|Year : 2020 | Volume
| Issue : 2 | Page : 41-50
Management of hematological malignancies during the COVID-19 pandemic
Aamer Aleem, Mashael Altowairqi, Yazeed Bajuaifer, Musa Alzahrani
Department of Medicine, Division of Hematology/Oncology (Oncology Centre), College of Medicine and King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
|Date of Submission||22-May-2020|
|Date of Decision||25-May-2020|
|Date of Acceptance||26-May-2020|
|Date of Web Publication||28-Jul-2020|
Prof. Aamer Aleem
Department of Medicine (Hematology/Oncology), King Khalid University Hospital, King Saud University, Riyadh 11472
Source of Support: None, Conflict of Interest: None
Patients with hematological malignancies (HM) appear to be at increased risk of acquiring COVID-19 infection and its complications. General measures to protect patients with HM from COVID-19 include limiting exposure of patients to medical environments with the use of telemedicine and virtual clinics, delaying elective diagnostic services, modifying treatment modalities in a manner that reduces the probability of further immune suppression such as shortening the treatment course or prolonging the interval between treatment courses, and growth factor support to reduce the risk of neutropenia. Reducing the threshold for packed RBC and platelet transfusions to mitigate reduced blood product supplies, and a careful attention to drug interactions in patients who get the COVID-19, are also important management measures. Physicians caring for patients with HM need to carefully evaluate each individual patient to optimize therapies, take measures to maximize safety of patients and staff, without significantly compromising outcomes. This paper discusses management of HM during the COVID-19 pandemic.
Keywords: COVID-19, hematological malignancies, management
|How to cite this article:|
Aleem A, Altowairqi M, Bajuaifer Y, Alzahrani M. Management of hematological malignancies during the COVID-19 pandemic. J Appl Hematol 2020;11:41-50
|How to cite this URL:|
Aleem A, Altowairqi M, Bajuaifer Y, Alzahrani M. Management of hematological malignancies during the COVID-19 pandemic. J Appl Hematol [serial online] 2020 [cited 2020 Nov 28];11:41-50. Available from: https://www.jahjournal.org/text.asp?2020/11/2/41/290965
| Introduction|| |
Following the novel coronavirus (severe acute respiratory syndrome-coronavirus-2 [SARS-CoV-2]) outbreak in Wuhan, China, in December 2019, the disease which is now termed COVID-19 has spread around the world to become a pandemic. Although COVID-19 mainly involves the respiratory tract, it appears to be a systemic disease and may affect many other organ systems of the body. Currently, no vaccine is available against this virus, and the United States Food and Drug Administration has issued an emergency use authorization for some therapies albeit with limited efficacy.,
Patients with hematological malignancies (HMs) are frequently immunosuppressed both due to the disease as well as the treatment and are at increased risk of infections and serious complications by the respiratory viruses. Moreover, many patients with HM have additional risk factors for severe COVID-19 disease, such as advanced age and comorbid medical conditions. Limited data are available for cancer patients with COVID-19 and suggest that cancer patients are at higher risk of severe COVID-19 disease and a case fatality rate of 5.6%., The survival of cancer patients presenting with reverse transcription–polymerase chain reaction (RT-PCR)-positive COVID-19 and received recent cancer treatment has been reported to be poor, with up to 30% mortality at 30 days.,
A recent study showed that patients with cancer had a significantly lower detection rate of SARS-CoV-2 antibodies 15 days or later after COVID-19 symptoms and RT-PCR-positive test than health-care workers, indicating likely poor immunity. Data are even sparse for patients with HM and COVID-19.,,
This study reviews the recommendations for the management of HM during the COVID-19 pandemic in light of limited published data and recommendations by the professional societies, mainly based on expert opinion.
| Challenges and General Considerations|| |
Management of patients with HM poses many challenges during the COVID-19 pandemic. Below are some of the challenges faced in the management of HM during the pandemic and some suggested measures.
- Patients with HM could be at elevated risk of severe COVID-19, so it is paramount to try everything possible to reduce the exposure to patients.
- Some of the measures recommended to reduce the risk of getting COVID-19 include to consider stopping the treatment temporarily, increasing the interval between treatments, and/or to reduce the doses of individual therapeutic agents, if feasible and likely not to compromise the outcomes; growth factor support to prevent or minimize the risk of neutropenia, and telemedicine/virtual clinic follow ups to avoid hospital visits
- Delivery of cancer therapies could be disrupted by quarantines, social distancing measures, and disruption to routine supply and delivery by the pandemic. Individual centers and local health-care authorities need to arrange for home delivery of medicines to the patients. In some cases, drive-through pharmacy services may be arranged if feasible, to minimize contact. A worldwide shortage of cancer drugs is expected because of production disruptions, so careful planning is required to maintain the supplies and inventories
- Availability of blood products has become limited due to lockdowns and travel restriction of donors. Apart from the measures to recruit and encourage the donors, reducing the threshold of packed red blood cell (PRBC) transfusion to a hemoglobin (Hb) level of ≤7.0 g/dl and platelet transfusion threshold to ≤10 × 109/L is recommended. In patients with low platelets and bleeding tendency, antifibrinolytic agents may be helpful. Consider using erythropoiesis-stimulating agents (ESAs) in patients with anemia to reduce PRBC requirement
- There may be potential drug interactions between cancer medicines and COVID-19 therapies. Keeping this in mind with a careful watch for potential interactions is the key for prevention and early detection of complications.
