Validating a Machine Learning Grading System for Acute Gvhd. a Study on Behalf of the EBMT Transplant Complications Working Party

Abstract Despite significantly improved preventive measures, acute graft-versus-host disease (aGVHD) remains as one of the most frequent complications after allogeneic hematopoietic stem cell transplantation (HCT). Its clinical grading is determined by the evaluation of its primarily affected organs, namely skin, liver and the gastro-intestinal tract. A number of existing grading systems, of which the 'Keystone Consensus' (Przepiorka D et al. BMT 1994) and MAGIC grading systems (Harris AC et al. BBMT 2016) are the most customary, have been proposed over the years to evaluate aGVHD severity based on the extent of aGVHD organ involvement. However, limitations remain regarding its association with clinical outcome. In the current era, particularly consensus grades I and II aGVHD are hardly distinguishable with respect to overall survival (OS). Given the discrepancies in aGVHD grading, we hypothesized that a data-driven approach would support the understanding and classification of aGVHD with respect to organ involvement, clinical outcome and risk cohorts. Here, we validated on a large, multi-national EBMT cohort a novel data-driven grading system for aGVHD that was previously developed by unsupervised learning applying principal component analysis on aGVHD organ stages (Turki AT et al. EHA 2020). The resulting Machine Learning (ML) aGVHD grading had 12 stages that were divided into 4 balanced ML-aGVHD grades to assess the severity of aGVHD, different from conventional grading. Our study included 19,617 adult patients with first HCT for hematologic malignancies between 2009 and 2018 and evidence of aGVHD. All donors except cord blood HCT were included. Detailed aGVHD organ involvement were required for the calculation of the ML-aGVHD score. Exclusion criteria were missing information on aGVHD organ involvement or follow up and very late onset aGVHD (> d+180). The baseline characteristics of this cohort reflect current HCT practice, with acute myeloid leukemia (55.3%) as predominant disease and a majority of unrelated donor HCT recipients (63.7%). Myeloablative conditioning was used in 46.7% of patients. In addition to baseline calcineurin inhibitors, 60.6% of patients received in-vivo T cell depletion with ATG or Campath. The ML-aGVHD grading distinguished 12 ML stages with significantly different clinical outcomes for OS (Figure 1a), non-relapse mortality (NRM) and relapse. The 4 ML-aGVHD grades (ML-I, stages 1-3; ML-II stages 4-6; ML-III, stages 7-9; ML-IV stages 10-12) revealed highly significant and clinically relevant differences for OS and NRM (p<0.0001). Utilizing the ML-aGVHD grading, 71.3% of patients were categorized ML-I, 18.3% ML-II, 7.98% ML-III and 2.38% ML-IV. The 6-month and 12-month OS probability from the diagnosis of aGVHD were 85.4% and 75.3% for ML-I, 72,7% and 61.5% for ML-II, 41.5% and 31% for ML-III and 14.8% and 9.1% for ML-IV, respectively (Figure 1b). We also analyzed the impact of covariates from the EBMT database on clinical outcome by Cox regression. All significant variables from univariate Cox regression were integrated into multivariate models for OS and NRM. Confounding factors for multivariate analysis for OS included patient age, gender, performance status, remission at HCT, HCT period, donor constellation and CMV status. The analysis confirmed the significant differences for OS as revealed by the ML-aGVHD grading system (p<0.0001), independent of these confounders. Also for NRM, the multivariate analysis confirmed the distinction as by the ML-aGVHD grading (p<0.0001). Finally, we compared the performance of the ML-aGVHD algorithm to the keystone consensus grading. Here 35.2% of patients were diagnosed with grade I aGVHD, 39.4% with grade II, 17.3 with grade III and 8.1% with grade IV aGVHD. In short, the ML-aGVHD grading system was successfully validated on an independent multi-national EBMT cohort. It integrated multi-organ aGVHD involvement different from conventional aGVHD grading by accounting for each affected organ. Our findings support the additional use of the ML-aGVHD grading system for the assessment of aGVHD severity in patients after HCT, in order to identify patients at risk for high NRM and reduced OS. Figure 1 Figure 1. Disclosures Turki: CSL Behring: Consultancy; Jazz Pharma: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau. Penack: Omeros: Consultancy; Shionogi: Consultancy; Priothera: Consultancy; Incyte: Research Funding; Takeda: Research Funding; Therakos: Honoraria; Pfizer: Honoraria; Neovii: Honoraria; Novartis: Honoraria; MSD: Honoraria; Jazz: Honoraria; Gilead: Honoraria; Astellas: Honoraria. Schoemans: Janssen: Membership on an entity's Board of Directors or advisory committees; CIBMTR: Consultancy, Other: travel grants; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: personal fees , Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants and personal fees; Gilead: Other: travel grants; BHS: Membership on an entity's Board of Directors or advisory committees, Other: travel grants and personal fees , Research Funding; Jazz Pharmaceuticals: Other: personal fees; Takeda: Other: personal fees. Socie: Alexion: Research Funding. Reinhardt: Abbvie: Consultancy; AstraZeneca: Consultancy; Vertex: Consultancy; Merck: Consultancy; Gilead: Research Funding; CDL Therapeutics: Current holder of individual stocks in a privately-held company. Blaise: Jazz Pharmaceuticals: Honoraria. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Mielke: DNA Prime SA: Speakers Bureau; Gilead/KITE: Other: Travel support, Expert panel ; Miltenyi: Other: Data safety monitoring board; Novartis: Speakers Bureau; Celgene/BMS: Speakers Bureau; Immunicum: Other: Data safety monitoring board. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Forcade: MSD: Other: Travel Support; Jazz: Other: Travel Support, Speakers Bureau; Gilead: Other: Travel Support, Speakers Bureau; Novartis: Consultancy, Other: Travel Support, Speakers Bureau. Basak: Saventic Health: Current holder of individual stocks in a privately-held company. Perić: therakos: Honoraria; servier: Honoraria; MSD: Honoraria; Astellas: Honoraria; NOVARTIS: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria.

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Characteristics and Outcomes of Newly Diagnosed Multiple Myeloma Patients with and without Extramedullary Disease after Autologous Transplant and Maintenance Therapy: A Study from the Cmwp-EBMT

Blood ◽

10.1182/blood-2021-152391 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 485-485

Author(s):

Nico Gagelmann ◽

Dirk-Jan Eikema ◽

Linda Koster ◽

Tanja Netelenbos ◽

Andrew McDonald ◽

...

