A Simplified Geriatric Assessment (sGA) Can Identify Older Patients with Relapse/Refractory (R/R) Aggressive Lymphoma Suitable for Autologous Stem Cell Transplantation (ASCT): Final Results of Recanz Multicentre Prospective Phase 2 Study By the Fondazione Italiana Linfomi (FIL)

Abstract Introduction: We recently demonstrated in a large multicentre study that sGA can identify fit older patients with aggressive lymphoma able to tolerate first-line intensive treatment with curative intent and to obtain similar results than younger people (Merli at al JCO 2021). Regardless of age, about 40% of patients with aggressive lymphoma are either refractory or will eventually relapse after treatment with curative intent. Salvage platinum-based regimens followed by ASCT in responsive disease is a standard of care to obtain longer second remission. However, in many case series, patients over 65 years are excluded from the transplant approach because of potential severe toxicities of high-dose therapy in older patients. This study was designed to evaluate the feasibility and activity of high-dose treatment followed by ASCT in older FIT patients with R/R aggressive lymphoma selected with a sGA. Methods: Patients with R/R aggressive lymphoma after one line of treatment, aged between 65 and 75, and FIT to sGA were eligible for the study. Salvage treatment could be chosen between R-DHAP, R-ICE or other platinum or gemcitabine-containing regimens and stem cells were mobilized after 1 or 2 cycles. Patients achieving at least partial response after 3 courses and who remained FIT to sGA evaluation were eligible for ASCT and were conditioned with either BEAM or FEAM. Results: From May 2014 to August 2019, seventy-five patients from 16 FIL centres were enrolled and 70 were eligible for the study. Sixty-six of them had a diffuse large B-cell lymphoma, one had follicular 3b, 2 mantle cell and 1 Burkitt histology. Salvage treatment was R-DHAP in 48 patients, R-ICE in seven and gemcitabine or oxalyplatinum containing regimens in the remaining ones. Overall response rate after three courses was 44% (21 complete and 10 partial remission). Among the 39 unresponsive patients, 29 had progressive and 4 stable disease, 2 patients died of septic shock and heart failure during salvage and 4 patients withdrew their consent to ASCT. Four patients relapsed soon after response achievement before undergoing the transplant. ASCT was performed in 27 patients with a median of 5.6 x 10 6 CD34/Kg reinfused. No differences emerged in demographic and clinical characteristics between patients reaching the ASCT timepoint or not (Tab 1a). By intention to treat analysis, 2-y overall survival (OS) and PFS of the entire intention-to-treat population were 65% (95%CI: 50-76%) and 34% (95%CI: 22-46%) respectively, without differences according to age (Tab 1b). After a median of 27 months, 2-y OS was 79% (95CI: 51-86%) and EFS 56% (95CI: 32-75%). Twenty-four patients obtained a complete remission (CR) and 20 of them are in continuous CR after more than 12 months. Three patients progressed 1-8 months after ASCT and died. Most common non-hematologic grade 3-4 adverse events were gastrointestinal (10%) and infectious (8%). Conclusion: This study shows that sGA can identify older patients with R/R aggressive lymphoma who are able to tolerate and can benefit from high-dose therapy and ASCT. The poor response to second-line immunochemotherapy remains the major drawback of this approach since less than 50% of patients could actually receive ASCT. Nevertheless the 2-y survival of 65% in the intention to treat population is remarkable and sets the stage for the evaluation of new approaches such as CAR-T or bispecific antibodies also in older patients. A next step should be to explore the usefulness of sGA in the selection of candidates to these innovative treatments. Figure 1 Figure 1. Disclosures Tucci: Takeda: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Musuraca: janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo: ROCHE: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Gilead: Speakers Bureau. Zilioli: Roche, Italfarmaco: Consultancy, Honoraria; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau; Takeda: Other: travel expenses, accommodation. Merli: EUSA Pharma: Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; MSD: Membership on an entity's Board of Directors or advisory committees; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Celgene: Other: Travel, Accomodations, Expenses. Marcheselli: sandoz: Membership on an entity's Board of Directors or advisory committees. Rossi: Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees.

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Superiority of Lenalidomide-Dexamethasone Versus Thalidomide-Dexamethasone as Initial Therapy for Newly Diagnosed Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.3884.3884 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3884-3884

Author(s):

Francesca Gay ◽

Suzanne Hayman ◽

Martha Q. Lacy ◽

Francis Buadi ◽

Morie A Gertz ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Initial Therapy ◽

