By AMY ELIZABETH DEZERN, MD, MHS
Director, Bone Marrow Failure and MDS Program
Associate Professor of Oncology Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Baltimore, Maryland
This article was first published on the MDS Foundation Fall/Winter 2021 Newsletter. Many thanks to our colleagues from the MDS Foundation.

Important: The article below is destined to an American audience, and it lists some drugs and trials only available in the USA. 

Few people would dispute that 2020 into 2021 has been an unprecedented time throughout the world. Much of this is attributable to Coronavirus disease 2019 (COVID-19). Briefly, COVID-19 is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2). The first known case was identified in Wuhan, China, in December 2019. The disease has since spread worldwide, leading to an ongoing pandemic. The disruptions have ranged from modest to supreme and have affected all differently. However, patients suffering with myelodysplastic syndromes (MDS) have had unique and specific challenges.

Older and immunocompromised populations appear to be at a higher risk for severe, potentially life-threatening illness related to COVID-19 compared with the general population, with reported case fatality rates as high as 15% in patients aged 80 years or older in early series from China.¹

The initial study of COVID-19 and Cancer Consortium (CCC19) data found that 30-day all-cause mortality was 13% among patients with active or prior cancer and confirmed SARS-CoV-2 infection.² This presents a particular concern for patients with MDS. More specific to MDS, a systematic review and meta-analysis quantified the outcomes (deaths, hospitalizations, and complications) of patients with hematologic malignancy and COVID-19.³ This included MDS as an acquired bone marrow failure syndrome. This analysis of 14 studies and a total of 231 patients included showed a pooled risk of death of 53% (95% CI, 34-72; I2, 77%) for patients with MDS, the highest of all hematologic malignancy subtypes. These sobering data nearly a year into the pandemic required us to “double-down” on our efforts to protect our patients.

Issues specific to MDS patients

As we know, patients diagnosed with MDS may have various disease manifestations depending on their disease phenotype. Management can range from close observation of mild cytopenias to supportive treatments with transfusions all the way through active chemotherapy and even early allogeneic hematopoietic stem transplantation (BMT).

Nonetheless, as the world was shutting down, all of these were impacted, disrupting the therapeutic pathway for patients with MDS. This interference with standard clinical care was compounded by the added fear that immunosuppressed MDS patients were at increased risk of morbidity and mortality from COVID-19. This led to many discussions (often via telemedicine) between patients, families, and providers. In the early days of the pandemic, there were few hard data to guide treatment or protective recommendations, and guidance was limited to expert opinion.^4,5

For patients whose disease required close observation and monitoring, care interruptions may have manifested as limited access to laboratory appointments for blood work assessment. Patients who required transfusional support, especially those who lived in areas with few transfusion facilities, were markedly impacted by the nationwide shortage of blood supply. And patients undergoing chemotherapy were faced with decreased clinic/infusion center operating hours and inaccessible providers.

Moreover, for patients in need of chemotherapy there was the ongoing concern that the ensuing immunosuppression after chemotherapy could further predispose them to COVID-19 infection and severe disease. In many cases, this may have altered the balance between risk and benefit of chemotherapy. Finally, there were simply the fear of unknown. How long could patients go without treatment? What risk does an active cancer, whether low- or high-grade, impart to an individual human being? And from a human perspective, how could patients weigh the risks of seeing family or friends, knowing both that social gatherings would increase the risk of infection and that their remaining time together may be shortened due to their diagnosis of MDS.

General recommendations ⁵

Expert consensus panels rapidly assembled to pool knowledge and provide guidance to patients and clinicians.⁶

These panels emphasized that, as always, treatment decisions should be based on category in the revised international prognostic scoring system.

Close observation without definitive treatment remained a reasonable strategy in patients with only modest cytopenias.⁷

For higher risk disease, newly diagnosed patients requiring treatment with a hypomethylating agent should commence therapy (and patients already on a hypomethylating agent should continue therapy).

It was thought reasonable to maintain normal treatment intervals until evidence of response is seen, but in order to balance risk of exposure with risk of disease progression, once a response is evident, lengthening the duration between treatment cycles and reducing dosing within each cycle is reasonable.

Subcutaneous azacitidine is preferred over intravenous azacitidine to decrease the time spent at infusion centers and in contact with potential COVID-19 exposures.

For lower risk MDS, consensus agreement favored a longer watch-and-wait approach for most patients. Erythropoiesis- stimulating agents (for patients naive to these agents) and early luspatercept initiated may avoid or delay the need for red blood cell transfusions.

Most experts agreed with deferral of lenalidomide in newly diagnosed patients with del(5q) disease given the risk for myelosuppression.

