scholarly journals BRAF V600E Targetable Mutation in Relapsed/Refractory Multiple Myeloma (R/R MM) Patients: A High Incidence in R/R MM Detected Using Cell Sorting Screening

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5638-5638
Author(s):  
Alina Danu ◽  
Sophie Cotteret ◽  
Ludovic Lacroix ◽  
Véronique Saada ◽  
Véronique Vergé ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Cell Sorting ◽  
Braf Mutation ◽  
Research Funding ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Newly Diagnosed ◽  
Braf Mutations ◽  
Advisory Committees

Abstract Background: The oncogenic BRAF V600E mutation activates the MAPK signaling pathway resulting in cell growth and survival of tumor cells carrying the mutation. Targeting BRAF has shown its efficacy in metastatic melanomas. BRAF V600E mutation has been described in multiple myeloma (MM), with an incidence of 4-10% in previous reports. We report here the incidence of BRAF mutations in a series of MM patients treated at our center. Methods: From February 2012 to March 2016, 94 MM patients were tested for BRAF mutations. Eighty-one samples came from patients with relapsed/refractory MM (R/R MM) and 13 samples from newly diagnosed patients. Eighty-eight samples were collected from bone marrow aspirates, 3 from extramedullary plasmacytoma biopsies, 1 from pleural effusion, and 2 from peripheral blood. Targeted sequencing for BRAF mutations using Sanger direct sequencing or targeted next generation sequencing were performed on all samples after CD138 cell (after 2015). In addition, NGS was performed for 2 patients. From 2012 to 2015, we used material obtained from scraping bone marrow smears with > 20% plasma cells. Since 2015, we began using immunomagnetic cell-sorting based on the CD138 cell surface marker (Stem Cells®). Results: BRAF mutations were detected in 8 samples out of the 84 that could have been screened (9.5%). When considering only the relapsed/refractory population, the incidence of BRAF mutations was 10.8%. One sample had the inactivating D594N BRAF mutation and the other 7 had the V600E BRAF mutation. The 8 mutated patients had relapsed/refractory MM at the time of analysis. Of note, 5 out of the 8 mutated patients (62.5%) had an IgA MM. Seventy-six samples had no BRAF mutation detectable. Ten samples were not tested because of the small percentage of MM cells on the bone marrow smears. The failure rate was 16% with the scraping technique and 3.4% with the sorting cell technique. Five out of 7 patients harboring the V600E BRAF mutation were treated with a BRAF inhibitor in different clinical trials. One mutated patient could not be treated due to exclusion criteria related to an underlying condition (terminal renal failure requiring chronic hemodialysis) and one patient received allogeneic stem-cell transplantation at relapse. No BRAF mutation was detected in the 13 newly diagnosed patients. Conclusion: Our results show that BRAF screening is feasible in routine practice and can help orienting therapy in relapsed/refractory MM patients. The incidence of 9.5% that we found in our series compares favorably with previously published results, and we observed a slightly increased incidence of 10.8% in the R/R population. The cell sorting technique seems to be more effective than the scraping technique for MM sample DNA acquisition and BRAF mutation screening. Results of BRAF inhibitors therapy in MM are eagerly awaited. Disclosures Lacroix: sanofi: Research Funding; qiagen: Membership on an entity's Board of Directors or advisory committees; roche: Membership on an entity's Board of Directors or advisory committees; astrazeneca: Membership on an entity's Board of Directors or advisory committees. Michot:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Ribrag:ArgenX: Research Funding; Esai: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; NanoString: Membership on an entity's Board of Directors or advisory committees.

The Ki67/CD138 Ratio Independently Predicts Overall Survival in the Upfront Treatment of Newly Diagnosed Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2016-2016
Author(s):  
Tomer M Mark ◽  
Peter Forsberg ◽  
Ihsane Ouansafi ◽  
Adriana C Rossi ◽  
Roger N Pearse ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Complete Response ◽  
Newly Diagnosed ◽  
First Line ◽  
Advisory Committees ◽  
Line Therapy

Abstract Background: Assessment of malignant plasma cell cycling via plasma cell labeling index (PCLI) has been a validated prognostic tool in multiple myeloma (MM) but the test requires specialized technical expertise and is not widely available. Ki67 is a well-known protein marker of cellular proliferation on immunohistochemical (IHC) staining with prognostic utility in other malignancies. In an effort to develop a simpler system to provide analogous information to PCLI, we used a novel IHC co-staining technique for CD138 and Ki67 to quantify plasma cells in active cycling. We then performed a retrospective analysis of the ratio of Ki67/CD138 (Ki67%) in newly diagnosed patients with multiple myeloma receiving 1st-line therapy to correlate with clinical outcomes. Methods: A retrospective cohort study of patients (pts) with treated symptomatic MM was performed by interrogation of the clinical database at the Weill Cornell Medical College / New York Presbyterian Hospital. For inclusion in the analysis, subjects must have started first-line treatment in the period of 2005-2010, and had available bone marrow biopsies. Double-staining with Ki67 and CD138 was performed by IHC. The Ki67% was calculated as the percent of plasma cells expressing CD138 that were also found to express Ki67. Treatment outcomes were stratified and compared based on %Ki67. Response was determined by monthly serum protein electrophoresis / immunofixation (IFX) with free light chain analysis according to International Multiple Myeloma Working Group (IMWG) guidelines. Pts who were IFX negative but had no subsequent bone marrow biopsy were classified as being in unconfirmed complete remission. Results: We identified 151 patients with newly diagnosed MM and available %Ki67 expression who received first-line therapy over the period of 2005-2010. Patient were subdivided into two groups based on %Ki67: Low: %ki67 <= 5%, n = 87; and High: %Ki67 >5, n=64, to allow for comparison of treatment response and survival analysis. Specific therapeutic agent exposure history did not differ significantly between patients. Both groups had similar depth of response rates (ORR) to front-line therapy, Table 1. Median progression-free survival for the high versus low %Ki67 groups approached statistical significance at 54 months (95% CI 30.8,67.4) versus 26.9 months (95% CI 21.6,40.2), respectively (P = 0.083). At data cut-off, there were 30 deaths in the low %Ki67 group (1-yr OS 93%, 5-yr OS 71%) and 36 deaths in the high %Ki67 group (1-yr OS 94%, 5-yr OS 62%). Median overall survival (OS) was not reached for Ki67% <= 5% (95% CI 97.3,NR) vs. 78.9 months (95% CI 55.9,93.1) for Ki67% > 5%, (P = 0.0434), Figure 1. Multivariate cox regression for factors with influence on OS showed that only high-risk cytogenetics (HR 2.05, 95% CI 1.17, 2.92, P = 0.027), ISS (HR 1.835, 95% CI 1.33, 3.60, P = 0.000), and %Ki67 group status had an independent effect on survival outcome. Low (<=5%) versus high (>5%) %Ki67 influenced overall survival with a hazard ratio of 1.76 (CI 1.07,2.92, P = 0.027). Survival after ASCT was significantly longer in the low %Ki67 group with median OS not reached (95%CI, 97.3, NR) versus 86.9 months (95% CI 43.9, NR) for high %Ki67 group (P = 0.04). Discussion: The ratio of IHC double positive Ki67 and CD138 of > 5% is an independent prognostic marker for overall survival in newly diagnosed MM undergoing 1st line therapy. The %Ki67 serves as a simpler and widely available analog to PCLI that can be presently performed in most hematopathology laboratories. Table 1: First Line Treatment and Best Response (modified IMWG Criteria) Ki67% <= 5(N = 87)n (%) Ki67% > 5(N = 64)n (%) P Treatment Exposure* Lenalidomide 59 (67.8) 48 (75) 0.34 Thalidomide 30 (34.5) 14 (21.9) 0.09 Bortezomib 25 (28.7) 14 (21.9) 0.34 Alkylating agent 11 (12.6) 4 (6.3) 0.19 ASCT 27 (31) 22 (34.4) 0.66 Best Response Overall Response (>= Partial response) 77 (88.4) 57 (89.1) 0.41 Complete response 15 (17.2) 22 (34.4) Unconfirmed complete response** 14 (16.1) 8 (12.5) Very good partial response 23 (26.4) 15 (23.4) Partial response 25 (28.7) 12 (18.8) Stable disease 9 (10.3) 5 (7.8) Progressive disease 1 (1.2) 2 (3.1) * Percentages do not add to 100% due to instances of concurrent therapy use ** Unconfirmed complete response: immunofixation negative, but no confirmatory bone marrow biopsy available Figure 1 Overall Survival by %Ki67 Figure 1. Overall Survival by %Ki67 Disclosures Mark: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Pekle:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perry:Celgene: Speakers Bureau. Coleman:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Honoraria. Niesvizky:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Targeting EZH2 in Multiple Myeloma Could be Promising for a Subgroup of MM Patients in Combination with IMiDs

