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

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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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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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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Survey of the Side Effects of ITP Therapies

Blood ◽

10.1182/blood.v120.21.3327.3327 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3327-3327 ◽

Cited By ~ 1

Author(s):

Charles W Shaffer ◽

Naznin Haq ◽

James B Bussel

Keyword(s):

Side Effects ◽

Board Of Directors ◽

Side Effect ◽

Research Funding ◽

Control Sample ◽

Control Group ◽

High Dose ◽

Advisory Committees ◽

High Dose Dexamethasone ◽

Equity Ownership

Abstract Abstract 3327 Introduction: Adult immune thrombocytopenia (ITP) is an autoimmune disorder characterized by an isolated low platelet count. Options for initial therapy in children and adults include corticosteroids (CS), intravenous immunoglobulin (IVIG), and anti-D. Second-line treatments include splenectomy, rituximab, and the thrombopoietin receptor agonists (TPO-A) eltrombopag and romiplostim. Treatments are usually effective in raising platelet counts, but there are often associated toxicities. We designed and administered a patient survey to compare side effects reported with different ITP therapies to an off treatment control group. Methods: A literature search identified 56 distinct side effects reported by patients on medical therapy for ITP. A self-report questionnaire was designed that asked patients how frequently (never, occasionally, regularly, almost always, always) they had experienced each side effect during the last 30 days. If a respondent had experienced the side effect, he/she was also asked to indicate the level of distress associated with the symptom on a rating scale. Adult non-pregnant patients with ITP were eligible for the IRB-approved study if they were currently taking one of the following therapies, and had done so for at least 30 days: CS, rituximab plus pulse high dose dexamethasone [Dex-Ritux], eltrombopag, IVIG, romiplostim, or no therapy (control group). Clinical details were obtained from patient records. Side effects in the treatment groups were compared to the control sample using the Wilcoxon rank-sum test (alpha = .05). Results: Ninety-one eligible patients completed the survey. Eleven (12%) were on CS (9 patients on prednisone [median dose 20mg/day] and 2 on pulse high dose dexamethasone), 11 (12%) on Dex-Ritux, 21 (23%) on eltrombopag, 9 (10%) on IVIG, 22 (24%) on romiplostim, and 17 (19%) on no therapy. Sixty-two percent overall and 71% of control patients were female (n=56, n=12). One hundred percent of patients reported experiencing at least one side effect. The most commonly reported side effects were fatigue (n= 78; 86%), stress (n=70; 77%), anxiety (n=56; 62%), joint pain (n=55; 60%), and muscle pain (n=55; 60%). Most side effects reported by patients on treatment did not occur with significantly greater frequency or distress than in the control sample. Side effects that occurred with significantly greater frequency compared to the control sample were found in every treatment group except eltrombopag. Most of these symptoms were mild and not associated with greater distress compared to control patients who experienced the same side effect. The number of side effects occurring with greater frequency was 15 with romiplostim, 5 with Dex-Ritux, 3 with CS, and 2 with IVIG. Side effects that occurred with significantly greater distress compared to the control sample were found in every treatment group. Greater distress was not necessarily associated with greater frequency (see Table). Many unwanted effects, such as fatigue, insomnia, dyspepsia, and skin irritation, that have traditionally been associated with CS treatment did not occur with greater frequency or distress in that group; however, few patients were on long term or high dose CS therapy. Surprisingly, unlike published series, we found that romiplostim patients experienced fatigue with significantly greater frequency and more distress than the control group (see Figure). Conclusion: These results suggest that, while unwanted effects of ITP treatment in adults are common, the great majority are not associated with significant patient distress. Patients who participated in this study were being treated at a clinic where treatment guidelines for adult ITP favored TPO-As over CS. Thus our findings may not reflect general experience. Disclosures: Bussel: Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shinogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Portola: Consultancy.

