To understand the entirety of Faron’s results, one must first understand the individual pieces. A significant number of patients with r/r MDS (relapsed/refractory MDS) achieved mCR (marrow Complete Response), meaning cancer cells in the bone marrow were suppressed to 5% or less, but not all blood cell counts rose above the criteria, in 50% of patients. Faron, however, reported that in 60% of mCR patients, some blood cell group improved. This mere mCR response has been criticized, arguing that giving strong cytostatics achieves the same phenomenon: cancer cells disappear, but so do healthy blood cells. An MDS patient dies due to the treatment, but at least there was “mCR” for a short time.
With Bex, such destruction of healthy blood cells has not been observed as a side effect. In the response criteria updated last year, such an mCR has been removed. Zeidan, who was involved in creating those guidelines with his expert panel, did not know, nor did anyone else, that there would be a drug that could eliminate blasts without destroying blood cells. Other tested drugs, such as magrolimab, also affect healthy blood cells; it is out of the game. Venetoclax is also toxic to healthy cells; it is also out of the game in r/r, and as the withholding of results in the first line has been wondered about, Juho reported on the change of primary endpoints in the Verona trial mid-way, where CR is no longer the main focus of measurement because not enough of them were observed. Hope has been placed on OS (Overall Survival) prolongation, and that takes time in the first line. It could happen that even in the first line, the path is clearer for competitors.
Does a bone marrow with reduced blasts, i.e., mCR, achieve anything if the disease-ravaged and azacitidine-inhibited bone marrow cannot properly form blood cells? At least it can increase the success of bone marrow transplantation, which is the only curative treatment. Success depends on many factors, including whether such treatment is even available, but if the number of blasts is examined in relation to transplant success, then:
On the connection between the success of stem cell or bone marrow transplants and mCR:
When the latest IWG2023 MDS criteria https://ashpublications.org/blood/article/141/17/2047/494297/Consensus-proposal-for-revised-International were being developed, the remarks subtly address the connection between mCR and stem cell transplantation:
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A few panelists felt that mCR could still have a value, especially in bridging patients to allo-HSCT, and should therefore, still be reported
First-line patients were studied regarding stem cell transplantation Feasibility of hypomethylating agents followed by allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome - PubMed
”In all, 2-year OS rates were 68%, and the overall outcomes of those who achieved CR/mCR with HMT tended to be superior to those without CR/mCR”
National Comprehensive Cancer Network Guidelines are evidence-based clinical practice guidelines:
https://jnccn.org/view/journals/jnccn/20/2/article-p106.xml
The guideline states that reducing blasts to 5% or less before stem cell transplantation (thus CR and mCR) is particularly important for those receiving only light treatment before transplantation, such as elderly and frail patients receiving BEXMAB. It prevents disease relapse. However, transplantation should still be attempted with a higher blast count (PR).
Furthermore, it must be remembered that we are now talking about the r/r population, not first-line patients, so perhaps the exact same cannot be demanded, but it will be interesting to see how these criteria evolve in the future and whether BEXMAB will bring research evidence that changes the criteria. If Bex truly enabled bone marrow transplants, it would be ethically questionable to say, “hey, OS (Overall Survival) was competed unfairly!” Of course, OS would also directly depend on the transplant capacity of the treatment center, and this should be taken into account in comparative analyses. According to current information, a total of 35 r/r patients are being recruited, and if half of them manage to achieve mCR, that already provides evidence of its significance.