Abstract
Coronavirus disease 2019 (COVID-19) has led to a global pandemic that has also challenged the management of various other life-threatening conditions, such as malignant disorders. In this study, we present the clinical features and treatment outcomes of twenty-seven COVID-19 positive patients with leukemia across seven different centers in Istanbul. From March 1st to December 31st 2020, 116 patients were diagnosed with acute leukemia. Thirty-two cases with acute lymphocytic leukemia (ALL), 82 cases with acute myeloid leukemia (AML), and 2 cases with mixed phenotype acute leukemia (MPAL) were identified. Of the 27 patients with the COVID-19 infection, seven patients had ALL, 19 patients had AML and one patient had MPAL. The mortality rate was 37% among the patients with AML, whereas there were no deaths in the ALL group. The mortality rate of AML patients with the COVID-19 infection was higher compared to cases without the infection (P<0.05). We could not detect any significant difference in the ALL cohort. This study, which includes one of the largest acute leukemia series in literature proved that acute myeloid leukemia patients with the COVID-19 infection have worse outcomes than patients without the infection. The high mortality among patients with acute leukemias hospitalized with COVID-19 highlight the need for aggressive infection prevention, increased surveillance and protective isolation and even modification of the therapy, in case of minimal residual disease (MRD) negativity.
Keywords: COVID-19, SARS-Cov2, acute leukemia, acute myeloid leukemia, acute lymphoblastic leukemia
Introduction
Coronavirus disease 2019 (COVID-19) is a highly contagious disease caused by the infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has led to a global pandemic affecting nations worldwide, with more than 189.0000 positive cases and 4.000.000 deaths due to COVID-19 being reported in the world. The virus affects mainly the respiratory tract, causing pulmonary damage and fibrosis. Furthermore, it can also affect other organ systems and present as a multisystem disease [1,2]. The diagnosis of COVID-19 is made by clinical evaluation and confirmed with the reverse transcription polymerase chain reaction (RT-PCR) test. In patients where RT-PCR tests are negative but there is still high clinical suspicion, imaging of the chest with computerized tomography (CT) can be of diagnostic value.
It is well known that co-existing comorbidities increase the mortality in COVID-19 infection. The presence of low lymphocyte counts, frequently observed in leukemia, and other comorbidities such as advanced age are positively associated with mortality [1-3]. During the pandemic, many patients with hematological malignancies confronted the virus, either at the time of diagnosis or during the treatment course. It is hypothesized that patients with hematologic malignancies and concomitant COVID-19 infection may have poorer disease outcomes and worse survival rates compared to patients without the disease.
The management of acute leukemia, which may cause death in days if patients are not promptly treated, became a challenge in the COVID-19 era. Several guidelines were published to decrease the mortality in acute leukemia patients [4-6].
Acute leukemia working party of EBMT (European Society for Blood and Marrow Transplantation) recommended to wait for cytogenetics and molecular biology results to properly stratify the risk of the acute leukemia cases [4]. They also advised screening of COVID-19 infection before initiation of chemotherapy and consideration of omission of one cycle of consolidation in case of MRD molecular remission achievement. They mentioned that outpatient visits should be deferred or performed as telemedicine visits. For AML cases fit for intensive therapy and with favorable and intermediate cytogenetic risk, authors recommended induction with “3+7” and consolidation with reduced dose (1.5 g/m2) of cytarabine. In case of adverse cytogenetic risk, consideration of allogeneic hematopoietic stem cell transplantation (allo-HSCT) was supported. For AML patents unfit for intensive therapy, azacytidine or low dose cytarabine monotherapy, hydroxyurea or supportive care were management options. For ALL cases, EBMT supported maintenance of recommended dose of glucocorticoids, specifically during prophase, induction and consolidation. They stated that nonurgent allo-HSCT should be postponed as much as possible. High risk allo-HSCT in refractory disease or in cases with high non-relapse mortality were advised not to proceed to transplantation. Case based discussion of the indication of allo-HSCT was recommended [4]. The participating centers to our study were in agreement with the approach of EBMT acute leukemia working group.
Herein we present the real-life results of acute leukemia patients co-diagnosed with COVID-19 in seven centers across Istanbul. We evaluated their clinical features, the management strategies, the clinic outcomes and the mortality rates to contribute to literature.
Methods
Study design
We identified adult patients (aged ≥ 18 years) diagnosed with acute leukemia across seven different hospitals that have hematology units in Istanbul from March 1st to December 31st, 2020. Inclusion criteria were the presence of acute leukemia and confirmed COVID-19 infection. Hundred and sixteen patients were diagnosed with acute leukemia (acute lymphocytic leukemia, acute myeloid leukemia, mixed phenotype acute leukemia). Acute leukemias were classified according to the 2016 WHO classification. In the majority of centers, COVID-19 testing via RT-PCR on specimens from nasopharyngeal swabs were performed before treatment initiation. Computerized chest tomography was also performed in some cases. As a result, twenty-seven cases (23%) were found to have the SARS-CoV-2 infection.
Data collection
Epidemiological, clinical, laboratory and radiological data were collected from clinical charts, and electronic medical records. This study was conducted in accordance with the national pandemic guidelines and the declaration of Helsinki. It was evaluated and approved by the national ethics board of the Turkish Ministry of Health, and by the institutional review board (Ethical Committee of Research, 2021.233.IRB1.077). Informed consent was not required because this was a retrospective case-study, and the need of informed consent was waived by the ethical committee of the institutional review board (Koc University School of Medicine).
