Venetoclax/Rituximab Administration & Toxicity Management

Nicole Lamanna, MD: The venetoclax combinations are obviously a highlight of the ASH [American Society of Hematology] meeting and looking at time-limited duration of therapy. We talked a little bit about some of the ibrutinib toxicities, but let’s talk a little bit about venetoclax. One of the issues with venetoclax is that it goes through what they call a dose ramp-up phase. So the drug needs to be administered 1 week 20 mg, 50 mg, 100 mg, 200, and 400. So it’s a 5-week ramp-up and it’s oral. However, the reason why it’s a ramp-up is because in some of the initial studies, there was a significant degree of what they called tumor lysis syndrome. As the patient’s leukemia cells are dying, they can play havoc with the electrolytes and the kidney function, and, obviously, that can lead to cardiac arrhythmias and death. And so when they recommended those initial studies looking at lowering the doses and doing this much more safely, this sort of eliminated that as a possibility.

Now, how do we do this in practicality? So patients who have bulky disease, being lymph nodes or organomegaly, but lymph nodes over 5 cm, or if they have very elevated white count, those are considered high-risk individuals. So white count over 25,000, those individuals would actually have to be admitted to monitor for this tumor lysis. It’s not that it’s difficult to do but it’s time consuming. And so patients with a greater degree of bulk have to be admitted to the hospital just to hydrate them and to monitor them, to give them allopurinol or rasburicase, to give them IV [intravenous] hydration and Lasix, and then they have to be monitored for a few days, depending upon what their electrolytes did in response to therapy. And you’d have to do that every week when you dose ramped up.

That can be a little bit of a challenge for folks in the community because they’re getting admitted to the hospital, and insurance companies, and things like that. That could be costly as well. So there have been several strategies that are not new and have been presented at this meeting and at other meetings, looking at initiating, so if you do a combination like venetoclax, there was venetoclax/obinutuzumab, presentations on ibrutinib and venetoclax. If you start the other agent first, you can debulk patients, and so their disease burden goes down. This really mitigates for profound tumor lysis, so then venetoclax is started later, and this can be done as an outpatient.

Still many of these protocols are looking at being careful, so the patient will still come as an outpatient every week to dose ramp-up, but they don’t have to get admitted to the hospital that way. And so it makes it much more easier because then the patient comes to the clinic, they start their next dose, you check their electrolytes. Then they can be checked again the next day, making sure that they’re OK and that they don’t need additional hydration. But then it’s all outpatient-driven. So I think there are ways to do this. Once they get through that 5-week ramp-up, you’re good, and then … you don’t have to worry about tumor lysis subsequent to that.

There are other adverse effects of venetoclax such as neutropenia and various ctyopenias, which you need to be aware of, and which can be managed quite well. It’s the dose ramp-up phase that proves a hindrance for management, especially for patients and oncologists in the community setting, depending upon their resources, experience, and ability to respond to abnormalities quickly and effectively; this issue can certainly preclude the success of venetoclax administration. But, again, I think time and experience is important. It is not difficult to do, it is not difficult to manage this at all, but you just need to have a forum so you can do this safely for patients and make it easier for them, more convenient, but making sure you’re not causing a problem by missing those laboratory tests. They are important to get. But there are ways by using other therapies in combination with venetoclax that it’s very easy then to do the rest as an outpatient.

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