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How I Treat In Brief: Managing Ibrutinib-Refractory Chronic Lymphocytic Leukemia

December 30, 2021

Jennifer A. Woyach, MD, associate professor at the Ohio State University Comprehensive Cancer Center, wrote about her strategy for the management of patients with chronic lymphocytic leukemia whose disease is refractory to ibrutinib. Below, we summarize her approach.

This material was repurposed from "How I manage ibrutinib-refractory chronic lymphocytic leukemia," published in Blood on January 17, 2017.

  • Ibrutinib-refractoriness is determined by progression on repeated evaluations so that an effective therapy is not abandoned.
  • There are two forms of ibrutinib relapse: progressive CLL and histologic transformation.
  • Ibrutinib should not be discontinued in a relapsing patient without a new treatment plan in place.
  • Karyotypic complexity at baseline and the development of BTK and PLCG2 mutations can help clinicians identify which patients will relapse on ibrutinib.
  • Short-term disease management options include venetoclax or idelalisib plus rituximab in certain patients.
  • Long-term disease control can include transplant for eligible patients or enrollment in a clinical trial of CAR T-cell therapies or a checkpoint inhibitor for transplant-ineligible patients.

The introduction of the oral Bruton tyrosine kinase (BTK) inhibitor ibrutinib for the treatment of patients with chronic lymphocytic leukemia (CLL) dramatically changed the management of this disease. In clinical trials, ibrutinib improved both progression-free survival (PFS) and overall survival for patients with relapsed and treatment-naive CLL, including those with high-risk disease, compared with prior standard of care.

While the remarkable data make it tempting to think that patients could be treated with ibrutinib for the rest of their natural lives, relapse does indeed occur, and ibrutinib-refractoriness is becoming an increasingly common clinical problem.

Defining Relapse on Ibrutinib 

Relapse on ibrutinib occurs in two forms:

  • progressive CLL, which typically occurs after at least 1 year of therapy and increases in frequency with time on therapy
  • histologic transformation, or Richter transformation, which generally occurs within the first 2 years of treatment, more frequently with large cell lymphoma or prolymphocytic leukemia

Because most patients who are on continuous ibrutinib therapy will not attain a complete response and many will have circulating leukemia cells for long periods of time, determining which patients are indeed relapsing can be a challenge.

Case #1: Ruling out Ibrutinib Resistance 

A 53-year-old man with relapsed CLL started ibrutinib seven months ago and had a partial response with lymphocytosis (PRL), along with a steadily decreasing absolute lymphocyte count (ALC; last recorded value was 20,000/μL 1 month prior). He was feeling well until about four days ago, when he began to have a lowgrade fever, myalgia, cough, and new cervical adenopathy. On exam, he has bilateral cervical nodes 2×2 cm and no other adenopathy. His white blood cell count (WBC) is 36×109/L, with an ALC of 30/μL.

Comments: This patient's scenario is common for an upper respiratory infection leading to cervical adenopathy and increased WBC. Infections are frequently accompanied by a rise in lymphocyte count, especially in patients with residual lymphocytosis on ibrutinib. The PRL status is a newer designation in which patients may meet criteria for a partial response (PR) by node resolution and blood count improvement long before lymphocytosis resolves; however, it has not been shown to result in an inferior remission duration compared with patients who achieve a standard PR.

For this patient, ibrutinib should be continued but, because constitutional symptoms can occasionally herald the development of Richter transformation in these patients, I would have the patient return if symptoms persist longer than one week and consider rechecking blood counts in one month.

Patients must show progression on repeated evaluations to avoid abandoning an effective therapy. If a relapse is confirmed, ibrutinib should not be discontinued until a new treatment plan is in place.

Case #2: Identifying Ibrutinib Relapse 

A 50-year-old woman with CLL has been receiving ibrutinib for three years as her third-line therapy and has been feeling well. On routine exam, she has no palpable lymphadenopathy, but ALC has increased from 3,000/μL to 6,000/μL. Two months later, her ALC has further risen to 8,000/μL, and, although she remains asymptomatic, she has a new 1.5 cm lymph node in her neck.

Comments: This patient is relapsing on ibrutinib with an increasing WBC count and the presence of new palpable adenopathy. It is important to closely monitor patients who show any signs of disease progression, so that relapse can be caught early. The tempo of relapse tends to escalate when ibrutinib is discontinued, so ibrutinib should be continued until the next therapy is started. If a wash-out period is necessary before a next-line clinical trial, the patient will need to be watched closely for disease escalation during the off-ibrutinib period.

Case #3: CLL Progression Without Ibrutinib Resistance 

A 75-year-old man with relapsed CLL who has been taking ibrutinib for two years has achieved a PR, with residual small abdominal nodes and low-level bone marrow involvement, but normal peripheral counts. Seven days before a planned procedure, he discontinues ibrutinib. On the morning of the procedure, he notes he has experienced three days of night sweats and fatigue and he has a WBC of 2×109/L, hemoglobin of 9.4 g/dL, and platelets of 110×109/L – similar to symptoms he had prior to initiating ibrutinib. He has previously stopped ibrutinib for three months with no symptoms.

