Global DNA Methylation Analysis Identifies Key Pathway Differences Between Poor (Low OCT-1 Activity) and Standard Risk CP-CML Patients At Diagnosis

Abstract Abstract 3730 Background: DNA methylation, specifically CpG methylation, is an essential mediator of epigenetic gene expression which is of vital importance to many biological processes and human malignancies. DNA hypermethylation has been previously described in a small number of genes in chronic myeloid leukemia (CML); however, current published studies have only examined the methylation status of selected genes, often based on the results of studies in other malignancies. Therefore, the global DNA methylation profile of chronic phase-CML (CP-CML) remains poorly understood, as does the impact of the epigenome on patient response to tyrosine kinase inhibitors (TKIs) including imatinib. The organic cation transport-1 (OCT-1) protein is the major active protein involved in imatinib transport, and we have previously demonstrated that measuring its function in leukemic mononuclear cells, expressed as OCT-1 activity (OA), in patient cells prior to imatinib therapy, provides a strong prognostic indicator. Notably, very low OA (poor risk cohort) is associated with patients at significant risk for poor molecular response, mutation development and leukemic transformation on imatinib therapy. Therefore, it is of particular interest to ascertain whether epigenetic changes are distinct and potentially biologically relevant in these poor risk patients. Aim: To investigate the global DNA methylation profile in CP-CML patients with a particular focus on poor risk patients (very low OCT-1 activity), and to ascertain whether aberrant epigenetic programming may underlie their poor response. Method: Cells were isolated from the blood of 55 CP-CML patients at diagnosis and 5 normal individuals. CP-CML patients were classified according to their OA values, with 29 classified as poor (very low OA) and 26 standard risk (high OA). Whole genome DNA methylation analysis was performed using the Illumina Infinium® HumanMethylation450 BeadChip. Analysis of array data was performed with R v2.15.0, using the minfiBioconductor package. Results: The methylation profile of CP-CML was significantly different to that of normal individuals, as shown in Table 1. GeneGo enrichment analysis revealed a significant enrichment in CML for genes known to be involved in other leukemias (p=4.92e−26) particularly AML and CLL, suggesting similar pathways may be under epigenetic control in CML. A significant number of polycomb group (BMI1 and EZH2) target genes were also identified, suggesting the likely involvement of this pathway in CML. Table 1: Summary of significant CpGs and corresponding genes when comparisons of CP-CML to normal individuals, and poor to standard risk patients, are made using methylation profiles. A significant difference was also observed when the methylation profiles of poor and standard risk CP-CML patients were analysed (Table 1). GeneGo analysis again identified polycomb group (SUZ12 and EZH2) target enrichment and significant enrichment of NOTCH, Hedgehog and WNT signalling (p=7.93e−9, p=2.42e−5 and p=3.66e−5 respectively) in poor risk patients, indicating these pathways may play a significant role in the unfavourable responses observed in many of these patients. Of particular interest were the ten CpGs where a fold change >4 was observed between the methylation profiles of poor and standard risk patients. Using the Prediction Analysis of Microarrays supervised learning algorithm, a classifier for patient OA prediction based on this 10 CpG signature was evaluated. This classifier had an overall accuracy of 94% (sensitivity: 95%, specificity: 93%). Conclusion: We present a comprehensive global DNA methylation analysis of CP-CML that indicates significant and widespread changes to the CML epigenome, compared with that of normal individuals. Importantly, we have generated a classifier, which identifies the poor risk patient subgroup (very low OA) with 94% accuracy. Validation of this classifier is currently in progress. The epigenetic changes identified here may contribute to CML pathogenesis, and also to the response heterogeneity observed between CP-CML patients treated with TKI therapy. Disclosures: Hughes: Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. White:Novartis Oncology: Honoraria, Research Funding; BMS: Research Funding; CSL: Research Funding.

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Differential Lineage Involvement Between Very Low and Higher OCT-1 Activity Chronic-Phase CML Patients

Blood ◽

10.1182/blood.v118.21.1675.1675 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1675-1675

Author(s):

Dale B. Watkins ◽

Chung Hoow Kok ◽

Timothy P. Hughes ◽

Cassandra Slader ◽

Richard D'Andrea ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Chronic Phase ◽

Cell Populations ◽

Molecular Response ◽

Advisory Committees ◽

Poor Risk ◽

The Poor ◽

Risk Patients ◽

Standard Risk

Abstract Abstract 1675 Background: While the use of tyrosine kinase inhibitors (TKI) for the treatment of chronic-phase chronic myeloid leukemia (CP-CML) has dramatically improved patient survival, clinical responses are heterogeneous. Approximately 28% of imatinib (IM), 55% of nilotinib and 46% of dasatinib treated patients achieve major molecular response (MMR) by 12 months. We have previously demonstrated that the functional activity of IM's major active transport protein, OCT-1 (OCT-1 activity, OA), performed on patient cells prior to IM commencement, provides a strong prognostic indicator of response. Importantly, very low OA (bottom 25%, poor risk cohort) is associated with CP-CML patients at significant risk for poor molecular response, mutation development and leukemic transformation. Furthermore, we have also demonstrated in the TIDEL II study that patients with very low OA frequently fail to achieve a MMR when switched to nilotinib. Identifying patients at diagnosis that are more likely to respond sub-optimally to TKI is critical to enable therapeutic intervention aimed at overcoming poor response. To date however, this assay is not widely used because of the requirement for live cells and 14-C IM. Aim: To determine the variation in CP-CML patient immunophenotype at diagnosis using the more widely transferable technique of flow cytometry and relate this to the patient OA characteristics at presentation. Method: Immunophenotyping of PB-MNCs from 27 newly diagnosed CP-CML patients [10 very low OA (poor risk), 17 higher OA (standard risk)] was undertaken using a 39-marker antibody panel. Cell surface antigen profiles were determined by multicolour flow cytometry with the Beckman Coulter FC500. Statistical analysis was performed using GraphPad Prism. Further analysis was performed using gene set enrichment analysis (GSEA) for comparison to publicly available microarray datasets. Results: Differential lineage involvement was identified between the poor risk and standard risk OA patients. A number of cell populations; CD45negGlyA+ (erythroid), CD14+ (monocytic), CD20+ (B-cell) and ITGB5+ (selective monocyte-associated expression and cell adhesion) displayed significant variation between these two patient groups. The CD45negGlyA+ population was significantly increased in poor risk patients (p=0.022), while the CD14+, CD20+ and ITGB5+ cell populations also displayed significantly increased mean fluorescence intensity (MFI) in the poor risk patients (p=0.029, p=0.029 and p=0.042 respectively), as shown in Table 1. Discussion: Our previous gene expression profiling of CP patients with poor or standard risk OA revealed significant lineage differences in these two groups based on GSEA. This preliminary data demonstrated enrichment of monocytic and erythroid cell populations in the poor risk patients, whereas the granulocytic cell population was enriched in the standard risk patients. Additionally the monocyte-associated gene ITGB5, which was initially identified from the microarray results, was also validated by the immunophenotyping. Thus, both the gene expression profiling and immunophenotyping results support differential lineage involvement in CP-CML patients. We postulate that poor risk CP-CML is characterised by an increased erythroid and monocytic component, with possibly increased cellular adhesion characteristics. These differences in cellular characteristics may allow the development of a predictive classifier that will enable quick and accurate identification of these patient groups. Importantly this analysis may provide a valuable tool for dissecting underlying disease biology which likely contributes to the response heterogeneity observed in TKI-treated CP-CML patients. Ultimately, accurate identification of poor risk patients will enable tailored therapeutic intervention, improving the poor outcomes currently observed for this patient cohort. Disclosures: Hughes: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Slader:Novartis Pharmaceuticals: Employment, Equity Ownership. White:Novartis Pharmaceuticals: Research Funding; BMS: Research Funding.

