Limited-stage Diffuse Large B-cell Research Articles

Favorable Outcome of Abbreviated R-CHOP in Patients with Primary Testicular Lymphoma

Background Primary testicular lymphoma (PTL) is a rare type of extranodal large B-cell lymphoma with an increased risk of relapse mostly involving the contralateral testis or central nervous system (CNS). To minimize the risk of relapse, Vitolo et al. (2011) introduced a multimodality approach in limited stage PTL including radical orchiectomy, 6 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) with 4 intrathecal methotrexate (MTX IT) administrations and radiotherapy of the contralateral testis. In limited stage diffuse large B-cell lymphoma, without involvement of the testis, 4 cycles of R-CHOP proved non-inferior to 6 cycles of R-CHOP (Poeschel et al. 2019; Persky et al. 2020). However, it is unknown whether the number of cycles of R-CHOP can be reduced in PTL. Therefore, we aimed to evaluate the impact of the number of R-CHOP cycles on outcome in PTL patients in the Netherlands. Methods PTL patients ≥18 years, Ann Arbor stage I-II, diagnosed in 2014-2021, who received at least 3 cycles of R-CHOP were identified in the Netherlands Cancer Registry, with survival follow-up through 2022. Patients with CNS involvement at diagnosis were excluded. Treatment modalities were categorized as 3 cycles R-CHOP or 6 cycles R-CHOP. Patients who received 4, 5 or more than 6 cycles of R-CHOP were included in the 6 cycles modality. The primary endpoints were progression-free survival (PFS), and overall survival (OS). PFS was defined as the time between end of primary treatment and relapse, or death from any cause, whichever came first, and OS was defined as the time between end of primary treatment and death from any cause. The secondary endpoint was cumulative incidence function (CIF) of CNS relapse, defined as the number of CNS relapses divided by the total number of patients in the study population at risk for a specific time. Uni- and multivariable analyses were conducted to establish independent predictors of risk of relapse and mortality among patients who received 3 cycles of R-CHOP versus 6 cycles of R-CHOP. Uni- and multivariable analysis to calculate risk of relapse and mortality after adjustment for the baseline and treatment characteristics was performed using Cox regression. Results A total of 139 patients were identified: median age, 68 years (range, 37-86 years); stage I, 68%; IPI 0, 87%. Of these patients, 43 received 3 cycles R-CHOP and 96 received 6 cycles R-CHOP (number of cycles 4:4%; 5:6%; 6 or more: 90%). Patients with stage I disease more commonly received 3 cycles of R-CHOP compared to patients with stage II ( p<0.01; Table 1). In combination with R-CHOP, most patients received MTX IT (93%), high-dose MTX (4%) or did not receive prophylaxis (4%). The median number of MTX IT cycles was 5 in patients who received 3 cycles R-CHOP and 6 in patients who received 6 cycles R-CHOP ( p=0.08). Of the patients who received 3 cycles R-CHOP, 29% received <4 MTX IT cycles, compared to 11% in patients who received 6 cycles R-CHOP ( p=0.02). Overall, 82% received radiotherapy, 5% orchidectomy and 13% no consolidation. The median follow-up from end of treatment was 42 months (inter quartile range [IQR], 22-70 months). Overall response rate (ORR; partial remission or greater) for patients who received 3 cycles R-CHOP and 6 cycles R-CHOP were similar (79% versus 86%, respectively, p=0.27). The 5-year PFS and OS were 66% and 75%, respectively. Regarding 3 versus 6 R-CHOP, the 5-year PFS and OS were similar, i.e. 65% versus 67% ( p=0.81) and 73% versus 76% ( p=0.69), respectively (Figure 1). In univariable analysis, risk of relapse and mortality were similar for patients who received 3 cycles of R-CHOP or 6 cycles R-CHOP. In multivariable analysis, none of the covariables influenced the risk of relapse or mortality. The 5-year CIF of CNS was 6.7%, with a median time from end of treatment to CNS relapse of 25 months. 6 (14%) out of 43 PTL patients with 3 cycles R-CHOP relapsed to CNS, and 1 (1%) out of 96 patients with 6 cycles R-CHOP ( p<0.01). The number of MTX cycles was not related on developing a CNS relapse (p=0.81). Conclusion In this nationwide population of PTL patients, nearly one-third of patients received 3 cycles of R-CHOP instead of 6 cycles. No difference in survival was observed between the two groups. These data support investigating reduction of systemic treatment from 6 cycles of R-CHOP in this patient group.

Extranodal Presentation in Limited Stage DLBCL As a Prognostic Marker in Three Sequential SWOG Trials S0014, S0313 and S1001 (NCT00005089, NCT00070018, NCT01359592)

Extranodal Presentation in Limited Stage DLBCL As a Prognostic Marker in Three Sequential SWOG Trials S0014, S0313 and S1001 (NCT00005089, NCT00070018, NCT01359592)

Characteristics and Outcomes of Patients with Double-Protein Expression in Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of SWOG Study S1001 (NCT01359592)

Characteristics and Outcomes of Patients with Double-Protein Expression in Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of SWOG Study S1001 (NCT01359592)

The impact of cell-of-origin, MYC/Bcl-2 dual expression and MYC rearrangement on disease relapse among early stage diffuse large B-cell lymphoma patients treated with combined modality therapy

We addressed the prognostic impact of cell-of-origin (COO), MYC and Bcl-2 overexpression as well as isolated MYC rearrangement among 111 patients with limited stage diffuse large B-cell lymphoma (DLBCL) treated with consolidative radiation therapy (RT) after a metabolic complete response to immunochemotherapy. With a median follow-up of 31.1 months (95% CI 27.4 − 34.8), 4 relapses occurred. The 3-year progression free survival (PFS), overall survival (OS), and loco-regional relapse free survival (LRFS) for the cohort were 95%, 96%, and 100%, respectively. There were no differences in OS, PFS, or LRFS based on COO or MYC/Bcl-2 dual expression (DE). Similarly, patients with MYC translocations without BCL2 or BCL6 rearrangements did not have worse outcomes. Consolidative RT produced excellent local control, regardless of DLBCL biology, with one late in-field failure.

