Page 1602 - Hematology_ Basic Principles and Practice ( PDFDrive )

1428 Part VII Hematologic Malignancies

R-CP. The results of this study suggest that in patients with WM, the Novel Therapeutics. The use of ibrutinib was recently approved
use of R-CP may provide treatment responses analogous to those of by the U.S. Food and Drug Administration for the treatment of
more intense cyclophosphamide-based regimens while minimizing symptomatic patients with WM. Ibrutinib targets BTK, a target of
. In a multicenter study
treatment-related complications. The extended alkylator bendamus- ibrutinib that is activated by MYD88 L265P 43
tine has also been evaluated in combination with rituximab in both in which researchers examined the role of ibrutinib in previously
untreated and previously treated patients with WM. A randomized treated (median 2 prior therapies, 40% refractory) patients with
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study by the German STiL Group examined bendamustine plus WM, the ORR was 87%. Patients on this study received 420 mg
rituximab (Benda-R) versus R-CHOP in patients with untreated, per day of ibrutinib by mouth. Posttherapy median serum IgM
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indolent B-cell lymphomas including WM. Patients with WM in levels declined from 3610 to 915 mg/dL; hemoglobin rose from
this study showed similar overall responses (96% vs. 94%), though 10.5 to 13.5 g/dL; and BM involvement declined from 60% to
progression-free survival was significantly longer (69 vs. 29 months) 30%. Decreased or resolved adenopathy was observed in 60% of
in patients who received Benda-R versus R-CHOP. Treatment was patients with extramedullary disease, and five of nine patients with
also better tolerated in patients receiving Benda-R. In the relapsed or IgM-related peripheral neuropathy had symptomatic improve-
refractory setting, an ORR of 83% was observed with bendamustine ment. The 18-month estimates for progression-free and overall
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in combination with a CD20 monoclonal antibody. The median survival were 83% and 93%, respectively. Although major response
time to progression was 13 months in this study. Prolonged myelo- rates were lower in patients with MYD88 wild-type and CXCR4 WHIM
suppression was more common in patients who had received prior mutations, it is not recommended that genotyping be used to select
nucleoside analogue therapy. which patients should be placed on ibrutinib until further data are
The use of two cycles of oral cyclophosphamide along with sub- available. Grade ≥2 treatment-related toxicities included neutropenia
cutaneous cladribine to 37 patients with previously untreated WM (25%) and thrombocytopenia (14%) that were more common in
led to a partial response in 84% of patients, and the median duration heavily pretreated patients, atrial fibrillation associated with a prior
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of response was 36 months. Fludarabine in combination with history of arrhythmia (5%), and bleeding associated with procedures
intravenous cyclophosphamide resulted in partial responses in 6 and marine oil supplements (3%). Serum IgA and IgG levels were
(55%) of 11 patients with WM with either primary refractory disease unchanged following treatment with ibrutinib, and treatment-related
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or who had relapsed on treatment. The combination of fludarabine infections were infrequent.