Keyword(s):

Clinical Trials ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Maintenance Treatment ◽

Data Safety Monitoring Board ◽

Hazard Ratio ◽

Organ Involvement ◽

Advisory Committees ◽

Autologous Transplant

Abstract Patient selection becomes crucial for newly diagnosed multiple myeloma (NDMM), to identify those who may benefit the most from specific treatments. This is particularly important for patients for whom evidence of current treatment options remains very limited. One such subgroup is MM with extramedullary disease (EMD), especially those with organ manifestation. Maintenance therapy after autologous transplantation improves outcome for eligible NDMM patients, but randomized trials only included a small proportion of EMD patients, and to date, no adequate data exist on maintenance in this cohort. Here, we aimed to evaluate the characteristics and outcomes of NDMM with or without EMD after autologous transplant and maintenance therapy. Cohorts were identified from NDMM patients undergoing first autologous transplant between 2008 and 2018. Involvement had to be documented as absent or present. Maintenance treatment was defined as single-agent treatment within 6 months after first autologous transplant without relapse. Outcomes were calculated from the start of maintenance therapy. Primary end points were progression-free survival (PFS) and overall survival (OS). Secondary end point was cumulative incidence of relapse. In total, 830 NDMM patients with or without EMD were eligible, receiving either thalidomide (n=287), lenalidomide (n=446), bortezomib (n=75), or daratumumab (n=22; results for these patients will be presented at the meeting). 107 had EMD (n=83 paraskeletal and n=24 organ involvement). Maintenance drug distribution did not differ between NDMM with or without EMD (P=0.69) and is shown in Table 1. Fewer patients with organ involvement had IgA MM (23% vs 21% for no EMD and paraskeletal involvement, respectively). Patients with organ involvement more frequently were ISS stage III (50% vs 24% for no EMD and 15% for paraskeletal involvement). The median follow-up of the entire cohort was 44 months (95% CI, 40-48 months). According to involvement, 3-year PFS was 52% (48-57%) for patients without EMD, 56% (44-69%) for paraskeletal involvement, and 45% (22-68%) for organ involvement (P=0.15). Of note, early outcome after maintenance start appeared to be significantly worse for organ involvement, with 1-year PFS of 58% vs 81% for paraskeletal involvement and 82% for no EMD. 3-year OS was 81% (77-84%) for no EMD, 88% (80-96%) for paraskeletal involvement, and 68% (47-89%) for organ involvement (p=0.06). Survival curves are depicted in Figure 1. Regarding relapse, organ involvement showed worse early 1-year cumulative incidence, with 42% vs 19% for paraskeletal involvement and 16% for no EMD. In terms of maintenance therapy in patients without EMD, 3-year PFS was 45% (38-52%) for thalidomide, 59% (52-65%) for lenalidomide, 45% (31-59%) for bortezomib (P=0.005). 3-year OS was 79% (73-85%), 83% (78-88%), and 74% (61-87%; P=0.30). Relapse incidence was also significantly different showing lower relapse rates for lenalidomide (P=0.002). In terms of maintenance therapy in patients with EMD, 3-year PFS was 52% (36-67%) for thalidomide, 43% (27-60%) for lenalidomide, 65% (32-97%) for bortezomib (P=0.90). Overall survival was 81% (69-93%) for thalidomide, 86% (76-97%) for lenalidomide, and 89% (68-100%) for bortezomib (P=0.70). In multivariable analysis on PFS (including ISS, performance score, age, remission status) adjusting for early events at 1 year, organ involvement was significantly associated with worse early outcome (hazard ratio, 3.35; P=0.002) and showed no significant difference vs patients with no EMD after 1 year of follow-up. Paraskeletal involvement was not associated with different PFS. Lenalidomide was associated with significantly reduced risk for death or relapse/progression (hazard ratio, 0.69; P=0.003) vs thalidomide, and no difference was seen for bortezomib vs thalidomide. For OS, organ involvement appeared to be associated with worse outcome (hazard ratio 1.71; P=0.17), while no difference was seen for paraskeletal and no EMD. Lenalidomide (hazard ratio 0.72; P=0.05) and bortezomib (hazard ratio, 0.56; P=0.06) appeared to be associated with better OS. In conclusion, organ involvement was associated with worse early PFS, despite maintenance treatment. Different maintenance treatment did not seem to affect outcome in EMD. For patients without EMD, lenalidomide showed significantly higher PFS compared with thalidomide. Figure 1 Figure 1. Disclosures McDonald: BioCryst Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kobbe: Celgene: Research Funding. Anagnostopoulos: Abbvie: Other: clinical trials; Sanofi: Other: clinical trials ; Ocopeptides: Other: clinical trials ; GSK: Other: clinical trials; Incyte: Other: clinical trials ; Takeda: Other: clinical trials ; Amgen: Other: clinical trials ; Janssen: Other: clinical trials; novartis: Other: clinical trials; Celgene: Other: clinical trials; Roche: Other: clinical trials; Astellas: Other: clinical trials . Deconinck: Stemline Therapetutics: Membership on an entity's Board of Directors or advisory committees; Imunogen: Membership on an entity's Board of Directors or advisory committees; Chugai: Research Funding; Novartis: Research Funding; Pfizer: Other: Travel Grants, Research Funding; Abbevie: Research Funding. Delforge: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Thurner: Takeda: Honoraria; Abbvie: Other: Travel support; Janssen: Other: Travel support; EUSA-Pharma: Honoraria, Other: Travel Support; Astra-Zeneca: Honoraria; Merck: Honoraria. Mielke: Immunicum: Other: Data safety monitoring board; DNA Prime SA: Speakers Bureau; Gilead/KITE: Other: Travel support, Expert panel ; Miltenyi: Other: Data safety monitoring board; Novartis: Speakers Bureau; Celgene/BMS: Speakers Bureau. Beksac: Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi: Consultancy, Speakers Bureau. Schönland: Pfizer: Honoraria; Takeda: Honoraria, Other: Travel grants; Janssen: Honoraria, Other: Travel grants, Research Funding; Prothena: Honoraria, Other: Travel grants; Sanofi: Research Funding. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria.

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Grading of Neurotoxicity in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (r/r DLBCL) Receiving Tisagenlecleucel Treatment in the JULIET Study

Blood ◽

10.1182/blood-2018-99-118595 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4183-4183 ◽

Cited By ~ 2

Author(s):

Richard T. Maziarz ◽

Stephen J. Schuster ◽

Vadim V. Romanov ◽

Elisha S. Rusch ◽

James Signorovitch ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Temporal Association ◽

