Abstract
Concerns about the potential toxicity of the dose-intensive regimens typically used as treatment for BL in HIV seronegative patients prompted us to modify the CODOX-M/IVAC regimen with the goal of preserving efficacy while improving tolerability. The primary objective was to improve the 1 year overall survival (OS) from 65% based on historical reports to 85%. The early stopping rule for excessive treatment related mortality was not met.
Major modifications of the original US NCI regimen include the addition of rituximab, reduction in cyclophosphamide to 800 mg/m2 x 2 days, vincristine 2 mg cap, methotrexate 3000 mg/m2 on day 15, reduction of lumbar punctures using combination chemotherapy and continuous infusion of the IVAC portion for the high risk patients. Antibiotic prophylaxis and growth factor support were required. HAART therapy was continued at the discretion of the local investigator.
Thirteen AMC centers entered 34 patients. Baseline characteristics included: Classical BL/unclassifiable between DLBCL and BL/other 71/21/9%; High Risk, 94% with stage III/IV 2 (6%)/25 (74%); Median age (range) 42 (19 – 55); CD4 count 195 (0 – 721), CD4 <100, 5 ( 27%); HIV viral load 1819 (Undetectable – 1,187,968). 12 patients had a viral load <100 and only 1 had undetectable plasma HIV RNA level. Only 14 patients were on HAART at study entry. Three/14 were on their second or greater antiretroviral regimen.
Treatment status
| Status | Low Risk (N=2) | High Risk (N=32) | Total (N=34) |
|---|---|---|---|
| Treatment Completed per protocol | 2 (100%) | 21 (66%) | 23 (68%) |
| Disease Progression | 0 | 3 (9%) | 3 (9%) |
| Early termination: adverse event* | 0 | 5 (16%) | 5 (15%) |
| patient withdrawal | 0 | 1 (3%) | 1 (3%) |
| persistent cytopenias | 0 | 1 (3%) | 1 (3%) |
| Other | 1 (3%) | 1 (3%) |
| Status | Low Risk (N=2) | High Risk (N=32) | Total (N=34) |
|---|---|---|---|
| Treatment Completed per protocol | 2 (100%) | 21 (66%) | 23 (68%) |
| Disease Progression | 0 | 3 (9%) | 3 (9%) |
| Early termination: adverse event* | 0 | 5 (16%) | 5 (15%) |
| patient withdrawal | 0 | 1 (3%) | 1 (3%) |
| persistent cytopenias | 0 | 1 (3%) | 1 (3%) |
| Other | 1 (3%) | 1 (3%) |
Terminations due to Adverse events (grade=gr)
| Gr 4 Thrombocytopenia and gr 3 infection(1) |
| Gr 3 hemiparesis (1) |
| Gr 3 confusion(1) unrelated to treatment |
| Gr 3 encephalopathy and grade 3 pneumonitis (1) |
| Gr 4 neutropenia and gr 3 WBC |
| Gr 4 Thrombocytopenia and gr 3 infection(1) |
| Gr 3 hemiparesis (1) |
| Gr 3 confusion(1) unrelated to treatment |
| Gr 3 encephalopathy and grade 3 pneumonitis (1) |
| Gr 4 neutropenia and gr 3 WBC |
Patients with gr 3-5 treatment related toxicity: any 27; hematologic 20; infection 14 including febrile neutropenia 8; 6 metabolic including 1 tumor lysis syndrome; 4 neurologic; 2 thrombotic; and 1 each coagulation, GI or pain. Notably, only 2 patients had gr 1/2 stomatitis/mucositis and none had gr 3/4. Deaths: Seven patients died. There were three treatment-related deaths including encephalopathy with hepatic failure, hepatitis B and pneumonia (1); fungal infection (1) and complications of HIV (1). There were 2 deaths due to progressive lymphoma. Despite the 5 early treatment terminations, the 1 year overall survival was 83.1% (95% CI 63.9%, 92.6%) and the one year progression free survival was 74.1% (55.5%, 86.4%).
Modifications of the CODOX-M/IVAC regimen resulted in a gr 3/4 toxicity rate significantly lower than the 100% seen in the parent regimen, and no grade 3/4 mucositis was observed. Despite a protocol completion rate of only 68%, the 1-year survival rate was 83% which compares favorably with 2 reported studies that excluded HIV + pts. (Magrath et al, 1995; Mead et al, 2008) Correlative studies to improve our understanding of HIV-BL will be presented at the meeting.
No relevant conflicts of interest to declare.
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