Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial

Abstract Follicular lymphoma (FL) is the most frequent low-grade lymphoma and survival duration is heterogeneous. Follicular lymphoma international prognostic index 2 (FLIPI2) is a useful prognostic tool for the identification of patients with FL at different risk in the rituximab era. On the other hand, Groupe d’Etude des Lymphomas Folliculaires (GELF) criteria is defined for patients in whom immediate therapy is necessary. In this study, we determined the value of FLIPI2 and GELF criteria as prognostic tools for follicular lymphoma. Among 181 consecutive FL patients newly diagnosed in our institute from 2000 to 2011, data of FLIPI2 and GELF criteria were available for 147 patients. Of the 147 patients, a total of 102 patients were diagnosed as clinical stage II to IV and received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) based chemotherapy. The remaining 45 patients were treated with CHOP like regimens or other treatment modalities. Of the 102 patients who had rituximab usage, 2 patients (2%) received rituximab maintenance therapy. Detailed patients characteristics were shown in Table 1. Survival analysis was carried out using the Kaplan–Meier product-limit method.Table 1Baseline patients’ characteristics (stage ≥II, received R-CHOP)ALL (n=102)Cross-validation cohort (n=65)n (%)n (%)Sex (Male)45 (44)33 (51)Median age (range)58.5 (39-84)58 (39-79)Age (>60)38 (37)24 (37)ECOG PS (>1)2 (2)1 (2)Stage ≥III85 (83)52 (80)Bulky (≥7 cm)19 (19)13 (20)Serum LDH level (>normal)29 (28)19(28)Histology (Grade1/2/3)15/74/1110/46/8FLIPI2Low17 (17)14 (22)Intermediate58 (57)38 (58)High27 (26)13 (20)GELF criteria (High)56 (55)32 (49)Rituximab maintenance2(2)1(2) First, we performed analysis using 102 patients who were diagnosed as clinical stage II to IV and received R-CHOP based chemotherapy. With a median follow-up of 6.3 years (range: 0.7-14.0 years), the 6-year overall (OS) and progression-free survival rates (PFS) of the 102 patients were 89% (95%CI: 78 to 98) and 62% (95%CI: 51 to 71), respectively. According to FLIPI2, three risk groups (low risk, intermediate risk and poor risk) were separated in OS analysis. Estimated 6-year OS rates in patients with high and low tumor burden defined by GELF were 82% and 98%, respectively (P=0.02, Log-rank). PFS rates of patients with high tumor burden defined by GELF criteria were worse compared to those with low tumor burden (53% vs. 72%, p=0.02, Log-rank). When we divided patients into two group using both FLIPI2 and GELF criteria (FLIPI2-GELF combined model), patients, who had high tumor burden defined by GELF criteria and who were classified intermediate risk or poor risk group defined by FLIPI2 (FLIPI2-GELF high) showed worse OS rates compared to the remaining (FLIPI2-GELF low) patients (83% vs. 95%, p=0.03, Log-rank). Patients with FLIPI2-GELF high also represented worse PFS rates compared to FLIPI2-GELF low patients (51% vs. 72%, p<0.01, Log-rank). The results suggested that FLIPI2-GELF combined model could more precisely separate patients into each risk group. For validation, we next performed cross-validation analysis using 65 patients who were diagnosed as clinical stage II to IV and received R-CHOP based chemotherapy. The patients were selected from the first cohort of 102 cases (Table 1). With a median follow-up of 6.2 years (range: 0.7-14.0 years), estimated 6-year OS rates in patients with high and low tumor burden defined by GELF were 80% and 97%, respectively (P=0.03, Log-rank). Estimated 6-year PFS rates in patients with high and low tumor burden defined by GELF were 51% and 66%, respectively (P=0.12, Log-rank). Using FLIPI2-GELF combined model, estimated 6-year OS rates in patients with FLIPI2-GELF high and low were 78% and 97%, respectively (P=0.02, Log-rank). Estimated 6-year PFS rates in patients with FLIPI2-GELF high and low were 47% and 68%, respectively (P=0.04, Log-rank). In 147 cases treated with R-CHOP, CHOP based regimens,or other treatment modalities, FLIPI2-GELF combined model also could divide the two group in OS (p=0.01) and PFS (p<0.01) analyses. In conclusion, we confirmed GELF criteria could be used for reproducible prognostic tool for newly diagnosed follicular lymphoma receiving R-CHOP based chemotherapy. GELF criteria combined with FLIPI2 might be a more precise and repeatable prognostic indicator for survival after first-line therapy in patients with follicular lymphoma. Disclosures: No relevant conflicts of interest to declare.

