COVID-19 in Hematological Malignancies: Case Series and Literature Review

Abstract

Earlier reports suggest that cancer patients were twice more likely to contract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this report, we describe two patients with hematological malignancies seen at the peak of the first wave of the coronavirus disease 2019 pandemic. A 61-year-old man was referred to our urology unit he was diagnosed with nodular hyperplasia and multiple myeloma and commenced on bortezomib, thalidomide, and dexamethasone combination chemotherapy. He developed a cough and fever, with SPO₂ 86%, He was positive for SARS-CoV-2 and died a few days later. A 42-year-old man with Hodgkin lymphoma on treatment with Adriamycin, bleomycin, vincristine, and dacarbazine with positive SARS-CoV-2 exposure was diagnosed with pleural effusion at A/E. Three days postadmission, his condition worsened with low SPO₂ despite intranasal oxygen. He died after testing positive for SARS-CoV-2. Patients with hematological malignancies tend to have a greater risk of SARS-COV-2 infection and severe disease due to immunosuppression from cancer and its treatment.

INTRODUCTION

A series of unexplained pneumonia was reported to the WHO from China on December 31, 2019.[1] A novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified to be responsible for the disease, now called coronavirus disease 2019 (COVID-19). The WHO on March 11, 2020, declared the COVID-19 outbreak a global pandemic, after noting that over the previous 2 weeks, the number of cases outside China had increased 13-fold and the number of countries with cases had increased 3-fold.

There are several reasons why patients with hematological malignancies are at high risk for developing opportunistic infections. These include bone marrow failure and immune suppression from myelosuppressive chemotherapy. Lymphoid cancers such as lymphomas and chronic lymphocytic leukemia are associated with profound immune suppression because of the direct involvement of the immune system in cancer. In myeloid cancers, however, granulocyte and macrophage production is defective, either because of the disease or its therapy. Therefore, myeloid neoplasms are mainly susceptible to bacterial, fungal, and parasitic infections, and not viral infections.[2]

At the beginning of the pandemic, reports from China appeared to suggest that cancer patients were about two times more likely to contract SARS-CoV-2 infection than the general population without cancer. These reports also suggested that when infected, cancer patients also had a higher risk of severe events (intensive care unit [ICU] admission, invasive ventilation, or death) compared to patients without cancer.[3,4,5] There is, therefore, a need to assess the impact of the COVID-19 pandemic in the management of hematological malignancies.

In this report, we describe two patients with hematological malignancies seen at the University of Nigeria Teaching Hospital, Enugu, Nigeria, at the peak of the first wave of the COVID-19 pandemic.

CASE REPORTS

Patient 1

A 61-year-old man was referred to our urology unit in May 2020 on account of recurrent acute urinary retention of 4-year duration, pathological fracture of the right humerus, low back pain, and progressive weakness of both lower limbs, within 4 months of presentation.

On examination, he was moderately pale. Review of his musculoskeletal system showed that the right upper limb was on an arm sling with swelling and tenderness over the right arm. The power on the right upper limb was 1/5 while that of the left upper limb was 5/5. The powers of the right and left lower limbs were each 4/5. There was normotonia globally with sensory level at T8.

A clinical diagnosis of metastatic cancer of the prostate, to rule out, multiple myeloma (MM) was made and the patient was referred to our hematology department on account of the anemia, pathological fracture, lytic bone lesions, and suspicion of MM in June 2020.

Results of the investigation showed that the renal function tests were essentially normal. Prostate-specific antigen was 44 ng/ml (reference range: 0–4 ng/ml). The histology of his prostate biopsy was reported as nodular hyperplasia.

Full blood count showed hemoglobin 9 mg/dl and total white blood cell count 8.9 × 10⁹/L (differentials neutrophils 70%, lymphocytes 23%, eosinophils 1%, and monocytes 6%). The platelet count was 297 × 10⁹/L. Erythrocyte sedimentation rate was 145 mm/1^st h Westergreen.

Radiological investigations revealed that the right humerus had multiple lytic lesions with a pathological fracture. There were lytic destructions of the medial end of the left clavicle. Similar lytic lesions were seen on the cranium. Lumbosacral X-ray showed that lumbar lordosis was lost with T11/T12 changes suggestive of lytic lesions. Chest X-ray showed lytic destruction of the medial end of the left clavicle.

Total proteins were high 94 g/L (60–80) with reversal of the albumin–globulin ratio (albumin – 38 g/L [30–50 g/L] and globulin – 56 g/L [18–30 g/L]). Bence Jones protein was positive in his urine.

Serum protein electrophoresis showed a markedly stained gamma globulin band.

Bone marrow aspiration showed bone marrow plasmacytosis with plasma cells constituting about 30% of the bone marrow nucleated cells. Abnormal forms of plasma cells were also seen.