Some of the challenges posed by COVID-19 pandemic and suggested/recommended measures are summarized in [Table 1].
|Table 1: Challenges posed by coronavirus disease-19 pandemic and summary of recommended measures|
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Detailed management of patients with different HM is discussed below.
| Lymphoma Management during Covid-19 Pandemic|| |
Lymphoma patients are considered to be at high risk to develop severe complications from COVID-19 infection and need to be shielded against the virus. Although this is based on limited evidence, it is understandably based on precautionary principles till further evidence becomes available. Expert opinion and recommendations can be found on a number of websites and professional societies' webpages.,,
In a true sense, lymphoma is a cancer of the adaptive immune system. Thus, intuitively, lymphoma patients are prone to viral infections and are considered immunocompromised from the disease itself even before commencing on treatment. This can be objectively seen in many patients, as reflected by low lymphocyte count and/or low immunoglobulin levels. When it comes to treatment, the current treatment paradigms for lymphoma patients are associated with a significant degree of immunosuppression, whether it is radiation therapy, chemotherapy, and/or immunotherapy.
For the purpose of simplicity, in this article, we will divide our discussion into curable lymphomas and incurable lymphomas. We believe that this distinction is important while weighing risks and benefits of the different treatment options. The main focus during this discussion will be on the major categories although the other subtypes should follow the same logic. It is prudent to screen all patients with a diagnosis of lymphoma for COVID-19 before commencing on treatment, and telemedicine/virtual visits should replace normal visits, whenever possible.
Hodgkin lymphoma initial therapy
Hodgkin lymphoma (HL) is a highly curable cancer. Cure rates have been generally in the range of 80%–95% depending on several factors. Thus, treatment should not be delayed or withheld because of the current crisis. However, a number of important considerations need to be taken into account while managing these patients. For example, an emphasis on bleomycin lung toxicity is raised as being of a potential threat to increase the chance of severe complications from COVID-19, and thus, strategies to reduce bleomycin lung toxicity should be sought and addressed carefully in all patients. When adding bleomycin in the treatment protocol, it might be especially advisable to screen patients for COVID-19 at the beginning of therapy.
For early favorable disease, a number of options are available. Chemotherapy-only protocols may be preferred, for example, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) × 4 with an interim positron emission tomography (PET) scan. Omitting bleomycin in this patient population could be safely justified based on extrapolation from the RATHL study in advanced-stage patients. The alternative is using combined modality therapy (CMT) with abbreviated cycles of ABVD plus limited radiotherapy (20–30 Gy). However, CMT may be discouraged during COVID-19 as it requires multiple visits to radiotherapy area, which may increase the risk of exposing patients to the virus. Having said that, the International Lymphoma Radiation Oncology Group has recently published new modifications to radiotherapy doses and schedules for lymphoma patients during the COVID-19 emergency. While physicians want to decrease the number of visits to the lowest possible during the pandemic, it might still be important to perform PET scans in HL patients, if available, because treatment modification depends on its interpretation.
For early unfavorable disease, chemotherapy-only regimens with interim PET scan using ABVD × 4–6 is preferred over CMT with ABVD × 4 plus involved site radiation therapy because of the higher number of visits associated with CMT. Moreover, similarly to the favorable patients, omission of bleomycin can be considered after a negative interim PET has been documented.
With regard to advanced-stage disease, applications of the RATHL trial still continue to be recommended as the standard of care with the use of ABVD chemotherapy × 6 with omission of bleomycin after a negative interim PET. The optimal management of advanced-stage patients with a positive interim PET is controversial and will remain uncertain during the COVID-19 pandemic. Weighing the risk of infection during escalation to a more aggressive treatment needs to be balanced with the benefits of that treatment. Finally, for elderly patients, appropriate chemotherapy dose reductions are needed along with the judicious use of growth factors to decrease the risk of neutropenia and hospital admissions. Furthermore, bleomycin should be omitted in all elderly patients.
Relapsed Hodgkin lymphoma
Outpatient salvage regimens such as gemcitabine, dexamethasone, and cisplatin may be more preferred compared to regimens that require hospitalization. Applications of chemotherapy-free salvage regimens that include brentuximab vedotin or checkpoint inhibitors targeting programmed cell death 1 ligand have been used by some experts during COVID-19 and typically administered monthly to reduce hospital visits. Postsalvage therapy plan should be individualized. Some patients could obtain long remissions with consolidative radiotherapy when possible. Otherwise, autologous stem cell transplant (ASCT) can be used with the caveat that blood banks and ICU beds are in considerable shortages which may very well make application of high-dose chemotherapy and ASCT, particularly challenging.
