Page 1412 - Hematology_ Basic Principles and Practice ( PDFDrive )

1258 Part VII Hematologic Malignancies

in PLCγ2 are both potentially gain-of-function mutations that lead expression by CLL cells. Based on these promising data, a phase I/
to autonomous B-cell–receptor activity. To improve the depth of II study of ofatumumab, given at doses of 500–2000 weekly for
response, ibrutinib is being combined with various other agents like four doses in 33 relapsed or refractory CLL patients, demonstrated
rituximab and BR or FCR. This has resulted in higher response rates that it is generally well tolerated even at higher doses. Ofatumumab
but improvements in PFS are yet to be demonstrated. The combina- was active, with an ORR of 50% in the cohort treated at 2000 mg.
tion of ibrutinib and rituximab in patients with high-risk CLL was Infusion-related adverse events were similar to those reported with
generally well-tolerated and resulted in an OR rate of 95% and a PFS rituximab and decreased after the first infusion. Infections were fairly
of 78% at 18 months in all patients, and 72% in patients with del17p. common, occurring in 51% of patients, including one fatal infection.
A randomized phase III trial comparing BR + placebo with BR + These results prompted a pivotal, single-arm study of ofatumumab
ibrutinib in patients with relapsed CLL demonstrated a significant administered as eight weekly infusions of ofatumumab followed by
improvement in PFS in the ibrutinib arm. From preliminary reports, 4 monthly infusions. Patients received 300 mg as the first dose to
PFS at 18 months was 79% for the BR + ibrutinib arm and 24% in minimize infusion-related reactions, and the dose was increased to
the BR + placebo arm. Therapy was generally well tolerated with a 2000 mg for all subsequent infusions. Patients included in this study
slightly higher percentage of patients in the ibrutinib arm discontinu- were required to be fludarabine-refractory and also alemtuzumab-
ing therapy. These promising results have resulted in the initiation of refractory (FA-refractory group; n = 95) or to have bulky lymph-
two pivotal trials for the initial treatment of patients with CLL. The adenopathy larger than 5 cm (BF-refractory group; n = 111). The
ECOG (ECOG 1912) trial is for patients younger than 70 years of ORR, as assessed by an independent review committee, was 51% for
age and is comparing patients treated with either FCR or ibrutinib + the FA-refractory group and 44% for the BR-refractory group, with
rituximab. The Alliance (A041202) trial is for patients ≥65 years of two CRs observed in the BF-refractory group. All other responses
age and is comparing BR versus ibrutinib + rituximab versus ibrutinib were partial. The median duration of response was 5.7 months in
alone. Participation in these trials is strongly encouraged and they the FA-refractory group and 6.0 months in the BF-refractory group
have the potential to change the treatment paradigms for this disease. with most patients progressing during treatment. The median PFS
was 5.5 months in both the FA-refractory and BF-refractory groups.
Idelalisib Median OS was 14.2 months and 17.4 months, respectively. For
Idelalisib (GS1101, CAL-101) is an orally bioavailable, isoform rituximab-treated (n = 117), rituximab-refractory (n = 98), and
specific, PI3-kinase-δ inhibitor that, at therapeutic levels obtained in rituximab-naive (n = 89) patients, the OR rates were 43%, 44%,
patients, does not inhibit other isoforms of PI3-kinase. Genetic and 53%, respectively; median PFS was 5.3, 5.5, and 5.6 months,
mouse models knocking out PI3-kinase-δ demonstrate predominantly respectively; and median OS was 15.5, 15.5, and 20.2 months,
a B-cell defect, absent B1 lymphocytes, and disrupted BCR signaling. respectively. Thus, prior exposure to rituximab did not affect the
Preclinical studies demonstrated that idelalisib promotes the apoptosis response to ofatumumab.
