12-Year Experience with High-Dose Rituximab-Containing Autologous Stem Cell Transplantation for SOX11-Positive Mantle Cell Lymphoma Patients in First Remission: Emerging Lymphoma-Free Survival Plateau After 3 Years,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4138-4138
Author(s):  
Zaher I Chakhachiro ◽  
Rima M Saliba ◽  
Grace-Julia Okoroji ◽  
Martin Korbling ◽  
Amin M Alousi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Lymph Node ◽  
Cell Lymphoma ◽  
High Dose ◽  
Ki 67 ◽  
Free Survival ◽  
Mantle Cell ◽  
Group A ◽  
Group B

Abstract Abstract 4138 Background: The addition of high-dose rituximab to conditioning regimens has been shown to improve outcomes of autologous stem cell transplantation (ASCT) for mantle cell lymphoma (MCL) patients (pts) in first partial (PR) or complete remission (CR)(Tam C et al. Blood 2009,113:4144). It has been suggested that absence of SOX11 expression can identify a subtype of indolent MCL with excellent outcomes that might be managed more conservatively than conventional MCL. We now report updated results of ASCT for 40 MCL pts treated at our center between 05/99 and 10/10. We also report on SOX-11 expression in a subset of these pts. Methods and Patients: Pts had a median age of 54 years (range, 38–72), and 30% were older than 60 years. At diagnosis, 60% had IPI>1, 30% had intermediate/high MIPI, 88% had stage IV disease, and 78% had bone marrow involvement. 28% had blastic features and Ki-67 was ≥30% in 11/23 (52%) pts who were tested. Pts were treated with R-CHOP or R-hyper-CVAD × 4 cycles induction in 30% and 45% respectively (Group A). Since 2001, pts were referred to ASCT only if they failed to achieve CR with >4 cycles of R-hyper-CVAD induction (n= 10, 25%) (Group B). Prior to transplant, CR (or CR unconfirmed-CRu) was present in 62% pts; 38% were in PR, and 18% were PET+. Conditioning was R-BEAM and R-Cy-TBI conditioning in 77% and 23% respectively. Pts received R during stem cell collection with R administered at 375 mg/m2 on the day before initiating chemotherapy for stem cell mobilization, and again at 1000 mg/m2, 7 days later. Pts then received additional R at 1000 mg/m2 on days +1 and +8 after ASCT, as previously described. Pts were staged with CT, PET (whenever indicated) scans, bone marrow biopsy, and colonoscopy (if history of GI involvement) every 3 months for the first year, every 6 months for 5 years, then yearly thereafter. Results: a. SOX11: Formalin-fixed, paraffin-embedded tissue biopsy sections were assessed by immunohistochemistry (IHC) using anti-Sox-11 rabbit polyclonal antibody (Abcam, Cambridge, MA; 1:1500). For IHC controls we used a tissue microarray including 13 cases of MCL in addition to one complete section of MCL serving as positive controls, and sections from two cases of small lymphocytic lymphoma involving lymph node serving as negative controls. The 11 cases consisted of five GI biopsies, three lymph node biopsies, two bone marrows and one testis. 10/11 showed positive staining for SOX11. The case with negative staining, a GI biopsy, had scattered positive cells. b. Clinical outcome : Following transplantation, CR/CRu was achieved in 100% pts. With a median follow-up of 37 months (range, 6–145), 10 pts experienced recurrent disease. All progressions occurred within 3 years, with a clear plateau emerging subsequently (Figure). The projected lymphoma-free-survival at 10-year, was 65% (95%CI, 44–80). A tendency for a higher risk of relapse was observed in R-hyper-CVAD resistant pts (Group B) pts [4/10 pts (40%) vs 6/30 (20%) in Group A; HR 2.5 (95%CI, 0.7–9.2), p=0.2)], and in pts with ki-67 ≥30% [HR 2.2 (95%CI, 0.4–11), p=0.3). MIPI, blastic histology, age (> 60 years), disease status at transplant (CR/PR) and conditioning were not found to be of prognostic value in our study. 2 pts (5%) developed myelodysplasia, one of which was concurrent with progression. Conclusions: ASCT with high-dose rituximab has the potential to cure a proportion of pts with MCL after response to induction chemotherapy. Our results are favorable despite the inclusion of pts who were resistant to R-hyper-CVAD. Randomized studies comparing this strategy to conventional chemo-immunotherapy are warranted. The prognostic significance of Ki-67 level needs to be assessed in a larger cohort of patients. Disclosures: No relevant conflicts of interest to declare.