Endpoints
The primary endpoint was the mortality rates among patients diagnosed with acute leukemia and COVID-19. The secondary endpoints were the improvement or worsening of the COVID-19 symptoms, laboratory and radiological parameters. We compared the mortality rates with patients who did not have the COVID-19 infection at the time of acute leukemia diagnosis.
Statistical analysis
Categorical variables were compared using the chi square test whereas the continous variables were tested by the t-test. Multivariate analysis was performed by using logistic regression to detect the predictors of fatality. Gender, Age ≥60, AML, and COVİD-19 positivity were included as independent variables. Statistical significance was accepted as a p value <0.05. STATA version 14.2 was used in the analysis.
Results
Baseline characteristics of patients
We analyzed 116 patients with acute leukemia: thirty-two patients were diagnosed with ALL, 82 with AML and two with mixed phenotype acute leukemia (MPAL). Among the AML patients, five had AML M3. There were 53 (46%) female and 63 (54%) male patients. In the entire leukemia population, median age at COVID-19 diagnosis was 46 (range: 17-80).
Seven patients with ALL, 19 patients with AML and one patient with MPAL were SARS-CoV-2 positive. Among the COVID-19 positive acute leukemia patients, the median age was 44 (range: 18-71), specifically among AML and ALL patients the median age was 49 (range: 18-71) and 32 (range: 29-40) respectively. There were 12 (44%) female and 15 (56%) male patients.
Disease status
Thirteen patients were diagnosed with acute leukemia concomitant with the COVID-19 infection and of which, six were in complete disease remission, five had relapsed disease, two had refractory disease and one patient’s disease status was unevaluated. Among the AML cases, one patient had favorable, five had intermediate and 10 had high risk disease according to the European LeukemiaNet criteria. Among the AML M3 patients, two had high risk and one had intermediate risk disease. Among the ALL patients, three had standard and four had high risk. The baseline characteristics and outcomes of the confirmed COVID-19 cases are shown in Table 1.
Table 1.
Characteristics and Outcomes of Leukemia Patients with COVID-19
| Nr | Age | Sex | Leukemia type | Disease risk score | Disease phase | Treatment protocol | Time to COVID-19 diagnosis (days) | Symp-toms | Time to respiratory failure (days) | Treatment for respiratory failure | Anti-viral treatment | Anti-inflammatory treatment | COVID due treatment changes | Out-come of infection | Out-come | Sur-vival (days) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 29 | M | ALL | High | CR | GMALL Consolidation V | 22 | no | 12 | Oxygen | Favipiravir | Corticosteroid Tocilizumab | Discontinuation | R | A | 24 |
| 2 | 40 | F | ALL | High | Onset | GMALL Induction I | 19 | yes | 0 | Oxygen | Favipiravir | Corticosteroid Anakinra | Delay | R | A | 18 |
| 3 | 30 | M | ALL | High | CR | GMALL Consolidation | 19 | yes | - | - | Favipiravir | Corticosteroid | Delay | R | A | 63 |
| 4 | 32 | M | ALL | High | CR | BFMA 1A | 3 | yes | - | - | Favipiravir | Corticosteroid | Delay | R | A | 61 |
| 5 | 30 | M | ALL | Standard | Onset | GMALL Induction I | 6 | yes | - | - | Favipiravir | - | Delay | R | A | 27 |
| 6 | 34 | F | ALL | Standard | CR2 | FLAG-IDA | 56 | no | - | - | Favipiravir | - | No change | R | A | 82 |
| 7 | 34 | M | ALL | Standard | Relapse | No treatment | - | no | - | - | Favipiravir | - | No change | R | A | 80 |
| 8 | 57 | M | AML | Favorable | Relapse | FLAG-IDA | 12 | yes | 5 | Oxygen, NIV, intubation | Favipiravir | Corticosteroid | No change | P | D | - |
| 9 | 38 | M | AML | Adverse | Onset | 3+7 Induction | 14 | yes | 5 | Oxygen, NIV, intubation | Favipiravir | Corticosteroid | No change | P | D | - |