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 311-311 ◽  
Author(s):  
Laurie Herviou ◽  
Alboukadel Kassambara ◽  
Stephanie Boireau ◽  
Nicolas Robert ◽  
Guilhem Requirand ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Myeloma Cells ◽  
Ezh2 Expression ◽  
Bone Marrow Plasma

Abstract Multiple Myeloma is a B cell neoplasia characterized by the accumulation of clonal plasma cells within the bone marrow.Epigenetics is characterized by a wide range of changes that are reversible and orchestrate gene expression. Recent studies have shown that epigenetic modifications play a role in multiple myeloma (MM) by silencing various cancer-related genes. We investigated the epigenetic genes differentially expressed between normal bone marrow plasma cells (BMPC ; N=5) and MM plasma cells from patients (N=206). Using SAM (Significance Analysis of Microarrays) analysis, only 12 genes significantly differentially expressed between BMPC and MM cells (ratio > 2 and FDR (false discovery rate) < 5%) were identified, including the EZH2 histone methyltransferase. EZH2, the enzymatic subunit of Polycomb Repressive Complex 2, is a histone methyltransferases able to repress gene expression by catalyzing H3K27me3 histone mark. EZH2 overexpression has been associated with numerous hematological malignancies, including MM. We thus studied EZH2 role in MM physiopathology and drug resistance. EZH2 expression was analyzed in normal bone marrow plasma cells (BMPCs; N=5), primary myeloma cells from newly diagnosed patients (MMCs; N=206) and human myeloma cell lines (HMCLs; N=40) using Affymetrix microarrays. EZH2 gene is significantly overexpressed in MMCs of patients (median 574, range 105 - 4562) compared to normal BMPCs (median = 432; range: 314 - 563) (P < 0.01). The expression is even higher in HMCLs (median 4481, range 581 - 8455) compared to primary MMCs or BMPCs (P < 0.001). High EZH2 expression is associated with a poor prognosis in 3 independent cohorts of newly diagnosed patients (Heidelberg-Montpellier cohort - N=206, UAMS-TT2 cohort - N=345 and UAMS-TT3 cohort - N =158). Furthermore, GSEA analysis of patients with high EZH2 expression highlighted a significant enrichment of genes involved in cell cycle, downregulated in mature plasma cells vs plasmablasts, and EZH2 targets. Specific EZH2 inhibition by EPZ-6438 EZH2 inhibitor induced a significant decrease of global H3K27me3 in all the HMCLs tested (P < 0.01) and inhibited MM cell growth in 5 out of the 6 HMCLs tested. The inhibitory effect of EZH2 inhibitor on MM cell growth appeared at day 6 suggesting that it is mediated by epigenetic reprogramming. To confirm that EZH2 is also required for the survival of primary MMCs from patients, primary MM cells (n = 17 patients) co-cultured with their bone marrow microenvironment and recombinant IL-6 were treated with EPZ-6438. As identified in HMCLs, EZH2 inhibition significantly reduced the median number of viable myeloma cells by 35% (P = 0.004) from a subset of patients (n=9) while the other group (n=8) was resistant. Of interest, EPZ-6438 induced a significant global H3K27me3 decrease in both groups of patient. RNA sequencing of 6 HMCLs treated with EPZ-6438 combined with H3K27me3 ChIP analyses allowed us to create an EZ GEP-based score able to predict HMCLs and primary MM cells sensitivity to EZH2 inhibitors. We also observed a synergy between EPZ-6438 and Lenalidomide, a conventional drug used for MM treatment. More interestingly, pretreatment of myeloma cells with EPZ-6438 significantly re-sensitize drug-resistant MM cells to Lenalidomide. Investigating the effect of EPZ-6438/Lenalidomide combination in MMC, we identified that IKZF1, IRF4 and MYC protein levels were significantly more inhibited by the combination treatment (65.5%, 63.9% and 14.8% respectively) compared with Lenalidomide (51.5%, 43% and 2.2%) or EPZ-6438 (45.2%, 38.7% and 6.2%) alone. Clinical trials are ongoing with EZH2 inhibitors in lymphoma and could be promising for a subgroup of MM patients in combination with IMiDs. Furthermore, the EZ score enables identification of MM patients with an adverse prognosis and who could benefit from treatment with EZH2 inhibitors. Disclosures Goldschmidt: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, 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, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: 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; Amgen: Membership on an entity's Board of Directors or advisory committees. Hose:EngMab: Research Funding; Takeda: Other: Travel grant; Sanofi: Research Funding.

