Use of MRD Status Following Obinutuzumab/Ibrutinib to Guide Subsequent Intensification of Therapy in CLL

[Jm954]

August 6, 2019

In this 2-part, single-arm, open-label, multicenter trial (Clinical Trials.gov Identifier: NCT02666898), medically fit, adult patients with treatment-naive CLL not characterized by a 17p deletion or a mutation in TP53 received 9 months of chemotherapy-free induction therapy with the combination of ibrutinib and obinutuzumab.

Following induction therapy, those patients with a complete response (CR) and bone marrow MRD status of less than .01% were treated with 6 months of ibrutinib; whereas those achieving a partial response (PR), or a CR and bone marrow MRD greater than or equal to .01%, received 6 months of ibrutinib plus combination therapy with fludarabine/cyclophosphamide, and obinutuzumab.

Although the author of an invited accompanying commentary described these findings as “encouraging,” they were skeptical regarding the impact of this study on current treatment recommendations for several reasons:

- Because results of phase 3 trials suggest that first-line targeted therapy approaches are superior to chemoimmunotherapy in patients with CLL characterized by unmutated IGHV

- There is the potential for increased toxicity with the combination of fludarabine, cyclophosphamide, obinutuzumab, and ibrutinib compared with other low-intensity regimens

- Preclinical evidence suggests that off-target effects of ibrutinib may inhibit obinutuzumab activity, and that ibrutinib activity is not increased in a synergistic way when combined with antibodies targeting CD20

Both the study authors and the author of the accompanying editorial concluded that use of bone marrow MRD status following a limited-course induction therapy is a promising approach for selecting some patients with CLL whom are likely to benefit from more intensive subsequent therapy. Nevertheless, there was also consensus that, prior to its implementation in clinical practice, this type of strategy should be evaluated in randomized trials.

More here: cancertherapyadvisor.com/ho...

Jackie

[CaptRon1976]

Jackie, you summarized from the article cited (which I read) that Ibrutinib activity is not enhanced by CD20 antibodies such as Obinutuzumab and that “I” may inhibit the activity of O.

The remaining question is: does the remaining diminished activity obinutuzumab still provide benefit to the patient independent of it not enhancing Ibrutinib activity.

[Jm954 Administrator in reply to CaptRon1976]

Yes, I believe so, in so far as the Obintuzumab itself will cause sequestration and clearance of CLL cells and this results in quicker responses and remissions.

Obintuzumab is a much more avid anti CD20 than Rituximab.

Jackie

[Justasheet1 in reply to Jm954]

Jackie,

I was just treated at MDA by Dr Wierda only a month ago. My WBC was 270,000 and climbing. He began treatment with obina the next day. I had 4 total infusions which is not the norm. He wanted to bring the counts down. It worked. WBC came down to 6 and all other labs improved to normal. Maybe giving the obina up front prevents the inhibition caused by the ibrutinib if given together?

Then I started the ibrutinib after I got home. He sent me home on 90 days of Valcyclovir and Allopurinol too. I had weekly labs for a month with monitoring of my BP too. All perfect.

The plan now is for monthly labs for 2 consecutive months then every 3 months. I go back to see him in a year. He wants to add Venetoclax at that time.

The advantage of going to a center of excellence like MDA is that my insurance initially denied his care plan for me. He got on the phone and miraculously they approved it. He also buried them in reams of paper full of studies he crafted.

I don’t profess to understanding this disease but I sure am glad that he does. Going to a CLL expert is a must.

Jeff

[avzuclav in reply to Justasheet1]

Wow, great combo and sequencing - sounds promising! What was the overall duration of your four obinutuzumab infusions?

I'm also interested in the opposite sequencing... adding obinutuzumab after a year of ibrutinib. It produced 50% UMRD-4 in this study:

bloodjournal.org/content/13...

"Patients receiving obinutuzumab after >1 year prior ibrutinib monotherapy achieved a higher response rate compared to ibrutinib-naive patients (IWCLL CR/CRi 50% vs. 30%), with a higher proportion of patients achieving <0.01% BM MRD (50% vs. 6%) and a greater depth of disease depletion (3.1 vs. 1.5 log reduction)."

[Justasheet1 in reply to avzuclav]

Avz,

The sequence was fast. Test dose and rest of dose back to back. Then full dose every week for 3 more doses.

Insurance squawked because its not approved for relapsed patients yet and because I live 3 states away, he gave it faster. If it wasn’t Dr Wierda directing my care, I would have had questions.

Jeff

[avzuclav in reply to Justasheet1]

Nice. Sounds like you got the normal dosing schedule for Cycle 1 and Cycle 2, or pretty close. No doubt you are in great hands with Dr. Weirda.

gazyva.com/hcp/cll/dosing/s...

[Smakwater in reply to Justasheet1]

I know that I am singing to the choir Justasheet1, but anyway,

Gazyva kills CLL in the same way that Pac Man would eat power pellets if on steroids. However, the magic is mainly in the peripheral blood and thus the need for special ops like ibrutinib and venetoclax.

Thank God for allopurinol, as it clears the uric acid that is in the blood from the dying cancer cells keeping the kidneys from choking and preventing gout. I am prone to gout, and CLL turns us into a gout factory even before treatment.

I believe that many accept substandard treatment simply because their health care team does not step up to the challenge of correctly addressing insurance needs. Great to have someone like Dr. Wierda who is knowledgeable about insurance nuances that make positive impacts on patient choices for treatment.

Good to hear that you have a good team and play first string.

JM

[avzuclav in reply to Jm954]

Obinutuzumab (GA101) Is Less Prone to Antagonism of Immune Effector Function By Ibrutinib Than Rituximab in Vitro and in Vivo:

bloodjournal.org/content/12...

Conclusions: Surprisingly, we found that the inhibitory effect of ibrutinib on the immune effector mediated activity of obinutuzumab is not observed when compared to rituximab.

[Justasheet1 in reply to avzuclav]

Avz,

That study is from 2014 and in vitro. It played out exactly in humans as in vitro. I’m hoping the same with obina.

Perhaps that’s why Dr Wierda gave it to me first.

Jeff

[Sushibruno in reply to Justasheet1]

What's obina? (Obinutisimab?)

[Jm954 Administrator in reply to Sushibruno]

yes, Obintuzumab

[Sushibruno in reply to Jm954]

Thank you😊

[Smakwater in reply to CaptRon1976]

Good Eye Capt'n Ron. And who better to hit the the nail on the head than Jackie 954!

Make mine a double!

JM