Polish Lymphoma Research Group Research Articles

The necessity of post-induction therapy in mantle cell lymphoma patients: A multicenter retrospective real-world analysis by Polish Lymphoma Research Group (PLRG)

Aim: Mantle cell lymphoma (MCL) patients have poor prognosis, due to development of chemoresistance in relapsing patients. Therefore, despite the features of indolent lymphoma at presentation, consolidation and/or maintenance strategies to achieve minimal tumor burden and postpone subsequent relapses remain the standard of care. Material/Methods: In the retrospective analysis of Polish Lymphoma Research Group (PLRG), post-induction strategies were assessed in 355 MCL patients. Those in complete or partial remission (CR or PR) after induction regimen (n = 263, 74.08%) were consolidated with autologous stem cell transplantation (ASCT) (n = 71, 20%) or radioimmunotherapy (RIT, n = 37, 10.42%), subjected to rituximab maintenance (MR, n = 17, 4.79%) or had none post-induction treatment (NPI, n = 138, 38.87%). Responses to therapy, progression and overall survival (PFS and OS) were compared. Results: CR after induction was significantly increased by consolidation strategies, from 68% to 95% in ASCT and from 43% to 90% in RIT cohort. Median PFS in patients subjected to ASCT and RIT was significantly higher compared to NPI group (2.3, 3.8 and 1.8 years respectively, p <0.05). Consolidation strategies also prolonged median OS (not reached in ASCT, 7.3 in RIT and 4 years in NPI cohort, p <0.005 ). Conclusions: Our data confirms the efficacy of ASCT consolidation in selected patients and demonstrates that RIT may be regarded as an alternative consolidation strategy for patients not eligible for ASCT. At the time the study was performed, there were few possibilities to retreat elderly and comorbid patients; therefore, despite PFS benefit of RIT, younger, transplanted patients experienced a longer median OS.

Nivolumab for relapsed/refractory classical Hodgkin lymphoma after brentuximab vedotin failure – Polish Lymphoma Research Group real-life experience

AbstractAimPolish centers analyzed retrospectively the real-life experience with nivolumab in relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) patients, after brentuximab vedotin (BV ) failure.BackgroundDespite the effective frontline treatment, for cHL patients relapsing after autologous stem cell transplantation, the only effective strategy remains the novel agents. Nivolumab, a checkpoint inhibitor, demonstrates the clinical benefit with an acceptable safety profile.Materials and methodsRetrospective analysis included 16 adult patients with R/R cHL after BV failure. All patients received single-agent nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity.ResultsAfter six cycles of nivolumab the overall response rate was 81% (complete remission rate of 56%, partial remission rate of 25%). The median PFS was not reached after a median follow-up of 19 months. Adverse events (AEs) of any grade occurred in 12 patients (75%), including grade 3 AEs observed in 5 patients (31%). There were no AEs of grade 4 or 5. After a median of 25 nivolumab doses, 62% of responding patients proceeded to allogeneic stem cell transplantation.ConclusionNivolumab monotherapy demonstrated a high efficacy and safety in R/R cHL patients after BV failure. More patients and longer follow-up may further establish the potential benefit.

Plerixafor for patients who fail cytokine-or chemotherapy-based stem cell mobilization: Results of a prospective study by the Polish Lymphoma Research Group (PLRG)

AbstractAutologous hematopoietic stem cell transplantation (autoHSCT) requires collection of sufficient number of hematopoietic stem cells. The goal of this study was to evaluate efficacy of plerixafor used in patients with lymphoid malignancies failing conventional stem cell mobilization.This was a prospective, non-interventional study. All consecutive patients (n = 109) treated with plerixafor in 11 centers were reported. The drug was used either in case of previous mobilization failure (n = 67) or interventionally, in case of insufficient CD34+ cell output during current mobilization (n = 42). Successful mobilization was defined as resulting in collection of ≥ 2 × 106 CD34+ cells/kg for single autoHSCT or ≥ 4 × 106 CD34+ cells/kg for double procedure.The overall rate of successful mobilization was 55% (55% for single and 56% for double autoHSCT). The median total number of collected CD34+ cells/kg was 2.4 (range, 0-11.5) for patients intended for a single transplantation while 4.0 (0.6-16.9) for double procedure. The number of circulating CD34+ cells increased after the use of plerixafor regardless of baseline values. The median fold increase was 3.3 (0.3-155). Data from this observational study confirm high efficacy of plerixafor used in routine clinical practice as salvage for patients with lymphoid malignancies failing conventional stem cell mobilization.

Brentuximab Vedotin Alone and in Combination with Bendamustine As Salvage Therapy for Primary Refractory or Relapsed Hodgkin Lymphoma: Multicentre Experience of the Polish Lymphoma Research Group (PLRG)