Advanced Imaging and Targeted Myeloma Lesion Biopsies to Enhance Global Response Assessment and Evaluate Spatial Heterogeneity in Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-22
Author(s):  
Sabrina L. Browning ◽  
Terri L. Parker ◽  
Noffar Bar ◽  
Tara Anderson ◽  
Madhav V. Dhodapkar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Assessment ◽  
Advisory Board ◽  
Newly Diagnosed ◽  
Advanced Imaging ◽  
Advisory Committees

Background: Multiple myeloma (MM) is a heterogeneous plasma cell neoplasm with significant genetic and biologic complexity. Limitations remain in our standard assessment of response to therapy, as random bone marrow biopsy may misrepresent the varied histologic and molecular features of this multifocal disease. Advanced imaging is crucial in evaluating bone and extramedullary (EM) lesions. We aim to refine global response assessment in MM, with incorporation of advanced imaging-guided lesion biopsies, to improve knowledge of residual tumor burden critical to patient outcomes. Methods: Patients ≥18 years of age with standard or high risk newly diagnosed clinical MM were eligible to participate in this study. Advanced imaging with positron emission tomography/computed tomography (PET/CT) or whole body magnetic resonance imaging (WB-MRI) based on access, standard bone marrow biopsy and aspiration, and targeted lesion biopsy occurred at enrollment and after 4 cycles of carfilzomib, lenalidomide, and dexamethasone (CRd). Carfilzomib was administered intravenously at a dose of 36 mg/m2 twice weekly, lenalidomide orally 25 mg daily days 1-21, and dexamethasone orally 40 mg weekly, with dose modifications as needed. Conventional clinical response, using IMWG Response Criteria (Kumar S et al, 2016), was assessed after each cycle of treatment. Results: An interim analysis was completed on 17 patients enrolled between June 2018 and March 2020, with 14 evaluable for global treatment response. Median age was 61 years (range, 43-76 years) and 82.4% of patients were male. 76.5% had Revised International Staging System (R-ISS) stage II or III disease and 58.8% had EM disease arising from bone (EM-B, 41.2%) or independently in soft tissue (EM-S, 17.6%). 70.6% of patients had at least one high risk feature at the time of diagnosis (Table 1). Of the 16 patients with conventional skeletal survey (CSS) at study entry, 68.8% had at least 1 myeloma-defining lesion on advanced imaging that was missed on CSS. Four patients had adequate sample from initial lesion biopsy for cytogenetics and fluorescence in situ hybridization (FISH), 3 of whom demonstrated discordant FISH results when compared to standard bone marrow samples. Clinical response rates after 4 cycles of CRd were notable with 85.7% of patients achieving ≥ very good partial response (VGPR) and 3 patients with stringent complete response (sCR) and minimal residual disease (MRD) negativity by flow cytometry with a sensitivity of 10-5. However, of the 12 patients with ≥ VGPR by conventional response assessment, 9 had residual disease on advanced imaging with PET/CT (2 patients), WB-MRI (6 patients), or total spine MRI (1 patient) (Figure 1). Repeat myeloma lesion biopsy was limited to 6 patients with targetable lesions after induction therapy, with diagnostic yield impacted by the presence of sclerotic tissue and insufficient marrow elements in some of the lesions sampled (Table 2). 85.7% of patients continued CRd or proceeded to high dose therapy and autologous stem cell rescue, with no patients transitioning directly to maintenance treatment after 4 cycles of CRd. At a median follow-up of 8 months, 14.3% (2/14) of patients have had progression of disease. Both individuals had residual lesions on imaging at end of treatment, despite one with flow MRD-negative sCR and normal FISH by standard assessment. There were no grade 4 serious adverse events or deaths. Conclusions: In our cohort of high risk newly diagnosed MM, CRd induction was potent and well-tolerated. While deep clinical responses were observed by conventional clinical assessment, two thirds of patients had persistent abnormalities on advanced imaging with concern that these sites could give rise to progressive MM. Our patients demonstrated spatial heterogeneity, highlighting the limitations of standard bone marrow evaluation. Use of advanced imaging and targeted lesion biopsies in response assessment enhances our understanding of tumor growth pattern in MM and consideration could be given to integrating these into clinical care when available. Current limitations of this study include a small number of patients with lesions amendable to repeat biopsy and their incomplete diagnostic yield. Ongoing investigation includes whole exome sequencing of paired bone marrow and focal lesion biopsies and application of a WB-MRI lesion scoring system to further augment this novel response assessment method. Disclosures Anderson: Celgene: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau. Dhodapkar:Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Lava Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Kite: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board. Prebet:Jazz Pharmaceuticals: Consultancy, Research Funding. Xu:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Haims:Pfizer: Consultancy. Neparidze:Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Diagnostic committee member ; GlaxoSmithKline: Research Funding; Janssen: Research Funding. OffLabel Disclosure: Carfilzomib has been shown to have significant anti-myeloma activity in relapsed myeloma. Phase I/II studies as well as one phase III study also showed favorable outcomes with carfilzomib-based regimens in newly diagnosed multiple myeloma, including in patients with high risk disease. We utilized an induction regimen with carfilzomib, lenalidomide, and dexamethasone given that patients enrolled in this study were required to have bone or soft tissue disease on advanced imaging, indicating a likely high risk feature with potentially aggressive disease biology. It has been shown that the combination of carfilzomib, lenalidomide, and dexamethasone is a safe regimen for patients with multiple myeloma. This combination is approved in the relapsed/refractory setting and included in NCCN guidelines for newly diagnosed multiple myeloma.

scholarly journals Overall Survival in Older Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) with >30% Bone Marrow Blasts Treated with Azacitidine By Cytogenetic Risk Status: Results of the AZA-AML-001 Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 621-621 ◽  
Author(s):  
Hartmut Döhner ◽  
John F Seymour ◽  
Aleksandra Butrym ◽  
Agnieszka Wierzbowska ◽  
Dominik Selleslag ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Older Patients ◽  
Research Funding ◽  
Risk Groups ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Poor Risk ◽  
Equity Ownership