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Use of High Dose Cytarabine (HiDAC) for Post-Remission or Re-Induction Therapy Is Safe and Effective in Select Older AML Patients

Blood ◽

10.1182/blood-2021-153143 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4422-4422

Author(s):

Jillian Lykon ◽

Ellen Madarang ◽

Nina Nguyen ◽

Wenhui Li ◽

Sunil G. Iyer ◽

...

Keyword(s):

Older Adults ◽

Febrile Neutropenia ◽

Board Of Directors ◽

Research Funding ◽

Average Dose ◽

Advisory Committees ◽

Poor Risk ◽

Risk Patients ◽

Dose Reductions

Abstract Introduction A standard therapy for fit older adults (≥60 years) with acute myeloid leukemia (AML) being treated with curative intent consists of induction chemotherapy with cytarabine and an anthracycline followed by 1-4 cycles of shorter course post-remission therapy with cytarabine +/- anthracycline. Historically, HiDAC has been reserved for younger patients due to the high incidence of cytarabine-induced neurotoxicity, febrile neutropenia, and hospital re-admissions in older patients (Mayer et al. 1994). In select older adults (e.g., those with good-risk cytogenetic/molecular abnormalities, or requiring reinduction for persistent AML), the risk/benefit for HiDAC may favor its use. Real world evidence is lacking on the safety of full dose HiDAC (total 18 grams/cycle) in fit older adults in the 60-75 age range. Methods We performed a retrospective analysis of AML patients ≥60 years who received at least one cycle of HiDAC, defined as 3g/m2 every 12 hours for 6 doses, either days 1-3 or days 1, 3, 5, as post-remission therapy or primary re-induction (i.e., after failure of primary induction with 7+3 or CPX-351) between July 1, 2014 and May 28, 2021. AML risk was defined by European LeukemiaNet (ELN) guidelines. All patients had daily neurologic exams including prior to each dose of HiDAC and at the beginning of each nursing shift. The primary endpoint was tolerability, defined as average dose per cycle, rate of dose reductions, incidence of febrile neutropenia, cerebellar toxicity, and rate of hospital re-admissions. Secondary endpoints were overall survival (OS), composite complete remission (CCR) for patients treated with HiDAC re-induction, and duration of relapse-free survival (RFS) (from day 1 of treatment) in all patients. Results From July 2014 to May 2021, 34 patients ≥60-years-old were treated with HiDAC at our center. Median age at HiDAC administration was 64 (60-73) [Table 1]. Approximately half the patients were Hispanic and male and almost all (97%) had ECOG performance scores of 0-1. HiDAC was used as post-remission therapy (following 7+3-type induction in 80%) in 25 patients and as re-induction in 14. Eleven patients (32%) were ELN favorable risk, 8 (25%) were intermediate, and 15 (44%) were poor risk. For post-remission therapy, the average total dose of cytarabine per cycle was 16.6 gm/m2 (6-18 gm/m2) and the median number of cycles was 4 (1-4) [Table 2]; 6 patients (24%) required dose reductions, the most common reason being upcoming allogeneic stem cell transplant (n=4). No cerebellar toxicity was observed. Duration of neutropenia was on average 15 days (7-53) in the re-induction group and 7.5 days (1-29) in the post-remission group, with 23 post-remission patients (92%) receiving granulocyte colony stimulating factors (G-CSF). Eleven hospital readmissions occurred, most commonly (73%) for febrile neutropenia. Early mortality rates were low, with one patient on the post-remission arm and one patient on the re-induction arm dying within 30 and 60 days, respectively, both due to sepsis. Median OS was 15.8 months (95% CI 0-31.8) in patients who received post-remission HiDAC, with 44% of patients still alive with a median follow up of 17.2 months (95% CI 7.2-55.8). Favorable risk patients (n=11) receiving post-remission HiDAC had median OS of 15.8 months (95% CI 0-43.1), while intermediate/poor risk patients (n=14) had median OS of 11.3 months (95% CI 9.3-13.2) [p=0.53]. Median OS was 9.8 months (95% CI 2.5-17.1) in patients who received HiDAC re-induction, with 29% of patients still alive with a median follow up of 28.6 months (95% CI 16.6-39.9) [Table 3]. Five patients (36%) achieved CCR after HiDAC re-induction, all of whom went on to receive post-remission HiDAC. Median RFS was 8.5 months for re-induction and 8.8 months for post-remission patients [Table 3]. Conclusions HiDAC (18 grams) can be safely given to select patients over age 60. Critical to tolerability is rigorous screening of "fitness," limiting the upper age receiving HiDAC to 75, ensuring adequate renal function and euvolemia, and advances in supportive care. Encouraging survival outcomes were observed in older adults receiving post-remission or re-induction HiDAC, independent of ELN risk. Figure 1 Figure 1. Disclosures Bradley: AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sekeres: Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Watts: Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding.

