Radioimmunotherapy versus autologous hematopoietic stem cell transplantation in relapsed/refractory follicular lymphoma: a Fondazione Italiana Linfomi multicenter, randomized, phase III trial.

BACKGROUND: Optimal consolidation for young patilents with relapsed/refractory (R/R) follicular lymphoma (FL) remains uncertain in the rituximab era, with an unclear benefit of autologous stem cell transplantation (ASCT). The multicenter, randomized, phase III FLAZ12 (NCT01827605) trial compared anti-CD20 radioimmunotherapy (RIT) with ASCT as consolidation after chemoimmunotherapy, both followed by rituximab maintenance. PATIENTS AND METHODS: Patients (age 18-65 years) with R/R FL and without significant comorbidities were enrolled and treated with three courses of conventional, investigator-chosen chemoimmunotherapies. Those experiencing at least a partial response were randomized 1 : 1 to ASCT or RIT before CD34+ collection, and all received postconsolidation rituximab maintenance. Progression-free survival (PFS) was the primary endpoint. The target sample size was 210 (105/group). RESULTS: Between August 2012 and September 2019, of 164 screened patients, 159 were enrolled [median age 57 (interquartile range 49-62) years, 55% male, 57% stage IV, 20% bulky disease]. The study was closed prematurely because of low accrual. Data were analyzed on 8 June 2023, on an intention-to-treat basis, with a 77-month median follow-up from enrollment. Of the 141 patients (89%), 70 were randomized to ASCT and 71 to RIT. The estimated 3-year PFS in both groups was 62% (hazard ratio 1.11, 95% confidence interval 0.69-1.80, P = 0.6662). The 3-year overall survival also was similar between the two groups. Rates of grade ≥3 hematological toxicity were 94% with ASCT versus 46% with RIT (P < 0.001), and grade ≥3 neutropenia occurred in 94% versus 41%, respectively (P < 0.001). Second cancers occurred in nine patients after ASCT and three after radioimmunotherapy (P = 0.189). CONCLUSIONS: Even if prematurely discontinued, our study did not demonstrate the superiority of ASCT versus RIT. ASCT was more toxic and demanding for patients and health services. Both strategies yielded similar, favorable long-term outcomes, suggesting that consolidation programs milder than ASCT require further investigation in R/R FL.

PO-03 - Khorana score and histotype predict the incidence of early venous thromboembolism (VTE) in Non Hodgkin Lymphoma (NHL). A pooled data analysis of twelve clinical trials of Fondazione Italiana Linfomi (FIL).

