Clinical Case Discussion Forum

We have to admit that more infections were reported with dasatinib 100mg QD than with imatinib 400mg QD in the DASISION trial. On a daily basis, I indeed see that during fall/winter, some but not all full-dose dasatinib treated patients have more upper respiratory tract infecttions than others, thus I routinely recommend flu vaccine for them, on a yearly basis and in some pneumococcus vaccine. However, I don't see a need for preventively and systematically switching our patients from dasatinib to imatinib because of the coronavirus epidemy, in the absence of infection. What I find reasonable is the following:

1- continue TKI treatment as it is, if no problem.
2- In case of coronavirus infection, inform hematologist immediately. For those patients in optimal molecular response on dasatinib, I recommend dasatinib interruption and reintroduction upon cure of the viral infection. For those not in optimal response or before optimal response induction (at early stages of CML therapy) in which interrupting the TKI due to COVID would jeopardize CML, I would then switch to a different TKI (choice made on patient personal background and CML characteristics).

Delphine Réa

This is a difficult dilemma because we know little about coronavirus in general. However, my impression is that the immunosuppressive effect of dasatinib is modest at most. I am not advising my patients to come off therapy or do anything special other than take the common precautions that we are all being advised to take, namely avoid contact with anyone with symptoms (whether proven coronavirus or not), good hand wash (soap better than sanitizer, but the latter good if not able to use soap and water like when traveling), etc. A dose reduction could be considered, acknowledging that we do not know what effect a modest change in dose could have on the immune competency. I hope this helps.

Regarding the same scenario in a 75 year old CML patient:
I would just be more emphatic about the other precautions, particularly some sort of social isolation.

For this young patient, as he is in MR4, I would simply be very careful during this period to avoid contacts and to reduce at maximum the risk of contamination, but I would continue the same dosage of dasatinib as at the end of the day we do not know if 70 or 50 mg have a different effect with respect to 100mg on the immune response (that is also only supposed and not demonstrated).

Regarding the same scenario in a 75 year old CML patient:
Probably my advice would be different. 50 mg just to maintain this molecular response achieved should be enough and not only for the risk of COVID-19 infection, but also for the other possible toxicities. In general, we do not use dasatinib at this age, but imatinib. However as this hypothetical patient has tolerated well dasatinib so far, I would not see the need to change the therapy, but I would reduce the dose.

I'm answering based on my experience with dasatinib, 2 cases where there was NO reason to expect a severe infection, no reason and both died of a septic shock. Due "to dasatinib"? Unclear but suspected at least. SO, I would say yes, switching to imatinib would be appropriate.

I think he will be at the same level of risk as anyone else of that age. In general with that response I might be inclined to reduce his dasatinib to 50mg

Definitely would not switch at this time. The dasatinib/infection controversy is probably related to the MD Anderson original data and DASISION which had more infections, the most identified of which were actually bacterial. Increased risk to the recent viral infection is theoretical at best. I think though, that given his degree of response, the French OPTIM data as well as the MDA data, would suggest that he does not need more than 50-70mg at this time and I think his dose could be reduced. Not sure that this reduces the risk, but definitely reduces the other risks such as pleural effusions.

My thoughts so far have been along the lines that we do not see significant incidence of opportunistic/viral/other infections with dasatinib (or any TKI for that matter) and consider a patient in remission to not be immune compromised per se. This would align imatinib and dasatinib and dissuade us from such a thought or change in therapy.

On the other hand, in trying to learn about prior pandemics and viral infections to manage the current issue of COVID, I understand that in some instances exaggerated immune/inflammatory response to such a virus can be more dangerous than older age/comorbid situations. I believe this was the case with the ‘spanish influenza’ later in the pandemic, where either a second wave/altered virus/re-exposure led to more effect on younger healthy people (essentially succumbing to severe inflammatory reaction/syndrome). I have a subtle concern that dasatinib could contribute to such a reaction- given its lymphocyte activation, NK effect, and the rare patient we see with inflammatory side effects (colitis, fevers, lymphadenopathy).

On the whole I would stay put and not change given the first thoughts; we have similar pathogens all around us, such as influenza, and we don’t see issues in CML patients differentially with different agents, etc. The second point is speculative and may not be likely for the same reason, we don’t see exaggerated response to other pathogens that I know of….

I am rather reluctant to advice CML specific measures based on CORONA, since data is rare.
A young man with perfect response to Sprycel should definitely continue full dose dasatinib until the trigger for discontinuation is reached.
There is no data the theoretical T cell inhibition will enhance the severeness of the CORONA infection.
In case of a 70 year old without a strong wish towards TFR and high risk of severe CORONA infection, I would switch do full dose imatinib.

In this young patient under dasatinib treatment and in MMR after 2 years, I would not consider dose reduction . We dont have scientific support to conclude that by reducing the dose , we will lower infections inmediately .
On the other hand, dose reduction on this patient could lead to a loss of molecular response adding another problem , not ideal at this time.
I would not recommend to reduce dasatinib dose nor TKI change.

ORIGINAL CASE:
One of my CML patients is a 30 year old health worker who was diagnosed 2 years ago in chronic phase, with a low ELTS score. 3 monthly BCR-ABL so far: 68% (diagnosis), 0.6%, 0.07%, 0.045%, 0.028%, 0.018%, 0.024%, 0.021%. Normal FBC otherwise – no cytopenia. No other medical diagnoses.

Give his workplace, he is very concerned about his risk of getting a COVID-19 infection and his risk of getting very sick with it. He has asked me if it would be worthwhile switching from Dasatinib 100mg to Imatinib 400mg in light of some suggestion that dasatinib is more immunosuppressive than imatinib. Alternatively, he asked if he should reduce his dasatinib dose to 70 or 50mg in light of the MDACC study with lower dose.

What would you advise him to do? Would your advice be different if he was 75 years old in the same clinical setting?

I wouldn't change. Although the risk of infection is increased it is uncommon to see opportunistic infection with dasatinib. If he is young and otherwise fit the excess risk is likely small. On the other hand, his CML response is good, but not outstanding, so this also argues against de-escalation of therapy. Of course, nilotinib is probably less immunosuppressive than dasatinib, but retains potency. I would feel more positive about a switch to nilotinib, but I still wouldn't recommend it.