Current Treatment Landscape of Relapsed or Refractory Chronic Lymphocytic Leukemia

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Novel agents such as ibrutinib (Imbruvica), idelalisib (Zydelig), and venetoclax (Venclexta) have transformed the treatment of chronic lymphocytic leukemia (CLL) and are increasingly used to treat the disease. The optimal sequencing of these agents is not clear in relapsed or refractory disease, but some real-world experience can provide insights, explained John N. Allan, MD, of Weill Cornell Medicine, New York, at the 2018 National Comprehensive Cancer Network® (NCCN®) Annual Congress: Hematologic Malignancies™.1

The identification of poor-risk cytogenetics was considered a major advance in selecting treatment for CLL, but this becomes less relevant with novel agents such as ibrutinib, he noted. “Guidelines recommend checking cytogenetics TP53 mutations, and IgVH before any treatment decision is made. This is becoming irrelevant in the era of novel agents, and the definition of high-risk disease is changing,” he told listeners.

Update on Role of Ibrutinib

The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib is now standard first-line treatment of relapsed or refractory CLL, with 1-year survival rates of 90%, based on the RESONATE trial.2 According to 5-year follow-up of phase II studies of 101 patients with relapsed or refractory CLL treated with ibrutinib, the objective response rate was 89%, the complete response rate was 10%, the 5-year progression-free survival was 44%, and the 5-year overall survival was 60%.3

The vast majority of studies support the use of venetoclax after ibrutinib or idelalisib, but there are no data vice versa.
— John N. Allan, MD

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“In those studies, IGVH status had no effect on overall or progression-free survival, but patients with del(17p) were destined to fail to respond to treatment, which is what we see with fludarabine/cyclophosphamide/rituximab (Rituxan),” he said. “Ibrutinib is a great drug but has limitations, including cytopenias, diarrhea, nausea, bruising and bleeding, musculoskeletal pain/fatigue, and infections. Rare but serious adverse events include fatal bleeding, atrial fibrillation, hypertension, and infection,” Dr. Allan continued.

Real-world experience from a retrospective review of 616 patients treated with ibrutinib either in the front-line setting or for relapsed or refractory disease showed that with a median follow-up of 17 months, an estimated 41% discontinued ibrutinib, mainly due to ibrutinib-related toxicities.4 “In my experience, I can get patients through these toxicities,” he said.

After ibrutinib discontinuation, rapid relapse is seen. “Do not discontinue ibrutinib without another plan,” he emphasized.

“Disease progression during the first year of ibrutinib may indicate a Richter’s transformation. If disease progression happens after the first year or year and a half, it is usually CLL but still it is worrisome,” he said.

Experience at Ohio University in 308 patients with CLL enrolled in 4 different clinical trials, with a median follow-up of 3.4 years, showed that close to 80% of patients whose disease progressed developed BTK mutations, and about 9% developed Richter’s transformation.5

Beyond Ibrutinib

For patients with CLL who are intolerant to ibrutinib, alternate BTK inhibitors can be used. Investigational BTK inhibitors include acalabrutinib (Calquence) and zanubrutinib. Choices for ibrutinib-refractory CLL include idelalisib, venetoclax, or chemotherapy.

Although idelalisib is another alternative to ibrutinib, it has been associated with adverse events that limit its use, Dr. Allan noted. They include serious to fatal diarrhea, hepatitis, pneumonitis, and infections.

According to Dr. Allan, ibrutinib appears to be superior to idelalisib as a first kinase inhibitor when comparing across studies, with significantly better progression-free survival both in the front-line setting and for relapsed or refractory patients, as well as for those with complex karyotype and del(17p). Moreover, in patients who discontinued ibrutinib due to disease progression or toxicity, the response rate to venetoclax appears superior. “Venetoclax is an impressive drug that can salvage ibrutinib failures,” Dr. Allan continued.