Survival outcomes in the elderly with limited stage diffuse large B-cell lymphoma treated with chemotherapy: SEER propensity-matched analysis.

e19046 Background: Current data shows a median age of diffuse large b-cell lymphoma (DLBCL) diagnosis of 70 years. More than 50% of elderly DLBCL patients can be expected to be cured by modern immunochemotherapy. Survival outcomes in elderly patients with limited stage DLBCL treated with chemotherapy outside of clinical trials are poorly characterized. Our objective is to determine survival pattern and factors that influence survival in elderly patients with limited stage DLBCL treated with chemotherapy through analysis of data from a large nationwide cancer registry in modern treatment era. Methods: The Surveillance Epidemiology and End Results (SEER 18) treatment database (2001-2013) was used to detect limited stage (Ann Arbor lymphoma stage I and II) DLBCL (ICD-O-3 code: 9680/3) adult cases with ages between 60-80 years treated with chemotherapy. Patients were divided into two cohorts. Cohort 1 included patients aged ≥60 to 70 yrs and Cohort 2 included patients aged > 70 to 80 yrs. The variable "First Malignant Primary Indicator" was used to differentiate between primary DLBCL and secondary DLBCL cases. Overall survival (OS) was calculated using the Kaplan-Meier methods and multivariate cox regression model to determine the impact of race, gender, radiation use and primary malignant indicator on survival using 1:1 propensity score matching. Chi square test was applied to delineate for any significant difference between two cohorts. Results: Overall, 11138 patients were included with 5569 patients in each cohort. The relative incidence of limited stage secondary DLBCL was greater for cohort 2 when compared to cohort 1 (26% vs. 15%, p < 0.01). The odds of receiving radiation was 27% higher in cohort 1 compared to cohort 2 (p < 0.0001). Compared to cohort 1 (median OS-130 months), cohort 2 had worse median OS of 72 months (p < 0.0001). Female gender, not receiving radiation and secondary status have shown strong relationship with increased risk of death on multivariate cox regression analysis in the elderly limited stage DLBCL patients. Conclusions: Overall survival was worse in age group 70-80 yrs when compared to age group 60-70 yrs in limited stage DLBCL patients treated with chemotherapy. This may be due to differences in treatment approaches. Female gender, not receiving radiation and secondary status are poor prognostic factors of survival in above group of patients. Race has no impact on survival.

Response-adapted therapy for limited stage diffuse large B-cell lymphoma based on interim PET-CT: preliminary results of a phase 2 study

BackgroundLimited stage diffuse large B-cell lymphoma is curable with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) immunochemotherapy. For patients achieving complete response by interim 18F-fluorodeoxyglucose PET-CT, a previous study showed therapy could be safely de-escalated by omitting the subsequent chemotherapy or radiotherapy. We aimed to adapt the therapy on the basis of the response as assessed by the interim PET-CT. MethodsWe did this phase 2 study in patients with low risk (International Prognostic Index 0–2), limited stage diffuse large B-cell lymphoma. Patients were initially treated with four cycles of R-CHOP. PET-CT scans were done at baseline and after four cycles. Patients with negative PET (Deauville scores 1–2) received two cycles of rituximab monotherapy, unless they had any risk factors (primary mediastinal large B-cell lymphoma, primary extranodal non-Hodgkin lymphoma, and bulky disease). Patients with these risk factors received another two cycles of R-CHOP as routine practice. Patients with partial response received another four cycles of R-CHOP and a repeated PET-CT scan at the end of treatment. Patients with stable and progressive disease were managed by salvage chemotherapy. The primary endpoint was progression-free survival at 3 years. The trial is registered with ClinicalTrials, number NCT0180412. FindingsFrom December, 2012, to September, 2015, a total of 143 patients were enrolled and we analysed the 129 patients with baseline and interim PET-CT scans for efficacy. By local assessment, 114 PET-CT scans (88%) were reported as negative and 15 (12%) as positive. With a median follow-up time of 28·2 months (range 15·0–47·4), the estimated 3-year progression-free survival was 91%. Patients with negative interim PET-CT scans had a 3-year progression-free survival of 93% compared with 79% for patients with positive results (p=0·062). The estimated 3-year progression-free survival did not differ between patients with nodal and extranodal primaries (92% vs 91%, p=0·978). InterpretationFor patients with limited stage diffuse large B-cell lymphoma, the results of interim PET-CT might predict progression-free survival and adapt the subsequent treatment. For complete response patients without risk factors, the extra two cycles of CHOP might be safely omitted without compromising the efficacy, which needs to be confirmed in a randomised study. FundingNone.