Abstract Background: Overall survival (OS) in older patients (pts) with AML and poor-risk cytogenetics is only ~2-3 months (mos) (Burnett, Cancer, 2007). Often these pts receive only palliative treatment (Tx) with best supportive care (BSC). Low-dose Ara-C (LDAC) provides no OS benefit in pts with poor cytogenetics (Döhner, Blood, 2010). Typically, intensive chemotherapy (IC) is either not suitable for older AML pts with poor cytogenetics or, when it is used, provides no OS benefit (Kantarjian, Blood, 2010). The phase 3, multicenter, randomized, open-label AZA-AML-001 trial showed azacitidine (AZA) Tx in older pts with newly diagnosed AML (>30% bone marrow [BM] blasts) prolonged median OS by ~4 mos vs conventional care regimens (CCR) (10.4 vs 6.5 mos; p=0.1009) and improved 1-year survival (46.5% vs 34.2%) (Dombret, EHA, 2014). Cytogenetic risk is a prognostic indicator in elderly AML and a frequent determinant of Tx approach and outcomes. Objective: To determine the effect of Tx with AZA vs CCR on OS and 1-year survival in AZA-AML-001 pt subgroups based on cytogenetic risk classification. Methods: Pts aged ≥65 years with newly diagnosed de novo or secondary AML who were ineligible for transplant, with intermediate- or poor-risk cytogenetics (pts with favorable cytogenetics were excluded from study), ECOG performance status 0-2, and WBC count ≤15x109/L, were eligible. Before randomization, each pt was preselected to receive 1 of 3 commonly used CCR for older pts with AML, per investigator choice: IC (standard 7+3 regimen), LDAC (20 mg SC BID x 10 days/28-day cycle), or BSC only. Pts were then randomized to AZA (75 mg/m2/day SC x 7 days/28-day cycle) or to CCR, in which case they received their preselected Tx. The primary endpoint was OS. Cytogenetic risk groups were assessed per NCCN criteria by central review: intermediate (INT; all cases), intermediate with normal karyotype (cytogenetic normal [CN]), and poor. Survival at 1 year was compared between Tx. Median OS for AZA vs CCR was calculated using Kaplan-Meier methods, hazard ratios (HR) and 95% confidence intervals (CI) were determined by unstratified Cox proportional hazards model, and p values by log-rank test. Results: In all, 488 pts were randomized, 241 to AZA and 247 to CCR. Cytogenetic risk was balanced between Tx groups: 315 pts had INT-risk cytogenetics (AZA n=155 [64%], CCR n=160 [65%]), including 218 who were CN (AZA n=113 [73%], CCR n=105 [66%]), and 170 pts had poor-risk cytogenetics (AZA n=85 [35%], CCR n=85 [34%]). Within each of the 3 cytogenetic risk subgroups, the distribution of pts receiving individual CCR was very consistent: ~18% of each cytogenetic risk subgroup received BSC, ~64% received LDAC, and ~18% received IC. Baseline characteristics were generally balanced among the AZA and CCR Tx arms and the 3 cytogenetic risk groups (Table). At baseline, proportionately more pts with poor-risk cytogenetics in the AZA group were aged ≥75 years (57.6% vs 47.1% with CCR) and more pts in the CCR group had AML with myelodysplastic changes (45.9% vs 37.6% with AZA). Median OS (95%CI) in poor-risk pts was significantly prolonged with AZA vs CCR: 6.4 mos (4.2, 8.1) vs 3.2 mos (2.2, 4.7), respectively; HR=0.68 (0.50, 0.94), p=0.019 (Figure). Median OS in INT-risk pts was 13.0 mos (11.2, 16.3) vs 10.1 mos (7.1, 13.3) with AZA vs CCR; HR=0.90 (0.70, 1.16), p=0.41. Median OS in the CN subgroup was 14.1 mos (12.6, 19.5) vs 10.0 mos (6.4, 13.3); HR=0.81 (0.59, 1.10), p=0.18. Estimated 1-year survival was higher with AZA vs CCR in all cytogenetic risk subgroups. Twice the proportion of AZA-treated pts in the poor-risk subgroup were alive at 1 year vs. CCR pts (30.9% vs 14.0%, respectively), a clinically meaningful difference of 16.9% (95%CI 4.4, 29.5). Similarly, in the CN subgroup, 60.7% vs 44.1% of pts were alive at 1 year in the AZA and CCR groups, a difference of 16.5% (3.2, 29.8). AZA effect on 1-year survival in the INT-risk subgroup was also favorable (55.2% vs 45.5% with CCR) (difference 9.7% [-1.4, 20.8]). Grade 3-4 hematologic adverse event rates with AZA were consistent with previous reports (Santini, Eur J Haematol, 2010), with no meaningful differences among all cytogenetic risk groups. Conclusions: Median OS in older pts with AML and poor-risk cytogenetics was meaningfully improved with AZA compared with the CCR currently used for AML, with those pts receiving AZA twice as likely to be alive at 1 year as those treated with CCR. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Döhner: Celgene: Consultancy. Off Label Use: Use of azacitidine in AML with blast count >30%. Seymour:Celgene: Consultancy, Honoraria, Speakers Bureau. Wierzbowska:Celgene: Honoraria, Speakers Bureau. Selleslag:Celgene: Consultancy, Research Funding, Speakers Bureau. Cavenagh:Celgene: Honoraria. Kumar:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Schuh:Celgene: Membership on an entity's Board of Directors or advisory committees. Candoni:Celgene: Consultancy, Speakers Bureau. Récher:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sandhu:Celgene: Honoraria. Bernal del Castillo:Celgene: Consultancy. Al-Ali:Celgene: Honoraria, Research Funding. Martinelli:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; ARIAD: Consultancy. Falantes:Celgene: Consultancy. Stone:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Minden:Celgene: Honoraria. McIntyre:Celgene: Employment. Songer:Celgene: Employment, Equity Ownership. Lucy:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership. Dombret:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Use of 2HG Levels in the Serum, Urine, or Bone Marrow to Predict IDH Mutations in Adults with Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2597-2597 ◽  
Author(s):  
Andrew M. Brunner ◽  
Donna S Neuberg ◽  
Seth A. Wander ◽  
Hossein Sadrzadeh ◽  
Karen K. Ballen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Predictive Value ◽  
Research Funding ◽  
Idh Mutation ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Mutation Status ◽  
Non Invasive ◽  
Idh Mutations

