Clinical Data and Third-Line Options for CLL

John F. Gerecitano, MD, PhD:Patients on venetoclax can get neutropenia, and this can happen in the short term or the long term. This, however, is not usually associated with the development of fever or with infection. And neutropenia can be managed in a couple of different ways. It has been shown on clinical trials that when neutropenia develops, if venetoclax is interrupted, the neutrophils generally come back relatively quickly and treatment can be restarted at the same dose.

Also, patients on clinical trials who were treated at investigators’ discretion didn’t have to interrupt the venetoclax dose and were able to receive growth factor support while venetoclax was ongoing. And in those cases, or in cases where treatment was interrupted and patients are treated with growth factor, the neutrophil count generally comes back relatively quickly.

Rituximab can be safely added to venetoclax. This has been shown in a phase Ib study that was presented at ASH in 2016 and was shown to be of benefit in both depths of response and duration of response.

The MURANO phase III trial, that will be presented at ASH 2017 in the late-breaking abstract session, compared the investigational arm, which is rituximab plus venetoclax with a standard arm, which was rituximab plus bendamustine. This included patients with 1 to 3 prior regimens of therapy for their CLL, and this only included patients with relapsed or refractory disease.

The biggest take-home messages about the MURANO data are that the MURANO study compared an investigational arm of a chemotherapy-free regimen with a targeted agent and immunotherapy, rituximab, with a commonly used standard regimen, rituximab and bendamustine. This is important because several other clinical trials in the field have compared the investigational arm with less relevant arms that don’t employ therapies that are more commonly used in the community or academic setting in the modern era. The biggest difference that was seen in the data for this study are the difference in progression-free survival, which was significantly longer in patients on the investigational arm than it was in patients with the traditional chemotherapy-containing arm.

These data are likely to be impactful on clinical practice. It tells us that patients can avoid traditional cytotoxic chemotherapy without sacrificing duration of remission or depth of response. The patients on the investigational arm achieved a favorable progression-free survival without higher risks. In fact, the side effect profile on the investigational targeted therapy arm was actually better than the side effect profile on the chemotherapy arm, and this will allow patients to have a favorable duration of remission or progression-free survival without the risks that are attendant to chemotherapy.

Patients selected for this regimen included patients with relapsed or refractory disease after 1 to 3 prior therapies for their disease. We know that patients treated even with the most effective therapies these days with CLL are likely to relapse. So, it is likely that this patient is going to need a third-line regimen for their disease. At that time, it’s unlikely that chemotherapy or chemoimmunotherapy will be of significant benefit for this patient because of their deletion 17p status and because we know they already failed 1 chemotherapy regimen. Therefore, we would favor targeted agents in this patient population.

Since the patient already got a BCL-2 inhibitor, it’s likely that the next choice of therapy will involve a different targeted agent. The most commonly used targeted agent at this point is ibrutinib, and we do know that ibrutinib benefits patients with deletion 17p as well as patients that don’t have deletion 17p orp53mutations. So, in the current landscape, that’s the most likely next line of therapy.

Treatment options other than ibrutinib include other PI3-kinase inhibitors. Right now, idelalisib is still a choice. Other PI3-kinase inhibitors, like copanlisib or duvelisib, may be of a choice in a patient like this. And other choices in the future will likely include second-generationBCL-2 inhibitors, second-generation Bruton’s tyrosine kinase or B-cell receptor inhibitors, and third-generation PI3-kinase inhibitors. Of course, what we recommend most highly for patients in that situation is to enroll in clinical trials, which help us improve the therapies that we have to offer in the future.

Transcript edited for clarity.

Case: A Young Male Patient with High-Risk CLL and Nodal Involvement

January 2017

• A 53-year-old male presents with fatigue, night sweats, and swollen glands
• PMH: hypertension managed with losartan
• PE: left axillary and bilateral cervical adenopathy, 4 cm X 3 cm
• Laboratory findings:
  • WBC; 117.3 X 10⁹/L
  • Lymphocytes; 109.2 X 10⁹/L
  • Hb; 9.6 g/dL
  • Platelets; 174 X 10⁹/L
  • ANC; 1,950/mm³
  • LDH 160 U/L
• Flow cytometry; CD19++, CD5+, CD20+, CD23++, CD38+
• BM; CLL in 86% of cells
• IgVH mutated
• Cytogenetics by FISH; del17p
• Diagnosis; chronic lymphocytic leukemia
• The patient was treated with FCR and achieved a partial response to therapy after 6 cycles
  • Left axillary lymph node, 2 cm X 2 cm
  • Lymphocytes; 10 X 10⁹/L
  • Symptoms resolved
• The patient was started on maintenance therapy with lenalidomide

December 2017

• The patient complained of increasing bouts of extreme fatigue, abdominal bloating and intermittent moderate to severe abdominal pain
• PE:
  • Bulky adenopathy in the cervical and axillary lymph nodes, inguinal lymphadenopathy
  • Fluid wave test positive for ascites
• Abdominal CT showed multi-station bulky lymphadenopathy, hepatomegaly, and splenomegaly
• Patient underwent large-volume paracenteses, ascites sampling positive for CLL involvement
• Laboratory findings:
  • WBC; 84,000, 97% lymphocytes
  • Hb; 9.4 g/dL
  • Platelets; 110,000/mm³
  • ANC; 1,600/mm³(WNL)
  • LDH; 262 U/L
  • Beta-2-microglobulin; 8.9 µg/L
• The patient was started on venetoclax
• The patient developed grade 3 neutropenia after 4 weeks on therapy which was managed and later resolved