Comments: The patient has developed signs of disease progression while holding the drug, but not ibrutinib resistance. The drug should be reinstated as soon as possible, and a quick response can be expected. Drug discontinuations need to occur for as short a period as possible with occasional steroid use for palliation until ibrutinib is restarted.

Predicting Disease Progression on Ibrutinib 

Although symptomatic disease progression upon ibrutinib withdrawal appears to be most common earlier in therapy and in patients with higher levels of residual disease, it cannot routinely be predicted. The most significant independent predictor for ibrutinib relapse appears to be baseline karyotypic complexity on stimulated karyotype, but other risk factors will likely emerge as clinical trial data mature, including a patient's number of prior treatments and del17p status.

Relapse while on ibrutinib primarily occurs through the acquisition of mutations in BTK (the most common is BTK C481S) or its immediate downstream target, PLCG2. These mutations have been detected using high-sensitivity assays in 85 to 90 percent of patients at disease relapse. Clonal evolution is a hallmark of ibrutinib resistance, with researchers noting a recurrent deletion in 8p in patients at the time of relapse.

At our center, we have begun to screen all patients with CLL every three months for BTK and PLCG2 mutations. The detection of these mutations reliably predicts patients whose disease will go on to relapse. In the context of a clinical trial, we will offer the addition of a novel agent to ibrutinib to patients who develop an ibrutinib-resistance mutation to try to prolong remission duration. Whether this strategy does indeed prolong remission duration remains to be seen; if effective, it would certainly be preferable to prevent relapse than to treat uncontrolled CLL.

Treatment Options for Ibrutinib- Refractory CLL 

My approach to treating a patient with ibrutinib-refractory CLL is summarized in the FIGURE. When I see patients in clinic who are relapsing on ibrutinib, we discuss short-term disease management and long-term disease control. In the short-term, I prefer enrolling a patient in a clinical trial whenever possible.

I always repeat FISH and cytogenetic testing at the time of relapse. The most promising treatment option for ibrutinib-resistant patients is venetoclax, a BCL2 inhibitor, which was approved by the U.S. Food and Drug Administration (FDA) in June 2018 for all patients with previously treated CLL, regardless of del17p status – expanding on its initial approval for only patients who harbored a del17p mutation.

Upregulation of PI3K commonly is seen in patients with ibrutinib-resistant lymphoma, suggesting that idelalisib-based therapy may be successful in the ibrutinib-refractory population. For patients without del17p-mutated CLL, treatment with the PI3K inhibitor idelalisib plus rituximab is a reasonable consideration although, given the limited PFS reported with PI3K inhibitors in this setting, I view idelalisib as a bridge to a long-term strategy. So far, a real-world experience of patients treated with idelalisib upon ibrutinib resistance showed a 28-percent response rate with a median PFS of eight months.

Duvelisib, another PI3K inhibitor, was approved by the FDA in September 2018 for the treatment of patients with relapsed or refractory CLL, although patients in the pivotal trial were not stratified based on BTK mutational status.

I do not consider chemoimmunotherapy or single-agent CD20 antibodies to be a reasonable intervention, as anecdotal reports have not indicated efficacy and there are no formal data about this approach.

For long-term disease control, hematopoietic cell transplantation with reduced-intensity conditioning is an option for eligible patients, including those with Richter transformation. For those who are transplant-ineligible, I would consider a clinical trial evaluating a chimeric antigen receptor (CAR) T-cell therapy.

Patients who relapse with Richter transformation present a treatment challenge, as there are limited trial data in this population and outcomes are dismal. For the few patients without complex karyotype or who have clonally unrelated Richter transformation, I use chemoimmunotherapy. I typically choose R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), based on data showing particularly good outcomes. Other chemoimmunotherapy regimens can be considered as well. For all other patients, I recommend a clinical trial of an investigational agent, if available, and all eligible patients with Richter transformation following ibrutinib should be considered for transplant.

Future Directions 

Patients with acquired resistance to ibrutinib have poor survival outcomes, underscoring the need for new, effective therapies for this high-risk patient population. Several agents for the treatment of CLL are under investigation.

Entospletinib, a spleen tyrosine kinase (Syk) inhibitor, is being studied in patients with CLL who were previously treated with a BTK inhibitor. This approach is supported by preclinical data suggesting that the inhibition of Syk can overcome PLCG2 mutations and thus could also be beneficial in the presence of upstream mutations. The preliminary response rate is 28 percent after 16 weeks of treatment.

Because the mutations that have been associated with relapse do not substantially alter the B-cell receptor (BCR) pathway, alternative targeting of the BCR pathway at or downstream of sites of mutation also may be an effective strategy to treat relapsed patients. Reversible BTK inhibitors have shown preclinical efficacy, and, for patients with PLCG2 mutations or BTK mutations, downstream targets such as PKCβ may be clinically relevant.

Agents that target BTK in a manner distinct from ibrutinib (including HSP90 inhibitors, HDAC inhibitors, and XPO1 inhibitors) also have the potential to be beneficial in ibrutinib-refractory patients.

As more research is performed to determine which patients are at risk for relapse on ibrutinib, it will be important to identify high-risk patients a priori and consider them for combination therapies, hematopoietic cell transplantation, or other long-term intervention. The identification of biomarkers of impending relapse also may allow for salvage therapies or combination strategies before the accelerated disease progression associated with relapse.


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