A diagnosis of MM was made, and the patient was commenced on bortezomib, thalidomide, and dexamethasone combination chemotherapy on July 2, 2020. He also received a dose of radiotherapy for severe low back pain.

On July 13, 2020, the patient developed a cough and fever for which COVID-19 infection was suspected. The infectious disease unit was immediately invited to review the patient. They sustained the suspicion of COVID-19 infection and commenced him on tablets of azithromycin 500 mg daily, tablets of Vitamin C 1 g daily, tablets of zinc 20 mg daily, tablets of vasoprin 75 mg daily, and tablets of calcium/Vitamin D 400 mg daily pending the nasal swab collection for the COVID-19 screening test.

Samples for SARS-CoV-2 testing were collected on July 19, 2020. SPO₂ done on July 22, 2020, was 86% in room air necessitating the commencement of intranasal oxygen therapy.

The SARS-CoV-2 test result came out positive on July 29, 2020. He died a few days after that.

Patient 2

A 42-year-old man was seen in our accident and emergency unit with a 2-week history of generalized body weakness and 6-day history of incoherent speech and loss of coordination. He had received several units of blood transfusion before this presentation. Incoherent speech and difficulty with coordination were noticed about 6 days before this presentation. Initially, he had occasional forgetfulness with intermittent incoherent statements while discussing with people. This progressively got worse and could no longer make any coherent statements other than irrational sounds and inaudible words. Before this presentation, he had received at the peripheral hospital two cycles of Adriamycin, bleomycin, vincristine, and dacarbazine (ABVD) chemotherapy based on histological diagnosis of Hodgkin's lymphoma (HL). Further courses of chemotherapy were delayed due to the temporary shutdown of the hospital where he was receiving treatment because some patients in that hospital were confirmed to have COVID-19 disease. This was the main reason for his self-referral to the University of Nigeria Teaching Hospital (UNTH). The patient had an intermittent high-grade fever, cough, weight loss, and drenching night sweats.

Physical examination revealed an acutely ill-looking man who was delirious, in respiratory distress, febrile, moderately icteric, moderately pale, and moderately dehydrated with no pedal edema. Systemic examination revealed bilateral supraclavicular and axillary lymphadenopathy, reduced air entry over the right lower lung zone, and bibasal crepitations (right >left).

A diagnosis of HL with central nervous system disease and right pleural effusion to rule out SARS-CoV-2 infection was made. The cardiothoracic surgeons reviewed the patient and made a diagnosis of right-sided pleural effusion on a background of HL. A bedside needle thoracocentesis yielded 10 ml of free-flowing straw-colored pleural aspirate, necessitating a thoracostomy with closed tube thoracostomy drainage.

Three days into his admission, a sample was taken for SARS-CoV-2 screening. The patient began declining clinically on the 4^th day of admission with progressive restlessness, worsening breathlessness, hypotension, and low oxygen saturation despite being on intranasal oxygen. Attempts at resuscitating, the patient was futile and the patient subsequently died. One day postdemise, the result of the SARS-CoV-2 screening was returned positive.

DISCUSSION

Our two patients with concurrent hematological malignancies and COVID-19 succumbed early to the diseases. In one patient, death occurred few days after the diagnosis of COVID-19, while in the second patient, the diagnosis of COVID-19 was made after death. It was later that we got to know that the patient with MM was being nursed close to a COVID-19 patient.

Patients with malignancies pose significant challenges to management because of their high risk for opportunistic infections. Lymphoproliferative neoplasms have the tendency to be associated with severe immune suppression due to the direct involvement of the immune system in the neoplastic process. A different scenario is seen in myeloid malignancies, in which macrophage and granulocyte production is defective as a result of the disease and or its therapy. In myeloid malignancies, patients are more prone to having bacterial, fungal, and parasitic infections, not viral infections.[2] In the setting of SARS-CoV-2 infection, many patients die, not primarily as a result of the SARS-CoV-2 infection but because of the resulting opportunistic infections and/or the subsequent uncontrolled host immune response identical or similar to cytokine release syndrome. Therefore, when COVID-19 disease coexists with any hematological malignancy, the resulting combined immunosuppression could overwhelm the patient with opportunistic infections if not properly managed.