An optimal treatment for patients with primary refractory or relapsed (R/R) Hodgkin lymphoma (HL) who did not respond to standard salvage therapy has not been established. Brentuximab vedotin (BV) and bendamustine (B) used as monotherapy were shown to be active in R/R HL and both are recommended as a therapeutic option. It has been proposed that the combination of BV with B (BVB) may improve the outcome of R/R HL patients. To test this hypothesis, we compared retrospectively the efficacy and safety of BV and BVB regimen in R/R HL patients. Methods: Since March 2014 all patients with R/R HL treated at PLRG centers were offered either BV in monotherapy every 21 days or in combination with B (B 90 mg/m² on days 1 and 2 of treatment cycle) according to the policy in each center. Results: BV or BVB therapy was administered to 94 patients (median age 33 years, range 18-68) with primary refractory (n=54) or relapsed HL (n=40), including 34 patients after autologous stem cell transplant (ASCT). The patients were treated with the median of 3 (range, 2-12) prior chemotherapy lines. Fifty-seven patients received BV and 37 patients BVB regimen. In 16 of them, BVB was de-escalated to BV after the median of 2 cycles (range, 2-7). The patients' and disease characteristics did not differ between two groups. In the whole study group, the median number of applied cycles per patient was 4 (range, 2-16). Dose-limiting toxicities were observed in 8% of patients. No difference was found between BV and BVB group, with similar rate of grade 3-4 neutropenia (16% vs 13%) and thrombocytopenia (4% vs 3%). Lung infection occurred in 1 patient treated with BV (2%) and 3 treated with BVB (2% vs 8%, p ns), with 2 treatment-related deaths in the BVB group. The response rate after 2 cycles of BV and BVB treatment defined as complete (CMR) or partial metabolic response (PMR) assessed by positron emission tomography was 69% (26% of CMR and 43% of PMR) and 89% (46% of CMR and 43% of PMR), respectively (p=0.036). After 4-6 cycles of treatment, CMR, PMR and stable metabolic disease was documented in 59%, 19% and 13% in the BV group vs. 71%, 17% and 3%, respectively, in the BVB group (p ns). Finally, 36 patients (22 from BV and 14 from BVB group) proceeded to ASCT, and 17 (9 from BV and 8 from BVB group) to allogeneic SCT. The overall and progression-free survival at 24 months were 80% and 51%. The survival curves did not differ between two study groups. In conclusion, our results suggest that BVB is a feasible regimen that provides higher response rate after 2 cycles compared to BV monotherapy. However, the overall response rate achieved after 4-6 cycles of treatment are comparable between BV monotherapy and combined BVB treatment. Infectious complications, including serious lung infections, were observed in both study groups, with two treatment-related deaths in the BVB group. DisclosuresDlugosz-Danecka:Roche: Consultancy; Servier: Consultancy. Jurczak:Nordic Nanovector: Research Funding; Epizyme: Research Funding; Beigene: Research Funding; Bayer: Research Funding; Celgene: Research Funding; Merck: Research Funding; Servier: Consultancy, Honoraria, Research Funding; European Medicines Agency: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy, Research Funding; Afimed: Research Funding; Morphosys: Research Funding; Janssen: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Roche: Research Funding; Pharmacyclics: Research Funding; Acerta: Consultancy, Research Funding; TG therapeutics: Research Funding. Zaucha:Roche: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria.

Hodgkin lymphoma of the elderly patients: a retrospective multicenter analysis from the Polish Lymphoma Research Group*

We retrospectively analyzed long-term disease outcome of 350 elderly Hodgkin Lymphoma (eHL) patients treated with ABVD/ABVD-like regimen enrolled in the PLRG-R9 study between 2001 and 2013 in Poland. Complete remission was reported for 73% of early (ES) and 61% advanced stage (AS) patients. Nine (10%) ES and 56 (20%) AS patients have died. With the median follow-up of 36 (1–190) months, 3-year EFS and OS was 0.74 (95%CI: 0.63–0.85) and 0.90 (95%CI: 0.82–0.98) for ES; 0.51 (95%CI: 0.44–0.57), and 0.81 (95%CI: 0.75–0.86) for AS patients, respectively. For ES patients, Cox regression revealed ECOG <2 and age >70 as predictive for inferior OS and EFS. For AS patients, the most predictive for OS was the presence of cardiovascular disorders (CVD) (p = .00044), while for EFS four factors were significantly associated with a poor outcome: ECOG< 2, age >70 years, CVD and extranodal disease. In conclusion, CVD significantly impacts outcomes of ABVD-treated advanced eHL patients.

The predictive role of interim PET after the first chemotherapy cycle and sequential evaluation of response to ABVD in Hodgkin’s lymphoma patients—the Polish Lymphoma Research Group (PLRG) Observational Study

BackgroundInterim PET after two ABVD cycles (iPET2) predicts treatment outcome in classical Hodgkin’s lymphoma. To test whether an earlier assessment of chemosensitivity would improve the prediction accuracy, we launched a prospective, multicenter observational study aimed at assessing the predictive value of iPET after one ABVD (iPET1) and the kinetics of response assessed by sequential PET scanning. Patients and methodsConsecutive patients with newly diagnosed classical Hodgkin’s lymphoma underwent interim PET scan after one ABVD course (iPET1). PETs were interpreted according to the Deauville score (DS) as negative (−) (DS 1–3) and positive (+) (DS 4, 5). Patients with iPET1 DS 3–5 underwent iPET2. ResultsAbout 106 early (I–IIA) and 204 advanced (IIB–IV) patients were enrolled between January 2008 and October 2014. iPET1 was (−) in 87/106 (82%) or (+) in 19/106 (18%) of early, and (−) in 133/204 (65%) or (+) in 71/204 (35%) of advanced stage patients, respectively. Twenty-four patients were excluded from response analysis due to treatment escalation. After a median follow-up of 38.2 (3.2–90.2) months, 9/102 (9%) early and 43/184 (23%) advanced patients experienced a progression-free survival event. At 36 months, negative and positive predictive value for iPET1 were 94% and 41% (early) and 84% and 43% (advanced), respectively. The kinetics of PET response was assessed in 198 patients with both iPETs. All 116 patients with iPET1(−) remained iPET2(−) (fast responders), 41/82 with IPET1(+) became iPET2(−) (slow responders), and the remaining 41 stayed iPET2(+) (non-responders); progression-free survival at 36 months for fast, slow and non-responders was 0.88, 0.79 and 0.34, respectively. ConclusionThe optimal tool to predict ABVD outcome in HL remains iPET2 because it distinguishes responders, whatever their time to response, from non-responders. However, iPET1 identified fast responders with the best outcome and might guide early treatment de-escalation in both early and advanced-stage HL.

Polish Lymphoma Research Group Experience With Bexarotene in the Treatment of Cutaneous T-Cell Lymphoma.