Grading System ◽

Advisory Committees ◽

T Cell Therapy ◽

Grading Systems ◽

Car T ◽

Grade 3

Abstract Introduction: CAR-T cell therapy has demonstrated prompt and durable clinical responses in patients with r/r DLBCL, but is associated with unique toxicities such as cytokine-release syndrome (CRS) and neurotoxicity (NT). NT is the second most common unique toxicity frequently attributed to CAR-T therapy and is present in boxed warnings for all approved CD19 targeted therapies. Similar to other organ toxicities, NT is graded using the Common Terminology Criteria for Adverse Events (CTCAE). However, the CTCAE grading system does not adequately characterize the severity, timing and spectrum of CAR-T related NT. New grading tools are needed for this syndrome-specific AE. The CARTOX working group introduced a novel system for CAR-T Related Encephalopathy Syndrome (CRES), i.e. the CRES grading (Neelapu, Nat Rev Clin Oncol, 2017). To better understand CAR-T related NT and move towards harmonized toxicity reporting, this study retrospectively assessed concordance and variances between the CTCAE and a modified version of the CRES (mCRES) grading system among JULIET patients. Methods: Patient level data from case report forms collected for JULIET, a single-arm, open-label, multicenter, global phase 2 trial of tisagenlecleucel in adult patients with r/r DLBCL (NCT02445248) were used. Four medical experts with experience treating DLBCL patients with different CAR-T therapy products independently reviewed the data and definitions of NT proposed by the FDA using CTCAE and mCRES system. Patients were graded using these two systems; however, only NT attributable to CAR-T therapy were considered. For example, headache without temporal association or evidence of cognitive impairment was graded 0. The CARTOX group's CRES grading criteria were modified in this study since the CARTOX-10 questionnaire, a new tool to assess overall cognitive function, was not prospectively utilized. Hence, mCRES grades 1 and 2, distinguished by CARTOX-10 score, could not be distinctly defined and were assigned based upon investigator report of cognitive or attention dysfunction by CTCAE. Results were discussed and reconciled among all medical experts in a live meeting. As per the research group charter, the highest grading by any of the four experts would determine the final grading for an individual event. Graded results were also compared with those in the FDA label of tisagenlecleucel, in which NT was broadly defined as the occurrence of any CTCAE graded neurological or psychiatric AE (e.g., anxiety, dizziness, headache, peripheral neuropathy, and sleep disorder). Results: Among 111 patients infused with tisagenlecleucel (as of December 2017), 68 who had NT per FDA definition were graded. With the CTCAE grading system, the medical experts identified 50 (45%) patients as having experienced CAR-T related NT, including 34 with grade 1/2, 11 with grade 3, and 5 with grade 4; the mCRES system identified 19 (17%) patients, 5 of whom were grade 1/2, 6 were grade 3, and 8 were grade 4 (Figure 1). Among the subgroup of 64 patients who experienced CRS, the CTCAE and the mCRES systems identified 30 (47%) and 15 (23%) patients with any grade NT, respectively (grade ≥3: CTCAE vs. mCRES: 11 vs. 10). For 47 patients without CRS, the CTCAE and the mCRES systems identified 20 (43%) and 4 (9%) patients with NT, respectively (grade ≥3: 5 vs. 4; Table 1). These grades by medical experts also varied from those reported by FDA: among 106 patients receiving tisagenlecleucel (as of September 2017), 62 (58%) had NT including 19 (18%) with grade ≥3. Conclusions: This exploratory study is the first to retrospectively apply a modified version of the new CARTOX-CRES grading system for CAR-T related NT. Using data from JULIET patients, medical experts were able to achieve consensus NT grading using both the CTCAE and the mCRES grading systems. Using the mCRES system, 19 (17%) patients had any grade NT (5 with grade 1/2, 6 with grade 3, and 8 with grade 4) versus the CTCAE system, which identified 50 (45%) patients as having NT (34 with grade 1/2, 11 with grade 3, and 5 with grade 4). The differences between the two grading systems and the NT grading the FDA reported highlight how the same patient data can be represented variably on different scales and highlight the divergent focus of each system, where encephalopathy is the principal focus of CARTOX-10. These results raise an urgent need for broader consensus on a specific grading scale for CAR-T related NT. Disclosures Maziarz: Athersys, Inc.: Patents & Royalties; Kite Therapeutics: Honoraria; Juno Therapeutics: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schuster:Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding. Romanov:Novartis Pharmaceuticals Corporation: Employment. Rusch:Novartis Pharmaceuticals Corporation: Employment. Ericson:Novartis Pharmaceuticals Corporation: Employment. Maloney:Janssen Scientific Affairs: Honoraria; Juno Therapeutics: Research Funding; Roche/Genentech: Honoraria; Seattle Genetics: Honoraria; GlaxoSmithKline: Research Funding. Locke:Novartis Pharmaceuticals: Other: Scientific Advisor; Kite Pharma: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy.

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Progressive but Previously Untreated CLL Patients with Greater Array CGH Complexity Exhibit A Less Durable Response to Chemoimmunotherapy

Blood ◽

10.1182/blood.v116.21.2406.2406 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2406-2406

Author(s):

Neil E. Kay ◽

Jeanette Eckel Passow ◽

Esteban Braggio ◽

Scott Van Wier ◽

Tait Shanafelt ◽

...

Keyword(s):

Clinical Outcome ◽

Board Of Directors ◽

Copy Number ◽

Research Funding ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Genomic Complexity ◽

Duration Of Response ◽

Gains And Losses

Abstract Abstract 2406 The outcome for a given CLL patient is difficult to predict. While there are promising models, they require collation of multiple clinical and laboratory parameters, and it remains to be seen whether they will apply to typical CLL patients in the community. To further dissect out explanations for this dramatic clinical heterogeneity, we sought to understand genomic complexity of clonal B-cells as a possible explanation of clinical variability with specific application to genomic complexity as a predictor of therapeutic response and clinical outcome in CLL. Thus we wished to identified global gains and losses of genetic material in order to define copy-number abnormalities (CNA) in 48 clinically progressive CLL patients who were about to be treated on a chemoimmunotherapy protocol. This protocol was previously reported by us (Blood. 109:2007) and had an induction phase with pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2) and rituximab (375 mg/m2) given every 3 weeks for 6 cycles and then responding patients were followed ever three months until relapse. In order to estimate CNA, we employed array-based comparative genomic hybridization (aCGH) using a one-million oligonucleotide probe array format on the leukemic B-cells from the 48 patients entering this trial. In those same patients, the aCGH data were compared to a) FISH detecxtable data using a panel for the common recurring genetic defects seen in CLL and b) to their clinical outcome on this trial. With aCGH we found that 288 CNA were identified (median of 4 per patient; range 0–32) of which 215 were deletions and 73 were gains. The aCGH method identified most of the FISH detected abnormalities with a complete concordance for 17p13.1- deletion (17p-) between aCGH and FISH. We also identified chromosomal gain or loss in ≥6% of the patients on chromosomes 3, 8, 9, 10, 11, 12, 13, 14 and 17. We found that CLL patients with ≥15 CNA had a significantly worse progression free survival (PFS) than patients with <15 CNA (p=0.004)(figure). Patients with ≥15 CNA also had a shorter duration of response than those with <15 CNA (p=0.0726). Of interest, more complex genomic features were found both in patients with a 17p13.1 deletion and in more favorable genetic subtypes such as 13q14.1. Thus, for 5 patients with >15 CNAs the following FISH patterns were seen: +12/13q14.1-x1/13q14.1 -x2, 13q14.1 ×1 (n=2), and 17p13.1 (n=2). In addition, a 17p- by FISH was positively associated with the number of CNA and total deletion size. The odds of having an overall response decreased by 28% (95% CI: 5–55%; p=0.015) with each additional CNA for the 17p13.1- patients. In addition to defining genomic complexity as the total number of CNA for each patient, we also defined complexity as the sum of the lengths of all interstitial chromosomal gains and losses. When defined as the total size of chromosomal gains or losses, genomic complexity was significantly associated with 17p13.1 and worse overall clinical response. In summary, this analysis utilized the global assessment of copy number abnormalities using a high-resolution aCGH platform for clinically progressive CLL patients prior to initiation of their treatment. One outcome was that we found higher genomic complexity was associated with shorter progression-free survival, reduced duration of response and predicted a poor response to treatment. In addition since we did find genomic complexity in more traditionally favorable FISH categories, such as 13q14.1 type defects, this may explain why some of the latter patients do not fare as well as might be expected even with aggressive chemoimmunotherapy approaches. This study adds information on the association between inferior trial response and increasing genetic complexity as CLL progresses. Disclosures: Off Label Use: Pentostatin. Kipps: GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding; Memgen: Research Funding; Igenica: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Research Funding; Abbott Laboratories: Research Funding.

