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 ◽  
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.

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

Blood ◽  
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.

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 ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 40-40 ◽  
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.

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

Blood ◽  
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.

scholarly journals The Outcome of Treatment-Free Remission after First-Line Nilotinib or Dasatinib in Chronic Phase Chronic Myeloid Leukemia Patients Is Different

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2552-2552
Author(s):  
Franck E. Nicolini ◽  
Vincent Alcazer ◽  
Stephanie Dulucq ◽  
Sandrine Hayette ◽  
Jean-Michel Cayuela ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Chronic Phase ◽  
Median Dose ◽  
First Line ◽  
Advisory Committees ◽  
French Group ◽  
Treatment Free Remission ◽  
The Impact

Abstract Aims: The absolute number of chronic phase CML patients (pts) reaching the treatment-free remission (TFR) criteria has been substantially increased by the use of second-generation TKI (TKI2), initiated since diagnosis, comparing to Imatinib first-line. However, the relative rate of unsuccessful TFR (i. e. pts loosing their MMR after TKI2 cessation) still remains around 50% at 2 years and beyond, whatever the TKI2 was. The aim of this study is to analyse the rate of successful TFR in pts receiving Nilotinib (Nilo) or Dasatinib (Dasa) first-line obtaining the appropriate criteria. Methods: Observational retrospective study in 3 reference centers of the French group of CML lead between 2010 and 2021. Eligible pts were CP CML pts initiating either Nilo 300 mg BID or Dasa 100 mg daily since diagnosis, until cessation for sustained MR4.5 (i.e. ≥2 years on ≥4 datapoints). Data were retrospectively collected according to the national regulations with pts' information. All pts were assessed and followed according to ELN recommendations 2009, 2013 and 2020 along treatment and to the recommendations from the French group of CML (D. Rea et al., Cancer 2018) for TFR. In this regard, the TKI2 was resumed in case of loss of MMR. All BCR-ABL1 assessments were performed in the 3 reference laboratories, standardised and expressed in % (IS) with ≥32,000 copies of ABL1 as control. All patients were harbouring major BCR-ABL1 transcripts. The primary endpoint was the survival without loss of MMR after TKI2 cessation. The secondary endpoints were the kinetics of MMR loss, and the identification of factors influencing MMR loss. Results: Seventy-two pts were reported (47 Nilo, 25 Dasa) with 57% females with a median age at diagnosis of 48 (36.75-61.25) years. The median follow-up since diagnosis was 9.26 (3.75-13.75) years (8.8 for Nilo and 9.47 for Dasa p=ns) and after TKI2 cessation 3.94 (0.7-8.8) years (3.92 for Nilo and 3.90 for Dasa p=ns). Sokal scores were 42% Low, 41% Intermediate, 17% High in Nilo and 39% L, 25% I and 35% H in Dasa pts (p=ns). ELTS scores were 50% L, 22% I, 9.5% H (18.5% Uk) in Nilo and 46.5% L, 28.5% I and 3.5% H (21.5% Uk) in Dasa pts (p=0.95). Five (9%) pts harboured ACA at diagnosis in the Nilo group and 2 (7%) in the Dasa group (p=1.00). The median time from TKI2 initiation to sustained MR4.5 was 19 (3.12-36) months in the Nilo group and 16 (6.3-39) months in the Dasa group (p=0.644). The duration of sustained MR4.5 until cessation was 3.04 (1.5-9.3) years for Nilo and 2.65 (1.11-7.95) for Dasa (p=0.96). The median dosing of Nilo was 600 (300-800) mg daily and 80 (20-100) mg at TKI2 cessation. None of these patients switched to another TKI during the follow-up. TKI2 cessation occurred after 60.5 (43-74.5) months in the Nilo group and 68 (39-90) months in the Dasa group (p=0.581). Thirty-seven pts out of 47 (79%) were BCR-ABL1 undetectable at Nilo cessation 18/25 (72%) at Dasa cessation (p=0.60). At M3 after discontinuation, 58% of pts remained undetectable after Nilo cessation and 30.4% after Dasa cessation (p=0.05).The median survival of pts without loss of MMR was not reached in the Nilo group, and was 14 (4.73-NR) months in the Dasa group, (p=0.042) as analysed by the KM method (Figure 1.). Two patients died (1 Nilo, 1 Dasa) from competing events (solid tumours) after unsuccessful TFR. Twenty-eight pts (14 Dasa, 14 Nilo) restarted their TKI2 after MMR loss and all regained ≥ MMR after 3 months of Dasa at a median dose of 75 (40-100) mg daily and all except one (who regained MMR at M12) after resumption of Nilo at a median dose of 350 (300-600) mg daily. Univariate analysis identified pts with H+I Sokal (as compared to low) as an unfavourable factor for successful TKI2 cessation [HR=0.35 (0.15-0.83), p=0.017] and type of TKI2 (Nilo as reference vs Dasa) was discriminant [HR=2.1 (1.01-4.35), p=0.047]. Multivariate analysis identified the type of TKI2 as a significant factor impacting on TFR outcome [HR 2.11 (0.97-4.55], p=0.05]. Conclusions: As it is likely that no prospective head-to-head comparison will be performed in this setting, on this limited series of pts, we conclude that the outcome of TFR seems to be different according to the TKI2 used since diagnosis, suggesting the impact of distinct biological variables modified by the type of TKI2 on the long run (such as immunological system, BM micro-environment, others) on TFR outcome. Figure 1 Figure 1. Disclosures Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Etienne: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Rea: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Ritumixab in Combination with Adapted-Dose of Ifosfamide and Etoposide As Salvage Treatment in Elderly Refractory/Relapsed Diffuse Large B-Cell Lymphoma Patients Non-Candidate for High Dose Therapy: A Retrospective Study of Lyon Hospital University