BACKGROUND: Recent studies show that the risk of VTE in NHL pts is similar to that observed in high risk solid tumors (i.e. pancreatic, ovarian cancer). VTE in NHL occurs in most cases within three months from diagnosis and can have substantial impact on treatment delivery and outcome as well as on quality of life. However few data are available on potential predictors. AIMS: To better clarify the epidemiology of early (within six months from treatment start) VTE in NHL we conducted a pooled data analysis of 12 clinical trials from FIL. Our analysis included basic demographic features, lymphoma-related characteristics as well the Khorana score (based on histology, BMI, platelets WBC and HB counts) which is extensively used in solid tumors to predict VTE risk. PATIENTS AND METHODS: From Jan. 2010 to Dec. 2014, all pts with B-cell NHL enrolled in prospective clinical trials from FIL for frontline treatment were included. For 9 studies study period included the entire trial population was included. The analyses were conducted based on CRFs as well as pharmacovigilance reports. VTE definition and grading was stated according to standard criteria of toxicity (CTCAE V4.0). Cumulative incidence of VTE from the study enrollment was estimated using the method described by Gooley et al. accounting for death from any causes as a competing risk. The Fine & Gray survival model was used to identify predictors of VTE among NHL pts. Factors predicting the grade of VTE were investigated using an ordinal logistic regression model. This pooled data analysis was approved by local IRB. RESULTS: Overall, 1,717 patients belonging to 12 studies were evaluated. Eight were phase I/II or II (25% of pts) and 4 phase III (75% of pts). M/F ratio was 1.41, Median age was 57, (IQ range (IQR) 49-66). Histologies were: DLCL-B 34%, FL 41%, MCL 18%, other 6%. Median BMI was 25 (IQR 22-28). Median Hb, WBC and platelets counts were 13g/dl) (IQR 11.5-14.2), 7.1*10^(9)/l (IQR 5.6-10.3), 224*10^(9)/l (IQR 169-298), respectively. 1189 pts were evaluable Khorana score: 58% low risk, 30% intermediate risk, 12% were high risk. Human erythropoetin support was given to 9% of patients. All pts received Rituximab. Planned therapeutic programs included ASCT in 27% of pts, conventional chemotherapy in 67% a conventional chemotherapy plus lenalidomide in 6%. Overall 59 any grade VTE episodes occurred in 51 pts (2.9%), including 21 grade III-IV VTE (18 pts). None was fatal. Median time from study enrolment to VTE was 63 days (IQR: 35-110). Considering death as a competitive event the 6 months cumulative incidence of VTE was 2,2% in low risk Khorana score, 4.5% (95%IC: 2.3-6.7) in intermediate and 6.6% (95%IC: 2.4-10.8) in high risk (p=0.012) (figure 1). Khorana score was predictive also for grade III-IV events as they were 0,7% (95% CI:0.1-1.4) in low risk and 2.0% (95% CI:0.8-3.3) in intermediate-high risk (p=0.048). The results were similar also after excluding lenalidomide containing studies. The Fine and Gray multivariate analyses, adjusted for age and stage, showed that Khorana score (intermediate risk adjHR=1.96; 95%IC: 0.84-4.56 and high risk adjHR=3.81; 95%IC: 1.51-9.58) and DLCL-B histotype (adjHR=2.58; 95% CI: 1.01-6.55) were independently associated to an increased risk of VTE. Moreover an ordinal logistical regression model indicated that the increase of one point in the Khorana score resulted in an increased risk of VTE (OR=1.85; 95% CI: 1.23-2.79). CONCLUSIONS: Our results suggest that DLCL-B histotype and Khorana score are predictors of VTE in NHL. The latter might become a simple and effective tool to assess the risk of VTE in NHL. Prospective validation including also patients not eligible for clinical trials is needed.

The prognostic role of post-induction FDG-PET in patients with follicular lymphoma: a subset analysis from the FOLL05 trial of the Fondazione Italiana Linfomi (FIL).

BACKGROUND: [18F]fluorodeoxyglucose-positron emission tomography (PET) is emerging as a strong diagnostic and prognostic tool in follicular lymphoma (FL) patients. PATIENTS AND METHODS: In a subset analysis of the FOLL05 trial (NCT00774826), we investigated the prognostic role of post-induction PET (PI-PET) scan. Patients were eligible to this study if they had a PI-PET scan carried out within 3 months from the end of induction immunochemotherapy. Progression-free survival (PFS) was the primary study end point. RESULTS: A total of 202 patients were eligible and analysed for this study. The median age was 55 years (range 33-75). Overall, PI-PET was defined as positive in 49 (24%) patients. Conventional response assessment with CT scan was substantially modified by PET: 15% (22/145) of patients considered as having a complete response (CR) after CT were considered as having partial response (PR) after PI-PET and 53% (30/57) patients considered as having a PR after CT were considered as a CR after PI-PET. With a median follow-up of 34 months, the 3-year PFS was 66% and 35%, respectively, for patients with negative and positive PI-PET (P<0.001). At multivariate analysis, PI-PET (hazard ratio 2.57, 95% confidence interval 1.52-4.34, P<0.001) was independent of conventional response, FLIPI and treatment arm. Also, the prognostic role of PI-PET was maintained within each FLIPI risk group. CONCLUSIONS: In FL patients, PI-PET substantially modifies response assessment and is strongly predictive for the risk of progression. PET should be considered in further updates of response criteria.

The use of FDG-PET in the initial staging of 142 patients with follicular lymphoma: a retrospective study from the FOLL05 randomized trial of the Fondazione Italiana Linfomi.