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Risk Adjusted Management of Newly Diagnosed High and Intermediate FLIPI Follicular Lymphoma Using (90)Y Ibritumomab Tiuxetan

Blood ◽

10.1182/blood.v128.22.1794.1794 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1794-1794

Author(s):

Neil L Berinstein ◽

Nancy M Pennell ◽

Rashmi Weerasinghe ◽

Matthew C. Cheung ◽

Eugenia Piliotis ◽

...

Keyword(s):

High Risk ◽

Follicular Lymphoma ◽

B Cell ◽

International Prognostic Index ◽

Prognostic Index ◽

Newly Diagnosed ◽

Ibritumomab Tiuxetan ◽

Cell Counts ◽

Post Therapy

Abstract Background: Although the natural history of follicular lymphoma is indolent with a median overall survival of about 12-15 years, the disease is heterogeneous. The 5 and 10 year overall survival (OS) of low, intermediate and high risk FLIPI is 91%, 78% and 53% and 71%, 51% and 36% using standard rituximab-based treatment. 5-year progression-free survival (PFS) is 80%, 70% and 48% respectively. Methods: Based upon this we conducted an investigator-initiated single-centre Phase II trial of intensified therapy with CHOP-R followed by (90)Y ibritumomab tiuxetan consolidation and 24 months of rituximab maintenance as treatment for patients with intermediate and high-risk newly diagnosed symptomatic follicular lymphoma. 33 patients were enrolled. Results: The addition of (90)Y ibritumomab tiuxetan was well tolerated but resulted in asymptomatic grade 3 or 4 thrombocytopenia and neutropenia in11-36% and 10-24% of patients between weeks 2-8 post (90) Y. After 9 years of follow-up (median follow-up 61 months) the 0S for intermediate and high risk FLIPI was 95% and 78%. The 5 year PFS was 79% and 64% for intermediate and high risk FLIPI, respectively. Responses at three months post consolidation were as follows: 3/33 (9%) achieved CR, 25/33(76%), achieved CRU, 1/33(3%) had PR, and 1/33(3%) had PD. Three patients did not receive (90)Y ibritumomab tiuxetan due to disease progression 2/33(6%), or death 1/33(3%). Of 19 patients who had a molecular marker for their lymphoma, 18 (95%) achieved molecular remissions in peripheral blood with CHOP-R therapy. Nine (47%) of these patients have been recently assessed for MRD and remain in molecular remission. The therapy resulted in decreased levels of IgG, IgM and IgA below the lower normal level in 33%, 40% and 23% of patients respectively post therapy. These levels did not recover in most of these patients. B cells were depleted to undetectable levels during therapy including rituximab maintenance. In 18 evaluable patients only 11 recovered normal B cell counts post maintenance rituximab. There was no correlation between normal B-cell recovery and Ig levels. Many patients with low or no B cell counts had normal IgG levels, whereas some patients who regained normal B cell counts were still unable to reach normal Ig levels. No patient developed human anti-mouse antibody. Immunity to measles, mumps, or rubella was retained post therapy. Patients did not have significant infections or opportunistic infections (although 2 developed Grade 1 shingles post (90)Y ibritumomab tiuxetan) and none required IVIG. Conclusions: We conclude that this intensified regimen is highly active in cyto-reducing lymphoma in high and intermediate risk FLIPI follicular lymphoma patients. The toxicity is tolerable although a significant percentage of patients will end up with persistent asymptomatic reductions in B cells and serum Ig. Only randomized trials will determine whether this regimen enhances outcome over standard of care in this higher risk follicular lymphoma population. References: 1.Examination of the follicular lymphoma international prognostic index (FLIPI) in the National LymphoCare study (NLCS): a prospective US patient cohort treated predominantly in community practices. Nooka AK, Nabhan C, Zhou X, Taylor MD, Byrtek M, Miller TP, Friedberg JW, Zelenetz AD, Link BK, Cerhan JR, Dillon H, Sinha R, Shenoy PJ, Levy D, Dawson K, Hirata JH, Flowers CR. Ann Oncol. 2013 Feb;24(2):441-8. doi: 10.1093/annonc/mds429. Epub 2012 Oct 5 2.Validation, revision and extension of the Follicular Lymphoma International Prognostic Index (FLIPI) in a population-based setting. van de Schans SA, Steyerberg EW, Nijziel MR, Creemers GJ, Janssen-Heijnen ML, van Spronsen DJ. Ann Oncol. 2009 Oct;20(10):1697-702. doi: 10.1093/annonc/mdp053. Epub 2009 Jun 23. PMID: 19549712 Disclosures Buckstein: Novartis: Honoraria; Celgene: Honoraria, Research Funding.