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4215-4215
Author(s):  
Guillaume Aussedat ◽  
Delphine Maucort-Boulch ◽  
Philippe Rey ◽  
Violaine Safar ◽  
Lionel Karlin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
High Dose ◽  
First Line ◽  
Advisory Committees ◽  
Previously Treated ◽  
Grade 3

Abstract Introduction: standard treatment for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is high-dose chemotherapy followed by autologous stem-cell transplantation (ASCT) but this strategy is not appropriate for elderly DLBCL patients (pts) related to a high risk of toxicities. Multiple chemotherapy regimens had been developed for heavily pretreated elderly DLBCL patients such as R-bendamustine, R-gemcitabine-oxaliplatin (R-GEMOX) and pixantrone; the median progression free survival (PFS) of these regimens were 2, 4 and 3.5 months, respectively in prospective phase II studies for patients previously treated with R (Sehn 2017, Mounier 2013, Pettengel 2016). Adapted dose of ifosfamide and etoposide was firstly developed as sequential consolidation regimen after high-dose CHOP (ACVBP regimen) in first line therapy of young DLBCL patients (Tilly 2003). This regimen with a safe toxicity profile was then used in combination with R in Lyon University Hospital in elderly R/R DLBCL ineligible to intensive strategy. Methods: we retrospectively reviewed the efficacy and the safety profile of this regimen performed in two Lyon University Hospitals (Centre Hospitalier Lyon Sud and Leon Berard Cancer Center). Between June 2004 and March 2017, 75 pts with R/R DLBCL (63 de novo DLBCL, 12 transformed DLBCL) received R (375 mg/m2) in combination etoposide (300 mg/m2) and ifosfamide (1500 mg/m2) on day 1 (N=72, 96%) and on days 1-2 (N=3, 4%) at 2 (N=46, 61%) or 3-week (N=29, 39%) intervals. All medical records were reviewed for clinical and biological characteristics, modality of treatment and supportive care, toxicities, responses and outcome. Results: the median age was 79 years (range, 64-92) at the beginning of R-ifosfamide/VP16 treatment with 46% of the patients over 80 years. 13% of pts had a CIRS-G grade 3 or 4 >2 categories and 35% had a cumulative CIRS-G score more than 6. The performance status according to EORTC scale was 2-4 in 37% of the pts and 93% had III-IV Ann Arbor stages. Age-adjusted IPI were 0-1 in 20 pts (27%) and 2-3 in 55 pts (73%). All patients were previously treated in first-line therapy by R in combination with chemotherapy (CHOP, N=56, 75%, low-dose CHOP, N=14, 19%, other, N=5, 6%). The patients received a median number of 1 previous line (range, 1-8) and no patient was previously treated by ASCT. The median time between initial diagnosis and R-ifosfamide/VP16 was 20 months (range 4-187). The median time between the last treatment and R-ifosfamide/VP16 was 5 months (range 0-181). A refractory disease to first-line treatment was showed in 14 pts (19%). 31% of the patients had a refractory disease to the last regimen performed before R-ifosfamide/VP16. Patients received a median of 6 cycles (1-12). At the end of treatment, the overall response rate (ORR), defined by the rate of complete response (CR) and partial response (PR) was 37%, with 18% of CR. Evaluations were assessed for 29% of the pts by TEP scanner. For toxicity, among the 387 cycles, 10 patients developed febrile neutropenia (2.6%); 15 (20%) a grade 3-4 neutropenia; 7 (9%) a grade 3-4 thrombocytopenia; 5 patients needed platelet units and 16 patients received packed red blood cell units. No grade 3-4 non-hematological toxicity was observed and no toxic death occurred. With a median follow up of 31.3 months (range, 5.0-202.8), the median progression-free survival (PFS) was 4.3 months with a 1-year PFS rate of 26.0% (95%CI, 17.7-38.3) (Figure 1A). The median overall survival (OS) was 8.2 months with a 1-year OS rate of 40.8% (95%CI, 30.9-54.0) (Figure 1B). The median duration of response was 4 months (range 1-97). The median PFS was adversely affected by response (refractory versus CR/PR) to the last treatment (3.0 months versus 5.5 months, P=0.001) (Figure 1C). Conclusions: in this retrospective study, R-Ifosfamide/VP16 regimen provided effective results in R/R DLBCL transplant-ineligible pts with 37% of ORR and a median of PFS of 4.3 months with a safe toxicity profile. This regimen could also be considered as a platform for combinations with novel targeted agents in these categories of patients. Disclosures Karlin: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sarkozy:ROCHE: Consultancy. Bachy:Gilead Sciences: Honoraria; Takeda: Research Funding; Sandoz: Consultancy; Amgen: Honoraria; Roche: Research Funding; Celgene: Consultancy; Janssen: Honoraria. Salles:Abbvie: Honoraria; Epizyme: Honoraria; Amgen: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Other: Advisory Board; Acerta: Honoraria; Novartis: Consultancy, Honoraria; Servier: Honoraria; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria; BMS: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Janssen: Honoraria, Other: Advisory Board; Merck: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria. Ghesquieres:Sanofi: Consultancy; Gilead: Consultancy; Celgene: Consultancy.