Abstract Mutations in genes encoding the isocitrate dehydrogenase 1/2 (IDH 1/2) enzymes increase production of the oncometabolite 2-hydroxyglutarate (2HG), resulting in elevated 2HG in patients with IDH-mutant AML. This may allow for non-invasive diagnostic and predictive markers of disease; however, the optimal threshold of 2HG levels to predict IDH mutation status, or whether 2-HG measurements in different compartments are equally predictive, is unknown. We measured 2-HG levels in serum, urine, bone marrow aspirate, and bone marrow cell pellet to determine the optimal predictive value of 2HG levels for IDH mutations at AML diagnosis. Patients with newly diagnosed AML had prospective measurements of 2HG levels at diagnosis by liquid chromatography-tandem mass spectrometry in serum, urine, marrow aspirate, and marrow pellet samples. Patients analyzed had IDH1 R132 and IDH2 R140 and R172 testing. Hotspot mutational profiling was performed for AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, KIT, KRAS, MAP2K1, NOTCH1, NRAS, PIK3CA, P53, and PTEN; patients were also tested for FLT3, NPM1, and CEBPA mutations. IDH1/2 mutant patients were compared to wildtype (WT) patients using a Wilcoxon rank sum, Fisher's exact, or Kruskal Wallis test, as appropriate. Performance characteristics of 2HG to predict the presence of IDH1/2 mutations were done using a recursive partitioning algorithm in R version 3.2.1, with the rpart package. 228 patients with newly diagnosed AML had 2HG levels in serum, urine, marrow aspirate, and marrow pellet samples. All patients had testing for IDH1 R132 and IDH2 R140 and R172 mutations. The patients were 56% male; 13 patients had APL, none with IDH mutations. IDH mutations were identified in 23% (n=52) of the cohort: IDH1 R132C (n=12), IDH2 R172 (n=9), and IDH2 R140Q (n=29), and 2 additional patients had mutations in both IDH1 R132 and IDH2 R140 (Table 1). The optimal test cut-off of 2HG to predict IDH status was 534.5 ng/mL in the serum (n=221), 16650 ng/mL in the urine (n=213), 2210 ng/mL in the marrow aspirate (n=190), and 1146 ng/2*10^6 cells in the pellet (n=159). Serum and pellet values had the greatest specificity for the presence of an IDH1/2 mutation (0.9882 and 1.000, respectively; Table 2). The positive predictive value of an elevated serum or pellet 2HG level at these cut-offs was 95.4% and 100%, given a 23% IDH mutation prevalence in this study population. The marrow aspirate had the greatest sensitivity (0.8837) and negative predictive value (96.6%). Urine 2HG levels were less sensitive than serum 2HG levels, although above the urine cut-off the specificity for IDH mutations was similar (Figure 1). 2HG levels in the serum, urine, and marrow can be used to identify IDH mutations in AML. Serum 2HG testing is an effective non-invasive mechanism to predict IDH1/2 mutation status. A serum cut-off of 534.5 ng/mL has a specificity of 0.9882 and, with an IDH mutation prevalence of 23%, was associated with a PPV of 0.9535.Table 1.Patient CharacteristicsNo IDH mutationIDH mutationTotalp-valueMale sex101 (57%)26 (50%)127 (56%)0.43Cytogenetics0.0002Favorable26 (15%)026 (12%)Intermediate95 (54%)41 (82%)136 (61%)Adverse52 (30%)9 (18%)61 (27%)Age (median, range)66 (20, 87)66.5 (41, 86)66 (20, 87)0.27WBC (median, range)5.35 (0.60, 315.4)3.65 (0.20, 333.2)5.25 (0.20, 333.2)0.33No IDH mutationIDH mutationNumber assessedp-valueNRAS27 (17%)9 (19%)2100.83KRAS16 (10%)0 (0%)2100.03TP5315 (9%)1 (2%)2100.13KIT2 (1%)1 (2%)2100.54FLT3ITD34 (20%)4 (8%)2180.06FLT3TKD10 (6%)2(4%)2180.74NPM129 (17%)15 (30%)2190.07CEBPA13 (13%)3 (10%)1021.002HG MeasurementsNo IDH mutationIDH mutationTotalSerum (ng/mL)79.5 [52,123] n=1701420 [675,2735] n=51101 [58,101] n=221Urine (ng/mL)3590 [2230,6220] n=16318300 [7260,59500] n=504330 [2450,8580] n=213Marrow aspirate (ng/mL)BQL [BQL,BQL] n=14718400 [4270,43100] n=43BQL [BQL,1430] n=190Pellet (1000 ng/2*10^6 cells)64 [BQL,169] n=1271420 [675,2735] N=32107 [BQL,500] n=159 Table 2. Test characteristics based on optimal 2HG cut-off, by compartment. Compartment 2HG cut-off Sensitivity Specificity 23% prevalence PPV NPV Serum 534.5 ng/mL 0.8039 0.9882 0.9535 0.9438 Urine 16650 ng/mL 0.5600 0.9877 0.9333 0.8798 Marrow Aspirate 2210 ng/mL 0.8837 0.9660 0.8837 0.9660 Marrow Pellet 1146 ng/2*10^6 cells 0.7813 1.000 1.000 0.9478 Figure 1. Relative frequencies of 2-HG levels according to cut-off values in serum (top) urine (bottom). Figure 1. Relative frequencies of 2-HG levels according to cut-off values in serum (top) urine (bottom). Figure 2. Figure 2. Disclosures Chen: Bayer: Consultancy, Research Funding. Stone:Agios: Consultancy; Celator: Consultancy; Pfizer: Consultancy; Merck: Consultancy; AROG: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Roche/Genetech: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Juno: Consultancy; Novartis: Research Funding. Fathi:Exelexis: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy; Takeda Pharmaceuticals International Co.: Research Funding.