High Dose ◽

Toxicity Profile ◽

Newly Diagnosed ◽

Advisory Committees ◽

Intention To Treat ◽

High Dose Dexamethasone ◽

Grade 3

Abstract Abstract 3884 Poster Board III-820 Background and Objective Thalidomide/dexamethasone (thal/dex) combination has shown high activity in newly diagnosed multiple myeloma (MM) (Rajkumar SV. at al, J Clin Oncol 2006;24:431-436). In newly diagnosed patients, lenalidomide/dexamethasone (len/dex) has demonstrated superiority compared with high-dose dexamethasone alone (Zonder JA et al, Blood 2007;110:77). Although both thal/dex and len/dex are active in newly diagnosed MM, no randomized trial has been reported comparing these two regimens, and unfortunately none are ongoing or planned. We compared the efficacy and the toxicity of thal/dex and len/dex as primary therapy in 411 newly diagnosed MM patients treated at the Mayo Clinic. Patients and methods 411 consecutive patients seen at Mayo Clinic between 2001 and 2008, who received induction with thal/dex (n=183) or len/dex (n=288) were retrospectively studied. Thalidomide was given at a dose ranging from 100 mg/day to 400 mg/day continuously; the lenalidomide dose was 25 mg/day, days 1-21 on a 28-day cycle. All patients received dexamethasone, either at high-dose (40 mg orally on days 1-4, 9-12, and 17-20) or at low-dose (40 mg orally day 1, 8, 15, 22); each cycle was repeated every 4 weeks. In addition, a case-matched subgroup analysis that adjusted for age, gender and transplantation status was performed among patients who received high-dose dexamethasone comparing the thal/dex (n=72) and len/dex (n=72) groups. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method and all comparisons were determined by the log-rank test and by the Cox proportional hazards model. Results On intention-to-treat analysis, of 411 patients, 80.3% versus 61.2% patients, respectively in the len/dex group and in the thal/dex group (p < 0.001), achieved at least a partial response. A significant difference between the 2 groups was found in terms of both very good partial response or better (34.2% vs 12.0%, p < 0.001) and complete response rate (13.6% vs 3.3%, p < 0.001). Duration of therapy was significantly longer in len/dex patients as compared to thal/dex patients: 36.7% vs 12.6% of patients who did not stop treatment to receive SCT were still receiving therapy at 1 year (p < 0.001).Time-to-progression was significantly better in the len/dex group than in patients receiving thal/dex (median 27.4 vs 17.2 months, HR 0.64; 95% CI 0.44-0.93; p = 0.019). Similarly, progression-free-survival was significantly higher in len/dex patients (median 26.7 vs 17.1 months, HR 0.69; 95% CI 0.48-0.98; p = 0.036). This translated into an increase in overall survival (OS) (median not reached for len/dex group compared to 57.2 months in thal/dex patients, HR 0.60; 95% CI 0.40-0.92; p = 0.018). Survival advantages were evident in patients presenting with International Staging System Stage (ISS) I/II (HR 0.57; 95% CI 0.32-1.00; p = 0.052) at diagnosis but not in patients with ISS stage III in subgroup analysis. There was a trend toward better OS in len/dex group compared to thal/dex group both for patients who underwent transplant and for patients who did not. A similar rate of patients experienced at least one grade 3 or higher adverse event (57.5% vs 54.6% in len/dex and thal/dex groups, respectively, p = 0.568). However, the toxicity profile was different in the two groups: major grade 3-4 toxicities of len/dex were hematological, in particular neutropenia (14% with len/dex vs 0.6% with thal/dex, p<0.001) while the most common toxicities in thal/dex were venous thromboembolism (15.3% vs 9.2%, p = 0.058) and peripheral neuropathy (10.4% vs 0.9%, p < 0.001). The data on efficacy and safety shown above were also confirmed in the subgroup case-matched analysis which included only high-dose dexamethasone patients. Conclusions This cohort study shows the superiority of len/dex in terms of response rates and survival, compared to thal/dex. The toxicity profile of the 2 regimens is different and len/dex treatment, although more active, was not associated with increased toxicity (grade 3-4 AEs). These data need to be carefully evaluated and randomized prospective phase III studies are necessary to confirm these results and determine the optimal initial therapy for MM. Disclosures: Off Label Use: research drugs in combination to standard care. Lacy:celgene: Research Funding. Gertz:celgene: Honoraria; genzyme: Honoraria; millenium: Honoraria; amgen: Honoraria. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; Novartis: Research Funding; Genzyme: Research Funding. Dispenzieri:celgene: Research Funding. Bergsagel:amgen: Membership on an entity's Board of Directors or advisory committees; genetech: Membership on an entity's Board of Directors or advisory committees; merck: Research Funding; celgene: Membership on an entity's Board of Directors or advisory committees. Witzig:celgene: Research Funding. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Greipp:celgene: Research Funding.

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Response to Rituximab Induction Is a Predictive Biomarker in Post-Transplant Lymphoproliferative Disorder (PTLD) and Allows Successful Treatment Stratification in an International Phase II Trial Including 152 Patients

Blood ◽

10.1182/blood.v126.23.816.816 ◽

2015 ◽

Vol 126 (23) ◽

pp. 816-816 ◽

Cited By ~ 2

Author(s):

Ralf Ulrich Trappe ◽

Daan Dierickx ◽

Heiner Zimmermann ◽

Franck Morschhauser ◽

Peter Mollee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Phase Ii Trial ◽

Solid Organ ◽

Transplant Recipients ◽

Advisory Committees ◽

Intention To Treat ◽

Kaplan Meier ◽

Treat Population

Abstract Background: The PTLD-1 trial has demonstrated the efficacy and safety of 4 cycles of weekly rituximab followed by 4 cycles of CHOP-21 + G-CSF in CD20-positive PTLD after solid organ transplantation. Median overall survival (OS) was 6.6 years, a clear improvement over the preceding rituximab monotherapy trials (2.4 years). However, response to rituximab induction predicted OS after completion of therapy. Based on the hypothesis that rituximab consolidation might be sufficient treatment for patients already in a complete response (CR) after rituximab induction, trial treatment was changed in 2007 through a protocol amendment introducing risk-stratified sequential treatment (RSST): rituximab consolidation for patients in CR after rituximab induction and R-CHOP-21 consolidation for all others. Methods: In this international, multicenter phase II trial (PTLD-1, 3rd amendment; NCT00590447), treatment-naïve adult solid organ transplant recipients diagnosed with CD20-positive PTLD were treated with rituximab (375 mg/m2 IV) on days 1, 8, 15 and 22. After restaging, patients in CR continued with four three-weekly courses of rituximab monotherapy while all others received 4 cycles of R-CHOP-21 + G-CSF. In case of disease progression during rituximab monotherapy R-CHOP was commenced immediately. The primary endpoint was treatment efficacy measured as response rates and response duration. Analysis was by intention to treat. This is the final analysis of 152 patients treated with RSST from 2007 to 2014 at centers in Germany (72), Belgium (36), France (24), Australia (7), Poland (7) and Italy (6) with a median follow-up of 4.5 years. The 70 patients treated with rituximab followed by CHOP-21 in the original PTLD-1 trial (median follow-up 5.1 years) served as a control population. Inclusion criteria and follow-up schedule were identical; there were no significant differences in the transplant- and lymphoma-related baseline factors listed below. Results: 115/152 patients were male. 69/152 were kidney, 40 liver, 18 lung, 15 heart, 5 heart/kidney, 3 kidney/pancreas and 2 heart/lung transplant recipients. Median age at diagnosis was 56 years. PTLD was late (> 1 year after transplantation) in 120/152 (79%) of patients. 67/145 (46%) PTLD were EBV-associated. 130/152 patients had monomorphic, 20 polymorphic and 2 early lesion PTLD. The overall response rate (ORR) was 111/126 (88%, CR: 88/126 [70%]). Median duration of remission (DR) was not reached; the 3-year Kaplan-Meier estimate was 82% (compared to 71% in PTLD-1). In the intention-to-treat population (152 patients), the median time to progression (TTP) was not reached either. The 3-year Kaplan-Meier estimate was 78% (69% in PTLD-1). Median OS by intention-to-treat was 6.6 years (95% CI 5.5 - 7.6) with a 3-year estimate of 70% in comparison to 61% in PTLD-1. There was no significant difference in ORR, DR, TTP or OS between EBV-positive and EBV-negative PTLD. On the other hand, response to 4 applications of rituximab was a highly significant predictor of OS, TTP and progression-free survival (PFS) despite treatment stratification (all p<0.001). 37/148 patients (25%) achieved CR with 4 cycles of rituximab and were allocated to rituximab consolidation. In this group, TTP in the intention-to-treat population was significantly longer than in the corresponding group in the PTLD-1 trial (37 patients versus 14 patients, p<0.05). In the 111 patients allocated to R-CHOP consolidation, ORR was 78/92 (85%) with 55/92 (60%) complete remissions (89% and 60%, respectively, in PTLD-1). Median TTP was not reached, the 3-year estimate was 73% (69% in PTLD-1). In patients refractory to rituximab induction, the CR rate was 22/38 (58%) with R-CHOP compared to 3/11 (27%) in PTLD-1 with CHOP (p=0.07); median PFS was 1.4 years versus 0.3 years in PTLD-1, p<0.05. The frequency of grade 3/4 leukopenia and infections was 63% and 34%, respectively. Treatment-related mortality occurred in 7%. Conclusions: This largest trial cohort in PTLD to date demonstrates for the first time that treatment stratification by response to rituximab induction is feasible, safe and effective. Rituximab consolidation in early rituximab responders results in significantly better disease control compared to CHOP consolidation. The addition of rituximab to CHOP chemotherapy improves outcome in patients refractory to rituximab monotherapy. Disclosures Trappe: Mundipharma: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; CSL Behring: Research Funding, Speakers Bureau. Zimmermann:Roche: Honoraria; Celgene: Other: Travel support. Morschhauser:Genentech Inc./Roche: Other: Advisory boards. Mollee:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zaucha:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau. Dührsen:Roche: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Hüttmann:Amgen: Research Funding; Roche: Research Funding. Salles:Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche and Gilead Sciences: Research Funding; Celgene Corporation; Roche: Speakers Bureau. Kliem:Astellas: Honoraria; Fresenius: Honoraria; Genzyme: Honoraria; Novartis: Honoraria; Roche: Honoraria; Raptor: Honoraria. Leblond:Janssen: Consultancy, Honoraria, Speakers Bureau; Mundipharma: Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau. Choquet:Janssen: Consultancy; Roche: Consultancy.

