Continuous Pattern Of Relapse Research Articles

Ibrutinib for Relapsed Mantle Cell Lymphoma after Standard First Line Therapy and ASCT Is Efficacious but Does Not Overcome the Impact of POD24 - a Retrospective Study from the LWP-EBMT

Ibrutinib for Relapsed Mantle Cell Lymphoma after Standard First Line Therapy and ASCT Is Efficacious but Does Not Overcome the Impact of POD24 - a Retrospective Study from the LWP-EBMT

PB2018 MANTLE CELL LYMPHOMA (MCL): A SINGLE CENTRE EXPERIENCE ON THE OUTCOME OF MCL BEFORE AND AFTER THE EMERGENCE OF NOVEL THERAPIES.

Background: Mantle cell lymphoma (MCL) is a B cell malignancy accounting for 3-10% of all Non-Hodgkin Lymphomas and arises mainly in older adults with a male predominance (McKey et al). Historically, median survival was 4–5 years (Herrmann et al, 2009) however this is now in the order of 8–12 years in younger fitter patients who are able to tolerate intensive therapies (Eskelund et al, 2016). The current standard treatment is chemoimmunotherapy with or without autologous stem cell transplantation (ASCT). Although intensive therapy can achieve durable responses most patients eventually succumb to their disease. Novel therapeutic agents have shown efficacy in relapsed/refractory disease and are now being tested as frontline treatment (Sharma et al., 2018). Aims: We report a single centre experience of MCL and its treatment. Methods: Retrospective data was collected on all patients diagnosed with MCL at Ipswich Hospital NHS Trust over a nine year period between January 2010 and January 2019. Results: Forty-two patients were included in the analysis. Median age was 68yrs with a male to female ratio of 5:1. Eastern Co-operative Oncology Group (ECOG) performance status ranged from 0-1 in 66%, ≥2 in 14% and 19% had no status documented. Twenty-four patients (57%) received a non-intensive chemoimmunotherapy regimen; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or rituximab-bendamustine (BR) as first line treatment with twenty of these patients receiving rituximab maintenance. Thirteen patients (31%) were fit enough to receive an intensive chemoimmunotherapy regimen with all but one consolidated with an ASCT. Of those transplanted five went on to receive rituximab maintenance. The remaining 12% of patients received either R-Chlorambucil, palliative radiotherapy, FCR or supportive care. The median Kaplan-Meier overall survival (OS) for all patients had not been reached. Median progression free survival (PFS) was 48 months. Comparing first line therapies, the median OS for those that received RCHOP/BR was 60 months with a median PFS of 35 months vs. not reached for both OS and PFS with intensive chemoimmunotherapy followed by ASCT. Eighteen patients had relapsed during the nine year period. There was no standard second line treatment. Eight patients received further chemoimmunotherapy including BR, R-cytarabine and FCR, one PEP-C, three ibrutinib, four palliative radiotherapy and two received supportive care only. After first relapse median PFS was 6 months and median OS was only 10 months. Nine patients received a third line treatment, of which 3 received ibrutinib and one venetoclax and the median OS was 9 months. The six relapsed/refractory patients that received Ibrutinib at either first or second relapse had a median OS of 8 months vs. 12 months in those that received other forms of therapy. Summary/Conclusion: As expected the best outcomes were with high intensity regimens consolidated by ASCT. Our data period was not long enough to show the continuous pattern of relapse despite durable responses that have now been shown by long term follow up data (Eskelund et al, 2016). The outlook was poor for relapsed/refractory disease with a median OS of 10 months. Rule et al analysed data from 370 patients receiving ibrutinib for relapsed/refractory MCL, enrolled across three different studies (PCYC-1104, SPARK, and RAY), and demonstrated an excellent outcome, with a median PFS of 13 months and median OS of 26.7 months. We did not see a beneficial effect on OS with the use of novel therapies in our patients (8 months vs. 12 months) although our study numbers were small.

Primary breast diffuse large B‐cell lymphoma in the rituximab era: Therapeutic strategies and patterns of failure

Primary breast diffuse large B‐cell lymphoma (PB‐DLBCL) is a rare subtype of DLBCL with limited data on patterns of failure. This multicenter study aimed to define the optimum treatment strategy and patterns of failure for PB‐DLBCL patients. We retrospectively reviewed data on 108 PB‐DLBCL patients from 21 Chinese medical centers. Only patients with localized disease (involvement of breast and localized lymph nodes) were included. After a median follow‐up of 3.2 years, 32% of patients developed progression or relapse. A continuous pattern of relapse was observed, characterized by frequent late relapses in the contralateral breast and central nervous system (CNS). Although rituximab significantly reduced the overall cumulative risk of progression or relapse (5‐year cumulative risk 57% vs 24%, P = .029), it had limited effect on the reduction of breast relapse (P = .46). Consolidative radiotherapy significantly decreased the risk of breast relapse, even in the subgroup of patients treated with rituximab (5‐year cumulative risk 21.2% vs 0%, P = .012). A continuous risk of CNS progression or relapse up to 8.2 years from diagnosis was observed (10‐year cumulative risk 28.3%), with a median time to CNS relapse of 3.1 years. Neither rituximab nor prophylactic intrathecal chemotherapy significantly decreased the risk of CNS relapse. In summary, our study indicates that PB‐DLBCL has a continuous pattern of relapse, especially with frequent late relapses in the CNS and contralateral breast. Rituximab and RT confer complementary benefit in the reduction of relapse. However, neither the addition of rituximab nor prophylactic intrathecal chemotherapy could effectively prevent CNS relapse for PB‐DLBCL patients.

15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau.

In recent decades, the prognosis of Mantle Cell Lymphoma (MCL) has been significantly improved by intensified first-line regimens containing cytarabine, rituximab and consolidation with high-dose-therapy and autologous stem cell transplantation. One such strategy is the Nordic MCL2 regimen, developed by the Nordic Lymphoma Group. We here present the 15-year updated results of the Nordic MCL2 study after a median follow-up of 11·4years: For all patients on an intent-to-treat basis, the median overall and progression-free survival was 12·7 and 8·5years, respectively. The MCL International Prognostic Index (MIPI), biological MIPI, including Ki67 expression (MIPI-B) and the MIPI-B including mIR-18b expression (MIPI-B-miR), in particular, significantly divided patients into distinct risk groups. Despite very long response durations of the low and intermediate risk groups, we observed a continuous pattern of relapse and the survival curves never reached a plateau. In conclusion, despite half of the patients being still alive and 40% in first remission after more than 12years, we still see an excess disease-related mortality, even among patients experiencing long remissions. Even though we consider the Nordic regimen as a very good choice of regimen, we recommend inclusion in prospective studies to explore the benefit of novel agents in the frontline treatment of MCL.

Efficacy of the GemOx‐R regimen leads to the identification of Oxaliplatin as a highly effective drug against Mantle Cell Lymphoma

Mantle Cell Lymphoma (MCL) is an aggressive lymphoma subtype that accounts for 6-8% of non-Hodgkin lymphomas. The disease is mostly incurable and characterized by a continuous pattern of relapse. Major changes have recently been implemented in the management of MCL, but continuous relapses still mark this disease as a challenge for clinicians. We previously reported the efficacy of GemOx-R (Gemcitabine, Oxaliplatin and Rituximab) in patients with refractory and relapsing MCL. We present results for a larger series with longer follow-up and including high-risk frontline patients, showing an overall response rate of 83%. The efficacy of each component of GemOx-R was evaluated in a panel of MCL cell lines. Also, patient-derived primary cells were used in exvivo experiments. The results show that oxaliplatin has a profound effect on cellular viability and is the most effective drug within this regimen. We further present synergistic efficacy of oxaliplatin combined with cytarabine in MCL cells. Interestingly, this synergistic effect was not seen when cisplatin and cytarabine were combined, indicating that among the platinum-derived agents oxaliplatin may be the preferred approach. Taken together our findings suggest that oxaliplatin alone or combined with cytarabine could constitute an alternative backbone for MCL regimens.

Progression-Free Survival at 24 Months (PFS24) and Complete Response at 30 Months (CR30) from Autologous Stem Cell Transplantation (ASCT) Should be Used As Surrogates for OS in Follicular Lymphoma (FL) Patients

Introduction: At present, determining OS (Overall Survival) remains the gold standard in clinical trial endpoints which evaluate the role of ASCT in FL. However, in the context of a disease characterized by very long median survivals with a continuous pattern of relapse, and still more with the advent of novel treatments, OS assessments seem elusive. In fact, PFS (Progression Free Survival) is the standard endpoint for new drug approvals in first-line FL, and some other earlier endpoints such 2-year PFS (Casulo et al , JCO 2015) or CR30 (Sargent, 2015) have been recently proposed as potential surrogates and as alternatives to PFS or OS as primary end-points in FL patients treated with 1st line chemoinmunoterapy. Objective: To assess if 2-year PFS and CR30 are feasible surrogates of OS in the setting of a very long follow-up series of FL patients treated with ASCT. Material and Methods: A total of 626 chemosensitive FL patients (mean age 47 years, male 49%) reported to the Spanish GELTAMO registry and intensified with ASCT between 1989 and 2007 were analyzed. The status of the disease at the moment of ASCT was either in 1st response [203 in 1st CR, 43% of them needing more than one therapy line to reach the CR, and 140 in 1st Partial Response (PR)] or in response after salvage therapy (174 in 2nd CR, 28 in 3rd CR and 81 in 2nd or 3rd PR). In 615 patients the status of the disease was evaluable after ASCT: 569 cases (92%) in CR, 27 cases (4%) in PR and 19 cases (3%) progressed or died. To assess 2-year PFS, two groups were defined: patients with progression of disease (POD) within 2 years from ASCT (early POD) and patients without progression within 2 years from ASCT. Cox model analysis was used to evaluate the association between early POD and OS from a risk - defining event, which is survival from time of POD for early progressors or from 2 years after ASCT for the reference group (Casulo et al, JCO 2015.Appendix). To asses CR30, two groups were defined: patients with and patients without CR at 30 months from ASCT. Cox model analysis was used to evaluate the association between being or not in CR at 30 months from ASCT. Results: Median follow-up is 12.2 years from ASCT and 14.2 years from diagnosis. Of the assessable patients, 31% were in the high-risk FLIPI group and 40% in the high-risk FLIPI 2 group. 30% of patients received rituximab prior to ASCT. Globally median PFS and median OS are 11 and 21 years, respectively. Patients transplanted in PR (n=221; 35%) had a worse OS than those transplanted in CR (n=405, 65%): HR 2.45 (95% CI, 2.2-2.7; P 10-5), fig. 3. Conclusion: 2-year PFS and CR30 could be used as subrogates for OS and as primary end points, not only in FL patients treated with 1st line chemoinmunoterapy, but also in FL intensified with an ASCT. To our knowledge this is the first study to establish that early relapse after ASCT is predictive of poor survival in FL patients; in both, patients treated or not with rituximab previously to the ASCT. This finding is even more evident in patients transplanted in CR. Likewise, best response achieved before ASCT is a robust prognostic factor for OS in FL patients. ![Figure 1.][1] Figure 1. ![Figure 2.][1] Figure 2. ![Figure 3.][1] Figure 3. Disclosures No relevant conflicts of interest to declare. [1]: pending:yes

Radiation therapy is an effective modality in the treatment of mantle cell lymphoma, even in heavily pretreated patients.

Mantle cell lymphoma has an aggressive clinical course and continuous relapse pattern with a median survival of 3 to 7 years. Multiple courses of chemotherapy are the basis of treatment. Radiotherapy is underutilized in this disease. We undertook this study to assess the role of radiation therapy. A total of 41 consecutive patients with mantle cell lymphoma diagnosed from December, 1999 to January, 2010 who received radiation therapy were reviewed retrospectively. The main endpoint was in-field lymphoma response at each irradiated disease site. There were 39 evaluable patients (68 symptomatic sites). Sites treated included: nodal stations (n = 31), soft tissue (n = 13), mucosal sites (n = 11), central nervous system (n = 10), gastrointestinal tract (n = 2), and bone (n = 1). Median maximum tumor size at presentation was 3.5 cm (range, 1.3 cm-9.6 cm). The median dose of radiation was 30.6 Gy (range 18-40 Gy). Median follow-up post radiation per site was 12.3 months (range, 0.6-80.9 months). Response to treatment was complete in 47 sites (69.1%), partial in 16 sites (23.5%), and 5 sites (7.4%) had stable disease. In 9 (13.2%) sites local relapse occurred (median 7 months; range 2-21). The mean size of lymphoma at time of RT correlated with relapse, with tumors with local relapse larger than those without a local relapse (P = .005). Our data add to accumulating evidence that mantle cell lymphoma is a radio-sensitive disease with excellent responses to relatively low radiation doses, even in patients with chemo-refractory disease.

Outcome of BEAM-Autologous and BEAM-Alemtuzumab Allogeneic Transplantation in Relapsed Advanced Stage Follicular Lymphoma

AbstractAbstract 2022▪▪This icon denotes a clinically relevant abstract Introduction:Follicular Lymphoma is the most common indolent lymphoma, characterized by an indolent course, multiple recurrence, responses to chemotherapy, risk of transformation into a high grade lymphoma and with a median overall survival of 10–12 years. Transplantation (autologous and allogeneic) has improved the overall outcome of this disease, however a continuous pattern of relapse is observed essentially in the autologous setting. Allogeneic transplant has shown encouraging results in terms of long term overall survival (OS) and disease free survival (DFS), with acceptable transplant related mortality (TRM) and with significantly lower relapse rate. Objective:To analyse retrospectively the outcome of relapsed follicular lymphoma patients who received BCNU (carmustine), cytarabine, etoposide, melphalan-alemtuzumab allogeneic HSCT (BEAM-C allo) or BEAM-autologous HSCT (BEAM-auto). Results:The study includes 74 consecutive patients with relapsed advanced stage follicular lymphoma who received BEAM-C allo (n=38) and BEAM-auto (n=36) between 1992 and 2010. Patients characteristics are summarized in Table 1. Median follow-up of surviving patients was 6.1 years. Patients undergoing allo transplants were younger than those who unbderwent and autologous procedure (50 vs 54 years, p=0.018). 1y and 5y TRM was higher in the allo transplant group (27% and 27% vs 6% and 6%; p=0,011). The Cumulative incidence of relapse (CIR) was lower in the allo at 1, 2 and 5 years (11%, 14% and 18% vs 28%, 49% and 60%, p=0,000).Significant differences were not observed in 1, 2 and 5 years OS between allo and auto transplant groups (74%, 74% and 69% vs 85%, 69% and 51%; p=0,217), but we found a strong trend in DFS difference between both groups at 1, 2 and 5 years (65%, 61% and 58% vs 69%, 43% and 33%; p=0.089) observing a plateau around 60% after 2 years in the allograft group.The rate of graft versus host disease (GvHD) was low with 14% acute GvHD (2.6% grade 3–4 GvHD) and 28% chronic GvHD (10% of extensive chronic GvHD).Analysis of the whole cohort (n=74) showed that patients in CR before transplant (n=28) had better 1, 2 and 5 years DFS following a allotransplant (69%, 69% and 69% vs 79%, 36% and 18%; p=0.012). These differences did not affect the 1, 2 and 5 years OS (76%, 76% and 76% vs 93%, 76% and 56%; p=0,214). TRM for the allo transplant group was 24% and 0% R in the auto (p=0,064) in patients when achieved CR before transplant. There were no difference in OS (p=0,785) and DFS (p=0,954) between allo or auto patients in partial response (PR) before transplant.A subgroup analysis of patients with high grade transformation before transplant did not show any differences in OS (p=0,823) or EFS (p=0,526).between allo and auto groups. Conclusions:Long term follow-up of Follicular Lymphoma patients has shown a continuous pattern of relapse when patients receive an autologous transplant, after 5 years. whereas patients undergoing allo transplant, despite a higher mortality, have a 5 year OS and DFS of 60% with a plateau been achieved in both curves after 2 years suggesting that these patients may be cured. Prospective randomised studies are still required to answer the the role of these two approaches in follicular Lymphoma. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Current treatment of mantle cell lymphoma: results of a national survey and consensus meeting

In most patients, mantle cell lymphoma (MCL) shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-5years. In the current study generation of the European MCL Network, the addition of high-dose Ara-C to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival in younger patients. In elderly patients, rituximab maintenance led to a marked prolongation of remission duration. Emerging strategies include mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, immune modulatory drugs, Bruton's tyrosine kinase inhibitors and others, all based on the dysregulated control of cell cycle machinery and impairment of several apoptotic pathways. Combination strategies are currently being investigated in numerous trials, but their introduction into clinical practice and current treatment algorithms remains a challenge. In the current survey, the application of the molecular targeted compounds were collected and evaluated by a representative national network of 14 haematological institutions. Optimised strategies are recommended for clinical routine. Future studies will apply individualised approaches according to the molecular risk profile of the patient.

Primary Testicular Lymphoma

Primary testicular non-Hodgkin lymphoma (PTL) comprises around 9% of testicular cancers and 1–2% of all non-Hodgkin lymphomas. Its incidence is increasing and it primarily affects older men, with a median age at presentation of around 67 years. By far the most common histological subtype is diffuse large B-cell lymphoma, accounting for 80–90% of PTLs. Most patients present with a unilateral testicular mass or swelling. Up to 90% of patients have stage I or II disease at diagnosis (60 and 30%, respectively) and bilateral testicular involvement is seen in around 35% of patients. PTL demonstrates a continuous pattern of relapse and propensity for extra-nodal sites such as the central nervous system and contralateral testis. Retrospective data have emphasised the importance of prophylactic radiotherapy in reducing recurrence rates within the contralateral testis. Recent outcome data from the prospective IELSG-10 trial have shown far better progression-free and overall survival than historical outcomes. This supports the use of orchidectomy followed by Rituximab- cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP), central nervous system prophylaxis and prophylactic radiotherapy to the contralateral testis with or without nodal radiotherapy in patients with limited disease. Central nervous system relapse remains a significant issue and future research should focus on identifying the best strategy to reduce its occurrence. Here we discuss the evidence supporting combination chemotherapy and radiotherapy in PTL.

A Decade of Stem Cell Transplantation in Lymphoma: Single Center Experience and Outcome of 938 Consecutive Allogeneic and Autologous Hematopoietic Stem Cell Transplants Performed At John Theurer Cancer Center

Abstract 3086 Introduction:The use of high dose therapy (HDT) and autologous stem cell transplantation (ASCT) remains the standard of care in chemo-sensitive relapsed diffuse large cell lymphoma (DLBCL) and Hodgkin Lymphoma (HL). The use of chemoimmunotherapy (rituximab based combinations in B-cell NHL) and dose-dense/-intensive regimens in the frontline setting seems to affect our ability to salvage patients with HDT-ASCT after relapse. The development of non-myeloablative transplantation has allowed us to explore this modality in patients with relapsed NHL in spite of a typically more advanced median age at presentation. However the role and benefit of each modality (auto vs allo) remains controversial and long-term survival follow-up data with large consecutive series are needed. For this analysis we report the outcomes of 938 consecutive lymphoma patients who underwent hematopoietic stem cell transplantation at our center. Methods: Utilizing Kaplan Meier survival and Cox regression analyses, we conducted a retrospective cohort analysis to describe the survival experience of 938 lymphoma patients who underwent either autologous (n=770) or allogeneic (n=168) transplantation between 1990–2011. The primary study endpoint was OS assessed by chart review and SSDI database. Secondary endpoints: comparison of allogeneic stem cell source (PB vs. BM source), comparison of radioimmunotherapy (RIT) as pre-conditioning for ASCT in CD 20 (+) NHL, and comparison of donor types (allo sib vs. URD vs. mismatched URD). The proportional hazards assumption was met for this analysis. Results: Survival data on 938 patients (median age at transplant 51, range 17–77) were analyzed, representing 408 failure events and 60353 total months at risk. Baseline characteristics included: sex (57% male); ethnicity (82% Caucasian, 8% Hispanic, 7% African American); performance status (97% ECOG 0–1); diagnosis: DLBCL: 432 pts (46%), HD: 245 pts (26%), MCL: 94 pts (9%), FCL grI-II: 76 pts (8%), PTCL: 66 pts 7%, other subtypes 4%); allo donor (sib 49%, URD 31%, mismatched URD 20%), allo stem cell source (72% PB, 24% BM, 4% cord) and allo transplant intensity (51% myeloablative vs 49% non-myeloablative). Results: The median OS for patients who underwent ASCT was 149 months (52 months median follow up) and 39 months (16 months median follow up) for patients who underwent allogeneic transplant. OS KM curves by selected disease subtype are represented in figure 1a-b. We performed a COX regression analysis to address outlined secondary endpoints: in univariate analysis patients undergoing allogeneic transplantation with a mismatched unrelated donor had an inferior OS (p=.02 vs. matched sib donor). The OS was similar when comparing sib-matched allogeneic donors vs. MUD donors (HR 1.4, p=.14). No difference in OS was detected when comparing allogeneic stem cells harvested from peripheral blood vs. bone marrow source (HR.7, p=.1). For the subset of patients with CD20 (+) NHL undergoing autologous HSCT, no difference in OS was detected whether radio-immunotherapy (n=38) was administered immediately prior to HSCT (HR.6, p=.3).Conclusions: This is a large and consecutive series of lymphoma patients who underwent ASCT or allogeneic stem cell transplantation in the relapse setting. In the ASCT group: long term follow up results show continuous pattern of relapse and our ongoing studies are looking at consolidation/immune based maintenance strategies (lenalidomide) post transplantation to improve patient’s outcome. In the allogeneic setting, a subset of patients with DLBCL, HL or MCL and FL can enjoy very long disease-free intervals and potentially be cured with no significant difference when comparing sib-matched allogeneic donors vs. matched URD (HR 1.4, p=.14). Our incidence of GVH has been dramatically reduced with the implementation of our donor TH2 amplification strategy (Blood Nov 2010; 116: 521) as recently shown. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Targeting malignant B cells as antigen-presenting cells: TLR-9 agonist induces systemic regression of lymphoma

Evaluation of: Brody JD, Ai WZ, Czerwinski DK et al.In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a Phase I/II study. J. Clin. Oncol. 28(28), 4324–4332 (2010).Despite high response rates of the follicular B-cell lymphoma to monoclonal antibodies, the clinical course of lymphoma is still characterized by a continuous pattern of relapse. Brody and colleagues treated 15 patients with relapsed, low-grade lymphoma using low-dose radiotherapy applied to one of the tumor sites with combined injection of a TLR-9 agonist at the same site. This strategy induced specific immunity and tumor regression in several patients with an objective response rate of 27%. The results indicate an involvement of the tumor TLR-9-expressing B cells acting as antigen-presenting cells. TLR-9 in situ vaccination combined with local radiotherapy clearly warrants further in-depth analysis and investigation in a Phase III randomized trial, and may provide a new opportunity for the treatment of B-cell malignancies.

Rituximab and Chlorambucil as Front-Line Treatment in Untreated Follicular Lymphoma: a Combination with a Durable Response and Low Toxicity Profile.

Abstract 3754Poster Board III-690 IntroductionFollicular lymphoma (FL), one of the most common B-cell non-Hodgkin's lymphoma (NHL), is an indolent disease characterized by a continuous relapse pattern. In the last years the treatment have changed with the introduction of Rituximab, that in combination with chemotherapy prolongs the progression-free survival (PFS) and the overall survival (OS) of FL pts. We report here the results of a regimen containing Rituximab and Chlorambucil (Chl) in untreaed FL pts. MethodsSince December 2001 48 pts (22 male and 26 female) with naive FL were treated in first-line with R-Chl. The schedule consisted of an induction phase with four weekly infusion of Rituximab at standard dose and 6 consecutive weeks of Chl at 6mg/mq/daily. Pts were restaged and in absence of disease progression received four cycles of consolidation with a monthly Rituximab infusion and 14 days of Chl each month. ResultsMedian age at diagnosis was 56 years (range 29-79). Ann Arbor stage was I-II in 13 pts and III-IV in 35 pts (73%); 15 pts had bulky disease and 14 pts presented an extranodal localization. B symptoms were present in 8 pts. Histological grading was available in 42 cases, and was 1 in 10 pts, 2 in 26 pts and 3 in 6 pts. FLIPI was evaluable in 46 pts, and was 0-1 in 25 pts (52%), 2 in 12 pts (25%), and >2 in 9 pts (18%). After the induction phase overall response rate (ORR) was 98% with 14 pts in complete remission (CR). After the consolidation phase 39 pts (81%) obtained a CR and eight (17%) a partial response (PR); the remaining patient had a stable disease and underwent high-dose chemotherapy and autologous transplantation. All pts but one concluded the planned treatment. The mean daily dose of Chl administered during the induction phase was 10 mg, while 8 mg in the prolonged treatment. Twenty-eight pts (58%) experienced a neutropenia during treatment, and Chl dose was reduced in 22 pts (46%); however, only 11 pts (23%) had a G3-4 neutropenia. The Chl was stopped only in a patient because of a persistent G3 neutropenia after the first consolidation cycle. After a median observation time of 42.5 months (range 7-94) nine pts relapsed (19%), with a median time to relapse of 20 months (range 7-66). Two pts died, one of disease progression and one of a pre-existing ovarian cancer. ConclusionsOur results described a safe and feasible combination of immuno-chemotherapy in untreated FL pts. With respect to traditional treatments, our regimen shows a similar efficacy and a lower toxicity, that leads to an easier handling. The schedule including four monthly additional Rituximab administrations confirms the superiority of a prolonged exposure to Rituximab over the standard 4-weekly administrations. In conclusion, our data suggest that this combination may be considered as a valid first-line treatment of FL patients, especially in those not eligible for more aggressive chemotherapy regimens. Disclosures:No relevant conflicts of interest to declare.

First Line Allogeneic Stem Cell Transplantation in Mantle Cell Lymphoma (MCL).

Abstract 3366Poster Board III-254 PURPOSE:Despite recent progress in treatment, MCL remains associated with a poor outcome demonstrating a continuous pattern of relapse. In 2002, we initiated a pilot study investigating the feasibility of allogeneic stem cell transplantation (SCT) as part of first line therapy for MCL. The results of the same approach done as part of second line treatment are also reviewed. PATIENTS AND METHOD:Newly diagnosed MCL patients referred to our center were offered participation in a tandem approach therapy. First line treatment consisted of 6 to 8 cycles of R-CHOP chemotherapy. Chemotherapy sensitive patients then underwent stem cell collection and were treated with high dose BEAM chemotherapy and autologous SCT. At day +100 post autologous SCT, consenting patients with an HLA identical sibling received out-patient non-myeloablative (NMA) stem cell transplantation with fludarabine and cyclophosphamide as conditioning regimen and tacrolimus + MMF based graft-versus-host disease (GVHD) prophylaxis. An unrelated donor search was initiated for patients younger then 50 years old. Patients with chemotherapy refractory or recurrent disease were proposed second line salvage chemotherapy. Chemotherapy sensitive patients in this group underwent a tandem approach as part of their salvage treatment and chemotherapy resistant patients received a standard myeloablative SCT with Cy-TBI or Bu-Cy conditioning. RESULTS:A total of 33 patients referred to our center with MCL received a stem cell transplant. 21 received an allogeneic SCT, of which 14 patients underwent NMA SCT and 7 standard myeloablative (MA) SCT while 12 received a single autologous SCT,16 patients were evaluated for first line tandem approach while 17 were referred for relapsed or resistant disease. 11/16 newly diagnosed MCL patients with a median age of 53, underwent an allogeneic SCT as part of their first line treatment while 5/16 median age 57, did not, lacking a compatible sibling or suitable unrelated donor and were treated with an autologous SCT after R-CHOP chemotherapy. With a median follow-up (FU) of 43 months from SCT (7/11) 64% patients receiving an allogeneic SCT (8 NMA and 3 MA) as part of their first line therapy are alive and free of disease while (4/11) patients respectively died (3 NMA and 1 MA) at 8, 12, 24 and 48 months post allo-SCT from TRM (3/4) or recurrent disease (1/4). Of the 17 patients referred for recurrent or refractory disease, 10/17 median age 52, received an allogeneic SCT. 6/10 received a NMA SCT while 4/10 received a standard myeloablative SCT. With a median FU of 42 months, 60% of patients receiving an allogeneic SCT as part of salvage therapy are alive and disease free. 5/6 patients receiving NMA SCT for resistant or recurrent disease are still alive and disease free while only one patient treated with myeloablative SCT is alive and disease free 87 months post transplant. While (4/10) patients died at 6, 7, 15 and 16 months post transplant (3/4) from TRM and (1/4) from relapse. Long term disease control was strongly associated with the development of chronic GVHD (86%). As expected and despite a shorter FU time of 22 months, relapse (33%) was the major cause of treatment failure after autologous SCT while TRM (28%) was the major cause of treatment failure post allogeneic SCT. NMA allogeneic SCT was associated with an estimated 1 year TRM of 10% and should be the modality selected in chemosensitive patients while the prevention and treatment of GVHD remains an important challenge. CONCLUSION:Despite the small sample size and short FU period, allogeneic SCT offers a promising approach to first line treatment of MCL. It should still be viewed as investigational and proposed as part of a larger prospective study. When applied to resistant or recurrent disease, allogeneic SCT remains an effective modality of treatment associated with acceptable toxicity in a rather incurable disease and should be considered the standard approach. Disclosures:No relevant conflicts of interest to declare.

Validation of Mantle Cell International Prognostic Index (MIPI) in Mantle Cell Lymphoma (MCL) in a Retrospective Single Institution Series

Introduction: The clinical course of MCL is characterized by a continuous pattern of relapse and a poor long term outcome with a median Overall Survival (OS) of four years and a 15% of long term survivors. Recently a new clinical prognostic score (MIPI), including performance status, age, LDH level and leukocyte count has been reported. This score allows a more reliable estimation of individual clinical course. We retrospectively applied the MIPI score to patients with MCL.Patients and methods: Between 1999 and 2007, 40 patients with MCL diagnosed and treated in a single institution entered into the study. Clinical characteristics were as follows: median age 56 years (range 37–81), 80% male; 82% stage IV; 78% bone marrow involvement and 15% MCL with blastoid variant. First line treatments were: high dose chemoimmunotherapy including Rituximab (R) with autologous stem cell transplantation (R-HDC) in 26 patients and Rituximab-CHOP like chemotherapy (R-CHOP) in 14. Crude Kaplan-Meier OS and progression-free survival (PFS) curves were estimated both overall and stratified by MIPI and International Prognostic Index (IPI) score. Differences between curves were tested using the 2-tailed log-rank test. In order to quantify the predictive discrimination of MIPI and IPI scores, univariate logistic models (with death and progression event as binary outcomes) were fitted and the area under the receiver operating characteristic (ROC) curves (c index) was estimated.Results: According to MIPI score 17 patients (43%) were at low risk (LR, score 0–3), 13 patients (32%) at intermediate risk (IR, score 4–5) and 10 patients (25%) at high risk (HR, score >5). According to IPI score 14 patients (35%) were at low risk (LR), 16 patients (40%) at low-intermediate risk (LIR) and 10 patients (25%) at intermediate-high and high risk (IH-HR). At the end of the treatment, 30 patients achieved a CR, five a PR and five did not respond. Relapses occurred in 17 patients and seven of them died of lymphoma. With a median follow-up (FU) of 29 months, OS was 85% (95% CI: 66%–93%); with a median FU of 21 months, PFS was 70% (95% CI: 51%–83%). Twenty-nine months OS rates for MIPI score were: LR 100%, IR 81%, HR 66% respectively (p=.07) and for IPI score were: LR 92%, LIR 94%, IH-HR 65% respectively (p=.09). Twenty-one months PFS rates for MIPI score were: LR 92%, IR 59%, HR 45% respectively (p=.006) and for IPI score were: LR 73%, LIR 87%, IH-HR 44% respectively (p=.09). MIPI score was more predictive than IPI score for the death event and for the progression event: the c index was 74% and 73% for MIPI compared to 72% and 69% for IPI respectively. In a subgroup analysis performed on 26 R-HDC patients, OS and PFS rates stratified for MIPI were: for OS, LR 100% vs IR 80% vs HR 69% (p=.4) and for PFS, LR 91% vs IR 80% vs HR 57% (p=.04) respectively.Discussion: in our retrospective series of patients, MIPI prognostic score discriminates among patients with different PFS. Relapses remain the most important issue for all patients affected by MCL, namely in HR group according to MIPI. New therapeutic strategies are warranted to improve the prognosis of MCL.

Rituximab Containing Autologous Stem Cell Transplantation May Be Curative in Mantle Cell Lymphoma for Patients in First Remission, but Not for Patients with Recurrent Disease.

In order to determine if the addition of rituximab (R) had changed the outcome of autologous stem cell transplantation (AUTO) in patients with mantle cell lymphoma (MCL), we examined the outcome of 86 patients transplanted at the MD Anderson Cancer Center, in first partial or complete remission (frontline AUTO, n=50) or for relapsed / refractory disease (salvage AUTO, n=36).<<<FRONTLINE AUTO>>> Among frontline patients, 29 were transplanted in the pre-R era (AUTO-R), and 21 in the post-R era (AUTO+R). AUTO-R patients received homogenous treatment with hyper-CVAD induction and Cy- TBI conditioning. AUTO+R patients were treated with R-hyper-CVAD, hyper-CVAD and R-CHOP induction in 62%, 10% and 29% respectively, and R-Cy-TBI and R-BEAM conditioning in 43% and 52% respectively. Median age (range) at transplantation was 57 (42–66) and 56 (38–73) for the AUTO-R and AUTO+R groups respectively (p=0.91); other baseline characteristics including sex, time from diagnosis, performance status, stage, B-symptoms, B2m, LDH and MIPI were similar. Prior to transplantation, CR or unconfirmed CR (CRu) was present in 38% and 57% of AUTO-R and AUTO+R patients respectively (p=0.18), and 33 of 34 patients were negative on Gallium/PET scan. Following transplantation, CR/CRu was achieved in 93% and 100% patients respectively (p=0.50). Progression free survival (PFS) was similar between AUTO-R and AUTO+R patients for the first 2 years. However, after 2 years a clear difference emerged on the PFS curve with no relapses occurring among 9 AUTO+R patients followed between 30 and 96 months. In contrast, AUTO1-R patients experienced a continuous pattern of relapse (p=0.03 compared with AUTO+R patients). For patients remaining in remission at 2 years, no deaths had occurred in the AUTO+R group, whereas 15 of 22 AUTO-R patients had died.<<<SALVAGE AUTO>>> The 36 salvage patients had similar baseline characteristics as frontline patients, except for the proportion of patients with chemosensitive disease (100% vs 86%, p=0.01) and negative Gallium/PET scans (97% vs 71%, p=0.01), favoring the frontline group. In contrast to the results of frontline patients, no difference was observed in salvage patients by the use of R (p=0.52 and 0.50 for PFS and OS respectively).<<<CONCLUSION>>> Autologous transplantation with rituximab has the potential to cure a proportion of patients with MCL, but only if performed during the first remission. Patients transplanted beyond first remission continued to experience a poor prognosis. [Display omitted]

Dose-intense treatment of mantle cell lymphoma: can durable remission be achieved?

Mantle cell lymphoma is a distinct subtype of malignant lymphoma, which displays an aggressive clinical course with a continuous relapse pattern and the worst long-term outcome of all B-cell lymphoma. Conventional-dosed chemotherapy achieves only temporary responses with a median duration of remissions of only 1-2 years. Addition of monoclonal antibodies has improved initial response but duration of response remained almost uninfluenced. In contrast, dose-intensified regimens including addition of high-dose Ara-C or myeloablative consolidation achieved significantly improved progression-free survival rates whereas the improvement of overall survival has not yet been definitely proven by recent multicenter trials. Various phase II studies suggest that further intensification (HyperCVAD followed by autologous stem cell transplantation) may be beneficial if tolerated. However, potentially improved efficacy has to be balanced against increased toxicity and feasibility of this approach. Dose-intensified approaches, either cyclophosphamide, hydroxydaunorubicin (adriamycin), oncovin (vincristine), and prednisone (CHOP) +/- high-dose Ara-C followed by autologous stem cell transplantation or HyperCVAD with the addition of rituximab remain the current standard approach in younger patients up to 65 years. Future strategies will focus in a slightly different direction, namely to integrate the increasing number of molecular targeted compounds (proteasome inhibitors, mammalian target of rapamycin antagonists or immunomodulatory drugs like lenalidomide) into multimodal approaches to overcome the still disappointing long-term prognosis of mantle cell lymphoma.

A Multi Center Trial of hyperCVAD+Rituxan in Patients with Newly Diagnosed Mantle Cell Lymphoma.

BACKGROUND: A Phase II Study multinstitutional study by the lymphoma group within the Southwest Oncology Group (SWOG 0213) was performed to determine the 1 year progression free survival of patients with newly diagnosed mantle cell lymphoma (MCL). Previously, this regimen was utilized in a similar group of newly diagnosed MCL patients in a single institution study by Romaguera et al (JCO 2005 23:7013) at the MD Anderson Cancer Center. They reported a 97% response rate, a 87% CR rate, and a 3 year failure free survival rate of 73%.PATIENTS AND METHODS: This study was a prospective phase II trial of rituximab plus fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyperCVAD; considered one cycle) alternating every 21 days with rituximab plus high-dose methotrexate-cytarabine (considered one cycle) for a total of eight cycles per the MD Anderson protocol. Newly diagnosed MCL patients under age 70 with adequate organ function and measurable disease were eligible. All cases were histologically confirmed.RESULTS: 49 eligible patients were enrolled. There was one probable treatment-related death due to colitis. Grade 4 hematologic toxicity was reported for 87% of patients. 40 patients have been evaluated for response. 3 patients had inadequate assessment and are assumed to be non-responders.16 patients (40%) had complete responses, 7 patients (18%) had unconfirmed complete responses, and 12 patients (30%) had partial responses for an overall response rate was of 88% (35/40; 95% CI, 73%–96%). Median follow-up among patients still alive is 1.6 years (range: 0.3–4.1 years). The progression-free survival estimate at 1-year is 89% (95% CI: 80%–98%) and at 2 years is 64% (95% CI: 46%–82%). The overall survival estimate at 1 year is 91% (95% CI: 82%–99%) and at 2 years is 76% (95% CI: 60%–91%). 13 of the 49 eligible patients have progressed or died. One year overall survival was 91% and one year progression free survival is 89%. Two year PFS is 63% (95% CI: 46%–82%). Two year OS is 76% (95% CI: 60%–91%). The 1-year progression-free survival estimate is 89% (95% CI: 80%–98%). The 1-year overall survival estimate is 91% (95% CI: 82%–99%). The overall response rate was 88% (35/40; 95% CI, 73%–96%).CONCLUSIONS: The hyperCVAD + rituximab regimen is active as reported in MCL with a one year progression free survival of 89%. However, similar to the reported MD Anderson experience, this regimen is toxic and a continuous pattern of relapse over time is observed.

