MRD Assessment and Treatment Selection in CLL

Danielle M. Brander, MD: When patients are initiated on ibrutinib in the frontline or relapsed setting, patients are started at the full dose of the drug, and monitoring is usually by in-visit, in-clinic visits that include a physical exam as well as routine blood work. The purpose of this monitoring is to ensure that the patient is responding to treatment and tolerating the therapy. Though many patients with bulky lymph nodes or other disease may be started on allopurinol or other medications to mitigate any cell turnover and rise in uric acid, tumor lysis monitoring is not otherwise standardly employed, or certainly not frequently for patients receiving ibrutinib.

In terms of response, patients can have response often within the week in terms of improvement in symptoms or their lymph nodes. Their subsequent follow-up appointments, again, will consist of an exam as well as testing to make sure that they are responding and tolerating their medication. If patients are doing well, these visits are spaced out to every several weeks. And moving forward, visits are adjusted if the patient develops any adverse effects or toxicities.

Monitoring patients’ responses outside of the clinical trial, as mentioned, should include the physical exam as well as bloodwork. CT scans and imaging are not necessarily required unless there’s bulky disease that needs to be monitored that way and there’s lack of evidence of response in other regions.

Development of resistance for ibrutinib, especially in the frontline setting, is not common and would be incredibly rare, especially in the first year on the drug. Therefore, if a patient has evidence of any kind of progressive disease early on during therapy, one should look for other causes such as transformation of the CLL [chronic lymphocytic leukemia].

In terms of response, this is looking for reduction in whatever symptoms or disease is the reason for patients to start on therapy. Complete responses to ibrutinib often take time, usually in the period of years. One study suggested that after 5 years of frontline follow-up, complete response rates increased to almost 30%. But these responses took time.

Minimal residual disease, or MRD-negativity, has historically been an important milestone to predict length of remission for patients receiving chemoimmunotherapy, and more studies are also showing the importance of MRD in predicting longitudinal responses and PFS [progression-free survival] with venetoclax. However, because MRD achievement is an uncommon event for patients receiving ibrutinib monotherapy and doesn’t necessarily mean that patients can’t have very long responses on the drug, MRD testing is not employed outside of clinical trials for ibrutinib, certainly not as monotherapy.

In terms of patients and their risk of relapse, as mentioned for ibrutinib monotherapy, as used in this case, one would not use MRD monitoring in clinical practice. In clinical trials, when the drug is used in combination with other targeted agents, or anti-CD20 antibodies, one might use MRD testing. But again, this is done within the context of clinical trials.

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