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Outcome of Multiple Myeloma with Chromosome 1q Gain and 1p Deletion after High-Dose Therapy and Autologous Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2018-99-115457 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4609-4609

Author(s):

Ankur Varma ◽

Neeraj Y Saini ◽

Dawen Sui ◽

Denái R. Milton ◽

Omar Hasan ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Chromosome Region ◽

Control Group ◽

High Dose ◽

Control Groups ◽

High Dose Therapy ◽

Advisory Committees ◽

Dose Therapy ◽

Normal Fish

Abstract Background and Aim The gain/amplification CKS1B gene at chromosome region 1q21 (1q+) is one of the most common genetic aberrations in multiple myeloma (MM). CKS1Bamplification and overexpression contribute to increased p27Kip1 degradation, cell cycle upregulation and poor outcomes in MM patients. Amplification of CKS1B is frequently associated with the deletion of CDKN2C gene at chromosome region 1p32 (1p-). Deletion of CDKN2C, a tumor suppressor gene, leads to an increased proliferative rate of plasma cells in MM patients and is also associated with inferior outcomes. There are limited data on the impact of 1q+/1p- on the outcomes after high-dose therapy and autologous stem cell transplantation (auto-HCT). Methods In this retrospective study, we evaluated outcomes of patients with 1q+ and/or 1p- after high-dose therapy and auto-HCT. From 2007 to 2015, 1365 MM patients underwent high-dose therapy and auto-HCT at our institution. We identified 100 patients with 1q+ and/or 1p- by fluorescent in situ hybridization (FISH) from that cohort. The cut off value used for gain/amplification of a 1q21/CKS1B was 7.9%; gain/amplification of two 1q21/CKS1B was 4.4%; and deletion of a 1p32.3/CDKN2C was 6.8%. A control group (N=287) with diploid cytogenetics and normal FISH panel with no high risk abnormalities was selected from the same cohort. From the above two cohorts, using a 1:1 propensity score-matched analysis without replacement, we were able to identify a matched control for 85 patients with 1q+/1p-. Results Baseline characteristics of the 1q+/1p- and control groups are summarized in table 1. Sixty-seven (79%), 4 (5%) and 14 (16%) patients had 1q+, 1p- or both 1q+ and 1p-, respectively. There was no significant difference in induction therapy, preparative regimen, or maintenance therapy between the two groups. The median follow-up time for all patients was 29.2 months (range: 0.29 -84.96). The cumulative incidence of 100-day nonrelapse mortality was 1.1% and 0% for the 1q+/1p- and the control groups, respectively. Forty-two patients (51%) in the 1q+/1p- group achieved a CR compared to 40 patients (49%) in the control group (P=0.6). VGPR rates in the 1q+/1p- and controls groups were 47% and 53% (P=0.5) respectively. The overall response rate for the 1q+/1p-and controls group was 96% and 100%, respectively (P=0.3). Median PFS for the 1q+/1p- and the controls groups were 26.5 months and 38.8 months, respectively. The estimated 3-year PFS for the 1q+/1p- and the control groups were 41% and 56%, respectively (HR 2.2, CI 1.18-4.16, P=0.01) (Figure 1A). The 3-year OS for the 1q+/1p- and the control groups were 79% and 86%, respectively (HR 1.5, CI 0.61-4.05, P=0.34) (Figure 1B). Conclusion 1q+/1p- abnormalities with amplification CKS1B and deletion of CDKN2C genes were seen in approximately 7% of MM patients undergoing auto-HCT between 2007 and 2015. They were associated with a shorter PFS when compared to a propensity matched group of patients with diploid cytogenetics and normal FISH panel. Patients with 1q+/1p- may need more aggressive therapeutic approaches. Disclosures Thomas: Amgen Inc: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Array Pharma: Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Shpall:Affirmed GmbH: Research Funding. Orlowski:Bristol-Myers Squibb: Consultancy; Kite Pharma: Consultancy; Celgene: Consultancy; Amgen: Consultancy, Research Funding; Sanofi-Aventis: Consultancy; Janssen: Consultancy; Spectrum Pharma: Research Funding; BioTheryX: Research Funding; Takeda: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.