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.

Nordic Mantle Cell Lymphoma (MCL) Project: Preemptive Rituximab Treatment of Molecular Relapse Following Autotransplant Can Reinduce Molecular Remission and Prolonged Disease-Free Survival.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2429-2429
Author(s):  
Christian H. Geisler ◽  
Erkki Elonen ◽  
Arne Kolstad ◽  
Anna Laurell ◽  
Lone B. Pedersen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Lymphoma ◽  
Disease Free Survival ◽  
High Dose ◽  
Clinical Relapse ◽  
Relapse Free Survival ◽  
Molecular Remission ◽  
Free Survival ◽  
Mantle Cell ◽  
Disease Free

Abstract The 2nd. Nordic Lymphoma Group mantle cell lymphoma (MCL2) protocol has demonstrated the importance of Ara-C and Rituximab in the induction chemotherapy and stem-cell mobilisation before high-dose therapy and autologous stem-cell transplant (1). By July 2005, 128 patients (83% stage IV) had completed protocol treatment consisting of 3 series of R-CHOP and 3 series of R-Ara-C, stem-cell harvest and high-dose therapy with BEAM/BEAC with ASCT. The 5-year failure-free and overall survival is 50% and 83% respectively, significantly higher than the historic control group of the Nordic MCL1 protocol with the same treatment without HD-Ara-C and Rituximab (P&lt;0.0001). Patients with a molecular marker (t(11;14) or clonal IgH rearrangement) identified at the time of diagnosis in bone marrow and blood, undergo regular molecular follow-up posttransplant,. Patients who turn PCR-positive or increase their qPCR signal, without clinical disease, are offered preemptive treatment with Rituximab 375 mg/m2 Wx4. Of 75 patients with molecular markers who had completed treatment, 55 remain PCR-negative and 20 have become/remained PCR-pos. posttransplant. Clinical relapse ocurred significantly more often in the latter group (11 of 20) than in the PCR-neg. patients (4 of 55) (P&lt;0.0001) (Fig.1). Ten of the 20 PCR-positive patient did not receive preemptive rituximab: five due to immediate clinical relapse, 2 due to stable qPCR signals, one due to protocol error and two await treatment. Of 10 patients who did receive preemptive rituximab 8 again became PCR-negative and 2 remain PCR-positive. Six of the 10 Rituximab treated patients remain in clinical and molecular remission 200–600 days after the Rituximab treatment (Fig. 2). Conclusions: In MCL, molecular relapse is a harbinger of imminent clinical relapse, whereas continuous molecular remission is associated with prolonged disease-free survival (89% at 4 years) Rituximab preemptive treatment can reinduce molecular remission and may delay clinical relapse. Following molecular relapse, only Rituximab treated patients (6 of 8 evaluable) remain disease-free. FIG. 1. NORDIC NCL-2 PROTOCOL: RELAPSE-FREE SURVIVAL ACC. TO MOLECULAR STATUS POSTTRANSPALNT FIG. 1. NORDIC NCL-2 PROTOCOL: RELAPSE-FREE SURVIVAL ACC. TO MOLECULAR STATUS POSTTRANSPALNT FIG. 2. NORDIC NCL-2 PROTOCOL: RELAPSE-FREE SURVIVAL FROM TIME OF MOLECULAR RELAPSE. FIG. 2. NORDIC NCL-2 PROTOCOL: RELAPSE-FREE SURVIVAL FROM TIME OF MOLECULAR RELAPSE.