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Prognostic Importance of Duration of MDS Prior to Randomization Between Decitabine (DAC) Vs. Best Supportive Care (BSC) In Elderly IPSS Intermediate-2 and High Risk MDS Patients: Results of the 06011 EORTC-GMDSSG Phase III Trial

Blood ◽

10.1182/blood.v116.21.4024.4024 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4024-4024

Author(s):

Michael Lubbert ◽

Stefan Suciu ◽

Uwe Platzbecker ◽

Aristoteles A.N. Giagounidis ◽

Dominik Selleslag ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Cox Regression ◽

Phase Iii ◽

Prognostic Impact ◽

Advisory Committees ◽

Phase Iii Trial ◽

Response Predictors ◽

Long Duration

Abstract Abstract 4024 Background: The hypomethylating agents 5-azacytidine (Vidaza) and 5-aza-2′-deoxycytidine (Decitabine, DAC) are active in different MDS subtypes. Compared to other response predictors to DAC, prior MDS duration has received only limited attention (1, 2), with conflicting results. Based on our finding that long duration of MDS prior to DAC treatment may be a novel factor linked to a better outcome (1), we now assess its value in the phase III trial 06011 (DAC versus BSC [3]). Immediate enrolment after diagnosis was allowed in that trial, median MDS duration prior to randomization thus only 3 months (mths). Methods: Comparison of progression-free (PFS), AML-free (AMLFS) and overall survival (OS) according to MDS duration >= vs. <3 mths in 233 patients (pts) with higher-risk MDS (median age 70 years) randomized to DAC (n=119) or BSC (n=114). Comparisons by long-rank test and multivariate analyses by Cox regression (Performance Status [PS], cytogenetics and IPSS high risk N/Y) were performed retrospectively: MDS duration had not yet been known as possible stratification factor at time of study initiation, and the trial thus not been powered to detect significant differences with regard to this discriminator. Results: A better prognosis of patients with MDS duration >=3 vs <3 mths was observed in DAC arm (B vs A) and BSC arm (D vs C). Conversely, DAC yielded better results than BSC in each MDS duration group: <3 mths (A vs C) and >=3 mths (B vs D). In both arms (n=233), Mult. indicated that MDS duration (>=3 vs <3 mths) adjusted for treatment, PS, cytogenetics and IPSS group was an independent prognostic factor regarding PFS (HR=0.75, 95%CI 0.58–0.99), AMLFS (HR=0.68, 95%CI 0.51–0.90), and OS (HR=0.75, 95%CI 0.56–0.99). The tests for interaction treatment × duration of MDS were not significant for 3 endpoints: PFS (p=0.38), AMLFS (p=0.90), OS (p=0.67). Conclusion: In intermediate-2 and high-risk MDS pts, long duration from MDS diagnosis to start of DAC or BSC appeared to be associated with a better outcome. This finding is in sharp contrast to the adverse prognostic impact of antecedent disease duration in patients who received intensive chemotherapy (4). It is supported by a similar analysis of pts with AML from MDS treated on the 00331 DAC phase II multicenter trial: those with longer MDS duration prior to DAC also had better outcome (5). Application of this discriminator in the evaluation also of other DAC schedules and MDS treatments therefore appears warranted. References: 1. Wijermans et al., Ann. Hematol. 84 (suppl. 1): 9–14, 2005 2. Kantarjian et al., Cancer 109:265-73, 2007 3. Wijermans et al., Blood 112 (suppl. 1): abs. 226, 2008 4. Estey et al., Blood 90:2969-77, 1997 5. Lübbert, Schmoor et al., abstract submitted, ASH 2010 Disclosures: Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Salih:Pfizer: Research Funding. Muus:Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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Gene Mutations and Treatment Outcome in CLL Patients Treated with Chlorambucil (Chl) or Ofatumumab-Chl (O-Chl): Results from the Phase III Study COMPLEMENT1 (OMB110911)

Blood ◽

10.1182/blood.v124.21.1992.1992 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1992-1992 ◽

Cited By ~ 1

Author(s):

Eugen Tausch ◽

Christina Galler ◽

Richard Schlenk ◽

Peter Hillmen ◽

Fritz Offner ◽

...

Keyword(s):