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Impact of Donor Search Strategy for Allogeneic Hematopoietic Stem Cell Transplantation from Haploidentical or Matched Unrelated Donor for Patients Older Than 55 Years with Hematological Malignancies: Randomized Prospective Phase III Study

Blood ◽

10.1182/blood-2020-139440 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 35-36

Author(s):

Samia Harbi ◽

jean Marie Boher ◽

Edouard Forcade ◽

Patrice Chevallier ◽

Peffault De Latour Régis ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

Unrelated Donor ◽

Advisory Committees ◽

Intention To Treat ◽

Donor Choice ◽

Intent To Treat ◽

Haplo Group ◽

Treat Analysis

Background Allogeneic stem cell transplantation (Allo-SCT) from a matched related donor (MRD) is rarely performed for older patients because of lack of such a donor. Matched unrelated donor (MUD) is considered as an alternative for this population with limited access due to excessive expected toxicity. Recently, the development of allo-SCT from haploidentical donors (Haplo) with the use of high dose post-transplant cyclophosphamide showed promising results with outspreading diffusion despite HLA disparity. Donor search is early implemented when patients are referred to transplant team. The impact of this strategy on patients with high risk malignancies outcomes is not well known. We propose to address this question through an intention-to-treat trial. We also hypothesized that Haplo-SCT could be a valid alternative to MUD-SCT for older patients with hematological disease whenever allo-SCT is recommended. Study design and methods We performed a prospective, multicenter, open-label, randomized controlled trial (NCT02623309) comparing two strategies of allo-HSCT from UD or Haplo. Patients older than 55 years with hematological malignancies were randomly assigned to a Haplo and a MUD search soon after the absence of MRD was established. The goals of the study were to prospectively evaluate feasibility, safety and efficacy of these approaches in an intent-to-treat analysis and a HSCT-performed analysis. Results From February 2016 to June 2018, 108 patients were enrolled. One hundred and six patients were analyzed. Median age was 65 years (range 55-70). Diseases were myeloid malignancies in 84 patients (79%).DRI was low, intermediate and high in 5(5%), 59(55%) and 42(40%),respectively. Fifty-five patients were assigned to Haplo group and 51 patients to MUD group. Fifteen patients in Haplo group could not proceed to allo-SCT because of progression (n=9), contraindication (n=5), no donor (n=1) and 14 patients in MUD group because of progression (n=8), contraindication (n=4) and loss of indication (n=2). Among 40 patients in Haplo group, 9 patients (22%) actually received allo-SCT from MUD because of donor contraindication (n=6), donor specific antibodies (n=1), no Haplo identified (n=2). Eleven patients out of 37 patients (30%) in MUD group received allo-SCT from Haplo because of no MUD identified (n=7), donor refusal (n=2), donor contraindication (n=1), excessive search delay to identify a MUD (n=1). After cross over, 42 and 35 patients actually underwent per protocol allo-HSCT from a Haplo and a MUD, respectively. Median time from randomization to allo-SCT was 3 months (range 0.7-10). In intention-to-treat analysis from date of randomization, 2-year PFS and OS did not differ between the two groups (Haplo vs MUD arm: PFS: 42 vs 48 %, p=0.463; OS: 44 vs 61%, p=0.126). Non-relapse mortality (NRM) at 2 years was 31% for both groups while the 2-year cumulative incidence of relapse (CIR) was 14% and 18 % (p=0.99) after Haplo and MUD arm, respectively. In per-protocol analysis, with a median follow up of 26 months (range 3-34) after transplant 2-year NRM was 37% and 35% (p=0.893) after Haplo and MUD SCT, respectively. The cumulative incidence of grades 3-4 acute GVHD at 100 days was 21% and 17% (p = 0.402) in the Haplo and MUD SCT, respectively. No difference was observed in 2-year extensive chronic GVHD (Haplo vs MUD: 10% vs 15%, p = 0.534). 2-year CIR was 17% and 18% (p=0. 952) after Haplo and MUD SCT, respectively. No significant difference in 2-year PFS (Haplo vs MUD: 46% vs. 47%, p = 0.948) and OS (Haplo vs MUD: 55% vs. 52%, p = 0.944) was observed. Conclusion In an intent-to-treat analysis from the time of randomization, outcomes do not differ between the 2 groups. However, we observed that almost half of the patients did not receive the randomly attributed treatment 1/ Twenty-nine (27%) patients did not succeed to go to transplant 2/ Twenty (19%) patients were transplanted from another donor source that the one initially randomized to. It notably indicates that defining an early donor choice may be somehow dogmatic and should invite to more flexibility. We were able to demonstrate for older patients with high risk malignancies (IR: 17% Haplo; 18% MUD) a good disease control. Our per protocol analysis prospectively confirm in randomized study that Haplo-HSCT is a valid alternative in older patients. This suggests that HLA matching should not be necessarily considered as the most important factor for donor choice Disclosures Harbi: Sanofi: Honoraria. Chevallier:Incyte Corporation: Honoraria. Malard:JAZZ pharmaceutical: Honoraria; Astellas: Honoraria; Theralos/Mallinckrodt: Honoraria; Keocyt: Honoraria; Sanofi: Honoraria; Biocodex: Honoraria; Janssen: Honoraria. Cluzeau:Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Rubio:Neovii: Research Funding; Novartis: Honoraria; MSD: Honoraria; Gilead: Honoraria; Medac: Consultancy. Mohty:Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Blaise:Jazz Pharmaceuticals: Honoraria.

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Response to Induction Chemotherapy with Novel Agents Does Not Predict Outcomes of Multiple Myeloma Patients Undergoing Autologous Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood.v116.21.1347.1347 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1347-1347

Author(s):

Salman Osman ◽

Abraham Sebastian Kanate ◽

Pamela Bunner ◽

Sonia Leadmon ◽

William Tse ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Cell Transplantation ◽

