Treatment Options for Relapsed CLL

Danielle M. Brander, MD: In this case, the patient received ibrutinib and was treated as one would be per the standard of care, which is continuously until the time of progression. However, after approximately 3 years on therapy, he was demonstrating evidence of progression by both his symptoms as well as palpable disease in the lymph nodes and in the spleen, and then he was confirmed to have progressive disease.

Because he was confirmed to have progressive disease, in this case, in the second-line setting, he would meet the indication for transitioning fairly quickly to the next line of therapy because the disease was progressive.

In other situations, like if a patient had received chemoimmunotherapy on the frontline setting, for example, they obviously would not have been receiving this continuously and may have been off treatment for a period of time until you saw the return of the CLL [chronic lymphocytic leukemia]. Or, in some cases, now with their approval of fixed duration therapy with venetoclax and obinutuzumab in the frontline setting, those patients are treated for 1 year then stop treatment.

In both of those latter cases, when patients have cessation of therapy they are monitored until the time of disease relapse. A patient may not need to start the second line of therapy right away. During the patient’s routine follow-up, you might notice that their white blood cell count and lymphocyte count are starting to increase, but they have no symptoms. Or, they might have slow return in their lymph nodes, but, again, they are not large or symptomatic.

In the second-line setting, if patients are not progressing on continuous therapy, you should monitor again and consider the iwCLL [International Workshop on Chronic Lymphocytic Leukemia] indications for a treatment option, as was discussed before, because patients might not need treatment right away upon initial relapse.

At the time of relapse, though, they should receive full work-up, including consideration to resend some of the prognostic markers, namely FISH [fluorescence in situ hybridization] testing, chromosome testing, and TP53 mutational analysis. Again, the results of those tests would not necessarily change whether they need to start treatment right away at relapse. However, patients who might not have had the highest-risk markers, such as deletion 17P or TP53 mutations, at the time of their first treatment may be found to have this at the time of relapse. That could inform several conversations with the patient, including consideration of clinical trials if found to have this higher-risk disease.

In this case, though, I want to go back to the fact that ibrutinib or other BTK [Bruton tyrosine kinase] inhibitors, or many B-cell receptor downstream targeted therapies are administered continuously until the time of progression. In this case, the patient does need treatment transitioned fairly quickly. And I should also point out that because they’re on active treatment, at the time of progression on ibrutinib one should not stop the medication abruptly until you’ve had time to review options with the patient and plan accordingly for the next line of therapy. Even though they’re progressing on treatment, it may still have some effect on some of the CLL cells. Stopping the drug quickly could result in a flare of the disease or an even more rapid progression.

In terms of options in the relapsed/refractory setting, or specifically for this patient with resistance to ibrutinib, multiple trials in the relapsed/refractory setting have shown an overall survival benefit to targeted agents. There is no evidence for transitioning this patient back to chemoimmunotherapy.

Among the other targeted agent options in the relapsed/refractory setting would be venetoclax, a BCL-2 inhibitor, either as monotherapy or in combination with rituximab; idelalisib with or without rituximab, which is a PI3-kinase delta isoform inhibitor. And if this was for third-line treatment, also duvelisib, which is a dual gamma-delta inhibitor.

If this patient was being transitioned to either of the targeted agents I mentioned, either the venetoclax-based regimen or idelalisib, I would have treatment planning for that patient, and again, not stop the ibrutinib until I was ready to start the next line of therapy.

Just like in the frontline setting, patient-specific factors are important in treatment planning—namely, the patient’s comorbidities. For example, this patient with a chronic kidney disease had reduced creatinine clearance. This is important because if venetoclax therapy is chosen, patients are at risk for tumor lysis, and this is part of the dose ramp-up and monitoring. Tumor lysis risk and the need for hospitalization during the initial dosing depends on the disease but also patient-specific factors such as renal dysfunction.

In terms of choosing a PI3-kinase inhibitor as the next line of therapy, the toxicities that one must be mindful of that can develop with treatment of these agents can include both early and late onset of symptoms such as colitis, which can lead to diarrhea and dehydration as it can be very profound. Patients can also have other immune-like conditions such as increases in their LFTs or pneumonitis. Many have looked at baseline clinical factors that might predict the development of these agents, but it is not entirely clear, for example, whether patients with a baseline dysfunction, such as lung disease, are necessarily at higher risk. All patients should be considered at risk for the development of these toxicities.

In any case, if this patient is transitioned, for example, to next-line therapy, we sometimes draw from some clinical trials that have specifically studied agents after ibrutinib progression. These studies are fairly limited and patient numbered to date, and that’s largely due to the timing of the development of these agents. Also, many patients on the initial relapsed/refractory clinical trials had been treated in earlier settings only with chemoimmunotherapy.

There is 1 series using venetoclax in patients following ibrutinib therapy. This explored approximately 90 patients. The patients were treated with venetoclax after ibrutinib, either if they stopped ibrutinib due to resistance or if they stopped it due to intolerance. Here, the response rates were approximately 60% for the entire population. Again, however, one must be considerate of tumor lysis. And in this case, with a patient with reduced renal function, if they were receiving venetoclax I would counsel the patient on the high tumor lysis risk and consider hospitalization for tumor lysis monitoring.

Transcript edited for clarity.

Case: A 73-Year-Old Man With Relapsed Chronic Lymphocytic Leukemia

Initial Presentation

• A 73-year-old man presented to his PCP for an annual checkup; he complained of mild intermittent fatigue and occasional night sweats
• PMH: hypertension, medically controlled
• PE: palpable axillary and right-sided cervical lymphadenopathy
  
  

Clinical Work-up

• Labs: WBC 48,000, lymphocyte 72%, ANC 3700/mm3, Hb 9.4 g/dL, plt 100 x 109/L, LDH 240 U/L, Beta-2-microglobulin 4.1 mg/L
• FC CD 5+, CD23+, CD20+ monoclonal B-cell population
• FISH: normal for all CLL probe set tested, no evidence t11;14
• IGHV mutational status: unmutated
• Rai stage IV; Binet stage B
• ECOG PS 0

Treatment and Follow-up

• He was started on ibrutinib 420 mg PO qDay; symptoms improved and achieved stable disease resolution of lymphadenopathy
• After about 3 years he complained of increasing fatigue and decreased appetite, on PE return of palpable lymphadenopathy spleen was palpable ~4 cm below costal margin; creatinine clearance 56 mL/min