Doxorubicin, vinblastine, and gemcitabine (CALGB 50203) for stage I/II nonbulky Hodgkin lymphoma: pretreatment prognostic factors and interim PET

Abstract

To reduce doxorubicin, bleomycin, vinblastine and dacarbazine toxicity, the Cancer and Leukemia Group B conducted a phase 2 trial of doxorubicin, vinblastine, and gemcitabine for newly diagnosed, nonbulky stages I and II Hodgkin lymphoma. Ninety-nine assessable patients received 6 cycles of doxorubicin 25 mg/ m 2 , vinblastine 6 mg/m 2 , and gemcitabine 800 mg/m 2 (1000 mg/m 2 in first 6) on days 1 and 15 every 28 days. Computed tomography (CT) and positron emission tomography (PET) were performed before and after 2 and 6 cycles. Complete remission (CR)/CR unconfirmed was achieved in 72 of 99 patients (72.7%) and partial remission in 24 of 99 patients (24.2%). The CR rate was 81% when using PET criteria. Two patients have died of Hodgkin lymphoma progression. Median follow-up for nonprogressing patients is 3.3 years. The progression-free survival (PFS) at 3 years was 77% (95% confidence interval, 68%-84%). The relapse rate was less than 10% for patients with favorable prognostic factors. The 2-year PFS for cycle 2 PETnegative and -positive patients was 88% and 54%, respectively (P ‫؍‬ .0009), compared with 89% and 27% for cycle 6 PETnegative and -positive patients (P ‫؍‬ .0001). Although the CR rate and PFS were lower than anticipated, patients with favorable prognostic features had a low rate of relapse. Cycle 2 PET and cycle 6 PET were predictive of PFS. This clinical trial is registered at www.clinicaltrials.gov as #NCT00086801. IntroductionMost patients with early-stage Hodgkin lymphoma (HL) are cured with treatment strategies, including radiation therapy (RT), chemotherapy such as doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), or combined modality treatment, 1 with relatively similar results. 2,3 Thus, the current challenge is to maintain excellent treatment results while reducing the serious and potentially life-threatening early and late toxicities. RT has been the major cause of late morbidity and mortality related to treatment. [4][5][6] Pulmonary toxicity from bleomycin has been the major cause of acute toxicity and rare mortality with ABVD. 2,7 Gemcitabine is one of the most active single agents for relapsed and refractory HL with response rates of 39% to 43%. 8,9 An impressive overall response rate of 70% with 19% complete remissions (CRs) was achieved in a Cancer and Leukemia Group B (CALGB) phase 2 trial of gemcitabine combined with vinorelbine and pegylated liposomal doxorubicin. 10 Based on these results, CALGB conducted a phase 2 trial of a variant of ABVD, doxorubicin, vinblastine, and gemcitabine (AVG), for newly diagnosed patients with stage I and II nonbulky classic HL in which gemcitabine replaced bleomycin, and dacarbazine was omitted because of the limited phase 2 data documenting its activity. 11 The goal was to assess the CR rate and progression-free survival (PFS) of AVG without RT with an attempt to reduce acute and long-term toxicity. A secondary objective was to evaluate positron emission tomography (PET) in predicting outcome after 2 cycles of AVG and at the completi...

Interim18F-FDG PET in Hodgkin Lymphoma: Would PET-Adapted Clinical Trials Lead to a Paradigm Shift?

“…In a prospective study of 88 patients with stage I-II, nonbulky HL treated with a nonstandard regimen-doxorubicin, vinblastine, and gemcitabine-using IHP criteria, the 2-y PFS was 88% and 54% for PET-2-negative and -positive groups, respectively (P 5 0.0009) (36,41). Similar results were obtained with Deauville 5PS for interim PET reporting (85% vs. 50%).…”

Lymph cancer chemotherapy: delivery of doxorubicin-gemcitabine prodrug and vincristine by nanostructured lipid carriers

“…Based on their (DOX, GEM and VCR [DGV]) different mechanisms of action, the combination chemotherapies of DGV are effective and well tolerated in relapse and refractory NHL. [16][17][18] However, free drugs without nano-based drug delivery system have severe toxicity or drug resistance: free DOX has side effects of irreversible cardiomyopathy and heart failure, which limit its clinical use; [19][20][21] free GEM has a short half-life (ranged from 42 to 92 min); and free VCR has severe side effects, such as dose-dependent neurotoxicity and MDR. 22,23 Therefore, prodrug-based nanodrug delivery systems (DOX-GEM prodrug and VCR nanostructured lipid carriers [NLCs]) are designed in our group and anticipated to solve these problems.…”

The role of FDG-PET in defining prognosis of Hodgkin lymphoma for early-stage disease

“…In a prospective study of 88 patients with early-stage nonbulky HL treated with a nonstandard chemotherapy regimen of AVG (doxorubicin, vinblastine, gemcitabine), 2-year PFS rates were 88% and 54% for FDG-PET-2 Ϫ and FDG-PET-2 ϩ groups, respectively (P ϭ .0009) ( Figure 2C). 38 Although PPV was better, the NPV (86%) appeared to be inferior to previously published early-stage HL data (95%-100%) in part due to the lower CR rate achieved with the AVG regimen (81%) compared with ABVD (94%).…”

“…9 Furthermore, there is comparatively much less data regarding the predictive value of interim PET in earlystage HL versus advanced-stage HL, especially in favorable earlystage HL. 12,14,15,18,22,38 In the observational study by Gallamini and Hutchings that ignited an intense interest into response-adapted therapy in HL, only a minority of patients had early-stage disease and most of these patients had adverse risk factors (ie, unfavorable/ intermediate early-stage HL). 12 In a retrospective analysis of 85 HL patients who had interim FDG-PET/CT after 2-3 cycles of ABVD, the predictive power of FDG-PET/CT was much less robust for early-stage versus advancedstage HL patients (Figure 2A,B).…”