scholarly journals Systematic Reviews of the Clinical Efficacy and Safety of First-Line Treatments for Patients with Mantle Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5868-5868
Author(s):  
Neerav Monga ◽  
Jamie Garside ◽  
Matthew S. Davids ◽  
Constantine S. Tam ◽  
Katherine Ward ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Eligible Patient ◽  
High Dose ◽  
Efficacy And Safety ◽  
First Line ◽  
Advisory Committees ◽  
Treatment Regimens ◽  
Mantle Cell

Abstract Introduction Mantle cell lymphoma (MCL) is a rare and aggressive form of Non-Hodgkin's lymphoma (NHL) with poor survival outcomes. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is recommended as first-line therapy in younger patients. However the comparative efficacy of such regimens, and of alternative therapy options (for patients unable to tolerate chemotherapy + ASCT), remain unclear. A comprehensive understanding of the current evidence is therefore required. Methods Two systematic reviews (SRs) were developed to identify efficacy and safety data for therapies used in the first-line treatment of MCL. One review identified randomised controlled trials (RCTs) and the other non-randomised studies (NRSs). Searches were carried out in EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Clinical Trials electronic databases. Additionally, conference materials were screened from ASH, EHA, ESMO and ASCO proceedings from the last 2 years. All review methodologies were performed according to Cochrane best practice guidelines Results The RCT SR was run in August 2017 and updated in April 2018. Overall, 2,787 abstracts were screened. The SR included 9 full-text articles and data from 2 conference proceedings, together reporting a total of 7 independent studies. Across the RCTs, the most commonly investigated treatment regimens were rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone (R-CHOP), and bendamustine + rituximab (BR). Frequently reported primary endpoints were response rates and progression-free survival (PFS). Table 1 presents the PFS and overall survival (OS) data reported in the included RCTs. Data from the RCT reporting on intensive induction chemotherapy followed by ASCT are separated from regimens that did not include ASCT. There were notable differences in median PFS rates, between both patients receiving ASCT versus patients not receiving ASCT and also between the two ASCT treatment arms. In pharmacotherapy studies, PFS ranged from 14.4 to 35.4 months, whereas the two arms of the ASCT RCT reported 51.6 and 109.2 months, respectively. Similar trends were observed in OS: the only result for patients undergoing ASCT (117.6 months) was higher than any result reported in patients not receiving transplant (range 40 - 60 months). However, study heterogeneity may affect the appropriateness of directly comparing these results. Frequently reported grade 3-4 adverse events included anemia, infusion-related reactions, nausea, neutropenia and thrombocytopenia (four of seven RCTs reported each event). The NRS SR was run in April 2018. A total of 3,290 abstracts were screened and 75 full papers were assessed. The SR included 25 full-text articles and 6 conference proceedings, together reporting a total of 18 independent single-arm studies. Several of the NRSs investigated treatment regimens that have not been described in RCT studies, including: R-CHOP with alternating or sequential rituximab + cytarabine (maxiCHOP), and cyclophosphamide + vincristine + doxorubicin + dexamethasone alternating with high dose methotrexate or cytarabine + rituximab (hyperCVAD + R). Across the NRSs, the longest median PFS was 8.5 years (102 months), in patients treated with maxiCHOP (who were young/ASCT-eligible patients). This outcome was reported in a patient population who had responded to induction therapy and were treated with consolidative ASCT. Across all studies there was heterogeneity in the eligible patient population, with some studies focusing on unfit patients and others focusing on high-dose-therapy-eligible patient populations. Many studies also reported maintenance or consolidation treatments, which would influence the long-term outcomes of the patients. Conclusions These SRs highlight the paucity of directly comparable evidence on the efficacy and safety of therapies for patients with MCL. Although there are some marked differences in patient outcomes according to therapy regimen, considerable heterogeneity in study design and patient populations make direct comparison difficult. Despite this, these SRs highlight that MCL remains a difficult subtype of NHL to treat, with short survival highlighting the high unmet need. With new and emerging therapies, additional research is essential to understand optimal regimens for first-line MCL. Table 1. Table 1. Disclosures Monga: Janssen Pharmaceutica NV: Employment. Garside:Janssen Pharmaceutica NV: Employment. Davids:Merck: Consultancy; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Research Funding; BMS: Research Funding; Surface Oncology: Research Funding; Celgene: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tam:BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, 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, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ward:Janssen Pharmaceutica NV: Consultancy. Quigley:Janssen Pharmaceutica NV: Consultancy. Parisi:Janssen: Employment. Tapprich:Janssen Pharmaceutica NV: Employment.

Superior CMR-Rates with Tolerability-Adapted Imatinib 800 Mg Vs. 400 Mg Vs. 400 Mg + IFN In CML: The Randomized German CML-Study IV

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 357-357 ◽  
Author(s):  
Rüdiger Hehlmann ◽  
Susanne Jung-Munkwitz ◽  
Michael Lauseker ◽  
Martin C. Müller ◽  
Armin Leitner ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Randomized Study ◽  
Chronic Phase ◽  
High Dose ◽  
Molecular Response ◽  
Advisory Committees ◽  
Good Tolerability ◽  
First Choice ◽  
The Impact