Supportive care in Hodgkin lymphoma
Supportive care needs to balance the risks and benefits of using antibiotic prophylaxis considering the local bacterial resistance in the same institution as well as the use of growth factors with its possible risk of potentiating bleomycin lung toxicity.
Diffuse large B-cell lymphoma
Initial therapy for diffuse large B-cell lymphoma
For advanced-stage diffuse large B-cell lymphoma (DLBCL) patients, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy should remain the standard of care. Infusional protocol with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) is discouraged given that is more aggressive and usually requires hospital admission. Nevertheless, DA-EPOCHR is still indicated for “double- or triple-hit” lymphomas and in selected patients with primary mediastinal B-cell lymphoma, in which case outpatient delivery is encouraged if the setup is available and possible. For the elderly with DLBCL, mini-R-CHOP regimen along with growth factor support is recommended. Patients who are deemed to be at high risk for central nervous system progression, high-dose methotrexate could be given, but the optimal number of cycles and timing is unknown.
Regarding limited-stage DLBCL, there is growing evidence in recent years supporting the omission of radiation in this patient population. Thus, R-CHOP × 4 rather than CMT is recommended during the COVID-19 pandemic.
It is notable to remember that for all patients with lymphoma for whom rituximab is part of the regimen, subcutaneous formulation is advisable as it can reduce the time spent in the treatment areas, thereby limiting the potential exposure to the virus.
Relapsed refractory cases with diffuse large B-cell lymphoma
In the relapsed setting, the high risk of mortality from progressive disease usually outweighs the risk of potential infections and administration of salvage chemotherapy is recommended followed by high-dose chemotherapy and ASCT. Again as noted earlier, outpatient salvage regimens are preferable, whenever possible. For those who are not candidates for high-dose chemotherapy and ASCT, polatuzumab vedotin plus bendamustine or regimens that include oral drugs such as lenalidomide are good alternatives.
Chimeric antigen receptor T-cell therapy
Chimeric antigen receptor T cell (CAR T-cell) and other cellular therapies are being delayed in some centers because of concerns of limited health-care resources during the pandemic such as intensive care unit beds. The impact is not only limited to patient care but is also extended to include logistics, administration, and delivery. For these reasons, recommendations have already been published based on the collective experience of the CAR T-cell Consortium investigators.
With regard to low-grade Non-Hodgkin lymphoma (NHL) and other incurable types, the treatment goals are usually balanced carefully with the potential risks of the available treatments. Given that these lymphomas are typically incurable, treatment is usually tailored at treating the symptoms and possibly prolonging survival. Thus, it is recommended that these patients should be observed under “watchful waiting” approach during the COVID-19 pandemic, whenever possible, and a higher threshold for initiating treatment is advised. Patients on “watchful waiting” could have telemedicine virtual clinics whenever clinically possible with visits delayed as appropriate. While some centers previously offered rituximab monotherapy to patients with low-burden disease, it might not be recommended during the pandemic given the lack of survival benefit of this approach.
Limited-stage patients with low-grade NHL could still have a chance of cure with radiation therapy, and this treatment should not be withheld. Patients for whom a clear indication for treatment is present, rituximab monotherapy could be considered. If the disease is felt to be unlikely to be controlled by rituximab monotherapy, then combination therapy is indicated. Among the different combinations, rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) serves as a good effective regimen with a lower risk of toxicity compared to R-CHOP and bendamustine and rituximab (BR)., Special concerns have been raised with the immunosuppressive effect of bendamustine, and thus, its use is discouraged. Maintenance rituximab therapy has been a standard of care after the PRIMA study showed progression-free survival benefit. However, given the lack of overall survival (OS) benefit and the potential risk of infections, many experts believe that maintenance rituximab could be withheld or given with increased intervals during COVID-19 pandemic. A notable exception is patients with mantle cell lymphoma, in whom an OS benefit has been demonstrated in randomized clinical trials., Oral therapies are particularly attractive in this setting. For example, ibrutinib has been shown to be effective in small lymphocytic lymphoma/chronic lymphocytic leukemia (CLL), Waldenstrom's macroglobulinemia, relapsed mantle cell lymphoma, and marginal zone lymphoma and should be considered.
Mantle cell lymphoma patients, who are young and fit, are typically treated with an aggressive approach that could include high-dose chemotherapy and ASCT. However, during the COVID-19 pandemic, it may not be recommended to proceed with transplantation given the potential higher complications with limited capacities of transfusion services.
In patients with recurrent infections, measuring IgG levels to look for immunoparesis, with monthly (or longer interval) immunoglobulin replacements may be of benefit in some patients to reduce the risk of infections.
