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ASCO 2019: Pick #1 RESONATE: 6 year follow-up in previously treated CLL (chronic lymphocytic leukemia) on ibrutinib

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Dr. Brian Koffman, the Executive Vice President (EVP) and Chief Medical Officer (CMO) of the CLL Society, counts down his top ten CLL related abstract from ASCO or the American Society of Clinical Oncology Annual Meeting held May 31 – June 4, 2019, Chicago, IL.

#1

Final analysis from RESONATE: Six-year follow-up in patients (pts) with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) on ibrutinib.

While this trial abstract didn’t bring any startling new results, which is a good thing, it the closing of an era, an era that saw the cracking of the biology of CLL, an era that began the irreversible shift away from chemo-immunotherapy towards novel targeted agents to treat chronic lymphocytic leukemia and that cemented the approval of the drug that changed everything. The study has finally closed, no more free drug for the brave volunteers, and one last look at the data at ASCO 2019.

Now we have second generation drugs and potent new molecules and powerful combinations, but it all started with this trial and the patients who volunteered to help get ibrutinib (ibr) to market.

This is the 6 year follow-up on the phase 3 RESONATE trial of 391 relapsed or refractory mostly high risk CLL patients with del(17p), del(11q), TP53 mutation, and/or unmutated IGVH that compared ibrutinib to ofatumumab (ofa).

Takeaways:

  • Median follow-up was 64 months.
  • A full 68% of the patients randomized to ofa eventually crossed over to ibrutinib when they progressed
    • Tragically, this was not allowed at first and only came after immense pressure from the patient and doctor community. Listen to Dr. O’Brien click on the link to her famous 2013 totally justified rant on equipoise in clinical trials.
  • Significant sustained Progression Free Survival or PFS benefit was observed with ibr vs ofa of 44.1 vs 8.1 months. That is a huge difference.
  • Almost 9 out of 10 of these difficult to treat CLL patients responded to Ibrutinib.
  • Overall survival of OS was better for those who got Ibrutinib first versus rather than getting it when allowed to “crossover” from failed ofa therapy.
  • Patients stayed on Ibrutinib on average a little less than 3½ years.
  • No new side effects emerged, but there are significant adverse events (AEs) that must be considered.
  • Cumulatively during long-term Ibrutinib therapy hypertension and atrial fibrillation occurred in 21% and 12% of patients, respectively; major hemorrhage occurred in 10%.
  • Most common reasons for Ibrutinib discontinuation (DC) prior to study closure were progressive disease in (37%) and AEs (16%).

Conclusions:

I chose this as my number one abstract from ASCO 2019 as this trial began the change in how we treat CLL. While ofa was an easy comparator to beat, it was the latest thing when this trial began some 8 years ago.

And now we have trials that demonstrated that ibrutinib is superior to both FCR and BR, much tougher chemo cocktails to beat, and the gold standard chemo-immunotherapies that are still widely used to treat CLL.

Now we have new drugs and new combos. But this started it all.

It also is reassuring that no new long-term problems popped up, though the cardiovascular issues are more common than we realized at first. It would nice if it was more that 41% of patients were still on ibrutinib >4 years.

And it is also the first big study that brought attention to trial design, equipoise and the need for crossover. Sadly, there are still trials out there that don’t allow crossover. Again, look at Dr. O’Brien’s loud call for justice.

This trial was one of the first major steps in the revolution that changed how we treat chronic lymphocytic leukemia.

Here is my short video synopsis.

Here is the actual ASCO abstract.

Please let me know if you disagree with any of my top 10 choices or if I missed an important paper.

Stay strong, we are all in this together

Brian