Abstract Abstract 357 Treatment of CML with imatinib of 400 mg can be unsatisfactory. Treatment optimization is warranted. The German CML-Study group has therefore conducted a randomized study comparing imatinib 800 mg vs 400 mg vs 400 mg + IFN. A significantly faster achievement of MMR at 12 months has been observed with imatinib 800 mg in a tolerability adapted manner and MMR by 12 months has been found to translate into better overall survival. Since stable CMR has been associated with durable off-treatment remissions we sought to analyse the impact of tolerability-adapted imatinib 800 mg on CMR and survival. Standardized determinations of molecular response and evaluation of its impact on outcome are goals of CML-Study IV. CMR4 is defined as a BCR-ABL/ABL ratio of <0,01 on the International Scale. From July 2002 – April 30, 2009 1022 newly diagnosed patients with CML in chronic phase were randomized, 1012 were evaluable (338 with imatinib 800 mg, 324 with imatinib 400 mg, 350 with imatinib plus IFN). Median observation time was 40 months. The median average daily imatinib doses were 628 mg in the 800 mg arm and 400 mg in the 400 mg based arms. The actual median daily doses in the 800 mg arm per 3-months periods were: 555 mg, 737 mg, 613 mg, 600 mg, and 600 mg thereafter, reflecting the run–in period with imatinib 400 mg for 6 weeks in the first period and the adaptation to tolerability from the third 3-months period onwards. Median daily imatinib doses in the 400 mg arms were 400 mg throughout. Adaptation of imatinib dose in the 800 mg arm according to tolerability is reflected by similar higher-grade adverse events rates (WHO grades 3 and 4) with all treatments. Significantly higher remission rates were achieved with imatinib 800 mg by 12 months. The cumulative incidences of CCR by 12 months were 63% [95%CI:56.4-67.9] with imatinib 800 mg vs 50% [95%CI:43.0-54.5] with the two 400 mg arms. The cumulative incidences of MMR by 12 months were 54.8% [95%CI:48.7-59.7] with imatinib 800 mg vs 30.8% [95%CI:26.6-36.1] with imatinib 400 mg vs 34.7% [95%CI:29.0-39.2] with imatinib + IFN. The cumulative incidences of CMR4 compared with the MMR incidences over the first 36 months are shown in Table 1. Imatinib 800 mg shows superior CMR4 rates over the entire 36 months period, CMR4 is reached significantly faster with imatinib 800 mg as compared to the 400 mg arms. The CMR4 rates reach 56.8% by 36 months [95%CI:49.4-63.5] as compared to 45.5% with imatinib 400 mg [95%CI:38.7-51.0] and 40.5% with imatinib plus IFN [95%CI:34.6-46.3]. Most patients have stable CMR4 over the entire period. Time after start of treat-ment (months) Cumulative incidences MMR(%) CMR4 (%) IM400 n=306 D IM800 n=328 D IM400 +IFN n=336 IM400 n=306 D IM800 n=328 D IM400 +IFN n=336 6 8.6 9.5 18.1 9.7 8.4 3 0.7 3.7 1.3 2.4 12 30.8 24.0 54.8 20.1 34.7 7.5 12.3 19.8 7.4 12.4 18 50.3 18.1 68.4 14.3 54.1 21.2 12.2 33.4 9.8 23.6 24 63 13.0 76.0 13.2 62.8 30.7 12.3 43 13 30.0 36 79.3 2.3 81.6 10.9 70.7 45.5 11.3 56.8 16.3 40.5 In summary, superior CMR4 rates are achieved with high-dose imatinib adapted to good tolerability, and more patients in the tolerability-adapted 800 mg arm have stable CMR4 qualifying for treatment discontinuation as compared to the 400 mg based arms. With improved application imatinib remains first choice for early CML. Disclosures: Koschmieder: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. German CML-Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; Roche: Research Funding; BMBF: Research Funding; Essex: Research Funding.

scholarly journals Adverse Cytogenetics, with or without Trisomies, in Patients Undergoing High Dose Therapy for Multiple Myeloma and Impact of Post-Transplant Maintenance Therapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3456-3456
Author(s):  
Gregory P Kaufman ◽  
Morie A Gertz ◽  
Angela Dispenzieri ◽  
Martha Q Lacy ◽  
Francis K Buadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Single Agent ◽  
Prognostic Significance ◽  
Common Mechanism ◽  
High Dose ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
The Impact