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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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Impact of t(11;14) on the Outcome of Autologous Transplantation in Multiple Myeloma: A Matched-Pair Analysis

Blood ◽

10.1182/blood-2018-99-116862 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4607-4607

Author(s):

Neeraj Y Saini ◽

Ankur Varma ◽

Junsheng Ma ◽

Denái R. Milton ◽

Romil Patel ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Propensity Score ◽

Board Of Directors ◽

Research Funding ◽

Matched Pair ◽

Control Group ◽

Control Groups ◽

Advisory Committees ◽

Standard Risk

Abstract Abstract: Background: The translocation t(11;14)(q13;q32) is the most common chromosomal translocation in multiple myeloma (MM) with a reported frequency of 15-20%. Most, but not all, reports in the literature have identified this translocation with a relatively favorable outcome. In a smaller cohort, we had previously reported the impact of t(11;14) on the outcomes of MM patients who underwent autologous hematopoietic transplantation (auto-HCT) at our institution1. In this study, we present an updated analysis with a larger cohort of t(11;14) patients, and compared their outcomes to a propensity-matched control group of MM patients with normal diploid cytogenetics and no high-risk abnormalities detected by Fluorescence in Situ Hybridization (FISH). Methods and patients: A total of 1365 MM patients underwent auto-HCT at our institution from 2007 to 2015. We identified 95 patients with t(11;14) by FISH before auto-HCT. Out of these 95 patients, 44 had t(11;14) alone, 26 had co-existent high-risk abnormalities and remaining 25 had standard-risk abnormalities. The control group included 287 MM patients with normal diploid cytogenetics and no abnormalities detected by FISH. From the above two cohorts, using a 1:1 propensity score-matched analysis without replacement, we identified matched controls for 79 patients with t(11;14). Clinical response, relapse, and progression were defined by the International Myeloma Working group criteria. The FISH technique was performed using a LSI IGH/CCND1 XT dual color, dual fusion translocation probe from Abbott Molecular, Inc. The normal cut off for IGH/MYEOV/CCND1 rearrangement using LSI IGH/CCND1 XT probe established at 95 (P<0.05) confidence level in the our Cytogenetics Laboratory is 0.4% for 1R1G2F; 1.1% for 2R2G1F; 3.4% for 3R2G; 7.4% for 2R3G and 0% for 1R3F signal patterns. Results: Table 1 includes the baseline characteristics of the matched doublets. Patients in both groups were well matched for age, ISS stage, serum creatinine, response to induction therapy, induction and preparative regimens, and maintenance therapy. The median follow-up time for the cohort was 48.1 months (range: 0.8-124.6). The overall response rate (CR+VGPR+PR) after auto-HCT was 77/79 (97%) and 78/79 (99%) patients in the t(11;14) and the control group, respectively (P = 1.00). Twenty eight (35%) and 37 (47%) patients achieved a CR in the t(11;14) and the control group, respectively. VGPR rate in the t(11;14) and the control group was 35 (44%) and 31 (39%), respectively. The median PFS for the t(11;14) and the control groups were 33.3 (95%CI: 25.8-not reached) and 39.7 (95%CI: 36.6-not reached) months, respectively (p = 0.24, stratified log-rank test). The median OS has not been reached for both groups (p=0.35). The 4-year PFS rates in the t(11;14) and the control groups were 42% (95%CI: 31%-57%) and 50% (95%CI: 38%-65%), respectively (Fig. A). The 4-year OS rates in the t(11;14) and the control groups were 76% (95%CI: 65%-90%) and 87% (95%CI: 79%-97%), respectively (Fig. B). Conclusions: On a propensity score matching analysis, multiple myeloma patients with translocation t(11;14) had similar response rates, PFS and OS to auto-HCT as standard-risk patients with normal cytogenetics or FISH studies. References: Qazilbash MH et.al. Impact of t(11;14)(q13;q32) on the outcome of autologous hematopoietic cell transplantation in multiple myeloma. Biol Bone Marrow Transplant 2013 Aug;19(8):1227-32. Disclosures Shpall: Affirmed GmbH: Research Funding. Thomas:Celgene: Research Funding; Acerta Pharma: Research Funding; Array Pharma: Research Funding; Amgen Inc: Research Funding; Bristol Myers Squibb Inc.: 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. Orlowski:Sanofi-Aventis: Consultancy; Kite Pharma: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Spectrum Pharma: Research Funding; Takeda: Consultancy; BioTheryX: Research Funding; Amgen: Consultancy, Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.