Cell Proliferation (Ki-67) As Prognostic Marker in Mantle Cell Lymphoma.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2677-2677 ◽  
Author(s):  
Eva Hoster ◽  
Wolfram Klapper ◽  
Andreas Rosenwald ◽  
Heinz-Wolfram Bernd ◽  
Sylvia Hartmann ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Prognostic Factors ◽  
Lymph Node ◽  
Mantle Cell Lymphoma ◽  
Prognostic Marker ◽  
Cell Lymphoma ◽  
High Dose ◽  
Ki 67 ◽  
Prognostic Relevance ◽  
Mantle Cell

Abstract Abstract 2677 Introduction: The percentage of proliferating cells evaluated on diagnostic tumor samples has been shown to be of high prognostic relevance in Mantle Cell Lymphoma (MCL) patients. As MCL is relatively rare, evaluation of proliferation has so far mostly been based on smaller patient cohorts that were retrospectively collected and inhomogenously treated. In 2004, the European MCL Network initiated two large European randomized trials for younger (“MCL Younger” trial) and older (“MCL Elderly” trial) MCL patients, primary results of which have recently been reported (Kluin-Nelemans et al., NEJM 2012, Hermine et al., ASH 2010). We aimed to clarify the prognostic relevance of the proliferation marker Ki-67 using pooled data from these two trials. Patients and Methods: Patients with histologically confirmed and previously untreated MCL of stages II-IV up to 65 years of age were randomly assigned in “MCL Younger” to either 6 cycles R-CHOP followed by myeloablative radio-chemotherapy and autologous stem cell transplantation (ASCT), or 6 cycles alternating R-CHOP/R-DHAP followed by high-dose-Ara-C containing conditioning and ASCT. Patients aged 60 years or older and not eligible for high-dose therapy were randomly assigned in “MCL Elderly” to either 8 cycles of R-CHOP or 6 cycles of R-FC; responding patients were subsequently randomized to either interferon-alpha or rituximab maintenance until progression. Histological diagnosis was confirmed by central review within the European MCL Pathology Panel. The percentage of Ki-67 positive cells was counted on diagnostic lymphoma samples among 2 times 100 cells by the central pathology labs according to published consensus guidelines (Klapper et al., J Hematopathology 2009). The outcome measures were time to treatment failure (TTF) from treatment initiation to stable disease, progression, or death from any cause, and overall survival (OS) from trial registration to death from any cause. We investigated the prognostic value of proliferation as a quantitative marker with regards to TTF and OS in univariable Cox regression and evaluated the previously established cut-off values of 10% and 30% (Determann et al., Blood 2008) using Kaplan-Meier estimates and log rank tests. We also adjusted for clinical prognostic factors (MIPI, Hoster et al., Blood 2008). Results: Counted Ki-67 values were available in 51% (543) of 1057 randomized patients (material not available, 30%; Ki-67 evaluation not possible due to technical reasons, 16%). The origin of tumor tissue was lymph node in 81%, gastrointestinal tract in 12%, bone marrow in 4% and other in 3%. The median proliferation rate was 20% (range, 0–97%; interquartile range, 12–34%) and did not significantly differ between tissue origins. In univariable analysis, a 10% higher proliferation rate was associated with hazard ratios of 1.18 (95% confidence interval, 1.12 to 1.25, p<0.0001) for TTF and 1.23 (95% CI, 1.15 to 1.31, p<0.0001) for OS. Patients with Ki-67 ≥ 30% had median TTF and OS of 19 and 45 months compared to 64 months and not reached with Ki-67 < 30% (p<0.0001 each). Patients with Ki-67 < 30% and either ≥ 10% or < 10% had similar TTF and OS. The separation of a high risk group as defined by Ki-67 ≥ 30% was consistently seen within “MCL Younger” and “MCL Elderly” as well as within the 4 different induction treatment arms. The prognostic impact of proliferation was independent of the MIPI prognostic score (adjusted hazard ratio for TTF, 1.11, 95% CI, 1.05 – 1.17, p=0.0005; for OS, 1.14, 1.07–1.23, p=0.0001), which was also independently highly prognostic (p<0.0001). Almost identical results were seen when the analyses were restricted to lymph node samples. Conclusions: Cell proliferation was confirmed as important biological prognostic marker independent of clinical prognostic factors on a large cohort of MCL patients uniformly treated within clinical trials. Since the evaluation of Ki-67 has been standardized, guidelines (e.g. Dreyling et al., Ann Onc, in press) recommend applying this parameter in clinical routine. Further analyses will focus on the joint correlation of Ki-67, MIPI and minimal residual disease with outcome to potentially allow a more individualized therapeutic approach in MCL patients. On behalf of the European Mantle Cell Lymphoma Network. Disclosures: No relevant conflicts of interest to declare.