Deletion of TP53 (17p13) Is Associated with Poor Outcome for Newly Diagnosed High-Risk Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2982-2982
Author(s):  
Erming Tian ◽  
Joshua Epstein ◽  
Pingping Qu ◽  
Christoph Heuck ◽  
Frits van Rhee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Chromosome 17 ◽  
University Of Arkansas ◽  
Newly Diagnosed ◽  
Medical Sciences ◽  
Advisory Committees ◽  
Risk Patients

Abstract Introduction In multiple myeloma (MM), deletion of chromosome 17 p13 (del17p) is a poor prognostic feature. The percentage of cells carrying an abnormality has been reported to be important with thresholds of 20% being taken generally but thresholds as high as 60% being suggested more recently. We have reported previously in the Total Therapy (TT)-2 trial (NCT00083551) for newly diagnosed (ND) MM that del17p is an adverse prognostic factor (Blood 112: 4235). The TT3 trial (NCT00081939) incorporated Brtezomib into tandem Melphalan-based autotransplants with DT-PACE for induction/consolidation and Thalidomide and Dexamethasone for maintenance to treat patients with newly diagnosed MM. In more recent iterations of these trials following the introduction of novel agents in induction and during maintenance the impact of carrying del17p has not been studied. In particular we have stratified patients into low- or high-risk molecular subgroups based on the GEP-70 (TT4 protocol [NCT00734877] or TT5 protocol [NCT00869232], respectively). We have used interphase FISH (iFISH) to detect the presence of del17p in baseline bone marrow samples. Method The iFISH slides were prepared with bone marrow aspirates after removing erythrocytes. A specific TP53 probe at chromosome 17 arm p13 combined with a control probe for the ERBB3 locus (HER2, 17q12), in different colors, were hybridized to bone marrow cells. Myeloma PCs were identified by restricted Kappa or Lambda immunoglobulin light-chain staining. We investigated role of 20% cutoffs per ≥100 tumor cells for significant deletion of the TP53 probe. Kaplan-Meier analysis was used to estimate the distributions of overall survival (OS) and progression-free survival (PFS) during the follow-ups. OS was calculated from registration until the date of decease. PFS was similarly calculated, but also incorporated progressive disease as an event. Results We examined 709 baseline samples from TT3, 4, and 5 trials with the two probes at chromosome 17. Overall, 66 of 709 patients (9.3%) had deletion of TP53 locus, including 44 of the 591 (7.5%) of low-risk patients and 20 of the 118 (17.0%) high-risk patients (Table). The range of TP53-deleted cells among newly diagnosed patients is 20-99% (median=75%) overall; 35-100% (median=62%) in TT3-low-risk; 30-97% (median=80%) in TT3-high-risk; 21-99% (median=76%) in TT4; and 20-97% (median=81%) in TT5. Deletion of TP53 was associated with significant shorter OS and PFS in HR patients treated on TT3. The 3 year estimated OS of patients for TT3-HR with del17p was 33% compared with 56% for TT3-LR with del17p, and PFS of patients for TT3-HR with del17p was 25% compared with 51% for TT3-LR with del17p (Figure). The comparison of TT4 to TT5 continued showing short OS in HR patients treated on TT5. The 3 year estimated OS of patients for HRMM with del17p was 17% compared with 75% for TT5 patients without deletion (p=0.0008). But, del17p was neutral in LR patients treated on TT4 (Figure). Conclusion Since the introduction of novel agents during various stages of the disease and a focus on HRMM and LRMM defined by GEP70 we show that while TP53 deletion is an adverse prognostic factor for patients with HRMM it is no longer prognostically relevant in LRMM. Table 1. Patients with iFISH results GEP-70 riskLow ≤0.66 High >0.66 Deletion TP53 in 20-59% PCs (n/N [%]) Deletion TP53 in ≥60% PCs (n/N, [%]) Total TT3 (N=329) Low=256 9/329, [2.7%] 9/329, [2.7%] 18/329, [5.5%] High=73 3/329, [0.9%] 9/329, [2.7%] 12/329, [3.7%] TT4 (N=313) Low=313 5/313, [1.6%] 21/313, [6.7%] 26/313, [8.3%] High=0 0 0 0 TT5 (N=67) Low=22 2/67, [3.0%] 0 2/67, [3.0%] High=45 0 8/67, [11.9%] 8/67, [11.9%] Sum (N=709) Low=591 (83.4%) 14/709, [2.0%] 30/709, [4.2%] High=118 (16.6%) 3/709, [0.4%] 17/709, [2.4%] 66/709 (9.3%) Figure 1. Figure 1. Disclosures Tian: University of Arkansas for Medical Sciecnes: Employment. Epstein:University of Arkansas for Medical Sciences: Employment. Qu:Cancer Research and Biostatistics: Employment. Heuck:Millenium: Other: Advisory Board; Janssen: Other: Advisory Board; Celgene: Consultancy; Foundation Medicine: Honoraria; University of Arkansas for Medical Sciences: Employment. van Rhee:University of Arkansa for Medical Sciences: Employment. Zangari:University of Arkansas for Medical Sciences: Employment; Millennium: Research Funding; Onyx: Research Funding; Novartis: Research Funding. Hoering:Cancer Research and Biostatistics: Employment. Sawyer:University of Arkansas for Medical Sciences: Employment. Barlogie:University of Arkansas for Medical Sciences: Employment. Morgan:Weismann Institute: Honoraria; CancerNet: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria; University of Arkansas for Medical Sciences: Employment; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Impact of FLT3 Mutation Clearance after Front-Line Treatment with Gilteritinib Plus Azacitidine, or Gilteritinib or Azacitidine Alone in Patients with Newly Diagnosed AML: Results from the Phase 2/3 Lacewing Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3445-3445
Author(s):  
Eunice S. Wang ◽  
Jessica K. Altman ◽  
Mark D. Minden ◽  
Ruishan Wu ◽  
Elizabeth Shima Rich ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Complete Remission ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Front Line ◽  
Advisory Committees ◽  
Flt3 Mutation

