Page 1411 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 77 Chronic Lymphocytic Leukemia 1257

expressed on all CLL cells and indolent B-NHL cells. Alemtuzumab and nodal sites. These findings prompted the introduction of several
has been demonstrated to mediate apoptosis, CDC, and ADCC of novel, orally available kinase inhibitors. In particular, agents targeting
CLL cells in vitro. CD52 is not shed, internalized, or modulated and the δ isoform of PI3-kinase and BTK have shown very promising
is therefore an ideal antigen for targeted immunotherapy. However, clinical activity and, importantly, durability of remission over time in
the ubiquitous expression of CD52 on normal lymphocytes and refractory CLL patients. Early results from these trials led to the
monocytes is predictive of the increased neutropenia, lymphopenia, approval of both ibrutinib and idelalisib for the treatment of patients
and infectious complications observed with alemtuzumab therapy. with relapsed CLL. Moreover, ibrutinib was also approved for treat-
Alemtuzumab has modest efficacy in patients with relapsed disease ment of patients with del17p disease. The results of these studies are
including patients with del17p disease but not in patients with bulky summarized later.
lymphadenopathy (>5 cm). Responses are better and more durable
when it was used in patients with previously untreated disease and Ibrutinib
comparable with other CD20 antibodies when used in combination Ibrutinib is a potent, irreversible, covalent inhibitor of BTK. BTK is
with chlorambucil. Similarly, the combination of alemtuzumab with a tyrosine kinase in the Tec family of tyrosine kinases and is an
chemotherapy resulted in improved responses but with significantly essential element of the BCR signaling pathway. Genetic knockout
higher toxicities. Alemtuzumab is not marketed in the U.S. anymore or inactivation of BTK in mice produces predominantly a B-cell
for CLL but is available from the manufacturer on request. Given its defect with absent B1 lymphocytes, diminished B cells, and disrupted
infrequent use, the discussion on alemtuzumab has been curtailed BCR signaling. Mutations in BTK in humans result in a more pro-
and readers are referred to previous editions of this chapter. found humoral immune defect with absent B cells, immunoglobulins,
and an increased incidence of infections. Preclinical work with
What is the Role of Ibrutinib in the Initial Management ibrutinib demonstrated disruption of BCR signaling and in vivo
activity in spontaneous canine lymphoma models with documented
of Patients With Del(17p13.1)? targeted inhibition of BTK. Preclinical trials demonstrated that
ibrutinib promotes apoptosis of CLL cells, inhibits activation of
Conventional chemotherapy has limited benefit in the initial treat- PI3-kinase, ERK1, and NFκB by external microenvironment signals,
ment of patients with del(17p13.1) deletion with the median PFS and also prevents CLL proliferation.
being in the range of 11–14 months. Limited and early data from Collectively, these preclinical studies prompted phase I/II studies
the use of ibrutinib has been extremely promising and ibrutinib use with ibrutinib in NHL and CLL. The phase I study of ibrutinib was
has resulted in an ORR of up to 97% in this high-risk group of completed at two dose levels above where BTK inhibition occurred
patients. Responses were rapid and deepened with time and resulted without obtaining a maximum tolerated dose. At the highest dose,
in a PFS at 24-months of 82%. This compares extremely well with toxicity was quite mild, including grade 1/2 nausea, diarrhea, infec-
historic data with alternative agents used for patients with del(17p.13) tions, rash, and fatigue. Activity was seen at all doses, including in 9
and along with activity observed in patients with relapsed disease, of 16 CLL/SLL patients. A subsequent trial used the 420 mg daily
resulted in the approval of ibrutinib for patients with del(17p13.1). oral dose of ibrutinib and demonstrated an ORR of 71% with an
additional 20% of patients experiencing PR with lymphocytosis
TREATMENT OF PATIENTS WITH RELAPSED CHRONIC (PR+L). The PR+L state observed with ibrutinib does not appear to
predict for inferior PFS. Importantly, the responses seen with ibruti-
LYMPHOCYTIC LEUKEMIA nib are sustained and resulted in a PFS of 69% at 30 months.
Responses to ibrutinib also tend to improve with time and after a
The approach to reinitiating therapy for CLL patients who have median follow up of 2-years CR rates improved from 2% to 7%.
relapsed after initial therapy is similar to that applied to the assess- Responses were also seen in patients with del17p who had an ORR
ment for initial therapy. Patients need not receive therapy at the first of 55.9% with a median duration of response of 25 months. This
sign of relapse. Rather, patients should have an indication for treat- compares favorably in historical comparison with either cyclin-
ment, as discussed earlier. Patients should have repeat interphase dependent kinase inhibitors or other conventional therapies used in
FISH analysis of the peripheral blood or a BM aspirate because the past for patients with del17p. Patients with previously untreated
patients may acquire additional cytogenetic abnormalities, most CLL also appear to benefit from ibrutinib monotherapy with an
notably del(17p13.1), as their CLL becomes more advanced. The ORR of 71% and 13% PR+L. PFS was 96% at 2 years. Ibrutinib
incidence of del(17p13.1) increases from 5% in patients at initial was also well tolerated and the most common side effects were diar-
diagnosis to nearly half of heavily treated patients with advanced rhea, nausea, and fatigue. A subsequent randomized study comparing
CLL, and acquisition of this abnormality has profound implications ibrutinib with ofatumumab in relapsed CLL confirmed the benefits
on treatment, as will be discussed later. IGHV mutational analysis of ibrutinib with an improved response rate, PFS and OS. However,
does not need to be performed if such information has been obtained these studies also demonstrated a higher incidence of both minor
previously because a patient’s IGHV mutational status does not bleeding possibly caused by a collagen-mediated platelet aggregation
change with time. A BM analysis should be performed if cytopenias defect and atrial fibrillation with ibrutinib. Ibrutinib should therefore
are present to confirm that CLL is the cause and to exclude other be used with caution in patients receiving concurrent anticoagulation
potential causes of cytopenias such as transformed lymphoma, pro- with warfarin and patients should be taken off treatment for 3–7 days
longed BM toxicity from prior therapy, or development of treatment- before and after surgical procedures. Patients experience a progressive
related myelodysplasia. Patients should be treated according to the decline in the incidence of infectious complications with continued
indications outlined in Table 77.5. Multiple novel agents have now use of ibrutinib and do not require routine antimicrobial prophylaxis.
been approved and more are in the advanced stages of development. There is also subjective improvements in stress, depressive symptoms,
The treatment for relapsed disease will continue to evolve with time. fatigue, and quality-of-life in patients.
In general, therapy is moving away from chemoimmunotherapy to Since treatment with ibrutinib does not result in CRs in the
better tolerated targeted oral agents especially for patients older than majority of patients, at this time it is recommended that treatment
70 years of age and those with multiple comorbid conditions. be continued indefinitely until disease progression or unaccept-
able toxicity, since ibrutinib discontinuation in heavily pretreated
Agents Targeting B-Cell Receptor patients often results in rapid disease progression. Development of
resistance has been rare but whole-exome sequencing has identified
Signaling Pathways a cysteine-to-serine mutation in BTK at the binding site of ibrutinib
and three distinct mutations in PLCγ2. Functional analysis revealed
BCR signaling and microenvironmental signals are now known to be that the C481S mutation of BTK results in a protein that is only
important in both proliferation and protection of CLL cells in BM reversibly inhibited by ibrutinib. The R665W and L845F mutations