Management of relapsed/refractory indolent lymphoma
Whenever possible, delaying treatment is preferable and treatment should be started only upon clear indications to alleviate symptoms or delay life-threatening progression. Options include oral agents such as ibrutinib and lenalidomide, with or without rituximab and radioimmunotherapy, if available.
| Multiple Myeloma Management during Covid-19 Pandemic|| |
Multiple myeloma (MM) patients are at particularly higher potential risk for complications from COVID-19. This is related to the biologic impairment in immunoglobulin production leading to immunoparesis, impaired plasma cell and B-cell functions, higher median age at the time of diagnosis with its associated comorbidities, as well as the immunosuppression that is related to the MM treatment itself.
All newly diagnosed patients with MM are recommended to undergo screening for COVID-19, particularly before staring treatment or before conducting ASCT. If COVID-19 is confirmed, delaying systemic myeloma treatment should be strongly considered until COVID-19 resolves. Meanwhile, supportive treatment such as bone protection strategies and management of complications should continue.
With regard to patients with smoldering myeloma, although before COVID-19 pandemic, patients with high-risk smoldering myeloma could be offered treatment with lenalidomide-based therapy, it is now recommended not to start treatment for these patients during the pandemic, regardless of the risk stratification.
For all myeloma patients who are transplant eligible, transplant should be delayed until the pandemic is over. Bone protection can continue with agents that can be given at longer intervals, for example, zoledronic acid every 3 months. For standard-risk patients, transplant can be delayed till the first relapse.
It is important to risk stratify myeloma patients who are deemed ready to start therapy. For simplicity, we will divide the patients into those who are high risk and those who are standard risk. Patients with high-risk genetic abnormalities, including t(11:14), t(4:14), t(6:14), t(14:16), 17p deletion and p53 mutations, and 1q+, should receive a triplet regimen for 6 and up to 12 cycles such as bortezomib, lenalidomide, and dexamethasone (VRD) or carfilzomib, lenalidomide, and dexamethasone. For standard-risk myeloma, an oral triplet regimen is preferable, such as ixazomib, lenalidomide, and dexamethasone, to try to avoid multiple visits to the treatment area for injections. Subcutaneous bortezomib at once-weekly dose is preferable over more frequent dosing.
For transplant-ineligible newly diagnosed patients, VRD or daratumumab, lenalidomide, and dexamethasone or even doublets can be given, keeping in mind the risk stratification and accompanying comorbidities.
Maintenance with lenalidomide for standard-risk patients and bortezomib or ixazomib for high-risk patients should still be continued because of the high risk of progression otherwise.
In patients with biochemical-only relapse without any clinical findings, delaying management can be considered.
Regarding follow-up, minimizing clinic visits is important. This can be done using virtual clinics or phone calls. An extended supply of prescriptions and spacing laboratory tests, as far as clinically possible, is also recommended.
Finally, the management of patients with MM during the current COVID-19 pandemic varies according to disease characteristics, the patient's risk category, and the burden of COVID-19 in the local community.
| Leukemia Management during Covid-19 Pandemic|| |
Acute myeloid leukemia
Induction and consolidation therapy in acute myeloid leukemia (AML) patients results in prolonged and severe neutropenia with neutrophil counts commonly dropping below 0.5 × 109/L with an increased risk of infectious complications, mostly of bacterial and/or fungal infections. Although AML induction therapy does not primarily affect the lymphocytes, patients with AML can get viral infections, particularly respiratory viruses, which may be complicated with bacterial and fungal co-infections with an increased risk of fatal outcome. Currently, there is no published experience of treating acute leukemia patients with COVID-19, and the management recommendations are based on expert opinion.
Most of the newly diagnosed patients with AML require therapy, and intensive induction chemotherapy with 7 + 3 or a similar regimen is recommended in most young and fit patients. Antibiotic, antifungal, and antiviral prophylaxis should be considered, and testing all patients for COVID-19 is recommended before starting therapy.,,
Low-intensity therapy with hypomethylating agents plus venetoclax may be an option, particularly in older and less fit patients, and can possibly be administered on an outpatient basis. This may help reduce the transfusion requirements and hospitalization although severe neutropenia is still common and safety of outpatient approach is not known.
Therapy may be deferred for a short period in COVID-19-positive patients regardless of the symptoms till they become negative., An exception to this may be asymptomatic patients who tested positive for COVID-19 and need urgent induction chemotherapy initiation. In older patients who tested positive for COVID-19, deferring treatment is advised. Cytoreduction with hydroxyurea can be started in patients with higher or rising white blood cell counts.
Consolidation therapy should be delayed in COVID-19-positive patients till they become negative. Although high-dose cytarabine remains the standard consolidation for AML patients in remission, intermediate-dose cytarabine is recommended (1.5 g/m2) during the COVID-19 pandemic to reduce the toxicity. Furthermore, the total number of consolidation cycles can be reduced to 3 instead of 4.,
Hematopoietic stem cell transplantation (HSCT) remains an important part of AML management. Despite the limitation of HSCT during the pandemic, it can be provided for high-risk patients and might require an additional consolidation cycle while waiting for the situation to improve. Cryopreservation of donor stem cells is advised to ensure availability before starting conditioning., For positively tested patients for COVID-19, regardless of symptoms, it is advised to delay HSCT up to 1 month from the negative COVID-19 test result.
