The Therapeutic Approach for High-Risk CLL - Episode 2

Therapeutic Approach for CLL Relapse

January 12, 2018

John F. Gerecitano, MD, PhD:This patient relapsed relatively soon after treatment and maintenance therapy with lenalidomide, so a little bit sooner than we would have expected based on the data. And when this patient relapsed, they relapsed in a bulky and symptomatic way. So, this patient had a high tumor burden with large bulky lymph nodes as well as ascites and fatigue from their disease. Their anemia was also recurrent and their platelets were a bit lower at the time of relapse than they were at the time of their initial diagnosis. Also, their LDH was high. These are all markers of high-burden disease.

In patients who fail initial chemotherapy or chemoimmunotherapy, there are more second-line choices than there are first-line choices at this stage. In patients with deletion 17p, the targeted therapies seemed to be most promising, and those include PI3-kinase inhibitors, BCL-2 inhibitors, B-cell receptor (BCR) inhibitors, and BTK inhibitors. All of these are reasonable choices in a patient like this. You do want to choose a therapy that’s likely to be active relatively quickly in a patient who has such symptomatic recurrences.

The rationale for starting venetoclax in this patient is that venetoclax is likely to lead to a response relatively quickly to alleviate the patient’s symptoms, and we know that venetoclax has a high degree of response in patients with deletion 17p.

The long-term safety profile for venetoclax is quite favorable. In fact, this is a drug that is tolerated very well by patients, and patients often feel better on the drug than they did before they started the drug. The short-term safety is the more important to be cognizant of, and that includes the risk of tumor lysis. The long-term safety concerns with venetoclax therapy are mostly hematologic, one of which is neutropenia. However, neutropenia was very easily managed for patients on venetoclax in phase I and phase II clinical trials to date.

The main concern with initiation of venetoclax therapy is the risk of tumor lysis syndrome. Tumor lysis syndrome is most common in patients with very high disease burden. And in the prescribing information for venetoclax, there are at least 3 categories listed for patients with different levels of risk for tumor lysis syndrome. In patients with the highest risk for tumor lysis syndrome, it’s recommended that they be treated in the inpatient setting where they can be monitored closely for tumor lysis syndrome, and where tumor lysis syndrome can be prevented by adequately hydrating patients with high doses of intravenous or oral fluids—but most likely intravenous fluids are recommended—with treatment at baseline, with rasburicase in patients who have elevated uric acid levels, and with pretreatment with allopurinol to mitigate the risk of tumor lysis syndrome affecting the kidneys. In addition, patients need to be monitored closely for the electrolytes that can be out of whack with tumor lysis syndrome, especially potassium.

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