Prognostic Factors ◽

Board Of Directors ◽

Research Funding ◽

Cox Regression ◽

Gene Mutations ◽

Phase Iii ◽

Response To Treatment ◽

Prognostic Impact ◽

Advisory Committees

Abstract BACKGROUND: Genomic aberrations and IGHV mutation status are established prognostic factors in CLL. With TP53, NOTCH1, SF3B1, ATM, MYD88, FBXW7, BIRC3 and POT1 recurrently mutated genes were found in CLL and were discussed to associate with disease characteristics and to affect therapy efficacy and outcome. METHODS: We assessed the incidence and impact of gene mutations in the COMPLEMENT1 trial (1st line Chl vs. O-Chl). Pretreatment samples were available from 376 patients (84.1%) and this cohort was representative of the full trial population. Mutations were analyzed by amplicon-based targeted NGS using Illumina Miseq for all coding exons (TP53, ATM, MYD88, FBXW7, BIRC3 and POT1) or hotspot exons (NOTCH1, SF3B1). Additionally, the exact variant frequency was determined. RESULTS: The incidences of gene mutations were: TP53 8.2%, NOTCH1 14.9%, SF3B1 14.1%, ATM 10.9%, MYD88 2.7%, FBXW7 3.5%, POT1 7.7%, and BIRC3 2.7%. Regarding baseline characteristics, we found significant associations: TP53mut with high ß2MG (p=0.01), 17p- (p<0.01), and unmutated IGHV (p=0.01); ATMmut with high WBC (p=0.02), and 11q- (p<0.01); MYD88mut with mutated IGHV (p=0.02); FBXW7mut with 17p- (p=0.02), and +12q (p<0.01). BIRC3mut was only present in IGHV unmutated cases (p<0.01), was more frequent in 11q- (p<0.01), +12q (p=0.05), and in cases with NOTCH1mut (p=0.05). POT1mut was more frequent in NOTCH1mut cases (p=0.02) without associations with any other baseline parameter. Regarding response to treatment, TP53mut was significantly associated with reduced ORR rate (p<0.01). CR rate was not correlated with mutations in the covered genes. At a median follow-up of 31.7 months, there were 249 (66%) events for PFS and 63 (16.8%) events for OS. O-Chl as compared to Chl resulted in significantly improved PFS (median 22.4 vs. 13.1 months, HR 0.54, p<0.01). In univariate analyses, TP53mut (HR 2.07, p<0.01), NOTCH1mut (HR 1.50, p=0.01) and SF3B1mut (HR 1.66, p=0.01) were associated with shorter PFS, whereas ATM and other candidate genes showed no association (ATMmut: HR 1.40, p=0.07). Analyzing both treatment arms separately, TP53mut had an impact on PFS with Chl and O-Chl treatment (HR 1.92, p=0.04 and HR 2.49, p<0.01). Notably, NOTCH1mut was associated with outcome in O-Chl only (HR 2.01, p<0.01 vs. HR 1.14, p=0.59) resulting in a reduced beneficial effect from the addition of Ofatumumab to Chlorambucil treatment. ATMmut and BIRC3mut mutations were only adverse prognostic factors with Chl monotherapy (ATMmut: HR 1.69, p=0.05 vs. HR 1.35, p=0.27; BIRC3mut: HR 2.84, p=0.04 vs. HR 0.99, p=0.99). OS was reduced significantly only in TP53mut cases (HR 3.69, p<0.01). Of note, none of the MYD88mut cases (n=10) had died within the follow-up period. To identify genomic factors of independent prognostic impact, we performed multivariable Cox regression analyses for PFS and OS including treatment arms, 11q-, +12q, 17p-, IGHV and all candidate gene mutations. For PFS, the following independent prognostic factors were identified: O-Chl (HR 0.46, p<0.01), 17p- (HR 3.14, p<0.01), 11q- (HR 1.57, p=0.01), unmutated IGHV (HR 1.43, p=0.02), TP53mut (HR 1.81, p=0.03), NOTCH1mut (HR 1.63, p<0.01) and SF3B1mut (HR 1.54, p=0.02). Regarding OS, only 17p- (HR 4.07, p<0.01), and unmutated IGHV (HR 1.81, p=0.05) were identified as independent adverse prognostic factors with TP53mut showing a trend (HR 2.14, p=0.10). CONCLUSION: We performed mutational analyses for the 8 most frequent mutated genes in CLL in the COMPLEMENT1 trial evaluating 1st line O-Chl against Chl. An independent prognostic impact was identified for TP53mut, NOTCH1mutand SF3B1mut regarding PFS. Notably, NOTCH1mut affected outcome mainly with O-Chl treatment, whereas ATMmut and BIRC3mut were associated with outcome with Chl monotherapy. In multivariate analysis for OS, none of the gene mutations, but the established parameters IGHV and 17p- had independent prognostic impact. Disclosures Tausch: GlaxoSmithKline: Research Funding, Travel support Other. Hillmen:GSK: Honoraria, Research Funding. Offner:GlaxoSmithKline: Honoraria, Research Funding. Janssens:GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Roche: Speakers Bureau; Mundipharma: Speakers Bureau. Mayer:Glaxo: Research Funding; Roche: Research Funding. Panagiotidis:GlaxoSmithKline: Consultancy, Honoraria. McKeown:GlaxoSmithKline: Employment. Gupta:GlaxoSmithKline: Employment. Stilgenbauer:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Update of Multicenter, Retrospective Evaluation of Overall Response and Failure Free Survival Following Ruxolitinib Therapy for Heavily Pre-Treated Chronic Gvhd Patients with Steroid-Failure: A Proposal of Risk Score Model for Failure-Free Survival

Blood ◽

10.1182/blood-2021-148859 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3905-3905

Author(s):

Jennifer White ◽

Mohamed Elemary ◽

Swe Mar Linn ◽

Igor Novitzky-Basso ◽

Anargyros Xenocostas ◽

...

Keyword(s):

