ASH guidance on Covid-19 and CLL

BY AMERICAN SOCIETY OF HEMATOLOGY (ASH) with input from DRS MAZYAR SHADMAN, JOHN BYRD, MICHAEL HALLEK, JENNIFER BROWN, PETER HILLMEN, ANTHONY MATO and PAOLO GHIA

ASH experts answer frequently asked questions about Covid-19 and chronic lymphocytic leukaemia (CLL) (Version 4.0; last updated November 17, 2020)

Are all or a specific group of patients with CLL at a higher risk of severe Covid-19 than other patients with haematologic malignancies or solid tumours?

In general, patients with CLL are considered high-risk for infections, mainly bacterial and herpes virus family (HSV, VZV, CMV, EBV) due to underlying immunodeficiency and inadequate immune response to infections. At this time, there is no evidence indicating a disproportionately higher incidence of severe Covid-19 in patients with CLL compared to patients with other malignancies.

However, two large multicentre studies have shown a high mortality rate in patients with CLL and severe Covid-19 in the range of ~30 per cent. This high-mortality rate was reported in patients with severe Covid-19 in both “watch and wait” and treated groups. There is also an indication that severity of Covid-19 in patients with CLL increases with age, as in the general population.

Are you changing your approach to initiating therapy for CLL during the pandemic?

In areas where Covid-19 is active, it is our recommendation to postpone treatment initiation if possible. For patients who require immediate therapy, we still offer the best treatment option considering disease and patient-specific factors.

When there is more than one option, preference should be given to treatments that can be provided in the outpatient setting and require fewer clinic visits and lab assessments. We try to avoid or skip treatment with monoclonal antibodies (rituximab, obinutuzumab) especially when given in combination with targeted agents.

Initiation of venetoclax requires multiple and extended clinic visits with lab testing and should be avoided if possible unless considered the most appropriate treatment for a particular patient.

When the Covid-19 pandemic is under control per local authorities, we follow standard treatment guidelines for CLL treatment and would not use Covid-19 as a factor in decision making.

Are you changing anything for patients without Covid-19 who are already on therapy for CLL?

In areas with a high prevalence of Covid-19, we try to minimise the number of visits for those who are stable and doing well. When follow-up is necessary, utilising laboratories closer to home and using telemedicine is recommended.

Most continue ongoing CLL-directed therapies in unaffected patients with exceptions being monoclonal anti-CD20 antibodies.

Should patients with CLL continue to get immunoglobulin replacement?

In patients without Covid-19, we only continue IVIG treatments for highly selected patients with a history of hypogammaglobulinaemia and active or recurrent severe infections where the potential benefits are outweighed by the risks of coming to clinic for the infusion.

As an alternative, we consider home subcutaneous infusion of IVIG when possible. Even in these cases, less frequent infusions should be considered when possible (eg, every six-to-eightweeks) targeting an IgG level of 400-500mg/dl.

In CLL patients with Covid-19, IVIG can be continued. Given the higher risk of thromboembolic (TE) events with Covid-19, we recommend assessment of risks vs benefits in each patient and close monitoring for TE symptoms.

For patients with CLL who report mild symptoms (no high fever and no respiratory symptoms), what is your testing strategy for SARS-CoV-2? Would your approach be different for patients who call and report symptoms vs those who have symptoms while in the clinic?

With better access to the PCR test, we recommend testing any symptomatic patient for SARS-CoV-2 even if symptoms are mild. We also test patients before admission to hospitals. Another reason for this approach is the risk of other pathogens and the desire to isolate anyone with a communicable respiratory virus.

During influenza season, any patient tested for influenza should have concomitant testing for SARS-CoV-2 as symptoms may overlap.

In a patient on treatment for CLL who tested positive for SARS-CoV-2, do you change/modify therapy? Will your approach be different based on the type of therapy (BTKi, PI3Ki, venetoclax, antibodies, chemoimmunotherapy, etc) or the severity of their viral infection?

For outpatients with mild symptoms, we don’t modify therapy. A decision regarding treatment modification in patients with more severe symptoms depends on weighing the aggressiveness of CLL and a history of frequent infections versus the theoretical risk of more severe Covid complications.

Currently, there is not enough evidence to suggest that the approach should be different for specific classes of targeted CLL drugs and decisions regarding holding or continuing treatments are made on a case-by-case basis.

There is general agreement on holding monoclonal antibodies for Covid+ patients. If the patient is on a BCR signalling inhibitor (ibrutinib, acalabrutinib, idelalisib, duvelisib), particularly if recently started or still with substantial disease burden, discontinuation can sometimes result in CLL flare and cytokine release that can mimic some of the symptoms of Covid-19. Generally, resumption of the BCR signalling inhibitor results in resolution of these symptoms in a relatively short period of time.

Recently published reports suggest a possible benefit from the BTKis (ibrutinib and acalabrutinib) in the setting of severe Covid-19 infection. While controlled studies are needed to confirm those results, it is our practice to continue BTKis in patients with CLL diagnosed with Covid-19. It is also our practice to hold venetoclax in patients diagnosed with Covid-19.

It should be noted that in SARS-CoV-2 positive patients, clinical pulmonary and radiographic findings may overlap with drug induced pneumonitis (PI3Ki) or associated opportunistic infections (PJP, CMV pneumonia).

If an RNA-based vaccine is approved, should I give it to my patient with CLL?

While the safety of a vaccine for each patient should be assessed on a case-by-case basis depending on its reported side effects and patient’s comorbidities, we would in general recommend it for patients with a CLL/SLL diagnosis.