BACKGROUND: The role of [¹8F] fluorodeoxyglucose (FDG)-positron emission tomography (PET) in follicular lymphoma (FL) staging is not yet determined. PATIENTS AND METHODS: The aim of the present study was to investigate the role of PET in the initial staging of FL patients enrolled in the FOLL05-phase-III trial that compared first-line regimens (R-CVP, R-CHOP and R-FM). Patients should have undergone conventional staging and have available PET baseline to be included. RESULTS: A total of 142 patients were analysed. PET identified a higher number of nodal areas in 32% (46 of 142) of patients and more extranodal (EN) sites than computed tomography (CT) scan. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score increased in 18% (26 of 142) and decreased in 6% (9 of 142) of patients. Overall, the impact of PET on modifying the stage was highest in patients with limited stage. Actually, 62% (15 of 24) of cases with limited disease were upstaged with PET. CONCLUSIONS: The inclusion of PET among staging procedures makes the evaluation of patients with FL more accurate and has the potential to modify therapy decision and prognosis in a moderate proportion of patients. Further prospective clinical trials on FL should incorporate PET at different moments, and the therapeutic criteria to start therapy should be re-visited in the views of this new tool.

Prolonged survival and low incidence of late toxic sequelae in advanced follicular lymphoma treated with a TBI-free autografting program: updated results of the multicenter consecutive GITMO trial.

This study provides an updated report of the consecutive multicenter Gruppo Italiano Trapianto Midollo Osseo trial employing an intensified, purging-free, total body irradiation-free, high-dose sequential chemotherapy schedule with peripheral blood stem cell autograft (i-HDS) in advanced-stage follicular lymphoma (FL). Special interest has been devoted to late toxicities and outcome in terms of molecular status. Ninety-two untreated FL patients aged

Point mutations of the BCL-6 gene: clinical and prognostic correlation in B-diffuse large cell lymphoma.

Although point mutations of the 5' noncoding regions of the BCL-6 proto-oncogene are frequently detected in B-diffuse large cell lymphoma (B-DLCL), a thorough analysis of the clinical correlation of these mutations has not been performed to date. In this study, BCL-6 mutations were examined by DNA direct sequencing in 103 patients with B-DLCL. BCL-6 mutations were found in 53/103 patients, including 38/76 treated with standard chemotherapy and 15/27 treated with autologous stem cell transplantation (ASCT) up front. The presence of BCL-6 mutations was correlated with clinical features at diagnosis and outcome. Mutated patients had a significantly higher LDH level (66% vs 38%, P < 0.05), and bulky disease (51% vs 32%, P = 0.05). In the whole series of patients BCL-6 mutations did not affect CR and OS. Patients with BCL-6 mutations tended to have a prolonged 5-years DFS and FFS compared to those without mutations (DFS 82% vs 63%, FFS 63% vs 49%). Among B-DLCL treated with standard chemotherapy, mutated patients showed a significantly improved 5-year DFS (85% vs 61%, P < 0.05) and, notably, the only four relapses observed among mutated patients occurred in less than 8 months. The multivariate regression analysis (P < 0.01) with DFS as endpoint confirmed the independent prognostic value of BCL-6 mutations. There was a trend for 5-year failure-free survival to be better for patients with BCL-6 mutations (63% vs 43%, P = 0.09). In the 27 patients treated with ASCT, BCL-6 mutations did not correlate with outcome. These results suggest that BCL-6 mutations may predict a higher chance of being free of disease in B-DLCL treated with standard chemotherapy. Larger series of patients need to be analyzed to evaluate the clinical relevance of BCL-6 mutations properly.

The Influence of advanced age on the treatment and prognosis of diffuse large-cell lymphoma (DLCL).