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Value of Minimal Residual Disease (MRD) Monitoring Using Real-Time Quantitative PCR in Patients with Acute Promyelocytic Leukemia (APL) Treated with ATRA, ATO, +/- GO

Blood ◽

10.1182/blood-2019-124599 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3851-3851

Author(s):

Jorge Cortes ◽

Hagop M. Kantarjian ◽

Tapan M. Kadia ◽

Guillermo Garcia-Manero ◽

Elias Jabbour ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Real Time ◽

Quantitative Pcr ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

Real Time Quantitative Pcr ◽

Risk Patients ◽

Standard Risk

Background: The combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is superior to ATRA plus chemotherapy in the treatment of standard risk patients (pts) with newly diagnosed APL. MRD monitoring has been successfully utilized for the early identification of relapse. Qualitative PCR has been superseded with the more accurate real-time quantitative PCR (RQ-PCR) for MRD detection in APL. Methods: We reviewed pts with newly diagnosed APL treated at our institution on 3 consecutive prospective clinical trials, using the combination of ATRA and ATO, with or without gemtuzumab ozogamicin (GO). GO was given to High risk pts (WBC >10 × 109/L) and pts with rising WBC. Real-time quantitative RT-PCR (RQ-PCR) was used to measure PML-RARα in bone marrow (BM) and peripheral blood (PB) specimens. We sought to determine the value of MRD monitoring in patients with APL treated with this regimen. Results: A total of 223 pts with APL have been followed from July 2002 to March 2019 with a total of 2007 samples (1622 BM, 385 PB) analyzed with a median number of samples of 8 per pt (range, 1-43). Median follow up is 55.6 months (range, 1-198). MRD positivity decreased over time on therapy; 218 pts (98%) were MRD positive after induction, while only 2 pts (1%) were positive after the first cycle of consolidation. Eight pts (3.5%) had positive MRD (all ≤0.1) during consolidation or after completing treatment but became negative after repeated MRD testing and none of them relapsed. Overall, seven pts relapsed (5 with high risk disease and 2 with low risk) and The median time to relapse after achieving CR was 9.4 months (range, 7.9-79.5).The time to the first relapse was between 7.9-12.4 months except for the pt who relapsed after 79.5 months (low risk pt), Among the high risk pts, molecular relapse preceded hematological relapse by 3.7 weeks (range, 2.1-4.1). There was a correlation between quantitative PCR values on PB and BM samples obtained concomitantly (r2=0.67, p=0.048). Conclusions: MRD monitoring may be useful for early detection of relapse in pts with high risk APL within first year after completion of therapy. Late molecular relapse is very rare and does not justify universal monitoring especially in standard risk patients. These data support the lack of need for MRD monitoring after completion of consolidation in pts with standard risk APL treated with ATRA plus ATO. Table Disclosures Kantarjian: Novartis: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; BMS: Research Funding; Astex: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding. Kadia:Celgene: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Bioline RX: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:Merck: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding. Jabbour:BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Takeda: Consultancy, Research Funding. Borthakur:Incyte: Research Funding; Merck: Research Funding; Strategia Therapeutics: Research Funding; Janssen: Research Funding; GSK: Research Funding; Agensys: Research Funding; Oncoceutics, Inc.: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; Polaris: Research Funding; NKarta: Consultancy; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Arvinas: Research Funding; PTC Therapeutics: Consultancy; Cantargia AB: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare AG: Research Funding; Oncoceutics: Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Daver:Karyopharm: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Servier: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy; BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Agios: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Celgene: Consultancy; Glycomimetics: Research Funding; Otsuka: Consultancy; NOHLA: Research Funding; Sunesis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Jazz: Consultancy; Novartis: Consultancy, Research Funding. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; BiolineRx: Consultancy; Immunogen: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Biopath Holdings: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding.

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Efficacy of Induction Thearapy with Lenalidomide, Bortezomib, and Dexamethasone (RVD) in 1000 Newly Diagnosed Multiple Myeloma (MM) Patients

Blood ◽

10.1182/blood-2018-99-119895 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3294-3294 ◽

Cited By ~ 2

Author(s):

Nisha Joseph ◽

Vikas A. Gupta ◽

Craig C Hofmeister ◽

Charise Gleason ◽

Leonard Heffner ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Response Rates ◽