| 10 | 49 | M | AML | Intermediate | Onset | 3+7 Induction | 19 | yes | 4 | Oxygen | Favipiravir | Corticosteroid | Delay | R | A | 36 |
| 11 | 51 | F | AML | Adverse | Onset | 2+5 Induction | 13 | yes | 0 | Oxygen | Favipiravir | Corticosteroid Anakinra | Delay | R | A | 18 |
| 12 | 33 | M | AML M3 | High | Onset | Not started yet | - | yes | 7 | NIV | Favipiravir | Corticosteroid | Delay | R | A | 30 |
| 13 | 48 | M | AML | Intermediate | CR | 3+7 Induction | 13 | yes | 2 | Oxygen | Favipiravir | Hyperimmune plasma, Corticosteroid | Delay | R | A | 85 |
| 14 | 46 | M | AML M3 | high | Onset | Not started yet | - | yes | - | - | Favipiravir | Corticosteroid | Dose reduction | R | A | 59 |
| 15 | 48 | M | AML M3 | Intermediate | Refractory | ATRA | 6 | yes | 6 | Oxygen, intubation | Favipiravir | Corticosteroid Tocilizumab | Discontinuation | P | D | - |
| 16 | 63 | F | AML | Intermediate | Onset | 3+7 Induction | 7 | yes | 20 | Oxygen, intubation | Favipiravir | Corticosteroid | No change | P | D | - |
| 17 | 32 | M | AML | Intermediate | Relapse | FLAG-IDA | 17 | yes | - | - | Favipiravir | - | - | R | A | 180 |
| 18 | 71 | F | AML | Adverse | Refractory | Azacytidine, Venetoclax | 54 | yes | ? | Oxygen | Favipiravir | - | Delay | R | A | 75 |
| 19 | 18 | F | AML | Adverse | CR | HD Cytarabine | 24 | no | - | - | Favipiravir | - | Delay | R | A | 131 |
| 20 | 63 | F | AML | ? | ? | No treatment | - | yes | - | Intubation | Favipiravir | Corticosteroid | - | P | D | - |
| 21 | 51 | F | AML | Adverse | Onset | 3+7 Induction | 25 | yes | 1 | Oxygen, NIV | Favipiravir | - | No change | R | A | 266 |
| 22 | 65 | F | AML | Adverse | Onset | 3+7 Induction | 5 | yes | 1 | Oxygen | Favipiravir | - | Dose reduction | R | A | 37 |
| 23 | 49 | F | AML | Adverse | Relapse | FLAG-IDA | 17 | yes | 0 | Oxygen, NIV, Intubation | Favipiravir | Corticosteroid | No change | P | D | - |
| 24 | 62 | F | AML | Adverse | Relapse | Best supportive care | - | ? | ? | ? | ? | ? | ? | P | D | - |
| 25 | 49 | F | AML | Intermediate | Onset | 3+7 Induction | 35 | no | - | - | Favipiravir | - | No change | R | A | 14 |
| 26 | 25 | M | AML | Adverse | Onset | Not started yet | - | no | - | - | Favipiravir | - | No change | R | A | 81 |
| 27 | 53 | M | MPAL | Onset | FLAG-IDA | 9 | yes | 5 | Oxygen | Favipiravir | - | No change | R | A | 19 |
MPAL: mixed-phenotype acute leukemia; Time to COVID-19 diagnosis: from the first day of the last chemotherapy (days); CR: complete remission; Symptoms at the time of the diagnosis of COVID-19: Yes/No; NIV: non-invasive ventilation; Time to respiratory failure: calculated from COVID-19 diagnosis to respiratory failure (days); Outcome of infection: Progressed (P), Resolved (R); Outcome: Dead (D), or Alive (A); Survival: calculated from the time of recovery to the end of study (days).
Treatment status of leukemia
In total, twenty-one patients received chemotherapy. Three patients had not started chemotherapy yet, two patients did not receive any treatment and one patient received best supportive care. Patients’s treatment modalities are described in Table 1. The details of the protocols are shown in Table 2.
Table 2.
Details of treatment protocols for acute leukemia
| A. AML treatment protocols |
|
|
| 3+7 Induction |
| Daunorubicin/Idarubicin (60 mg/m2; 12 mg/m2; i.v.) d1-d3 |
| Cytarabine (100 mg/m2; i.v.) d1-d7 |
| 2+5 induction |
| Daunorubicin/Idarubicin (60 mg/m2; 12 mg/m2; i.v.) d1-d2 |
| Cytarabine (100 mg/m2; i.v.) d1-d5 |
| High dose (HD) cytarabine |
| Cytarabine (3000 mg/m2; i.v., every 12 hours) d1, d3, d5 |
| FLAG-IDA |
| G-CSF (0.5 mcg/kg; s.c.) d1-d7 |
| Fludarabine (30 mg/m2; i.v.) d2-d6 |
| Cytarabine (2 g/m2; i.v.) d2-d6 |
| Idarubicin (8 mg/m2; i.v.) d4-6 |
| Azacitidine-Venetoclax |
| Azacitidine (75 mg/m2; s.c.) d1-d7 |
| Venetoclax (start 100 mg, with daily ramp-up to the target dose of 400 mg; p.o.) d1-d28 |
