MURANO: Venetoclax Plus Rituximab in Patients With Relapsed/Refractory CLL

EP: 1.Patient Profile: A 70-Year-Old Man with Relapsed/Refractory CLL

EP: 2.CLL: Prognostic Factors and Treatment Considerations

EP: 3.Overview of Treatment Options for Relapsed/Refractory CLL

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EP: 4.MURANO: Venetoclax Plus Rituximab in Patients With Relapsed/Refractory CLL

EP: 5.Recent Data on CAR T-Cell Therapy and BTK Inhibitors in Relapsed/Refractory CLL

EP: 6.Unmet Needs and Clinical Pearls for Treating Relapsed/Refractory CLL

Case: A 70-Year-Old Man with R/R Chronic Lymphocytic Leukemia (CLL)

• Patient AL is a 70 y/o man.
  • PMH: T2DM and Hypertension (both well controlled with medication)
  • SMH: Does not smoke or drink alcohol.

Clinical Presentation:

• In July 2022, AL was diagnosed with CLL and had been previously treated with venetoclax plus obinutuzumab upon initial diagnosis. Less than 6 months later, AL presented to his oncologist reporting an unresolved fever and increased fatigue.

Clinical Workup and Molecular Testing:

• Laboratory Findings:
  • WBC: 120,000
  • Hgb, 9.1 g/dL
  • Platelets, 92 x 109/L
• Molecular Testing:
  • Elevated serum beta-2-microglobulin
  • Flow cytometry, CD5+, CD19+, CD23+
  • IGHV/TP53 mutational status: unmutated
  • FISH detect del(17p)
• ECOG PS 1

Disease Relapse and Treatment(s):

• Further disease progression was documented, and a joint decision was made to initiate AL on venetoclax plus rituximab.
  • Venetoclax Dosing Ramp-Up Schedule
    • Starting dose of 20 mg PO QD x 7 days, then weekly ramp up to 50 mg, 100 mg, 200 mg, and 400 mg PO daily. The recommended daily dose (400 mg) continues from week 5 and beyond for 24 months.
  • Rituximab 375 mg/m2 on C1D1 (28-day cycle), then 500 mg/m2 on Day 1 for 5 cycles (completing after month 6).

Transcript:

Catherine C. Coombs, MD: Regarding the MURANO (NCT02005471) trial, this study compared the standard-of-care regimen bendamustine and rituximab, to venetoclax and rituximab. BR [bendamustine and rituximab] was given as a standard 6 cycles, venetoclax with rituximab was given as a 24-month fixed-duration therapy of the venetoclax with 6 cycles of rituximab. The study found that VenR [venetoclax and rituximab] led to superior progression-free survival and overall survival as compared with BR, which is what leads me to always use VenR over any sort of chemoimmunotherapy regimen in an appropriately selected patient. The longer-term follow-up of the VenR regimen shows that the median PFS [progression-free survival], when looking at all patients in the study, was around 54 months. So, with just 2 years of therapy, patients are able to have a very nice treatment-free interval until ultimately progressing and needing their second therapy. This was significantly longer than the BR regimen where it had a median PFS of under 2 years.

When we look at MRD [minimal residual disease] as potential for being a surrogate end point in CLL, I do think that that can be considered with this particular regimen because follow-up correlative studies to the MURANO trial demonstrate that patients who achieve undetectable MRD have superior progression-free and overall survival as compared with those patients who don’t. However, the caveat is that I don’t think this can be applied to other studies because MRD is somewhat different, especially in the context of BTK and BCL2 inhibitor trials where more unmutated patients with that combination achieve MRD, but that doesn’t necessarily seem to correlate with PFS and the data are too immature to find the correlations between OS [overall-survival].

Speaking about the VenR regimen in a little more detail, how well do patients tolerate this regimen? In general, I think it is a well-tolerated regimen. However, there are some toxicities that one needs to counsel the patient about. The most common adverse effect is cytopenias, and these can be either thrombocytopenia or neutropenia. The thrombocytopenia, in my own practice, has not been a clinical concern in the great majority of patients. I don’t recall any cases where I had to do any transfusion support or dose holds. However, the neutropenia is a different story. Probably around half of patients can get grade 3 or 4 neutropenia. In my view, the best way to manage this is to prevent it from getting to severe neutropenia, because the last thing I want is for my patient to end up with an infection. The way that I support my patients is through liberal use of G-CSF [granulocyte colony-stimulating factor] in order to support the neutrophils through the treatment process whenever that does occur. The other adverse effects are GI [gastrointestinal], and so diarrhea can occur. This is usually not so significant, although I have had some cases [in which] patients need to take Imodium; I’ve only rarely needed to dose reduce for that. Overall, this is a regimen that performs quite well without an unmanageable adverse effect profile.

Regarding how the regimen affects a patient’s immune profile, this is actually interesting. In the height of the COVID-19 pandemic, a lot of us had concerns about using CD20s, given the B-cell–depleting effect and the subsequent potential risk to immunity with vaccination, which we already know is a problem even in therapy-naive patients with CLL. Certainly, it can be worse in the setting of patients on therapy. So I do warn my patients about that risk and prior to starting therapy, I always have them complete all of their vaccinations if they’re not up to date. However, I don’t see that as a reason to withhold the anti-CD20, because I do think that there is an additive benefit as far as the efficacy of the regimen for doing the CD20 with the venetoclax as opposed to venetoclax as a monotherapy, acknowledging of course that these have not been compared head-to-head.

One interesting correlative analysis that was presented by Dr [Arnon P.] Kater at ASH [American Society of Hematology] in 2022 is looking at, after completion of therapy, is there some degree of immune reconstitution? We know that there’s this decline following exposure to an anti-CD20. However, in the 5-year follow-up, this correlative exploratory analysis showed recovery of immunoglobulins, both IgA, IgG, and IgM, which suggests that though there are transient depressions, which we always expect when patients are on therapy, that time off therapy does allow for recovery of somewhat normalization of the immune system, which is a promising aspect of this treatment.

Transcript edited for clarity.