CLL: Clinical Data for Rituximab/Venetoclax

Danielle Brander, MD:For patients who may have considered to start on venetoclax therapy for treatment of their relapsed refractory CLL with deletion of 17p, I do consider adding rituximab to that regimen once they have reached the targeted dose. That is, rituximab is added after they reach the 400 mg of venetoclax. And it’s generally given monthly by the CLL rituximab dosing for up to 6 months. The only exception to this, of course, would be if patients have a specific contraindication to receiving rituximab therapy. This recommendation is based on a phase IIb study where patients with venetoclax were started on rituximab, and it was felt that this was at least additive to their responses and, hopefully, their duration of response as well.

Out of that phase I, IIb study, there was a metaanalysis of several different venetoclax trials that looked at with and without rituximab, and rituximab was felt to provide a benefit without significantly added toxicity. Again, however, I’ll highlight that the rituximab is only added in after patients reach the full dose of the venetoclax.

The consideration to add rituximab to venetoclax, which is listed in the NCCN guidelines as well, was largely based on phase I or phase II studies of adding this regimen. The MURANO study, which will be presented this year at ASH, is the first phase III study of using venetoclax in previously treated patients with CLL. In the MURANO study, patients were randomized between venetoclax and rituximab versus bendamustine and rituximab when they require treatment for their CLL. They were stratified by deletion 17p status and response to prior therapy as well as geographic region. Patients could have had prior bendamustine to be entered into the study. However, the duration of response to the bendamustine was required to be greater than 24 months. And the primary endpoint was to look at investigator-assessed PFS, or progression-free survival, after the treatments that the patient was randomized to.

Almost 400 patients were treated on the MURANO study—so about 200 patients in each arm—and they were fairly well balanced between the groups in terms of age, prior treatment, and response to prior treatment, as well as deletion 17p status, about one-quarter in each arm. At a median follow up of 24 months, there was a significant difference in the investigator-assessed progression-free survival of venetoclax/rituximab versus bendamustine/rituximab. It was a median not reached of response for the venetoclax/rituximab, compared to about 17 months’ progression-free survival for the bendamustine/rituximab arm.

The safety profile of both regimens was, as we expected, there was a higher incidence of grade 3-4 neutropenia in the venetoclax rituximab arm. However, importantly, this was not associated with an increase in febrile neutropenia or other adverse events.

In this first primary analysis of MURANO, there was a significant improvement in the progression-free survival of the venetoclax/rituximab arm. Importantly, there are also seen improvements in some of the secondary endpoints looking at the depth of response, such as complete response, and on peripheral blood minimal residual disease, or MRD status, which is increasingly being recognized as an important potential target in CLL treatment.

Transcript edited for clarity.

Case: An Older Patient with Relapsed CLL

March 2015

• A 70-year-old female reported symptoms of weight loss, fatigue, and pain in the upper left portion of her abdomen
• PE showed moderate axillary lymphadenopathy and splenomegaly, spleen palpated 7 cm below the costal margin
• Otherwise, the patient is overall well-appearing and continues to exercise
• Laboratory results:
  • WBC, 48,000; 73% lymphocytes
  • Hb, 10 g/dL (1 year ago Hb, 12 m/dL)
  • Platelets, 125,000/mm³(1 year ago platelets, 165,000/mm³)
  • ANC 1,800/mm³(WNL)
  • LDH, 250 U/L
  • Beta-2-microglobulin, 4.2 µg/L
• Cytogenetics by FISH showed 17p deletion in 56%
• IgVH unmutated
• Bone marrow biopsy; diffuse infiltration by CLL
• The patient was enrolled in a clinical trial and was treated with ibrutinib 420 mg daily
• After 18 months, she achieved complete remission of her disease and resolution of her symptoms

November 2017

• The patient developed had developed atrial fibrillation and despite cardiology interventions could not restart ibrutinib
• During routine follow up, the patient reported increasing fatigue
• PE: cervical lymphadenopathy, ~4 cm; spleen, palpable 8 cm below the costal margin
• Normal kidney function
• Laboratory results:
  • ALC; 112,000 cells/mL
  • Hb; 10.8 g/dL
  • Platelets; 105,000 cells/mm³
• The patient was started on venetoclax