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Selinexor in Combination with R-GDP for Patients with Relapsed/Refractory B-Cell Lymphoma: Results of the Selinda Phase Ib Lysa Study

Blood ◽

10.1182/blood-2021-145150 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1411-1411

Author(s):

Marie Maerevoet ◽

Olivier Casasnovas ◽

Guillaume Cartron ◽

Franck Morschhauser ◽

Catherine Thieblemont ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Metabolic Response ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

High Dose ◽

Phase 2 ◽

High Dose Therapy ◽

Advisory Committees

Abstract Background: Salvage chemotherapy followed by high-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) is the standard treatment of young patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). A complete remission before ASCT is the most important prognosis factor for a better outcome. Selinexor is a first-in-class, oral selective inhibitor of nuclear export compound, an exportin 1 [XPO1] inhibitor, which, through XPO1 blockade, causes nuclear accumulation and activation of tumor suppressor proteins, reduction in oncoproteins and cancer cell apoptosis. Selinexor has been approved by the US Food and Drug Administration for the treatment of R/R DLBCL, de novo or transformed from follicular lymphoma (FL) pts after ≥2 therapies. The phase Ib SELINDA (EUDRACT 2015-005612-15) study assessed safety and efficacy of selinexor, in combination with R-GDP for pts with R/R B-cell lymphoma. Patients & methods: Eligible pts < 70 years with R/R B-cell lymphoma after first or second treatment failure received every 21 days (d) 3 cycles of rituximab 375 mg/m² on d1, dexamethasone 40 mg on d1 to 4, cisplatin 75 mg/m² d1 and gemcitabine 1 gr/m² on d1 and 8 (R-GDP) in combination with escalating doses of selinexor. The starting dose (dose level 1, DL1) 40 mg was given on days 1, 3, 8, 10 (Cohort A), and from December 2017 on days 1, 8 and 15 (Cohort B). The dose-variation scheme followed a traditional "3+3" design (DL1: 40 mg; DL2: 60 mg). The primary endpoint of SELINDA was the determination of the recommended phase 2 dose of selinexor in combination with R-GDP. Secondary and exploratory endpoints were safety, efficacy, and feasibility of ASCT after selinexor-R-GDP. Results: The R2PD for selinexor in combination with R-GDP was established as 40 mg on days 1, 8, and 15 (Maerevoet, IMCL 2021#176). Between January 2017 and January 2021, 32 pts received selinexor-R-GDP. We focused on the 18 pts who received the R2PD: 15 had DLBCL, 2 FL, 1 marginal zone lymphoma. In this cohort, median age was 61 years (range 44-69); 14 pts (78%) has stage III/IV. Thirteen pts received 1 previous line before inclusion, 5 pts received 2 previous lines. At inclusion, 6 pts had refractory disease and 12 relapsed. Four pts prematurely discontinued treatment: 2 for thrombocytopenia, 1 for COVID, 1 for progression. Major adverse events (AEs) in >10% of pts were reversible neutropenia (50%), thrombocytopenia (39%), and nausea (22%). No AEs leading to death were observed. Seven pts (39%) achieved a complete metabolic response (CMR), 5 pts (28%) partial metabolic response (PMR). Overall response rate (CMR+PMR) assessed at the end of treatment according to Lugano classification was 67% (12 of 18). Nine of the 15 pts (60 %) with DLBCL had metabolic response (CMR:4, PMR:5). Per protocol, peripheral stem cell collection and ASCT were optional, 4 pts of this RP2D cohort proceeded to high dose therapy (BEAM) and ASCT. Conclusion: This study established the safety profile of weekly 40mg of Selinexor in combination with R-GDP for R/R B cell lymphoma with an ORR of 67%. Reversible AEs are expected for platinum-based regimen. An ongoing randomized phase 2 study comparing R-GDP and R-GDP plus selinexor in pts with R/R DLBCL will now establish the safety and efficacy of the combination. Disclosures Casasnovas: Janssen: Consultancy; BMS: Consultancy; Gilead/Kite: Consultancy, Research Funding; TAKEDA: Consultancy, Research Funding; ROCHE: Consultancy, Research Funding; Amgen: Consultancy. Morschhauser: Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Genentech, Inc.: Consultancy; Chugai: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Genmab: Membership on an entity's Board of Directors or advisory committees. Thieblemont: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Feugier: Amgen: Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astrazeneca: Consultancy, Honoraria.

