ABSTRACT
Background: Follicular lymphoma (FL) is a systemic neoplasm of the lymphoid tissue arising from B cell proliferation. The novel monoclonal anti-CD20 antibody obinutuzumab in combination with chemotherapy has been widely accepted as the first choice in front line treatment of FL. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVID-19) is causing increased mortality among patients with lymphoproliferative disorders compared with the general population. Furthermore, there are some concerns in terms of morbidity and mortality for patients with FL because of their immunocompromised status induced by recent exposure to cytotoxic chemotherapy, especially bendamustine and anti-CD20. Aims: To investigate efficacy and safety of immunochemotherapy protocols for patients with newly diagnosed FL during COVID-19 pandemic. Methods: We retrospectively investigated medical data of all patients with newly diagnosed FL grade 1, 2 or 3A from Croatian hematologic registry in period from April 2019 to March 2021. Only patients which required systemic treatment were included in the analysis. All patients received obinutuzumab (G) in combination with either CHOP, bendamustine (B) or CVP chemotherapy protocol. Treatment response was evaluated using international lymphoma response criteria. Results: We analyzed a total of 114 FL patients treated with G-chemotherapy. Mean age was 62.4 ±10.5 years. Majority of patients were female (71/114 (62.3%)). FL grade I was present in 45/114 (39.5%), grade II in 28/114 (24.6%), grade III in 27/114 (23.7%) and not specified (but not IIIB) in 14/114 (12.3%) patients. A total of 61/114 (53.5%) patients were treated with G-B, 49/114 (43%) with G-CHOP and 4/114 (3.5%) with G-CVP immunochemotherapy. Similar rates of adverse events were observed in patients treated with G-CHOP and G-B Median follow up was 17 months. Overall response rate was 94%, complete remission (CR) in 68% and partial remission (PR) in 25% of patients. Median overall survival (OS) and progression free survival (PFS) were not reached with 12-months rates of 94% and 92%, respectively. Patients treated with G-CHOP had statistically significantly superior OS and PFS compared to patients treated with G-B (P=0.002 and P=0.006, respectively, Fig. 1). More favorable survival course associated with G-CHOP in comparison to G-B persisted in multivariate analysis (P=0,026, HR=15,12) after adjustment for age, sex, FLIPI grade and SARS-CoV-2 infection. Total of 12 patients died during the follow up and COVID-19 was cause of death in 5 patients. During the follow-up SARS-CoV-2 infection was diagnosed in 20/114 (17,5%) patients with overall mortality rate of 25%. All of the 7 patients treated with GCHOP recovered from SARS-CoV-2 infection and mortality rate in infected group of patients treated with G-B was 33% (4/12 patients). Image: Summary/Conclusion: Increased COVID-19 mortality in patients with lymphoproliferative disorders was observed in this study. Our group of patients had reduced OS and PFS compared to the GALLIUM trial and SARS-CoV-2 infection was the most pronounced risk factor for death. Even though in some studies bendamustine has shown to be less toxic and more effective than CHOP in FL, there are some important pandemic aspects that must be considered. Bendamustine exposure seems to be associated with worse outcome in case of the infection with SARS-CoV-2. These intriguing differences could play important role in treatment approach in COVID-19 pandemic. Future studies investigating hematological malignancies in COVID-19 pandemic are warranted.