Benefit of Consolidative Radiotherapy in Patients with Limited Stage Diffuse Large B-Cell Lymphoma in the Rituximab Era

Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma and the most common lymphoid neoplasm in adults. In the pre rituximab era, the standard therapy for patients with limited stage DLBCL had been three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) followed by involved-field radiotherapy (IFRT). The addition of rituximab has revolutionized the treatment of DLBCL. Rituximab combined with CHOP (R-CHOP) has been established as the standard treatment for patients with DLBCL. However, the role of consolidative radiotherapy (RT) in the treatment of limited stage DLBCL in the rituximab era is controversial.Patients and Methods: We retrospectively analyzed 108 patients with limited stage DLBCL who received R-CHOP or R-THP-COP (rituximab plus, cyclophosphamide, pirarubicin, vincristine and prednisone) regimen between June 2004 and August 2015. We compared overall survival (OS) and progression-free survival (PFS) according to the treatment. OS was calculated from the date of initiation of chemotherapy to the date of the last follow-up or death. PFS was calculated from the date of initiation of chemotherapy to the date of progression disease, death, or last contact, whichever occurred first. Survival was estimated from Kaplan-Meier curves and compared using the log-rank test. P < 0.05 was considered statistically significant. Weighted Cox proportional hazards regression modeling with the inverse probability weighted (IPW) estimators method adjusting to propensity for RT was used to account for differences in baseline characteristics.Results: Median age at diagnosis was 66 years (19-88 years), with 61 males and 47 females. Forty-three patients (40%) had stage I, and 65 patients (60%) received consolidative RT after chemotherapy. Patients who received consolidative RT were significantly younger (65 vs 72, P < 0.01) and were more likely to have stage I disease (51% vs 23%, P < 0.01). The median number of chemotherapy cycles was 4 (range 3-8) in patients who received RT, and 6 (range 3-8) in patients who did not. Median follow-up was 4.3 years (0.3-10.9 years), and the 5-year OS (92% vs 63%, P < 0.01) and PFS (87% vs 65%, P < 0.01) were significantly higher for patients who received RT than those who did not. Using IPW adjustment, RT remained predictive of OS (HR 0.30, CI 0.13-0.72, P < 0.01) and PFS (HR 0.47, CI 0.22-0.99, P < 0.05).Conclusion: Our results suggest that consolidative RT improves OS and PFS in patients with limited stage DLBCL in the rituximab era. Although consolidative RT seems to be gradually phased out by chemotherapy alone, it is still an important treatment strategy. DisclosuresNo relevant conflicts of interest to declare.

Phase 2 Study of Abbreviated 3 Cycles of Rituximab Plus CHOP (Cyclophosphamide, Adriamycin, Vincristine, and Prednisolone) Immunochemotherapy in Patients with Completely Excised Stage I or II CD20+ Diffuse Large B-Cell Lymphoma (CISL 12-09)

▪Introduction: Full cycles of R-CHOP chemotherapy or abbreviated chemotherapy followed by radiotherapy are recommended as standard of care for limited stage (LS) diffuse large B-cell lymphoma (DLBCL). There are occasions when lesions are completely excised during the diagnostic surgical resection. In addition, initial surgical resection of the involved area is often performed in the treatment of intestinal lymphomas with LS disease due to obstructive lesions or perforation risk. As to these patients without residual gross lesions, however, the number of cycles of chemotherapy has not so far been questioned and full cycles of chemotherapy are usually performed. Thus, we aimed to investigate the effectiveness of an abbreviated three courses of R-CHOP chemotherapy in patients with completely excised stage I or II CD20+ DLBCL.Methods: This is a multicenter, single arm, phase 2 study designed to evaluate efficacy and safety of 3 cycles of R-CHOP chemotherapy in low risk LS DLBCL. Key inclusion criteria were as follows: pathologically confirmed CD20 positive DLBCL, age >18 years, stage I or II, and complete resection with no residual lesion after surgical resection. Patients with B symptoms, bulky disease, primary breast, testicular or CNS lymphomas were excluded. R-CHOP chemotherapy started within 6 weeks from surgical resection and was repeated every 3 weeks for 3 cycles. Prophylactic G-CSF was not administered. Radiologic tumor assessment was performed at baseline, every 3 months until 2 years, then every 6 months until 5 years after completion of study treatment. The primary endpoint was 2-year disease-free survival (DFS). Secondary endpoints included overall survival and safety. (ClinicalTrials.gov: NCT01279902.)Results: Twenty-three patients were enrolled between Dec 2010 and May 2013. Of these, one was excluded because of ineligibility and the remaining 22 patients were included in the analysis. The median age at diagnosis was 57 years (range, 29-77 years). Fourteen patients had stage 1 disease and the other eight had stage 2. Preoperative LDH level was available in 11 patients and it was elevated in two of them. Thus, preoperative IPI scores could be calculated in those 11 patients; 0 in 8, 1 in one, and 2 in one patients, respectively. Postoperative IPI scores were 0 in 11, 1 in 10 and 2 in one patients. Primary sites included intestine (n=15), cervical lymph nodes (n=4), stomach (n=1), tonsil (n=1) and spleen (n=1). All the 22 patients completed 3 cycles of R-CHOP chemotherapy as planned. With a median follow-up of 39.5 months (95% CI, 29.9-47.1 months), only one patient showed disease progression and died with the estimated 2-year DFS and OS rates of 95.0%. It was the only one patient with IPI of 2 with elevated LDH and age>60 that showed disease progression at 12.7 months. He had a splenic mass and underwent splenectomy followed by 3 cycles of R-CHOP. He underwent one cycle of salvage R-ESHAP chemotherapy but died of rapid disease progression. No grade 3 or 4 non-hematologic toxicities were observed. Neutropenia was the most common grade 3 or 4 hematologic toxicity which was noted in 8 (36.4%) patients. Three patients experienced G3 febrile neutropenia.Conclusions: Three cycles of abbreviated R-CHOP chemoimmunotherapy is an effective and safe therapeutic approach for patients with localized and completely excised DLBCL especially in those with low-risk IPI. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Impact of Radiotherapy and Rituximab on Outcome of Stage I(E) Diffuse Large B-Cell Lymphoma