Over the course of the pandemic, this guidance has migrated back to baseline practice patterns of more aggressive treatment. This is primarily due to increasing comfort and confidence in infection prevention practices.

Unfortunately, clinical trials, a long-time priority in MDS, were dramatically and negatively affected by the COVID-19 pandemic. Many studies were paused, and study participation was nearly non-existent.⁸ For studies that continued, rates of study deviations increased, and the shortage of laboratory supplies was a significant barrier to continued sample collection.

Blood is an (even more) limited resource

MDS patients have always been counseled that blood is not an unlimited resource, but relatively few have truly not had potential access to transfusional support. However, during the first summer of the pandemic, the US national and even world- wide blood supply reached an all-time low.^9,10

This posed an even greater challenge for patients in whom supportive care with red cells or platelets represented a way of life. Certainly, anemia from MDS causes decreased quality of life, but there are relatively sparse data regarding the minimum hemoglobin values for which a MDS patient may safely forgo transfusions with no evidence of end-organ damage. The work of Dr. Abel and colleagues provided some guidance on this topic during COVID.

The authors applied a modified Delphi method with 13 expert MDS clinicians to discussions of minimum safe hemoglobin for this population. There was a 100% consensus that it be no greater than 7.5 g/dL.¹¹

This was a comfort to patient and physicians alike as we were able to pull back on individual transfusions to lower levels as well as single unit (as opposed to two) transfusion episodes to ration the blood supply where feasible.

Drugs approved during the pandemic

Ironically, given that it had been over 15 years since the last regulatory approval for a drug for patients with myelodysplastic syndromes, two drugs were approved during the pandemic timeframe. Both actually have particular relevance in the setting of goals to decrease healthcare interactions and space out clinic visits.

On April 3, 2020, the Food and Drug Administration approved luspatercept- aamt (REBLOZYL, Celgene Corporation) for the treatment of anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell (RBC) units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T). It is a first- in-class erythroid maturation agent that binds to the select transforming growth factor-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis.

In the MEDALIST trial ¹² randomized, multi-center, double-blind, placebo-controlled trial in 229 patients with IPSS-R very low, low, or intermediate-risk myelodysplastic syndromes who had ring sideroblasts and required RBC transfusions (2 or more RBC units over 8 weeks), patients were randomized 2:1 to luspatercept or placebo. All patients received best supportive care, which included RBC transfusions. The main efficacy endpoint in MDS-RS and MDS- RS-T was the proportion of patients who were RBC-transfusion independent (RBC-TI), defined as the absence of any RBC transfusion during any consecutive 8-week period between Weeks 1 and 24. Of the 153 patients who received luspatercept, 58 (37.9%, 95% CI: 30.2, 46.1) were RBC-TI for at least 8 weeks, compared to 10 patients (13.2%, 95% CI: 6.5, 22.9) who received placebo (treatment difference 24.6% (95% CI: 14.5, 34.6; p<0.0001.) The most common (>10%) adverse reactions to luspatercept are fatigue, headache, musculoskeletal pain, arthralgia, dizziness/ vertigo, nausea, diarrhea, cough, abdominal pain, dyspnea, and hypersensitivity. The recommended starting dose of luspatercept is 1 mg/kg once every 3 weeks by subcutaneous injection. This was adopted efficiently in eligible patients in hopes of augmenting hemoglobin enough to avoid transfusion during the pandemic and beyond.

Also approved during the pandemic (July 7, 2020) was Inqovi (decitabine and cedazuridine) for treatment of adult patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). The approval was based on two open-label, randomized, crossover clinical trials that showed similar drug concentrations between IV decitabine and oral decitabine/cedazuridine. Additionally, about half of the patients who were formerly dependent on transfusions no longer required transfusions during an eight- week period. Both trials provided comparisons of exposure and safety in the first two cycles between oral decitabine-cedazuridine and IV decitabine and a description of disease response to the new medication. Comparison of disease response between decitabine- cedazuridine and IV decitabine was not possible because all patients received decitabine-cedazuridine starting in cycle 3. The overall safety profile of oral decitabine- cedazuridine was similar to IV decitabine.

Data on active covid infections in MDS patients

For ASH 2020, Feld and colleagues ¹³ prospectively reviewed the records of all patients seen in the MDS clinic in New York City in the spring of 2020 to report on the effects of COVID specifically on MDS patients. Overall, 27.1% of the patient population was diagnosed with COVID-19 and 39.1% of these patients died, or 10.6% of the overall cohort. The mortality rate reported here is higher than anticipated, but at the time of the abstract, the majority of patients recovered and have resumed MDS directed therapy.