The incidence of non-Hodgkin's lymphoma (NHL) in elderly patients has increased in recent years. Approximately 36% of elderly patients with NHL are diagnosed with diffuse large-cell lymphoma (DLCL), an aggressive lymphoma subtype. Some authors have suggested that lymphoma in the elderly is intrinsically different from that seen in younger patients. Diffuse large-cell lymphoma, for example, is curable in about 50% of patients younger than 65 years of age but has a significantly lower cure rate in older subjects. Elderly patients with DLCL represent a group that is difficult to treat because of comorbidity, diminished organ functions, altered drug metabolism, and irregular drug clearance rates. These factors must be carefully considered when evaluating treatment options for older patients. The quality of life (QOL) associated with various regimens should obviously be evaluated, though QOL has so far received little attention in clinical trials. Analyses of the results from numerous phase II and phase III trials in patients with advanced aggressive NHL have demonstrated that overall survival is reduced when chemotherapy regimens more toxic than CHOP (cyclophosphamide/doxorubicin/ vincristine/prednisone) are employed, whereas therapeutic regimens that are less toxic are often less effective. CHOP, therefore, may be regarded as the current gold standard of therapy for elderly patients with DLCL. The addition of granulocyte colony-stimulating factors to CHOP chemotherapy is recommended to limit myelosuppression. Intensive chemotherapy followed by autologous stem cell transplantation has recently been extended to patients older than 60 years, with encouraging results, albeit in a highly selected groups of patients. Other promising lymphoma treatments with improved toxicity profiles are being developed. Clinical trials are recommended to determine if these new therapies are safe and active in elderly patients with DLCL.

Clinical activity and safety of combination immunotherapy with IFN-alpha 2a and Rituximab in patients with relapsed low grade non-Hodgkin's lymphoma.

BACKGROUND AND OBJECTIVES: To determine the clinical activity and safety of the combination immunotherapy of the chimeric anti-CD20 antibody, Rituximab, and Interferon (IFN)- alpha 2a DESIGN AND METHODS: Sixty-four patients with relapsed low-grade or follicular B-cell non Hodgkin's lymphoma received 4 infusion of Rituximab (375 mg/m(2) x dose) after priming and simultaneous treatment with IFN- alpha 2a. RESULTS: The overall response rate was 70% with 33% complete responses. Median for duration of response is 19 months, after a median follow-up of 22 months. By univariate analysis none of the most common prognostic factors predicted for response to therapy. After treatment 10 patients become bcl-2 negative in the bone marrow, but no correlation between molecular and clinical response was found. Fifty-three patients (83%) had drug related or unknown origin adverse events. The number of adverse events per patient varied from 1 to 21. Considering all 272 events, 231 (85%) were grade 1 or 2, 36 (13%) grade 3 and 5 (2%) grade 4. Twenty-three patients required reduction in the dose and/or short discontinuation of IFN treatment, either during priming or subsequent treatment. The most frequent adverse events were leukopenia, fever, neutropenia, hypotension and thrombocytopenia. INTERPRETATION AND CONCLUSIONS: this report shows that combination immunotherapy Rituximab + IFN- alpha 2a is active and relatively well tolerated. The overall response rate of 70% and the median duration remission of 19 months compare favorable with the results obtained with Rituximab alone in similar subset of patients. Randomized trials, investigating Rituximab versus combination immunotherapy are needed.

Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases. Intergruppo Italiano Linfomi.

Patients (n-987) with a histologically confirmed diagnosis of follicular lymphoma were studied with the aim of developing a prognostic model specifically devised for this type of lymphoma. We collected information on age, sex, Ann Arbor stage, number of extranodal disease sites, bone marrow (BM) involvement, bulky disease, B symptom criteria (fever, night sweats, and weight loss), performance status (PS), serum lactate dehydrogenase (LDH) level, serum albumin level, hemoglobin level, and erythrocyte sedimentation rate (ESR). In the training sample of 429 patients with complete data, multivariate analysis showed that age, sex, number of extranodal sites, B symptoms, serum LDH level, and ESR were factors predictive for overall survival. Using these 6 variables, a prognostic model was devised to identify 3 groups at different risk. The 5- and 10-year survival rate was 90% and 65% for patients at low risk, respectively; 75% and 54% for patients at intermediate risk; and 38% and 11% for those at high risk (log-rank test, 86.62; P <. 0001). The model was also predictive (P =.0001) in the validation sample of 265 patients with complete data only for the 6 variables used in the development of the model and even in the group of 210 patients from the validation sample uniformly treated with doxorubicin-containing regimens (P =.0001). The prognostic model appears to be very useful in identifying patients with follicular lymphoma at low, intermediate, or high risk.