Patients with relapsed or refractory disease who are eligible to receive salvage therapy should proceed with treatment according to the local protocols. Salvage therapy should be deferred if the patient is not suffering from high disease burden or tested positive for COVID-19.,
Screening all patients undergoing induction, consolidation, salvage therapy for refractory disease, or HSCT is advised before treatment initiation and before each cycle regardless of the presence or absence of symptoms.,
For acute promyelocytic leukemia, the use of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) is recommended in low-risk patients with a suggestion to delay ATO in order to reduce the risk of differentiation syndrome. Treatment with ATRA and ATO in addition to cytoreductive agent (s) is recommended for high-risk patients. Adding steroids as prophylaxis for differentiation syndrome is also suggested, but the significance of resulting lymphopenia during COVID-19 is not known.
General supportive measures and precautions for HM have been discussed in the earlier section. Reduced transfusion thresholds and antifibrinolytic agents should be used for platelet transfusion-dependent patients. Granulocyte-colony-stimulating factor (G-CSF) should be routinely considered as prophylaxis to reduce the duration of neutropenia and during febrile neutropenia, to decrease hospital visits, admissions, and hospital stay. Precautions need to be taken for interactions between the AML therapeutic agents and medications for COVID-19, particularly the possibility to affect QTc interval.
Acute lymphoblastic leukemia
For newly diagnosed acute lymphoblastic leukemia (ALL) patients, COVID-19 screening is recommended for all patients before starting therapy, whether symptomatic or not. Deferring chemotherapy is recommended if the patient tested positive for COVID-19. An exception is made for intrathecal (IT) treatment in the presence of neurological involvement, and IT chemotherapy should not be delayed.
For Philadelphia-negative ALL, it is recommended to start the therapy as per protocol with the curative intent because delaying therapy is likely to negatively affect the patient outcomes. The use and dosing of corticosteroids during the pandemic remains controversial. Corticosteroids are an essential part of ALL induction therapy, but a reduction of doses should be considered. Decreasing chemotherapy agents' dosage should also be considered for patients who are vulnerable to develop complications. Keeping the patient admitted till cytopenias improve is an option if secured environment is ensured, compared to regular outpatient follow-ups. For Philadelphia-positive ALL, proceeding with tyrosine kinase inhibitors (TKIs) and the lowest possible dose of corticosteroids may be preferred for induction, to decrease the length of inpatient stay.
Consolidation therapy should be administered as per plan because it is extremely important for cure. Some adjustments to dosing and schedule can be made to reduce the admission and hospital visits. There are concerns regarding rituximab use during postremission therapy because of the likelihood of reduced immunoglobulin levels and risk of infection. G-CSF should be considered during all phases of therapy to enhance neutrophil recovery. For high-risk ALL patients, management plan needs to be personalized based on the availability and feasibility of HSCT and the risks involved during the pandemic.
During the maintenance, systemic and IT chemotherapy should continue as per protocol with reduced doses of steroids.
In case the patient tested positive for COVID-19, postponing the maintenance is recommended till the infection clears. Omitting vincristine and home delivery of medicines could help reduce the hospital visits.
In patients with relapsed/refractory B-ALL, immunotherapy with inotuzumab and blinatumomab should be considered, if available, instead of the usual salvage regimens. However, caution is required if blinatumomab is considered because of its potential to cause cytokine release syndrome, which is also a complication of severe cases of COVID-19. For T-ALL, the usual treatment is recommended before the COVID-19 pandemic. For patients who achieve remission, it is recommended to proceed with HSCT even with the current COVID-19 pandemic as otherwise their prognosis is very poor.
Precautions need to be taken for interactions between ALL chemotherapeutic agents and COVID-19 therapies. Some of the antivirals such as Kaletra (lopinavir/ritonavir) can increase the levels of methotrexate and vincristine, and tocilizumab can decrease the levels of doxorubicin and vincristine.
Chronic myeloid leukemia
Recently diagnosed patients with chronic myeloid leukemia (CML) are recommended to proceed with treatment initiation with a TKI. Delay is not justified because of the risk of CML progression, and high leukocyte count might worsen gas exchanges in case of severe COVID-19 disease.
Screening for COVID-19 should be considered on an individual basis. Routine complete blood count is advised as follow-up to detect bone marrow suppression that may require treatment adjustment by temporary dosage reduction or suspension of TKI., For patients who are already receiving active treatment for CML in the form of a TKI, it is advised to continue.
Currently, there is no evidence that any of the approved first-line TKIs is preferable to others during the pandemic, so the choice should be according to clinical indications and individual patient profile, for example, comorbidities, etc. If a patient develops COVID-19 while on a TKI more likely to cause adverse lung effects (dasatinib), temporary cessation of the TKI should be considered to minimize the risk of additional complications.
