Episode 097: Treatment of Relapsed/Refractory CLL

Written By TheFellowOnCall HemeOncPodcast

This week, we continue our discussion of treatment of CLL, this time focusing on the relapsed/refractory CLL. If you have not done so, we recommend checking out our prior episodes since we will be building on these conversations!

Recap of last episode:

  • CLL 12 study showed how early treatment of ibrutinib improved 3-year event free survival but no impact on overall survival. 

Prognostication and treatment indications

  • Refer to Episode 095 on prognostication for CLL and Episode 096 for indications for treatment.  

  • Note that peripheral blood is sufficient for flow cytometry and FISH analysis. 

  • Rai stage and Binet stage were developed in the 1970’s so aren’t quite as relevant alone for survival prediction in the modern era. 

How do we approach management for those that are candidates for treatment?

  • Obtain PET CT vs CT to evaluate for nodal burden. 

  • Excisional lymph node biopsy to rule out Richter’s transformation to a large cell lymphoma

  • TFOC tip: median SUV in Richter transformation: ~15; otherwise median SUV ~7. 

  • Richter portends a very poor prognosis and vastly changes the treatment paradigm. Refer to the end of show notes for treatment approach for Richter’s. 

What is the 1st line treatment?

  • Fixed duration:  Obinutuzumab + venetoclax (frequent lab checks & visits for the first 2 months). 

    • These are promising options in del17p or TP53 mutations as they are known to be resistant to chemo. 

  • Indefinite: BTK inhibitor using acalabrutinib or zanubrutinib +/- 6 months of Obinutuzumab

Who is at risk for TLS with venetoclax?

  • Vigorous monitoring upon starting the treatment: 

  • Start allopurinol 300 mg daily and encouraged to drink 1.5-2L of oral hydration daily

  • High risk (LN >10 cm or LN 5-10 cm with ALC >25K):  

    • usually require admission (as in the trial)  

    • Consider starting off with single agent Obinutuzumab x 3 and consider starting venetoclax on day 22. This will allow for the downgrade in the risk group. 

What is the approach to management of relapsed disease?

  • Restage these patients with a PET/CT (ideally) and excisional biopsy of the most PET avid LN. 

  • Other than Richter’s, another risk is transformation to prolymphocytic leukemia which also has a poor prognosis.  

  • These transformation events represent clonal evolution for most cases.  

  • For relapsed CLL,  treatment is opposite of what was done in the front line. 

What is the data behind use of BTK inhibitors for relapsed CLL?

3 studies to look at the use of BTK inhibitors in relapsed/refractory CLL

  • RESONATE trial: compared ibrutinib to ofatumumab (we don’t use this CD20 monoclonal antibody). 

    • Outcome: Weak comparator arm and ibrutinib won by a landslide. 

    • There was PFS and OS benefit, regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. 

    • Adverse events: Afib for 12% of patients; HTN 21% median onset 13.6 mo.

Two other trials that compared the newer generation BTK inhibitors to ibrutinib in the relapsed/refractory setting. 

  • ELEVATE RR: ibrutinib vs acalabrutinib: no difference in PFS or OS but there was half the rate of AFib and Aflutter.

  • ALPINE: ibrutinib vs zanubrutinib:

    • zanubrutinib which had a superior overall response rate. NOTE: This should not have been the appropriate endpoint as this is not a good surrogate for what matters which is overall survival. 

    • This was not powered for PFS but did show a statistically significant PFS and we can’t draw any definitive conclusion on improved efficacy over something like acalabrutinib. 

    • However, zanubritinib showed half the rate of AFib and Aflutter.

2nd generation BTK inhibitors (acalabrutinib and zanubrutinib) still have a ~5% risk of cardiac arrhythmia and around 20% risk of hypertension.

What is the explanation of lymphocyte flare with BTK inhibitors?

  • Ibrutinib, acalabrutinib, and zanubrutinib: small molecule inhibitors that irreversibly and covalently bind to Bruton’s tyrosine kinase which is essential for signaling through the B cell receptor. 

  • CLL cell survival is driven through the B cell receptor and blocking this pathway leads to cell death by promoting apoptosis.  

  • After binding, these BTK inhibitors cause a redistribution of CLL cells residing in the lymph nodes to the peripheral blood

  • This anatomic cellular redistribution results in shrinkage of lymph nodes and increase in the overall lymphocyte count in the peripheral blood

  • Typically, after a few months, the ALC decreases and peaks after the first month

What are treatment options for disease states that are refractory to both BTK inhibitor and BCL2 inhibitor?

  • Consider allogeneic stem cell transplant in fit patients: referral for consideration of an allogeneic transplant as this can be a curative option, especially in younger patients. 

    • EBMT database: 2500 patients with 35% OS at 10 years. 

    • Non Relapse Mortality 40%. Disease relapse 30%

  • CD19 CAR-T therapy: not worked as well for patients with CLL. Ongoing trials. 

  • Pirtobrutinib (BRUIN Trial)

    • Phase I/II trial of non covalent BTK inhibitor pirtobrutinib 

    • C481 mutation occurs with BTK inhibitors and pirtobrutinib overcomes the resistance mechanism. 

    • ORR ~70% with median PFS 19 months. 

      • Caveat is that about 25% of patients who were intolerant (rash, hypertension, atrial fibrillation, etc.), but didn't necessarily progress on prior BTK. 

    • This is a potential option to use as a bridge to allo transplant. 

What other classes of drugs?

  • Idelalisib - PI3 kinase inhibitor. This drug is very toxic! 

    • Approved based on a trial comparing idelalisib and rituximab vs. rituximab + placebo

    • Can cause pneumonitis, hyperglycemia, pancreatitis → therefore we do NOT like to use this 

What is Richter’s transformation and why is this important to identify? 

  • Richters is aggressive compared to transformation from follicular lymphoma to large cell 

  • Med os: ~6 months. 

  • Chemo (R-EPOCH) with consideration of venetoclax addition and then consider HSCT for consolidation. 

  • CAR-T may be an option. 

  • Consider referral for clinical trials. 

References:

The crew behind the magic:

  • Show outline: Vivek Patel

  • Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath

  • Editing: Resonate Recordings

  • Shownotes: Srijan Valasapalli

  • Social media management: Ronak Mistry

We are proud to partner with HemOnc.org!

Want to learn more about the trials that lead to the regimens discussed today? What about dosing schedules? See links in the show notes for a link to HemOnc.org

TheFellowOnCall HemeOncPodcast
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Episode 096: Treatment of CLL