Bexarotene, a synthetic retinoid licensed for the treatment of refractory cutaneous T-cell lymphoma (CTCL), has been used clinically in Poland since 2007 in 21 patients. The objective of our retrospective, multicenter study was to evaluate our experience with bexarotene therapy, including efficacy, safety, and survival outcomes. We retrospectively identified 21 adult patients who were treated with bexarotene between the years 2007 and 2012. Starting dose of bexarotene was 300 mg/m per day. The analysis included 3 patients with early-stage mycosis fungoides (MF), 16 patients with advanced-stage MF, and 2 patients with Sézary syndrome (SS). The mean duration of therapy with bexarotene was 14.5 months. Use of bexarotene resulted in an overall response rate of 81.0%, although the overall mortality rate was 52.8%. In our study, early-stage CTCL responded better than advanced-stage CTCL (100.0% vs. 77.8%, respectively). The mean time to observable response was 1.8 months, and the mean duration of the response was 16.4 months. Most significant side effects were hyperlipidemia, hypothyroidism, and a bleeding gastric ulcer. Based on the results of our analysis, bexarotene is a valuable tool in the treatment of refractory early-stage CTCL. Although a majority of patients initially responded to therapy, the high mortality rate in the advanced-stage group suggests that bexarotene does not completely resolve the therapeutic problems in all stages of CTCL. Patient stratification for bexarotene treatment may need a thorough reassessment, in that bexarotene may not be an effective drug in the very advanced stages of CTCL.

The Prognostic Role of Interim PET after First Chemotherapy Cycle and PET Sequential Evaluation of Response to ABVD in Hodgkin Lymphoma Patients - the Polish Lymphoma Research Group (PLRG) Observational Study

Background: Several studies confirmed the predictive role on treatment outcome of interim-PET after 2nd ABVD cycle (iPET2) in Hodgkin lymphoma (HL). We hypothesized that interim PET after 1st cycle (iPET1) might define chemosensitivity with a better accuracy than iPET-2. To test this hypothesis, PLRG launched in 2008 a prospective multicenter observational study aiming at assessing the prognostic role of iPET1 and the dynamic of sequential PET response to ABVD.Methods: Adult pts with newly diagnosed early (stage I-IIA) and advanced (stage IIB-IV) consecutively enrolled in 11 Polish centers were risk-stratified by the EORTC/GELA criteria and treated according to the ESMO guidelines: ABVD x 3-4 cycles + IFRT in early stage, ABVD x 6 ± consolidation RT in advanced stage disease. Patients were scanned with iPET1 and iPET2 and no treatment change was permitted based solely on iPET results, with the exception of clinical or radiological evidence of overt HL progression. After the first interim analysis (52 pts enrolled, 2010), which demonstrated that all the iPET1 negative patients had also a negative iPET2, the protocol was amended, limiting the iPET2 scans only to pts with iPET1 Deauville score 5,4,3. Quality control for PET-CT was supervised by the Italian-Polish core lab using a standard methodology. PET scans were interpreted locally according to the Deauville 5-point scale: Score 1 to 3, was considered a negative (-), score 4 to 5 a positive (+) scan. Subsequently all PET scans were uploaded to the web platform WIDEN® for central review and Italian-Polish expert panel (EP) scored them afresh. Discorcondant cases were discussed in a joint review session with all the five EP members. Binary and overall concordance rates were calculated using k Cohen's and alpha Krippendorf's coefficients, respectively. Negative (NPV) and positive predictive values (PPV) of iPET1 were calculated using time to progression free survival (PFS) event.Results: Between 2008 and 2014, 346 pts were registered. 35 pts were excluded from the analysis for absence/poor quality of images resulting in 108(35%) assessable pts with early and 203(65%) with advanced HL. Median age at diagnosis was 31(18-80) years. iPET1 was scored 1-3 in 87/108(81%), and 4-5 in 21/108(19%) of pts with early and in 133/203(65%), and 70/203(35%) with advanced stage, respectively. Out of 91pts with positive iPET1, 83 pts underwent iPET2, which remained (+) in 41/83(49,4%) pts. In 22 pts treatment was escalated. 11 of those pts, in whom the treatment escalation was decided solely on positive iPET were excluded from the analysis; the remaining had symptoms or CT evidence of progression. After a median follow-up of 40,2 (3,2-90,2) months 300 pts (103 "early" and 197 "advanced") were evaluable. 65(21,7%) of them (9 in early and 56 in advanced group) had a PFS event: in "early" group 9(9%) showed disease progression (4 with iPET1(-) and 5 with IPET1(+)) and 1 of them died. In advanced stage 49(25%) pts showed disease progression (16 with iPET1(-) and 33 withiPET1(+)) out of whom 13 died; 7 additional pts died without HL progression: 4 from toxicity and 3 from unrelated events. At 36 months NPV and PPV of iPET1 was 93% and 45% in "early" and 81% and 52% in "advanced" group, respectively. The dynamic of response to ABVD was assessed in 189 pts who underwent both iPETs. All 116 pts with iPET1(-) remained (-) in iPET2-(fast-responders). Out of 83pts with IPET1(+) 39 (47%) became iPET2(-)-(slow responders); the rest (34pts: 41%) remained iPET2(+)-(no responders). PFS for fast-responders @36 months was 85%, for slow-responders 80% (log rank p=0,36) and for no-responders 25% (log rank p=0,0000). The EP changed the local iPET1 score in 27 cases: in 14 from (+) to (-) in 13 from (-) to (+). The inter-observer-agreement among reviewers on evaluating a positive vs. negative interim PET scans was good, Fleiss' kappa = 0.73, comparable to that found in analogous studies (IVS, HD0607).Conclusion: iPET1 fails to better identify chemosensitivity in ABVD-treated HL compared to iPET2. PPV of iPET1 is substantially inferior to the published results for iPET2. However NPV of iPET1 is comparable to iPET2 and therefore might guide early treatment de-escalation strategies. DisclosuresZaucha:Roche: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Knopinska-Posluszny:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Teva: Other: travel, accommodation, Speakers Bureau. Walewski:Mundipharma; Roche; Takeda: Honoraria, Other: Travel expenses; Amgen; Boehringer Ingelheim; Celgene; Janssen-Cilag; Mundipharma; Roche; Takeda; Teva: Consultancy; Bayer (Inst); Bayer/Onyx (Inst); Boehringer Ingelheim (Inst); Celgene (Inst); Celltrion (Inst); Gilead Sciences (Inst); GlaxoSmithKline (Inst); GlaxoSmithKline (Inst); Mundipharma (Inst); Pfizer (Inst); Roche (Inst); Roche/Genentech (Inst); Seattle Geneti: Research Funding.

