10 gallon hat tip to Rori YMB, more good stuff

[biopearl123]

Hello all,

The indications or needs for blood transfusion differ greatly between patients based on age, sex, subjective feeling of fatigue and weakness, cardiac history, and several other co-morbidities . while some patients may do okay and do not need or want to be transfused until their Hb drops below 7, others may become very symptomatic, develop angina or severe shortness of breath once their hemoglobin approach 9.

The IMerge study design did not set a Hb cutoff for transfusion, it left it to physicians discretion to order transfusions as indicated.

While setting a hemoglobin value for transfusion would have made the data interpretation “cleaner” and the statisticians happy, it could have lead to serious “drop out” from the trial. Some patients become very accustomed to transfusions and don’t take a no for an answer when it is time to get “their” transfusion. Some patients plan their trips and families events around the time of their transfusion as they usually feel better and get a boost of energy for few days, it would be hard to keep them in the study if they were told they are “not anemic enough” to get transfused.

Having said that, while the data for transfusion independency in the published Ph2 study is very impressive, we need to understand that it is subjective and not completely objective based on a clear cutoff value as a triggering reason for transfusion.

Thus, In my opinion, the 3gm rise in hemoglobin and the positive changes in the bone marrow are more important indicators of the Imetelstat positive activities in MDS. These findings, if were to be replicated and verified at a larger scale in the current Ph3 study, would prove IMetelstat clinical and meaningful effectiveness.

Best,

Rori,

[CKTC]

The target goal of imetelstat in MDS is improving a patient’s quality of life by reducing the need for, and hopefully, eliminating transfusions for as long as possible. Many subjective and objective factors go into a doctor’s decision to transfuse. Considering those many competing factors, statistically analyzing imetelstat’s ability to reduce transfusions with no pre-qualifiers on the transfusion decision is the most robust way of testing the drug’s effectiveness. Adding a hemoglobin trigger value to the trial would make the transfusion data less convincing because transfusion decisions are not made solely on hemoglobin levels in real life.

An important point to consider is this: If the primary transfusion endpoint is not hit, any improvements in hemoglobin and bone marrow will be a footnote in a failed trial.

[biopearl123]

On the other hand if a study physician is faced with a patient who might be “ready” for a transfusion at 7.9 weeks or could stretch a day or two to 8 weeks (and this physician knew they need this drug in their armamentarium) and no danger would be assumed by the patient to wait a day or two, what might happen? If that patient were a control patient it might slightly skew the data in one direction (unlikely since spontaneous 8 week tx in this group should be low) or if its an Imet patient it might slightly skew in another more positive direction, hence the need for other objective supporting data such as Hgb rise. To have a 3 gm Hgb rise is a real effect and not likely to occur spontaneously without a little help. I agree that failing to reach the primary end point would doom the study and make waiting for MF data in 2024 a pink sheet event. Let us hope this does not occur and the PII data showing improvement in other markers as well as transfusion requirement will correctly predict confirmatory PIII data, independent of any potential subjective clinical judgements even if present is some small way.