Purpose:For patients with limited stage diffuse large B-cell lymphoma (DLBCL) the overall survival (OS) in the pre-rituximab era was initially reported to be superior for abbreviated CHOP followed by radiotherapy compared to full course CHOP chemotherapy. At long term follow-up this benefit was lost. Rituximab(R) has increased the outcome of advanced stage patients, but the impact on limited stage DLBCL is less clear. Whether abbreviated R-CHOP followed by radiotherapy or full course R-CHOP is the treatment of choice remains controversial.Patients and methods:We performed an observational population-based cohort study of patients with stage I (E) DLBCL identified from 2 databases from the northern part of the Netherlands. Patients had been treated with abbreviated CHOP (3 cycles) followed by radiotherapy or full course CHOP (6-8 cycles). R was given to all patients after the drug became available in the Netherlands from 2004 onward. Primary endpoints were time to tumor progression (TTP) and OSResults:From 1984 until 2014 196 patients with stage I(E) were identified. Median follow-up was 53 and 110 months for patients treated with R and without R respectively Characteristics at diagnosis: median age 63 years (range 15-90), 20% ≥ 75 years; IPI-score 0-1: 88%; extranodal disease: 58%.Treatment: 190 patients completed at least 3 cycles of (R-)CHOP, 63% R and 37% without R . Full course (R-)CHOP was administered in 35% of patients. Patients with extranodal disease more often received full course (R-)CHOP (44%) compared to nodal disease (22%).Outcome: There were 32 relapses; 10 / 66 (15%) in full course (R-)CHOP and 22 / 124 (18%) in abbreviated (R-)CHOP followed by radiotherapy. Of the latter 19% were infield relapses. 5-year TTP and OS for the entire cohort were 83% (95%CI 78-89%) and 77% (95%CI 71-83%) respectively. In univariate analysis only IPI and age had significant impact on OS. Patients with an IPI-score of 0 had a hazard ratio (HR) of 0.50 compared to patients with an IPI-score ≥1 (95%CI 0.28-0.89, p 0.013). Patients ≤60 years and 60-75 years had a HR of 0.13 (95%CI 0.06-0.27, p < 0.01) and 0.34 (95%CI 0.18-0.63, p< 0.01) respectively compared to patients ≥75 years for OS. No difference was found in OS between patients treated with abbreviated chemotherapy followed by radiotherapy or full course chemotherapy (HR 1.09, 95%CI 0.62-1.91, p 0.77); nor for treatment with or without R (HR 1.03, 95%CI 0.56-1.89, p 0.93). In univariate analysis only age ≤75 years was prognostic (HR 0.37 95%CI 0.17-0.84, p 0.017) for TTP. Of the relapses 25% occurred ≥ 3 years after treatment irrespective of rituximab exposure.Conclusions:In this large population-based analysis of patients with stage I(E) DLBCL no differences in OS and TTP were found between abbreviated R-CHOP followed by radiotherapy and full course R-CHOP. No clear benefit of R on OS, TTP and late relapses was found. With similar outcomes, toxicity should primarily determine the chose of treatment regimen. DisclosuresHoogendoorn:Gilead: Consultancy; Novartis: Consultancy.

Consolidation Radiotherapy Improved Survival in Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): A Nationwide Multi-Institutional Registry of 816 Cases in Thailand