Newly Diagnosed ◽

Advisory Committees ◽

Entire Cohort ◽

Risk Patients ◽

Standard Risk

Abstract Background : Lenalidomide, bortezomib and dexamethasone (RVD) has been shown to be a well-tolerated and efficacious induction regimen in newly diagnosed myeloma patients. Two large randomized phase III trials show an overall response rate (ORR) >95% (Durie et al, Attal et al) supporting this combination regimen. We have conducted a retrospective analysis utilizing our institutional data of 1000 patients treated with RVD induction therapy at the Winship Cancer Institute of Emory University. Methods: 1000 newly diagnosed MM patients were treated with RVD induction therapy [R - 25 mg/day (days 1-14), V - 1.3 mg/m2 (days 1, 4 8, 11) and D - 40 mg once/twice weekly as tolerated every 21 days] from January 1st 2005 until August 31st 2016. Dose-adjustments were made based on the treating physician's discretion and patient tolerability. Demographic and outcomes data for the patients were obtained from our IRB approved myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: The median age of this cohort was 61 years (range 16-83). Other notable patient characteristics include: M/F 54.3%/45.6%; W/AA 56.4%/34%; ISS I and II/III 54%/17%; Isotype IgG/IgA/FLC 59.1%/19%/15.8%; standard risk/high risk 72%/28%. High risk disease was defined as the presence of t(4;14), t(14;16), del(17p), and/or complex karyotype. A total of 835 patients (83.5%) underwent autologous stem cell transplant (ASCT) upfront after attaining at least a partial response with induction therapy, and 165 patients (16.5%) were offered deferred transplant. Among the patients that opted for deferred transplant, 56 of these patients (33.9%) underwent ASCT at first relapse with a median time to transplant of 30 months (3-96). 755 (75.5%) of patients received risk-stratified maintenance therapy following transplant. Evaluation of responses to induction therapy for the entire cohort show an ORR 97.3% with ≥VGPR of 68% post-induction therapy. Response rates 100 days post-transplant show an ORR 98% with 30.7% of patients achieving a sCR. Response rates are summarized in table 1. Median PFS was 63 months for the entire cohort, and 72 months for standard risk patients (61.75-82.25) versus 37 months for the high-risk patients (30.84-43.16), p<0.001. Median OS has not been reached at median of 38 months follow up (Figure 1). Conclusions: This is the largest reported cohort of myeloma patients treated with RVD induction. These results illustrate both the activity of this induction regimen with impressive response rates and long-term outcomes in both standard and high risk patients. Disclosures Hofmeister: Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Heffner:ADC Therapeutics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Kaufman:BMS: Consultancy; Karyopharm: Other: data monitoring committee; Abbvie: Consultancy; Janssen: Consultancy; Roche: Consultancy. Lonial:Amgen: Research Funding. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: 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; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Long-Term Carfilzomib for High-Risk Patients with Newly Diagnosed Multiple Myeloma: A Pooled Analysis of Two Phase 1/2 Studies

Blood ◽

10.1182/blood-2018-99-112075 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3240-3240

Author(s):

Roberto Mina ◽

Alessandra Larocca ◽

Maria Teresa Petrucci ◽

Gianluca Gaidano ◽

Stelvio Ballanti ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Advisory Board ◽

Induction Phase ◽

Advisory Committees ◽

High Risk Patients ◽

Risk Patients ◽

Standard Risk

Abstract INTRODUCTION: High-risk cytogenetic abnormalities, such as del(17p), t(4;14), and/or t(14;16), are associated to an unfavorable prognosis. Several trials investigating current approved regimens have shown that high-risk multiple myeloma (MM) patients have shorter progression-free survival (PFS) and overall survival (OS) as compared to standard-risk patients. Carfilzomib, a second generation proteasome inhibitor, demonstrated to be able to improve the survival of high-risk MM patients in the relapse setting. Here we present a pooled analysis of two phase 1/2 studies to investigate the role of carfilzomib in high-risk, newly diagnosed (ND) MM patients. METHODS: Transplant ineligible patients with NDMM enrolled in the IST-CAR 561 and IST-CAR 506 studies were pooled together and analyzed. All patients received 9 28-day induction cycles of carfilzomib, either 70 mg/m2 once weekly (IST-CAR 561) or 36 mg/m2 twice weekly (IST-CAR 506), combined with weekly cyclophosphamide (300 mg/m2) and dexamethasone (40 mg) (CCyd). After the induction phase, patients proceeded to maintenance with single-agent carfilzomib until progressive disease or intolerable toxicity. The primary objective was to compare response to treatment, PFS, PFS-2 and OS in standard versus high-risk FISH, defined by the presence of del(17p), t(4;14), and/or t(14;16). A 15% cut-off point was used for detection of translocation [t(4;14) and t(14;16)] and 10% for detection of del(17p). RESULTS: 121 NDMM patients were enrolled in the IST-CAR 561 (n=63) and in the IST-CAR 506 (n=58) study. Cytogenetic data were available in 94 patients: 37 (31%) had high-risk chromosomal abnormalities by FISH, including 10% of patients with t(4;14), 3% with t(14;16) and 18% with del(17p), while 57 patients (47%) were classified as standard-risk. After the induction phase, no difference in terms of overall response rate (ORR; 86% vs. 92%; p=0.52) and at least near complete response (39% vs. 41%; p=1) was observed between standard and high-risk patients. After a median follow-up of 39 months, median PFS from enrollment was NR in standard-risk patients and 27.8 months in high-risk ones (HR: 0.76; p=0.38) (Figure 1); at 3 years, 52% and 43% of patients, respectively, were alive and free from progression. The PFS benefit for the comparison between standard and high-risk patients was more pronounced in patients who received once weekly carfilzomib at 70 mg/m2, (median: NR vs. 39.6 months; HR: 0.78, p=0.63) as compared to those treated with twice weekly carfilzomib at 36 mg/m2 (median: NR vs. 24.2 months; HR: 0.52, p=0.12). Median PFS-2 from enrollment was NR in standard-risk patients and 44.1 months in high-risk ones (HR: 0.66; p=0.26), without significant differences in the once weekly (median, NR vs. 39.6; p=0.27) and the twice weekly group (median; NR vs. 44.1; p=0.63). Median OS from enrollment was NR in standard-risk patients and 47.5 months in high-risk ones (HR:0.71; p=0.36) (Figure 1). In patients who received once weekly carfilzomib, median OS was NR and 47.5 months (HR:0.66, p=0.48) in standard and high-risk patients, respectively, while median OS in the twice weekly group was NR in standard-risk patients and 44.1 months (HR:0.73; p=0.55) in high-risk ones. CONCLUSION: In transplant ineligible patients with NDMM, carfilzomib combined with cyclophosphamide and dexamethasone as initial treatment mitigated the poor prognosis of high-risk FISH in terms of PFS, PFS-2 and OS. The median PFS of high-risk patients treated with CCyd compares favorably with those reported with current standard of care. As compared to twice weekly carfilzomib at 36 mg/m2, once weekly carfilzomib, at the dose of 70 mg/m2, confirmed to be effective in high-risk patients. These data support the use of carfilzomib for the treatment of high-risk NDMM patients. Figure 1. Figure 1. Disclosures Larocca: Janssen-Cilag: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Petrucci:Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board. Gaidano:AbbVie: Other: Advisory Board; Janssen: Other: Advisory Board, Speakers Bureau. Musto:Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Offidani:Janssen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board. Cavo:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Caravita di Toritto:Bristol-Myers Squibb: Honoraria, Other: Travel and Accomodation EMN; Amgen: Other: Advisory Board; Johnson & Johnson: Other: Advisory Board, Travel and Accomodation EHA; Celgene: Other: Advisory Board, Travel and Accomodation ASH, Research Funding; Takeda: Other: Advisory Board. Montefusco:Janssen: Other: Advisory Board; Amgen: Other: Advisory Board; Celgene: Other: Advisory Board. Palumbo:Takeda: Employment. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding. Bringhen:Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria.