|
|
| B. AML M3 treatment protocols |
|
|
| Induction Therapy |
| ATRA (22.5 mg/m2, every 12 h; p.o.) d1- to max. 60 days |
| Idarubicin (12 mg/m2; i.v.) d1, d3, d5, d7 |
| Consolidation Therapy |
| ATRA (22.5 mg/m2, every 12 h; p.o.) d1-d15 |
| Idarubicin (5 mg/m2; i.v.) d1-d4 |
| Cytarabine (1000 mg/m2; i.v.) d1-d4 |
| ATRA (22.5 mg/m2, every 12 h; p.o.) d1-d15 |
| Mitoxantrone (10 mg/m2; i.v.) d1-d5 |
| ATRA (22.5 mg/m2, every 12 h; p.o.) d1-d15 |
| Idarubicin (12 mg/m2; i.v.) d1 |
| Cytarabine (150 mg/m2; i.v.) d1-d4 |
|
|
| C. ALL BFMA treatment protocol |
|
|
| Induction protocol 1A (35 days) |
| Prednisolone (60 mg/m2; p.o) d1-d28 |
| Methotrexate (12 mg; i.t) d1, d12, d33 |
| Daunorubicin (30 mg/m2; i.v) d8, d15, d22, d29 |
| Vincristine (2 mg; i.v) d8, d15, d22, d29 |
| L-asparaginase (5000 IU/m2; i.v) d12, d15, d18, d21, d24, d27, d30, d33 |
| Consolidation 1B (29 days) |
| Cyclophosphamide (1000 mg/m2; i.v) d1, d29 |
| Mesna (400 mg/m2) d1, d29 |
| 6-mercaptopurine (60 mg/m2; p.o) d1-d28 |
| Cytarabine (75 mg/m2; s.c) d3-d6, d10-d13, d17-d20, d24-d27 |
| Methotrexate (12 mg; i.t) d10, d24 |
| Protocol M (56 days) |
| 6-mercaptopurine (25 mg/m2; p.o) d1-d56 |
| Methotrexate (500 mg/m2; i.v) d8, d22, d36, d50 |
| Methotrexate (4500 mg/m2; i.v) d8, d22, d36, d50 |
| Methotrexate (12 mg; i.t) d8, d22, d36, d50 |
| Calcium folinate (15 mg/m2 every 6 hours; i.v) d9, d23, d37, d51 |
| Reinduction Protocol II (50 days) |
| Dexamethasone (10 mg/m2; p.o) d1-d21 |
| Doxorubicin (30 mg/m2; i.v) d8, d15, d22, d29 |
| Vincristine (2 mg; i.v) d8, d15, d22, d29 |
| L-asparaginase (5000 IU/m2; i.v) d8, d11, d15, d18 |
| Thioguanine (60 mg/m2; p.o) d36-d49 |
| Cyclophosphamide (1000 mg/m2; i.v) d36 |
| Mesna (400 mg/m2 at 0, 4, 8 hours post each cyclophosphamide dose; i.v) d36 |
| Cytarabine (75 mg/m2; s.c) d38-d41, d45-d48 |
| Methotrexate (12 mg; i.t) d38, d45 |
| High Risk Block I (11 days) |
| Dexamethasone (10 mg/m2; p.o) d1-d5 |
| Vincristine (2 mg; i.v) d1, d6 |
| Methotrexate (500 mg/m2; i.v) d1 |
| Methotrexate (4500 mg/m2; i.v) d1 |
| Methotrexate (12 mg; i.t) d1 |
| Cytarabine (30 mg; i.t) d1 |
| Hydrocortisone (50 mg; i.t) d1 |
| Calcium folinate (15 mg/m2, every 6 hours; i.v) d2 |
| Cyclophosphamide (200 mg/m2 every 12 hours, 5 doses; i.v) d2-d4 |
| Mesna (70 mg/m2 at 0, 4, 8 hours post each cyclophosphamide dose; i.v) d2-d4 |
| Cytarabine (2000 mg/m2 twice daily; i.v) d5 |
| L-asparaginase (25000 IU/m2; i.v) d6, d11 |
| Filgrastim (5 microgram/kg; s.c) d7-until neutrophil recovery |
| High Risk Block II (11 days) |
| Dexamethasone (10 mg/m2; p.o) d1-d5 |
| Vincristine (2 mg; i.v) d1, d6 |
| Methotrexate (500 mg/m2; i.v) d1 |
| Methotrexate (4500 mg/m2; i.v) d1 |
| Methotrexate (12 mg; i.t) d1 |
| Cytarabine (30 mg; i.t) d1 |
| Hydrocortisone (50 mg; i.t) d1 |
| Calcium folinate (15 mg/m2, every 6 hours; i.v) d2 |
| Ifosfamide (800 mg/m2 every 12 hours, 5 doses; i.v) d2-d4 |
| Mesna (300 mg/m2 at 0, 4, 8 hours post each ifosfamide dose; i.v) d2-d4 |
| Daunorubicin (30 mg/m2; i.v) d5 |
| L-asparaginase (25000 IU/m2; i.v) d6, d11 |
| Filgrastim (5 microgram/kg; s.c) d7-until neutrophil recovery |
| High Risk Block III (11 days) |
| Dexamethasone (20 mg/m2; p.o) d1-d5 |
| Cytarabine (2000 mg/m2 twice daily; i.v) d1, d2 |
| Etoposide (100 mg/m2 every 12 hours, 5 doses; i.v) d3-d5 |
| Methotrexate (12 mg; i.t) d5 |
| Cytarabine (30 mg; i.t) d5 |
| Hydrocortisone (50 mg; i.t) d5 |
| L-asparaginase (25000 IU/m2; i.v) d6, d11 |
| Filgrastim (5 microgram/kg; s.c) d7-until neutrophil recovery |
| Maintenance |
| 6-mercaptopurine (50 mg/m2; p.o) daily |
| Methotrexate (20 mg/m2; p.o) weekly |
|
|
| D. ALL GMALL treatment protocol |
|
|
| Prephase (d1-d5) |
| Methotrexate (15 mg; i.t) d1 |
| Dexamethasone (10 mg/m2; p.o) d1-d5 |
| Cyclophosphamide (200 mg/m2; i.v) d3-d5 |
| Induction I (d6-d20) |
