Should therapy for hematologic malignancies be modified to mitigate poor COVID-19 outcomes?
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Yes.
COVID-19 infections in patients with hematologic malignancies tend to have a much worse prognosis, with mortality rates twice as high as those of patients without hematologic malignancies. These rates are currently up to 34% overall among adults and up to 47% among those aged older than 60 years. Underlying immunosuppression related to the malignancy itself and further potentiated by the therapy likely contributes to high mortality seen among these patients.
Maintenance therapy has become an important part of therapy for many patients with hematologic malignancies, including routine use of the following:
- rituximab maintenance for patients with B-cell non-Hodgkin lymphoma;
- lenalidomide (Revlimid, Celgene) maintenance for patients with multiple myeloma;
- multiagent maintenance therapy for patients with acute lymphoblastic leukemia; and
- maintenance therapy after induction and consolidation therapy or after stem cell transplantation for patients with AML carrying FLT3 mutations.
Maintenance therapy, especially when given parenterally, could increase the chances of exposing the patient to COVID-19 and, in addition, increase the degree of immunosuppression. Conversely, maintenance therapy is important for achieving longer remission and increasing cure rates in some hematologic malignancies. The decision to alter maintenance therapy should be made on case-by-case basis, balancing the COVID-19 risks and the risk for relapse or progression of underlying malignancy.
In the case of patients undergoing maintenance therapy for ALL and FLT3-positive AML, we do not recommend altering the maintenance therapy, as this can affect the cure rates of the malignancy and potentially long-term survival.
Among patients with B-cell malignancies, such as low-grade B-cell lymphomas, rituximab maintenance has not been associated with improved survival and the PFS benefit is modest, as well. Further, as a parenteral drug, rituximab also increases the risk for exposure to COVID-19. Among patients who have good disease control, rituximab maintenance can be safely held with careful monitoring of disease status.
In multiple myeloma, lenalidomide maintenance has been shown to improve PFS and OS. With modern therapies, a significant number of patients with multiple myeloma can achieve minimal residual disease (MRD) negativity, and those with sustained MRD negativity tend to have excellent outcomes. Patients who have achieved sustained MRD negativity and who are at high risk for COVID-19 mortality (such as older patients and those with comorbidities) may be candidates for holding lenalidomide maintenance.
References:
Passamonti F, et al. Lancet Haematol. 2020;doi:10.1016/S2352-3026(20)30251-9.
Perrot A, et al. Blood. 2018;doi:10.1182/blood-2018-06-858613.
Salles G, et al. Lancet. 2011;doi:10.1016/S0140-6736(10)62175-7.
Vijenthira A, et al. Blood. 2020;doi:10.1182/blood.2020008824.
Divaya Bhutani, MD, is associate professor of medicine at Columbia University Medical Center and physician at NewYork-Presbyterian. He can be reached at Columbia University Medical Center, 161 Fort Washington Ave. G, New York, NY 10032; email: db3203@cumc.columbia.edu.
No.
Not it many cases.
There are four factors to consider when answering this question: 1) type of hematologic malignancy; 2) type of chemotherapy employed; 3) performance status of the patient; and 4) COVID-19 severity.
Decisions on treatment, dose reductions or delays are patient- and disease-specific. Some disorders may have a poor outcome if treatment is modified, delayed or interrupted. In these cases, careful continuation of treatment is recommended when feasible if COVID-19 disease is under control or asymptomatic. On the other hand, patients experiencing severe COVID-19 infection are not candidates for active treatment.
At Montefiore-Einstein Cancer Center, treatments not considered emergent were delayed early in the pandemic given the high case fatality rate of patients with cancer observed and reported by Mehta and colleagues. However, in cases in which delaying the treatment was expected to have a poor outcome, therapy was provided judiciously. In our experience, most patients who received chemotherapy had similar outcomes compared with those who were not treated, as we reported in December during ASH Annual Meeting and Exposition.
