NcXHF

NEW TARGETED THERAPIES FOR iNHL
TABLE 4. Selected Phase II Trial Data for mTOR Inhibition in iNHL
Median
Age
(Years)
Overall
Response
Rate (%)
Regimen
Disease
Subtype(s)
Progression-Free
Survival (Months) Grade 3 or Higher Toxicity (%)
Treatment-Related
Deaths (%)
Toxic
Discontinuation (%) Reference
Everolimus MZL 71 25 14 - 4 42 40
Everolimus WM 63 50 21 67 0 10 41
Everolimus CLL 74 18 5.1 68 hematologic, 41 nonhematologic 9 14 43
Temsirolimus FL 59 54 12.7 - 1 18 42
CLL, WM 57 11 4.6
Abbreviations: MZL, marginal-zone lymphoma; WM, Waldenström macroglobulinemia; CLL, chronic lymphocytic leukemia; FL, follicular lymphoma.
patients with the del(17p) cytogenetic abnormality. A phase
Ib/II, multicenter trial of ibrutinib was conducted in 85 patients
with relapsed CLL; the median age was 66, and 35% of
patients were age 70 or older. Patients had received a median
of four prior therapies, and 33% of patients harbored the
del(17p). In the study, 71% of patients responded to therapy
and 18% of patients had a partial response (PR) with lymphocytosis.
Patients with a del(17p) experienced a 68% ORR. The
discontinuation rate was 4% in the 420-mg cohort and 12% in
the 840-mg cohort. The most common severe adverse events
were pneumonia (12%) and dehydration (6%). Serious bleeding
occurred in 5% of patients and death occurred in 8% of
patients. Considering the age and prognostic features of the
study population, ibrutinib was well tolerated with no decrease
in effıcacy for patients with a del(17p). 45
Ibrutinib was also studied as fırst-line therapy in a phase
Ib/II trial of 31 patients with CLL/SLL age 65 or older; the
median age was 71. The ORR was 71%, with a 13% complete
response (CR) rate. Toxicity was mainly grade 1 to 2 in severity,
with serious adverse events including diarrhea (13%), fatigue
(3%), and infection (10%). Neither grade 4 nor grade 5 infections
were reported. 46 Thus, in the fırst-line setting among
older patients, ibrutinib is an effıcacious, well-tolerated
option.
Ibrutinib has also been studied versus ofatumumab in relapsed
or refractory CLL/SLL in a multicenter, open-label,
phase III trial that enrolled 391 patients; the median age was
67, and 32% of patients had a del(17p). The primary endpoint
was PFS. Compared with ofatumumab, ibrutinib had superior
PFS (HR, for progression 0.22; p 0.001), OS (HR, 0.43;
p 0.005), and ORR (63% versus 4%; p 0.001). Ibrutinib
also demonstrated superior effıcacy for patients with
del(17p). Severe adverse events occurred in 57% of patients
who received ibrutinib and 47% of patients who received ofatumumab.
Bleeding events occurred more in the ibrutinib
group (44%) compared with the ofatumumab group (12%).
Grade 3 or higher infections occurred in 24% of patients in
the ibrutinib arm and in 22% of patients in the ofatumumab
arm. Discontinuation because of adverse events occurred
in 4% of patients in each group. Fatal adverse events
occurred in 4% and 5% of patients in the ibrutinib and ofatumumab
arms, respectively. The relatively low rate of response to
ofatumumab compared with the study that resulted in the initial
FDA approval may have been attributable to more rigorous requirements
for serial CT scanning to assess response. 47 The effıcacy
of ibrutinib (versus placebo) is also being studied in
combination with bendamustine and rituximab in refractory
and relapsed CLL; the phase III HELIOS trial is currently
ongoing. 48
Ibrutinib has also shown effıcacy in relapsed or refractory
WM. In a phase II study of 63 patients of median age 63 who
had received a median of two prior therapies, ibrutinib induced
PRs in 57% of patients and minor responses in 24% of
patients. Treatment was discontinued by 6% of patients.
Common grade 2 or higher toxicities included thrombocytopenia
(14%) and neutropenia (19%). 49 On January 29, 2015,
the FDA approved ibrutinib for treatment of WM. In FL, a
phase II study of ibrutinib in 38 evaluable patients of median
age 64, demonstrated a more modest 30% ORR in the ibrutinib
arm, but 65% of patients had tumor size reduction. Grade
3 to 4 events occurred in 30% of patients, and 5% of patients
discontinued treatment because of adverse events. There was
one death due to gastric hemorrhage. 50
Ibrutinib has developed a track record as an effıcacious and
well-tolerated agent in CLL, especially in older patients. The
potential for bleeding in patients treated with ibrutinib and
the exclusion of patients on warfarin from most clinical trials
suggest that ibrutinib should be avoided in anticoagulated
patients or those patients with a history of serious bleeding
(such as intracranial hemorrhage). Importantly, it also offers
effıcacy for patients without regard to cytogenetic risk. Ibrutinib
has shown effıcacy in mantle cell and diffuse large cell
histologies as well. Later-generation BTK inhibitors are also
in development. 51,52
IMMUNOMODULATORY AGENTS
The immunomodulatory drugs (IMiDs) are thalidomide
analogs that have the capacity to alter immune microenvironments,
have antiangiogenic effects, promote T-cell costimulation,
and activate NK cells. 53 Lenalidomide has been
shown to stimulate T-cell– and NK-cell–mediated cytotoxicity
in indolent lymphomas. 54 Molecularly, IMiDs interfere
with the function of the ubiquitin ligase cereblon (CRBN),
which may be the key mediator for their microenvironmental
and immunomodulatory effects. CRBN has been shown to
interact with potassium and chloride channels, AMP-
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