Abstract Background FISH abnormalities including t(14;16), t(14;20), t(4;14) and the loss of P53 remain a common mechanism for classifying patients (pts) with newly diagnosed multiple myeloma (MM) as adverse risk. In contrast, trisomies in MM are associated with superior outcomes and may ameliorate the negative prognostic significance conferred by adverse FISH abnormalities. High dose therapy (HDT) consisting of high dose melphalan and autologous stem cell transplantation with consideration of maintenance therapy is a common treatment strategy for transplant eligible MM pts. However, there is limited information regarding the impact of various cytogenetic abnormalities, alone or in combination with trisomies, in the context of HDT, and the efficacy of maintenance approaches in the novel agent era. Aim To determine the clinical significance of FISH abnormalities in MM pts undergoing HDT and subsequent consideration of maintenance therapy in recent years. Methods We retrospectively examined a cohort of all pts with MM who underwent first HDT at Mayo Clinic Rochester between 2008 and 2012. Medical records were reviewed under IRB approval in accordance with the principals of the Helsinki declaration. FISH results were obtained from within 6 months of diagnosis (Dx), and if unavailable pts were excluded. Pts were considered for maintenance therapy following response assessment by their treating hematologist, typically around day 100 following HDT, and were categorized based on the intent of that discussion; length of maintenance and dose reductions were not evaluated. PFS and OS were calculated from date of transplant and OS was also estimated from Dx. Timing of HDT was restricted to within one year of MM Dx (early HDT). Results 300 pts had available FISH and underwent early HDT. Median age at dx was 60 (23-75), and median follow up from Dx was 40 months (7.5-90) with 229 (76%) alive at time of analysis. The median time to HDT from Dx was 5.8 months (95% CI 5.4-8.0). At the time of HDT 249 pts (83%) were in a partial response or better. Overall, 73 pts (24%) had adverse risk FISH from dx as described, 154 pts (51%) had at least one trisomy, and 32 pts (10.7%) had a concomitant adverse FISH abnormality and a trisomy. Of all pts, 112 (37%) received maintenance therapy of some sort, most commonly single agent lenalidomide (n=67 pts) or bortezomib (n=36). Of the 73 pts with adverse FISH, 54 (74%) received maintenance therapy following initial HDT compared with 58 of 227 pts (26%) with non-adverse FISH. Among pts with adverse FISH, median PFS and OS was 21 months (95% CI 16-24) and 57 months (95% CI 41-NR) respectively, compared with 24 months (95% CI 21-26) and not met respectively for pts with no adverse FISH (p =0.08 and p=0.04). The OS from Dx was 63 months (95% CI 46-NR) and not met, respectively for pts with adverse FISH and no adverse FISH (p=0.04). Among adverse FISH pts, PFS following initial HDT was improved with any maintenance therapy (23 months (95% CI 18-33) versus 13 months (95% CI 6-22), p=0.0016). OS was not statistically different among pts with adverse FISH whether or not they received maintenance therapy, both from date of HDT as well as from Dx. For pts with non-adverse FISH at Dx similar findings were observed, with an increase in PFS following HDT with any maintenance therapy (30 months (95% CI 23-48) versus 22 months (18-24)), without a difference in OS. Further analysis of the group of pts with adverse FISH status revealed the PFS benefit seen with maintenance therapy was greatest for a subgroup of pts with concomitant trisomies (29 months (95%CI 18-38) versus 14 months (95%CI 8-16) p=0.0003) as compared to pts with adverse FISH without concomitant trisomies (19 months (95%CI 13-35) versus 12 months (95% CI 3-24) p=0.204) (figure 1). However, OS either from HDT or Dx did not differ for pts with adverse FISH with or without concomitant trisomies regardless of maintenance status. Conclusions Our data support an improvement in PFS with maintenance therapy following initial HDT amongst adverse risk FISH MM pts, however no OS benefit was observed with maintenance therapy irrespective of FISH status. Among pts with adverse FISH, maintenance strategies improve PFS for pts with a concomitant trisomy. No PFS benefit was seen with maintenance therapy in pts without concomitant trisomies. Future trials of maintenance therapy post HDT should consider evaluating and reporting on the subgroup of adverse FISH pts with concomitant trisomies. Figure 1 Figure 1. Disclosures Kumar: Janssen: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi-Aventis: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Millennium: The Takeda Oncology Co.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Skyline Diagnostics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals The Impact of Degree of Anticoagulation on Thrombotic and Other Complications in Hospitalized COVID-19 Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1051-1051
Author(s):  
Rena Zheng ◽  
Alexandra Solomon ◽  
Madeline DiLorenzo ◽  
Iniya Rajendran ◽  
Joseph Park ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Advisory Committees ◽  
Icu Admission ◽  
Group A ◽  
Group B ◽  
The Impact ◽  
D Dimer ◽  
Privately Held

