I finished Cycle 4 of the fixed duration Pirtobrutinib combo trial at M.D. Anderson for Pirtobrutinib, Obinutuzumab, and Venetoclax on June 13, 2023.
clinicaltrials.gov/study/NC...
In addition to the usual blood tests - CBC, differential, metabolic, electrolyte, and immunoglobulin tests, they did a Flow Cytometry MRD4 test that I can compare to my pre-treatment Flow Cytometery MRD4:
Feb 14: Aberrant cells as percentage of total analyzed events 91%
June 13: Negative for minimal residual chronic lymphocytic leukemia/small lymphocytic leukemia, at a sensitivity of 0.01%
So, after only 4 cycles, we've achieved MRD4 status (<1 CLL cell in 10,000 WBCs) in the blood. No bone marrow biopsy was done - I have that scheduled for the end of Cycle 7. I was elated, to say the least!
A separate Flow Cytometry indicated that all of my lymphocytes in my blood are T-cells and NK cells - there were no CD19+ cells.
Selected other results:
WBC 5.9K/uL
RBC 5.53 M/uL
Hgb 14.4 gm/dL
Platelets 191 K/uL
Neutrophil Abs 3.64 K/uL
Lymphocyte Abs 1.3 K/uL
Monocyte Abs 0.95 K/uL - a little high
CD4+/CD8+ Ratio 1.76 - a little low still
They informed me that the trial protocol has been changed. For non-Richter's patients, they've extended the trial from a mininum of 7 cycles to a minimum of 9 cycles, and added more ClonoSEQ MRD testing. They have not updated the clinicaltrials.gov page above to reflect it. I asked for, and was given a revised protocol that was more detailed than the original protocol they gave me. It clarified the conditions for ending at Cycle 9, and the level of MRD needed.
"Patients will have MRD assessed in PB at the end of C4 by NGS. Patients will have MRD assessed by NGS in PB and BM at the end of C7.
(1) Patients who achieve U-MRD in BOTH PB and BM (by next generation sequencing [clonoSEQ) under a threshold of 10-5 at the end of C7 AND confirm U-MRD by NGS under 10-5 in PB at the end of C9 can stop both pirtobrutinib and venetoclax at that time (treatment will stop once the results of NGS MRD are available which can take up to 2-3 weeks from the time of sample collection). These patients will be monitored by PB MRD by NGS approximately every 3 months for the first 12 months off therapy, and then approximately every 6 months.
(2) All other patients, including those patients with inconclusive NGS MRD testing or missed sample will continue pirtobrutinib and venetoclax until the end of C13 and stop therapy end of C13 (irrespective of MRD status at end of C13). These patients will have NGS MRD assessed in PB at end of C9 and then in both PB and BM at the end of C13. These patients will be monitored by PB MRD by NGS approximately every 3 months for the first 12 months off therapy, and then approximately every 6 months."
Note that NGS here means ClonoSEQ. ClonoSEQ can indicate MRD down to 1 CLL cell in 1 million WBCs, which is called MRD6 (1 in 10 to the 6th power). Their target, however, is MRD5 (1 in 100,000 cells).
I think the researchers really value the extra MRD data, and the opportunity to track it while still treating. I think the added 2 cycles are to respond to possible questions that 7 cycles is just too short, and might not be as durable as MRD after a longer regimen.
I was surprised and very happy to hear that they did a ClonoSEQ on my PB (peripheral blood) as part of my End of Cycle 4 testing. It takes a couple of weeks for those results to come back, and the results are not posted in the M.D. Anderson patient portal. So I emailed the doctor, and received a reply:
"Residual Sequence Detected ESTIMATED MRD VALUE: Detected below LOD: Range >0 -1 residual cells/million."
I take this to mean that we may have achieved MRD6, so I emailed asking for the full report for clarification, and am still waiting. I also note that it does still say Residual Sequence Detected, which I take to mean that there are indeed CLL cells in the blood enough to sequence. When Adaptive Biotechnologies submitted their test for FDA approval, they had to pick a standard cutoff, and the cutoff has to be above the detectablility level for the genetic sequencing, since that can vary somewhat at low levels.
If anyone else has done ClonoSEQ and can comment, please do!
Meanwhile, I had a brain and neck MRI for a presumably unrelated neuropathy problem in my face and right hand, and it showed that the parotid gland lump on my face is still 2cm. That's greater than the 1.5cm size required for Complete Remission by iwCLL standards. So it seems entirely possible to achieved MRD4 or MRD6 and be in a Partial Remission. I expect it's also possible for remaining CLL cells to lurk in lymph nodes or spleen at a higher level than in blood and bone marrow. Even so, as long as the lymph and nodes are small, I care not about their size. I think MRD is a better indication of remission.
But even so, I am thrilled with the results! I will continue to fight the fatique that started at the beginning of Cycle 3 when Venetoclax hit 400mg.
=seymour=
A somewhat old (2 years) MRD Reference, but useful especially for terminology:
ncbi.nlm.nih.gov/pmc/articl...
Measurable residual disease in chronic lymphocytic leukemia: expert review and consensus recommendations
Leukemia. 2021; 35(11): 3059–3072.
OSU Trial Update Cycle 9, Day 1