ABSTRACT
Background: Patients with hematologic malignancies have a high risk of dying from COVID19 due to inability to mount humoral and cellular immune responses to the virus. Remdesvir is an inhibitor of viral RNA-polimerase. Some, but not all studies suggest it hastens recovery and reduces mortality in patients with COVID19. In a large randomized trial, convalescent plasma obtained from persons recovering from the infection was not proven to be useful in treatment of COVID19 in the general population, but other studies suggest it is useful in hematologic patients unable to produce antibodies against the virus. Recommendations on the use of these two drugs vary, some recommend its use only in severely immunocompromized individuals, some only in serious cases and some not at all. Reflecting these differences, the practice of using them varied between Croatian centers during the current pandemic. Aims: To analyze the effect of remdesvir and convalescent plasma on mortality in patients with hematologic malignancies by performing a matched-pair analysis. Methods: KroHem, the Croatian Cooperative Group for Hematologic Diseases, collected data on the outcome of patients with hematologic malignancies who became infected with SARS-COV2 while on concurrent systemic antineoplastic therapy during 2020 and 2021, before the appearance of the omicron strain. Patients treated with remdesvir and/or convalescent plasma were matched to those untreated according to age, disease type and antineoplastic therapy, factors found in our previous analyses to be related to outcome. Patients with Hodgkin lymphoma and myeloproliferative neoplasms were excluded, due to low risk of COVID19 mortality. Death during infection was considered as due to COVID19. Results: We identified 119 patients fulfilling the entry criteria. Three could not be matched, 2 with T-PLL treated with alemtuzumab and one with plasmablastic lymphoma and newly diagnosed HIV infection. All three died. In the remaining 116 patient pairs remdesvir significantly reduced the mortality: 36 out of 106 treated patients died, in comparison to 54 untreated (p=0.0207, McNemar's test). The effect of plasma was not significant: 26 of 73 treated patients died, in comparison to 33 untreated (p=0.2812). Therapy was substantially more effective in patients who received treatment within a week from symptom onset;11 of 58 patients treated with remdesvir died in comparison to 33 untreated (p<0.0001) and 8 out of 35 treated with plasma in comparison to 20 untreated (p=0.0095). Patients treated with remdesvir only had similar outcomes as those treated with remdesvir and plasma (15% vs. 19% respectively). (Figure Presented ) Summary/Conclusion: Our study suggests that patients with hematologic neoplasia, who are at a high risk of dying from COVID19, should receive treatment with remdesvir and convalescent plasma as soon as possible, resulting in a 2.5-3 times reduction in mortality. The effect of later treatment, if any, is less prominent.
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. [Formula presented] 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.
ABSTRACT
Background Patients with hematologic malignancy have a higher risk of death from COVID-19 compared to the general population. A blunted immune response from both the underlying disease and applied treatment may contribute to development of more severe forms of COVID-19, absence of seroconversion, prolonged viral shedding, and might also impair humoral vaccine response. Factors influencing efficacy of SARS-CoV-2 vaccines in this patient population are still insufficiently explored. Methods We prospectively enrolled 143 patients with malignant or non-malignant hematologic diseases from University Hospital Centre Zagreb vaccinated between January and June 2021 with either mRNA-1273 (Moderna), BNT162b2 mRNA (Pfizer-BioNTech), or ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines. A qualitative assay against SARS-CoV-2 nucleocapsid antigen was used to detect prior infection;these patients (n=23) were excluded from the final analysis. Humoral response following vaccination was monitored using serological immunoassay registered for quantitative measurement of serum anti-SARS-CoV-2 RDB-spike protein antibodies. Both electrochemiluminescent assays performed by Cobas e801 analyzer (Roche Diagnostics, Mannheim, Germany) detect total antibodies (including IgG). Response was recorded after the first and second doses. A positive response was defined as > 0.8 U/mL. Upper and lower limits of quantification were 0,4 U/mL and 250 U/mL respectively. We reviewed patient records for demographics, underlying hematological diseases, current treatment, the total number of lines of therapy received, IgG levels, application of anti-CD20 monoclonal antibodies (mAbs) and corticosteroids in the last 6 months before vaccination, and subsequent SARS-CoV-2 infection. Inter-group comparisons were performed with Mann-Whitney U, χ 2, or Fisher's exact test as appropriate. ROC curve analysis was used to find optimized cut-off values of numerical variables regarding response to the second dose. P values <0.05 were considered statistically significant. MedCalc statistical software v 20.008 was used for all analyses. Results We evaluated a total of 120 patients who received at least one dose. Patient