Several studies have been carried out in Wuhan, the epicenter of the SARS-CoV-2 pandemic, and other centers, about SARS-CoV-2 infection, COVID-19 disease, and various hematological malignancies. A study by Liang et al. revealed that there was an estimated two-fold increased risk of contracting SARS-CoV-2 in patients with hematological malignancies compared with the general population. They also found out that if patients with hematological malignancies were infected with SARS-CoV-2, they had a higher risk of severe events (ICU admission, invasive ventilation, or death) compared to patients without cancer.[4] In another study, Zhang et al. found that the administration of anticancer chemotherapy within 14 days from COVID-19 diagnosis was significantly associated with the risk for severe disease.[6] In another study evaluating 128 patients with hematologic malignancies who were hospitalized at two centers in Wuhan, China, 13 (10%) of the patients developed COVID-19. Among 226 health-care providers who were also studied, only 16 (7%) developed COVID-19. This study concluded that COVID-19 appeared to be more severe, and more deaths were reported, in the patients with hematologic malignancies compared to the cohort of health-care providers who developed COVID-19.[5] Li et al., in another study, evaluated 530 subjects with chronic myeloid leukemia (CML) in the Hubei Province of China. Five developed confirmed (n = 4) or probable COVID-19 (n = 1). The prevalence of COVID-19 (0.9%) was 9-fold higher than the 0.1% reported in normal individuals. They also observed that CML patients diagnosed in the advanced phase had an increased risk of contracting COVID-19 even after achieving a complete cytogenetic response or major molecular response at the time they developed COVID-19.[7]

In France, 25 consecutive hematology patients with confirmed COVID-19 were studied, with at least 10-day follow-ups. Twenty had lymphoid malignancies, including 10 patients with MM. Many patients were in the older age group (>65 years), with one or more comorbidities, which could have increased the severity of COVID manifestations.[8] In Spain, Martín-Moro et al. studied 19 patients with concurrent hematological cancers and COVID-19 and compared their outcomes with 11 hospitalized health-care providers who only had COVID-19.[9] They observed that 13 of the 19 patients with concurrent hematological cancers and COVID-19 had more severity and higher mortality (8 deaths out of 13 cases) compared to the 11 hospitalized health-care providers with COVID-19 in whom there was no single death. In Nigeria, Akanmu et al. evaluated 356 patients with COVID-19 admitted at the Lagos University Teaching Hospital.[10] Only seven patients had malignancies as comorbidity. Two of the seven were hematological cancers (acute myeloblastic leukemia [AML], and lymphoma). The AML patient was dead at the time of the report while the lymphoma patient was doing well.

Risk factors for SARS-CoV-2 infection in patients with hematological malignancies include immunosuppression from cancer, immunosuppression from treatment, age, and comorbidities. Factors linked with poor prognosis include age over 60 years, preexisting cardiovascular disease, and preexisting respiratory disease.

One of our patients had MM. The peculiarities of a myeloma patient in the setting of SARS-CoV-2 infection include immunocompromised state, older age, and comorbidities. All these findings make myeloma patients probably more susceptible to COVID-19. SARS-CoV-2 infection has been associated with an increased risk for venous thromboembolism. These factors support the assumption that myeloma patients are at increased risk for poor outcomes if infected by SARS-CoV-2.[3] Some of the modifications in the management of patients with concurrent MM and COVID-19 include switching from twice to once weekly regimens (e.g. bortezomib), and reducing dexamethasone dose, especially in patients with borderline lymphocyte count. For myeloma patients, yet to be confirmed to have SARS-CoV-2 infection, the guidelines suggest that all patients should be screened for potential COVID-19-related signs and symptoms or contact with any person with suspected or confirmed COVID-19 infection. Treatment breaks should be considered when the risk of SARS-CoV-2 infection is high and the use of granulocyte colony-stimulating factor should be considered primary prophylaxis. There is also always the need to balance the risk of a potentially lethal infection with the risk of a potentially lethal and incurable disease.[3]

Our second patient had HL. The followings are some of the suggestions for the management of patients with concurrent HL and COVID-19:[11] In patients with advanced-stage HL, the ABVD combination chemotherapy (consisting of ABVD) should be given with an interim positron emission tomography/computed tomography scan to allow for the elimination of bleomycin in cycles 3–6.[11] An alternative in Stage III/IV HL is to replace bleomycin with brentuximab vedotin. Bleomycin should be omitted from therapy in all elderly patients (variably defined as >60 years in most centers).[11] For patients with relapsed/refractory HL, outpatient second-line regimens such as oral gemcitabine-based treatment are being used more commonly rather than regimens that require hospitalization. For pediatric patients with HL, no significant modifications have been suggested as SARS-CoV-2 infection has been described as having a milder clinical course in children than in adults with cancer.

CONCLUSION

Patients with hematological malignancies tend to have a greater risk of SARS-CoV-2 infection and severe disease due to immunosuppression as a result of cancer and its treatment, myelosuppression, and opportunistic infections. The COVID-19 pandemic has changed the way we live, behave, and think, and has profound and multifaceted consequences in society and health-care systems. We need to optimize our therapeutic approaches, as we have to balance the risk of a potentially lethal infection with the risk of potentially lethal and incurable cancers.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.