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Kinase Inhibitors in Relapsed CLL
Utility of Kinase Inhibitors in the Management of Relapsed CLL

Released: April 27, 2015

Expiration: April 25, 2016

Farrukh Awan
Farrukh Awan, MD, MS
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Patients with relapsed CLL can now be effectively managed with novel kinase inhibitors, which target different mediators of B-cell receptor signaling and provide the critical survival and growth signals to CLL B cells through a variety of downstream kinases including LYN, PI3K, SYK, and BTK. Ibrutinib is approved as a single agent for patients with relapsed disease who have failed at least 1 previous line of therapy. Idelalisib is approved for relapsed patients in combination with rituximab for whom rituximab alone would be considered appropriate therapy due to other co-morbidities.

Ibrutinib
Targeting of BTK with ibrutinib in patients with relapsed disease resulted in an ORR of 71% (mostly PRs) with an additional 20% of patients experiencing PRs with lymphocytosis (PR+L). Response quality and duration was recently shown to improve over time, and after a median follow-up of approximately 2 years, the rate of CRs increase from approximately 2% to 7% with a PFS of 69% at 30 months. Ibrutinib is generally well tolerated and the most common adverse events are diarrhea, nausea, and fatigue. Atrial fibrillation and bleeding complications have also been observed, and it is advisable to avoid concomitant use of warfarin with ibrutinib and to hold treatment for 3-7 days before and after surgical procedures.

Idelalisib
Idelalisib inhibits the p110σ isoform of PI3K, which is constitutively overexpressed in CLL B cells. Single-agent idelalisib use in relapsed patients demonstrated an ORR of 72% (including PR+L) with a median PFS of 15.8 months. The combination of idelalisib and rituximab in the registration trial resulted in an ORR of 81% and PFS at 1 year in excess of 90%. Idelalisib is generally well tolerated with the most commonly reported adverse events being pneumonia and neutropenic fever. Other significant toxicities include transaminitis, pneumonitis, and diarrhea with colitis that are primarily observed after prolonged drug exposure.

Lymphocytosis
Patients treated with kinase inhibitors experience redistribution lymphocytosis during the first few weeks of therapy. The absolute lymphocyte count peaks at approximately 4-8 weeks of treatment and slowly declines thereafter. A subset of patients, however, will continue to have persistent lymphocytosis. This is not predictive of a worse prognosis, and these patients may actually experience better outcomes. As such, the increase in lymphocyte count should not be construed as a sign of disease progression as these patients report symptomatic improvement with reduction in the nodal burden of the disease and rarely require any intervention. Kinase inhibitors should be continued during this phase of treatment and the addition of various antibodies decrease the extent of lymphocytosis and affect a much quicker response.

Kinase Inhibitors in Clinical Trials
Kinase inhibitors either alone or in combination with antibodies are being evaluated in comparative trials to chemoimmunotherapy and these early efficacy and toxicity results, although preliminary, compare very well to historic data with chemoimmunotherapy-based regimens. Similarly, no data are available that compare outcomes among various kinase inhibitors or establishes the optimal sequence or duration of their use. Therefore, oral kinase inhibitors should be considered for continuous use until disease progression or unacceptable toxicity in patients relapsing after first-line chemoimmunotherapy or immunotherapy-based regimens.

My Decision
Let us consider the treatment options for an older patient: A 75-year-old, otherwise healthy male presents for treatment of relapsed CLL. The patient was diagnosed 6 years ago with unmutated IGHV, del(11q) CLL and subsequently underwent therapy with 6 cycles of FCR 5 years ago for symptomatic disease progression. The first cycle of FCR was complicated by a severe infusion reaction to rituximab and our patient had similar severe, life-threatening infusion reactions with the second and third infusions of rituximab. The subsequent cycles of treatment were administered without rituximab. The patient eventually achieved a CR that lasted for 3 years and during the last year has had slowly progressive lymphadenopathy and now has symptomatic anemia and thrombocytopenia.

In this particular case, the patient has had life-threatening reactions to rituximab infusions despite appropriate management. Therefore, further use of rituximab might be difficult and associated with significant infusion reactions. Of the given choices, ibrutinib without rituximab is the most optimal choice of therapy for this patient. No data are currently available that compare ibrutinib to idelalisib directly or guide us toward the correct sequence of their use. Patients who fail one class of kinase inhibitor do respond to the others, but data are limited. The decision to use a specific kinase inhibitor should be based on patient and provider preference, comorbid conditions, and use of concomitant medications with potential drug–drug interactions. For example, it would be better to avoid ibrutinib in patients receiving concurrent warfarin treatment and similarly avoid idelalisib in patients with existing gastrointestinal issues. Clinical trial participation is strongly recommended whenever feasible to enable us to answer existing management questions related to duration and sequence of therapy.

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1.
A 75-year-old otherwise healthy male presents for treatment of relapsed CLL:
  • • Diagnosed 6 years ago with unmutated IGHV, del(11q) CLL and underwent therapy with 6 cycles of FCR 5 years ago for symptomatic disease progression
  • • First cycle of FCR was complicated by a severe infusion reaction to rituximab.
  • • He achieved a CR that lasted for 3 years
  • • During the last year, he has had slowly progressive lymphadenopathy and now has symptomatic anemia and thrombocytopenia
How would you treat this patient?
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