Why is it critical to achieve a deep molecular response ?

[Manouche]

 »Reaching a Deep Molecular Remission is now considered a goal of therapy by many clinicians. The importance of a DMR for patients aiming to achieve Treatment Free Remission is recognized by the inclusion of DMR as an endpoint measure in clinical trials. Additionally, TFR is increasingly acknowledged as an avenue to save money in over-stretched healthcare budgets. However, not all patients and clinicians consider TFR as the goal of therapy. Prolonged survival with minimal side-effects are equally important goals and the patient’s choice is central for treatment decisions.The take-home messages from this review are: (i) it can take many years to reach a DMR for some patients…  »

ncbi.nlm.nih.gov/pmc/articl...

[EPguy]

This is for CML and they have had MR as an endpoint for a while:

"The 2013 ELN recommendations for the management of CML were the first time that molecular response was incorporated into therapeutic decisions by an expert group"

MR is now the main criteria for CML it seems.

They use TKI therapy which makes MR possible. We're now discussing MR only recently because IFN has made it possible in MPNs. But we would be lucky to have something that works as well as their TKIs.

Interesting note, CML is BCR-ABL1 positive condition and they measure this gene specifically for MR. I think BCR-ABL1 is easier to target.

MPN is BCR-ABL1-negative so our MR targets and measures other more difficult things.

This plot from that study shows amazing results for deep MR4 (less than 0.01% allele) This explains why Deep MR is an endpoint for them, and less so for us. We're not there at all yet, so the deep MR discussion for most of us is more aspirational. Likely we're in need of immune therapies to see this, nothing in the current MPN pipeline gives this result.

I think CML is the one my 1st Hem said I should have caught instead of MPN since there is a near cure but I chose the wrong cancer.

I've not gone thru it in detail, but a summary.

MR for CML

[Manouche in reply to EPguy]

Hi EPguy,

« I think CML is the one my 1st Hem said I should have caught instead of MPN since there is a near cure but I chose the wrong cancer »

As you know, a normal life expectancy is possible with PV. Unlike PV and « Despite the excellent results achieved with TKI therapy, the survival of patients with CML in the United States remains lower than in the general population ». So, I’m not 100% sure you’ve picked up the wrong cancer.

ascopubs.org/doi/full/10.12...

[EPguy in reply to Manouche]

Good point, CML and PV both with treatment may have similar outcomes. I wonder on QoL with CML. PV can be lacking there.

[Manouche in reply to EPguy]

 »While patients with CML are fortunate to have excellent therapies available to control their disease, many are unable to lead normal lives »

ncbi.nlm.nih.gov/pmc/articl...

[EPguy in reply to Manouche]

This is a neat discussion of a wider view of blood disorders. In the reference here, "Interestingly, most adverse reactions occurred in the first 1–3 years of imatinib treatment, and no new late toxicities were observed.5" In the further ref: "Most patients had their first ADR early with decreasing frequency later on."

Could be patients need patience to get to that long term stability. But it is a long time to suffer before feeling ok. We have some of the same with IFN, but it does not consistently improve for all.

They also found adding IFNa made more ADRs for CML.

[hunter5582 in reply to EPguy]

As an interesting note, the MPN Specialist compared JAK2 molecular response for PV treatment to CML molecular response. While the benefit of a molecular response for PV treatment remains to be seen, her thinkin g is that it may well prove the same as CML. She and I both agree with Dr. Kiladjian's commentary.

"Please experts, help me... are there hematological malignancies where reducing the driver mutation is not clinically beneficial? I'm confused, this is disputed for PV and JAK2 mutation, so finding another example could be helpful... I can also take examples in solid tumors..."

My own thought is that a positive molecular response is way better than getting a stick in the eye. It really cannot help but to be a good thing. We just cannot prove how good yet.

[EPguy in reply to hunter5582]

He must be referring to CML where MR is top billing. If/when we can get near all with CMR I'm sure it will also be the primary goal for all in MPNs. For now CMR is still rare for us, esp at the 0.01 level and less they see in CML so having that as a primary goal would likely disappoint many of us.

But I totally agree as I say, I'd like to try for any MR and find it didn't matter than not try and find it did.