Newly diagnosed patients with accelerated phase CML should proceed with a TKI as per the guidelines. CML patients progressing to accelerated phase while on TKI therapy can be managed with an alternative TKI. Patients in blast phase usually need intensive chemotherapy along with a TKI, followed by HSCT. Younger, fit patients should be considered for intensive treatment as outlined in acute leukemia section, depending on whether blast transformation is myeloid or lymphoid. This type of therapy depends on local conditions and availability of supportive measures. Older patients with comorbidities are more prone to complicated COVID-19 infection and may be managed with an alternative TKI till the pandemic situation improves.,
Patients recently started on a trial of treatment-free remission (TFR) require frequent monitoring (every 4–6 weeks). It is not advisable to start a trial of TFR during the pandemic because of the likely difficulties and interruptions in monitoring and follow-up. TFR trial can be continued for patients who were already initiated on it, as long as regular follow-ups and monitoring can be assured. Monitoring frequency can be reduced to 2 monthly during the first 6 months, and 3 monthly during the second 6 months of TKI discontinuation. If regular follow-ups are not possible in these patients, it is advisable to consider resuming TKI therapy till after the pandemic is over.
Management of a CML patient confirmed to have COVID-19 infection depends on the individual patient status. CML patients in remission on a TKI do not appear to be at a higher risk of COVID-19 infection or its severe complications as compared to the general population. For patients in remission, treatment of the infection is similar to healthy individuals. For uncomplicated infection, it is advisable to continue therapy. If a patient develops COVID-19 while on a TKI more likely to cause adverse pulmonary effects (such as dasatinib), temporary cessation of the TKI should be considered to minimize the risk of additional complications., It is recommended to discontinue therapy in patients who develop pulmonary or cardiac adverse effects from the TKI (such as pleural effusion and pulmonary hypertension) and become positive for COVID-19.
Possible interactions between the CML therapies and treatment options proposed for COVID-19 need to be checked and reviewed by a specialized pharmacist., Most TKIs used for CML can prolong QTc interval and have strong interactions with chloroquine and azithromycin, which may lead to serious arrhythmias.
Chronic lymphocytic leukemia
Patients with chronic lymphocytic leukemia (CLL) are considered immunocompromised and prone to bacterial and viral infections. Currently, relation between CLL and severity of COVID-19 infection is not known as there are no available data.
Treatment initiation in CLL patients during the COVID-19 pandemic should be deferred, if feasible. However, if urgent treatment is indicated, it is recommended to avoid immunotherapy with anti-CD20 antibodies and consider agents that can be managed and followed without hospitalization.
In case a patient with CLL is already receiving immunotherapy, discontinuation should be considered during the COVID-19 pandemic. However, other CLL therapies can be continued without adjustment in unaffected patients, although patients receiving chemotherapy may need to be switched to other regimens. In case of complicated CLL patients with COVID-19 infection, the decision for therapy adjustment should be individualized.
Patients on active treatment for CLL should be followed by phone or video calls to limit the hospital visits and do routine laboratory investigations in a local facility, if feasible, unless a patient is receiving immunotherapy, which is deemed necessary.
Intravenous immunoglobulin (IVIG) can be given and continued for CLL patients, whenever strongly indicated, but increasing the interval between doses is advisable. In a COVID-19-affected patient, the risks of IVIG infusion such as increased likelihood of thrombosis should be carefully considered.
The risk for acquiring COVID-19 infection is thought to be increased among myeloproliferative neoplasm (MPN) population, especially with intermediate- and high-risk myelofibrosis (MF) patients receiving Janus kinase (JAK) inhibitors and the presence of other chronic illnesses, which may contribute in prolonging healing duration. In this section, the discussion will involve polycythemia vera (PV), essential thrombocythemia (ET), and MF. CML is discussed in chronic leukemias' section.
Thromboembolism (TE) is a recently noticed complication of COVID-19 infection, mainly with severe infection., As MPN patients are already predisposed to TE with their underlying disease, the risk is likely to be higher if they get COVID-19. Below is a suggested management outline for patients with MPNs, based on the COVID-19 status.
- In noninfected patients, continue treatment for PV keeping hematocrit <45, antiplatelets, and cytoreductive agents whenever indicated
- In infected patients, follow the same treatment and administer a prophylactic or medium dose of low-molecular-weight heparin (LMWH)/heparin for patients admitted to critical care or on mechanical ventilation, taking into account their increased risk of bleeding. If a patient deteriorates despite the infection management, consider pulmonary embolism as the cause in the presence of a rapidly rising D-dimer.
In addition to thrombosis, bleeding tendency is also a known complication among MPN population and the risk is higher in patients with a previous history of bleeding, extreme thrombocytopenia or thrombocytosis, and liver or renal impairment. For optimal management and balancing of the thrombosis versus bleeding tendency, a hematologist should be involved.
MPN therapies, including cytoreductive agents and JAK inhibitors, should be continued during the pandemic as there are no data regarding their effect on acquiring the infection or worsening it. In addition, such therapies stabilize the disease and may decrease TE risk among MPN patients who might be infected. The same is recommended for patients who are tested positive for COVID-19 unless there is a risk for adverse reaction with COVID-19 potential treatments.
