Page 1820 - Williams Hematology ( PDFDrive )

1794 Part XI: Malignant Lymphoid Diseases Chapter 109: Macroglobulinemia 1795

CHOP alone. R-CHOP was also used in 13 WM patients, 10 of whom Carfilzomib which is associated with a low risk of treatment-re-
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had relapsed or refractory disease. Among 13 evaluable patients, 10 lated peripheral neuropathy has been evaluated in combination with
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patients achieved a major response (77 percent), including three com- rituximab and dexamethasone (CaRD) in WM patients. Carfilzomib
2
2
plete and seven partial remissions. Two other patients achieved a minor was administered intravenously at 20 mg/m (cycle one), then 36 mg/m
response. In a retrospective study of symptomatic WM patients who (cycles two to six), together with dexamethasone (20 mg) on days 1, 2,
received either R-CHOP; rituximab, cyclophosphamide, vincristine, 8, and 9 as part of a 21-day cycle. As part of this regimen, rituximab 375
2
and prednisone (R-CVP); or cyclophosphamide, prednisone, and rit- mg/m was given on days 2 and 9 every 21 days. Maintenance therapy
uximab (R-CP) and were similar in most pretreatment variables, the was given 8 weeks following induction therapy with intravenous carfil-
2
overall response rates to therapy were comparable among all three treat- zomib (36 mg/m ) and dexamethasone (20 mg) administered on days 1
ment groups—R-CHOP (96 percent), R-CVP (88 percent), and R-CP and 2 and rituximab 375 mg/m on day 2 every 8 weeks for up to eight
2
(95 percent)—although there was a trend for more complete remissions cycles. Overall response rate with this regimen was 87.1 percent (one
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among patients treated with R-CVP and R-CHOP. Adverse events complete response, 10 very good partial responses, 10 partial responses,
attributed to therapy showed a higher incidence for neutropenic fever and six minimal responses) and was not impacted by MYD88 L265P or
and treatment related neuropathy for R-CHOP and R-CVP versus CXCR4 WHIM mutation status. With a median followup of 15.4 months,
R-CP. The results of this study suggest that in WM, the use of R-CP 20 patients remained progression free. Grade 2 or higher toxicities
may provide analogous treatment responses to more intense cyclophos- included asymptomatic hyperlipasemia (41.9 percent), reversible neu-
phamide-based regimens while minimizing treatment-related compli- tropenia (12.9 percent), and cardiomyopathy in one patient (3.2 per-
cations. The extended alkylator bendamustine has also been evaluated cent) with multiple risk factors. Treatment-related neuropathy, which
in combination with rituximab in both untreated, as well as previ- was grade 2, occurred in one patient (3.2 percent). Declines in serum
ously treated WM patients. A randomized study by the German STiL IgA and IgG were common, and some patients required intravenous
Group examined bendamustine plus rituximab (BR) versus R-CHOP in gammaglobulin therapy for recurring sinus and bronchial infections.
patients with untreated, indolent B-cell lymphomas including WM.
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Patients with WM in this study showed similar overall responses Novel Therapeutics
(96 percent vs. 94 percent), although progression-free survival was The use of Ibrutinib was recently approved by the FDA for the treat-
significantly longer (69 vs. 29 months) in patients who received BR ment of symptomatic patients with WM. Ibrutinib targets BTK, a target
versus R-CHOP. Treatment was also better tolerated in patients receiv- of ibrutinib that is activated by MYD88 L265P 43
. In a multicenter study that
ing BR. In the relapsed or refractory setting, an overall response rate examined the role of ibrutinib in previously treated (median: two prior
of 83 percent was observed with bendamustine in combination with a therapies, 40 percent refractory) WM patients, the overall response rate
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CD20 monoclonal antibody. The median time to progression was 13 was 91 percent. Patients on this study received 420 mg/day of ibrutinib
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months in this study. Prolonged myelosuppression was more common by mouth. Posttherapy, median serum IgM levels declined from 3610 to
in patients who received prior nucleoside analogues. 915 mg/dL; hemoglobin rose from 10.5 to 13.5 g/dL; and marrow involve-
The use of two cycles of oral cyclophosphamide along with sub- ment declined from 60 percent to 25 percent. Decreased or resolved
cutaneous cladribine to 37 patients with previously untreated WM led adenopathy was observed in 60 percent of patients with extramedullary
to a partial response in 84 percent of patients and the median dura- disease, and five of nine patients with IgM-related peripheral neuropathy
tion of response was 36 months. Fludarabine in combination with had symptomatic improvement. The 24-month estimate for progression-
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intravenous cyclophosphamide resulted in partial responses in six of free and overall survival was 70 percent and 95 percent, respectively.
11 (55 percent) WM patients with either primary refractory disease Although major response rates were lower in patients with MYD88
WT
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or who had relapsed on treatment. The combination of fludarabine and CXCR4 WHIM mutations, it is not recommended that genotyping be
plus cyclophosphamide was also evaluated in 49 patients, 35 of whom used to select which patients should go on ibrutinib until further data
were previously treated. Seventy-eight percent of the patients achieved is available. Grade 2 or higher treatment-related toxicities included neu-
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a response, and the median time to treatment failure was 27 months. tropenia (25 percent) and thrombocytopenia (14 percent), which were
Hematologic toxicity was frequent, and three patients died of treat- more common in heavily pretreated patients; atrial fibrillation associated
ment-related toxicities. Two important findings in this study were the with a prior history of arrhythmia (5 percent); and bleeding associated
development of acute leukemia in two patients, histologic transforma- with procedures and marine oil supplements (3 percent). Serum IgA and
tion to diffuse large B-cell lymphoma in one patient, and two cases of IgG levels were unchanged following treatment with ibrutinib, and treat-
solid malignancies (prostate and melanoma), as well as failure to mobi- ment-related infections were infrequent.
lize stem cells in 4 of 6 patients. Everolimus is an oral inhibitor of the mammalian target of rapamy-
The combination of bortezomib, dexamethasone, and rituximab cin (mTOR) pathway that is active in WM. A multicenter study exam-
(BDR) as primary therapy in patients with WM resulted in an overall ined everolimus in 60 previously treated patients that showed an overall
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response rate of 96 percent, and a major response rate of 83 percent. response rate (ORR) of 73 percent, with 50 percent of patients attaining
The incidence of grade 3 neuropathy was approximately 30 percent, but a major response. The median progression-free survival in this study
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was reversible in most patients following discontinuation of therapy. An was 21 months. Grade 3 or higher related toxicities were observed in
increased incidence of herpes zoster was also observed prompting the 67 percent of patients, with cytopenias constituting the most common
prophylactic use of antiviral therapy. Alternative schedules for adminis- toxicity. Pulmonary toxicity occurred in 5 percent of patients, and dose
tration of bortezomib (i.e., once weekly at higher doses) in combination reductions as a result of toxicity occurred in 52 percent of patients.
with rituximab in patients with WM have achieved overall response A clinical trial examining the activity of everolimus in 33 previously
rates of 80 to 90 percent. 177,178 The European Myeloma Network (EMN) untreated patients with WM has also been reported that included serial
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recently showed that transitioning bortezomib from twice weekly intra- marrow biopsies in response assessment. The ORR in this study
venous dosing during the first cycle to weekly administration thereafter was 72 percent, including partial or better responses in 60 percent of
reduced grade 3 neuropathy to less than 10 percent in patients treated patients. However, discordance between serum IgM levels upon which
with BDR. There have been no studies addressing the safety and effi- consensus criteria for response are based, and marrow disease response
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cacy of subcutaneous bortezomib use in WM. were common and complicated response assessment. In a few patients,

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