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The Prognostic Power of Gene Expression Profiling with Cytogentics and Routinely Acquired Serum Markers: SKY92 Combined with Revised ISS

Blood ◽

10.1182/blood-2020-139987 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 24-25

Author(s):

Rowan Kuiper ◽

Mark van Duin ◽

Martin H Van Vliet ◽

Erik H Van Beers ◽

Berna Berna Beverloo ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Low Risk ◽

Ensembl Gene ◽

Private Company ◽

Advisory Committees ◽

High Risk Patients ◽

Risk Patients ◽

Standard Risk

Background Updating prognostic models for multiple myeloma is important in the context of changing treatment options. Previously we have described the value of the prognostic marker SKY92, which identifies high-risk multiple myeloma patients, as well as the value of the combined SKY92-ISS marker. With the introduction of revised ISS, it is of interest to evaluate the value of the updated combination of SKY92 with R-ISS. Within the HOVON87/NMSG18 trial, stratification into 3 groups was described: high-risk: 11% SKY92 high-risk (HR) + R-ISS II-III, low-risk: 15% SKY92 standard risk (SR) + R-ISS I and intermediate risk (74%, other). The 3-year PFS rates were 54% (95%CI: 38-77%), 27% (95%CI: 21-37%) and 7% (95%CI: 1-46%) for SKY-RISS I, II and III, respectively (p < 0.001). The 3-yr OS rates for SKY-RISS I to III were 88%, 66% and 26% (p=6×10-7). Here we describe the validation of SKY92-RISS in the CoMMpass dataset. Methods SKY92 was determined using RNA-seq data available from the CoMMpass dataset. Briefly, the SKY92 score was obtained as a weighted summation of the expression given by the available Ensembl gene IDs, corresponding to the probe sets of the SKY92 classifier. Renormalization of the original SKY92 discovery data (HOVON65/GMMG-HD4) allowing a direct remodeling between the Affymetrix probe-set expressions (i.e. SKY92) and RNAseq Ensembl gene IDs. Only Ensembl gene IDs with an average log2 expression >8 were used. Revised ISS status was determined as described. For optimal comparison to the discovery cohort of the HOVON87/NMSG18 trial, the analysis was limited to 93 patients older than 65 years in the CoMMpass data set, that did not receive transplant, and for whom RNA-Seq at diagnosis, R-ISS and follow-up data were available. Results The median follow-up is 41 months. SKY92 identified 24 high-risk patients (24/93: 26%). The 3-yr PFS and OS rates of standard-risk patients were 49% and 80% respectively, compared to 23% and 44% for high-risk, resulting in a significant log rank test (p < 0.005). The R-ISS classified patients into the low-risk R-ISS I (24% of patients), intermediate-risk R-ISS II (63%) and high-risk R-ISS III (13%). The 3-yr PFS rates were 76% (RISS I), 33% (RISS II) and 33% (RISS III); for OS: 100% (RISS I), 68% (RISS II) and 33% (RISS III; PFS, p = 0.07; OS, p < 0.001). SKY92 and R-ISS were independent prognostic factors in terms of OS and PFS. The SKY-RISS classification resulted in 20% low-, 61% intermediate- and 18% high-risk patients (Figure 1). The 3-yr PFS rates were 81% (95%CI: 64-100%), 42% (95%CI: 30-59%) and 12% (95%CI: 3-44%; p < 0.001) and 3-yr OS rates were 100% (95%CI: 100-100%), 77% (95%CI: 66-89%) and 32% (95%CI: 16-61%; p <0.001). Out of 69 patients classed as standard risk using the SKY92 classifier (80% 3-yr OS rate), 17 and 52 were classified as SKY-RISS I and II, respectively, resulting in a 3-yr survival rate of 100% and 74%, respectively. In contrast, out of 24 SKY92 HR patients (44% 3 yr OS rate), 5 were classified as SKY-RISS II (100% alive at 3 years) with the remainder true high-risk patients (32% alive at 3 years). Out of 12 RISS III patients (3-yr OS, 33%), 5 were classified as SKY-RISS II (3-yr OS: 60%) and 7 as SKY-RISS III (3-yr OS: 14%). Conclusion This study demonstrates the value of gene expression profiling - SKY92 - alongside revised ISS. They form a solid combination, improving on either marker separately. Both models combined clearly identified more high-risk patients correctly, whilst also placing low risk patients into a more appropriate risk category. This was shown in the discovery set and was subsequently applied to an independent set, confirming the validity and usability of the SKY-RISS. Disclosures Kuiper: SkylineDx: Current Employment, Current equity holder in private company. Van Vliet:SkylineDx: Current Employment, Current equity holder in private company. Van Beers:SkylineDx: Ended employment in the past 24 months. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Broijl:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sonneveld:Sanofi: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

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Efficacy and Safety of Carfilzomib at 56mg/m2 with Cyclophosphamide and Dexamethasone (K56Cd) in Newly Diagnosed Multiple Myeloma Patients Followed By ASCT or K56Cd Consolidation: Initial Results of the Phase 2 Cardamon Study

Blood ◽

10.1182/blood-2019-127992 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 861-861 ◽

Cited By ~ 3

Author(s):

Kwee Yong ◽

Rakesh Popat ◽

William Wilson ◽

Gavin Pang ◽

Richard Jenner ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Cell Transplant ◽