characteristics are summarized in Table 1. The majority received the Pfizer-BioNTech vaccine (66.7%), followed by Oxford-AstraZeneca (24.2%) and Moderna (9.2%). Data on humoral response after the first dose was available in 66 patients, among whom 20 (33%) achieved response with median specific IgG levels 6.1 U/mL. Response after the second dose was available in 90 patients;58 (64.4%) achieved response with median specific IgG levels 250 U/mL. The second dose significantly improved response both in terms of achieved response (P=0.031) and specific IgG levels (P<0.001). There were no significant differences in response or specific IgG levels regarding the type of the vaccine (P>0.05). Lower response rates after the second dose were achieved in patients aged >67 years (P<0.001;response in 32.4% vs. 83.9%), with specific diagnosis (P=0.002, driven by response in patients with non-Hodgkin's lymphoma (NHL;response in 29.2% NHL vs. 77.3% non-NHL) and chronic myeloid leukemia (CML;100% response in CML vs. 61.4% non-CML)), those receiving active treatment (50% vs. 88%;P<0.001), no prior hematopoietic stem cell transplantation (HSCT;51% vs. 93%;P<0.001) and prior anti-CD20 mAbs therapy (4% vs. 85%;P<0.001). Corticosteroid therapy (>120 mg prednisone equivalent dose) did not influence the response significantly (response in 88.9% vs. 42.1%;P=0.056), and neither did steroid type. Four (3,3%) patients tested positive for SARS-CoV-2 after vaccination, 2 of which had no humoral response, and 2 had received only one dose. Three patients required in-hospital treatment and oxygen supplementation. Conclusions Patients with hematologic diseases have lower serological response rates to SARS-CoV-2 vaccines than those previously reported in clinical trials. Our results also suggest they benefit from receiving both doses with no significant difference between vaccine types. Those in active treatment, no prior HSCT, diagnosed with NHL, and receiving anti-CD20 mAb seem more likely to be seronegative after receiving both doses. However, the present study did not examine potential confounding effects between these factors and these findings should be elaborated further in larger patient cohorts. [Formula presented] Disclosures: Aurer: Novartis: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;Swixx/BMS: Honoraria;sanofi genzyme: Consultancy, Honoraria;Teva/Pilva: Honoraria;Abbvie: Consultancy, Honoraria;Eusapharma: Consultancy, Honoraria;Amgen: Consultancy, Honoraria;takeda: Consultancy, Honoraria. Durakovic: Takeda, Novartis, Genyzme: Honoraria.
ABSTRACT
Background: Acquired haemophilia A (AHA) is a rare autoimmune disease, caused by antibodies (inhibitors) against coagulation FVIII and characterized by spontaneous hemorrhage in patients with no previous history of bleeding. Risk factors for the occurrence of AHA include advanced age and underlying diseases (malignancy, autoimmune disorders, pregnancy, and the postpartum period). Aims: The aim is to analyze treatment outcomes of patients with acquired hemophilia A during the last ten years at the University Hospital Center Zagreb. Methods: We analyzed retrospectively treatment outcomes of patients with AHA in the Department of Hematology, University Hospital Center Zagreb from 2010-2020. Response to treatment was assessed as partial (PR) or complete remission (CR). Results: We analyzed the outcomes of twenty patients (11 (55%) male, 9 (45%) female), median age was 68 (33-81) years, and with median FVIII activity 5 (1 - 15) IU/dL and median inhibitor titer at the time of AHA diagnosis was 9 (2,3 - 2000) BU/ml. Severe bleeding had 75 % patients requiring erythrocyte transfusion. In 12 patients (60%) were identified underlying diseases: malignancies 2 (oligodendroglioma, B-CLL), autoimmune diseases 9 (autoimmune haemolytic anaemia - 2 rheumatoid arthritis - 2, polymyalgia rheumatica - 3, pemphigus -1 and myasthenia -1). One patient had postpartal AHA. The last female patient with myasthenia was diagnosed in December 2020. and she developed COVID19 bilateral pneumonia with ARDS. 90% of patients recieved hemostatic treatment (65 % - aPCC, 10% aPCC and rFVIIa, 25 % - rFVIIa). All patients were treated with immunosuppressive therapy, combination of cyclophosphamide and steroids in 18/20, steroids alone in 2/20 patients, while 3/20 patients (15%) were treated in the second line therapy. The response rate to the first line eradication therapy was 90%. Inhibitor eradication time was 18 (3-300) days, time to achieve CR was 32 (15- 300) days. At follow up of 31 (1-90) months 13 patients (65%) are alive, 7 (35%) dead. No death was due to bledding. Two patients died of pneumonia, two deaths were associated with sepsis, one with progressive malignant disease and one with cardiogenic shock. One female patient died of COVID19 at the age of 55 years, 25 days after AHA was diagnosed. Higher inhibitor activity, known underlying cause of AHA with advanced age, comorbidities were unfavourable factors of survival. Summary/Conclusion: Our treatment outcomes are very similar to the large European Registries, with the quite high response rate of eradication therapy in the first line treatment (90%). Infective complications and comorbidities were the leading causes of death. Patients with AHA and COVID19 could have a worse outcome due to immunosuppressive therapy.
