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A 35-year-old man with sickle cell disease (SCD, S/β 0 ) was admitted to our emergency department (ED) for right upper quadrant abdominal pain (RUQ) associated with fever (38 C) and jaundice (Charcot's triad; Total Bil. 3.19 mg/dL). Pain was constantly midepigastric, often radiated to the back. Laboratory tests showed increased CRP (93 mg/dL), ALT (71 U/L), and LDH (347 U/L); whereas, AST (32 U/ L), γGT (19 U/L), albumin (34.1 g/L), total protein (74.1 g/L), amylase, aPTT, PT were within normal range. CBC documented Hb 8.7 g/dL, circulating erythroblasts 510.000/mm 3 , WBC 11 800/mm 3 , PLTs 286 000/ mm 3 . The collection of patient history revealed: splenectomy at the age of 8 years and cholecistectomy at age of 19 years.He was taking hydroxyurea (20 mg/kg/d) therapy since the age of 17 years due to recurrent pain crisis, requiring hospitalization, and aspirin (100 mg/d) since splenectomy. Two previous episodes of superficial venous thrombosis were reported by the patient.RUQ pain occurs in almost 10% of SCD patients during acute vaso-occlusive crisis (VOC) and it is one of the first three causes of access to the ED admission. 1 RUQ pain is generally associated with increased AST/ALT ratio, which rapidly decreases at resolution of the VOC. Although RUQ pain is generally related to VOCs, a wide variety of conditions has been recognized to possibly sustain abdominal pain and jaundice in SCD (Table 1). 1-3 However, emergency physician rarely considers other causes of RUQ pain than VOC in SCD subjects (see also Table 1). This might expose SCD patients to the risk of undertreatment or misdiagnosis of RUQ pain and possibly mismanagement. Thus, it is mandatory to discriminate with the patient whether the abdominal pain episode has characteristics similar to previous once experienced by the patients in order to consider causes others than VOCs and to decide a more aggressive diagnostic approach. 4At the admission in the ED, patient VAS pain-score was 7. Multimodal analgesia with tramadol (7.2 mg/kg/d), ketorolac (0.86 mg/ kg/d) and metoclopramide associated with intravenous hydration (saline solution 20-30 mL/kg/d) and ceftriaxone (2 g/d) was started. 5,6 Abdominal ultrasound (US) was negative and portal vein velocity was normal at the admission to the ED and at 48 hours after hospitalization.Abdominal-US is generally used to exclude biliary obstruction and/or dilation (intrahepatic, extrahepatic, or both) or to document primary liver disorders, such as infections/abscesses or portal vein disease as well as pancreatic diseases such as acute or chronic pancreatitis or gallstone-related pancreatic disease. However, US does not allow the identification of choledocholithiasis, which requires MR cholangiopancreatography (MRCP). Multidetector Computed Tomography (MDCT) is, overall, the gold standard imaging approach for undifferentiated abdominal pain, especially in presence of fever and nonlocalized symptoms. MDCT can also better delineate complicated biliary disorders, such as gas-forming processes, abscesses, hemorrhage, ...

Introduction The outcome of conventional allogeneic hematopoietic cell transplantation (HCT) for the treatment of patients with refractory myeloid malignancies remains poor. Thiotepa-based sequential conditioning has shown promising results for various refractory hematological malignancies (Duléry R et al. Biol Blood Marrow Transplant. 2018; 24(5):1013-1021). However, no study has evaluated the outcome of this sequential approach specifically in refractory myeloid malignancies. The optimal dose of chemotherapeutic agents used in the conditioning regimen and the feasibility of this sequential approach in patients aged 60 years and above also need to be assessed. Methods All consecutive patients with refractory myeloid malignancy who underwent allogeneic HCT with a thiotepa-based sequential conditioning regimen in Saint Antoine hospital between April 2013 and October 2020 were included. The sequential approach consisted of a broad spectrum cytoreduction with thiotepa, etoposide, and cyclophosphamide (TEC) from day -15 to -10. Then, after a 3-day rest, a reduced-intensity conditioning (RIC) regimen was administered with fludarabine 150 mg/m 2, intravenous busulfan 6.4 mg/kg and thymoglobulin 5 mg/kg from day -6 to -2. From 2013 to 2018, doses of thiotepa (10 mg/kg), etoposide (400 mg/m 2) and/or cyclophosphamide (1600 mg/m 2) could be reduced in patients older than 60 years or with comorbidities. Since September 2018, the use of a reduced TEC-RIC regimen (thiotepa at 5 mg/kg, etoposide 300 mg/m 2 and cyclophosphamide 1200 mg/m 2 from day -13 to -10) became the new standard of care for all patients. After transplant, patients could receive a hypomethylating agent or targeted therapy to prevent relapse. Prophylactic donor lymphocyte infusions were given to enhance the graft-versus-leukemia effect, in the absence of contraindication. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine A and mycophenolate mofetil for all patients. Post-transplant cyclophosphamide was added in the case of haploidentical HCT. Results Seventy-one patients (median age 61 years, range 15-76) were included. Diagnoses comprised acute myeloblastic leukemia (n=65) and myelodysplastic syndrome/chronic myelomonocytic leukemia (n=6). Donors were haploidentical (n=36), matched related (n=13), unrelated (n=21) and umbilical cord blood (n=1). A reduced TEC-RIC was administrated to 43 (61%) patients, a full dose TEC-RIC to 18 (25%), and a TEC-RIC with a dose reduction only for thiotepa to 10 (14%). With a median follow-up of 45.4 months (95% CI: 36.7-63.6), the 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) were 51%, 41%, and 24%, respectively. Patients receiving a reduced TEC-RIC had a lower cumulative incidence of acute and chronic GVHD (acute grade II-IV GVHD: 14%, acute grade III-IV GVHD: 0%, chronic GVHD: 19%) than the other patients (acute grade II-IV GVHD: 29%, acute grade III-IV GVHD: 18%, chronic GVHD: 29%). The outcomes were not significantly different according to the TEC dose in terms of relapse incidence, OS, and PFS, although the NRM was lower with the reduced TEC-RIC (21% versus 28%, p=0.72). Most notably, patients aged 60 years and above had a 2-year OS and PFS of 48% and 39%, respectively, with no significant difference compared to patients younger than 60 years (Figure). Conclusion Our findings endorse the feasibility and efficacy of a thiotepa-based sequential approach for refractory myeloid malignancies undergoing HCT. The dose reduction did not compromise disease control and expanded the transplant option to older patients, ineligible for a higher dose regimen. Thus, a reduced TEC-RIC sequential regimen can be proposed for selected patients older than 60 years and allows promising outcomes for the treatment of refractory myeloid malignancies. Figure 1 Figure 1. Disclosures Duléry: Gilead: Other: travel support and meeting fees; Takeda: Consultancy; Novartis: Honoraria. Malard: Therakos/Mallinckrodt: Honoraria; Biocodex: Honoraria; Astellas: Honoraria; JAZZ pharmaceuticals: Honoraria; Sanofi: Honoraria; Janssen: Honoraria. Legrand: Servier: Consultancy. Fenaux: Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Labopin: Jazz Pharmaceuticals: Honoraria. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.