IntroductionThe additional benefit of consolidation radiotherapy (RT) following chemotherapy in limited stage DLBCL remains controversial. Previous 5 randomized trials, 4 trials before rituximab era (SWOG 8736, ECOG 1484, GELA 93-1 and 93-4 studies) and 1 trial with R-CHOP combination (Lysa/Goelams 02-03), could not demonstrate a remarkable benefit of RT. The purpose of this study is to explore the benefit of combined modality treatment including the combination of RT and rituximab (R)-based chemotherapy in limited stage DLBCL.MethodsFrom the 4,371 patients in a multi-institutional registry of newly diagnosed lymphoma in Thailand between 2007-2014, there were a total of 2,399 patients with DLBCL. We included patients with limited stage DLBCL receiving CHOP/CHOP-liked chemotherapy +/- R and +/- RT. The baseline patient characteristics and clinical outcomes were analyzed according to treatment modalities.ResultsA total of 816 patients with a median age of 56 years (range, 15-91) were included in the study. Male:female was 1:1.1. Majority of patients had primary extranodal diseases (58%), stage II (68%), good performance status (89%), normal LDH (55%) and no B-symptoms (59%). The IPI scores were 0 (30.6%), 1(45%), 2 (20%) and 3 (3.9%), respectively. The modalities of treatment were CHOP alone (48.5%), R-CHOP (26.5%), CHOP+RT (17.9%) and R-CHOP+RT (7.1%). Patients in R-CHOP group were older than in other groups (P =0.001) (Table 1).There was a higher proportion of patients in stage II disease in R-CHOP (74.1%) and R-CHOP+RT (74.1%) groups than in CHOP (66.9%) and CHOP+RT (57.5%) groups (P =0.007), whereas the patients were relatively equally distributed between the IPI scores. Complete response (CR) rate was higher in R-CHOP+RT group (82.8%) than in R-CHOP (75%), CHOP+RT (70%) and CHOP groups (58%) (P<0.001). CR was independently associated with consolidation RT (OR 0.65, 95%CI: 0.45-0.97), rituximab-based therapy (OR 0.66; 95%CI: 0.55-0.79) and IPI score (OR 1.90; 95%CI: 1.41-2.57). With a median follow up of 52 months, 4-year progression free survival (PFS) were 76.4%, 69.4%, 61.4% and 49.9% in R-CHOP+RT, R-CHOP, CHOP+RT and CHOP alone, respectively, (P<0.001) (Figure. 1). The corresponding figures of 4-year OS for each group were 78.6%, 76.3%, 64.3% and 59.6%, respectively (P<0.001) (Figure. 2). Multivariate analysis showed that factors associated with survivals were consolidation RT (HR for PFS 0.63, 95%CI: 0.48-0.82; HR for OS 0.70, 95%CI: 0.53-0.94), rituximab-based therapy (HR for PFS 0.72, 95%CI: 0.64-0.83; HR for OS 0.69, 95%CI: 0.60-0.81) and IPI scores (HR for PFS 1.87, 95%CI: 1.54-2.26; HR for OS 1.96, 95%CI: 1.60-2.41)ConclusionIn limited stage DLBCL, consolidation RT plus R-CHOP yielded a superior outcome compared to R-CHOP, CHOP + RT and CHOP alone. Thus, RT continues to have an important role and should not be omitted in management of limited stage DLBCL in rituximab era.Table 1Comparison of characteristics of patients according to treatment modalitiesClinical characteristicsCHOP alone(n= 396)CHOP + RT(n = 146)R-CHOP alone (n = 216)R-CHOP + RT (n = 58)p-valueMale211 (53%)75(51.4%)125 (57.9%)24 (41.4%)0.14Median age (years)56 (15-90)52 (15-86)60 (17-91)55 (15-81)0.001Age ≥ 60155 (39.1%)51 (34.9%)109 (50.5%)20 (34.5%)0.008Primary extranodal disease226 (57.1%79 (54.1%)136 (63.0%34 (58.6%)0.35Stage Stage I Stage II131 (33.1%) 269 (66.9%)62 (42.5%) 84 (57.5%)56 (25.9%) 160 (74.1)15 (25.9%) 43 (74.1%)0.007B-symptom116 (32.6%)47 (36.2%)58 (31.4%)13 (28.9%)0.76HIV seropositivity15 (4.6%)9 (7.0%)--0.004High serum LDH173 (43.7%)74 (50.7%)95 (44.0%)26 (44.8%)0.51ECOG ≥ 231 (7.8%)22 (15.1%)25 (11.6%)7 (12.1%)0.08IPI Low (IPI =0-1) Low-intermediate (IPI =2) High-intermediate (IPI = 3)312 (78.8%) 75 (18.9%) 9 (2.3%)107(73.3%) 32 (29.1%) 7 (4.8%)157 (72.7%) 48 (22.2%) 11 (5.1%)46 (79.3%) 9 (15.5%) 3 (5.2%)0.35Response Overall response Complete response258 (65.2%) 230 (58.1%)116(79.4%) 103(70.5%)179 (82.9%) 162 (75%)51 (88%) 48 (82.8%)<.0001 [Display omitted] [Display omitted] DisclosuresKhuhapinant:Roche: Honoraria.

Stage Adjusted International Prognostic Index (St-IPI) Is a Simple and Better Prognostic Model in Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): A Nationwide Multi-Institutional Registry in Thailand