In a phase II trial including 107 patients with relapsed or refractory CLL and del(17p), the objective response rate was 77%, and the complete response rate was 20%. In some patients, minimal residual disease negativity was achieved. This led to U.S. Food and Drug Administration (FDA) approval of venetoclax in patients with 17p deletion.6

We need new treatments for Richter’s transformation, and single-agent therapy is probably not going to be the answer.
— John N. Allan, MD

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The phase III MURANO study compared venetoclax/rituximab with bendamustine/rituximab in 389 patients with relapsed or refractory CLL. The progression-free survival rates were significantly higher with venetoclax/rituximab, and the median progression-free survival was not reached in the venetoclax arm vs 17 months in the bendamustine arm, leading to FDA approval of this combination in all patients with a prior line of therapy.7

It is important to note that venetoclax is associated with a risk of tumor-lysis syndrome. Oral hydration and allopurinol are recommended for prophylaxis in the outpatient setting and with or without rasburicase (Elitek) in the inpatient setting. “Tumor-lysis syndrome is not likely if you follow the guidelines,” Dr. Allan noted.

The optimal sequencing of new agents is unknown in CLL. “The vast majority of studies support the use of venetoclax after ibrutinib or idelalisib, but there are no data vice versa,” he added. “Patients who fail to respond to chemoimmunotherapy should get novel agents and should not receive more chemoimmunotherapy. In fact, the earlier we start the novel agents, the better.”

Richter’s Transformation

Richter’s transformation is a rare but dreaded disease. About 10% of all patients with CLL develop Richter’s transformation, and outcomes are poor after CLL. “Survival is measured in months,” Dr. Allan said. “Patients can also transform to Hodgkin lymphoma, and although outcomes are better than those with diffuse large B-cell lymphoma transformation, outcomes appear worse than those seen with de novo Hodgkin lymphoma. Richter’s transformation is one of the biggest unmet needs in the field,” he added.

Therapeutic Update in Resistant CLL

  • Novel agents such as ibrutinib, idelalisib, and venetoclax are enjoying more widespread use for the treatment of relapsed or refractory CLL.
  • Although optimal sequencing of new agents has not been established by randomized, controlled trials, real-world experience suggests starting with ibrutinib followed by idelalisib or venetoclax.
  • Chemotherapy is not preferred after ibrutinib or idelalisib.

Treatment recommendations for Richter’s transformation include a clinical trial. About 20% of cases are not clonally related to CLL, and in these patients, “you can get away with R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone),” he noted. “If it is clonally related to CLL, patients typically have a very poor prognosis.”

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for the treatment of Richter’s transformation are categorized as to whether it is de novo or clonally related.8 These guidelines are based on small studies, with complete response rates frequently less than 10%. If complete response is not achieved, transplant won’t improve outcomes, Dr. Allan said.

Small studies suggest that anti–programmed cell death ligand 1 (PD-L1) strategies may hold promise, he continued. However, more data are needed. “We need new treatments for Richter’s transformation, and single-agent therapy is probably not going to be the answer,” Dr. Allan told listeners. ■

DISCLOSURE: Dr. Allan reported no conflicts of interest.


1. Allan JN: Updates in the management of CLL: Histologic transformation and relapsed/refractory disease. 2018 NCCN Annual Congress: Hematologic Malignancies. Presented September 22, 2018.

2. Byrd JC, Brown JR, O’Brien S, et al: Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 371:213-223, 2014.

3. O’Brien S, Furman RR, Coutre S, et al: Single-agent ibrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia: A 5-year experience. Blood 131:1910-1919, 2018.

4. Mato AR, Nabhan C, Thompson MC, et al: Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: A real-world analysis. Haematologica 103:874-879, 2018.

5. Woyach JA, Guinn D, Ruppert AS, et al: The development and expansion of resistant subclones precedes relapse during ibrutinib therapy in patients with CLL. 2016 ASH Annual Meeting. Abstract 55.

6. Stilgenbauer S, Eichhorst B, Schetelig J, et al: Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion. J Clin Oncol 36:1973-1980, 2018.

7. Seymour JF, Kipps TJ, Eichhorst B, et al: Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 378:1107-1120, 2018.

8. NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, version 1.2019. Available at Accessed October 4, 2018.