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13-year update of the R-HDS vs. CHOP-R trial in FL
The 13-year estimates for EFS and PFS were 37.3% and 46.3% among all patients, respectively. Both EFS and PFS curves remained significantly superior in the R-HDS com- pared to CHOP-R arm. For CHOP-R and R-HDS, 13-year EFS estimates were respectively 26.6% (median EFS: 1.6 years) and 48.5% (median EFS: 7.4 years) (Figure 5A). The 13-year PFS estimates were 28.8% (median PFS: 1.9%) and 59.1% (median PFS: not reached), for the CHOP-R and R-HDS arms, respectively (Figure 5B).
Rescue of patients with refractory and relapsed disease
Overall, 72 patients (53.7%) had disease progression (45 CHOP-R and 27 R-HDS), following partial response (PR) or refractory disease after induction (33 patients) or recur- rence after CR achievement (39 patients). Five patients had progression with documented histological transfor- mation and four with central nervous system involve- ment. As of the last follow up, 38 (52.8%) out of 72 pro- gressing patients were long-term survivors following sal- vage therapies after disease recurrence. Among rescued patients, 28 patients were in the CHOP-R and ten in the R-HDS arms. At the last follow up, besides the 50 patients alive in their first CR, 20 patients were long-term survivors in their second CR (14 CHOP-R and 6 R-HDS) and 18 were surviving beyond a second CR (14 CHOP-R and 4 R- HDS).
High-dose therapy and autograft were employed as sal- vage therapy in 28 patients with disease progression fol- lowing initial CHOP-R. Nineteen of them at this follow up were long-term survivors, with a median PFS-2 of 6.2 years. Nine patients eventually died because of lymphoma (7 patients) or secondary malignancy (2 patients).
Allogeneic stem cell transplant was employed as the ulti- mate rescue approach in five patients; two of them were long-term survivors at this follow up, while three died (one from graft-versus-host disease, one from lymphoma progression, and one from a secondary tumor).
Factors affecting long-term survival
In univariate analysis, the main features at disease pres- entation and treatment end that significantly favored long-term survival were female sex, age <50 years, treat- ment completion, MR and CR achievement (see Table 2). When these factors were evaluated in multivariate analy- sis, CR still showed a strong impact along with a border- line value for female sex (Table 2). When PCR status (assay performed on 60 patients only) was excluded from the multivariate analysis, CR was still the strongest factor favorably affecting survival. In addition, younger age had a strong significant impact along with female sex (Table 2).
Secondary tumor occurrence
The respective cumulative incidences of sMDS/AL at 5, 10, and 13 years were 5.9%, 8.9% and 10.5% for the R-HDS arm and 0.0%, 10.7%, and 10.7%, respectively, for the CHOP-R arm (P=0.832). The respective cumulative incidences of secondary non-MDS/AL neoplasms at 5, 10, and 13 years were 5.9%, 10.4%, and 11.9% for the R- HDS arm and 0%, 4.9%, and 8.8% for the CHOP-R arm (P=0.792). Secondary neoplasms in the R-CHOP arm were carcinomas (five total: two laryngeal, two urothelial, one pancreatic), Hodgkin’s lymphomas (two), MDS (two total, one of which evolved in AML), AML (one), and ALL Ph+ (one). In the R- HDS arm, we observed five carcinoma cases (three head-and-neck, one mammary, one gastric), one non-melanoma skin cancer, one plasma cell dyscrasia, four MDS cases, and four AMLs.
Table 2. Univariate and multivariate proportional hazard models for overall survival.
Univariate Multivariate Multivariate (with PCR) (without PCR)1
HR P HR P HR P
Sex
(F vs. M)
Age
(> 50 y vs. < 50 y)
Spleen involvement
(Yes vs. No)
MRD
(Pos vs.neg)
Treatment completed
(Yes vs. No)
Response
(no CR vs. CR)
Arm
(R-HDS vs. CHOP-R)
(95% CI)
0.46
(0.24-0.88)
2.21
(1.18-4.15)
1.62
(0.9-2.9)
2.26
(1.07-6.65)
0.39
(0.22-0.70)
6.61
(2.53-17.25)
1.21
(0.68-2.17)
0.019
0.013
0.109
0.036
0.002
<0.001
0.524
(95% CI) (95% CI)
0.38 0.06 0.43 0.013 (0.14-1.04) (0.22-0.84)
2.11 0.137 2.76 0.002
(0.79-5.66) (1.45-5.23)
NA - NA -
0.94 0.919 - - (0.28-3.2)
0.49 0.248 0.56 (0.15-1.64) (0.26-1.22)
0.139
6.79 <0.001
(2.66-17.32)
NA -
3.82 <0.001
(2.12-6.89)
NA -
HR: Hazard Ratio; CI: Confidence Interval; MRD: minimal residual disease; F: female; M: male; y: years; Pos.: positive; neg.: negative; CR: complete remission; R-HDS: high-dose chemotherapy with rituximab and autograft; CHOP-R: conventional chemotherapy with rituximab. 1Polymerase chain reaction (PCR) data are available for a subgroups of 60 patients. NA: not included in the analysis.
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