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Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses

Blood ◽

10.1182/blood-2019-124981 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1884-1884 ◽

Cited By ~ 1

Author(s):

Alfred Chung ◽

Gregory P. Kaufman ◽

Surbhi Sidana ◽

David Iberri ◽

Erik Eckhert ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Control Group ◽

Al Amyloidosis ◽

Cell Transplant ◽

Advisory Committees ◽

Free Interval ◽

Significant Difference

Daratumumab (DARA) is a CD38-targeted antibody FDA-approved for the treatment of multiple myeloma (MM) and its efficacy has recently been demonstrated in the treatment of AL amyloidosis. DARA is conventionally given indefinitely until evidence of disease progression or intolerance for the treatment of MM. In AL amyloidosis, the optimal duration of therapy is not known, and patients may be treated indefinitely on maintenance, extrapolating from MM data. However, the plasma cell burden observed in AL amyloidosis is often lower than in MM, and thus certain patients achieving deep responses may have durable responses with time-limited treatment. Outcomes for patients who are observed after DARA discontinuation are not known. We report the outcomes of patients at our institution who received time-limited DARA. A retrospective analysis of AL amyloidosis patients treated at Stanford University from 2016 to 2019 with DARA monotherapy and dexamethasone for at least 2 months was performed, and patients who subsequently had DARA discontinued for reasons other than disease progression or lack of response were selected for the study. Hematologic responses were assessed by consensus guidelines. Duration on and off therapy were explored, along with time-to-next treatment or death (TTNT), defined as the time from DARA initiation to restarting/switching therapy or death. An exploratory analysis comparing TTNT between the study population and a control cohort who achieved hematologic CR and were maintained on DARA was conducted with the Kaplan-Meier method and log-rank testing. 67 patients received at least 2 months of DARA monotherapy and dexamethasone; among these, 15 patients discontinued therapy for reasons other than disease progression and were included. Median age was 66 years old and median lines of prior therapies was 4 (range: 1 - 6). Baseline difference between involved and uninvolved free light chains (dFLC) prior to DARA initiation was 2.6 mg/dL (range: 0 - 16.8 mg/dL). 10 of 15 patients had cardiac involvement with median NT-proBNP of 1982 pg/mL and 9 of 15 patients had renal involvement with median 24-hour proteinuria of 6.2 g and eGFR of 32 mL/min/1.73m2 at DARA initiation. Median duration from starting to stopping DARA was 7.8 months (range: 2 - 21 months). Median duration from achieving best hematologic response to stopping DARA was 3 months (range: 0 - 17 months). Reasons for discontinuation included: patient preference (5), fatigue/body aches (4), infection (2), other active medical comorbidities (3), and lack of perceived further benefit (1). At DARA discontinuation, median dFLC was 0.1 mg/dL (range: 0 - 2.2 mg/dL) and there were 12 hematologic CR, 1 VGPR, 1 PR, and 1 not assessable for response. Outcomes for all 15 patients are shown in Figure 1. The median treatment-free interval was 17.5 months (range: 5 - 34 months); estimated 2-year TTNT-free survival was 83% (95% CI: 61 - 100%). All 14 evaluable patients eventually achieved CR. 3 patients restarted DARA for rising dFLC, and all 3 patients demonstrated response to retreatment (2 achieving CR and 1 near PR with ongoing follow-up). There were 2 deaths. One patient with severe baseline cardiac amyloidosis developed sudden rise in dFLC after treatment-free interval of 21 months; although he rapidly achieved hematologic CR on retreatment, he died of heart failure within 2 months of restarting DARA. The other patient developed therapy-related AML while off therapy and underwent allogenic stem cell transplant but died of leukemia (censored for AL amyloidosis outcomes at transplant). There was no significant difference in the TTNT between the study group and a control group of 16 patients who achieved CR and were on continuous maintenance (Figure 2; p=0.807). AL amyloidosis patients achieving deep responses with DARA can have favorable outcomes after treatment discontinuation, including a long treatment-free interval. Although our sample size is small, the outcomes of these patients appeared comparable to those achieving CR on continuous DARA maintenance, and patients were able to regain responses when retreatment was necessary. These results suggest that DARA may be safely discontinued in patents achieving deep hematologic responses, which has significant implications for quality of life and financial burden of treatment. Future studies evaluating time-limited versus continuous DARA maintenance after achievement of deep responses are warranted. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Daratumumab for treatment of AL amyloidosis

