Purine Analogues Increase the Risk of Lethal and/or Prolonged COVID19 While Obinutuzumab Increases the Risk of Prolonged but Not Lethal Infection in Patients Treated for Lymphoid Malignancies -a Study of Krohem, the Croatian Group for Hematologic Diseases
Authors: Aurer Igor , Jaksic Ozren , Bašić-Kinda Sandra , Mrdenovic Stefan , Ostojic Kolonic Slobodanka , Lozic Dominik , Holik Hrvoje , Novakovic Coha Sabina , Bernes Petra , Krecak Ivan , Moric Peric Martina , Narancic Marino , Mitrovic Zdravko , Valkovic Toni 
Published: November 2021

Abstract
Patients with lymphoid malignancies are at increased risk of death due to COVID19. Currently, it is not completely clear whether this is mainly due to disease biology or to anti-lymphoma treatment and whether the prognosis of infection differs in patients treated with different therapies. Anti-CD20 monoclonal antibodies increase the risk of prolonged infection. It is not known whether this risk is affected by the choice of the antibody. To study these questions, KroHem collected data on patients with lymphoid malignancies diagnosed with COVID19 between October 2020 and April 2021.
Death during infection was considered as due to COVID19. Patients were considered to have prolonged disease if they were continuously or repetitively positive by PCR for more than 6 weeks. Percentage of patients with prolonged disease was calculated based on the number of patients with available data who were alive 6 weeks after beginning of infection. Treatment regimens were divided into those containing purine analogues (PA), mainly bendamustine and fludarabine, standard-dose chemotherapy without PA (e.g. CHOP, CVP, chlorambucil, etc.), high-dose chemotherapy without PA (e.g. DHAP, ICE, etc.), B-cell receptor inhibitors (iBCR) and venetoclax.
We identified 314 patients, 20-88 years old (median 66), 180 male and 134 female; 75 were untreated, 61 off treatment and 178 on treatment (Table). Eleven (15%) untreated patients died; 10% had prolonged infection none of whom died. Ten (16%) off-treatment patients died; 9% had prolonged infection none of whom died. In the on-treatment group 6 (3%) are still prolonged positive, 110 (62%) recovered and 62 (35%) died; 42% had prolonged infection of whom 47% recovered and 42% died. The single allografted patient died as did both patients treated with CAR-T cells after prolonged infection.
We analyzed prognostic factors for lethal and prolonged infection in the 175 conventionally treated patients. Disease type, use of anti-CD20 monoclonal antibodies, prior autologous stem-cell transplantation (ASCT) and line of treatment did not significantly affect mortality. Mortality was higher in older (p=0.0078) and those treated with PA in comparison to standard-dose chemotherapy without PA and iBCR (47% vs. 26%, p=0.012). The effect of anti-lymphoma therapy on mortality was similar in all age groups. All of the 7 patients who received neither cytotoxic agents nor iBCR (4 were on rituximab monotherapy, 2 on cyclosporine and 1 on vemurafenib) recovered, none had prolonged infection. Prolonged COVID19 was significantly more frequent in patients treated with anti-CD20 monoclonal antibodies (p=0.012), especially obinutuzumab (67% in comparison to 42% in those treated with rituximab and 21% in those treated without anti-CD20 antibodies). Treatment with PA also increased the risk of prolonged disease (69% vs. 25-45% in other groups, p=0.012). The effect of PA on prolonged infection was similar in patients treated with rituximab and obinutuzumab. Age, prior ASCT and treatment line did not significantly affect risk of prolonged infection.
Our data suggest that the type of anti-lymphoma therapy is, besides age, a main determinant of prognosis of COVID19 in patients with lymphoid malignancies. Use of purine analogues, such as bendamustine and fludarabine, is related to increased risk of lethal and/or prolonged COVID19. These drugs should probably be avoided in patients with indolent NHL and CLL, diseases for whom other effective treatments are available, during the current pandemia. Anti-CD20 monoclonal antibodies seem to have a smaller effect on mortality, with obinutuzumab increasing the risk of prolonged disease, but not of death, in comparison to rituximab.
Figure 1 Figure 1.

Disclosures
Aurer: takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Swixx/BMS: Honoraria; Teva/Pilva: Honoraria; Abbvie: Consultancy, Honoraria; sanofi genzyme: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Eusapharma: Consultancy, Honoraria. Jaksic: Roche, Oktal-Pharma/Celtrion, Sandoz: Consultancy, Honoraria. Mrdenovic: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria. Ostojic Kolonic: Roche, Oktal-Pharma/Celtrion, Sandoz: Consultancy, Honoraria. Lozic: Roche, Oktal-Pharma/Celtrion, Sandoz: Consultancy, Honoraria. Holik: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria. Novakovic Coha: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria. Bernes: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria. Krecak: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria. Moric Peric: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria. Mitrovic: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria.