Minimal Residual Disease (MRD) Status Following Induction Chemo-Immunotherapy Predicts Progression-Free Survival In Mantle Cell Lymphoma (MCL): CALGB 50403 (Alliance)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3002-3002 ◽  
Author(s):  
Noreen Fulton ◽  
Jeffrey Johnson ◽  
Lawrence D. Kaplan ◽  
Greg Koval ◽  
Greg Malnassy ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Residual Disease ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
Gene Rearrangements ◽  
Free Survival ◽  
Mantle Cell ◽  
Minimal Residual

Abstract CALGB 50403 was a randomized phase II clinical trial to test the benefit of maintenance vs consolidation bortezomib therapy following aggressive chemo-immunotherapy and autologous stem cell transplant for adults < 60 years old with previously untreated mantle cell lymphoma (MCL). Eradication of minimal residual disease has been found to be an important biomarker of Progression Free Survival (PFS) in MCL. One goal of this study was to assess the kinetics of MRD during treatment of 50403: intensive chemo-immunotherapy induction; autologous stem cell mobilization and transplant; and post transplant therapy with rituximab followed by intensive bortezomib consolidation or prolonged bortezomib maintenance therapy. Methods 151 patients were enrolled in this study. 93 patients had adequate follow-up samples available and were screened for IgH/BCL-1 gene rearrangements using standardized primer sets (InVivoscribe). The sensitivity of this assay is from 1X104-105. 61/93 (66%) had an evaluable MRD marker and sequential samples for study of MRD kinetics. Patient specific oligonucleotides were generated from pre-treatment bone marrow for quantitative PCR (qPCR) amplification using previously published, standardized methods. The sensitivity of detection of MRD ranges from 1X104-105. 49 patients with sequential bone marrow samples at a minimum of 3 timepoints during and following treatment are included in this analysis. Presenting characteristics: the median age was 59 years (29-69); 32 (65%) were male; Stage IV MCL in 46 (94%); 16 (33%) had B-symptoms, 46 (94%) had PS 0 or 1; 17 (35%) had elevated LDH; MIPI risk group: Low 25 (51%), Intermediate 13 (26%) and high 11 (23%) ; 24 (49%) were randomized to maintenance bortezomib; 19 (39%) to bortezomib consolidation, and six were not randomized (12%). Results With a median f/u of 3.3 years from study registration, there have been 12 events amongst these 49 Patients: 10 with disease progression and 2 deaths from other causes (censored at time of death). PFS is defined as time from study entry until progression, or date of last follow-up. Early eradication of MRD following 2 cycles of intensive induction chemo-immunotherapy was significantly and independently associated with PFS (p =0.017), (Figure 1). None of the patients who achieved MRD negative status (n=15) following chemo-immunotherapy induction have progressed. Conversely, 10/32 patients with any level of MRD positivity at this time-point have suffered disease progression. No other clinical variables described above were associated with PFS or MRD status. MRD status prior to bortezomib randomization is also significantly associated with PFS, but to a lesser degree (p=0.05) while MRD measurements in the apheresis product did not predict for PFS. Conclusions Early achievement of undetectable MRD using qPCR for IgH gene rearrangements is highly prognostic for PFS for patients with MCL treated on CALGB 50403, with an observed 100% PFS amongst these patients. Longer follow-up is required to determine whether one of the two bortezomib arms improves treatment outcome compared to earlier CALGB studies in MCL. Nevertheless, these data suggest that the early introduction of novel agents into the 50403 treatment regimen may be a useful strategy for improving MRD eradication and PFS in MCL. Disclosures: Cheson: MedImmune: Research Funding.

scholarly journals Molecular Monitoring and Tailored Strategy with Pre-Emptive Rituximab Treatment for Molecular Relapse; Results from the Nordic Mantle Cell Lymphoma Studies (MCL2 and MCL3) with Median Follow-up of 8.5 Years

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 146-146 ◽  
Author(s):  
Arne Kolstad ◽  
Lone B Pedersen ◽  
Christian Winther Eskelund ◽  
Simon Husby ◽  
Kirsten Grønbæk ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Research Funding ◽  
Residual Disease ◽  
Cell Lymphoma ◽  
Risk Groups ◽  
Clinical Relapse ◽  
Mantle Cell ◽  
Minimal Residual

Abstract Background: Minimal residual disease monitoring has been shown to be of relevance in mantle cell lymphoma (MCL) to evaluate quality of remission and predict clinical relapse. The main objectives of the present study were to determine the value of minimal residual disease (MRD) monitoring to guide pre-emptive treatment with rituximab, and to predict clinical relapse in MCL following autologous stem cell transplantation (ASCT) in two prospective trials (MCL2 and MCL3) with long-term follow-up conducted by the Nordic Lymphoma Group. Methods: Patients treated in the two studies received a total of 6 alternating cycles with R-CHOP and R-Ara-C followed by a peripheral blood stem cell harvest and high-dose therapy with ASCT. Additionally, responding patients not in CR before ASCT in the MCL3 trial received yttium-90 ibritumomab tiuxetan (0.4 mCi/kg) as intensification one week prior to the standard conditioning with BEAM/C. Staging included physical examination, blood tests, computed tomography (CT) scans and bone marrow (BM) aspiration and biopsy. Clinical and molecular response evaluation was repeated 2-3 months and 6 months after transplant, and then every 6 months until relapse or 5 years follow-up. A combined standard nested and quantitative real-time PCR assay was used to estimate MRD involvement in consecutive post-transplant BM/PB samples. Molecular relapse after ASCT was defined as; 1. Conversion from standard nested PCR negative to standard nested PCR positive, or 2. For patients who were MRD positive post-ASCT, a significant (>5 fold) increase of the real time quantitative PCR detectable MRD level in two consecutive BM samples. Patients in clinical remission who developed a molecular relapse in both studies received 4 weekly doses of rituximab (375 mg/m2). This treatment could be repeated in case of recurrent molecular relapses. Results: An MRD marker for Bcl-1 or IgH rearrangement was obtained for 94 out of 160 patients (59%) recruited in the Nordic MCL2 trial, and for 121 out of 160 (76%) in the consecutive MCL3 trial. 183 patients, who had completed induction therapy and autologous stem cell transplantation (ASCT) in the two studies and where a PCR marker in blood or bone marrow was obtained, were included in the current analysis. Median follow-up from inclusion was 8.5 years among survivors. Patients who were MRD negative post-ASCT had significantly longer relapse-free survival (RFS) and overall survival (OS) compared to those who were MRD positive (P<0.001). Eighty-six patients remained in continuous molecular remission. Of those, 73% also remained in clinical remission after 10 years. For all patients, median time from ASCT to molecular relapse was 55 months and with no signs of a plateau on the curve (Figure 1). Fifty-eight patients with MRD relapse received pre-emptive treatment with 4 weekly doses of rituximab (375 mg/m2) on one or more occasions. Conversion back to MRD negative state was achieved in the majority (82%) of cases after rituximab treatment. Median time from molecular relapse to clinical relapse in patients who received pre-emptive rituximab was 55 months (Figure 2). In a multivariate analysis, significant predictors for molecular relapse were MIPI high risk category at diagnosis (HR 1.91, 95% CI 1.37-2.66, P=0,0001) and detection of MRD prior to ASCT (HR 2.47, 95% CI 1.49-4.09, P=0.0005). Late MRD relapses continued to occur 5-10 years after ASCT even in lower risk groups. Conclusion: We observed a continuous pattern of MRD relapses that did not subside even after 5-10 years and included all risk groups. Hence, it is fair to consider MCL as a chronic incurable lymphoma entity and novel approaches will be necessary to change the natural course of this disease. Detection of MRD was shown to be a predictor for clinical relapse and inferior survival. Additionally, the data strongly suggests that pre-emptive rituximab treatment delayed clinical relapse in MCL. We recommend MRD monitoring post-ASCT in MCL as a useful approach to select the MRD positive patients for novel strategies in future trials and as an alternative to maintenance therapy for all patients. The MCL2 and MCL3 trials were registered at www.isrctn.com as ISRCTN 87866680 and at www.clinicaltrials.gov as NTC 00514475, respectively. Disclosures Kolstad: Nordic Nanovector: Other: Membership of Scientific Advisory Board. Jerkeman:Janssen: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Mundipharma: Research Funding; Gilead: Research Funding. Geisler:Roche: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy.

High Remission Rates and Prolonged Progression Free Survival in Newly Diagnosed Patients with Mantle Cell Lymphoma Treated with R-MACLOIVAM-T

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3597-3597 ◽  
Author(s):  
Peter J Hosein ◽  
Daniel Morgensztern ◽  
Francine Coleman ◽  
Gail Walker ◽  
Maricer Escalon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mantle Cell Lymphoma ◽  
Relapse Rate ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Mantle Cell ◽  
Grade 3

Abstract Background: Mantle cell lymphoma (MCL) is an unfavorable subtype of B-cell non-Hodgkin lymphoma characterized by median progression-free survival (PFS) and median overall survival (OS) of only 1.5 and 3–4 years respectively. Although high-dose therapy and an autotransplant may prolong OS, it does not result in a long-term disease free survival. Therefore, there is a need for novel therapeutic approaches for this entity. Methods: We conducted a single-arm phase II study in subjects with newly-diagnosed MCL to assess efficacy and safety of a novel intensive regimen R-MACLO-IVAM-T, a modification of a protocol designed by Magrath et al (JCO1996;14:925). The study size of 22 patients was based on precision of a two-sided 95% confidence interval for the 18-month progression free survival rate. Eligible subjects had a confirmed diagnosis of MCL using WHO criteria, age 18–75 years, ECOG PS ≤ 2, adequate organ function and no history of HIV or prior cancer. Lymphoma extent at presentation was assessed by standard staging procedures as well as esophagogastroduodenoscopy and colonoscopy. Prior to initiating thalidomide maintenance, subjects were enrolled in the STEPS® program. Cycle 1 consisted of R-MACLO: rituximab 375 mg/m2 IV on day 1, doxorubicin 45 mg/m2 IV on day 1, cyclophosphamide 800 mg/m2 IV on day 1 and 200 mg/m2/day on days 2–5, vincristine 1.5 mg/m2 on days 1 and 8 capped to 2mg, methotrexate 1.2 g/m2 IV on day 10 over 1 hour followed by 5.52 g/m2 IV over 23 hours followed by leucovorin 36 hours later. G-CSF was begun on day 13. When the ANC was >1.5×109/L, cycle 2 with R-IVAM was begun: rituximab 375 mg/m2 IV day 1, cytarabine 2 g/m2 IV every 12 hours on days 1 and 2, etoposide, 60 mg/m2 on days 1–5 and ifosfamide 1.5 g/m2 on days 1–5 with mesna. Fourteen days after ANC recovery from cycle 2, cycles 3 and 4 were given in identical fashion to 1 and 2. Four weeks after ANC recovery from cycle 4, subjects were re-staged and responses were assessed by standard criteria. Subjects achieving CR at the end of therapy received thalidomide 200 mg/day until MCL relapse or intolerable toxicity. Results: Accrual started in 4/2004 and ended in 3/2008 when the planned 22 subjects were enrolled. All subjects were evaluable for toxicity and 21 were evaluable for response. Median age was 56.5 years (range 39–73). All subjects had at least stage 3 disease with bone marrow involvement in 19 and gastrointestinal involvement in 10. Distribution according to IPI: 0–1 factor, 3; 2 factors, 8; 3 factors, 8; and 4 factors, 3. Twenty subjects had diffuse variant and 2 had blastic variant. Nineteen subjects completed all 4 cycles of therapy; treatment was stopped in 2 subjects after 2 and 3 cycles respectively, and one subject died during the first cycle. Of the 21 subjects completing 2 cycles of therapy, 20 achieved CR and one PR. Two subjects relapsed at 9 and 33 months respectively, while 19 remain relapse free after median follow-up of 25 months (range 5–51). With a total follow-up of 545 months, the estimated relapse rate is 4.4 per 100 patients per year. There were two deaths: 1 from sepsis on cycle 1 day 8 and the other in CR at 38 months from non-small cell lung cancer diagnosed 19 months after MCL. Common severe toxicities were grade 3–4 neutropenia, thrombocytopenia and anemia in 33%, 19% and 17% of R-MACLO cycles and in 50%, 88% and 68% of R-IVAM cycles respectively. There were 14 bacteremias in 82 cycles, 12 of which were after R-IVAM therapy. Six episodes of reversible grade 1–2 renal toxicity occurred after methotrexate. The thalidomide maintenance dose was reduced in 6 subjects due to grade 3–4 neutropenia and reduced or stopped in 8 subjects because of grade 3–4 peripheral neuropathy. Patients remain under follow-up for relapse and survival. Conclusions: R-MACLO-IVAM-T results in a high overall response rate of 100% (95% CR and 5% PR) and a low relapse rate. At a median follow-up of 25 months, median PFS and OS were not reached. The 2-year actuarial PFS of 94% compares favorably with previously reported 2-year actuarial PFS of 40% and 67% for CHOP-like regimens without and with upfront bone marrow transplantation (Blood2005;105: 2677). The contribution of thalidomide maintenance to this outcome requires additional study. A multicenter clinical trial is suggested.

Early Consolidation with Myeloablative Radiochemotherapy Followed by Autologous Stem Cell Transplantation in First Remission Significantly Prolongs Progression-Free Survival in Mantle Cell Lymphoma - Long Term Follow up of a Prospective Randomized Trial of the European MCL Network.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 7-7 ◽  
Author(s):  
Martin H. Dreyling ◽  
Georg Lenz ◽  
Eva Schiegnitz ◽  
Achiel van Hoof ◽  
Christian Gisselbrecht ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
Advanced Stage ◽  
Free Survival ◽  
Mantle Cell ◽  
First Remission

Abstract Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma with an especially poor prognosis and a median survival of only 3–4 years. In 1996, the European MCL Network initiated a randomized trial to improve the otherwise dismal outcome of MCL, comparing early consolidation with myeloablative radiochemotherapy (TBI 12 gray, cyclophosphamide 120 mg/kg bw) followed by autologous stem cell transplantation (ASCT) to a conventional a -interferon maintenance (6x106 IE IFNa 3x weekly) in first remission after a CHOP-like induction regimen. Until March 2004, a total of 269 previously untreated patients (up to 65 years) were randomized upfront. 189 (82%) of 230 patients with advanced stage MCL completed initial induction chemotherapy and 142 (75%) achieved either a complete (45 pts., 24%) or partial response (97 pts, 51%). 122 pts proceeded to consolidation therapy, 62 pts received ASCT consolidation and 60 patients were assigned to IFN maintenance. Patients in the ASCT study arm experienced a significantly longer progression-free survival (PFS) as compared to patients in the IFNa arm. The PFS at 2 years was 73% after ASCT as compared to only 43% in the IFNa arm (p = 0.0108). Similar results were achieved in the intent to treat analysis of all initially randomised MCL patients (p=0.0001). Accordingly, this advantage resulted in a trend towards an improved overall survival (OS) in the ASCT arm. After a follow-up of up to nearly 7 years (median follow-up of patients: 2.8 years), 3 year survival after ASCT was 83% in comparison to 77% under IFNa maintenance (p = 0.18). As expected, acute toxicity was higher in the ASCT group with an early mortality of 4.8%, whereas long-term effects were more frequently encountered under IFNa maintenance. Conclusion : In first line treatment of advanced stage MCL, dose-intensified consolidation with myeloablative radiochemotherapy followed by ASCT after CHOP-like induction results in a significant prolongation of PFS. Current study concepts evaluate the benefits of combined immuno-chemotherapy to further improve the overall survival.

Eradication of Minimal Residual Disease during Treatment of Mantle Cell Lymphoma: CALGB 59909.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1652-1652 ◽  
Author(s):  
Dorie Sher ◽  
Jeffrey Johnson ◽  
Mariah Siddiqui ◽  
Michael A. Caligiuri ◽  
Lloyd E. Damon ◽  
...  
Keyword(s):  
Stem Cell ◽  
Copy Number ◽  
Gene Rearrangement ◽  
Residual Disease ◽  
Cell Lymphoma ◽  
Patient Specific ◽  
Mantle Cell ◽  
Kinetics Of ◽  
Minimal Residual

Abstract Recent studies suggest that detection of subclinical, or minimal residual disease (MRD) in apheresis products used for autografting correlates with poor disease-free survival following ASCT for mantle cell lymphoma (MCL). To validate this observation and to gain insights into the kinetics of MRD during treatment, we are performing a prospective analysis of MRD using quantitative real-time PCR (Q-PCR) in patients (pts) undergoing treatment for MCL on a CALGB study (59909). Q-PCR of sequential paired bone marrow (BM) and blood (B) samples and of apheresis products was performed using either a patient-specific immunoglobulin heavy chain (IgH) or BCL-1 gene rearrangement. All samples were analyzed in triplicate using LightCycler technology and reported as a normalized ratio of IgH or BCL-1 copy number to GAPDH copy number. The sensitivity of the assay ranged from 1 X 104–1 X 105. To date, a clonal IgH or BCL-1 gene rearrangement was detected in 36 of 41 (88%) pts entered on study. Patient-specific primers and consensus probes were used for Q-PCR monitoring of MRD following two courses of intensive induction therapy, during stem cell mobilization, and 3 and 12 months after ASCT and post-transplant immunotherapy with Rituximab (R). 27 pts have completed all protocol treatment with a median follow-up of 7 months (range: 0–28). 26 pts were evaluated for MRD following two courses of induction therapy with cyclophosphamide, methotrexate, doxorubicin, vincristine, prednisone, and R. 10 of 26 became MRD negative (−) following induction while 16 remained MRD positive (+). Following mobilization with high-dose cytarabine, etoposide and R, apheresis products from 9 of 10 MRD- pts were evaluated and all products were MRD- (1 pt not evaluable). Of the 16 pts who were MRD+ prior to mobilization therapy, MRD- apheresis products were collected in 8; 5 had MRD+ stem cell collections, and 3 were not evaluable. In total, apheresis products were evaluable in 22 of 26 pts; 17 (77%) had MRD- stem cells collected prior to ASCT. None of these MRD- pts has relapsed to date although 2 pts with MRD- products became weakly MRD+ 12 months following ASCT and R. Of the 5 pts with MRD+ apheresis collections, 4 have remained persistently MRD+ following ASCT and R; 1 has relapsed 19 months after completion of all treatment. Rising levels of MRD in BM and B samples were noted in this patient 3 and 12 months post-ASCT. Statistical comparison of MRD values in paired BM and B samples prior to, and post-ASCT demonstrated good agreement with an intraclass correlation coefficient of.814 and.777, respectively. In conclusion, our results demonstrate that prospective MRD monitoring using Q-PCR provides important insights into the kinetics of response during treatment of MCL. MRD- apheresis products were collected in the majority of pts following intensive induction and mobilization chemo-immunotherapy with R on CALGB 59909. To date, no pts with MRD- apheresis products have relapsed following ASCT. In contrast, it appears that pts with MRD+ apheresis products remain MRD+ following ASCT and R and may be more likely to relapse. Longer clinical follow-up is needed to clarify the significance of the persistence of MRD in apheresis products and following ASCT for MCL.

scholarly journals Treatment of Older Patients With Mantle Cell Lymphoma (MCL): Long-Term Follow-Up of the Randomized European MCL Elderly Trial

2020 ◽  
Vol 38 (3) ◽  
pp. 248-256 ◽  
Author(s):  
Hanneke C. Kluin-Nelemans ◽  
Eva Hoster ◽  
Olivier Hermine ◽  
Jan Walewski ◽  
Christian H. Geisler ◽  
...  
Keyword(s):  
Cell Lymphoma ◽  
Progression Free Survival ◽  
Interferon Alfa ◽  
Random Assignment ◽  
Free Survival ◽  
Rituximab Maintenance ◽  
Mantle Cell ◽  
Grade 3

PURPOSE In an update of the randomized, open-label, phase III European Mantle Cell Lymphoma (MCL) Elderly trial (ClinicalTrials.gov identifier: NCT00209209 ), published in 2012, we aimed to confirm results on long-term outcome focusing on efficacy and safety of long-term use of rituximab maintenance. PATIENTS AND METHODS Five hundred sixty patients with newly diagnosed MCL underwent a first random assignment between rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and rituximab, fludarabine, and cyclophosphamide (R-FC) induction, followed by a second random assignment in 316 responders between rituximab and interferon alfa maintenance, to be continued until progression. We compared progression-free survival from the second randomization and overall survival (OS) from the first or second randomizations. RESULTS After a median follow-up time of 7.6 years, the previously described difference in OS between the induction arms persisted (median, 6.4 years after R-CHOP [n = 280] v 3.9 years after R-FC [n = 280]; P = .0054). Patients responding to R-CHOP had median progression-free survival and OS times of 5.4 and 9.8 years, respectively, when randomly assigned to rituximab (n = 87), compared with 1.9 years ( P < .001) and 7.1 years ( P = .0026), respectively, when randomly assigned to interferon alfa (n = 97). In 58% and 32% of patients treated with R-CHOP, rituximab maintenance was still ongoing 2 and 5 years from start of maintenance, respectively. After R-FC, rituximab maintenance was associated with an unexpectedly high cumulative incidence of death in remission (22% at 5 years). Toxicity of rituximab maintenance was low after R-CHOP (grade 3-4 leukopenia or infection < 5%) but more prominent in patients on rituximab maintenance after R-FC, in whom grade 3-4 leukopenia (up to 40%) and infections were frequent (up to 15%). CONCLUSION The excellent results of R-CHOP followed by rituximab maintenance until progression for older patients with MCL persisted in a mature follow-up. Prolongation of rituximab maintenance beyond 2 years is effective and safe.

Rituximab and Stem Cell Transplantation Produces Durable Remissions in Mantle Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1390-1390
Author(s):  
Francisco J. Capote ◽  
M. J. Pascual ◽  
E. Gonzalez-Barca ◽  
J. M. Bergua ◽  
A. Jimenez ◽  
...  
Keyword(s):  
Stem Cell ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Mantle Cell Lymphoma ◽  
Cell Transplantation ◽  
Cell Lymphoma ◽  
High Dose ◽  
Free Survival ◽  
Mantle Cell

Abstract Introduction: Mantle cell lymphoma (MCL) is a CD20+ malignancy comprising up 5% of non-Hodgkin’s lymphomas, and has a poor prognosis under standard chemotherapy. The HyperCVAD-M/A regimen (fractionated high-dose cyclophosphamide, vincristine, doxorubicin and prednisolone alternated with methotraxate and cytarabine) has yielded encouraging results when combined with autologous stem cell transplantation (ASCT) in MCL, with 5-year failure-free survival of 54% and overall survival 72%. In an effort to improve these results further, we have combined rituximab in vivo purging and post-transplant consolidation with HyperCVAD-M/A plus ASCT. Methods: Patients aged <65 years with previously untreated or relapsed MCL were treated with four courses of HyperCVAD-M/A followed by four once-weekly doses of rituximab 375mg/m2 as purging prior to stem cell mobilization and harvesting, high-dose chemotherapy (ICT-CY or BEAM), stem cell reinfusion and four further doses of rituximab immunotherapy post-transplant. Results: Of the 34 patients enrolled so far, 15 (12 male, 3 female; 12 previously untreated) have been transplanted. The median age was 52 years (range 47–63 years). After the final post-ASCT immunotherapy all 15 patients were in clinical complete remission. With a median follow-up of 30 months from diagnosis (range 7–52 months), 14 patients remain alive with 13 in first complete remission. One patient died 15 months post-ASCT without evidence of disease recurrence. Kaplan-Meier estimates of 4-year overall and event-free survival are 93.3% and 86.6% respectively. Conclusions: This approach seems safe and feasible and produces durable remissions; longer follow-up of a more patients will be required to assess the effect of the procedure on survival.

Extranodal Diffuse Large B Cell Lymphoma In The Rituximab Era and The Risk of Central Nervous System (CNS) Relapse. A Single Center Experience From 2008-2012

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4330-4330
Author(s):  
Christina Tsao ◽  
Kate Fisher ◽  
Ji-Hyun Lee ◽  
Julio C Chavez ◽  
Samir Dalia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Lymphoma ◽  
Bone Marrow Involvement ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
Cns Relapse ◽  
Musculoskeletal Involvement

Abstract Background Diffuse large b-cell lymphoma (DLBCL) with CNS relapse or progression has a poor prognosis. Prior studies noted certain factors which increased the risk of CNS relapse: bone marrow involvement, type as well as number (1+) of extra-nodal sites, age over 60, and increasing International Prognostic Index (IPI) score. However, these were prior to the advent of rituximab (R), which has been suggested to lower CNS relapse when used in combination with CHOP therapy. To our knowledge, no one has looked at the incidence of CNS relapse with regards to extranodal disease in the rituximab era. Methods Retrospective chart review of patients with DLBCL treated with multiagent induction therapy including rituximab from July‘08 to Jan’12 at Moffitt Cancer Center. Age, stage, IPI score, extra-nodal site, number of nodal sites, and use of intrathecal prophylaxis (IT), were evaluated for their impact on the risk of developing CNS relapse. For those who had complete response to initial therapy, time to progression(TTP) for CNS relapse was measured from completion date of first set of chemo cycles to date of CNS relapse (those who did not CNS relapse were censored at last follow up). TTP was censored at 6 years. Progression free survival(PFS) was measured from date of diagnosis to date of CNS or systemic relapse or death (those who were alive without relapse were censored at last follow up). Overall survival (OS) was measure from date of diagnosis to date of death. Stratified Kaplan Meier curves(with log rank p-values) and Cox PH models(with Wald p-values) were used to explore potential risk factors associated with relapse. Results Sixty-four patients with DLBCL who received induction therapy were evaluated: median age (range) = 65 (24-93) years; male =56%; IPI scores at diagnosis: 1 (43.8%), 2(21.9%), 3(15.6%); median length of follow up from time of diagnosis = 32 months. All the patients received a regimen containing rituximab, and 92% of patients received R-Chop as treatment. IT prophylaxis with methotrexate was used in 28% of the patients. Incidence of CNS relapse in our study population= 17.3% (n=9) The risk of CNS relapse varied depending on the extranodal site. Those with bone marrow and/or musculoskeletal involvement had an increased risk, with 78% of the CNS relapses occurring in patients with one or both of these sites of involvement. The hazard ratio (HR) for CNS relapse for patients with bone marrow and musculoskeletal involvement was 2.53 and 2.74, respectively (p=0.20 and p=0.13). Other extranodal sites of disease such as visceral organs, genital urinary tract, nasopharynx, or skin did not seem to significantly contribute to the risk of CNS relapse. Patients with bone marrow involvement also had an inferior overall survival (HR=3.05, Wald p=0.02) (see figure 1). Though not statistically significant (log rank p=0.126), those receiving IT methotrexate prophylaxis appear to have longer PFS than those who did not, with 83% alive without relapse at 6 years compared to 43% (see figure 2). Conclusions Despite the addition of rituximab to multiagent chemotherapy, those with bone marrow and musculoskeletal involvement still had a significantly higher risk of CNS relapse. There is a trend which suggests intrathecal prophylaxis with methotrexate can improve progression free survival and is still possibly beneficial in high risk DLBCL patients even in the rituximab era. Larger prospective studies are needed to determine the true benefit of prophylactic IT therapy in this population. Disclosures: No relevant conflicts of interest to declare.

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