Increased efficacy of intermediate-dose cytarabine + G-CSF compared to DHAP + G-CSF for stem cell mobilization in patients with lymphoma: an analysis by the polish lymphoma research group.

Salvage regimens, like DHAP (dexamethasone, cytarabine, and cisplatin) are frequently used for stem cell mobilization in lymphoma. The aim of this study was to compare the efficacy of DHAP + G-CSF with intermediate-dose cytarabine (ID-AraC) + G-CSF, recently proposed as an alternative schedule. Consecutive patients with Hodgkin's or non-Hodgkin lymphoma who had received at least 2 lines of chemotherapy, mobilized with either DHAP (n = 51) or ID-AraC (n = 50) + G-CSF were included in the analysis. AraC was administered at the dose of 400mg/m [1] bid intravenously for 2days followed by filgrastim starting from day 5. In the AraC group, 96% of patients collected at least 2 × 10 [2] CD34(+) cells/kg compared to 71% in the DHAP group (p = 0.0006). The CD34(+) cell yield was 9.3 (0-30.3) × 10 [2]/kg vs. 5.6 (0-24.8) × 10 [2]/kg, respectively (p = 0.006). A single apheresis was sufficient to achieve the threshold number of CD34(+) cells in 82% of the cases after AraC compared to 45% after DHAP (p = 0.001). We conclude that stem cell mobilization using ID-AraC is associated with a significantly higher efficacy than DHAP, allowing for collection of the transplant material in almost all patients with lymphoma. Our observation suggests that ID-AraC + G-CSF may be a preferable mobilization regimen in this setting.

Role of rituximab in the first-line therapy of high-risk diffuse large B-cell lymphoma: a retrospective analysis by the Polish Lymphoma Research Group.

R-CHOP immunochemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is a standard first-line treatment for diffuse large B-cell lymphoma (DLBCL). None of the randomized trials have proved a statistically significant overall survival (OS) benefit in high-risk subgroups according to the International Prognostic Index (IPI). We retrospectively investigated the role of adding rituximab to anthracycline-based chemotherapy in patients with high-risk DLBCL according to the IPI. A total of 371 patients with high-risk DLBCL treated at 15 Polish hematology centers were retrospectively analyzed in 2 distinct age groups: older than 60 years and 60 years old or younger. Response rates, OS, and progression-free survival (PFS) were compared and analyzed. The overall response rate (ORR) of high-risk DLBCL patients significantly improved in rituximabtreated patients compared with patients treated without rituximab (76.7% vs 95.6%; P <0.05). The R-CHOP immunochemotherapy prolonged survival in both older and younger subgroups. The 5-year projected OS and PFS in younger patients treated with rituximab vs chemotherapy alone were 42% vs 38% and 46% vs 27%, respectively (P <0.05), while the 5-year projected OS and PFS in older patients treated with rituximab vs chemotherapy alone were 82% vs 52% and 67% vs 45%, respectively (P <0.05). With all the limitations of a retrospective analysis, the superiority of adding rituximab to CHOP combination chemotherapy has been clearly demonstrated regarding ORR, OS, and PFS in both age subgroups of patients with high-risk DLBCL.

Liposomal cytarabine in the prophylaxis and treatment of CNS lymphoma: toxicity analysis in a retrospective case series study conducted at Polish Lymphoma Research Group Centers.

Lymphomas with primary or secondary involvement of central nervous system (CNS) have poor prognosis despite specific treatment protocols which include whole brain radiotherapy and high-dose systemic and/or intrathecal chemotherapy. Toxicity of intrathecal liposomal cytarabine-based regimens collected between November 2006 and January 2012 was assessed retrospectively. Data from 120 adult lymphoma patients with, or at high risk of CNS involvement who received intrathecal liposomal cytarabine-based regimens at six Polish Lymphoma Research Group centres between November 2006 and January 2012 were assessed retrospectively. Patients were divided into three cohorts: A (high risk of CNS disease, n = 88), B (cerebrospinal fluid pleocytosis without neurological symptoms or pathological imaging findings, n = 7), and C (CNS disease/neurological involvement; n = 25). In all examined groups, toxicity of treatment was found to be acceptable (including the prophylactic setting). None of the patients in cohorts A or B who took intrathecal liposomal cytarabine 50 mg, repeated every 2–4 weeks (mean 3.8 doses) had experienced a CNS relapse at a median follow-up time of 3 years. Patients in cohort C had a 76 % overall neurological response rate (including a 40 % complete response rate) and median overall survival of 4.8 years. Regimens incorporating liposomal cytarabine seem to be safe and effective treatments for lymphomas with CNS involvement.

The use of Yttrium-90 Ibritumomab Tiuxetan ((90)Y-IT) as a consolidation therapy in high-risk patients with diffuse large B-cell lymphoma ineligible for autologous stem-cell transplantation.

Aim of the studyTo evaluate the efficacy and safety of Yttrium-90 Ibritumomab Tiuxetan (90Y-IT) as a consolidation therapy in the management of DLBCL.Material and methodsPatients with primary refractory or high-risk DLBCL (n = 18), ineligible for autologous stem-cell transplantation, were included in a retrospective study performed at three centers by the Polish Lymphoma Research Group (PLRG). All patients (mean age 61, range 35–82) either didn't achieve a complete response or didn't complete the scheduled therapy due to its complications. Response rates (CR, PR, SD, PD) according to Cheson criteria, overall survival (OS), progression-free survival (PFS) and adverse effects of radioimmunotherapy were analyzed.ResultsConsolidation radioimmunotherapy increased the CR rate from 38% (n = 7) to 82% (n = 15). One patient remained in PR, one patient remained in SD, while one patient remained in PD. During a median follow-up of five years, 11 patients (62%) were alive with no recurrence, 4 patients (22%) were alive with relapse while 3 patients (16%) died. There was no statistically significant difference in PFS between those in CR and those in PR before 90Y-IT.ConclusionsRadioimmunotherapy is an effective consolidation therapy for high risk/refractory DLBCL patients and worthy of further investigation in prospective trials.

