ImetelChat

This is an interesting post from Hoosier (SA) regarding the latest MDS poster that was presented at ASH. He highlights the PR's and CR's, which we have wondered about.

Hoosier, SA 12 December 2017

My (+) observations & interpretations of the MDS poster........

1) No patient deaths attributable to Imetelstat.
* No mention of patient deaths at all.

2) Imetelstat produced a CR + m-CR rate of 13%.
* I didn't expect any PRs or CRs.
* One of the CRs and both m-CRs are within the subgroup of 13 patients.
* That means one CR is a patient previously treated by Lenalidomide and/or HMA.
* CRs require bone marrow improvements per 2006 IWG criteria (see below).

2006 IWG MDS Criteria for CRs:
The criteria for complete remission (CR) and partial remission (PR) involve specific improvements in marrow and peripheral blood measurements obtained on 2 or more successive assessments. The response parameters in peripheral blood must be maintained for at least 8 weeks. Responses designated as CR include less than 5% marrow blasts without evidence of dysplasia and normalization of peripheral blood counts, including a hemoglobin level of 110 g/L (11 g/dL) or more (in patients not receiving erythropoietin or transfusions), a neutrophil count of 1.5 109/L or more, and a platelet count of 100 109/L or more.

3) Two of the TI responses are in excess of 60 weeks duration and ONGOING. These are likely associated with the CR responses, and may be indicative of a 'curative' level of response by way of a cytogenic/molecular responses with reversal of bone marrow fibrosis.

4) In Fig.2, it appears one patient experienced a transfusion reduction (improvement) of 12 units from baseline within an 8 week period. This almost has to be the patient with a baseline transfusion burden of 14 units within the 8 weeks prior to enrollment. What a response, and what a story it will make if this person went on to become one of the CRs.

5) As Curion reported, we went from an 8-week TI rate of 34% to 38% by way of the updated data set.

6) A 71% mean relative reduction from baseline transfusion burden in the subgroup of 13 patients.

Another comment from Hoosier regarding the MDS poster:

Hooiser, SA 15 December 2017

Anybody notice the successful deployment of the 4.7mg/kg maintenance dose in the MDS study? Take a closer look at Fig. 3 of the ASH poster. The patient achieved TI at the 7.5mg dose, maintained their TI for nearly a year at a 6.0mg/kg dose, and have continued to maintain their TI status for ~3 months at a 4.7mg/kg maintenance dose.
http://bit.ly/2jQ7rL6

This type of dosing reductions also tells us Janssen is more interested in obtaining valuable data at this point than trying to boost/pad the trial results. They wouldn't be implementing such dose reductions (following TI achievement) if they were simply trying to maximize TI responses and/or response durations (my opinion).

Fish, for completeness, you might want to append CKTK's response to Hoosier. Each one of the two are easily the most respected contributors to the SA Geron board. CKTK makes the point that the dose reduction was required to manage the cytopenias induced at the higher dose. Hoosier graciously acknowledged the correction. bp

tx, bio. I will look it up and bring it over.

Here is CKTC's response to Hoosier's 2nd comment.

by Curiosity Killed The Cat, SA 15 December 2018:
The 4.7mg/kg is not a maintenance dose. That’s a dose reduction due to Grade 3 thrombocytopenia the patient developed around week 69. The patient also developed Grade 3 thrombocytopenia around week 8, and in response was given a cycle delay until around week 12. The 6.0mg/kg dose reduction was due to Grade 3 neutropenia the patient experienced around week 24. The patient was kept on the 6.0mg/kg dose for a year due to consistent grade 2 neutropenia and thrombocytopenia.

Apparently, 50% of the patients were subject to dose reductions and 59% experienced cycle delays due to adverse events. This is common with imetelstat, and the deftness with which this patient’s dosing was managed is a testament to the better understanding doctors now have after years of administration in the clinical setting. This is why they run these trials.