In newly diagnosed PV patients, treatment should be started with venesection and antiplatelets, as clinically indicated. It is preferable to start cytoreductive agents instead of venesection to decrease the risk of exposure. For ET patients, the decision to initiate a cytoreductive agent should also be based on clinical indication(s). A cytoreductive agent should be started in case of previous history of thrombosis or bleeding and to postpone it if the indication was due to old age or cardiac risk. Treatment strategy for MF is selected based on risk stratification; options include observation, symptomatic treatments, and a JAK inhibitor or HSCT in eligible candidates, taking into account that HSCT might need to be postponed because of the COVID-19 pandemic.
For MPN patients on oral anticoagulation (OA) who have COVID-19 infection and initiated on antiviral treatment, OA should be shifted to subcutaneous LMWH/heparin, while patients on antiplatelet agents should continue. In patients receiving antiplatelet therapy who need prophylactic anticoagulation, bleeding tendency versus thrombosis risk needs to be evaluated, in addition to regular observation for blood counts.
In regard to the management of myelodysplastic syndromes (MDS) during the COVID-19 pandemic, data are very scarce, and recommendations are mainly based on expert opinion. Patients with MDS can be particularly vulnerable to infections because they are often elderly, neutropenic, and have neutrophils dysfunction.,
We suggest screening for COVID-19 for all newly diagnosed patients who are going to start treatment. Prophylactic antimicrobials and growth factor support should be considered in all patients.
Applying risk stratification in MDS patients such as the revised International Prognostic Scoring System can help identify patients at higher risk for progression in whom starting treatment without delay is important. Reducing the threshold for transfusion down to an Hb of ≤7.0 g/dl and platelet count of ≤10 × 109/l can help reduce the hospital visits to a minimum. Higher risk patients should be started on hypomethylating agents, preferably in the outpatient setting, without delay. On the other hand, management for low-risk patients with MDS can be individualized depending on the need for transfusion, the predominant cell line being affected, and certain cytogenetic abnormalities such as 5q syndrome. Accordingly, treatment with one of the following can be considered as appropriate: lenalidomide, ESAs, or other growth factors.,
Care of patients with high-risk MDS who are being considered for allogeneic HSCT is challenging during COVID-19. Delaying transplant is advisable in case of a local shortage in essential services such as limited ICU beds or limited supply of blood products.
| Conclusion|| |
Patients with HM seem to be particularly vulnerable and deserve special attention during the COVID-19 pandemic. Several pharmacologic and nonpharmacologic changes in their management need to be considered in order to mitigate the risk and complications of COVID-19. Physicians need to carefully evaluate each patient with HM to optimize therapy and safety. Finally, further studies are needed to improve our knowledge on how to best manage these patients during such difficult times.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al
. Compassionate use of remdesivir for patients with severe Covid-19. N
Engl J Med 2020. pii: NEJMoa2007016.
Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al
. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA 2020;323:1582-9.
Hirsch HH, Martino R, Ward KN, Boeckh M, Einsele H, Ljungman P. Fourth European Conference on Infections in Leukaemia (ECIL-4): Guidelines for diagnosis and treatment of human respiratory syncytial virus, parainfluenza virus, metapneumovirus, rhinovirus, and coronavirus. Clin Infect Dis 2013;56:258-66.
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al
. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020. [doi: 10.1001/jama.2020.1585].
Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020. [doi: 10.1001/jama.2020.2648].
Liang W, Guan W, Chen R, Wang W, Li J, Xu K, et al
. Cancer patients in SARS-CoV-2 infection: A nationwide analysis in China. Lancet Oncol 2020;21:335-7.
Zhang L, Zhu F, Xie L, Wang C, Wang J, Chen R, et al
. Clinical characteristics of COVID-19-infected cancer patients: A retrospective case study in three hospitals within Wuhan, China. Ann Oncol 2020. pii: S0923-7534(20)36383-3.
Solodky ML, Galvez C, Russias B, Detourbet P, N'Guyen-Bonin V, Herr AL, et al
. Lower detection rates of SARS-COV2 antibodies in cancer patients vs. healthcare workers after symptomatic COVID-19. Ann Oncol 2020. pii: S0923-7534(20)39793-3.
Malard F, Genthon A, Brissot E, van de Wyngaert Z, Marjanovic Z, Ikhlef S, et al
. COVID-19 outcomes in patients with hematologic disease. Bone Marrow Transplant 2020. [doi: 10.1038/s41409-020-0931-4].
Jin XH, Zheng KI, Pan KH, Xie YP, Zheng MH. COVID-19 in a patient with chronic lymphocytic leukaemia. Lancet Haematol 2020;7:e351-2.
Zhang X, Song K, Tong F, Fei M, Guo H, Lu Z, et al
. First case of COVID-19 in a patient with multiple myeloma successfully treated with tocilizumab. Blood Adv 2020;4:1307-10.