IntroductionIn pre-rituximab era, the IPI has been developed and widely used to predict the prognosis of aggressive lymphoma while Miller's stage modified IPI1 was reported as a better prognostic model for limited stage DLBCL. Recently, NCCN-IPI2 was stated to be a better predictor of prognosis for DLBCL in rituximab era. We aim to compare the prognostic significance between IPI, Miller's stage modified IPI, NCCN-IPI and the new proposed stage adjusted IPI (St-IPI) in limited stage DLBCL patients treated with rituximab based regimens.MethodsFrom the 4,371 patients in a multi-institutional registry of newly diagnosed lymphoma in Thailand between 2007-2014, there were a total of 2,399 patients with DLBCL. We included patients with limited stage DLBCL receiving R-CHOP or R-CHOP-liked chemotherapy. The clinical outcomes were analyzed according to IPI, Miller's stage modified IPI, NCCN-IPI and St-IPI. To generate the St-IPI, we used 3 predictors from IPI namely, age > 60, elevated LDH and ECOG ≥ 2, classified patients into 3 risk cohorts, i.e., the low (score 0), intermediate (score 1-2), and high risk (score 3) group.ResultsA total of 274 patients with a median age of 58 years (range, 15-91) were included. Seventy-four percent of the cohort had stage II disease, 44% and 32% of them had elevated LDH and ECOG ≥ 2, respectively. According to St-IPI, 77, 183 and 14 patients were categorized as low (score 0), intermediate (score 1-2) and high risk groups (score 3), respectively. Most of the patients (96%) received R-CHOP regimen and one fifth of them underwent consolidation radiotherapy, contributing to a complete response rate of 76%. With a median follow up of 52 months, the 5-year progression free survival (PFS) according to St-IPI among low, intermediate and high risk groups were 79%, 66% and 22%, respectively (HR 2.48, 95%CI: 1.55-3.86). The corresponding figures for 5-year overall survival (OS) were 84%, 73% and 49%, respectively (HR 2.95, 95%CI: 1.54-4.37). The 5-year PFS and OS according to IPI, NCCN-IPI and Miller's stage modified IPI were described in Table 1. When comparing between risk models, St-IPI was able to discriminate more accurately low risk PFS than IPI, distinguished more precisely high risk PFS than NCCN-IPI and Miller's stage modified IPI (Figure 1). All risk models had no differences in predicting OS at 5 years, nevertheless, there was a trend of inferior survivals after 5 years among limited stage DLBCL patients with high risk St-IPI (Figure 2).ConclusionSt-IPI is a simple and better model in predicting PFS for limited stage DLBCL treated with R-CHOP. The model is able to predict the lower risk disease more discriminately than the IPI which would suggest the tailor therapy approach to avoid unnecessary treatment related toxicities. Moreover, the St-IPI is better in predicting patients with high risk of relapses in whom more aggressive treatment is warranted to improve the cure rate of the patients.1 Miller, et al. N Engl J Med 1998; 339: 21-62 Zhou, et al. Blood. 2014;123: 837-842Table 15-year PFS and OS according to risk groups categorized by St-IPI, IPI, NCCN-IPI and Miller's stage modified IPIRisk model5-year PFS (%)HR (95%CI)P -value5-year OS (%)HR (95%CI)P -valueSt-IPI (Age > 60, elevated serum LDH, ECOG ≥ 2)2.48 (1.55-3.86)<0.0012.95 (1.54-4.37)<0.001Low (score 0, n= 77)7984Intermediate (score 1-2, n=183)6673High (score 3, n=14)2249IPI (Age > 60, elevated LDH, ECOG ≥ 2, Stage ≥ III, extranodal involvement >1)1.99 (1.43-2.78)<0.0012.03 (1.40-2.97)<0.001Low (score 0-1, n =203)7379Low-intermediate (score 2, n=57)6169High-intermediate (score 3, n=14)2249High (score 4-5, n=0)--NCCN-IPI (Age ≤40, >40-60, 60-75, >75; elevated serum LDH 1-3X, > 3X; ECOG ≥ 2, Stage ≥ III, extranodal disease in bone marrow, liver/GI tract or lung)1.83 (1.30-2.57)<0.0012.13 (1.45-3.13)<0.001Low (score 0-1, n=82)7986L-I (score 2-3, n=152)6774H-I (score 4-5, n=40)4454High (score ≥ 6, n=0)--Miller's stage modified IPI (Age > 60, elevated serum LDH, ECOG ≥ 2, Stage II)1.71 (1.28-2.28)<0.0011.69 (1.22-2.35)0.02Low (score 0-1, n=107)7884Intermediate (score 2, n=109)6573High (score 3-4, n=58)5149 [Display omitted] [Display omitted] DisclosuresKhuhapinant:Roche: Honoraria.

Additional Survival Benefit of Involved-Lesion Radiation Therapy After R-CHOP Chemotherapy in Limited Stage Diffuse Large B-Cell Lymphoma

The purpose of this study was to evaluate the role of involved-lesion radiation therapy (ILRT) after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy in limited stage diffuse large B-cell lymphoma (DLBCL) by comparing outcomes of R-CHOP therapy alone with R-CHOP followed by ILRT. We identified 198 patients treated with R-CHOP (median, 6 cycles) for pathologically confirmed DLBCL of limited stage from July 2004 to December 2012. Clinical characteristics of these patients were 33% with stage I and 66.7% with stage II; 79.8% were in the low or low-intermediate risk group; 13.6% had B symptoms; 29.8% had bulky tumors (≥ 7 cm); and 75.3% underwent ≥ 6 cycles of R-CHOP therapy. RT was given to 43 patients (21.7%) using ILRT technique, which included the prechemotherapy tumor volume with a median margin of 2 cm (median RT dose: 36 Gy). After a median follow-up of 40 months, 3-year progression-free survival (PFS) and overall survival (OS) were 85.8% and 88.9%, respectively. Multivariate analysis showed ≥ 6 cycles of R-CHOP (PFS, P=.004; OS, P=.004) and ILRT (PFS, P=.021; OS, P=.014) were favorable prognosticators of PFS and OS. A bulky tumor (P=.027) and response to R-CHOP (P=.012) were also found to be independent factors of OS. In subgroup analysis, the effect of ILRT was prominent in patients with a bulky tumor (PFS, P=.014; OS, P=.030) or an elevated level of serum lactate dehydrogenase (LDH; PFS, P=.004; OS, P=.012). Our results suggest that ILRT after R-CHOP therapy improves PFS and OS in patients with limited stage DLBCL, especially in those with bulky disease or an elevated serum LDH level.

R‐CHOP therapy alone in limited stage diffuse large B‐cell lymphoma

Long-term observation has identified a pattern of continuing relapse in limited stage diffuse large B-cell lymphoma (DLBCL) treated by three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus involved-field irradiation. We retrospectively analysed 190 untreated patients with limited stage DLBCL treated by R-CHOP alone. All the patients were scheduled to undergo primary therapy with six cycles of full-dose R-CHOP. Cases with a dose reduction of more than 20% were excluded from the study. Additional local irradiation was allowed in patients with partial response (PR). Five patients received additional local irradiation after PR at the end of the R-CHOP therapy. The median observation period was 52 months. Median age at diagnosis was 63 years. The responses to therapy were 180 complete responses, eight PR, and two progression of disease (PD). The 5-year progression-free survival and 5-year overall survival rates were 84% and 90%, respectively, both in plateau. During the observation period, 29 patients experienced PD. The progression sites were the primary sites in 15 patients, outside the primary sites in 10, and undetermined in four patients. These results suggest that the 'standard' strategy of three cycles of R-CHOP followed by involved-field radiotherapy for limited stage DLBCL could be effectively replaced by six cycles of R-CHOP alone.