| Rituximab (375 mg/m2; i.v) d6 (if B-ALL and CD20 ≥20%) |
| Dexamethasone (10 mg/m2; p.o) d6-d7+d13-d16 |
| Vincristine (2 mg; i.v) d6, d13, d20 |
| Daunorubicin (45 mg/m2; i.v) d6-d7+d13-d14 |
| PEG-Asparaginase (2000 u/m2; i.v) d20 |
| Induction II (d24-d44) |
| Rituximab (375 mg/m2; i.v) d23, d44 |
| Cyclophosphamide (1000 mg/m2; i.v) d24, d44 |
| Cytarabine (75 mg/m2; i.v) d26-d29, d33-d36, d40-d43 |
| 6-mercaptopurine (60 mg/m2; p.o) d31-d44 |
| Methotrexate (15 mg; i.t) d25, d32, d39 |
| Consolidation I (d61-d72) |
| Rituximab (375 mg/m2; i.v) d60 |
| Dexamethasone (10 mg/m2; p.o) d61-d65 |
| Vindesine (3 mg/m2; i.v) d61 |
| Methotrexate (1.5 g/m2; i.v) d61 |
| Etoposide (250 mg/m2; i.v) d64, d65 |
| Cytarabine (2×2 g/m2; i.v) d65 |
| Methotrexate/Cytarabine/Dexamethasone (15/40/4 mg; i.t) d72 |
| Consolidation II (w14-w16) |
| Rituximab (375 mg/m2; i.v) d0 |
| Methotrexate (1.5 g/m2; i.v) d1, d15 |
| PEG-Asparaginase (2000 U/m2; i.v) d2, d16 |
| 6-mercaptopurine (25 mg/m2; p.o) d1-d7, d15-d21 |
| Reinduction (w19) |
| Rituximab (375 mg/m2; i.v) d0 |
| Prednisolone (60 mg/m2; p.o) d1-d14 |
| Vindesine (3 mg/m2; i.v) d1, d7 |
| Adriamycin (25 mg/m2; i.v) d1, d7 |
| PEG-Asparaginase (2000 U/m2; i.v) d14 |
| Methotrexate/Cytarabine/Dexamethasone (15/40/4 mg; i.t) w19, w21 |
| Consolidation III (w24) |
| Cytarabine (1000 g/m2; i.v) d1, d3, d5 |
| Cyclophosphamide (200 mg/m2; i.v) d1, d3, d5 |
| Consolidation IV (w27+w29) |
| Methotrexate/Cytarabine/Dexamethasone (15/40/4 mg; i.t) d1 |
| Rituximab (375 mg/m2; i.v) d0 |
| Methotrexate (1.5 g/m2; i.v) d1, d15 |
| PEG-Asparaginase (2000 U/m2; i.v) d2, d16 |
| 6-mercaptopurine (25 mg/m2; p.o) d1-d7, d15-d21 |
| Consolidation V (w32) |
| Cytarabine (1000 g/m2; i.v) d1, d3, d5 |
| Cyclophosphamide (200 mg/m2; i.v) d1, d3, d5 |
| Consolidation VI (w35+w37) |
| Methotrexate/Cytarabine/Dexamethasone (15/40/4 mg; i.t) d1 |
| Rituximab (375 mg/m2; i.v) d0 |
| Methotrexate (1.5 g/m2; i.v) d1, d15 |
| PEG-Asparaginase (2000 U/m2; i.v) d2, d16 |
| 6-mercaptopurine (25 mg/m2; p.o) d1-d7, d15-d21 |
| Maintenance (w41-w130) |
| Methotrexate (20 mg/m2; i.v) weekly |
| 6-mercaptopurine (50 mg/m2; p.o) daily |
| Methotrexate/Cytarabine/Dexamethasone (15/40/4 mg; i.t) (w41, w53, w65, w77, w89, w101) |
A total of 10 cases had treatment delay due to concomitant COVID-19 infection. Dose modification was performed in two patients and the treatment was stopped in two cases. There was no need to change the treatment protocol in 10 patients.
Treatment of COVID-19 infection
Favipiravir was suggested as an antiviral agent for the initial treatment for COVID-19 according to the guidelines of the Turkish Ministry of Health. Corticosteroids, Tocilizumab and Anakinra were used as anti-inflammatory agents for patients with impaired oxygen saturation, pulmonary damage, or uncontrolled and persistent fever with pneumonic infiltration. In terms of the severity of the COVID-19 disease, 14 (52%) of the acute leukemia patients had transient conventional oxygen supplementation, five (18%) required noninvasive ventilation support and four (15%) needed invasive mechanical ventilation.
Outcomes of COVID-19 infection
There was no significant difference between COVİD-19 positive and negative patients in terms of gender, age, diagnosis, and mortality (Table 3).
Table 3.
Characteristics of the patients with COVİD-19 (+)
| COVİD-19 (+) n=27 | COVİD-19 (-) n=89 | p | |
|---|---|---|---|
| Female gender | 12 (44) | 41 (46) | 0.882 |
| Mean age (SD) | 44 (13) | 46 (18) | 0.562 |
| Diagnosis | |||
| AML | 19 (70) | 63 (71) | 0.659 |
| ALL | 7 (26) | 25 (28) | |
| MPL | 1 (4) | 1 (1) | |
| Dead | 7 (26) | 16 (18) | 0.364 |
Of the 27 patients with COVID-19 disease, seven (26%) died due to COVID-19 and all of them had AML, meaning a mortality rate of 37% among the 19 patients with AML. There were no deaths in the ALL cohort.