Abstract Introduction: In hospitalized patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the frequency of venous thromboembolism (VTE) is increased. Retrospective studies suggested that an elevated D-dimer level is associated with increased mortality and predictive of thrombosis in these patients. In the spring of 2020, our institution developed a risk protocol for stratification of hospitalized COVID-19 patients into high, intermediate, or low risk groups, based upon history of thrombosis and D-dimer level. These patients were treated with full-dose anticoagulation, high- or standard-dose prophylaxis, respectively. The goal of this project was to determine the impact of this protocol on VTE frequency, need for intensive care unit (ICU) admission, organ failure and in-hospital mortality while assessing the frequency of hemorrhagic complications when compared to standard prophylactic anticoagulation. Methods: We performed a retrospective chart review of adults hospitalized between March 1 - June 1, 2020 who tested positive for SARS-CoV-2 by nasopharyngeal polymerase chain reaction (PCR). Patients were excluded if they were initially admitted to the ICU. VTE was defined as either a deep vein thrombosis (DVT) on Duplex ultrasound and/or pulmonary embolism (PE) on computed tomography (CT) angiogram. We collected demographic data, medical histories, laboratory and radiologic data on all subjects. Data were analyzed using the Chi Square test and Fisher's Exact Test to establish significant association with clinical outcomes between 3 anticoagulation regimens. Statistical significance was assessed at the p&lt;0.05 level. Results: Data were analyzed from 910 patients; 496 (54.6%) were male and the mean age was 57.8 ± 16.9 years. 419 (46%) subjects were Black, 151 (16.6%) Caucasian, 133 (14.6%) Latinx. Diabetes mellitus (35.3%) and hypertension (59.8%) were common in our cohort as were tobacco (12.6%) and alcohol (20.4%) use. Only 69 (7.6%) were treated with chronic anticoagulation and 216 (23.7%) were on antiplatelet agents. 123 (13.5%) required an ICU transfer and the overall mortality was 5.3%. Most patients, 809 (88.9%), received standard prophylactic anti-coagulation initially (Group A); 32 (3.5%) received high dose prophylaxis (Group B) and 69 (7.6%) received therapeutic dose anticoagulation (Group C). In the entire cohort, 46 (5.1%) developed VTE; 29 (3.6%) in Group A, 2 (6.3%) in Group B, and 15 (22%) in Group C (p&lt;0.0001). ICU admission was required for 102 (12.6%) in Group A, 7 (21.9%) in Group B, and 14 (20.3%) in Group C (p=0.075). 73 ICU patients (8%) required vasopressors, including 57 (7%) in Group A, 6 (18.8%) in Group B and 10 (14.5%) in Group C (p=0.175). 81 ICU patients (8.9%) required mechanical ventilation, including 66 (8.2%) in Group A, 6 (18.8%) in Group B, and 9 (13%) in Group C (p=0.513). One patient in Group B developed an intracerebral hemorrhage. Gastrointestinal hemorrhage occurred in 11 (1.2%) of the cohort; similar rates were observed across treatment arms. The overall in-hospital mortality was 5.3% in this cohort (4.7% in Group A, 12.5% in Group B, and 8.6% in Group C, p=0.064). Conclusion: The rate of VTE in COVID-19 patients receiving any form of anti-coagulation was low. There was an increased rate of VTE, but not rates of ICU admission, mortality, mechanical ventilation nor vasopressor use in those receiving either high dose prophylaxis or therapeutic anticoagulation, suggesting an increased propensity for thrombosis either related to prior thrombotic events or reflected by increased D-dimer levels. These findings need to be confirmed in prospective studies. Disclosures DiLorenzo: Abbott: Current holder of individual stocks in a privately-held company; Merck & Co: Current holder of individual stocks in a privately-held company; Glaxo Smith Kline: Current holder of individual stocks in a privately-held company. Sloan: Pharmacosmos: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Stemline: Honoraria. Weinberg: Janssen Pharmaceuticals: Other: Serve on data safety monitoring boards; Merck & Co: Current holder of individual stocks in a privately-held company. Klings: CSL Behring: Other: Consultant; Omeros: Other: Consultant; Bluebird Bio: Other: Consultant; Bayer: Research Funding; Novartis: Research Funding; FORM therapeutics: Research Funding.

scholarly journals The e13a2 BCR-ABL1 Transcript Is Associated with Higher Rates of Molecular Recurrence after Treatment-Free Remission Attempts: Retrospective Analysis of the Adelaide Cohort

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1731-1731 ◽  
Author(s):  
Naranie Shanmuganathan ◽  
Susan Branford ◽  
Agnes S. M. Yong ◽  
Devendra K Hiwase ◽  
David T Yeung ◽  
...  
Keyword(s):  
Retrospective Analysis ◽  
Board Of Directors ◽  
Research Funding ◽  
Adelaide Hospital ◽  
Molecular Response ◽  
Royal Adelaide Hospital ◽  
Significant Finding ◽  
Advisory Committees ◽  
Treatment Free Remission ◽  
The Impact