High-dose chemo-radioimmunotherapy with autologous stem cell support for relapsed mantle cell lymphoma

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3158-3162 ◽  
Author(s):  
Ajay K. Gopal ◽  
Joseph G. Rajendran ◽  
Stephen H. Petersdorf ◽  
David G. Maloney ◽  
Janet F. Eary ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Stem Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Remission Rate ◽  
Disease Free Survival ◽  
High Dose ◽  
Specific Monoclonal Antibody ◽  
Free Survival ◽  
Mantle Cell

Abstract Relapsed mantle cell lymphoma is a radiation-sensitive malignancy that is unlikely to be cured by treatment with conventional high-dose therapy and autologous stem cell transplantation. We tested the safety and efficacy of using a CD20-specific monoclonal antibody conjugated with 131I to deliver high-dose radiation selectively to all lymphoma sites. Patients with relapsed or refractory mantle cell lymphoma received infusions of 131I-labeled CD20-specific monoclonal antibody (Tositumomab). The antibody dose was 1.7 mg/kg body weight, and the amount of 131I was calibrated to deliver 20 to 25 Gy to vital normal organs. This treatment was followed 10 days later by administration of high-dose etoposide (30-60 mg/kg), cyclophosphamide (60-100 mg/kg), and infusion of cryopreserved autologous stem cells. The 16 patients in this study had received a median of 3 prior treatments, and 7 had chemotherapy-resistant disease. The median dose of 131I was 510 mCi (18.87 GBq). There were no therapy-related deaths. Among the 11 patients with conventionally measurable disease at the time of treatment, the respective complete and overall response rates were 91% and 100%. Fifteen patients remain alive, and 12 have had no progression of lymphoma at 6 to 57 months from transplantation and 16 to 97 months from diagnosis. Overall survival at 3 years from transplantation is estimated at 93%, and progression-free survival is estimated at 61%. High-dose treatment with 131I-Tositumomab, etoposide, and cyclophosphamide results in a high remission rate and may provide long-term disease-free survival for patients with relapsed or refractory mantle cell lymphoma.

Rituximab Given after High Dose Therapy and Autologous Stem Cell Transplantation Induces Durable Clearance of Minimal Residual Disease in about Half of the Patients with Follicular Non Hodgkin’s Lymphoma : 36 Months Results of a Multicenter Open Label Phase II Trial (M39012 Trial).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 747-747 ◽  
Author(s):  
Franck Morschhauser ◽  
Christian Recher ◽  
Noel Milpied ◽  
Remi Gressin ◽  
Gilles Salles ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Residual Disease ◽  
Post Treatment ◽  
High Dose ◽  
Molecular Response ◽  
High Dose Therapy ◽  
Free Survival ◽  
Group A ◽  
Group B ◽  
Minimal Residual