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Therapy-Related Myeloid Neoplasm Has a Distinct Pro-Inflammatory Bone Marrow Microenvironment and Delayed DNA Damage Repair

Blood ◽

10.1182/blood-2020-137277 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 37-38

Author(s):

Monika M Kutyna ◽

Li Yan A Wee ◽

Sharon Paton ◽

Dimitrios Cakouros ◽

Agnieszka Arthur ◽

...

Keyword(s):

Dna Damage ◽

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Cytotoxic Therapy ◽

Advisory Committees ◽

Myeloid Neoplasm ◽

Myeloid Neoplasms ◽

Damage Repair

Introduction: Therapy-related myeloid neoplasms (t-MN) are associated with extremely poor clinical outcomes in otherwise long-term cancer survivors. t-MN accounts for ~20% of cases of myeloid neoplasms and is expected to rise due to the increased use of chemotherapy/radiotherapy (CT/RT) and improved cancer survivorship. Historically, t-MN was considered a direct consequence of DNA damage induced in normal hematopoietic stem cells (HSC) by DNA damaging cytotoxics. However, these studies have largely ignored the bone marrow (BM) microenvironment and the effects of age and concurrent/previous cancers. Aim: We performed an exhaustive functional study of mesenchymal stromal cells (MSC) obtained from a comparatively large cohort of t-MN patients and carefully selected control populations to evaluate the long-term damage induced by cytotoxic therapy to BM microenvironment and its impact on malignant and normal haematopoiesis. Methods: Four different cohorts were used: (1) t-MN, in which myeloid malignancy occurred after CT/RT for a previous cancer (n=18); (2) patients with multiple cancer and in which a myeloid neoplasm developed following an independent cancer which was not treated with CT/RT (MC-MN; n=10); (3) primary MN (p-MN; n=7) untreated and without any prior cancer or CT/RT; (4) age-matched controls (HC; n=17). Morphology, proliferation, cellular senescence, differentiation potential and γH2AX DNA damage response was performed. Stem/progenitor supportive capacity was assessed by co-culturing haematopoietic stem cells on MSC feeder-layer in long-term culture initiating assay (LTC-IC). Cytokine measurements were performed using 38-plex magnetic bead panel (Millipore) and RNA sequencing libraries were prepared with Illumina TruSeq Total RNA protocol for 150bp paired-end sequencing on a NextSeq500 instrument. Functional enrichment analysis was performed using EnrichR software. Results: MSC cultured from t-MN patients were significantly different from HC, p-MN and MC-MN MSC according to multiple parameters. They exhibited aberrant morphology consisting of large, rounded and less adhesive cells compared to typical spindle-shaped morphology observed with controls. MSC from myeloid neoplasm also showed impaired proliferation, senescence, osteo- and adipogenic differentiation with t-MN MSC showing the greatest differences. DNA repair was dramatically impaired compared to p-MN and HC (Fig.1A). Importantly, these aberrant t-MN MSC were not able to support