Page 1563 - Williams Hematology ( PDFDrive )

1538 Part XI: Malignant Lymphoid Diseases Chapter 92: Chronic Lymphocytic Leukemia 1539

KINASE INHIBITORS from whole-exome sequencing of paired samples at baseline and at the
The introduction of BCR kinase inhibitors has significantly improved time of relapse while being treated with ibrutinib identified a cysteine-
the management options for patients with CLL and represents a group to-serine mutation in BTK at the binding site of ibrutinib and three dis-
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of agents that very likely will change the natural history of this disease. tinct mutations in PLCγ . Functional analysis revealed that the C481S
2
Early results with these agents including ibrutinib and idelalisib that mutation of BTK results in a protein that is only reversibly inhibited by
target BTK and PI3K, respectively, have shown promising efficacy and ibrutinib. The R665W and L845F mutations in PLCγ are both poten-
2
excellent tolerability but long-term data is limited to 4 years of followup tially gain-of-function mutations that lead to autonomous BCR activ-
and decision rules need to be developed that allow for eventual treat- ity. Interestingly, these mutations were not found in any of the patients
ment discontinuation. Much of what was learned from the transition with prolonged lymphocytosis who were taking ibrutinib, suggesting
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of chemoimmunotherapy management of chronic myeloid leukemia an alternative and as yet unidentified mechanism for the persistence of
will likely become relevant to CLL as additional follow up develops with lymphocytosis in those patients. Furthermore, the clinical impact of this
the use of BCR antagonists in this disease. persistent lymphocytosis was not demonstrated, with individuals hav-
ing persistent lymphocytosis actually having similar outcome to those
patients with PRs or better.
Ibrutinib Ibrutinib is being combined with various other agents to improve
Ibrutinib is a first-in-class, irreversible inhibitor of BTK and covalently the depth of response and outcomes. The combination of ibrutinib and
binds to Cys-481 near the ATP binding domain of the BTK molecule, rituximab in patients with high-risk CLL was generally well-tolerated and
and abrogates enzyme activity and BCR-mediated survival signals. resulted in an ORR of 95 percent and a PFS of 78 percent at 18 months.
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Ibrutinib also has the ability to irreversibly target ITK in T cells and PFS was 72 percent at 18 months in patients with del 17p. Multiple trials
other Tec family of kinases. 274 are ongoing with ibrutinib in the frontline setting and in comparison to
A 420-mg daily oral dose of ibrutinib has been used in the treat- chemoimmunotherapy. These trials and the development of newer BTK
ment of patients with relapsed CLL and demonstrated an ORR of inhibitors have the potential to change the treatment paradigms for CLL.
71 percent with an additional 20 percent of patients experiencing partial
response (PR) with lymphocytosis (PR+L), which, interestingly, does
not appear to predict for inferior PFS. The responses observed with Idelalisib
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ibrutinib are sustained and resulted in PFS of 75 percent at 26 months. Idelalisib is an orally bioavailable, first-in-class isoform selective PI3K-δ
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Patients with del 17p had an ORR of 55.9 percent with a median dura- inhibitor that promoted apoptosis of CLL B cells ex vivo, along with
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tion of response of 25 months. Historical comparisons reveal a signifi- abrogating the survival signals provided by the microenvironment.
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cantly improved response rate and PFS when ibrutinib was compared to The PI3K family of enzymes are involved in an extraordinarily diverse
either cyclin-dependent kinase (CDK) inhibitors or other conventional group of cellular functions, including cell growth, proliferation, dif-
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therapies used in the past for patients with del 17p. Similar excit- ferentiation, motility, survival, and intracellular trafficking. Many of
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ing results were reported in elderly, treatment-naïve patients treated these functions relate to the ability of class I PI3Ks to activate the PI3K/
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with ibrutinib with ORR of 71 percent and 13 percent PR+L. These AKT/mTOR (mammalian target of rapamycin) pathway. The p110δ
responses also appear to be sustained over time with PFS of 96.1 per- isoform regulates different aspects of cellular proliferation and sur-
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cent at 2 years. Ibrutinib in general is well-tolerated, with the most vival and is constitutively overexpressed in CLL B cells ; consequently,
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common side effects being mild diarrhea, nausea, and fatigue. A ran- targeting it with specific inhibitors has become a useful therapeutic
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domized study comparing ibrutinib to ofatumumab in relapsed CLL option.
confirmed the benefits of ibrutinib with improved response rate, PFS, In a phase I trial of 54 patients, with relapsed/refractory high-risk
and OS. However, this study also demonstrated a higher incidence CLL patients, idelalisib resulted in an ORR of 72 percent (including
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of both minor bleeding and atrial fibrillation with ibrutinib. The bleed- PR+L). The median PFS was 15.8 months. Therapy was generally well-
ing diathesis observed with ibrutinib is possibly caused by a collagen- tolerated with the most commonly observed grade 3 or greater adverse
mediated platelet aggregation defect. 278,279 Caution should be taken to events being pneumonia (20 percent), neutropenic fever (11 percent),
avoid the use of ibrutinib in patients on concurrent anticoagulation and diarrhea (6 percent). The combination of idelalisib and rituximab
with warfarin and treatment should be held 3 to 7 days before and after was also compared to rituximab and placebo in a phase III trial and
surgical procedures. The pathophysiologic reason for increased risk of resulted in an ORR of 81 percent versus 13 percent and PFS at 1 year
atrial fibrillation with ibrutinib is uncertain. Ibrutinib treatment also in excess of 90 percent versus 5.5 months in the rituximab and placebo
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results in a progressive decline in the incidence of infectious compli- arms, respectively. Serious toxicities observed with idelalisib included
cations with ongoing therapy, primarily as a result of disease control. transaminase elevations, diarrhea with colitis, and pneumonitis that
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Most patients do not require routine antimicrobial prophylaxis com- were primarily observed after continued drug exposure. Based on these
monly used with chemoimmunotherapy. Moreover, improvements are results, idelalisib was approved in 2014 in combination with rituximab
also observed in stress, depressive symptoms, fatigue, and quality-of-life for the treatment of patients with relapsed CLL with significant comor-
in patients treated with ibrutinib. Based on these exciting data, ibruti- bid conditions that would make them ineligible for treatment with stan-
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nib was approved in 2014 for the treatment of all patients with relapsed dard chemotherapy.
CLL and for the treatment of all patients with del 17p CLL regardless of
prior therapy. Lenalidomide
Treatment with ibrutinib does not result in CRs in most patients Lenalidomide is an immunomodulatory analogue of thalidomide and
and discontinuing this treatment in heavily pretreated patients often is approved for the treatment of multiple myeloma and myelodysplastic
results in patients experiencing rapid disease progression. Therefore, we syndrome. Lenalidomide has also shown exciting efficacy in patients
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currently recommend that ibrutinib be continued in responding patients with previously treated and untreated CLL in multiple studies. 289–293
until disease progression or unacceptable toxicity. However, this chronic Multiple dose levels and schedules have been tested in CLL with varying
exposure to kinase inhibitors might result in the emergence of resistant responses. From compilation of all the data it appears that 5 mg daily
malignant cell clones, although this has been quite rare. Data derived continuous dose of lenalidomide appears to be the best-tolerated dose
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Kaushansky_chapter 92_p1527-1552.indd 1538 9/18/15 10:47 AM