The mortality rate was similar between COVID-19 positive and negative acute leukemia cohorts (P=0.364). However, it was significantly higher in COVID-19 positive AML patients (seven over nineteen cases; 37%) compared to COVID-19 negative (nine over sixty-three cases; 14%) AML group (P=0.028) (Table 4).
Table 4.
Mortality of COVID by AML patients
| Death in COVID-19 positive cases (n=7) | Death in COVID-19 negative cases (n=16) | p | |
|---|---|---|---|
| AML (n=82) | 7/19 (37%) | 9/63 (14%) | 0.028 |
| ALL (n=32) | 0/7 (0%) | 6/25 (24%) | 0.204 |
| MPL (n=2) | 0/1 (0%) | 1/1 (100%) | NA |
NA: non-applicable.
In the univariate and multivariate analysis, the female gender was the only factor to significantly increase the risk of death (in the unvariate analysis, P=0.04 [95% CI: 1.04-7.03] and in the multivariate analysis P=0.044; [95% CI: 1.02-7.15]) (Table 5).
Table 5.
Predictors of fatality among acute leukemia patients
| Univariate Analysis | Multivariate Analysis | |||||
|---|---|---|---|---|---|---|
|
|
|
|||||
| OR | CI | P | OR | CI | P | |
| COVİD-19 | 1.5 | 0.57-4.41 | 0.367 | 1.6 | 0.58-4.76 | 0.334 |
| Female gender | 2.7 | 1.04-7.03 | 0.040 | 2.7 | 1.02-7.15 | 0.044 |
| Age ≥60 | 1.2 | 0.46-3.42 | 0.654 | 1.1 | 0.38-3.19 | 0.839 |
| AML | 0.9 | 0.34-2.52 | 0.895 | 0.9 | 0.33-2.56 | 0.875 |
Discussion
During the COVID-19 pandemic, patients with hematological malignancies were particularly considered as having a high risk of worse disease outcomes because of immunosuppression and long hospital stays for treatment delivery. Here we present the outcomes of this high-risk group, consisting of patients with acute leukemia, with or without the COVID-19 infection.
From the beginning of March to the end of December 2020, 116 cases with acute leukemia were treated. The majority of cases (n=82) were diagnosed with AML. The mortality rate in our entire acute leukemia population was 20%. The mortality rate was 26% among all COVID-19 positive cases and it was 37% among AML cases with COVID-19 infection. There was no significant difference in the mortality rate between COVID-19 positive and negative cases among all patients with acute leukemia. Thirty-seven percent of AML cases with the COVID-19 infection and 14% AML cases without the infection were dead. The mortality rate was significantly higher in the COVID-19 positive group (P=0.028).
In recent studies, heterogeneous groups of patients with various hematological diseases and co-existing COVID-19 infection were presented. Data about treatment outcomes, disease course and mortality for patients with acute leukemia that had the infection were published in the literature. Ferrara et al. reported a mortality rate of 50% in a study including 10 patients with AML that had COVID-19 infection [7]. It was shown that patients with hematological malignancies have an increased risk for being infected with COVID-19 [3] and that patients with cancer and concomitant COVID-19 infection have poorer disease outcomes and may have more severe complications than patients without cancer and COVID-19 infection [8]. In the largest study evaluating COVID-19 infection in hematological malignancies, Passamonti et al. reviewed 536 cases with symptomatic COVID-19 infection and hematological cancer. In their cohort, they had 51 patients with AML (10%) and 16 patients with ALL (3%). Hundred and ninety-eight (37%) of 536 patients died; 11% of the non-survivors had AML and 2% had ALL. They reported that patients with hematological malignancies and COVID-19 infection have a high mortality risk. Older age, progressive disease, having AML, non-Hodgkin’s lymphoma or plasma cell neoplasms are shown to have worse outcomes in their cohort [9].
Furthermore, Martin-Moro et al. published the results of 34 cases with hematological malignancies of which seven had leukemia, and a death rate of 36% for patients with the COVID-19 infection was shown [10]. In the study presenting the results of 12 cases with acute leukemia and COVID-19 infection, eight patients (67%) had AML, four patients (33%) had ALL or lymphoblastic lymphoma (LBL). Two of the AML patients died, whereas all ALL/LBL patients survived [11]. In our study, the mortality rate was 37% among 19 AML cases, and none of our ALL patients with COVID-19 infection died. It was hypothesized that the higher median age of AML patients could be associated with increased mortality compared to ALL patients. Furthermore, severe and prolonged neutropenia is more common in the treatment course of AML compared to ALL, which may also result in higher mortality rate in the AML cohort.
Leukemia patients are immunocompromised and frequently develop multiple complications during their management, such as severe infections due to leukopenia and/or neutropenia, which may also complicate the treatment of COVID-19. There is limited data on the clinical course and outcomes of SARS-CoV-2 infections in patients with leukemia and there are no established guidelines for their treatment. Therefore, the management of COVID-19 becomes more challenging for patients with leukemia and should be based on the individual assessment of the patient.