Newly Diagnosed ◽

Advisory Committees ◽

Risk Patients ◽

Standard Risk

Introduction: Carfilzomib (20/36mg/m2) triplets with Lenalidomide-Dexamethasone (KRd), or Cyclophosphamide-Dexamethasone (KCd) are safe and effective in patients with newly diagnosed multiple myeloma(NDMM). The higher dose of 56mg/m2 is effective as a doublet with Dexamethasone in the relapsed setting, but there is limited data on this dose in triplet combinations in the frontline setting. Aim: The CARDAMON study evaluated KCd with bi-weekly carfilzomib (56mg/m2) as induction in NDMM patients, and the benefit of ASCT versus K56Cd consolidation followed by carfilzomib maintenance. Co-primary endpoints were major response (≥VGPR rate) to 4 induction cycles of K56Cd, and 2-year PFS for ASCT versus K56Cd consolidation. Here we report interim analysis of the first primary endpoint of ≥VGPR rate to K56Cd induction. Methods: Transplant eligible ND patients received 4 x 28d cycles of K56Cd (carfilzomib:20/56mg/m2, IV d1, 2, 8, 9, 15, 16, cyclophosphamide 500mg orally d1, 8, 15 and dexamethasone 20mg d1, 2, 8, 9, 15, 16). Responding patients with a successful stem cell harvest (PBSCH) were randomised to autologous stem cell transplant (ASCT) or 4 more cycles of K56Cd as consolidation, followed by 18 months carfilzomib maintenance (K56 days 1, 8, 15) for both arms. Trial recruitment completed in July 2019. Response was assessed by IMWG criteria; all patients had MRD testing by multi-parameter flow cytometry (10-5) after PBSCH. Adverse risk genetics was any one of t(4;14), t(14;16), t(14,20) or del(17p). Results: 281 pts were registered between 06/2015 and 07/2019; we report outcomes for 252 patients who either completed induction or came off study before end of induction. Median age was 58yrs(33-74), 91% ECOG 0-1, 45.2% ISS I, 24.7% adverse risk (48.5% when including 1p/1q+). Best response at end of induction or after PBSCH (n=250) was: ≥VGPR 59.2%, ORR 87.6%. ≥VGPR rate in adverse risk patients was 53.4% vs 61.9% in standard risk(SR), (p=0.25), ORR was similar: adverse risk, 87.9% vs standard risk, 88.1%. Post-PBSCH, 24.1% of patients were MRD-negative (patients who were withdrawn due to insufficient induction response or toxicity and those with an inconclusive result were grouped with the MRD-positive). Of 19 patients in sCR/CR, 9 were MRD-negative(47.4%) while 40/110 (36.4%) of VGPR patients were MRD-negative. MRD-negative rates in adverse and standard risk patients were 22.8% and 24.7% respectively. 10 patients progressed during or at end of induction, and 12 were withdrawn for toxicity. There were 4 deaths during induction, one from myocardial infarction, the other 3 from cardiac arrest, associated with bronchopneumonia and sepsis. During induction, 114 serious adverse events (SAEs) were reported in 72/252 patients, notable ones were thrombotic microangiopathy (2), grade 3 cardiac ischaemia (4), infection (16.3%, mainly lung), renal impairment (6), G3 hypertension (3), thromboembolism(2). Specific guidance for hypertension management was incorporated. 25% of patients are currently reported to have received a dose modification during induction. Full details of adverse events and dose intensity will be presented at the meeting. Conclusion: K56Cd is an effective induction regimen in NDMM patients, and has equivalent MRD negative rates in adverse and standard risk disease. The SAE profile is in keeping with published safety data with carfilzomib. Disclosures Yong: Sanofi: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Autolus: Consultancy; Janssen: Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Popat:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; Janssen: Honoraria, Other: travel support to meetings; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria; Takeda: Honoraria, Other: travel, accommodations, expenses. Ramasamy:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; NAPP Pharmaceuticals Ltd.: Research Funding; Janssen-Cilag Ltd.: Research Funding; Oncopeptides and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chapman:Takeda: Honoraria. Benjamin:Allogene: Research Funding; Gilead: Honoraria; Novartis: Honoraria; Pfizer: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Servier: Research Funding; Eusapharm: Consultancy. Owen:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel/ meeting support. OffLabel Disclosure: Carfilzomib is used with cyclophosphamide as 1st line treatment for myeloma

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Validation of the EMC92/SKY92 Signature in HOVON-87/Nmsg-18: Gene Expression Based Prognostication Is Applicable in Elderly Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.2967.2967 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2967-2967

Author(s):

Mark van Duin ◽

Rowan Kuiper ◽

Martin van Vliet ◽

Annemiek Broijl ◽

Leonie de Best ◽

...

Keyword(s):

