LAUSR

TO THE EDITOR: Given the considerable overlap between endothelial dysfunction caused by the coronavirus disease 2019 (COVID-19)-associated endotheliitis and the one observed after allogeneic HSCT such as veno-occlusive disease (VOD), transplant associated-thrombotic microangiopathy (TA-TMA), idiopathic pneumonia syndrome (IPS) and graft-versus-host disease (GvHD) we analyzed longterm outcomes of patients who received allogeneic-HSCT with recovered COVID-19 [1, 2]. Favorable short-term outcomes after HSCT were previously reported by our group [3]. A total of 14 patients with a history of resolved COVID-19 were transplanted at the University Medical Center Hamburg Eppendorf UKE (n= 9) and Department of Medicine of Goethe University Frankfurt (n= 5) and provided informed consent for data collection and analysis. Patients were 57.1% female and 42.9% male with a median age of 56.5 (range 33–69) years (Table 1). COVID-19 was diagnosed between February 2020 and June 2021 by polymerase chain reaction (PCR) a median of 26 (−99 134) days before or after induction chemotherapy for advanced or high-risk acute myeloid (AML), lymphoblastic leukemia (ALL) and blast crisis of CML. During COVID-19, 11 patients (79%) developed lung infiltrates, six patients (43%) required ICU admission and two were treated with casirivimab/imdevimab (H8) or bamlanivimab (Fr2, Table 1). All patients recovered after median 47.5 (11–70) days after diagnosis of COVID-19 and were transplanted a median of 94 (35–136) days after COVID-19 resolution in CR1 (n= 8), PR or CR3 (n= 2) of high risk AML, high risk ALL (n= 3) or second chronic phase after CML blast crisis (n= 1). Donors were matched related (n= 3) or unrelated (n= 4), haploidentical related (n= 4) or mismatched unrelated (n= 3). Conditioning was myeloablative (MAC; n= 6), of reduced intensity (RIC; n= 7) and of reduced toxicity (RTC; n= 1). All patients received fludarabine in combination with fractionated total body irradiation (TBI; 8 or 12 Gy, n= 7), thiotepa/busulfan (n= 3), melphalan (n= 3) or treosulfan (n= 1). GvHD prophylaxis was performed with antithymocyte globulin (ATG) followed by cylosporine and mycofenolate mofetil (MMF) in 10 patients and with post-transplant cyclophosphamide (PT-CY) and tacrolimus/MMF in the haploidentical (4) and in one mismatched unrelated HSCT. Ursodiol as prophylaxis was given to all patients transplanted in Frankfurt/Main. TA-TMA was defined as previously described [4] and VOD diagnosed according to Seattle criteria [5]. Differences between groups were analyzed with the Fisher’s exact test. After a median follow-up of 221 (69–492) days, 11 (79%) of the 14 patients are alive. One patient died on day +146 from complications following AML relapse, one from cardio-pulmonary insufficiency following fungal infection (d+208) and one from not further specified liver failure (d+179). Three patients developed VOD, TA-TMA or both, all of them associated with polyserositis, at a median of day +67.5 (9–242) and are still alive a median of 451 (221–492) days after HSCT. Additional four patients had serositis without clinical signs of TA-TMA or VOD. Patients with TA-TMA/VOD were exclusively female transplanted from a male mismatched unrelated or family donor (p= 0.01) in comparison to patients without TA-TMA/VOD. In addition, seven out of the 14 patients developed pleural, pericardial effusion and ascites after HSCT. In contrast, no differences in age, interval diagnosis leukemia to COVID-19, COVID-19 duration, interval from COVID-19 diagnosis to HSCT, conditioning including TBI, conditioning intensity and GvHD prophylaxis were detected between the nonand TA-TMA/VOD patients (Table 1; p= n.s.). In a subgroup of patients (n= 9) median peak levels of acute phase proteins such as ferritin (3440 vs 3817 μg/l), IL-6 (323.45 vs 767.8 ng/l), procalcitonin (PCT; 2.48 vs 1.87 μg/l) and C-reactive protein (CRP; 185 vs 256 mg/l) during COVID-19 were found to be not significantly different in patients with as compared to those without endothelial damage. One 69 years old female patient (H1) with AML achieved CR1 after induction with azacytidine and venetoclax and developed on the day of leukemia diagnosis pulmonary COVID-19 requiring mechanical ventilation. Peak ferritin reached 2875 μg/l, IL-6 538 ng/l, PCT 5 μg/l and CRP 361mg/l. She was tested PCR negative after 12 days. Haploidentical HSCT was performed 106 days after COVID-19 following a conditioning regimen with thiotepa, busulfan, fludarabine and ATG. Tacrolimus/MMF in combination with PT-CY were administered for GvHD prophylaxis. Cytomegalovirus (CMV) status was negative in both donor and recipient. After engraftment on day +17, she developed histologically (renal biopsy) confirmed TA-TMA eight months after HSCT. CMV, urogenital and clostridium difficile infections may have triggered TA-TMA. The patient recovered from TA-TMA after steroids and antiviral therapy and deteriorated again in a subsequent CMV reactivation. The newly diagnosed polyserositis was treated with prednisone. The patient is alive 492 days after HSCT. One patient (H4) with ALL was treated according to GMALL (German ALL) protocol and three courses of blinatumomab and recovered from COVID-19 after treatment with convalescent serum with peak levels of ferritin 4006 μg/l, IL-6 109 ng/l, PCT 0 μg/l and CRP of 85mg/l. Duration of infection was 56 days. After conditioning regimen of TBI and fludarabine a haplo-identical HSCT from a male, CMV positive donor (recipient positive) was performed. For GvHD prophylaxis, immunosuppression with tacrolimus/MMF and PT-CY