Postponement of the treatment of hematological malignancies constitutes an option for patients with COVID-19 infection. Nevertheless, leukemia often requires urgent and aggressive treatment at the time of diagnosis. The “watch and wait” strategy may not always be an option, and clinicians must be cautious in the case of treatment delay. Nunez-Torron et al. recommended initiation of chemotherapy for patients with AML following the resolution of COVID-19 symptoms and achievement of a negative PCR test [12]. Raza et al. suggest delay of the induction therapy for up to 14 days in hematologically asymptomatic patients [13]. The risks of treatment delay should be evaluated cautiously based on each individual case.
There are contradicting results about therapy delay in patients with acute myeloid leukemia and COVID-19 disease in the literature. Sekeres et al. found out that delaying treatment for more than 5 days could lower the overall survival among young patients, whereas older cases may benefit from the delay [14]. On the other hand, Bertoli et al. did not report any negative effect of treatment postponement on disease outcome [15]. Hence, there is no consensus on the management of leukemia cases with COVID-19 infection.
Several guidelines were published to optimize the management of acute leukemia patients with COVID-19 disease [4-6]. Brissot et al. from the working party of EBMT recommend to screen the patients for COVID-19 before initiating chemotherapy. An induction therapy with 3+7 is offered for AML patients with a good performance status and favorable or intermediate risk. They advised to discuss omission of one of the three consolidation treatments in case of achievement of minimal residual disease negativity. They offered hypomethylating agents or low dose cytarabine monotherapy for patients with poor performance status, unsuitable for intensive treatment. G-CSF is recommended following each cycle of chemotherapy. For ALL cases, no change in glucocorticoid dosage is recommended during prophase, induction and consolidation. Unurgent allogeneic transplantations are proposed to be deferred [4]. We agree with the EBMT recommendations and we think that their guideline is more suitable within daily practice.
At the beginning of the pandemic, we were looking for the optimal approach for the treatment of leukemia patients. Hematologists became more experienced with time and can now make recommendations about the management of acute leukemia during the pandemic. The patients and their companions should be informed in detail about the COVID-19 infection, its mortality potential and the ways the patient can get the disease. They should be warned about the potential risks of outside contact and visiting the patient should be forbidden. According to our real-life experience, we recommend to perform the regular COVID-PCR tests on all patients before starting each chemotherapy cycle. The results are mostly available within 6-24 hours. In case of strong suspicion of COVID-19 infection or active infection, we recommend delay of leukemia treatment. The regimens to treat acute leukemia induces long term myelosuppression, which can often be life-threating if viral infections occur. Dose reduction in chemotherapy protocols for AML may be an alternative approach. Induction treatment with curative intend should be initiated in young acute leukemia cases. Allo-HSCT of favorable or intermediate risk acute leukemia cases in complete remission should be postponed, as they are evaluated as nonurgent SCT. Low-intensity regimens such HMA and venetoclax or supportive care may be preferred for the elderly and for patients with poor performance status.
In our daily practice, we do not change the number of planned treatment cycles, their duration or the dosage of the medications in the ALL management. Use of G-CSF to hasten neutrophil count recovery may be beneficial. In our cohort, we did not experience any treatment failure or relapse due to treatment delay. In other words, postponement of the treatment does not always lead to worse outcomes. In contrary, five of the seven patients with AML (71%), who died from the COVID-19 infection, had neutropenia at the time of COVID-19 diagnosis. Four of those patients had chemotherapy related neutropenia and one of them had refractory disease and was receiving supportive care.
Conclusion
In conclusion, it is evident that the management of leukemia patients with the COVID-19 infection is challenging. Our data presents recent information about the clinical courses and mortality rates among patients with acute leukemia and concomitant COVID-19 infection. Delay in the leukemia treatment does not always result in progressive disease and, sometimes the decision of delaying chemotherapy can even save lives. On the other hand, patients should not lose the chance to receive adequate treatment due to prolonged delays. Because of the increased risk of mortality and morbidity in this group, an effective and multidisciplinary approach should be planned. Clinicians should recognize that the prompt resumption of hematological treatment following the clearance of COVID-19 infection is crucial for the patient’s survival. It is evident that larger case series are needed to prepare reliable treatment guidelines for patients with acute leukemia and COVID-19 infection. We think that our case-series will contribute to the establishment of these essential treatment protocols.
Disclosure of conflict of interest
None.