ABSTRACT
Background: Autoimmune hemolytic anemia (AIHA) is an autoimmune- mediated disease in which erythrocytes are destroyed through (auto)antibodies against their surface antigens, resulting in premature lysis. It is a rare disorder and data about characteristics of AIHA from clinical practice are rare, especially if collected prospectively. Aims: This prospective study was conducted in order to analyze characteristics of patients with newly diagnosed AIHA. Methods: A single-center prospective study was performed at the University Hospital Center Zagreb (UHC), a tertiary center and the largest Croatian hospital, which included all consecutive patients with a newly diagnosed direct antiglobulin test positive AIHA from 1st Jan 2019 to 31th Dec 2020. Study was approved by UHC Ethical Committee. Descriptive statistics were performed and results are reported as frequencies (percentage) for categorical and as means (±standard deviation) or medians (minimum-maximum), as appropriate, for continuous values. Results: Data includes 17 patients (41% men), median age at diagnosis 52 (5-76) years. Majority of patients had secondary AIHA (14/17, 82%), mostly due to underlying lymphoproliferative malignant disease (7/14 patients, 50%). 4 had underlying autoimmune disorders, 1 solid cancer, 1 developed AIHA after allogeneic bone marrow transplantation, and 1 after M. pneumoniae infection. Median hemoglobin (Hb) at diagnosis was 74 (39-124) g/L;12 (71%) patients required hospital care with admission Hb of 58 (39-124) g/L, and 10 (59%) received erythrocyte transfusion. 15 (88%) patients required therapy with corticosteroids, and 6 (35%) received rituximab (as the first line therapy in 3/6 (50%) of patients). Patients were followed with a median time of 474 (22-648) days during which 13 (76%) achieved complete remission (CR) without signs of hemolysis or anemia, 1 showed improvement but failed to achieve normal Hb levels, 1 was refractory to therapy, and 2 were lost to follow-up. Median time from diagnosis to best response was 137 (43- 606) days. Of 13 patients in CR, 2 (15%) relapsed which was observed 260 and 363 days after remission. During follow up 2 patients suffered from COVID-19 infection, but neither showed signs of AIHA relapse. 2 patients died during follow-up due to AIHA-unrelated causes. Summary/Conclusion: Although with relatively small number of patients, this prospective study of newly diagnosed AIHA patients showed increased percentage of rituximab administration (from 17.6% to 35%) comparing to our previous retrospective single-center analysis from 2014 to 2018 (EHA library: Pulanic D, et al. 2019;PB 1963.). This is probably due to the increase of rituximab availability due to lower costs and more experience with this treatment modality.
ABSTRACT
Background: Reports on outcomes of COVID-19 in hematologic patients vary. Aims: To describe outcomes and risk factors of SARS-CoV2 infection in patients treated in a large university medical center. Methods: We analyzed the outcomes of our patients diagnosed with COVID-19 between July 2020 and January 2021. The diagnosis was made by PCR from nasopharyngeal/oral swabs or bronchoalveolar lavage. Outcomes were classified as: recovered, persistently positive, died. Results: We identified 116 patients. Median age was 59 years (range 20-92);55% were male. 13% had no symptoms;49% had mild disease with no need for oxygen therapy;14% with moderately severe disease were treated with low flow oxygen therapy;25% had severe COVID-19 with respiratory failure and/or septic shock. Except for seven palliative patients, severe cases were treated with noninvasive ventilation (3%), mechanical ventilation (13%) and ECMO (1%). 27% received no treatment for COVID-19;38% were treated with antibiotics, corticosteroids and/or anticoagulant therapy;34% received remdesivir, 6% in combination with convalescent plasma;5% were treated with extracorporeal blood purification. 65 patients recovered (56%), 17 are still positive (15%) and 34 (29%) died. All 4 untreated and 16 patients that were off treatment for more than 3 months recovered. The outcome of those on treatment is presented in Table 1. Allotransplanted patients had the worst outcome, 5 died, 3 are persistently positive and 1 recovered. Untransplanted patients with acute lymphoblastic and chronic myeloid leukemia fared best, 3 out of 3 in each group recovered. Treatment with anti-CD20 monoclonal antibodies (MoAbs) resulted in an increase in persistent positivity, frequently longer than 8 weeks. Of the 34 patients, 9 died, 12 have persistent infection and 13 recovered. There was no clear-cut correlation between outcome and other types of treatment within diagnostic groups. Summary/Conclusion: COVID19 in hematologic patients, who are currently on treatment, follows a significantly worse course than in the general population or other cancer types. Allotransplanted patients have the highest mortality, while those treated with anti-CD20 MoAbs frequently have a persistent infection with dubious outcome.