Induction Chemotherapy ◽

Hematopoietic Cell Transplantation ◽

High Dose ◽

High Dose Therapy ◽

Advisory Committees ◽

Remission Status ◽

Autologous Hematopoietic Cell Transplantation

Abstract Abstract 1347 Introduction: High dose therapy and autologous hematopoietic cell transplantation (AHCT) is a standard therapy option for at least young (<65 years) and otherwise transplant eligible multiple myeloma (MM) patients. While outcomes of AHCT in Hodgkin's and non-Hodgkin lymphoma patients showing evidence of chemo-sensitive disease pre-transplant are clearly superior, the prognostic significance of pre-AHCT remission status in MM is controversial. Failure to achieve at least a partial remission (PR) in response to induction chemotherapy before AHCT has not been shown to negatively impact transplant outcomes, at least in the pre-thalidomide (Thal)/lenalidomide (Len)/bortezomib (Bor) era (Kumar S, BMT 2004 & Singhal S, BMT 2002). Whether this paradigm holds true for novel agent-containing induction therapies is not known. Recently <50% reduction in ‘serum M-protein’ following induction with Thal or Len based induction therapy has retrospectively been shown to predict poor outcome after AHSCT (Gertz M, Blood 2010). However, data evaluating transplant outcomes relative to pre-transplant remission status assessed by strict IMWG criteria, and data in Bor-based regimens is still scant. We report here the impact pre-transplant remission status on outcomes of AHCT after chemotherapy with novel agents. Methods: The study involves 63 consecutive patients who underwent a planned, single AHCT within 1-year of starting induction chemotherapy with regimens containing Thal, Len, or Bor, between 2000–2009. All patients with normal renal function received uniform conditioning with Mel200 (MEL140 if serum creatinine was >2 mg/dl). The disease response pre- and post transplant was determined by using the IMWG criteria. SPSS version 16.0 was used for statistical analysis. Kaplan-Meier method was used to calculate overall survival (OS) and progression free survival (PFS). Outcomes of patients achieving at least a PR (P-group; n=54) before AHCT were compared with one not achieving at least a PR (NO-P-group; n=9). As an exploratory analysis outcomes of patient achieving at least a very good partial response (VGPR) (V-group; n=40) with ones not achieving at least a VGPR (NO-V-group) was also performed (no-V group; n=23). Results: The mean age of the patients at transplant was 53yrs (range 44 –72yrs). 68 % (n=43) of patients were male. At diagnosis 42 patients (66%) had Salmon-Durie stage III disease, while 21 (34%) had stage I/II disease. Median Karnofsky performance status was 90. At the time of AHCT, the median HCT-CI score was 0. 33 % (n=21) of the patients received radiation therapy prior to transplant. At a median follow-up of 36 months, the 3 year OS of patients in P-group and NO-P-group was 58% vs. 60% (p=0.93) respectively. The 3 year PFS in similar order was 22% vs. 31% (p=0.74). The 3 year OS of patients in V-group and NO-V-group (44% vs. 62%) was also not significantly different (p=0.53). Respective figures of 3 year PFS are 22% vs. 24% (p=0.72) respectively. 3yr non relapse mortality was 5% for the whole cohort. Of the 31 patients that entered an AHCT with a PR, 15 improved to a CR post transplant, 2 improved their status to a VGPR whereas 14 remained in a PR. A total of 9 patients entered an AHCT with a stable disease (SD) of which 5 advanced to a CR, 3 a PR and one remained in SD. On the other hand of the 6 patients who entered an AHCT with a VGPR, 2 improved to a CR whereas the rest maintained their status. Finally, all the 17 patients entering an AHCT with a CR maintained their status. Conclusion: Our limited, retrospective data suggest acceptable AHCT outcomes in MM patients who do not achieve at least a PR in response to novel induction chemotherapies pre-transplantation. Failure to achieve a PR following novel induction therapies should not ‘routinely’ preclude consideration for high-dose therapy and AHCT. Disclosures: Abraham: Genentech: Membership on an entity's Board of Directors or advisory committees. Craig:Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hamadani:celgene: Honoraria, Speakers Bureau; otsuka: Research Funding, Speakers Bureau.

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HOVON-65/GMMG-HD4 Randomized Phase III Trial Comparing Bortezomib, Doxorubicin, Dexamethasone (PAD) Vs VAD Followed by High-Dose Melphalan (HDM) and Maintenance with Bortezomib or Thalidomide In Patients with Newly Diagnosed Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v116.21.40.40 ◽

2010 ◽

Vol 116 (21) ◽

pp. 40-40 ◽

Cited By ~ 26

Author(s):

Pieter Sonneveld ◽

Ingo Schmidt-Wolf ◽

Bronno van der Holt ◽

Laila el Jarari ◽

Uta Bertsch ◽

...

Keyword(s):

Board Of Directors ◽

Subgroup Analysis ◽

Research Funding ◽

High Dose ◽

Newly Diagnosed ◽

High Dose Therapy ◽

Advisory Committees ◽

Full Dose ◽

Dose Therapy ◽

High Dose Melphalan

Abstract Abstract 40 Introduction: This independent trial was designed to evaluate the efficacy of bortezomib (B) during induction and maintenance on progression-free survival (PFS) in patients with newly diagnosed symptomatic MM, who were candidates for high-dose therapy. Patients were randomly assigned to 3 cycles of standard VAD (arm A) or PAD (Arm B); PAD was dosed as B 1.3 mg/m2, days 1,4,8,11, doxorubicin 9 mg/m2, days 1–4, dexamethasone 40 mg, days 1–4, 9–12, 17–20). Patients received one (HOVON) or two (GMMG) high-dose melphalan (HDM) 200 mg/m2 with ASCT. Maintenance consisted of thalidomide (T) 50 mg daily (arm A) or B 1.3 mg/m2, 2-weekly (arm B) for 2 years. Primary endpoint was PFS, other endpoints were complete response (CR) (EBMT), immunofixation positive CR (nCR), VGPR pre-and post HDM and survival (OS). The protocol specified analysis was intention-to-treat and censored for patients who received allo-SCT after HDM1 (n=46). We report the analysis of the first 626 randomized patients. The final analysis of all patients will be presented at the meeting. Results: 13 patients were excluded (7 not eligible, 6 not evaluable). The two arms (A:n=305;B:n=308) were well balanced for age, Salmon/Durie stage II/III, renal failure (11%), and serum B2M. Medium follow-up is 40 months. 89% of patients completed induction and HDM1. In GMMG after HDM1 80% of patients received 2nd HDM. Full dose B could be administered in 82% of patients. Polyneuropathy (PNP) WHO gr 3+4 occurred in 7% (arm A) and 16% (arm B). 204 (67%, arm A) and 174 (57%, arm B) patients started maintenance. 64% of patients tolerated full dose B and 27% reduced dose. 47% of patients on B maintenance went off protocol because of toxicity (9%), progression (29%) or other (9%). In contrast 64 % on T maintenance went off protocol because of toxicity (31%), progression (31%) or other (2%). nCR/CR rates were 7/9% (arm A) vs 9/21% (arm B) at 3 months after HDM-1 and 12/26% (arm A) vs 12/38% (arm B) on protocol. ≥VGPR in arm-A vs arm-B were 40% vs 60% after HDM-1 and 61% vs 75% on protocol. PFS was superior in arm B (HR 0.81, p=0.047; adjusted for ISS: HR 0.81, p=0.056). PFS at 36 months was 42% (arm A) vs 46% (arm B). Multivariate Cox regression showed treatment arm (p=0.037), IgA (p=0.007), ISS stage (p=0.007), WHO Performance Status (p<0.0001), del13/13q- (p=0.015) and study group (2nd HDM) (p=0.015) as significant PFS variables. Patients treated with bortezomib had a better OS (HR 0.74, p=0.048), with study arm, WHO, IgA, ISS stage and del13/13q- as significant variables. Subgroup analysis of response at 12 months showed no impact on PFS and an impact of VGPR/nCR/CR on OS only in arm A. Adverse cytogenetic markers (p<0.05) in the combined group were 13q14, 17p-, t(4;14) for PFS and OS. Detailed FISH data are reported separately. The response and survival data of the subgroup analysis are given below. We conclude that B achieves high nCR/CR during induction, that B maintenance is well tolerated and is associated with additional responses. Bortezomib achieves superior PFS and results in an improvement of survival. This trial (EudraCT no. 2004-000944-26) was supported by the Dutch Cancer Foundation, the German Federal Ministry of Education and Research and a grant from Janssen-Cilag. Disclosures: Sonneveld: celgene: Membership on an entity's Board of Directors or advisory committees; janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; millennium: Membership on an entity's Board of Directors or advisory committees. Off Label Use: bortezomib, induction treatment prior to high dose therapy. Schmidt-Wolf:celgene: Membership on an entity's Board of Directors or advisory committees; janssen-Cilag: Research Funding. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Delforge:celgene: Membership on an entity's Board of Directors or advisory committees; janssen-cilag: Membership on an entity's Board of Directors or advisory committees. Weisel:orthobiotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees. Scheid:orthobiotech: Honoraria. Goldschmidt:celgene: Honoraria, Research Funding; amgen: Honoraria, Research Funding; novartis: Honoraria, Research Funding; orthobiotech: Honoraria, Research Funding; roche: Honoraria, Research Funding.