normal or autologous in vitro long-term haematopoiesis (Fig.1B). The biological characteristic and poor haematopoietic supportive capacity of MSC could be "cell-intrinsic" or driven by an altered paracrine inflammatory microenvironment. Interestingly, several inflammatory cytokines were higher in t-MN compared with marrow interstitial fluid obtained from p-MN patients (Fig.1Ci) and many of these including Fractalkine, IFNα2, IL-7 and G-CSF were also significantly higher in t-MN MSC conditional media (Fig.1Cii). Together, this data suggest that t-MN microenvironment is distinct from p-MN with paracrine production of pro-inflammatory milieu that may contribute to poor HSC supportive capacity. Preliminary whole transcriptome analysis revealed differential gene expression between t-MN and HC (Fig.1Di) and p-MN MSC. Importantly, the deregulated genes play critical role in cell cycle, DNA damage repair, and cellular senescence pathways explaining phenotypical characteristic of t-MN MSC (Fig.1Dii). Moreover CXCL12 expression, a key regulator of haematopoiesis, was significantly lower in t-MN compared to HC (p=0.002) and p-MN MSC (p=0.009), thus explaining poor HSC supportive capacity. The key difference between the p-MN, MC-MN and t-MN is prior exposure to CT/RT. To study this we obtained MSC from two t-MN patients for whom we had samples at the time of their primary cancer, post high-dose chemotherapy and at the time of t-MN. MSC displayed aberrant proliferation and differentiation capacity after high-dose cytotoxic therapy (2 to 4 years prior to developing t-MN) and remained aberrant at t-MN diagnosis (Fig.1E). Conclusions: BM-MSC from t-MN patients are significantly abnormal compared with age-matched controls and typical myeloid neoplasm. Importantly, prior CT/RT leads to long-term irreversible damage to the BM microenvironment which potentially contributes to t-MN pathogenesis. Disclosures Hughes: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiwase:Novartis Australia: Research Funding.

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Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽

10.1182/blood-2019-123637 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1589-1589

Author(s):

Fabian Frontzek ◽

Marita Ziepert ◽

Maike Nickelsen ◽

Bettina Altmann ◽

Bertram Glass ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

High Dose ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

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Reduced Intensity Conditioned Sibling Transplantation Versus No Transplant in Intermediate or High Risk Acute Myeloid Leukemia: A Prospective Multi-Center Study in Patients 50-70 Years in First Complete Remission and with at Least One Potential Sibling Donor (ClinTrialGov 00342316)

Blood ◽

10.1182/blood-2018-99-110260 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 205-205

Author(s):

Mats Brune ◽

Thomas L. Kiss ◽

Elisabeth Wallhult ◽

Harald Anderson ◽

Robert Delage ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Study Groups ◽