Predictive and Prognostic Significance of Immunohistochemical Markers and Blood Absolute Lymphocyte Count in Diffuse Large B-Cell Lymphoma in Rituximab Era: A Polish Lymphoma Research Group (PLRG) Multicenter Retrospective Analysis

This report is a retrospective analysis of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who were treated with R-CHOP-21. The aim of the study was to determine the impact of peripheral blood absolute lymphocyte count (ALC), Ki67 proliferation index and immunohistochemical expression of Bcl-2 and Bcl-6 at diagnosis on complete response rate and survival.The study group consisted of 161 patients with stage II-IV who were treated with six cycles of R-CHOP-21 between January 2004 and December 2013. With International Prognostic Index (IPI), 29% patients were low, 29% low-intermediate, 25% high-intermediate and 17% high risk. Bcl-2 and Bcl-6 expression was detected with immunohistochemical staining on paraffin sections in 83% and 77% of patients, respectively. Bcl-2 expression with high Ki67 proliferation index, greater than 80%, was found in 15% of patients. BcL-6 expression with Ki67 index of 80% or lower was detected in 52% of patients. Median ALC at diagnosis was 1.4 G/L (0.1-4.2). ALC below 1.0 G/L was revealed in 27% patients.Results: The complete response rate to R-CHOP was 69%. In univariate logistic regression for complete response to immunochemotherapy, the variables that were correlated with lower response rate were IPI > 2 (p=0.016) and ALC < 1.0 G/L (p=0.014). In multivariate logistic regression, ALC < 1.0 G/L remained the only independent variable associated with failure to achieve complete response (OR 2.6; 95%CI 1.2-5.9; p=0.03). After the median follow-up time of 37 months (6-109), the 5-year progression free and overall survival (OS) estimated with Kaplan-Meier method were 67% (95% CI 56-76) and 66% (95% CI 55-75), respectively. In univariate analysis IPI (log-rank test, p=0.001), ALC (log-rank test, p=0.009) (fig.1), Bcl-2 expression with high Ki67 index (log-rank test, p=0.015) (fig.2) and Bcl-6 expression with low Ki67 index (log-rank test, p=0.05) were statistically significant for OS. In the multivariate analysis with Cox model, ALC at diagnosis (HR 2.9; 95%CI 1.1-7.3; p=0.024) and Bcl-2 expression with high Ki67 index (HR 2.8; 95%CI 1.1-7.5; p=0.039) remained significant for OS. IPI higher than 2 tended to impact negatively OS (HR 2.4; 95%CI 0.9-6.3; p=0.067).In conclusion, our results indicate that low ALC at diagnosis is independent predictor of poor response to R-CHOP for patients with DLBCL. In addition, low ALC and Bcl-2 expression with high Ki67 index adversely influence patient survival in the rituximab era. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

High Incidence of Cardiovascular Complications After CHOP-Like Chemotherapy In Lymphoma Patients From Poland – Retrospective Analysis of Polish Lymphoma Research Group (PLRG)

AbstractAbstract 1764 Introduction:Cardiovascular System disorders are among the leading causes of mortality in general population ranging from 10% in Sub Saharan Africa, 38 % in Western Europe and US to even 58% in Eastern Europe and Central Asia. CHOP and it's modifications, with or without Rituximab is the most frequently used chemotherapy regimen for lymphoma patients. Antharcyclin related cardiotoxicity is a well described, dose dependent adverse effect, increasing in frequency with time after therapy, described in 3–5% of patients at 5 years to even 15% of patients at 10 or more years after diagnosis. It was postulated, that higher incidence of cardiovascular mortality, may increase the frequency of anthracyclin cardiotoxicity in Central Europe. Materials and Methods:A retrospective analysis was performed to investigate the frequency of cardiovascular complications after CHOP-like chemotherapy in 428 lymphoma patients treated in 5 oncohematological centers. The median observation time was 3 years (range 0.5–8), therefore it covered acute and early chronic progressive cardiotoxicity. Patients characteristics: average age 55 years (range 18–90), male to female ratio 221/207, clinical stage III/IV – 347 cases (81.5%), general symptoms – 302 cases (71%), large tumor burden defined as it's diameter of 10 cm or more – 41 cases (8.5%), IPI 3–5 in 174 cases (40%). There were 320 patients with DLBCL, 45 – MCL, 32 – FL, 24 – PTCL and 7 – MZL. Initial assessment was based on medical histories including echocardiography in 166 cases (38%). All patients were contacted at the time of analysis, and questioned in detail about symptoms and signs of left ventricular failure (LVF). Results:At a time of diagnosis risk factors for cardiovascular disorders were identified: arterial hypertension (29%), hypercholesterolaemia (13%), diabetes mellitus (8.2%), truncal obesity (17%) and smoking (18.5%). Minority of patients had a previous history of LVF (n=10, 2.3%) and/or myocardial infarction (n=6, 1.4%). The average dose of anthracyclins was 336,5 mg/m2 (range 50 – 680): 391 (91.9%) patients received Doxorubicin, 17 (3.9%) – Nonpegylated Liposomal Doxorubicin, 13 (3,1%) – Farmorubicin and 5 (1.1%) Dauborubicin. Acute cardiotoxicity was reported in 21 cases (4,9%) and resulted in dose reduction, postponing chemotherapy or it's premature termianation. The overall response rate was reasonable, with 297 (69.5%) CR, 83 (19.5%) PR, 10 (2.2%) SD and 38 (8.8%) progressions. At the time of analysis 100 patients (23.4%) relapsed and 63 (14.7%) died: 29 due to disease progression, 24 due to cardiovascular disease, 7 due to infectious complications and 3 due to unknown causes. The average Left Vetricular Ejection Fraction (LVEF), assessed by echochardiography in 166 patients decreased from 63% (range 42–85%) at diagnosis to 56,8% (range 20–72%) at the end of treatment (p<0.001). It corresponded to clinical picture: 51 patients (11.7%) required cardiological treatment after chemotherapy, including 15 cases (3.5%) with myocardial infarction, and further 37 (8.6%) with ischaemic heart pain. Even more revealed signs and symptoms of LVF on direct questioning: exertional dyspnea – 67 (15.7%), pretibial oedema – 72 (16.8%), Nycturia – 48 (11.2%). Conclusions:Our retrospective analysis revealed an important role of anthracyclin cardiotoxicity in lymphoma patients from Poland. At relatively short average time of observation (3 years, range 0.5–8), cardiovascular disorders were the second most common cause of death (24/63 – 38% of deaths, 24/428 – 5.6% of all cases). Further 51 patients (11.7%) required cardiological treatment for at least one life threatening event (myocardial infarction or ischaemic heart pain). [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Overall Survival (OS) Benefit of Rituximab Based Immunochemotherapy Followed by Post-Induction Treatment in Mantle Cell Lymphoma (MCL): a Retrospective Analysis of 279 Patients Treated by Polish Lymphoma Research Group (PLRG) Centers.