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Safety and Efficacy of a Six Month Full Dose Lenalidomide Consolidation Treatment After First-Line High-Dose Therapy in Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.1982.1982 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1982-1982

Author(s):

Roland Fenk ◽

Julia Baier ◽

Aristoteles Giagounidis ◽

Mathias J. Rummel ◽

Nicolaus Kröger ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Maintenance Treatment ◽

High Dose ◽

First Line ◽

High Dose Therapy ◽

Advisory Committees ◽

Consolidation Treatment ◽

Consolidation Phase ◽

Grade 3

Abstract Abstract 1982 Background: Consolidation with 2 cycles of 25 mg lenalidomide and/or maintenance treatment with a dosage of 10–15 mg lenalidomide after high-dose therapy (HDT) and autologous stem cell transplantation (SCT) improves event-free survival (EFS) in patients with multiple myeloma (MM), as has been shown recently by two randomised clinical trials in the US and France with patients up to the age of 70 and 65, respectively. So far data on longer consolidation treatment and different dosages in the maintenance setting is lacking. Methods: In the randomized, open label phase III LenaMain trial (clinical trials gov: NCT00891384) patients up to the age of 75 years are treated with six cycles of lenalidomide consolidation at a full dosage of 25 mg starting three months after first-line treatment with HDT and autologous SCT. After consolidation patients receive maintenance treatment with either lenalidomide 5 mg or 25 mg, both until disease progression. Here we present data of an interim safety analysis of the consolidation phase of the study. The trial is conducted in 4 transplant centers in Germany und plans to enrol 194 patients. Enrolment started in April 2009, and interim safety analysis was conducted in September 2011 with the first 68 patients enrolled and 50 patients finishing the consolidation phase. Myeloma subtype was IgG, IgA, others in 55, 23, 23% of patients, respectively, who had a median age of 64 years (range 37–73) and an ISS stage of I in 50%, II in 27% and III in 23% of cases at the time of diagnosis. All patients were treated with a median of 3 (range: 1–6) cycles of induction treatment followed by cytotoxic stem cell mobilisation with cyclophosphamide (4g/m2) and HDT and autologous SCT. Thirty-seven patients younger than 66 yrs received conditioning with melphalan 200 mg/m2, which was repeated in 7 patients not achieving at least a very good partial response. Tandem-HDT with melphalan 100 mg/m2was used for 32 patients older than 65 yrs. A median of 113 days (range:56–153) after the last HDT, consolidation treatment with lenalidomide 25 mg daily for 21 days of a 28 days cycle was initiated. All patients received aspirin for prevention of deep-vein thrombosis. Results: Response rates at baseline 3 month after HDT for sCR, CR, vgPR, PR, MRSD, PD were 0%, 14%, 53%, 31%, 2% and 0%, respectively. Three patients developed an early relapse during the six cycles of consolidation therapy. After cycle 6 of consolidation treatment response rates for sCR, CR, vgPR, PR, MRSD, PD were 10%, 16%, 41%, 24%, 2% and 7%, respectively. The remission status was improved in one third of patients. After 6 cycles of consolidation treatment 4 patients had discontinued treatment due to AEs, 2 patients withdrew consent and sudden death of unknown cause occurred in one patient during cycle 1. A lenalidomide dosage of 25 mg for 6 cycles could be applied to 53% of patients. Dose reductions were necessary in 47% of patients. Lenalidomide dosage after cycle 6 was 20 mg, 15 mg, 10 mg and 5 mg in 21%, 6%, 15%, and 2% of patients, respectively. The most common hematologic AE was neutropenia (Grade 1–2 in 42%, Grade 3–4 in 39%). Anemia (Grade 1–2: 88 %, Grade 3–4: 3%) and thrombocytopenia (Grade 1–2: 67 %, Grade 3–4: 7 %) occurred less frequently. No bleeding AE was documented. Infectious complications were seen in 59% of patients including 7% with Grade 3–4. Non-hematologic toxicity was low, and Grade 3–4 AEs included pain (2%), skin symptoms (2%), and neurological and constitutional symptoms (7%). There was no statistically significant difference in toxicity and tolerated dosage between patients younger or older than 65 years. Conclusion: Dose-escalation with lenalidomide 25 mg for 6 cycles as consolidation treatment was very well tolerated and the toxicity was consistent with published data with lower lenalidomide exposure. This was also true for patients aged 66–75 who did not experience an increased toxicity. Lenalidomide 25 mg for six cycles appears to be an effective consolidation treatment, with approximately one third of patients improving their response status. Disclosures: Fenk: OrthoBiotec: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Lenalidomide is not approved for maintenace treament of patients with myeloma. Giagounidis:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kröger:Celgene: Research Funding. Schroeder:Celgene: Travel support Other. Kobbe:OrthoBiotec: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Benda-BEAM High-Dose Therapy Prior to Auto-SCT Is Effective in Resistant/Relapsed DLBCL

Blood ◽

10.1182/blood.v126.23.1999.1999 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1999-1999 ◽

Cited By ~ 1

Author(s):

Alessandro Isidori ◽

Stefano Guidi ◽

Potito Rosario Scalzulli ◽

Attilio Olivieri ◽

Emanuele Angelucci ◽

...