of CLL cells via a PI3-kinase-δ pathway and inhibits signals from the The presence of del(17p13.1) was associated with a lower response
microenvironment that protects CLL cells from apoptosis. Based in rate and shorter median PFS in both patient groups (37% vs. 56%
part on these data, a phase I study in healthy volunteers showed this and 3.3 months vs. 5.5 months in FA-refractory group; 22% vs. 49%
agent to be well tolerated, and subsequently a large phase I study in and 3.8 vs. 5.6 months in BF-refractory group). Thus, in contrast to
NHL, CLL, multiple myeloma, and AML was undertaken. Idelalisib rituximab, ofatumumab is active as a single agent in del(17p13.1)
was active at all dose levels tested, with the dose-limiting toxicity CLL but has less activity as compared with alemtuzumab. Toxicity
being reversible transaminitis that generally occurs during the first 2 included infusion-related reactions, infections, and cytopenias. This
months of therapy in approximately 5% to 20% of patients, depend- trial led to accelerated approval of ofatumumab for the treatment of
ing on histology. Although patients with NHL experienced a higher patients with fludarabine- and alemtuzumab-refractory CLL, however,
incidence of transaminitis, the cause of which is poorly understood, a phase III study of ofatumumab versus physician’s choice of therapy
the incidence of transaminitis was less than 5% in CLL patients. In in bulky, fludarabine-refractory CLL has preliminarily not docu-
a phase I trial of 54 patients, with relapsed/refractory high-risk CLL mented a significant improvement in PFS. Determination of the
patients, idelalisib resulted in an ORR of 72 percent (including clinical superiority of ofatumumab over rituximab will require ran-
PR+L). The median PFS was 15.8 months. Therapy was generally domized trials comparing equivalent doses and as a result the use of
well-tolerated with the most commonly observed grade ≥3 adverse ofatumumab has been limited in CLL. In addition, the approval of
events being pneumonia in 20%, neutropenic fever in 11% and BCR signaling inhibitors has further diminished the use of this
diarrhea in 6% of the patients. Subsequent studies have been under- option in salvage therapy of CLL.
taken with idelalisib combining it with rituximab, ofatumumab,
obinutuzumab and bendamustine/rituximab, showing that combina-
tion therapy with idelalisib is feasible. The combination of idelalisib Other Emerging Therapeutic Modalities for Chronic
and rituximab was also compared with rituximab and placebo in a Lymphocytic Leukemia
phase III trial and resulted in an ORR of 81% versus 13% and PFS
at 1 year in excess of 90% versus 5.5 months in the rituximab and Several other promising therapeutics are in late phase II/III clinical
placebo arm respectively. Serious toxicities observed with idelalisib trials for CLL. Those with documented activity in this disease that
were similar to the ones observed with the single agent. Based on have potential to be approved for use in CLL are described here.
these results, idelalisib was approved in combination with rituximab
for the treatment of patients with relapsed CLL who would not be BCL2 Inhibitors
considered suitable for conventional chemotherapy. The BCL2 antiapoptotic protein is overexpressed in CLL and has
been shown to disrupt apoptosis of CLL cells. Although the BCL2
Ofatumumab in Relapsed Chronic antisense molecule genasense did not meet the bar for regulatory
Lymphocytic Leukemia approval in CLL, attempts to target BCL2 with small molecule
Ofatumumab is a fully human type I anti-CD20 monoclonal anti- inhibitors have proceeded. Another potent inhibitor of BCL2, navi-
body that was initially approved for the treatment of CLL in late toclax (formerly ABT263), demonstrated single agent activity in
2009. In vitro, it has improved CDC, ADCC, and direct killing relapsed CLL with a target specific (BCL-XL) dose-limiting toxicity
(with cross-linking), compared with rituximab. Ofatumumab has a of profound thrombocytopenia. A second-generation oral BCL2
different binding epitope of CD20 than rituximab, binding to both inhibitor venetoclax (ABT-199) that lacks off-target effects on
the small and large extracellular loops of CD20, and a slower off rate BCL-XL is currently being evaluated in clinical trials and has shown
as well. Ofatumumab is able to kill rituximab-resistant CLL cells impressive activity with deep remissions in patients with relapsed and
caused by its greater induction of CDC and its ability to kill cells with refractory CLL including those who have del17p. Therapy with
low CD20 expression, which may be relevant given the limited CD20 venetoclax has been complicated by the development of episodes of