Abstract Background: The presence of measurable residual disease (MRD) after achievement of remission with induction therapy is a prognostic marker of relapse risk in patients with acute myeloid leukemia (AML). Gilteritinib is an oral FLT3 inhibitor approved as a single agent for the treatment of patients with FLT3-mutated (FLT3mut+) relapsed or refractory AML. Evaluation of gilteritinib in the front-line setting is under way. We evaluated FLT3 internal tandem duplication (FLT3-ITD) mutation clearance using two different thresholds and correlated mutation clearance with survival outcomes in patients with newly diagnosed AML ineligible for intensive chemotherapy who were treated with front-line gilteritinib plus azacitidine (AZA) or either agent alone in the phase 2/3 LACEWING trial. Methods: Adult patients with newly diagnosed FLT3mut+ AML ineligible for intensive induction chemotherapy received 28-day cycles of once-daily gilteritinib plus AZA in the Safety Cohort (80 or 120 mg/day gilteritinib plus 75 mg/m 2 AZA, Days 1-7) and in Arm AC (120 mg/day gilteritinib plus 75 mg/m 2 AZA, Days 1-7), gilteritinib (120 mg/day) alone in Arm A, or AZA (75 mg/m 2, Days 1-7) alone in Arm C. A subset of patients who had a best overall response of composite complete remission (CRc; defined as the sum of patients who achieved complete remission with or without complete hematologic or platelet recovery) and who had bone marrow-derived DNA samples available at baseline and at least one additional post-baseline timepoint were assessed for FLT3-ITD mutation clearance using next-generation sequencing. An Illumina ® sequencing platform was used to quantify FLT3-ITD and total FLT3 alleles. The FLT3-ITD variant allelic frequency (VAF) was defined as the ratio of FLT3-ITD to total FLT3 frequency. Data were analyzed using two different mutation clearance thresholds, FLT3-ITD VAF &lt;10 −4 or &lt;10 −3, where 10 −4 was based on previously published findings in patients with relapsed or refractory FLT3mut+ AML who were treated with gilteritinib (Altman JK et al., Cancer Med. 2021;10[3]:797-805) and 10 -3 was an additional exploratory threshold used because it provided a more balanced distribution of patients, given the small number of patients achieving mutation clearance at the 10 -4 threshold. Results: The median age of patients enrolled in LACEWING was 77 years (range, 59-90), with 73% of patients aged &gt;75 years. Although baseline characteristics of the overall LACEWING population were generally well balanced across treatment arms, higher proportions of patients treated with gilteritinib plus AZA (47%) or gilteritinib alone (59%) had an Eastern Cooperative Oncology Group (ECOG) performance status of ≥2 compared with patients treated with AZA alone (33%). Overall, 40 patients who achieved CRc and had sufficient DNA samples from bone marrow aspirates obtained at baseline and at least one additional post-baseline timepoint were included in the analysis (Safety Cohort, n=8; Arm A, n=7; Arm AC, n=17; and Arm C, n=8). Across both thresholds, the proportions of patients with FLT3 mutation clearance did not markedly differ between patients treated with gilteritinib or AZA (Table). In patients who received gilteritinib, FLT3-ITD mutation clearance using either threshold was associated with a similar increase in median overall survival (OS) compared to patients who did not achieve mutation clearance (Figure). Conclusions: Regardless of MRD threshold, rates of MRD negativity were not substantially different between newly diagnosed FLT3mut+ AML patients ineligible for intensive induction chemotherapy who received gilteritinib alone, gilteritinib plus AZA, or AZA alone. Advanced age coupled with a worse baseline ECOG performance score at baseline may have compromised treatment response and achievement of FLT3 mutation clearance in patients treated with gilteritinib. The mutation clearance thresholds used in this analysis showed similar median OS in patients who received gilteritinib. Figure 1 Figure 1. Disclosures Wang: Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Takeda: Consultancy, Honoraria, Other: Advisory board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Mana Therapeutics: Consultancy, Honoraria; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Altman: Kartos: Research Funding; Theradex: Consultancy, Other: Advisory boards; Biosight: Consultancy, Other: Travel fees, Research Funding; Daiichi Sankyo: Consultancy; AbbVie: Consultancy, Other: Advisory Board, Research Funding; BMS: Research Funding; Amgen: Research Funding; Astellas: Consultancy, Other: Advisory Board, Research Funding; Fujifilm: Research Funding; ALZ Oncology: Research Funding; Immunogen: Research Funding; GlycoMimetics: Other: Participation on an advisory board; Syros: Consultancy; Kura Oncology: Consultancy; Boehringer Ingelheim: Research Funding; Aprea: Research Funding; Kura: Research Funding. Minden: Astellas: Consultancy. Wu: Astellas: Current Employment. Rich: Astellas Pharma Global Development, Inc.: Current Employment. Hill: Ligacept, LLC: Current holder of individual stocks in a privately-held company, Other: Stockholder; Astellas Pharma Global Development: Current Employment.

scholarly journals First Report of Non-Genotoxic Conditioning with JSP191 (anti-CD117) and Hematopoietic Stem Cell Transplantation in a Newly Diagnosed Patient with Severe Combined Immune Deficiency

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-10
Author(s):  
Rajni Agarwal ◽  
Kenneth I. Weinberg ◽  
Hye-Sook Kwon ◽  
Anne Le ◽  
Janel R Long-Boyle ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Board Of Directors ◽  
B Lymphocytes ◽  
Hematopoietic Stem Cell ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Cd34 Cells

