MURANO Trial and Time-Limited Therapies

Nicole Lamanna, MD: If you think that this patient with high-risk features has gone through many of these novel agents, when we look at venetoclax and rituximab, given the recent MURANO data that got presented or re-presented with longer follow-up, actually 3-year follow-up, how do we look at that in the setting of a patient such as this with high-risk features? The MURANO data were very nice because, even though it was in this exact situation of relapsed/refractory patients with CLL [chronic lymphocytic leukemia], we looked at levels of minimal residual disease [MRD] in these individual patients; it was time-limited duration of therapy. The venetoclax actually was only for 2 years. What the data did provide is that looking at individuals based on their MRD level, folks who had high MRD are likely to progress sooner than folks who had undetectable minimal residual disease or even just low levels.

And so one may be able to use that information in a patient that is high-risk such as this and say, do we end it at 2 years? Should we be checking for minimal? In fact, that’s what I would be doing, is we should be checking for minimal residual disease in a patient who’s young with aggressive features, to think about whether they should be stopped. And so now you can actually start being more specific about how to finesse these therapies. And, even though the protocol obviously did stop individuals, at 2 years everybody stopped regardless; it was amended to allow patients who then progressed to reintroduce venetoclax therapy.

If this patient wasn’t on that protocol, you might consider looking at the minimal residual disease. If they were undetectable, the question remains do you stop therapy because they’re high-risk or do you be true to what we just presented with the MURANO data, stop therapy, and wait till they relapse? And I think that is one area that we still need longer term follow-up in patients who are high-risk. Is it a benefit then to stop if they have undetectable levels and wait, or should we not because eventually we know that they’ll probably relapse, and is that good enough? Will they be sensitive again because they’re high-risk? I think that’s an area that we still need a lot more investigation and further follow-up and data on. I am a little nervous about stopping my 17p patients regardless. And so even if they were undetectable, I’d be happy that they’re undetectable, but I would likely still continue the drug.

When we look at combinations such as venetoclax, or rituximab, or some of the other combinations that are being explored, the reason some of these are being explored is everybody is very interested in how to use a short or a time-limited duration of these therapies. So, in other words, that patients won’t be on ibrutinib indefinitely for the rest of their life or on venetoclax indefinitely for the rest of their life, both for toxicity issues that might be mounting. We’ve been seeing, if we look at some of the real-world data sets that have been presented at these meetings, that there’s no doubt, and I think this is not unique to CLL; I think this has to do with many disease states, whether oncology or not oncology patients. It’s a little bit of fatigue in terms of their medications and there is a noncompliance issue that patients have.

All of these novel therapies are oral—if they’re indefinite, there is a degree of noncompliance that happens over time, even for some adverse effects that are completely manageable but are nagging to the patient. A little diarrhea here and there can be nagging. And so they just will take less. They’ll skip some pills. I think there is an area of concern about resistance, and there’s an area of how do we make this better for patients in the long run. And so looking at some of these strategies of time-limited duration of these therapies, deepen these responses. So by these combinations, really look at achieving deep responses so we can stop therapy and then see how long they would go until time to their next treatment. Because in chemoimmunotherapy, that’s what we did. We could not continue FCR [fludarabine/cyclophosphamide/rituximab] or BR [bendamustine/rituximab] indefinitely because these were intense therapies. So you would give 6 cycles, you were done until you needed treatment again. Hopefully, that wouldn’t be for years down the road, but that’s how it was because you couldn’t just keep that going.

Maybe now that we have deeper responses, particularly with the venetoclax combinations, deeper responses, we can shorten the time period and make an analogy like we did in the chemoimmunotherapy, although hopefully better, but that we can stop people and then reintroduce drug. That will also save on not just hopefully toxicity but cost. These medications are extremely expensive. I think this is an issue. We’ve talked and highlighted at this American Society of Hematology meeting that there are many countries that patients don’t have availability to these novel therapies or even in the United States. I can speak to the folks in the United States. There are some patients’ insurances that their copays are too large for even drugs like ibrutinib, which is now standard of care. I think this is going to be a problem, so if we can pursue this, it is the future of where CLL is going, if we can get deep remissions, decreased toxicity, shorter durations of therapy, cheaper, then it will be a benefit in the long run for patients.

Transcript edited for clarity.

A 58-Year-Old Man With Relapsed CLL

• A 58-year—old man presented with symptoms of fatigue and left upper quadrant fullness
• PMH: cervical lymphadenopathy, ~2.5 cm; spleen, palpable ~6 cm below left costal margin
• PE: vital signs WNL, right cervical lymphadenopathy, spleen palpable 5 cm below costal margin, otherwise well-appearing
• Laboratory findings:
  • WBC, 160,000; 68% lymphocytes (ALC, 112,000 cells/mL)
  • Hb; 9.4 g/dL
  • Platelets; 130 X 10⁹/L
  • ANC; 174/mm³
• Flow cytometry; CD5+, CD19+, CD23+
• Cytogenetics, IgVH unmutated; del 17p
• β2M, 4.0 mg/L
• BM biopsy; diffuse infiltration by CLL
• Diagnosis; chronic lymphocytic leukemia
• The patient was treated with fludarabine, cyclophosphamide, and rituximab and achieved a complete remission

Three years later, on routine follow up

• Laboratory findings:
  • WBC; 93,000; 97% lymphocytes
  • Hb; 10.4 g/dL
  • Platelets; 123 X 10⁹/L
  • ANC; 1,600/mm³(WNL)
  • LDH; 242 U/L
  • Beta-2-microglobulin; 9.1 µg/L