Abstract In patients with follicular non hodgkin’s lymphoma (FL), high dose therapy and autologous stem cell transplantation (ASCT) can improve disease free survival. However, patients with minimal residual disease (MRD) after ASCT relapse in most cases. The use of immunotherapy in patient with a MRD state after ASCT is an attractive strategy. Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy alone or in combination with chemotherapy in FLNH. The purpose of the present study is to evaluate the efficacy of rituximab on MRD after ASCT. Methods : Three months after ASCT, 39 patients (median age: 48 years) including 14 patients with clinical MRD (group A: nodal or extra-nodal mass > 1 cm but < to 3 cm; bone marrow infiltration less than 30% allowed) and 25 patients with molecular MRD (group B: complete clinical response but bcl-2 gene rearrangement detectable by clonospecific PCR in blood and/or marrow) were eligible to receive Rituximab (375 mg/m2 IV, once a week for 4 weeks). Clinical examination, imaging and blood and bone marrow sampling for centralized molecular MRD studies by clonospecific PCR (sensitivity of the PCR assay : 10-6) were performed at day 50 and every 6 months post treatment. Results: In group A, overall clinical response rate was 36 % (5/14) at day 50 and 71 % (10/14) at 12, 24 and 36 months post treatment, respectively. Median time to response was 183 days. Median Progression free survival (PFS) was not reached and PFS was 62 % at M36. In responders, no relapse was observed. In group B, molecular response (conversion from PCR positive to PCR negative status) was achieved in 12/23 (52 %), 11/22 (50 %), 10/22 (45 %) and 11/24 (46 %) assessable patients at day 50, 12, 24 and 36 months post treatment, respectively. Median time to response was 185 days. Four molecular responders became persistently PCR positive and had a clinical relapse. Median clinical PFS was not reached. Treatment was well tolerated. Only one serious adverse event (AE) was reported as related during the study (grade 3 NCI granulocytopenia). No patient was withdrawn for AE. Conclusion: Rituximab is effective in 71 % of the patients with clinical MRD after ASCT with a response maintained at 3 years. The molecular response induced by rituximab persisted after 3 years of follow-up in 46 % of the patients. These results demonstrate that in FL patients with MRD after ASCT, Rituximab is well tolerated and effective completing the effect of intensive chemotherapy and inducing durable response. Further studies are required to identify the most effective program in combination with rituximab which may result in a chance of cure.

A Retrospective Analysis of Mantle Cell Lymphoma Patients Series Treated Upfront by Sequential High Dose Immunochemotherapy Supported by In Vivo Purged Stem Celle Double Autologous Transplantation: A Monocentric Experience

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4949-4949
Author(s):  
Andrea Ferrario ◽  
Giorgia Saporiti ◽  
Nicola Orofino ◽  
Francesco Onida ◽  
Daniele Vincenti ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Lymphoma ◽  
Standard Dose ◽  
Autologous Transplantation ◽  
Disease Free Survival ◽  
High Dose ◽  
Free Survival ◽  
Mantle Cell ◽  
High Dose Cytarabine ◽  
Disease Free