Keyword(s):

Clinical Trials ◽

Board Of Directors ◽

Hodgkin Lymphoma ◽

Median Time ◽

Real World ◽

Median Number ◽

High Dose ◽

High Dose Therapy ◽

Advisory Committees ◽

Non Hodgkin Lymphoma

Abstract Background: The most important drawback of clinical trials of high-dose therapy (HDT) followed by autologous stem cell transplant (ASCT) in lymphomas is the high heterogeneity of histological entities. Therefore, the statistical power is reduced, and data are not conclusive. We previously demonstrated the safety of a new conditioning regimen with bendamustine, etoposide, cytarabine, and melphalan (BeEAM) prior to ASCT in resistant/relapsed lymphoma patients. This combination of drugs was able to induce a high CR rate in a population that did not have an opportunity of being cured with other therapies. However, that study enrolled both Hodgkin and non-Hodgkin lymphoma patients. Aims: We designed a phase II study to evaluate the efficacy of the BeEAM conditioning in resistant/relapsed diffuse large B-cell non-Hodgkin lymphoma (DLBCL) patients. Patients and methods: The study was registered at European Union Drug Regulating Authorities Clinical Trials (EudraCT) N. 2011-001246-14. Until now, 61 patients (median age 54 years, range 19-69) with resistant/relapsed DLBCL were enrolled. The primary end-point of the study is to evaluate the 1-year complete remission rate. Results: Briefly, 46/61 patients had advanced stage disease (III-IV); 20 were primary refractory and 41 had relapsed after a median number of 2 lines of therapy (range: 1-3). Twenty-one patients had 1 or more relevant comorbidities (range: 1- 5). 30 patients were in II or subsequent CR after salvage therapy, whereas 27 were in PR and 4 had stable or progressive disease. A median number of 5.72x106 CD34+/kg cells (range 2.21-10.60) collected from peripheral blood was reinfused to patients. All patients engrafted, with a median time to ANC>0.5x109/l of 10 days. Median times to achieve a platelet count >20x109/l and >50x109/l were 12 and 17 days respectively. Twenty-two out of 61 patients presented a fever of unknown origin (36%), whereas 24 patients (39%) presented a clinically documented infection. All patients received G-CSF after transplant for a median time of 8 days (range: 8-13). One patient died due to an incomplete hematological recovery after transplant, producing an overall transplant related mortality of 2.7%. Fifty-seven patients are evaluable for response: 48/57 (84%) obtained a CR, 3/57 (5%) a PR, whereas 6/57 (11%) did not respond to therapy. After a median follow-up of 10.5 months after transplant (range 3-37), 6/57 (11%) patients were refractory, 12/57 (21%) relapsed and 39/57 (68%) are still alive, in continuous CR. Conclusion: Our clinical trial was designed to closely resemble real-world treatment for these patients. During the study, we transplanted a similar proportion of the patients that would have received ASCT in a real-world scenario. While we cannot make sound comparisons without head-to-head trials, results from previous studies using HDT regimens in DLCBL have not been as encouraging as ours. Accordingly, our data preliminary provide the evidence that the Benda-BEAM regimen is safe and has promising high efficacy in resistant-relapsed aggressive DLBCL patients. Acknowledgments: The study was supported in part by AIL Pesaro Onlus. Mundipharma Italy is grateful acknowledged for providing Bendamustine free of charge. Disclosures Patriarca: Janssen-Cilag, Celgene, Merck Sharp & Dohme: Honoraria. Zinzani:Gilead: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

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Bortezomib Consolidation Following Autologous Transplant Equalizes the Outcome for Older Patients with Less Intensive Pretreatment Compared to Younger Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.516.516 ◽

2016 ◽

Vol 128 (22) ◽

pp. 516-516 ◽

Cited By ~ 3

Author(s):

Christian Straka ◽

Stefan Knop ◽

Martin Vogel ◽

Jurgen Müller ◽

Martin Kropff ◽

...

Keyword(s):

Multiple Myeloma ◽

Treatment Group ◽

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

High Dose ◽

Consolidation Therapy ◽

Newly Diagnosed ◽

Advisory Committees ◽

Younger Patients

Abstract Background High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the established standard-of-care for patients with newly diagnosed multiple myeloma (NDMM) who are young and/or fit. The number of older patients receiving HDT-ASCT is increasing, although they often receive lower-intensity treatment. Novel agent-based consolidation therapy can be used to improve responses following ASCT and prolong progression-free survival (PFS). The proteasome inhibitor bortezomib, given as post-ASCT consolidation therapy, resulted in an improved PFS compared with observation alone (median 33.6 vs 27.8 months, adjusted hazard ratio [HR] 0.70, p=0.0058) in a combined analysis of two phase 3 trials (MMY3012 [DSMM XIb; NCT00416273] and MMY3013 [DSMM X; NCT00416208]; JCO 2015;33:8511). These studies enrolled 222 patients aged ≤60 years and 158 aged >60 years. In this post-hoc analysis we investigated the effect of age and related treatment factors on PFS in more detail. Methods In both trials, 371 patients were randomized 1:1 following ASCT to receive four 35-day cycles of bortezomib consolidation (n=186; bortezomib 1.6 mg/m2 IV administered on days 1, 8, 15, and 22) or observation (n=185; no treatment). The primary endpoint was PFS from the start of induction chemotherapy. Response and progression were assessed at the start of each bortezomib cycle and at the end-of-treatment/observation visit (week 25), as well as during the follow-up period of 30-60 months. Patient characteristics and treatments were compared between trials; PFS following randomization was assessed separately for each study. Univariate, bivariate, and multivariate Cox regressions were conducted to evaluate the impact of treatment group, age (≤60 vs >60 years), single vs tandem ASCT, melphalan conditioning dose (MEL <200 vs 200 mg/m2), bortezomib exposure during induction (exposed vs naïve), post-ASCT response (partial response vs ≥very good partial response [VGPR]), and cytogenetics on PFS. Results A number of relevant factors were different between age groups (median age in ≤60 group 53 years vs 66 years in >60 group), including the HDT regimen received (MEL100 7% vs 10%; MEL140 3% vs 59%; MEL200 88% vs 31%). The rate of double transplantation was similar for the younger and older cohorts (55% vs 59%), likely due to the older patients receiving age-adjusted high-dose melphalan with a lower toxicity, allowing a similar rate of double transplantation as younger patients receiving MEL200. Among the 357 patients included in these analyses, median PFS from start of induction was 33.6 vs 27.8 months with bortezomib consolidation vs observation (log-rank p=0.0243). Median PFS for bortezomib vs observation was 33.6 vs 29.0 months (HR 0.86; p=0.3599) in the younger cohort and 33.4 vs 26.4 months (HR 0.60; p=0.0073) in the older cohort. PFS for older patients who received bortezomib consolidation was very similar to PFS in younger patients (p=0.861); survival curves were superimposable despite the older patients having received less intensive pretreatment. Univariate analysis demonstrated that treatment group (bortezomib vs observation) had an effect on PFS (HR 0.75; exploratory p-value <0.05), as did age (>60 vs ≤60 years; HR 1.30), melphalan dose (200 vs <200 mg/m2; HR 0.74), single vs tandem ASCT (HR 1.35), and cytogenetics (high-risk vs no change; HR 2.62). On bivariate analysis of treatment group plus other covariates, the PFS benefit of bortezomib consolidation vs observation remained consistent (HR 0.71-0.76) across analyses with other covariates. On multivariate Cox regression analysis (Table), bortezomib consolidation (HR 0.72), prior bortezomib during induction (HR 0.69), ≥VGPR post-ASCT (HR 0.76), high-risk cytogenetics (HR 2.58), and single vs tandem ASCT (HR 1.54) were independent prognostic factors for PFS. Conclusions For patients with NDMM, bortezomib consolidation post-ASCT appeared to equalize the outcome for older patients who had received less intensive pretreatment than younger patients prior to randomization. A consistent PFS benefit was demonstrated with bortezomib consolidation vs observation in the context of other prognostic factors. In a multivariate analysis, the use of tandem transplantation retained independent prognostic relevance, whereas MEL200 as first HDT did not. Table. Table. Disclosures Straka: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel/Accommodation/Expenses, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel/Accommodation/Expenses; Chugai: Research Funding. Knop:Takeda: Consultancy. Vogel:Janssen-Cilag GmbH: Employment. Kropff:Celgene: Consultancy, Other: Travel/Accommodation/Expenses, Speakers Bureau; Janssen: Consultancy, Other: Travel/Accommodation/Expenses, Speakers Bureau; Onyx: Consultancy, Speakers Bureau. Metzner:Amgen: Consultancy; Sanofi: Consultancy; Celgene: Other: Travel/Accommodation/Expenses; Takeda: Other: Travel/Accommodation/Expenses. Langer:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Sayer:Riemser Pharma: Consultancy. Bassermann:Celgene: Other: Travel/Accommodation/Expenses. Gramatzki:Janssen: Other: Travel/Accommodation/Expenses, Research Funding. Rösler:Janssen: Consultancy, Other: Travel/Accommodation/Expenses. Engelhardt:MSD: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel/Accommodation/Expenses , Research Funding. Fischer:Novartis: Consultancy, Honoraria. Einsele:Celgene: Consultancy, Honoraria, Other: Travel/Accommodation/Expenses , Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel/Accommodation/Expenses , Research Funding, Speakers Bureau; Novartis: Consultancy, Other: Travel/Accommodation/Expenses , Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