NCCN Hematopoietic Growth Factors Short-Term Recommendations Specific to Issues with COVID-19 (SARS-CoV-2): National Comprehensive Cancer Network; 2020. Available from: https://www.nccn.org/covid-19/pdf/HGF_COVID-19.pdf
. [Last accessed on accessed on 2020 May 15].
Jones SE, Griffith K, Dombrowski P, Gaines JA. Immunodeficiency in patients with non-Hodgkin lymphomas. Blood 1977;49:335-44.
Moccia AA, Donaldson J, Chhanabhai M, Hoskins PJ, Klasa RJ, Savage KJ, et al
. International Prognostic Score in advanced-stage Hodgkin's lymphoma: Altered utility in the modern era. J Clin Oncol 2012;30:3383-8.
Radford J, Illidge T, Counsell N, Hancock B, Pettengell R, Johnson P, et al
. Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma. N
Engl J Med 2015;372:1598-607.
Johnson P, Federico M, Kirkwood A, Fosså A, Berkahn L, Carella A, et al
. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma. N
Engl J Med 2016;374:2419-29.
Raemaekers JM, André MP, Federico M, Girinsky T, Oumedaly R, Brusamolino E, et al
. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol 2014;32:1188-94.
O'Kelly B, McGettrick P, Angelov D, Fay MP, McGinty T, Cotter AG, et al
. Outcome of a patient with refractory Hodgkin's Lymphoma on pembrolizumab, infected with SARS-CoV-2. Br J Haematol 2020. [doi: 10.1111/bjh.16798].
Martin WG, Ristow KM, Habermann TM, Colgan JP, Witzig TE, Ansell SM. Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin's lymphoma. J Clin Oncol 2005;23:7614-20.
Poeschel V, Held G, Ziepert M, Witzens-Harig M, Holte H, Thurner L, et al
. Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): A randomised, phase 3, non-inferiority trial. Lancet 2020;394:2271-81.
Bachanova V, Bishop MR, Dahi P, Dholaria B, Grupp SA, Hayes-Lattin B, et al
. Chimeric antigen receptor T cell therapy during the COVID-19 pandemic. Biol Blood Marrow Transplant 2020. pii: S1083-8791(20)30217-2.
Ardeshna KM, Qian W, Smith P, Braganca N, Lowry L, Patrick P, et al
. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: An open-label randomised phase 3 trial. Lancet Oncol 2014;15:424-35.
Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, et al
. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: An open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 2013;381:1203-10.
Federico M, Luminari S, Dondi A, Tucci A, Vitolo U, Rigacci L, et al
. R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: Results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol 2013;31:1506-13.
Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, et al
. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): A phase 3, randomised controlled trial. Lancet 2011;377:42-51.
Kluin-Nelemans HC, Hoster E, Hermine O, Walewski J, Trneny M, Geisler CH, et al
. Treatment of older patients with mantle-cell lymphoma. N
Engl J Med 2012;367:520-31.
Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, et al
. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N
Engl J Med 2017;377:1250-60.
Jung SH, Bae SY, Ahn JS, Kang SJ, Yang DH, Kim YK, et al
. Lymphocytopenia is associated with an increased risk of severe infections in patients with multiple myeloma treated with bortezomib-based regimens. Int J Hematol 2013;97:382-7.
Al Saleh AS, Sher T, Gertz MA. Multiple myeloma in the time of COVID-19. Acta Haematol 2020;1-7. doi: 10.1159/000507690. Online ahead of print.
Malard F, Mohty M. Management of patients with multiple myeloma during the COVID-19 pandemic. Lancet Haematol 2020. pii: S2352-3026(20)30124-1.
Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, et al
. Ixazomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma: Long-term follow-up including ixazomib maintenance. Leukemia 2019;33:1736-46.
Ferrara F, Schiffer CA. Acute myeloid leukaemia in adults. Lancet 2013;381:484-95.
McCarthy MW, Walsh TJ. Prophylactic measures during induction for acute myeloid leukemia. Curr Oncol Rep 2017;19:18.
Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, et al
. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia 2020;34:966-84.
Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost 2020;18:1421-4. https://doi.org/10.1111/jth.14830
Klok FA, Kruip M, van der Meer NJ, Arbous MS, Gommers D, Kant KM, et al
. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020. pii: S0049-3848(20)30120-1.
Elliott MA, Tefferi A. Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia. Br J Haematol 2005;128:275-90.
Montalban-Bravo G, Garcia-Manero G. Myelodysplastic syndromes: 2018 update on diagnosis, risk-stratification and management. Am J Hematol 2018;93:129-47.
Paul S, Rausch CR, Jain N, Kadia T, Ravandi F, DiNardo CD, et al
. Treating Leukemia in the Time of COVID-19. Acta Haematol. 2020;1-13. doi: 10.1159/000508199. Online ahead of print.
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al
. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study. Lancet Oncol 2009;10:223-32.