Abstract Abstract 4949 Mantle Cell Lymphoma (MCL) is a rare lymphoma that accounts for 3–10% of all non Hodgkin's Lymphoma in adults. Being associated with rapid progression and high recurrence rate, although some treatment improvements during the last years, it is still considered an incurable disease. In order to overcome the poor outcome obtained with conventional chemotherapy, new treatment strategies using high dose chemotherapy supported by autologous stem cell transplantation (ASCT) have been developed in young patients. In particular the use of high dose cytarabine and rituximab prior to ASCT has been demonstrated to improve outcome in terms of response and disease free survival. The present study is a restrospective analysis conducted in our centre in order to evaluate the outcome of 16 MCL patients treated upfront with sequential high dose immunochemotherapy followed by double ASCT. From 2000 to 2011, 16 MCL patients, eligible for ASCT, have been consecutively treated as follow: a) standard dose phase: APO: doxorubicin, 75 mg/sqm i.v., day 1; prednisone, 60 mg/sqm orally, day 1 to 5 and day 9 to 12; vincristine, 1.4 mg/sqm i.v., day 1 and 8; DHAP: cisplatin 70 mg/sqm, day 1; cytarabin 1500 mg/sqm i.v., days 2–3; dexametasone 40 mg i.v., days 1 to 3; b) rituximab high dose sequence: high dose cyclophosphamide (CTX 5 g/sqm) and high dose cytarabine (Ara-C 2 g/sqm every 12 hours for 6 consecutive days) followed by peripheral blood stem cell (PBSCs) collection; c) high dose melphalan (180 mg/sqm) and high dose mitoxantrone plus melphalan (60 mg/sqm and 180 mg/sqm, respectively) followed by PBSCs infusion. Rituximab (375 mg/sqm) was infused twice after CTX, cytarabine and double autologous transplantation (modified from Gianni et al, Blood, 102, 749, 2003). All patients (9 female and 7 male) had a histological diagnosis of MCL according to the WHO classification criteria; molecular rearrangement of bcl-1 locus was detected by PCR in the bone marrow of 8 patients. The median age at diagnosis was 57 years (range 50–68); 14 patients were in stage IV and 2 in stage III; 2 patients had bulky disease at presentation. Four patients were in overt leukemic phase and 2 had extranodal localization. According to MIPI score, 14 patients (87%) were classified as low risk and 2 (13%) as intermediate risk. Double transplant was performed in all patients except one (who refused it). The standard dose phase, including a median number of 4 cycles (range 3–5), was generally well tolerated, with only one patient experiencing tumor lysis syndrome. After induction, clinical CR was achieved in six patients. PBSCs were successfully collected after both the CTX/rituximab (1.8-9.7×10̂6/Kg) and the Ara-C/rituximab (7.1- 40.0×10̂6/Kg) cycles. At the end of these phases, 7 patients (44%) were in CR while 9 (56%) were in PR. Following transplants, median times to ANC >500/μL were 11 days (range 10–14) in both the procedures, whereas median times to platelet recovery (>50000/μL) were 19 days (range 10–44) after the first transplant and 24 days (range 11–298) after the second one. After a median follow-up of 38 months (range 14–111), 10 patients (62%) were alive (8 in CR, 2 in relapse), whereas 6 died from disease progression. Our study confirmed that in MCL the use of sequential high dose immunochemotherapy including rituximab and high dose cytarabine followed by double autologous transplantation is associated to high remission rates with long-term disease-free survival in a significant proportion of patients. Disclosures: No relevant conflicts of interest to declare.

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.

Rituximab Maintenance after Autologous Stem Cell Transplantation Prolongs Survival in Younger Patients with Mantle Cell Lymphoma: Final Results of the Randomized Phase 3 LyMa Trial of the Lysa/Goelams Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 145-145 ◽  
Author(s):  
Steven Le Gouill ◽  
Catherine Thieblemont ◽  
Lucie Oberic ◽  
Anne Moreau ◽  
Krimo Bouabdallah ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Standard Of Care ◽  
High Dose ◽  
Advisory Committees ◽  
Free Survival ◽  
Mantle Cell ◽  
High Dose Cytarabine