This has been my personal experience as well. Further results hinted at another problem others were seeing as well: persistently positive PCR tests up to 6 weeks post infection and COVID-19 antibodies were found in 85.7% of COVID-19 PCR+ patients tested. This suggested that MDS patients may have delayed viral clearance, but can mount a humoral response. ¹⁴ We encouraged our patients to limit exposures but get tested where feasible. There have been persistently positive patients by PCR who required longer term isolation. We look forward to MDS specific data on convalescent plasma to inpatients, and monoclonal antibody therapy for outpatients as we have gained knowledge and use.

Vaccination

Based on randomized phase III clinical trials, several COVID-19 vaccines became available throughout the world in late 2020, early 2021, with the BNT162b2 (Pfizer/ BioNTech), ChAdOx1 nCoV-19 (Oxford/ AstraZeneca), mRNA-1273 (Moderna) vaccines and the Johnson & Johnson single- dose COVID-19 vaccine approved. ^14-16

Ten patients with MDS were evaluated in a larger cohort for data on immunogenicity of SARS-CoV-2 vaccine in patients with hematologic malignancies.¹⁷ Through robust evaluation of immune response after 2 BNT162b2 inocula including functional seroneutralization assay and assessment of T- cell response, the authors concluded a second BNT162b2 inoculum translates into a significant increase in humoral response, allowing almost half of the patients to achieve immune protection against COVID-19. Given the increase in seroconversion rate between the first and second vaccine injections, the authors noted that evaluation of the effectiveness of such a third inoculum will be imperative.

As such, in the late summer 2021, the U.S. Food and Drug Administration (FDA) has recently authorized a booster shot of either the Moderna or Pfizer COVID-19 vaccine for certain immunocompromised people. Studies show that some people with weakened immune systems — those who have received solid organ transplants and people with conditions considered to have an equivalent level of immunocompromise — are less likely to create an antibody response from two doses of the Pfizer or Moderna COVID-19 vaccine, and these people could benefit from a third dose.

Changes here to stay and future directions

MDS patients are special. No reader (provider or patient or family and beyond) of this editorial will disagree. We learned from our colleagues and listened to our patients as we tried to protect them and still carry on with appropriate treatment. One innovation quite helpful was the development of dedicated “biomode” treatment and infusion spaces (negative pressure) to allow for a person under investigation or diagnosed with COVID to receive treatments and transfusions in an ongoing fashion. Centers also pioneered the concept of drive-up phlebotomy and shot clinics to allow patients to avoid even exiting their car to obtain routine labs and quick injections.

Perhaps the largest paradigm shift, however, was the rapid expansion of telemedicine. Not only does this allow infirm or driverless patients to see their provider, but also allowed a larger number of patients to consult both with their local hematologist as well as MDS experts. For their part, providers enjoyed seeing patients in their homes and perhaps with several generations of family members. Concerns about access to care and drug availability were mitigated through increased prescription allowances: for example, Celgene REMs allowed a 56-day supply during the pandemic. Many of these initiatives were mandated by the COVID times but are likely a permanent part of MDS care in many areas.

The NHLBI MDS Natural History Study (NCT02775383) is an ongoing prospective cohort study conducted across 144 sites in the U.S. and Israel intended to establish a data and biospecimen repository to advance the understanding of MDS. In response to the COVID-19 pandemic, the study also collected data on COVID-19 infection and management. We will look forward to summary of COVID-19 outcomes from participants in this study and the impact of the pandemic in this population of MDS patients.

Clinical trial opening and accrual are also recovering as the pandemic enters a new stage. Uniquely, in 2021, there are more phase III studies in higher risk MDS than ever before. This has produced an interesting dynamic in which agents (and their developers) are competing both for accrual and to become the new standard of care. The trials all share a similar design in their phase III registration studies with the novel product in combination compared to single-agent azacitidine. Each trial has reasonable earlier phase data, usually in both AML and/or higher risk MDS, upon which they have based their current clinical investigations.

A trial of magrolimab (NCT04313881) will examine first-in-class macrophage immune checkpoint inhibitors that targets CD47, a key molecule mediating cancer cell evasion of phagocytosis by the innate immune system. Venetoclax (NCT04401748) will be studied in higher risk MDS at a truncated dosing schema (14 days) relative to its AML trials. Dual targeting of immune effectors and leukemic cells by sabatolimab (NCT04266301) is also a trial enrolling the same higher risk patients. SY-1425, a selective RARα agonist called Tamibaterone (NCT04797780), is a biomarker driven study for those MDS patients who overexpress RARα. Having this plethora of options brings back hope to MDS patients for the future after the pandemic.

References

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