. All pts in Arms B and C achieved CR. Conclusions: These preliminary results suggest CPX-351 can be combined with VEN and MIDO with manageable toxicities in newly diagnosed AML pts, with DL1 determined to be the RP2D. The study is ongoing and actively enrolling pts; updated results will be presented at the meeting. Clinical trial information: NCT04075747. [Table: see text]