Gene Expression ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Low Risk ◽

Advisory Committees ◽

Hazard Ratios ◽

Risk Patients ◽

Standard Risk

Abstract Improved prognostication is required for multiple myeloma (MM). So far, marker development has been based on clinical trials with a study population predominantly younger than 65 years. However, the median age of newly diagnosed MM patients is 66 years old. Based on gene expression profiles of the HOVON-65/GMMG-HD4 dataset, we previously developed the EMC92 prognostic signature, consisting of 92 probe sets for improved prognostication in MM. The EMC92 was validated in the MRC-IX, TT2, TT3 and APEX datasets. These studies were mostly aimed at younger patients with a median age of 57 years. The EMC92 signature was subsequently developed for clinical use as part of the MMprofiler, and termed the SKY92 signature. To assess the validity of the SKY92 signature in older MM patients, we used the HOVON-87/NMSG-18 study, in which induction therapy with melphalan, prednisone and thalidomide, followed by thalidomide maintenance, was compared with melphalan, prednisone and lenalidomide, followed by lenalidomide maintenance (MPT-T vs. MPR-R). The median age of all patients included in this trial was 73 years, with 34% of patients 76 years or older. The median follow up of the patients still alive was 39 months. Of 143 patients both gene expression profiling and clinical data were available (median age 73; 30% ≥76; n=83 MPT-T; n=60 MPR-R). The MMprofiler was used to obtain SKY92 scores, classifying a patient as high risk or standard risk (MMprofiler- CE IVD assay, performed according to the manufacturers' instructions for use at the SkylineDx reference lab, Rotterdam, The Netherlands). The association between survival and the SKY92 signature was evaluated using Cox regression analysis. Kaplan-Meier curves were constructed for visualization. Using the SKY92 signature 22/143 patients were identified as high risk (15.4%). The median overall survival (OS) for high risk patients was 21 months, compared to 53 months for standard risk patients (hazard ratio (HR): 2.9 (95% confidence interval (CI): 1.6-5.4; p=5.6 x 10-4)). The median progression free survival (PFS) in the high risk and standard risk groups were 12 months and 23 months, respectively (HR: 2.2 (95% CI: 1.4-3.7; p=1.2 x 10-3)). In this subset of 143 patients, deletion of 17p (del17p) and gain of 1q (gain1q) were also adversely associated with OS in a univariate analysis. Including SKY92, del(17p) and gain(1q) in a multivariate model demonstrated that SKY92 and del(17p) remained significantly associated with OS (subset of 143 (n=101) with all data known; Table 1). We previously developed the combination of ISS with SKY92: low risk (ISS I-SKY92 standard risk (SR)), intermediate-low (ISS II-SKY92 SR), intermediate-high (ISS III-SKY92 SR) and high risk (ISS I-III, SKY92 high risk; Kuiper et al., ASH 2014, #3358). The Cox model for this combined marker has a p-value for the likelihood ratio test of p=3 x 10-3 for OS (Figure 2) and p=0.016 for PFS. In conclusion, the SKY92 signature (MMprofiler) is a useful prognostic marker to identify a high-risk subgroup in the elderly population. Figure 1. Performance of the SKY92 signature in the HOVON-87/NMSG-18 study. Red line indicates high risk patients (n=22), blue line indicates standard risk patients (n=121). PFS (A); OS (B). Figure 1. Performance of the SKY92 signature in the HOVON-87/NMSG-18 study. Red line indicates high risk patients (n=22), blue line indicates standard risk patients (n=121). PFS (A); OS (B). Table 1. SKY92 in relation to FISH markers in the HOVON-87/NMSG-18 (Hazard ratios (HR), 95% confidence intervals (CI) and p-values (2-sided; p) for Cox proportional hazards analysis). The multivariate analysis (bottom) was performed using the markers significant in the univariate analysis (top). Bold: p<0.05, pos: positive, neg: negative and na: not available. Table 1. SKY92 in relation to FISH markers in the HOVON-87/NMSG-18 (Hazard ratios (HR), 95% confidence intervals (CI) and p-values (2-sided; p) for Cox proportional hazards analysis). The multivariate analysis (bottom) was performed using the markers significant in the univariate analysis (top). Bold: p<0.05, pos: positive, neg: negative and na: not available. Figure 2. Combining ISS with SKY92. Groups are defined in the text. Hazard ratios of the individual groups are given relative to the low risk group. Figure 2. Combining ISS with SKY92. Groups are defined in the text. Hazard ratios of the individual groups are given relative to the low risk group. Disclosures Kuiper: SkylineDx: Employment. van Vliet:SkylineDx: Employment. Broijl:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. de Best:SkylineDx: Employment. van Beers:SkylineDx: Employment. Bosman:SkylineDx: Employment. Dumee:SkylineDx: Employment. van den Bosch:SkylineDx: Employment. Waage:Amgen: Research Funding; Celgene: Research Funding; Janssen: Research Funding. 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. Sonneveld:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Research Funding; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Research Funding.

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Targeted Deep Sequencing As a Clinically Effective Approach to Profile the Mutational Landscape in Multiple Myeloma

Blood ◽

10.1182/blood-2020-137754 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 37-38

Author(s):

Samuel Cutler ◽

Dan Gaston ◽

Philipp Knopf ◽

Andrea Thoni ◽

Nicholas Allen Forward ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Cell Lines ◽

Research Funding ◽

Advisory Committees ◽

Clinical Correlates ◽

High Severity ◽

Risk Patients ◽

Standard Risk

Introduction: Multiple Myeloma (MM) is the second most common hematological malignancy in North America. It is characterized by invasion of the bone marrow by malignant plasma cells. This malignancy presents with a broad range of primary genomic lesions that dichotomize cases into hyperdiploidy or IgH translocated. Less recurrent secondary focal events, including indels and SNPs, are also reported, however, their clinical correlates are poorly described. In this study, we examine the exonic landscape of 26 genes reported to be mutated in >1% of myeloma patients via deep sequencing using a custom panel. We assess a cohort of 76 patients banked in the QEII Myeloma Tumor Bank with detailed clinical correlates and 4 MM cell lines for their mutational profile. Methods: DNA Library preparations were performed from CD138+ cells (76 MM) and 4 MM cell lines according to Illumina TruSeq protocol and sequenced at a depth of 1000x using a custom designed mutation panel. Variants were called by six somatic variant callers and correlates with patient clinical data were assessed. Results: A total of 376 mutations were identified within 63 patients (325) and 4 cell lines (51); no mutations were identified in 13 patients. ATM was the most mutated gene and KRAS had the highest number of mutations per kilobase. Forty three patients harbored 1-4 mutations, 12 patients harbored 5-9, and 8 patients harbored ≥10 mutations. Progression-free survival (PFS) was found to be significantly reduced in patients harboring high-severity mutations (frame shift, splice site, and stop altering mutations) (n =15 HR = 2.85; 95% CI: 1.3-6.35; p = 0.01). We also assessed mutations by the pathogenicity scoring algorithms rfPred, SIFT, MutationTaster, Polyphen2, and FATHMM-FX, as well as SPLICEAI which predicts splicing impacts of mutations. FATHMM-FX was the only algorithm to identify mutations that define a group with significantly altered PFS (n = 5; HR = 6.7; 95% CI: 2.5-18; p < 0.001). We then combined these indicators to define high-risk patients such that a patient is considered high risk if they harbor one or more mutations that are high-severity or predicted by FATHMM-FX to be pathogenic. Of the 376 in our cohort, 23 were high-risk markers, 19 of which were in patient samples. This classified 16 of 76 patients as high risk which had significantly reduced PFS (n = 16; HR = 3.5; 95% CI: 1.6-7.6; p = 0.002) (Fig. 1 A-B). Notably, 2 high risk mutations were found in 3 patients, one of whom had plasma cell leukemia (PCL) and the other progressed to PCL. This group had a markedly reduced PFS (n = 3; HR = 16; 95% CI: 2.9-83; p = 0.001) (Fig. 1 C-D). Additionally, focal copy-number alterations (CNVs) were probed from panel data, and patients harboring 2 or more focal CNVs had significantly reduced PFS (n = 10, HR = 3.2, 95% CI: 1-9.1, p = 0.043). Combining focal CNV and mutation risk identified 24 patients with significantly reduced PFS (HR = 4.2; 95% CI: 1.9-9.1; p < 0.001) (Fig. 1 E-F). Harboring a high-risk mutation or more than one focal CNV was independent of age, ISS stage, Beta-2 microglobulin, serum albumin, LDH, and bone marrow plasma cell burden. Of 48 fluorescent in situhybridization (FISH) assessed patients, 12 had 'high risk' FISH findings, none of whom had severe mutations though 1 harbored two focal CNVs. Of the 36 patients standard-risk by FISH, 12 had high-risk mutations, and 5 had more than one panel identified focal CNV. Combined, these identified 15 high-risk patients in the FISH standard-risk group which had significantly reduced PFS (HR = 3.7; 95% CI: 1.1-12; p = 0.031) (Fig. 1 G-H). Conclusion: Our custom mutation panel demonstrates novel findings that independently redefine prognosis in multiple myeloma in our cohort of Nova Scotian patients. Figure 1 Disclosures Forward: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Calgene: Membership on an entity's Board of Directors or advisory committees; IMV: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Astellas: Research Funding; IMV: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding. White:Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Amgen: Honoraria.