Hla Typing ◽

Control Groups ◽

Advisory Committees ◽

Sibling Donor ◽

Secondary Endpoints ◽

And Control ◽

Reduced Intensity

Abstract Background and study design. Reduced intensity conditioning transplantation (RICT) is a commonly applied treatment option for AML patients >50 years of age. Prospective, controlled studies comparing RICT with standard chemotherapy are warranted. In this study, we aimed to prevent selection biases. Thus, patients were included prior to HLA typing of potential sibling donors, and statistical analyses were based on an intention-to-transplant, donor versus no-donor approach. Hence, the analyses also include events occurring during the donor search period and also the transplantation procedures along with post-transplant events. Patients and procedures. Between 2003 and 2016, 163 patients with AML in CR1 were included in Canada (n=69), Sweden (n=63), and Germany/Finland/Norway/New Zealand (n=31). Eighteen patients were excluded due to enrolment after the start of donor typing (n=14), lack of data (n=1), low-risk AML (n=2) or withdrawn consent (n=1). Thus, results from 145 patients with high (n=48) or intermediate (n=97) risk disease were available for analysis. Included patients were a median of 63 (50-70) years old, deemed fit for RICT and had at least one willing and healthy but not yet HLA typed sibling. The ensuing HLA typings thus yielded one RICT group including patients with ≥1 confirmed matched sibling donor (MSD), and one control group with no MSD. Date of inclusion was defined as date of HLA typing of the first potential MSD. The protocol-specified conditioning regimen for RICT was fludarabine (150-180 mg/m2) and busulfan (8 mg/kg orally or 6.4 mg/kg i.v., used in 95% of patients). Immunosuppression was ciclosporin alone (9%), with methotrexate (53%) or with MMF (35%). Peripheral blood stem cells were used in 95% of transplantations. Control patients received consolidation chemotherapy as per local routines. Statistics. Baseline factors were compared between study groups using Fisher´s exact test and rank sum tests. The primary endpoint was overall survival (OS) with secondary endpoints of relapse-free survival (RFS), relapse incidence (RI) and non-relapse mortality (NRM). Kaplan-Meier curves were used to estimate OS and RFS and cumulative incidence functions were used to estimate NRM and RI considering competing risks. The logrank test was employed for group comparisons of event rates with time censored at 5 yrs post inclusion. Results. The median follow-up time of surviving patients was 7.9 (0.24-14) yrs. Age, AML risk group and time from CR to inclusion did not differ between the study groups. Time lag from diagnosis to study inclusion was 65 (32-256) days (Controls) and 64 (29-319) days (RICT), P=0.74, Mann-Whitney test. Time from CR1 to inclusion was 22 (0-218) days (Controls) and 19 (0-131) (RICT). Excluding conditioning, patients in the RICT group received fewer chemotherapy cycles than controls. The time from start of last chemotherapy to transplant was median 63 (36-212) days. The incidence of acute (grade 2-4) and chronic extensive GvHD in transplanted patients was 25% and 39%, respectively. The non-relapse mortality at 3 years post inclusion (Table) was 12% (RICT group) and 4% (Controls). Causes of death was primarily AML, accounting for 73% and 88% of all deaths in the RICT and control groups, respectively. Twenty pts with an identified donor did not reach RICT due to relapse (n=12), co-morbidities (n=5), death (n=2), other (n=1). Total mortality at time of analysis was slightly lower in the RICT group (66% vs 75%). Overall survival (primary endpoint) at 3 years was 45% (CI 33-56) and 48% (36-60), in RICT and control groups, respectively. At 10 years after inclusion, OS in study groups were similar; RICT 27% (CI 15-41), Control 25% (CI 15-36). There were no significant differences between study groups with respect to primary or secondary endpoints (OS: P=0.27, RFS:P=0.98, RI: P=0.50, NRM: P=0.10, logrank tests. Figure). Conclusions. Applying an intention-to-treat analysis we did not demonstrate clinical benefit of sibling donor search and stem cell transplantation after a reduced intensity busulfan/fludarabine based regimen in AML patients ≥50 years in CR1. Early relapse was the main reason for preventing transplants in patients with an identified donor. Support from study groups: Canadian BMT Group, Australasian Leukaemia and Lymphoma Group, Norwegian/Swedish BMT Group, Swedish AML group Disclosures Kiss: Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wallhult:Jazz Pharmaceuticals: Speakers Bureau; Amgen: Speakers Bureau; Daichii-Sankyo: Speakers Bureau. Finke:Riemser: Consultancy, Honoraria, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding. Sabloff:Celgene: Membership on an entity's Board of Directors or advisory committees.

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