plus cyclophosphamide was also evaluated in 49 patients, 35 of whom Everolimus is an oral inhibitor of the mammalian target of rapamycin
were previously treated. Seventy-eight percent of the patients achieved (mTOR) pathway that is active in WM. In a multicenter study, inves-
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a response, and the median time to treatment failure was 27 months. tigators examined everolimus in 60 previously treated patients and
Hematologic toxicity was frequent, and three patients died as a result showed an ORR of 73%, with 50% of patients attaining a major
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of treatment-related toxicities. Two important findings in this study response. The median progression-free survival in this study was 21
were the development of acute leukemia in two patients, histologic months. Grade 3 or higher related toxicities were observed in 67% of
transformation to diffuse large B-cell lymphoma in one patient, and patients, with cytopenias constituting the most common toxicity. Pul-
two cases of solid malignancies (prostate and melanoma), as well as monary toxicity occurred in 5% of patients, and dose reductions owing
failure to mobilize stem cells in four of six patients. to toxicity occurred in 52% of patients. In a clinical trial in which
The combination of bortezomib, dexamethasone, and rituximab researchers examined the activity of everolimus in 33 previously
(BDR) as primary therapy in patients with WM resulted in an ORR untreated patients with WM, serial BM biopsies were included in
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of 96% and a major response rate of 83%. The incidence of grade response assessment. The ORR in this study was 72%, including
3 neuropathy was approximately 30%, but this was reversible in most partial or better responses in 60% of patients. However, discordance
patients following discontinuation of therapy. An increased incidence between serum IgM levels upon which consensus criteria for response
of herpes zoster was also observed, prompting the prophylactic use are based and BM disease response was common, which complicated
of antiviral therapy. Alternative schedules for administration of response assessment. In a few patients, discontinuation of everolimus
bortezomib (i.e., once weekly at higher doses) in combination with led to rapid increases in serum IgM levels and symptomatic hyperviscos-
rituximab in patients with WM have achieved ORRs of 80% to ity. Grade ≥2 hematologic and nonhematologic toxicities in this study
90%. 177,178 The European Myeloma Network recently showed that that were related to everolimus were predominately hematological,
transitioning bortezomib from twice-weekly intravenous dosing including anemia (40%), thrombocytopenia (12%), and neutropenia
during the first cycle to weekly administration thereafter reduced (18%). Nonhematologic toxicities included oral ulcerations (27%) that
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grade 3 neuropathy to under 10% in patients treated with BDR. improved with oral dexamethasone swish and spit solution, as well as
There have been no studies addressing the safety and efficacy of pneumonitis (15%), the latter leading to treatment discontinuation.
subcutaneous bortezomib use in WM.
Carfilzomib, which is associated with a low risk of treatment- Maintenance Therapy. The outcome of rituximab-naïve patients
related peripheral neuropathy, has been evaluated in combination with who were either observed or received maintenance rituximab categori-
34
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rituximab and dexamethasone in patients with WM. Carfilzomib cal responses was examined in a large retrospective study. Categori-
2
was administered intravenously at 20 mg/m (cycle 1), then 36 mg/ cal responses improved after induction therapy in 42% of patients
2
m (cycles 2–6), together with dexamethasone (20 mg) on days 1, 2, who received maintenance rituximab versus 10% in patients in the
8, and 9 as part of a 21-day cycle. As part of this regimen, rituximab observation group. Additionally, both progression-free (56.3 vs. 28.6
2
375 mg/m was given on days 2 and 9 every 21 days. Mainte- months) and overall (>120 vs. 116 months) survival were longer in
nance therapy was given 8 weeks following induction therapy with patients who received maintenance rituximab. Improved progression-
2
intravenous carfilzomib (36 mg/m ) and dexamethasone (20 mg) free survival was evident despite previous treatment status, induction
2
administered on days 1 and 2 and with rituximab 375 mg/m on with rituximab alone, or in combination therapy. Best serum IgM
day 2 every 8 weeks for up to 8 cycles. The ORR with this regimen response was also lower, and hematocrit higher, in those patients who
was 87.1% (1 complete response, 10 very good partial responses, 10 received maintenance rituximab. Among patients who received
partial responses, and 6 minimal responses) and was not impacted maintenance rituximab therapy, an increased number of infectious
by MYD88 L265P or CXCR4 WHIM mutation status. With a median events, predominantly grade 1 or 2 sinusitis and bronchitis, was
follow-up of 15.4 months, 20 patients remained progression-free. observed, along with lower serum IgA and IgG levels. A prospective
Grade ≥2 toxicities included asymptomatic hyperlipasemia (41.9%), study examining the role of maintenance rituximab has also been
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reversible neutropenia (12.9%), and cardiomyopathy in 1 patient initiated by the German STiL Group. In this study, patients
(3.2%) with multiple risk factors. Grade 2treatment-related neu- received up to six cycles of bendamustine and rituximab, and respond-
ropathy occurred in one patient (3.2%). Declines in serum IgA ers were randomized to either observation or maintenance rituximab
and IgG were common, and some patients required intravenous every 2 months for 2 years. Enrollment for this study is complete,
immunoglobulin therapy for recurring sinus and bronchial infections. and response outcome for maintenance rituximab therapy is awaited.