Risk Factor ◽

Board Of Directors ◽

Risk Score ◽

Research Funding ◽

Chronic Gvhd ◽

Organ Involvement ◽

Advisory Committees ◽

Prednisone Dose ◽

Free Survival ◽

Overall Response

Abstract Background The REACH3 trial evaluating Ruxolitinib (RUX) treatment for steroid-refractory chronic GVHD concluded that RUX leads to significantly greater overall response and failure-free survival (FFS) than best available therapies (NEJM 2021). We reported a real-world experience of RUX in 47 chronic GVHD (cGVHD) patients, with 36% overall response rate (ORR) at 6 months (ASH 2020). The present study expanded this to 115 pts, evaluating ORR, FFS and overall survival (OS), and explored prognostic factors associated with clinical outcomes. Patients and methods A total of 115 patients treated with RUX for cGVHD from 2016 to 2021 at 5 sites were evaluated retrospectively. Patients and disease characteristics are as follows: median age 57.5 years; males 67 (60%); organ involvement at the time of RUX: skin 75.7%, mouth 51.3%, eye 42.6%, gastrointestinal 19.1%, liver 39.1%, lung 31.3%, and musculoskeletal 38.3%. Out of 108 pts with available HCT-CI prior to HCT, 29 pts (26.9%) had HCT-CI score 3 or higher, while 79 (73.1%) had HCT-CI score 0-2. The ORR were assessed at months 3, 6 and 12, retrospectively. Treatment failure was defined as 1) resistance requiring treatment switch, 2) non-relapse mortality (NRM), 3) relapse, 4) intolerance to treatment. FFS and OS were calculated from the day of starting RUX therapy for cGVHD treatment. For risk factor analysis, logistic regression was adopted for ORR at 6 months, while Cox's proportional hazard model was implemented for FFS and OS at 12 months. The following variables were evaluated for risk factor analysis: GVHD-related factors (cGVHD severity, no. of organ involvement, prednisone dose or RUX dose at start, previous history of acute GVHD); host factors (age or performance status at RUX starts, sex, HCT-CI comorbidity score pre-HCT); transplant factors (conditioning intensity; donor type, HLA match, T-cell depletion). From those variables identified as significant in the multivariate analysis, a prognostic risk score was generated as the sum of adverse risk factor scores. Results A total of 115 pts had severe (n=69, 60%) or moderate grade (n=44, 38.3%) cGVHD except 2 (1.7%) who had mild grade cGVHD with high-risk features. The median number of organ involvement was 3 (range 1-7). 96 pts (84.2%) received RUX as 4 th line or beyond for cGVHD treatment. The previous treatments included mycophenolate mofetil (n=46, 40.0%), extracorporeal photopheres (n=45, 39.1%), Imatinib (n=13, 11.3%), and Ibrutinib (n=9, 7.8%). RUX was started at 10-20 mg daily as the initial dose, then maintained at 20mg daily in two divided doses on months 3, 6 and 12. With a median follow-up duration of 12 months, ORR was attained in 46.8%, 61.8% and 62.3% at 3, 6 and 12 months, similar to 49.7% ORR rate at 6 months in the REACH3 study. ORR in the range of 48.1-64.5% at 6 months was observed across all the organs involved. No difference in ORR was noted between steroid-resistant vs steroid-dependent cGVHD, or according to previous treatment with TKI drug for GVHD. For ORR, severe grade cGVHD showed a lower ORR rate at 46.8% at 6 months compared to those with moderate/mild grade cGVHD at 81.1% (p=0.001). In terms of prednisone dose reduction, by 12 months, more than half of pts (63.8%) could taper prednisone doses below 0.1mg/kg/day, while the proportion of pts on prednisone dose below 0.1mg/kg/day was 14.83%, 33.6%, 47.6%, and 63.8% at month 0, 3, 6 and 12, respectively. A total of 39 failures (33.4%) were noted, including resistance requiring switch to other therapy (n=17), NRM (n=14), relapse of primary disease (n=3) and intolerance (n=5). The FFS rate in the overall population was 64.6% (54.1-73.2), while the OS rate was 83.3% (74.4-89.4%) at 12 months. For FFS, two risk factors were identified for FFS (Figure): 1) Severe grade cGVHD at RUX start (p=0.008, HR 2.496 [1.229-5.072]); 2) HCT-CI comorbidity 3 or higher (p=0.001, HR 2.802 [1.493-5.259]). When a risk score model was generated, it stratified pts according to the FFS at 12 months (p=0.0001): 85.8% in score 0 (n=32); 58.7% in score 1 (n=57); and 36.8% in score 2 (n=19). Conclusion: Updated results confirm that RUX is an effective treatment option for cGVHD pts, even including heavily treated pts. Also, favorable response was observed across all organs involved with GVHD. Failure of RUX is associated with cGVHD severity and HCT-CI score. Figure 1 Figure 1. Disclosures White: Novartis: Honoraria. Elemary: Jazz, BMS, Abbvie, Novartis, Pfiz: Membership on an entity's Board of Directors or advisory committees; Pfizer, Janssen: Membership on an entity's Board of Directors or advisory committees. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Law: Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Mattsson: MattssonAB medical: Current Employment, Current holder of individual stocks in a privately-held company. Kim: Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Paladin: Consultancy, Honoraria, Research Funding; Bristol-Meier Squibb: Research Funding. OffLabel Disclosure: This presentation discusses the use of ruxolitinib for chronic GVHD. This indication is under FDA review.

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Gabarap Loss Mediates Immune Escape in High Risk Multiple Myeloma

Blood ◽

10.1182/blood-2021-148621 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 891-891

Author(s):

Annamaria Gulla ◽

Eugenio Morelli ◽

Mehmet K. Samur ◽

Cirino Botta ◽

Megan Johnstone ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Clinical Outcome ◽

Board Of Directors ◽

Research Funding ◽

Immune Escape ◽

Publicly Traded ◽

Advisory Committees

Abstract Immune therapies including CAR T cells and bispecific T cell engagers are demonstrating remarkable efficacy in relapsed refractory myeloma (MM). In this context, we have recently shown that proteasome inhibitor bortezomib (BTZ) results in immunogenic cell death (ICD) and in a viral mimicry state in MM cells, allowing for immune recognition of tumor cells. Induction of a robust anti-MM immune response after BTZ was confirmed both in vitro and in vivo: treatment of 5TGM1 MM cells with BTZ induced tumor regression associated with memory immune response, confirmed by ELISPOT of mouse splenocytes. We have confirmed the obligate role of calreticulin (CALR) exposure in phagocytosis and the ICD process, since BTZ-induced ICD is impaired in CALR KO MM cells both in vitro and in vivo. We further showed that the therapeutic efficacy of BTZ in patients was correlated with ICD induction: BTZ-induced ICD signature was positively correlated with OS (p=0.01) in patients enrolled in the IFM/DFCI 2009 study. Together, these studies indicate that ICD is associated with long-term response after BTZ treatment. In this work, we reasoned that genomic or transcriptomic alterations associated with shorter survival of MM patients after BTZ treatment may impair activation of the ICD pathway. To this aim, we performed a transcriptomic analysis of purified CD138+ cells from 360 newly diagnosed, clinically-annotated MM patients enrolled in the IFM/DFCI 2009 study. By focusing on genes involved in the ICD process, we found that low levels of GABA Type A Receptor-Associated Protein (GABARAP) were associated with inferior clinical outcome (EFS, p=0.0055). GABARAP gene locus is located on chr17p13.1, a region deleted in high risk (HR) MM with unfavorable prognosis. Remarkably, we found that correlation of low GABARAP levels with shorter EFS was significant (p=0.018) even after excluding MM patients with del17p; and GABARAP is therefore an independent predictor of clinical outcome. GABARAP is a regulator of autophagy and vesicular trafficking, and a putative CALR binding partner. Interestingly, among a panel of MM cell lines (n=6), BTZ treatment failed to induce exposure of CALR and MM cell phagocytosis by DCs in KMS11 cells, which carry a monoallelic deletion of GABARAP. This effect was rescued by stable overexpression of GABARAP. Moreover, CRISPR/Cas9-mediated KO of GABARAP in 3 ICD-sensitive cell lines (AMO1, H929, 5TGM1) abrogated CALR exposure and ICD induction by BTZ. GABARAP add-back by stable overexpression in KO clones restored both CALR exposure and induction of ICD, confirming GABARAP on-target activity. Similarly, pre-treatment of GABARAP KO cells with recombinant CALR restored MM phagocytosis, further confirming that GABARAP impairs ICD via inhibition of CALR exposure. Based on these findings, we hypothesized that GABARAP loss may alter the ICD pathway via CALR trapping, resulting in the ICD resistant phenotype observed in GABARAP null and del17p cells. To this end, we explored the impact of GABARAP KO on the CALR protein interactome, in the presence or absence of BTZ. Importantly, GABARAP KO produced a significant increase of CALR binding to stanniocalcin 1 (STC1), a phagocytosis checkpoint that mediates the mitochondrial trapping of CALR, thereby minimizing its exposure upon ICD. Consistently, GABARAP KO also affected CALR interactome in BTZ-treated cells, which was significantly enriched in mitochondrial proteins. Importantly, co-IP experiments confirmed GABARAP interaction with STC1. These data indicate a molecular scenario whereby GABARAP interacts with STC1 to avoid STC1-mediated trapping of CALR, allowing for the induction of ICD after treatment with ICD inducers; on the other hand, this mechanism is compromised in GABARAP null or del17p cells, and the STC1-CALR complex remains trapped in the mitochondria, resulting in ICD resistance. To functionally validate our findings in the context of the immune microenvironment, we performed mass Cytometry after T cell co-culture with DCs primed by both WT and GABARAP KO AMO1 clones. And we confirmed that treatment of GABARAP KO clones with BTZ failed to activate an efficient T cell response. In conclusion, our work identifies a unique mechanism of immune escape which may contribute to the poor clinical outcome observed in del17p HR MM patients. It further suggests that novel therapies to restore GABARAP may allow for the induction of ICD and improved patient outcome in MM. Disclosures Bianchi: Jacob D. Fuchsberg Law Firm: Consultancy; MJH: Honoraria; Karyopharm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Richardson: AstraZeneca: Consultancy; Regeneron: Consultancy; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; GlaxoSmithKline: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Chauhan: C4 Therapeutics: Current equity holder in publicly-traded company; Stemline Therapeutics, Inc: Consultancy. Munshi: Legend: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Abbvie: Consultancy; Takeda: Consultancy; Adaptive Biotechnology: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy. Anderson: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees.

