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RiBVD regimen as first-line treatment for older MCL patients
Toxicity
Fifteen patients of 74 (20%) stopped treatment before the sixth cycle, four because of death (1 case each of pneu- monia and progressive multifocal leukoencephalopathy and 2 cardiac arrests), five because of grade 3-4 toxicity [septicemia (n=1), neuropathy (n=2), digestive tract toxic- ity (n=1) and pleural effusion (n=1)], three because of pro- gression or stable disease and three for other causes (Figure 1). During treatment, 49 of 74 patients (66.2%) developed grade 3-4 hematologic toxicities (51% neu- tropenia, 35% thrombocytopenia and 19% anemia) (Table 3). Neutropenia translated into febrile neutropenia in 11 patients (11%), which was grade 3-4 in six. Lymphopenia at the end of treatment was reported in 65% of the patients (48/70) and was mainly grade 3-4 (lymphocytes <0.5x109/L) (Table 3). Persistent grade 3-4 lymphopenia was seen in 28.8% of patients at 1 year after the comple- tion of treatment (17 of 59 surviving patients who could be evaluated). Forty-two patients (56.7%) had non-hema- tologic grade 3-4 toxicities at the end of treatment (Table 3). The most frequent non-hematologic toxicities (seen in more than 10% of patients) were fatigue, peripheral neu- ropathy and fever with or without neutropenia, which occurred in 18.5% (n=14), 15% (n=11) and 15 (n=11) of cases, respectively (Table 3). Other toxicities were report- ed in four or fewer patients (i.e. less than 6%) and were as follows: pulmonary toxicity, cardiac toxicity, hyper- glycemia, elevated transaminases, digestive tract toxicity, cutaneous rash, allergy and fever without neutropenia. No patient experienced cytomegalovirus reactivation or pneu- mocystis infection.
Table 3. Hematologic and non-hematologic toxicity. All Grades
Twenty-four episodes of infection were declared as seri- ous adverse events. These represented one-third of the 76 serious adverse events reported during the 406 cycles of therapy, or during follow up. They included seven cases of opportunistic infection (4 cases during treatment and 3 further cases 1 year after the end of treatment), which were as follows; herpes zoster (n=3), progressive multifo- cal leukoencephalopathy (n=1), cytomegalovirus colitis (n=1), listeriosis (n=1) and oral candidosis (n=1). Additional infections were pneumonia (n=9), staphylococ- cal infection (n=2), followed by non-recurring infections of various types (no more than 1 case each, as follows; acute pyelonephritis, bronchitis, catheter site infection, upper aero-digestive tract infection and Clostridium difficile- induced colitis).
Regarding neurotoxicity, grade 2 to 4 neuropathy was observed in 21.5% of patients (16 of 74 patients) (Table 3). Neuropathy was generally reported after cycle 3 of treat- ment. Bortezomib was stopped indefinitely in ten of the 11 patients with grade 3-4 neurotoxicity but not in cases of grade 2 toxicity. Partial reversibility of neuropathy was reported in 13 of the 16 patients (81%) with grade 2 to 4 neurotoxicity.
Discussion
We report the results of a prospective, phase II study by the French LYSA group. The study aimed to test the effi- cacy of six cycles of RiBVD, without maintenance thera- py, for first-line treatment of MCL patients aged ≥65
Grade 3
Grade 4
% N. %
23 21 28.5
24 8 11
Events
N. % N.
Neutropenia 52 70 17
Thrombocytopenia 67 90.5 18 Lymphopenia 67 95.7 38
Anemia 70 94.5 Fatigue 56 75.5 Neuropathy 32 43* Fever 35 47 Febrile neutropenia 8 11 Lung 26 35 Cardiac 16 21.5 Hyperglycemia 23 31 Rash 25 34 GOT/GPT 29 39 Digestivetract 35 47 Allergy 24 32 Weightloss 25 34 Nausea 25 34 Bilirubin 12 16 Creatinine 24 32.5 Ear 2 3 Infusion-related reaction 18 24
Calcium 4 5
54 8 11 6 8 0 0
12 16 2 2.5 10 13.5 1 1.5 5 6.5 2 2.5 4 5.5 2 2.5 4 5.5 2 2.5 4 5.5 1 1.5 4 5.5 0 0 3 4 0 0 3 4 0 0 3 4 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0
GOT/GPT: glutamic oxaloacetic transaminase/glutamic-pyruvic transaminase; CMV: cytomegalovirus. *includes grade 2 = 6.8% (n=5/74).
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