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Correlation of chemotherapy delivery and survival outcomes of follicular lymphoma in the immunchemotherapy era.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.8563 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 8563-8563

Author(s):

Kitsada Wudhikarn ◽

Anna M Button ◽

Brian J. Smith ◽

Thomas Matthew Habermann ◽

Carrie A. Thompson ◽

...

Keyword(s):

Follicular Lymphoma ◽

Systemic Therapy ◽

Cox Regression ◽

Dose Intensity ◽

Survival Outcomes ◽

Lower Grade ◽

Newly Diagnosed ◽

University Of Iowa ◽

Clinicopathologic Factors

8563 Background: Optimal initial treatment of follicular lymphoma (FL) is unknown. Rituximab as monotherapy (R) or as a component of immunochemotherapy (R+Chemo) is established as effective and it is now reasonable to re-examine the role of chemotherapy dosing. We explored clinical features, systemic treatment and chemotherapy delivery with comparative effectiveness of delivered dose intensity (DDI) on outcomes. Methods: We reviewed the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource database along with medical records on newly diagnosed grade I-IIIa FL who received systemic therapy from 2002 to 2009. Presenting clinicopathologic factors, outcomes and systemic therapy details including doses of chemotherapy were collected. The event-free (EFS) and overall survival (OS) effects of systemic therapy and chemotherapy DDI were analyzed with multivariate Cox regression. Confounding effects of FLIPI, grade, stage, and age were considered in the analysis. Results: From 2002 to 2009, 631 newly diagnosed FL were enrolled. Median follow up duration was 52.7 months. We identified 322 grade I-IIIa FL treated with systemic therapy including 93 R and 229 R+Chemo. Age and stage were similarly distributed between the R and R+Chemo groups; however, patients in the R group had lower grade (p<0.01) and FLIPI (p=0.03). Multivariate analysis showed no significant differences in EFS (HR=1.24, p=0.28) or OS (HR=0.55, p=0.13) for R compared to R+Chemo. Among R-CVP or R-CHOP treated FL, DDI data were collected for 73 doxorubicin (dox) and 137 cyclophosphamide (cyc) patients. Eighty-five percent of patients received 90% or more pre-planned DDI. After controlling for confounding factors, higher cycDDI was associated with improved EFS (HR 0.55, P=0.04) and OS (HR 0.74, P=0.03). No significant OS or EFS effects of doxDDI were observed. Conclusions: Addition of chemotherapy to rituximab was not associated with a detectable difference in survival outcomes in grade I-IIIa FL at a median follow-up of 52.7 months. Among R+Chemo treated FL, chemotherapy was delivered completely in most patients and more completed delivery of cyclophosphamide was associated with improved EFS and OS.

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