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Higher Expression of Nuclear Cereblon in Bone Marrow Biopsies of Patients with Multiple Myeloma Treated with Imids in the HOVON-87/Nmsg-18 Trial Is Associated with Longer PFS and OS

Blood ◽

10.1182/blood-2019-128584 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3071-3071

Author(s):

Ruth Wester ◽

M Duin ◽

King Hong Lam ◽

Suzana Couto ◽

Yan Ren ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cox Regression ◽

Employment Equity ◽

Advisory Committees ◽

Cytoplasmic Staining ◽

Cox Regression Analysis ◽

Cytogenetic Aberrations ◽

Equity Ownership ◽

Response Groups

Introduction Response to treatment in patients with multiple myeloma (MM) is variable. With increasing possibilities of treatment regimens, predictive factors for response are important. Immune modulating agents (IMiDs) require Cereblon (CRBN) for activity. Therefore, the aim of this study was to identify the genes involved in the CRBN pathway which predict the response to therapy with IMiDs. Methods Paraffin embedded bone marrow (BM) biopsies were used from newly diagnosed patients included in HOVON-87/NMSG-18 trial obtained at inclusion. In this trial, elderly patients with MM were randomized between treatment with Melphalan-Prednisone (MP)-Thalidomide (MPT) followed by thalidomide maintenance versus MP-Lenalidomide (MPR) followed by lenalidomide maintenance (Zweegman et al. Blood 2016;127:1109-1116). BM biopsies were stained with a fully automated dual color, bright-field immunohistochemical assay for CRBN, its neosubstrates Ikaros and Aiolos and the downstream targets IRF4 and c-MYC. CD138 was used to identify MM plasma cells in the BM samples. For CRBN, both nuclear and cytoplasmic staining was evaluated. The distribution and intensity of the immunostaining was assessed using the H-score. The H-scores were calculated using the following formula: [1 × (% cells 1+) + 2 × (% cells 2+) + 3 × (% cells 3+)] and range from 0-300 (0-600 for combined cytoplasmic-nuclear CRBN H-score). For the Cox regression analysis H-scores were corrected by dividing these by a factor 100: hazard rates were considered per 100 points increase of the H-score. Protein levels of the CRBN pathway were compared between patients with complete response (CR) or very good partial response (VGPR) vs partial response (PR) and no change/progressive disease (NC/PD). High-risk cytogenetic aberrations (FISH) were defined as having deletion of 17p, and/or translocation t(4;14) and/or t(14;16). Statistical analysis was done using univariate and multivariate Cox regression analysis for progression free survival (PFS) and overall survival (OS), and the Mann-Whitney test for comparing response groups. Kaplan-Meier survival curves were generated to illustrate survival. Results BM samples obtained at diagnosis from 149 patients were evaluated. Seventy-one patients were treated in the thalidomide arm vs 78 patients in the lenalidomide arm. Median age was 73 years [range 60-90]. Revised ISS stages I/II/III were 12%/80%/8% respectively. At the time of analysis, median follow up of the 45 patients still alive was 83 months [range 23 - 114 months]. Best response on protocol treatment was sCR/CR in 22%, VGPR in 30%, PR in 36% and NC/PD in 12%. Protein expression across the response groups showed higher nuclear CRBN in patients who responded better (sCR/CR/VGPR; median H-score: 178 (49-273)) compared to patients with a worse response (PR/NC/PD; median H-score: 157 (67-251)), albeit not statistically significant (Mann-Whitney p-value=0.06). Higher H-score of nuclear staining of CRBN was associated with a longer PFS and OS, with a hazard ratio (HR) of 0.52 for PFS (95% confidence interval (CI)=0.37-0.86, p<0.001) and a HR of 0.56 for OS (95% CI=0.36-0.78; p<0.01). Patients with the top quartile nuclear CRBN levels had a median PFS of 21 months longer compared to patients with the lowest quartile (38 months vs 17 months). In terms of OS, patients with the highest quartile nuclear CRBN expression demonstrated a median survival that was 2 times as high as found in patients with the lowest quartile (75 months vs 35 months; Figure 1). In addition, cytoplasmic staining of CRBN was associated with improved PFS (HR = 0.66 (95% CI=0.47-0.94; p=0.02), but not with OS (HR = 0.73 (CI=0.48-1.11); p=0.14). None of the other markers were associated with survival. In a multivariate analysis (which included study arm (MPT vs MPR), nuclear CRBN, high-risk cytogenetic aberrations and R-ISS), nuclear CRBN remained independently associated with OS as well as R-ISS and study arm. For PFS, only nuclear CRBN remained statistically significant after backward selection. Despite treatment arm being a statistically significant term in the multivariate Cox model for OS, no relation was found for treatment arm and nuclear CRBN, in terms of OS. Conclusions In this study we demonstrate that higher expression of nuclear CRBN in myeloma cells in BM of patients with MM was associated with a superior PFS and OS. Disclosures Couto: Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Ren:Celgene Corporation: Employment, Equity Ownership. Wang:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene: Employment, Equity Ownership. Zweegman:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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. Broyl:Celgene, amgen, Janssen,Takeda: Honoraria. Sonneveld:Amgen: Honoraria, Research Funding; BMS: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; SkylineDx: Research Funding.

