Now that generic Dasatinib is being made, you can hear the push for starting it as a first line TKI for CML instead of Imatinib. Let's take a look at some of the evidence underlying this claim. (Note: Discussion is initiated by a drug patent ending: the times we live in!)

What is your choice for first line TKI for CML?

Dasatinib as first line Tx is suggested in the DASISION study: 519 Tx naïve patients with CML randomized to Dasatinib 100 OD / Imatinib 400 OD. Primary End Point CCyR, Secondary MMR. Baseline cx matched: ~ 66-67% in both arms were int/high risk Hasford group.

Higher rates of CCyR and MMR noted with Dasatinib vs. Imatinib. Progression similar (5 vs 9 pts). Hidden quiet text away from graphs and abstract: PFS and OS with Dasatinib/Imatinib respectively were: 96%/97% and 97%/99%. Any difference there?

Adverse events: Everything appears similar: But 10% have pleural effusions with Dasatinib.
Final word:
1. Higher and Faster CCyR and MMR, better 'outcomes' for new CML.
2. Estimate that a 5-year follow-up of patients in this and other studies will answer this question.
Will it?

Five year F/U: This is most interesting. Five-year OS was 91% for Dasatinib and 90% for Imatinib. [Note 83% OS in IRIS].
Also, pleural effusion is now in 28% of Dasatinib (10% in initial study) patients. Have you seen more overlapping curves!
No change in OS. What's different?

As EMR is touted as the benefit, what is the 5 yr response based on EMR? Surprise! No change at all!! Those without EMR get a molecular response eventually. Hidden in the supplementary index are these two graphs.

SPIRIT2 study (UK) looking at the same:
1. No difference in OS or EFS but higher MMR and CCyR
2. Value of EMR: 3 month transcript level strongly predicts for CCyR and MMR. Surrogate marker alert!
https://doi.org/10.1182/blood-2018-99-110128

Back to DASISION 5 year F/U: As we are talking about deeper responses, this study looked at MR4.5 as well. No difference between the two at five years. Even more interesting is the “high risk” group, where Imatinib has similar rates of MMR and MR4.5 compared to Dasatinib.

So we have a soft indication to start 2nd line TKI upfront for CML based on high SOKAL/Hasford scores. Loophole alert! Sokal (1984) and Hasford (1985) validated for Bu/HU and Interferon respectively. See the problem applying these TKI era.
DOI: 10.3332/ecancer.2016.679

Most studies for these scores will predict for 'surrogate' markers: achieving CCyR and MMR, probably EMR.
What does a patient actually want? A paper saying 0.0001% or a similar survival at a much lower cost and toxicity?

On a pragmatic note, we in India have a different set of problems.
1. Adherence
Indian data: 443 patients, OS at ten years is only 76%, with adherence issues. In the GiPAP program in India, 29% were non adherent to Imatinib (with free medication!). https://doi.org/10.1007/s12288-018-1009-y

2. Molecular Testing: Indian scenario nicely shown in DOI: 10.4103/0971-5851.133704. Not many pts undergo PCR testing routinely, and many labs EQAS and CF for IS is doubtful. Higher stakes if you try to stop Tx when anyone reporting deeper than MR3 may not be reliable.

3. Cost & Cost: Dasatinib goes for $200/month, and generics promise at $100/month. Imatinib is $20/month. All this for just getting an EMR? Great editorial by @DrPMPGI and Dr Uday at https://doi.org/10.1007/s12288-019-01074-0. Agree that Imatinib toxicity is overhyped!

To summarize,
A. Dasatinib 6X to 10X the cost of Imatinib, similar five year survival, ~ similar rates of molecular response at 5 years, with a 28% incidence of pleural effusions (vs. 0.8%)

B. In the Indian scenario, we have different challenges than thinking about stopping Tx. OS already lesser than West. Better adherence and timely molecular testing will improve outcomes.

C. Journals make you read what they want. Imatinib's strengths: similar efficacy, lower toxicity and cost are never highlighted, but importance of EMR and risk adapted Tx for CML are highlighted. Many graphs are hidden in supplementary indices.

D. Big pharma makes you read what you want, and influence practice in unseen ways! Subliminal discussion on EMR, TFR, Sokal & Hasford Scores, all to imprint that 2nd Gen TKIs are a valid first line option for India. This will bode disaster for management of CML if catches on.

E./fin: May be better to read the whole paper than the abstract! Now, what would your preferred first line TKI for CML in India be?