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ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

Blood ◽

10.1182/blood-2019-128198 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1565-1565 ◽

Cited By ~ 1

Author(s):

Patrizia Mondello ◽

Irene Dogliotti ◽

Jan-Paul Bohn ◽

Federica Cavallo ◽

Simone Ferrero ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advanced Stage ◽

Advisory Committees ◽

Free Survival ◽

High Risk Patients ◽

Risk Patients

Purpose: Hodgkin's lymphoma (HL) is a highly curable disease even in advanced-stage, with >90% of long-term survivors. Currently, the standard of care is ABVD (doxorubicin, etoposide, vinblastine and dacarbazine), as it is less toxic and as effective as other more intensive chemotherapy regimens. Alternatively, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) has been proposed as front-line intensified regimen with a better initial disease control and prolonged time to relapse when compared to ABVD. However, this advantage is associated with higher rates of severe hematologic toxicity, treatment-related deaths, secondary neoplasms and infertility. To date, the debate regarding which regimen should be preferred as first line for advanced-stage HL is still ongoing. To shed some light on this open question we compared efficacy and safety of both regimens in clinical practice. Patients and Methods: From October 2009 to October 2018, patients with HL stage III-IV treated with either ABVD or BEACOPP escalated (BEACOPPesc) were retrospectively assessed in 7 European cancer centers. Results: A total of 372 consecutive patients were included in the study. One-hundred and ten patients were treated with BEACOPPesc and 262 with ABVD. The baseline characteristics of the two groups did not differ significantly, except for a higher rate of high-risk patients in the BEACOPPesc group in contrast to the ABVD one (47% vs 18%; p= 0.003). Complete response rate (CR) assessed by PET imaging at the end of the second cycle was 67% and 78% for the ABVD and BEACOPPesc group (p= 0.003), respectively. Thirteen patients of the ABVD group achieved stable disease (SD) and 6 had a progression disease (PD). On the other hand, 4 of the patients in the BEACOPPesc group progressed, another 2 interrupted therapy because life-threatening toxicity. At the end of the therapy, CR was 76% in the ABVD group and 85% in the BEACOPPesc group (p= 0.01). A total of 20% patients in the ABVD group and 14% patients in the BEACOPPesc group received consolidation radiotherapy on the mediastinal mass at the dose of 30Gy. After radiotherapy, the number of patients with CR increased to 79% and 87% in the two groups (p= 0.041), respectively. Thirty-nine patients (35%) in the BEACOPPesc group required dose reduction of chemotherapy due to toxicity compared to 12 patients (5%; p= <0.001) in the ABVD group. Overall, the rate of severe toxicities was higher in the BEACOPPesc group in comparison with the ABVD cohort. In particular, there was a significant increased frequency of acute grade 3-4 hematologic adverse events (neutropenia 61% vs 24%; anemia 29% vs 4%; thrombocytopenia 29% vs 3%), febrile neutropenia (29% vs 3%), severe infections (18% vs 3%). Myeloid growth factors were administered to 85% and 59% of patients in the BEACOPPesc group compared to the ABVD group. Blood transfusions were required in 51% and 6% of patients in the BEACOPPesc group compared to the ABVD cohort. Progression during or shortly after treatment occurred in 5 patients in the BEACOPPesc group (4%) and in 16 patients in the ABVD group (6%; p= 0.62). Among the 96 patients who achieved a CR after BEACOPPesc and radiotherapy, 8 relapsed (8%), compared to 29 of 208 patients in the ABVD group (14%; p= 0.04). At a median follow-up period of 5 years, no statistical difference in progression free survival (PFS; p=0.11) and event-free survival (EFS; p=0.22) was observed between the BEACOPPesc and ABVD cohorts. Similarly, overall survival (OS) did not differ between the two groups (p=0.14). The baseline international prognostic score (IPS <3 vs ≥ 3) significantly influenced the EFS with an advantage for the high-risk group treated with BEACOPPesc (Figure 1A; p=0.03), but not the PFS (Figure 1B; p=0.06) and OS (Figure 1C; p=0.14). During the follow-up period, in the BEACOPPesc group one patient developed myelodysplasia and one acute leukemia. Second solid tumors developed in one patient in the ABVD group (lung cancer) and one in BEACOPPesc group (breast cancer). Conclusion: We confirm that the ABVD regimen is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control especially in high-risk patients, the long-term outcome remains similar between the two regimens. Disclosures Ferrero: EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau. Martinelli:BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Novartis: Consultancy. Willenbacher:European Commission: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujimoto: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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