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J. Svoboda et al.
evaluable for efficacy. Of those, 15 patients (52%) received consolidative radiation after completing BV-R- CHP and final end-of-treatment response assessment. This number included 13 (59%) of 22 evaluable PMBCL patients. Of those, 8 patients received radiation using pro- tons. Twenty-six patients had archival formalin-fixed paraffin-embedded diagnostic tissue available for Lymph3Cx gene expression analysis.
Safety and feasibility
Toxicities of this outpatient regimen are listed in Table 3A and B. There were no treatment-related or on-study deaths. Using a de-escalation design during the phase I portion of the trial, the first six patients were treated with the initial dose of 1.8 mg/kg (maximum 180 mg) in com-
Table 3A. All adverse events at least possibly related to the BV-R-CHP regimen.
bination with standard dose R-CHP with plans to reduce BV to 1.2 mg/kg (maximum 120 mg) should there be dose-limiting toxicities. As there were no dose-limiting toxicities during phase I, the BV dose of 1.8 mg/kg (max- imum 180 mg) was used as the phase II dose. Overall in all patients (combining phase I and phase II cohorts), any grade 3 or 4 toxicity occurred in 84% of study patients. Hematologic adverse events of any grade were recorded in the majority of patients and in 77% of patients with grade 3 or 4 toxicities. Of note, 16% of patients received no G-CSF and 6% had G-CSF support for only one or two of the six cycles. Non-hematologic grade 3 and 4 toxici- ties were seen in 32% of patients, including infections in 15% of patients (Table 3B). Toxicities occurring in over 10% of patients included peripheral sensory neuropathy in 19 patients (61%) which were either grade 1 (48%) or grade 2 (13%) (Table 3A). Three patients (10%) reported motor neuropathy, two with grade 1 (6%) and one with grade 2 (3%). One patient discontinued protocol treat- ment after cycle 4 because of sepsis and grade 3 car- diomyopathy. One patient discontinued BV after cycle 5 because of transient grade 2 pneumonitis which was deemed at least possibly related to BV. Only three patients required BV dose reductions to 1.2 mg/kg because of persistent grade 2 peripheral sensory neuropa- thy outside of the period of dose-limiting toxicities. In total, two patients enrolled on the study died in the fol- low-up period. One PMBCL patient developed acute myeloid leukemia 2 years after completion of study treat- ment and mediastinal radiation therapy and ultimately died of acute myeloid leukemia 39 months after complet- ing study treatment. One patient died of progressive lym- phoma 40 months after completing study treatment.
Thromboembolic events were noted in eight patients (36%) in the PMBCL cohort. Pulmonary embolism was seen in three patients and upper extremity deep vein thrombosis in five patients. Of those, three events were diagnosed prior to initiating BV-R-CHP and five events were diagnosed while patients were on study treatment. Three of the five patients who had on-treatment events were asymptomatic and thrombosis was reported as an incidental finding on their first computed tomography with intravenous contrast (1 with pulmonary embolism and 1 with internal jugular vein thrombosis). Two of the five patients with on-treatment events had line-associat- ed thromboses.
Table 3B. Grade 3 or 4 adverse events at least possibly related to the BV-R-CHP regimen.
All AE
Hematologic AE Leukopenia Lymphopenia Neutropenia Febrile neutropenia Anemia Thrombocytopenia
Non hematologic AE* Abdominal pain ALT elevation ALKP elevation Allergic rhinitis Anorexia
Anxiety
Arthralgia
AST elevation
Chills
Constipation
Cough
Diarrhea
Dizziness
Dyspnea
Fatigue
Fever
GERD
Headache
Hot flashes Hyperglycemia Hypoalbuminemia Hypocalcemia Hypokalemia Hyponatremia
Infusion reaction Insomnia
Motor neuropathy Mucositis
Myalgia
Nausea
Pain
Sensory neuropathy Thromboembolic event Urinary frequency Urinary tract infection Vomiting
Total (%)
77 84 58 23 68 23
16 16 13 13 13 13 10 19 10 52 19 42 29 16 65 26 19 35 13 16 10 10 10 32 13 10 10 29 10 68 16 61 16 10 16 13
G1 (%)
13 6 3
48 13
10 13 10 13 6 13 10 19 10 52 19 29 29 16 58 19 16 32 13 10 3 6 6 32 10 10 6 26 10 52 16 48 3 10 9 9
G2 (%)
32 32 13
16 6
3 3 6
13
6 6 3 3
3 6 3
3
3 3
16
13 6
6
3
G3 (%)
16 23 19 23 3
3 3
G4 (%)
16 23 23
3
3
3
6
Grade 3/4 AE
All*
Hematologic Non-hematologic
Infections Thromboembolic event ALT elevation Abdominal pain
LV dysfunction Hypokalemia
Muscle weakness Lactic acidosis Hyperglycemia
% Total (n=31)
84 77 32 15 6 3 3 3 3 3 3 3
*In ≥10% of patients. AE: adverse events; G: grade; ALT: alanine transaminase; ALKP: alkaline phosphatase; AST: aspartate transaminase; GERD: gastro-esophageal reflux disease.
*Some patients experienced multiple grade 3/4 toxicities so the percentages do not add up. AE: adverse events: ALT: alanine transaminase; LV: left ventricular.
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