Abstract 1702Poster Board I-728 BackgroundASCT consolidation in the first remission is the treatment of choice in MCL patients. However lack of adequate response to the first line therapy, elderly age and co-existing co-morbidities makes it feasible for less than a third of patients. MethodsRetrospective analysis of 279 MCL cases treated at 10 PLRG centers was performed: 52% of them (144 pts) received Rituximab in induction therapy; 35% (97 pts) were subjected to post-induction therapy (ASTC – 16%, radioimmunotherapy consolidation – 13% and Rituximab maintenance – 6%). There were no significant differences in risk factor distribution among analyzed subgroups. Results1) At 5 years OS was 40% in the whole group: 77% for those subjected to post-induction therapy vs 25% for those who were not; 5 year PFS is 20%, 48% and 5% respectively (p<0,0001, in both comparisons).2) Pts with initial good response, whose treatment was NOT continued after induction, had inferior results (5 year OS and PFS – 30 and 10 % respectively) to those subjected to post-induction therapy (p<0,0001).3) Rituximab included in the first line regimens increased RR, increasing % of pts that could be subjected to post-induction therapy: progression/ death during the first line therapy were 5,5% (8/144 Rituximab treated pts) as compared to 15,5% (21/135 treated without Rituximab). ConclusionsWith all limitations of retrospective analysis, it strongly supports the necessity of Rituximab immunochemotherapy followed by post induction treatment in MCL pts. The role of ASCT is established in younger patients, radioimmunotherapy consolidation or Rituximab maintenance should be considered in elderly and unfit ones. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Survival benefit of post induction consolidation therapy in MCL (mantle cell lymphoma): A Polish Lymphoma Research Group (PLRG) retrospective multicenter analysis

e19510 Background: In MCL, early intensification and consolidation of the first line therapy by ASCT is the treatment of choice. Elderly age and co-existing co-morbidities makes it however feasible for less than a third of patients. Methods: All MCL cases consulted in 8 PLRG centers within the last 5 years (n=140) were included in a retrospective analysis. Only 23% (n=32) were consolidated with ASCT, further 28% (n=40) by radioimmunotherapy (Ibritumomab), while in 49% (n=68) neither consolidation was performed. Rituximab was used in 36/72 patients subjected to consolidation and 25/68 treated without consolidation. There were no statistically significant differences in IPI, CS (clinical stage), frequency of extranodal manifestations and B symptoms between analyzed subgroups ( Table ) although patients subjected to ASCT were younger (median age 54 vs 62) and tend to have higher LDH (556 IU vs 473), while those who were not consolidated more frequently had a large tumor burden (defined as a mass &gt; 7 cm, 24 vs 15%). Results: There was a clear impact of consolidation on overall and progression-free survival (OS,PFS): at 5 years OS 65 vs 20 % (p= 0.0003 in Gehan Wilcoxon test); and PFS 40 vs 0 % (p= 0.0003 in Gehan Wilcoxon test). Rituximab used in the first line therapy further increased it's efficiency in terms of PFS, prolonging median time to progression from 15 to 26 months, however the OS benefit was seen only in consolidated patients (at 5 years 75% OS in those with Rituximab including induction followed by consolidation). Conclusions: With all limitations of retrospective analysis, it strongly supports the necessity of post induction therapy in MCL patients. The role of ASCT is established in younger patients, radioimmunotherapy may prove to be a feasible approach for the elderly and unfit ones. [Table: see text] No significant financial relationships to disclose.

Survival Benefit of Post Induction Consolidation Therapy in MCL (Mantle Cell Lymphoma): a Polish Lymphoma Research Group (PLRG) Retrospective Multicenter Analysis