Phase II Study of R-CHOP Followed by 90Y-Ibritumomab Tiuxetan in Untreated Mantle Cell Lymphoma: Eastern Cooperative Oncology Group Study E1499.

Background: As MCL has a continuous relapse pattern with current treatments, we designed a study to determine the safety and efficacy of the anti-CD20 radio-immunoconjugate,90Y-ibritumomab tiuxetan (90Y-RIT), following 4 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) induction.Methods: Patients (pt) with untreated stage II-IV MCL (CD20+, cyclin D1+) ≥18 yr with measurable/evaluable disease and adequate organ function were eligible. At 4–8 weeks after 4 cycles of R-CHOP, responding (CR/PR) and stable pt received 0.4 mCi/kg 90Y-RIT. The primary endpoint was failure-free survival (FFS) and secondary objectives were evaluation of response and toxicity after R-CHOP and after 90Y-RIT. The study design required 52 eligible pt to demonstrate a prolongation of FFS by 50% compared with R-CHOP alone (median FFS 16 mo, Howard et al., JCO 20:1288, 2002).Results: The characteristics of 56 eligible pt are: 73% male, median age 61 (33–83) yrs, 91% stage III/IV, 68% >1 extranodal site, 78% marrow-positive. IPI was 0–2 in 51%, 3–5 in 49%. Fifty-one (91%) pt received all treatment and best response (n=50) was 42% CR/CRu, 32% PR, 12% stable and 4% unevaluable, with an improvement in response in 16 pt after 90Y-RIT. After 90Y-RIT, 55% had grade 3/4 neutropenia with no febrile neutropenia and 45% had grade 3/4 thrombocytopenia with recovery at 12 weeks in 22/23 pt. Median follow-up (all pt) is 24.4 months. Median FFS for all 56 pt is 27 months with an estimated 71% FFS and 93% overall survival at 18 months. Among pt who completed all treatment and have been followed ≥1.5 yr (n=45), 33 remain failure-free and 12 have progressed (4 dead).Conclusions: 90Y RIT after 4 cycles of R-CHOP in untreated MCL is safe and improves the number and quality of responses. These data suggest prolongation of FFS over that expected with R-CHOP alone. Consolidation of remission in MCL with 90Y-RIT shows potential as a strategy to prolong remission duration and is applicable to most pt with MCL. However, longer follow-up in needed to evaluate the durability of remissions achieved.

Allogeneic Stem Cell Transplantation with Dose-Reduced Conditioning in Relapsed Follicular and Mantle Cell Lymphoma - A Prospective Phase II Trial of the German Low Grade Lymphoma Study Group (GLSG).

Background: Conventional therapy achieves high initial response rates in follicular (FL) and mantle cell lymphoma (MCL), but even after introduction of combined immuno-chemotherapy, a continuous relapse pattern has been observed. The introduction of dose-reduced conditioning prior to allogeneic peripheral blood stem cell transplantation significantly reduced early treatment-associated toxicity of this curative approach. In 2003, the German Low Grade Lymphoma Study Group initiated a prospective phase II trial to investigate the feasibility and efficacy of this approach in a multi center approach.Methods: Patients with a high risk profile (bulky disease, 3 lymph nodes >3 cm, elevated LDH, >20% bone marrow infiltration, hematopoietic insufficiency) received a conventional salvage chemotherapy, e.g. 2–4x (R-)FCM. Subsequently, all patients received a dose-reduced conditioning (30 mg/m2 fludarabine d-7-4, 30 mg/m2 cyclophosphamide d-4-3) and an optional low dose TBI (2–4 Gray, d-8). Immunosupression consisted of ATG-Fresenius (10mg/m2 bs d-3-1 if unrelated donor), cyclosporine A starting day −1 and mycophenolat (2× 15mg/kg). If T-cell chimerism was established after discontinuation of immunosuppression, donor lymphocyte infusion was applied on days +120, +150 and +180 with increasing doses (2× 105–107/kg) in cases of persistent lymphoma.Results: After a median follow-up of 17 months, a total of 32 patients are evaluable (21 FL and 11 MCL). Median age was 48.5 years (34–62) with a median of 3 prior therapies (1–8). Eigth patients had a family donor and 24 were transplanted from an unrelated donor (no mismatch in 25 and 1 mismatch in 8 cases). 2 early infectious deaths were observed at day 30 and 87 resulting in a treatment-associated mortality (d100) of 6% and another death after 1014 days. After 2 years follow-up, failure-free and overall survival rates were 73% and 77%, respectively. As expected, failure-free survival rates differed significantly between FL (80%) and MCL patients (60%).Discussion: This multicenter trial confirms allogeneic stem cell transplantation with dose-reduced conditioning achieving long-term remissions especially in patients with relapsed FL with rather low mortality. Thus, in younger high risk patients, this therapeutic option should be discussed in relapsed disease. Randomized or case-control trials are warranted to exactly define the role of allogeneic transplantation in FL and MCL.