Abstract Background: For patients with chronic-phase chronic myeloid leukemia (CML), treatment-free remission (TFR) is increasingly becoming a goal of therapy. While the safety of TFR has been established [Mahon, Lancet Oncol 2010; Ross, Blood 2013], the ability to predict success following attempted TFR remains limited. Recent publication of Euro-Ski [Saussele, Lancet Oncol 2018], the largest tyrosine kinase inhibitor (TKI) cessation study to date, demonstrated that duration of MR4 (BCR-ABL1 <0.01% IS) prior to attempted TFR was the main factor predicting TFR success. Aim: To identify the predictors of TFR in a single academic centre. Methods: We performed a retrospective analysis of adult CML patients receiving their primary CML management at the Royal Adelaide Hospital between January 2008 and March 2018, reviewing both clinical and molecular data. Criteria for qualifying for a TFR attempt included a minimum of 3 years (yrs) of TKI therapy and 2 yrs of deep molecular response (DMR: BCR-ABL1 <0.0032% IS; MR4.5). History of blast crisis, allogeneic stem cell transplantation and non-quantifiable atypical BCR-ABL1 transcripts precluded TFR qualification. Patients were monitored with monthly BCR-ABL1 qRT-PCRs for at least the first 12 months of the TFR attempt. In the event of molecular recurrence, defined as loss of major molecular response (MMR; BCR-ABL1 ≥ 0.1% IS) on a single test, TKI was recommenced. Our population also included 20 patients enrolled in the Australian CML8 (TWISTER) study where restart criteria was more stringent, requiring TKI restart in the event of BCR-ABL1 becoming detectable on 2 consecutive tests. Results: A total of 298 patients were treated at our institution within the defined time frame and 280 patients qualified for inclusion into our retrospective analysis. TFR eligibility was attained in 114 patients and 96 (84%) attempted TFR. Table 1 details patient characteristics of patients attempting TFR. Of the 82 patients with >12 months of follow-up, 52% (n=43) remain off TKI at 12 months in MMR. Variables were assessed by univariate Cox proportional hazards regresssion analysis for their association with TFR. The most significant finding was that patients attempting TFR with e14a2 BCR-ABL1 transcripts were more likely to remain in TFR at 12 months (65%; n=24/37) in comparison to the e13a2 transcript (34%; n=10/29), p = 0.008. This advantage also translated to patients with both e14a2 and e13a2 transcripts when grouped with the e14a2 cohort and compared with e13a2 alone, p = 0.006. The negative effect of the e13a2 transcript was further confirmed on multivariate analysis (Figure 1a) as patients with either e14a2 or both transcript types were 2.24 times more likely to remain in TFR at 12 months compared with the e13a2 transcript, p=0.032. Patients with sustained MR4.5 >3.4 yrs prior to cessation were more likely to remain in TFR at 12 months (42 vs. 64%, p = 0.014). We postulated that the higher rate of TFR in patients with e14a2 might be due in part to the longer time in MR4.5 prior to cessation. The median duration of MR4.5 prior to stopping in the e14a2 cohort was 4.1 yrs (2.05 - 10.76) compared to 3.01 yrs (2 - 10.41) in the e13a2 group (Table 2). Cumulative incidence curves of all 280 patients in our analysis demonstrated that by 6 yrs of TKI therapy, 70% of patients with e14a2 transcripts achieved MR4.5 whereas only 52% of patients with e13a2 transcripts attained MR4.5; confirming that patients with e14a2 transcripts are more likely to achieve DMR earlier (Figure 1b). Furthermore by 8 yrs, 48% of patients with e14a2 transcripts became eligible for a TFR attempt compared with only 32% of e13a2 transcripts (Figure 1c). While patients with e13a2 transcripts eventually achieve the same frequency of MR4.5 as the e14a2 group, the earlier achievement of MR4.5 in e14a2 patients may have contributed to the difference in TFR success. Conclusion: The factors that we identified as most predictive for TFR success were duration of MR4.5 and the presence of the e14a2 transcript, which has not been described previously. We also observed earlier achievement of MR4.5 in the e14a2 cohort, consistent with other studies [Jain, Blood 2016]. These observations, taken together, raise important questions about the impact of transcript type on disease biology, drug sensitivity, and immunological response which warrant further investigation. Disclosures Shanmuganathan: Novartis: Honoraria, Other: Travel sponsorship; Janssen: Honoraria; Royal Adelaide Hospital Research Fund: Other: Scholarship; Bristol-Myers Squibb: Honoraria, Other: Travel sponsorship. Branford:Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cepheid: Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yong:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Research Funding. Hiwase:Celgene: Research Funding; Novartis: Research Funding. Yeung:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Honoraria; Specialised Therapeutics Australia: Honoraria. Ross:BMS: Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Research Funding. Hughes:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Honoraria.

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