The bibliography on hematologic malignancies treatment and COVID-19 outcomes is controversial. Shah and colleagues from King’s College in London reported worse outcomes for patients with hematologic malignancies receiving intensive chemotherapy (defined as causing severe cytopenia requiring inpatient admission). Similarly, Garcia-Suarez and colleagues observed increased mortality with monoclonal antibodies, whereas other studies (such as those by Aries and colleagues and Infante and colleagues) did not show worse outcomes among patients with several hematologic malignancies receiving active treatment.
There has been significant improvement in COVID-19 outcomes based on our increased knowledge of the disease pathophysiology, improved management and decreasing mortality observed later in the pandemic. Hence, I would not delay treatments for disease with a rapidly fatal outcome when left untreated if the patient has only minor or moderate COVID-19 symptoms. On the other hand, severely ill patients with COVID-19 should not receive treatment until disease control has been achieved. Maintenance therapy for indolent disorders can be safely held in most cases but, given that the risk for relapse is always present, therapy should be restarted as soon as it is safe to do so.
In most cases, when curative-intent therapy is deployed, treatment intensity should be maintained. COVID-19 can be life-threatening in the absence of chemotherapy. At the same time, chemotherapy can cause severe infectious complications in the absence of COVID-19. Therefore, it might be difficult to attribute worsening COVID-19 severity to chemotherapy when this disease can be independently fatal. It is worth noting that Lee and colleagues showed patients with hematologic malignancies had worse outcomes independent of treatment, with 57% higher odds of severe disease if they contracted COVID-19. Röllig and colleagues indicated that a 7- to 14-day delay in starting treatment for AML is acceptable, but this should be reevaluated on a case-by-case basis.
ASH has set forth guidelines based on expert opinion on how and when to proceed with management and treatment of the most common hematologic malignancies. Notably, in most cases experts agreed with continuing therapy in cases of acute hematologic malignancies in which delaying such treatment will lead to a worse outcome.
Importantly, transplant activity was delayed due to the pandemic and most centers require a negative COVID-19 test before admission. In a recent study from Memorial Sloan Kettering Cancer Center, Shah and colleagues showed favorable COVID-19 outcomes among patients undergoing allogeneic, autologous or cellular therapies. Most of these patients undergo intense chemotherapy regimens. Nevertheless, a recent CIBMTR report by Sharma and colleagues indicated worse outcomes for autologous and allogeneic transplant recipients.
When a patient is actively receiving chemotherapy and develops severe COVID-19 infection, it would be prudent to withhold or delay treatment. Similarly, acute progression of COVID-19 or clinical suspicion of it should lead to therapy modification.
References:
Aries JA, et al. Br J Haematol. 2020;doi:10.1111/bjh.16852.
ASH. COVID-19 resources. Available at: www.hematology.org/covid-19#faq. Accessed Jan. 27, 2021.
D’Aiello A, et al. Abstract 3484. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
Infante M-S, et al. Int J Lab Hematol. 2020;doi:10.1111/ijlh.13301.
Garcia-Suarez J, et al. J Hematol Oncol. 2020;doi:10.1186/s13045-020-00970-7.
Isidori A, et al. Front Oncol. 2020;doi:10.3389/fonc.2020.01439.
Lee LYW, et al. Lancet Oncol. 2020;doi:10.1016/S1470-2045(20)30442-3.
Mehta V, et al. Cancer Discov. 2020;doi:10.1158/2159-8290.CD-20-0516.
Röllig C, et al. Blood. 2020;doi:10.1182/blood.2019004583.
Shah GL et al. J Clin Invest. 2020;doi:10.1172/JCI141777.
Shah V, et al. Br J Haematol. 2020;doi:10.1111/bjh.16935.
Sharma A, et al. Lancet Haematol. 2021;doi:10.1016/S2352-3026(20)30429-4.
Vijenthira A, et al. Blood. 2020;doi:10.1182/blood.2020008824.
Roberto Alejandro Sica, MD, is an attending physician at Montefiore Hospital and assistant professor of medicine at Albert Einstein College of Medicine. He can be reached at Montefiore Medical Center, 111 E. 210th St., Bronx, NY 10467; email: asica@montefiore.org.
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