Background: In MCL, early intensification and consolidation of the first line therapy by ASCT is the treatment of choice. Elderly age and co-existing co-morbidities makes it however feasible for less than a third of patients.Methods: All MCL cases consulted in 8 PLRG centers within the last 5 years (n=140) were included in a retrospective analysis. Only 23% (n=32) were consolidated with ASCT, further 28% (n=40) by radioimmunotherapy (Ibritumomab), while in 49% (n=68) neither consolidation was performed. Rituximab was used in 36/72 patients subjected to consolidation and 25/68 treated without consolidation. There were no statistically significant differences in IPI, CS (clinical stage), frequency of extranodal manifestations and B symptoms between analyzed subgroups (Table 1) although patients subjected to ASCT were younger (median age 54 vs 62) and tend to have higher LDH (556 IU vs 473), while those who were not consolidated more frequently had a large tumor burden (defined as a mass > 7 cm, 24 vs 15%).Results: There was a clear impact of consolidation on Overall and Progression Free Survival (OS,PFS): at 5 years OS 65 vs 20 % (p= 0.0003 in Gehan Wilcoxon test); and PFS 40 vs 0 % (p= 0.0003 in Gehan Wilcoxon test). Rituximab used in the first line therapy further increased it's efficiency in terms of PFS, prolonging median time to progression from 15 to 26 months, however the OS benefit was seen only in consolidated patients (at 5 years 75% OS in those with Rituximab including induction followed by consolidation).Conclusion: With all limitations of retrospective analysis, it strongly supports the necessity of post induction therapy in MCL patients. The role of ASCT is established in younger patients, radioimmunotherapy may prove to be a feasible approach for the elderly and unfit ones.NIPIAgeLDHWHOCS (IV)Extra-nodalB sympt.X (>7 cm)Radioimmunotherapy402,4961,75421,4383%78%63%12%ASCT322,62545561,2480%84%68%17%No Consolidation682,9862,84731,7485%83%68%24%All cases1402,7660,134971,5581%81%67%20%

90Y-Zevalin® (90Y-Ibritumomab Tiuxetan) Radioimmunotherapy (RIT) Consolidation in Mantle Cell Lymphoma (MCL) Patients, Not Illegible for Intensive Therapy Protocols.

Background: MCL is a prognostically unfavorable subtype of B-cell non-Hodgkin's lymphoma, where autologous stem cell transplant (ASCT) is regarded a standard consolidation of the Ist-line therapy. However most of the pts are elderly or otherwise not illegible for intensive therapy protocols (i.e. only 6 out of 17 MCL patients diagnosed in our Dpt during last 6 months could be subjected to ASCT). Addition of Rituximab to induction chemotherapy increases the response rate, but still most patients subsequently relapse and some kind of consolidation is necessary.Aims: It is postulated, that radioimmunotherapy with 90Y-Zevalin® (90Y-Ibritumomab tiuxetan), could be an efficient consolidation in patients not illegible for ASCT.Methods: In our analysis we included 45 MCL cases subjected to RIT. The first 30 patients were enrolled in the Polish Lymphoma Research Group Trial (PLRG MCL1), a II phase multicenter study, where 90Y-Zevalin consolidated the response after FCM±R. The average follow-up of the study is now over 2 years (13 – 33 months). Further 15 cases with a shorter follow-up, initially treated with FC-R or CHOP - R, are included only in response and toxicity analysis. Only pts responding to initial chemotherapy (<25% BM infiltration, <30 mm lymph node and <12 cm spleen diameter), were offered Zevalin consolidation step. They received 2 doses of 250 mg/m2 R on days 1 and 8, followed by Z (0.3 or 0.4 mCi/Kg, based on initial PLT count; max dose=32 mCi). Responce rate and hematologic toxicity were determined. Response was monitored at 6 wks, 3 mo, and 3-mo intervals for up to 2 yrs to assess TTP.Results: 45 patients responding to initial chemotherapy (7 CR, 38 PR) were subjected to 90Y-Zevalin consolidation. A further regression was achieved in 37 patients (25 CR and 12 PR), one pt progressed. Hematological toxicity was important, with WBC < 2000/ul and Plt < 50 000/ul for 7.8 and 9.1 weeks respectively. In 3 cases (alive, in CR) cytopaenia was very prolonged (23, 24 and 40 weeks). One procedure related mortality was reported (hemorrhagic stroke at day +80). 32/45 pts required RBC or Platelet transfusions, 8/45 G-CSF support. No pts developed life-threatening infections, however hospital admission was necessary in 11 cases. Overall survival (OS) and time to progression (TTP) was analyzed in patients included in PLRG MCL1 trial. In 20 patients where RIT consolidated the 1st line therapy, at 30 months OS and TTP is 85% and 78% respectively (Fig 1). Responses are shorter in pts treated at relapse, even if CR is achieved after RIT (medium TTP and OS is 10 and 15 months).Conclusions: Z consolidation is a feasible, outpatient approach for MCL patients not illegible for ASCT; it might have curative potential for patients treated at diagnosis or at first PR and may afford palliation for relapsed cases. [Display omitted]

90Y-Zevalin® (90Y-Ibritumomab Tiuxetan) Radioimmunotherapy (RIT) Consolidation of FCM Induction Chemotherapy in Mantle Cell Lymphoma (MCL) Patients: Results from the PLRG upon Completed Enrollment.