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Prolonged Remission Duration with Interferon Maintenance After Rituximab-Containing Induction in First-Line Advanced Stage Lymphoplasmacytic Lymphoma – a Retrospective Analysis of the German Low-Grade Lymphoma Study Group (GLSG)

Blood ◽

10.1182/blood.v118.21.1639.1639 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1639-1639

Author(s):

Eva Hoster ◽

Michael Unterhalt ◽

Bernd Metzner ◽

Michael Pfreundschuh ◽

Peter Staib ◽

...

Keyword(s):

Retrospective Analysis ◽

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Lymphoplasmacytic Lymphoma ◽

First Line ◽

High Dose Therapy ◽

Advisory Committees ◽

Dose Therapy ◽

The Impact

Abstract Abstract 1639 Introduction: Maintenance using interferon-α (IFN) had previously been shown to be effective in indolent lymphoma (Solal-Celigny et al., NEJM 1993, Hagenbeek et al., JCO 1998). However, data on the impact of IFN in lymphoplasmacytic lymphoma (LPL) and after immuno-chemotherapy are rare. In two GLSG first-line trials which included LPL patients, IFN-maintenance was intended in all patients responding to induction therapy and not assigned to high-dose therapy. We performed a retrospective analysis to compare the clinical outcome in LPL patients who received IFN-maintenance versus no consolidation or maintenance. We adjusted for potential confounders that might have influenced the decision not to start IFN-maintenance. Methods: In the GLSG first-line trials “CHOP vs. MCP” and “CHOP vs. R-CHOP” patients younger than 60 years had been randomized between consolidating high-dose radio-chemotherapy followed by autologous stem cell transplantation (ASCT) and IFN-maintenance. IFN-maintenance was also intended in all responding patients older than 60 years. Patients with LPL achieving a partial or complete remission after MCP, CHOP, or R-CHOP and who did not start ASCT were included in the current analysis. We compared patients in which IFN-maintenance was not started to patients with IFN-maintenance. We investigated patient and treatment characteristics of these groups in order to detect possible reasons why IFN-maintenance was not started. Outcome parameters were remission duration (RD) and overall survival (OS). RD, calculated from the end of induction to relapse or death, was censored at the latest follow-up date in patients without event, but also when a new antilymphoma therapy was initiated without any sign of progression. No censoring was done for any form of dose reduction or stopping of IFN, which was recommended in the trials if inacceptable side effects were observed. RD and OS were analysed by Kaplan-Meier curves and log rank test and we adjusted for potential confounders in multiple Cox-Regression. In order to assess the impact of IFN-maintenance after R-containing induction, we performed a subgroup analysis of R-CHOP treated patients. Results: IFN-maintenance was started in 56 (75%) of 75 responding LPL patients not treated with high-dose therapy. Patients with IFN-maintenance were younger (60 vs. 69 years, p=0.001), but other baseline characteristics (ECOG performance status, haemoglobin, LDH, platelets, β2-microglobulin, IgM) were comparable, as well as the percentage of patients with R-CHOP induction (64% vs. 63%). More patients treated with IFN had achieved a CR (18% vs. 0%). Patients with IFN-maintenance had significantly longer RD (hazard ratio, HR, 0.27, 95% CI 0.12 to 0.59, p=0.001) and OS (HR 0.19, 95% CI, 0.06 to 0.58, p=0.004) which was similarly seen after adjustment for age (RD: 0.32, 95% CI 0.14 to 0.78, p=0.012, OS: 0.30, 95% CI 0.08 to 1.04, p=0.058), or the achievement of a CR. Of 48 patients responding to R-CHOP, IFN-maintenance was started in 36 (75%). RD after 3 years was 87% vs. 41% (p<0.001) and the HR for IFN adjusted for age were 0.19 for RD (95% CI 0.06 to 0.66 p=0.009) and 0.21 for OS (95% CI 0.04 to 1.05, p=0.058). Conclusions: Although this is a non-randomized comparison based on a relatively small patient number, our results suggest that IFN-maintenance is effective in LPL also in the era of immuno-chemotherapy. It seems relevant to keep in mind that interferon-a may be a therapeutic option when other strategies are not possible. It may also be relevant for future investigations in lymphoma therapy. Disclosures: Hoster: Roche: Honoraria. Off Label Use: Interferon-alpha in lymphoplasmacytic lymphoma. Pfreundschuh:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiddemann:Roche: Research Funding.

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