ASH 2018: Dr. Nitin Jain on combining Ibrutinib with Fludarabine, Cyclophosphamide and Obinutuzumab for IGVH mutated CLL patients.

Dr. Nitin Jain is part of the creative team of CLL researchers and doctors at MD Anderson Cancer Center (MDACC) in Houston, Texas.

We have already published my interview with him on the combination of venetoclax and ibrutinib for high-risk, treatment-naïve chronic lymphocytic leukemia patients here where 92% had a complete response and 68% were U-MRD (undetectable minimal residual disease) in the bone marrow. To better understand U-MRD, please listen to this interview with Dr. Wierda, also at MDACC.

But are there even better combinations?

Could we cherry-pick the patients most likely to respond to the best chemoimmunotherapy we have, improve on that by using an even better antibody and a potent targeted agent, and at the same time reduce the toxicity by reducing the amount of chemo delivered?

In other words, could we have the best of both worlds: the fast-kill and fixed-dose of chemo and the power of a targeted agent?

I had the opportunity to interview Dr. Jain at the annual meeting of the American Society of Hematology in San Diego in Dec. 2018, where he describes his early research results with just such a cocktail.

Takeaways:

• The trial uses IFCG or Ibrutinib, Fludarabine, Cyclophosphamide, and obinutuzumab (Gazya or GA101)
• For young, fit patients with low-risk CLL (mutated IGVH and no negative FISH finding or TP53), we already know that 6 months of FCR can keep >60% disease-free for more than 10 years.
• This trial only targeted that very same small slice of chronic lymphocytic leukemia patients that could likely benefit from chemotherapy.
• We know based on the groundbreaking ECOG trial that compared ibrutinib-based therapy to FCR, FCR should have no role to play in CLL patients with unmutated IGVH or other high-risk features.
• Adding ibrutinib and switching the rituximab to obinutuzumab should increase the response rate in this “good” group most likely to get a very long remission from chemoimmunotherapy (CIT) such as FCR.
• Instead of the usual 6 cycles of chemoimmunotherapy, this trial halved the number to 3, lowering the toxic exposure while possibly lowering the risk of long-term sequelae. There is about a 5% long-term risk after FCR of getting MDS (myeloid dysplastic syndromes) and AML (acute myeloid leukemia), 2 bad blood cancers that no one wants.
• RESULTS:
  • Report of the first 45 patients.
  • 89% were U-MRD (undetectable minimal residual disease of < 1 in 10,000 cells) with IFCG versus 26% with FCR at 3 cycles.
  • 100% of patients were U-MRD at 1 year and were able to stop the ibrutinib.
  • Though follow-up is short, none has seen their disease come back.

Comments:

For 90% of CLL patients, CIT should be off the table. But for the 10% with mutated IGVH and other “good” markers, the option of combining a targeted therapy with a potent CIT should be discussed, especially based on the early results from this trial. Similar combination studies using other novel agents such as duvelisib and other CIT are ongoing.

We don’t know yet how durable responses will be with the novel agent combinations, but we do know that for the right patients (and Dr. Jain only targeted the right patients in this trial), FCR can offer more than ½ of them what looks very much like cure with a decade or more of being cancer-free. While there is limited data, there is compelling reason to believe those numbers may prove to be considerably higher with IFCG. We just have to wait.

Chemo carries risk, both serious long and short term, and we don’t know if those risks will be halved when the dose is halved. We don’t know how durable these responses will be, and we have even less certainty as to what the length of the responses will be with the novel combinations.

Many of us want a chemo-free treatment and we have great options now.

But for approximately 1 in 10 CLL patients, the IFCG option is worth discussing with the doctor. It is hard to argue with 100% undetectable disease at 1 year, and then being off all meds with no relapses yet.

It’s good to have all these options.

There is another question that begs to be answered: How do we make sure that 90% of patients who should not get chemo don’t get it? That is what we are here for, because SMART PATIENTS GET SMART CARE™.  We don’t need another trial to answer that, we need patients getting smarter care.

Please enjoy my interview with Dr. Jain from MDACC. We have a candid discussion of the role of chemo in treating CLL today.

Here is Dr. Jain’s ASH 2018 abstract:

http://www.bloodjournal.org/content/132/Suppl_1/695

Enjoy!

Brian Koffman

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Dr. Brian Koffman, a well-known retired doctor, educator, and clinical professor turned patient has dedicated himself to teaching and helping the CLL community since his diagnosis in 2005. He serves as the Executive Vice President and Chief Medical Officer of the CLL Society Inc.