Pilot trial of yttrium-90 ibritumomab tiuxetan consolidation following rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy in patients with limited-stage, bulky diffuse large B-cell lymphoma

The clinical efficacy and safety of yttrium-90 (90Y)-ibritumomab tiuxetan consolidation treatment following rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) chemotherapy was investigated in patients with limited-stage and bulky diffuse large B-cell lymphoma (DLBCL). This prospective, multi-center, pilot trial included 21 patients who were newly diagnosed with stage I/II, bulky DLBCL and achieved a complete or partial response after six cycles of R-CHOP. The median size of bulky disease was 10.0 × 7.0 cm. After a median follow-up of 28.8 months, the overall response rate after 90Y-ibritumomab tiuxetan consolidation treatment was 80.9%, including 4.8% partial response. However, six patients (28.6%) experienced a progression or relapse. The 3-year overall and progression-free survival rates were 85.0 ± 8.0% and 75.0 ± 9.7%, respectively. Grade 3–4 adverse events were mainly hematologic toxicities, such as thrombocytopenia (35%) and neutropenia (60%). One patient experienced grade 3 Pneumocystis carinii pneumonitis. Thus, 90Y-ibritumomab tiuxetan consolidation following six cycles of R-CHOP resulted in an acceptable response with tolerable toxicity in patients with limited-stage and bulky DLBCL.

Long term outcome of patients with localized aggressive non-Hodgkin lymphoma treated with PROMECE-CYTABOM plus involved-field radiation therapy: a study by the Gruppo Italiano Studio Linfomi

We conducted a retrospective analysis on 168 adult patients with newly diagnosed, limited-stage (I and II) diffuse large B-cell lymphoma (DLBCL) treated from 1988 to 2004 with PROMECE-CYTABOM (P-C) plus involved-field radiation therapy (IF-RT). At the end of P-C, the overall response rate was 92%. Radiotherapy (RT) was delivered to 84% of cases. With a median follow-up of 95 months, overall survival (OS), relapse free survival (RFS), and failure free survival at 5 and 10 years was 84% and 77%, 81% and 75%, 71% and 67%, respectively. Age (>60 years, p = 0.002), serum albumin (<3.5 g/dL; p = 0.015), and RT (p < 0.001) were independent predictors of OS. For patients in complete remission the administration of RT didn't improve both RFS and OS. This study confirms that patients with localized aggressive lymphoma have a high chance of cure with anthracycline containing regimens. Though the regimen used to treat these patients does not contain rituximab, results are considered excellent both in terms of efficacy and safety.

Involved Field Radiation Therapy in Limited Stage Diffuse Large B-cell Lymphoma of Head and Neck: Is it Whole Neck Irradiation?

To report the treatment outcomes after combined modality therapy (CMT) in patients with stage I/II head and neck (HN) diffuse large B-cell lymphoma (DLBL). A retrospective review was performed on 86 patients with stage I/II DLBL of HN who received CMT from 1995 till 2006 at Samsung Medical Center. The most common involved sites were oropharynx (40.7%) and cervical lymph node (38.4%). Involved field radiation therapy (IFRT) was given following median 4 cycles of CHOP or R-CHOP chemotherapy. The RT target volume was individually determined to cover the known gross lesion with adequate margin (2-3cm), and the median radiation dose was 39.8 Gy over 4-5 weeks. Overall survival rate (OS) and relapse-free survival rate (RFS) at 10 years were 74.0%, and 88.9%. After median follow-up of 57 months (11-131), eight treatment failures were observed: distant metastasis in eight; and loco-regional failure in four patients. Among four patients with loco-regional failure, three presented with in-field failures, and one did with out-field failure at contralateral recurrence. During and after completion of RT, there was no severe side effect except one patient with grade 3 mucositis. Multivariate analyses showed that B symptom (p = 0.022) and abnormal LDH (p = 0.017) were related with poor OS, age older than 60 (p = 0.033) was with RFS, and International prognostic index (IPI, p = 0.03) was related with OS and RFS. The results of this study demonstrated that stage I, II head and neck DLBCL patients did not need ipsilateral whole neck irradiation. Reasonable margin from tumor may reduce radiation toxicity with same treatment results.

Primary Diffuse Large B-Cell Lymphoma of the Colon: Surgery for Local Disease Control Does Not Improve Outcome.

Purpose: Primary colorectal large B-cell lymphoma is rare and accounts for less than 1% of all malignancies in the colon. Standard treatment for limited stage diffuse large B-cell lymphomas (DLBCL) includes systemic therapy combined with involved field radiation therapy. However, radiation therapy may often not be feasible in patients with primary colon lymphoma. For primary DLBCL of the colon particularly the cecum, surgical resection prior to the administration of systemic chemotherapy has been considered to improve local control. The goal of this study was therefore to determine whether surgical resection improves the outcome of patients with primary DLBCL of the colon.Methods: Clinical information and outcomes on all the patients with primary DLBCL of the colon seen at Mayo Clinic, Rochester, between January 1980 and June 2005 were retrospectively reviewed.Results: There were 28 patients identified with primary colon DLBCL. Pre-existing conditions like colon polyps, Crohn's disease and diverticulosis were uncommon. The most common presenting symptom was bleeding per rectum seen in 13 patients (46.5%). Other symptoms included abdominal pain, diarrhea and anemia. All patients had early stage disease (stage1–22 patients, stage2–6 patients) at diagnosis. Of the 28 patients, 16 underwent initial surgery followed by chemotherapy, 7 were treated with chemotherapy alone, and 5 patients had inadequate data to determine time to progression or overall survival. Chemotherapy was anthracycline based, with the most common regimen being CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone). There was no difference in overall survival or time to progression between the 16 patients who received combined modality therapy compared to the 7 patients who received chemotherapy alone. Of the 16 patients who underwent surgical resection followed by chemotherapy, all 5 patients who relapsed, relapsed at other sites in the colon. Conclusion: Surgery as part of combined modality therapy did not appear to improve the outcome of patients with primary DLBCL of the colon. Systemic chemotherapy with an anthracycline-based regimen in combination with rituximab is therefore likely to be sufficient treatment for these patients. Follow-up for these patients should include a colonoscopy to monitor for recurrences at other sites in the colon.