Background: The 5-yr survival rate is <20% for MCL. Standard chemotherapy for MCL includes fludarabine, cyclophosphamide, and mitoxantrone (FCM). Adding rituximab (R) to FCM increases the overall response rate (ORR) from 46% to 58%. MCL patients (pts) with large tumor burdens and no initial cytoreduction have a limited response to conventional non-myeloablative RIT.Aims: The Polish Lymphoma Research Group Trial (PLRG MCL1) assessed whether 90Y-Zevalin (Z) could consolidate the response achieved from FCM ± R and improve ORRs and time to progression (TTP).Methods: Thirty MCL pts (stage III–IV) not suitable for SCTs were enrolled in 8 PLRG centers: 13 pts were newly diagnosed, 7 pts had a PR after first-line therapy, and 10 pts were in first relapse. Tumor burden was reduced by induction therapy with 3–6 cycles of FCM ± R (375 mg/m2) in all pts and staged after the third and subsequent cycles to assess tumor regression. Pts were in CR (no palpable lymph nodes or measurable masses on CT) or PR (<25% bone marrow [BM] infiltration, <30 mm lymph node diameter, <12 cm spleen diameter, no massive extranodular involvement). All CR and PR pts with PMNs >1500/mL, PLTs >100,000/mL, and no BM hypoplasia received Z consolidation, starting with 2 doses of 250 mg/m2 R on days 1 and 8, followed by Z (0.3 or 0.4 mCi/kg, based on initial PLT count; maximum dose 32 mCi). ORR (CR + PR) and hematologic toxicity were determined. Response was monitored at 6 wk, 3 mo, and 3-mo intervals for up to 2 yr to assess TTP.Results: To date, 29 pts were evaluated. Of the 13 newly diagnosed pts 2 were in CR after completing FCM and 10 achieved CR after Z consolidation. Five of the 7 pts treated at first PR achieved a CR after Z and 2 pts achieved a PR. For the 10 pts treated at first relapse, 5 shifted from a PR after FCM to a CR after Z, 1 shifted from a CRu to a CR, and 3 pts achieved a further PR after Z. However, 5 of these 10 pts relapsed and 1 died due to hemorrhagic stroke. Of the 17 pts who shifted from PR to CR after Z, 13 continue in CR 8–20 mo after Z and 3 continue in CR 1–4 mo after Z. Overall, 19 of 20 pts treated at diagnosis or first PR are alive. Responses were accompanied by neutro- and thrombocytopenias 4–5 wk after Z, lasting 3–21 wk. To date, 7 pts required G-CSF (mean 21.3 doses; range 5–60), and 14 pts received red blood cell (mean 5.1 units; range 1–18) and/or PLT (mean 4.2 units; range 1–24) transfusions. No pts developed life-threatening infections. Hematologic toxicity was less severe in pts who had received only 3 FCM cycles, compared with patients requiring 5–6 FCM cycles.Conclusions: Following Z consolidation, 22 of 29 pts achieved a CR and 17 of these 22 shifted from a PR after FCM ± R to a CR. Therefore, Z consolidation is a feasible approach for MCL patients; it might have curative potential for pts treated at diagnosis or at first PR and may afford palliation for relapsed cases. Hematologic toxicity from FCM-Z is significant, but manageable, and correlates with the number of FCM cycles. Survival with FCM-Z seems superior to that reported for R-CHOP×4-Z. FCM-Z may be the preferred therapeutic approach.

Manageable and Transient Hematologic Toxicity Associated with 90Y-Ibritumomab Tiuxetan (90Y-Zevalin) Consolidation of FCM Chemotherapy in Mantle Cell Lymphoma (MCL) Patients.

Background: We have shown that administration of 90Y-Zevalin to consolidate the therapeutic effects of fludarabine, cyclophosphamide, and mitoxatrone (FCM) ± rituximab (R) in the FCM ± R à 90Y-Zevalin MCL trial from the Polish Lymphoma Research Group (PLRG) Multicenter Study resulted in PRs with FCM ± R becoming CRs after 90Y-Zevalin. This finding could potentially benefit many MCL patients whose disease prognosis is poor. Our initial findings indicate that hematologic toxicity, as measured by duration of PMNs < 1000/ml and PLTs < 50,000/ml, is manageable, with recovery complete within 7–13 wks after 90Y-Zevalin. Other researchers have reported that low dose rate radiation therapy is known to cause prolonged marrow damage to progenitors and stromal cells and reduce stem cell yields. Therefore, we specifically studied the hematologic toxicity of this consolidation regimen with 90Y-Zevalin and the radiosensitizing drug fludarabine.Methods: We enrolled 10 histopathologically confirmed MCL patients (stage III-IV) who were ineligible for SCTs. Patients were treated with 3–6 cycles of FCM ± R. Patients were given 250 mg/m2 of R followed 1 wk later with a second dose of R + 90Y-Zevalin (11 or 15 MBq = 0.3 or 0.4 mCi/Kg based on PLT count; maximum dose = 32 mCi). Cytopenia was assessed with full blood counts every wk until recovery. Trephine biopsies were performed before 90Y-Zevalin dosing and at 2 and 6 wks after 90Y-Zevalin to assess marrow cellularity and stromal cells. At the same time points, mantle cell (CD19+CD20+CD5+CD23−) infiltration of bone marrow (BM) was assessed by flow cytometry; myeloid clonogenic capacity (CFU-GM, BFU-E, CFU-GEMM, CFU-Meg) was evaluated by cell culture; and BM stroma function was measured by assaying 5 cytokines: GM-CSF, EPO, TPO, IL-3, and SCF. Results were compared with 7 historical follicular lymphoma (FL) patients who received 90Y-Zevalin without fludarabine following relapse after chemoimmunotherapy (R-CHOP).Results: The level of neutro- and thrombocytopenia was greater in patients who received FCM ± R à 90Y-Zevalin than in patients who received only 90Y-Zevalin. A 2- to 4-fold greater degree of clonogenic capacity impairment was seen with FCM ± R 90Y-Zevalin compared with only 90Y-Zevalin, except for the CFU-Megs profiles, which were similar in both groups. A 7- to 10-fold ↓ in myeloid stem and progenitor cells in response to FCM + R à RIT was associated with a ↓ in PMNs and PLTs. However, hematopoietic recovery was not prolonged in the fludarabine-pretreated group and did not correlate with the duration of CFU-GM and CFU-GEMM suppression. Stromal cells experienced minimal, transitory (fully reversible by 2 wks) impairment, suggesting a negligible adverse effect of 90Y-Zevalin on BM stroma. Compared with pre-90Y-Zevalin values, GM-CSF levels ↓ 2-fold at wk 4, and TPO and IL-3 ↓ 30% and 3-fold, respectively, at wk 2. EPO levels ↓ 3-fold during the first 4 wks and paralleled decreases in BFU-Es.Conclusions: The consolidation of FCM ± R with 90Y-Zevalin in MCL patients is a promising therapeutic approach. The FCM + R 90Y-Zevalin treatment resulted in significant damage to myeloid stem and progenitor cells and increased neutro- and thrombocytopenia compared with 90Y-Zevalin alone, but cytopenias are still manageable and hematopoietic recovery occurs within 9–12 wks after 90Y-Zevalin. Clinicians must monitor the amount of BM infiltration and the BM hypocellularity after FCM + R before administering 90Y-Zevalin.