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Patient Reported Financial Toxicity in Acute Leukemia

Blood ◽

10.1182/blood-2018-99-119163 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4796-4796 ◽

Cited By ~ 1

Author(s):

Thomas G. Knight ◽

Myra Robinson ◽

Michael R. Grunwald ◽

Lauren M. Bohannon ◽

Erin Blackwell ◽

...

Keyword(s):

Acute Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Safety Monitoring ◽

Data Safety Monitoring Board ◽

Financial Toxicity ◽

Advisory Committees ◽

Data Safety ◽

Safety Monitoring Board ◽

Data Safety Monitoring

Abstract Background: Financial Toxicity (FT) is increasingly recognized as a major contributor to morbidity and mortality in a variety of cancers. Treatment of acute leukemia is associated with heavy healthcare utilization and high costs. The purpose of this study was to define rates, risk factors, and mortality implications for FT in patients with acute leukemia using patient reported data. Methods: All patients seen at the Levine Cancer Institute, a tertiary hospital-based leukemia practice, were surveyed prior to each visit over a six-month period. All patients were aged ≥18 years and were diagnosed with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). The survey consisted of the PROMIS Global-10 measure and two questions from the COST measure. FT was defined as scoring 4 or less (maximum: 10) in agreement with the COST questions: "I know that I have enough money in savings, retirement, or assets to cover the costs of my treatment" and "I am satisfied with my current financial situation." Demographic data and disease characteristics were abstracted from the medical record. Model selection was carried out using logistic regression to identify factors impacting the incidence of financial toxicity. Correlation of numerical financial toxicity scores with PROMIS scores and with mortality data was assessed using linear regression. Results: Of the 106 patients, 58 (54%) met the definition of exhibiting FT. The factors associated with incidence of FT included: age, race, and insurance type. The odds of FT in those patients <65 years of age were 2.7 times the odds of FT in those ≥65, adjusting for race, insurance, and time since first treatment (95% CI: 0.884 - 8.438, p = .081). The odds of FT in African American patients were 4.3 times the odds of FT in Caucasian patients, adjusting for age, insurance, and time since first treatment (CI: 0.408 - 44.824, p = .150). The odds of FT in patients with Medicaid insurance were 14.2 times the odds of FT in patients with commercial insurance, adjusting for age, race, and time since first treatment (CI: 1.658 - 121.862, p = .106). Gender, distance from the hospital, type of acute leukemia, history of blood/marrow transplant, and history of relapsed disease were not found to be significant. There was a significant correlation for both the PROMIS global physical (p < .001) and mental (p < .001) scores with the FT score. Lower FT score (higher degree of FT) was associated with lower mental and physical scores. There was no statistically significant difference in survival between patients with FT scores >4 compared to patients with FT scores <=4; however, there was a trend toward decreased survival in those with lower FT scores (Figures 1 and 2). Conclusions: Patients with acute leukemia represent an extremely vulnerable population for financial toxicity with rates of distress even higher than other reported malignancies. Urgent interventions are indicated in this population. Disclosures Grunwald: Medtronic: Equity Ownership; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Janssen: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Avalos:Juno: Membership on an entity's Board of Directors or advisory committees. Symanowski:Five Prime Therapeutics: Other: Data Safety Monitoring Board ; Boston Biomedical: Other: Data Safety Monitoring Board ; Eli Lily & Co: Other: Data Safety Monitoring Board; Immatics: Other: Data Safety Monitoring Board.

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Systematic Review of the Published Evidence on the Pharmacokinetic Characteristics of Factor VIII and IX Concentrates

Blood ◽

10.1182/blood.v124.21.2818.2818 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2818-2818

Author(s):

Menchen Xi ◽

Tamara Navarro-Ruan ◽

Sunil Mammen ◽

Victor S. Blanchette ◽

Cedric R. Hermans ◽

...

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Safety Monitoring ◽

Data Safety Monitoring Board ◽

Advisory Committees ◽

Safety Monitoring Board ◽

Population Pk ◽

Viii And Ix ◽

Factor Concentrate

Abstract Introduction: The efficacy of factor VIII and IX concentrates administered to prevent bleeding episodes in patients with hemophilia A and B is correlated with the plasma levels measured over time after the infusion. The inter-patient variability of pharmacokinetic (PK) parameters is large, and it is difficult to assess individual PK profiles due to the need for multiple time points. This is often not feasible, particularly for pediatric patients. Population PK modeling potentially provides a practical solution to this problem. The successful modelling of PK parameters at the population level requires knowledge of disposal characteristics and relevant covariates. We performed a systematic review of the available evidence in order to identify available PK data for factor VIII and IX concentrates to facilitate the implementation of a population PK approach. Methods: We conducted a literature search in MEDLINE and EMBASE from January 1997 to May 2014, using the keywords "hemophilia" and "pharmacokinetic". We included only articles that published original PK data for factor VIII and IX concentrates in humans and published in English. Two authors independently screened the studies and extracted the relevant data. Results: We retrieved 237 unique articles published between 1998 and 2013. We excluded 185 articles that did not meet our research criteria. We included 52 articles, with a total of 1365 patients included in PK analyses. 26 articles reported PK data on factor VIII concentrates, 18 articles report PK data on factor IX concentrates, and one article reported on both factor VIII and IX concentrates. Seven articles reported pharmacokinetic data on both factor VIII and Von Willebrand factor concentrates. We extracted the following data: number of patients, type and severity of hemophilia, patient age, factor concentrate infused, dose infused, sampling data points, half-life, clearance, recovery and the model used for pharmacokinetics, and inclusion of patients undergoing surgery or with inhibitors. The main results are summarized in table 1. Conclusions: This review provides the first systematic appraisal of the methods and results of published papers in the field. The data gathered confirms the intra-patient variability of factor concentrate PK and provides useful information on which to build population based PK models. *3 FIX articles and 2 FVIII articles did not report lab test; one article reported PK data for both FIX and FVIII †11 articles reported FVIII PK data for both one-stage clotting and chromogenic assays ǂPapers reporting on long-acting FVIII and FIX were included in the review, but not summarized in the table. For this reason, not all 1365 patients are accounted for in the table §Estimate of the range of the means found in the papers Disclosures Xi: Baxter: Research Funding. Navarro-Ruan:Baxter: Research Funding. Mammen:Baxter: Research Funding. Collins:Baxter: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL: Consultancy, Honoraria, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Neufeld:Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: data safety monitoring board, data safety monitoring board Other; Biogen IDEC: Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Membership on an entity's Board of Directors or advisory committees; Pfiser: consultancy, data and safety monitoring board Other; Octapharma: Research Funding. Dunn:CSL Behring,: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; Pfiser: Membership on an entity's Board of Directors or advisory committees. Iorio:Baxter: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; NovoNordisk: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; Pfiser: Honoraria, Research Funding.

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