Survival of Limited Stage Peripheral T-Cell Lymphoma Is Similar To Diffuse Large B-Cell Lymphoma.

Background: Peripheral T-cell lymphomas (PTCL) represent a heterogeneous group of diseases with an overall poor prognosis. Little information is available regarding the outcome of PTCL patients who present with limited stage disease. We sought to determine the outcome of PTCL patients presenting with limited disease in comparison with a cohort of patients with limited stage diffuse large B-cell lymphoma (DLBCL).Methods: In a retrospective analysis we identified all patients with limited stage (non-bulky (<10cm) stage I/II disease no symptoms) PTCL diagnosed at the British Columbia Cancer Agency (BCCA) between 1983 and 2004. Patients were excluded if they had cutaneous anaplastic large cell lymphoma (CutALCL) (n=13), NK/T-cell lymphoma nasal type (n=9) or primary CNS/ocular involvement (n=6).Results: Thirty-seven patients with PTCL were identified according to the World Health Organization Classification: ALK-neg ALCL 8 (22%); PTCL-unspecified (PTCLUS) 28 (78%); enteropathy associated TCL (EATL) 1 (3 %). The majority received CHOP-type chemotherapy (n=31, 86%), most with brief chemotherapy followed by involved-field radiation (n=19, 61%). The 5 y OS and PFS was similar between PTCLUS and ALK-neg ALCL. There was no difference in survival between extranodal and nodal cases. The outcome of PTCL patients (including ALK-neg ALCL and PTCLUS) was compared to a cohort of limited stage DLBCL patients (excluding CNS/ocular lymphoma) (n=305) diagnosed over the same time period and treated similarly. There was no difference in 5 y OS or PFS (Figure 1,2). Interestingly, there were no late relapses observed in PTCLUS, in marked contrast to DLBCL.Conclusions: Limited stage PTCL is rare, however outcomes appear to be comparable to early stage DLBCL, supporting that they should be treated in a similar manner. Unlike limited stage DLBCL where late relapses occur, a plateau in the progression-free survival curve is observed, highlighting a distinct natural history for limited stage PTCL. [Display omitted] [Display omitted]

A Predictive Model for Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): A Retrospective Analysis of 1,252 Cases Performed by the Intergruppo Italiano Linfomi (IIL).

Introduction: few studies have explored the usefulness of a prognostic index specifically devised for patients with localized DLBCL. The IIL has performed a retrospective analysis of a large group of patients with limited stage DLBCL and developed a new prognostic model.Results: 1,252 patients with localized (Ann Arbor stage I-II) aggressive B-cell lymphoma (IWF: G or H, WHO:DLBCL) diagnosed from 1988 to 2002 and without CNS involvement, treated by 4 cooperative groups and 2 single institutions, are the subject of this analysis. Patient's median age was 57 years (range, 17–91) and M/F ratio was 1.26. Clinical stage was I in 239 (19%), IE in 303 (24%), II in 356 (28%) and IIE in 354 (28%) patients, respectively. Supradiaphragmatic disease was present in 56% of patients, 13% had > 3 nodal sites, 53% had extranodal involvement, and 7% had >1 extranodal site. Bulky disease (≥10 cm) was present in 26% of patients, ECOG-PS >1 in 12% and B symptoms in 14%. Abnormal biochemical data included: elevated LDH (28%), β2-microglobulin (B2M;19%) and ESR (38%) and reduced albumin (< 3.5 g/dL) in 21% of the cases. Patients were treated with anthracyclin-containing regimens ± IF-RT. After a median follow-up of 62 months for alive patients (range 1–183 months), 3 and 5-year OS rates were 73% and 71%, respectively. By univariate analysis the following 11 variables were found to be predictive of a short survival: age ≥65 yrs (P=0,0001), stage II nodal (P=0,0001), number of nodal sites (P<0.0001), poor ECOG-PS (P<0.0001), B symptoms (P=0.0009), bulky disease (P=0.0001), elevated ESR (P=0.0001), LDH (P<0.0001), Radiotherapy (P<0.001), B2M (P=0.007) and reduced serum albumin (<0.0001). By Cox multivariate analysis, age ≥65 years (p<0.001), stage II nodal (P<0.001), high LDH (P<0.001) and bulky disease (P<0.01) were indipendent risk factors (RF) for a short survival. The prognostic model was calculated with the sum of scores assigned to each variable; a score of 2 was assigned to advanced age, high LDH, and Bulky; for Stage a score of 1 was considered for stage Ie-IIe and 2 for stage II nodal. Three groups of patients with a different probability of survival (P<0.000001) were identified. Patients at low (Score 0–1; 387 pts), intermediate (Score 2–3; 484 pts) or high risk (Score 4–8; 381 pts) had a 5 years OS of 87%, 77%, 51% respectively. The predictive performance of the model was internally validated through a non parametric Bootstrap method and through residues' analysis.Conclusions: This prognostic model, developed and validated on a very large series of patients with localized DLBCL, will allow us to select appropriate therapeutic approaches on the basis of different risk categories.