Allogeneic stem cell transplantation in acute leukemia patients after COVID-19 infection

The risk for severe and fatal courses of COVID-19 is particularly high after allogeneic hematopoietic stem cell transplantation (alloSCT) [1–4]. Cardiovascular and renal morbidity is increased post COVID-19 [5]. Neither data nor recommendations exist regarding alloSCT in survivors of COVID-19 [6, 7]. Seven patients (n= 5 acute myeloid leukemia, AML, ELN intermediate or adverse risk, n= 2 acute lymphatic leukemia, ALL, each one standard risk with induction failure, BCRABL positive) with an indication for alloSCT who had survived COVID19 were referred to our department. They had been diagnosed with AML/ALL between December 2019 and April 2020 and contracted COVID-19 in March/April 2020 during a hospital stay. COVID-19 had been diagnosed briefly after admission in 3 patients, 4 patients had received the diagnosis of COVID-19 2 weeks, 2 months, 2 months and 4 months after diagnosis of acute leukemia. Four patients had been infected during or briefly before induction chemotherapy/prephase chemotherapy. Three patients were infected during salvage therapy (Blinatumomab, FLAG-Ida). COVID-19, measured as time from first PCR [8, 9] positive throat and nose swab (TNS) to first of consecutive negative TNS had lasted 45 (median, range 12–70) days. ICU treatment had been necessary for 6 patients for 9 (median, range 2–22) days, 3 patients had been mechanically ventilated for 4, 4, and 12 days. Specific treatment had included plasma of convalescent donors, Lopinavir/Ritonavir, and pentaglobin. ARDS, deep vein thrombosis, sepsis and catheter related blood stream infection had complicated COVID-19. Inflammation parameters were high. Anti-SARS-CoV-2 antibodies (Diasorin SARS-CoV-2 IgG (Diasorin, Italy) and Elecsys Anti-SARS-CoV-2 Ig assay (Roche, USA)) were found in 5/7 patients, 2 were antibody negative. The leukemia remission status necessitated antineoplastic treatment in all patients during the phase of COVID-19. COVID-19 courses of the patients are summarized in Table 1. Institutionally and with health authorities, consent was developed to devise a dedicated team (7 physicians, 8 nurses, 1 physiotherapist) to treat these patients during the period of alloSCT in a designated area. Psycho-oncological care was provided via phone consultation. Patients were single-roomisolated. Separate rooms with air management (e.g., HEPA filtration) were not available. Staff was protected by specific single-use gear. Potential reactivation of SARS-CoV-2 was PCR-monitored by TNS (3×/week), oral throat rinses and plasma testing (each 1×/week). Patients were also regularly tested for SARS-CoV-2 IgM and IgG antibodies. Additionally, every patient received a thoracic CT scan in order to assess morphologic lung infiltrations after COVID-19. Beyond this, usual standard operating procedures were followed. Antimicrobial prophylaxis consisted of ciprofloxacin, acyclovir, cotrimoxazole or alternative anti-pneumocystis drug, micafungin or alternative antifungal, detailed elsewhere [10]. Written informed consent was adapted to the situation. At the time of admission for alloSCT, all patients tested negative for SARS-CoV-2 (TNS). Thoracic computed tomography (CT) at admission revealed small remnants of former COVID-19 infiltrations in 6 patients. Signs of pneumonia other than COVID-19 were visible in 2 patients, consistent with pulmonary mold infection. One patient was without signs of pneumonia. Pulmonary function testing immediately before the start of conditioning revealed moderate airway restrictions in 2 patients, with total lung capacity of 74%/70% and vital * Nicolaus Kröger nkroeger@uke.de

Institutionally and with health authorities, consent was developed to devise a dedicated team (7 physicians, 8 nurses, 1 physiotherapist) to treat these patients during the period of alloSCT in a designated area. Psycho-oncological care was provided via phone consultation. Patients were single-roomisolated. Separate rooms with air management (e.g., HEPA filtration) were not available. Staff was protected by specific single-use gear. Potential reactivation of SARS-CoV-2 was PCR-monitored by TNS (3×/week), oral throat rinses and plasma testing (each 1×/week). Patients were also regularly tested for SARS-CoV-2 IgM and IgG antibodies. Additionally, every patient received a thoracic CT scan in order to assess morphologic lung infiltrations after COVID-19. Beyond this, usual standard operating procedures were followed. Antimicrobial prophylaxis consisted of ciprofloxacin, acyclovir, cotrimoxazole or alternative anti-pneumocystis drug, micafungin or alternative antifungal, detailed elsewhere [10]. Written informed consent was adapted to the situation.
At the time of admission for alloSCT, all patients tested negative for SARS-CoV-2 (TNS). Thoracic computed tomography (CT) at admission revealed small remnants of former COVID-19 infiltrations in 6 patients. Signs of pneumonia other than COVID-19 were visible in 2 patients, consistent with pulmonary mold infection. One patient was without signs of pneumonia. Pulmonary function testing immediately before the start of conditioning revealed moderate airway restrictions in 2 patients, with total lung capacity of 74%/70% and vital   Table 1.
After a median follow-up of 77 (range 40-109) days, no reactivation of SARS-CoV-2 occurred. Leukocyte engraftment was reached in all patients after 14-31 (median 17) days. The 52 patients consecutively transplanted with peripheral blood stem cells in the same institution from April to May 2020 showed leukocyte engraftment after 11 (median, range 7-21) days (p = 0.0003, Mann-Whitney test). Thus, though comparison is flawed by a high degree of mismatch transplantation in the 7 patients reported here, time to leukocyte engraftment is significantly longer. Thrombocyte engraftment ≥20.000/µl was reached in 5 patients after 19-43 days (median 23 days) with 2 patients still in need of prophylactic thrombocyte infusions. Acute graft versus host disease (aGvHD) developed in 4 patients, 2 of which were grade 2 of the gastrointestinal tract and 2 grade 1, each n = 1 gastrointestinal tract and polyserositis. Steroidrefractory aGvHD necessitated treatment with Ruxolitinib in 1 patient. Infectious complications included fever of unknown origin, pneumonia and CMV reactivation, and did not lead to an intensive care unit stay. The patients (n = 5) who had developed antibodies against SARS-CoV-2 remained antibody positive after transplant. Two patients never showed antibodies against SARS-CoV-2. All patients were discharged alive. Four patients had to be readmitted due to complications (each n = 1 sinuisoidal obstruction syndrome, relapse, infection, alloimmune phenomena).
Taken together, alloSCT post severe COVID-19 is feasible even 1-3 months after resolution of infection. We did not observe reactivation of SARS-CoV-2. On the basis of the 7 patients presented, we tend to negate a correlation between a complicated course of COVID-19 before and a complicated course after transplantation. Larger analyses will have to evaluate if a history of SARS-Cov2 infection does present a significant risk for alloSCT with a complicated course.
Funding Open Access funding enabled and organized by Projekt DEAL.

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