Abstract Mantle cell lymphoma (MCL) accounts for approximately 6% of non-Hodgkin's Lymphoma (NHL) in adults. MCL commonly responds to initial therapy but inevitably patients relapse and response duration decreases from one salvage therapy to the next. Indeed, there is an urgent need to control and/or eradicate residual MCL cells that are responsible for early and late relapses. Maintenance with Rituximab (RM) after R-CHOP has been shown to prolong OS in elderly MCL patients treated with R-CHOP (Kluin-Nelemans et al. NEJM). Induction with high-dose cytarabine followed by autologous stem cell transplant (ASCT) consolidation is standard of care for young patients but RM after ASCT has never been investigated so far. The LyMa trial (ClinicalTrials.gov, NCT00921414) is a prospective international randomized phase III trial that investigated RM after ASCT in young previously untreated MCL patients. Patients were included at diagnosis (<66y; stage >I, untreated, diagnosis of MCL according to WHO 2008 classification). Induction immuno-chemotherapy consisted of 4 courses of R-DHAP every 21 days (Rituximab, Dexamethasone, High-dose cytarabine, salt Platinum) followed by ASCT consolidation. Patients who were not in response (CR/CRu or PR) after R-DHAP received 4 additional courses of R-CHOP-14 before ASCT. The conditioning regimen for ASCT was R-BEAM. Patients in response after ASCT were randomized (1:1) between RM or no RM. RM consisted of one infusion of Rituximab (375mg/m2) every 2 months for 3 years. The primary endpoint was event-free survival (EFS) calculated from time of randomization; events were defined as disease progression, relapse, death, severe infection or allergy to Rituximab. Progression-free survival (PFS) and overall survival (OS) from time of diagnosis and time of randomization were secondary endpoints. The interim analysis showed a trend for a longer EFS and PFS in favor of RM arm. (Le Gouill et al, ASH 2014, abs 146). Herein, we present the results of the final analysis. RESULTS. Two hundred and ninety nine patients were enrolled from September 2008 to August 2012. Demographic and clinical characteristics of the patients were as followed: median age of 57y (27-65), 79% of male, MIPI-low in 53.2%, MIPI-I in 27.4% and MIPI-H in 19.4%. After inclusion, 277 patients completed the 4 courses of R-DHAP. The CR/CRu rate after R-DHAP was 77.3% and ORR was 89.3%. Twenty patients received R-CHOP. In all, 257 patients (including 12 patients who received R-DHAP/R-CHOP) underwent ASCT. After ASCT, 240 patients were randomized (RM, n=120; no RM, n=120). Median follow-up (mFU) from inclusion and from randomization were 54.4m (52.7-59.2) and 50.2m (46.5-54.2), respectively. The mPFS and mOS from inclusion in an intention to treat analysis were not reached; the 4y-PFS and OS were 67.8% (95%CI, 62.1 to 72.8) and 78% (95%CI; 72.8 to 82.3), respectively. According to EFS definition, 47 (39.2%) patients had an event in the no RM versus 25 (20.8%) in the RM arm. The mEFS from randomization was not reached in both arms. The 4y-EFS was 61.4% (95%CI; 51.3 to 69.9) in the no RM arm vs 78.9% (95%CI; 69.6 to 85.6) in the RM arm (p=0.0012). The EFS duration was significantly superior in the RM arm with a 54.3% reduction in the risk of event (Hazard ratio (HR)= 0.457; 95%CI, 0.28 to 0.74; p=0.0016). The median PFS and OS from randomization were not reached in both arms. The 4y-PFS and OS from randomization were superior in the RM arm: 82.2% (95%CI; 73.2 to 88.4) vs 64.6% (95%CI; 54.6 to 73) (p=0.0005) and 88.7% (95%CI; 80.7 to 93.5) vs 81.4% (95%CI; 72.3 to 87.7)(p=0.0413). Patients in the RM arm had a 60% reduction of risk of progression (HR=0.4; 95%CI, 0.23 to 0.68; p=0.0007) and a 50% reduction of risk of death (HR=0.5; 95%CI, 0.25 to 0.98; p=0.0454). The per protocol analysis yielded similar results. In conclusion, The LyMa trial demonstrates for the first time that RM after ASCT prolongs EFS, PFS and OS. Thus, 4 courses of R-DHAP plus ASCT (without TBI) followed by RM maintenance (one infusion every 2 month for 3 years) is a new standard of care for young MCL patients. Disclosures Thieblemont: Gilead: Consultancy; Roche: Consultancy; Janssen: Consultancy. Ribrag:Pharmamar: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; NanoString: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding. Casasnovas:BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; ROCHE: Consultancy, Honoraria, Research Funding. Haioun:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hermine:Celgene: Research Funding; AB science: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Novartis: Research Funding; Alexion: Research Funding.

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