References
- 1.Pollard CA, Morran MP, Nestor-Kalinoski AL. The COVID-19 pandemic: a global health crisis. Physiol Genomics. 2020;52:549–557. doi: 10.1152/physiolgenomics.00089.2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Stasi C, Fallani S, Voller F, Silvestri C. Treatment for COVID-19: an overview. Eur J Pharmacol. 2020;889:173644. doi: 10.1016/j.ejphar.2020.173644. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Malard F, Genthon A, Brissot E, van de Wyngaert Z, Marjanovic Z, Ikhlef S, Banet A, Lapusan S, Sestilli S, Corre E, Paviglianiti A, Adaeva R, M ‘Hammedi-Bouzina F, Labopin M, Legrand O, Dulery R, Mohty M. COVID-19 outcomes in patients with hematologic disease. Bone Marrow Transplant. 2020;55:2180–2184. doi: 10.1038/s41409-020-0931-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Brissot E, Labopin M, Baron F, Bazarbachi A, Bug G, Ciceri F, Esteve J, Giebel S, Gilleece MH, Gorin NC, Lanza F, Peric Z, Ruggeri A, Sanz J, Savani BN, Schmid C, Shouval R, Spyridonidis A, Versluis J, Nagler A, Mohty M. Management of patients with acute leukemia during the COVID-19 outbreak: practical guidelines from the acute leukemia working party of the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2021;56:532–535. doi: 10.1038/s41409-020-0970-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Rahi MS, Jindal V, Reyes SP, Gunasekaran K, Gupta R, Jaiyesimi I. Hematologic disorders associated with COVID-19: a review. Ann Hematol. 2021;100:309–320. doi: 10.1007/s00277-020-04366-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Percival MM, Lynch RC, Halpern AB, Shadman M, Cassaday RD, Ujjani C, Shustov A, Tseng YD, Liu C, Pergam S, Libby EN, Scott BL, Smith SD, Green DJ, Gopal AK, Cowan AJ. Considerations for managing patients with hematologic malignancy during the COVID-19 pandemic: the seattle strategy. JCO Oncol Pract. 2020;16:571–578. doi: 10.1200/OP.20.00241. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Ferrara F, Zappasodi P, Roncoroni E, Borlenghi E, Rossi G. Impact of COVID-19 on the treatment of acute myeloid leukemia. Leukemia. 2020;34:2254–2256. doi: 10.1038/s41375-020-0925-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Liang W, Guan W, Chen R, Wang W, Li J, Xu K, Li C, Ai Q, Lu W, Liang H, Li S, He J. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol. 2020;21:335–337. doi: 10.1016/S1470-2045(20)30096-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Passamonti F, Cattaneo C, Arcaini L, Bruna R, Cavo M, Merli F, Angelucci E, Krampera M, Cairoli R, Della Porta MG, Fracchiolla N, Ladetto M, Gambacorti Passerini C, Salvini M, Marchetti M, Lemoli R, Molteni A, Busca A, Cuneo A, Romano A, Giuliani N, Galimberti S, Corso A, Morotti A, Falini B, Billio A, Gherlinzoni F, Visani G, Tisi MC, Tafuri A, Tosi P, Lanza F, Massaia M, Turrini M, Ferrara F, Gurrieri C, Vallisa D, Martelli M, Derenzini E, Guarini A, Conconi A, Cuccaro A, Cudillo L, Russo D, Ciambelli F, Scattolin AM, Luppi M, Selleri C, Ortu La Barbera E, Ferrandina C, Di Renzo N, Olivieri A, Bocchia M, Gentile M, Marchesi F, Musto P, Federici AB, Candoni A, Venditti A, Fava C, Pinto A, Galieni P, Rigacci L, Armiento D, Pane F, Oberti M, Zappasodi P, Visco C, Franchi M, Grossi PA, Bertù L, Corrao G, Pagano L, Corradini P. Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study. Lancet Haematol. 2020;7:e737–e745. doi: 10.1016/S2352-3026(20)30251-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Martín-Moro F, Marquet J, Piris M, Michael BM, Sáez AJ, Corona M, Jiménez C, Astibia B, García I, Rodríguez E, García-Hoz C, Fortún-Abete J, Herrera P, López-Jiménez J. Survival study of hospitalised patients with concurrent COVID-19 and haematological malignancies. Br J Haematol. 2020;190:e16–e20. doi: 10.1111/bjh.16801. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Ghandili S, Pfefferle S, Roedl K, Sonnemann P, Karagiannis P, Boenisch O, Kluge S, Schmiedel S, Ittrich H, Rohde H, Lütgehetmann M, Weisel K, Bokemeyer C, Wichmann D, Fiedler W, Jarczak D, Modemann F. Challenges in treatment of patients with acute leukemia and COVID-19: a series of 12 patients. Blood Adv. 2020;4:5936–5941. doi: 10.1182/bloodadvances.2020002543. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Núñez-Torrón C, García-Gutiérrez V, Tenorio-Núñez MC, Moreno-Jiménez G, López-Jiménez FJ, Herrera-Puente P. Poor outcome in patients with acute leukemia on intensive chemotherapy and COVID-19. Bone Marrow Transplant. 2021;56:267–269. doi: 10.1038/s41409-020-0961-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Raza A, Assal A, Ali AM, Jurcic JG. Rewriting the rules for care of MDS and AML patients in the time of COVID-19. Leuk Res Rep. 2020;13:100201. doi: 10.1016/j.lrr.2020.100201. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Sekeres MA, Elson P, Kalaycio ME, Advani AS, Copelan EA, Faderl S, Kantarjian HM, Estey E. Time from diagnosis to treatment initiation predicts survival in younger, but not older, acute myeloid leukemia patients. Blood. 2009;113:28–36. doi: 10.1182/blood-2008-05-157065. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Bertoli S, Bérard E, Huguet F, Huynh A, Tavitian S, Vergez F, Dobbelstein S, Dastugue N, Mansat-De Mas V, Delabesse E, Duchayne E, Demur C, Sarry A, Lauwers-Cances V, Laurent G, Attal M, Récher C. Time from diagnosis to intensive chemotherapy initiation does not adversely impact the outcome of patients with acute myeloid leukemia. Blood. 2013;121:2618–2626. doi: 10.1182/blood-2012-09-454553. [DOI] [PubMed] [Google Scholar]