Successful hematopoietic stem cell transplantation (HSCT) requires vacating recipient hematopoietic stem cell (HSC) niches in the bone marrow to permit donor HSC engraftment that can provide life-long hematopoietic and immune function. Currently, HSCT in SCID relies on DNA damaging chemotherapy to eliminate recipient HSC and achieve niche clearance. We have pursued a non-toxic approach to target and deplete HSC using a humanized monoclonal antibody, JSP191, that binds human CD117 (c-Kit). We previously showed the safety and successful HSC engraftment in a Phase 1 trial of the first 6 patients with severe combined immunodeficiency (SCID), who underwent a second transplant because of HSC engraftment failure and poor immunity after their first transplantation. In these re-transplant patients even a low level of stringently measured myeloid chimerism resulted in significant and sustained generation of naive T cells and clinical improvement. Based on these results, the study of JSP191 (NCT#02963064)has opened a cohort of newly diagnosed infants with SCID. Here we report data from the first patient in this cohort, a SCIDX1 patient who received a primary HSCT with haploidentical CD34+ cells after conditioning with JSP 191. The patient had a c.270-15A&gt;G variant in the IL2RG gene, which is predicted to cause a null phenotype. Besides a T- B+ NK- phenotype typical of SCIDX1 including dysfunctional B cells, the patient had anemia and intermittent neutropenia and thrombocytopenia. Despite evidence of maternal T cell engraftment, the patient had no clinical graft-versus-host disease (GVHD). The patient was initially enrolled in a trial of lentiviral gene therapy, but harvested bone marrow cells died in vitro during transduction and culture. The patient also mobilized poorly with G-CSF/Plerixafor. Further investigation revealed heterozygosity for loss-of-function mutations in two genes involved in DNA repair, BRCA1 and RAD51; Diepoxybutane (DEB) breakage study showed greater than normal pathologic chromosomal breaks, but less than that seen in Fanconi anemia. Because of concern for possible hypersensitivity to alkylating agent-based conditioning, the patient was referred for transplant with JSP191 conditioning. The patient received a CD34+ peripheral blood HSCT from his father after conditioning with 0.3 mg/kg of JSP 191 antibody intravenously over an hour on Day -8 and rATG (Thymoglobulin) on Day -5, -4, -3 and -2 (3.5 mg/kg total) to prevent rejection by the maternal T cells. The cryopreserved donor CD34+ cells were administered after sufficient clearance of the JSP191 serum level. The antibody infusion was well tolerated without toxicity, and the post-transplant course was uneventful without acute toxicities or GVHD. As a surrogate marker for HSC engraftment, CD15+ myeloid cells from peripheral blood were stringently sorted by flow cytometry and donor levels were quantified by short-tandem repeat (STR) analysis. Progressive levels of myeloid engraftment were observed beginning at Week 4. The level of donor chimerism at 12 weeks was 8% in the sorted CD15+ blood cells, and a marrow aspirate showed 25% donor CD34+ cells. By 3 months pre-existing abnormal CD19-CD20+ host B lymphocytes were significantly reduced, and CD19+ donor-derived B lymphocytes were emerging. At 2 months, CD4+ recent thymic emigrant and naïve T lymphocytes were observed, and by 3 months, overall T and NK lymphocyte numbers were 390/uL and 117/uL, respectively. Normal blastogenic responses to the T cell mitogen PHA were observed at 3 months. These first-in-class results provide proof of concept of the safety and efficacy of the use of JSP191 antibody to clear host marrow niche space to enable sufficient donor HSC engraftment and immune reconstitution as primary therapy of SCID. Non-genotoxic conditioning with JSP191 may replace conventional conditioning for newly diagnosed infants with SCID, thereby avoiding toxicities of chemotherapy. Disclosures Kohn: Allogene Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Patents & Royalties, Research Funding. De Oliveira:Orchard Therapeutics: Research Funding; bluebird bio, Inc.: Research Funding. Czechowicz:Rocket Pharmaceuticals, Inc.: Research Funding. Brown:Merck: Membership on an entity's Board of Directors or advisory committees; Ansun: Membership on an entity's Board of Directors or advisory committees; Cidara: Membership on an entity's Board of Directors or advisory committees; Allogene: Membership on an entity's Board of Directors or advisory committees; Cellerant Therapeutics: Membership on an entity's Board of Directors or advisory committees. Shizuru:Jasper Therapeutics, Inc: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Bone Marrow-Based and Longitudinal Blood-Based MRD Tracking in Newly Diagnosed Multiple Myeloma Patients Treated with Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (DKRd): A Correlative and Clinical Phase II Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3281-3281 ◽  
Author(s):  
Ola Landgren ◽  
Katie Thoren ◽  
Malin Hultcrantz ◽  
Alexander M. Lesokhin ◽  
Nikoletta Lendvai ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Single Tube ◽  
Maldi Tof Ms ◽  
Maldi Tof ◽  
Tof Ms

Abstract INTRODUCTION Using Carfilzomib, Lenalidomide and Dexamethasone (KRd) combination therapy in newly diagnosed multiple myeloma patients lead to ~40% minimal residual disease (MRD) negativity rate. Here, we use KRd in combination with daratumumab (DKRd); and treatment response is assessed with extensive correlative science including parallel bone-marrow-based and blood-based MRD tracking, together with targeted DNA sequencing of baseline bone marrow samples. Primary end-point is to rule out 60% and to target up to 80% MRD negativity rate. METHODS This is a single-arm, Phase II clinical trial based on Simon's optimal two-stage design. The first cohort (twice-a-week carfilzomib) (N=41) has the following treatment schedule: 8 cycles of treatment; 28-day cycles with carfilzomib 20/36 mg/m2 days 1, 2, 8, 9, 15 and 16; lenalidomide 25 mg days 1-21; dexamethasone 40 mg weekly cycles 1-4, 20 mg after cycle 4; and daratumumab 16 mg/kg days 1, 8, 15, and 22 cycles 1-2, days 1 and 15 cycles 3-6, and day 1 cycles 7-8. The second cohort (once-a-week carfilzomib) (N=41): 8 cycles of treatment; 28-day cycles with carfilzomib 20/56 mg/m2 days 1, 8, and 15; lenalidomide, dexamethasone, and daratumumab are given at the same doses/schedules as the first cohort. For fit patients, stemcell collection is recommended after 4 to 6 cycles of therapy; DKRd therapy is resumed after collection to a total of 8 cycles DKRd. Treatment response is being assessed with parallel bone-marrow-based (10-color single tube flowcytometry, invivoscribe V(D)J sequencing) as well as blood-based (MALDI-TOF and QTOF-mass spectrometry [MS]) for MRD tracking. Baseline bone marrow samples are evaluated with targeted DNA sequencing for FISH-Seq and somatic mutational characteristics (myTYPE). Here, we present the first stage (N=28) of the first cohort (twice-a-week carfilzomib). We are waiting for the results to mature before the second stage (N=13) of the first cohort can open. The second cohort (once-a-week carfilzomib) is opening for enrollment in August 2018 (N=41). RESULTS The first stage of the first cohort is fully enrolled; 28 patients meeting eligibility criteria were enrolled onto study (14 males, 14 females) between October 2017 and July 2018. Baseline characteristics include; median age 60 years (range 32-80 years); 12(43%) patients had high-risk FISH/SNP signature defined as one or more of the following: 1q+, t(4,14), t(14,16), t(14,20), and 17p-. At the submission of this abstract, 20 patients have completed one or more cycles DKRd; among these, 3 patients have completed all 8 cycles. The median number of cycles delivered is currently 4 (range 1-8). Full assessments with MRD assays have been completed in 3 patients: -Pt #1 obtained complete response (CR) after 3 cycles, and workup after the last cycle of therapy showed MRD-negativity (by 10-color single tube flowcytometry and V(D)J sequencing) in the bone marrow; and peripheral blood (serum) was negative by MALDI-TOF MS after completion of cycle 2. -Pt#2 obtained CR after 4 cycles, however, workup after cycle 5 showed MRD-positivity (by 10-color single tube flowcytometry and V(D)J sequencing) in the bone marrow; and peripheral blood (serum) was positive by MALDI-TOF MS throughout the end of the last cycle. -Pt#3 obtained CR after 4 cycles and after 6 cycles both 10-color single tube flowcytometry and V(D)J sequencing showed MRD-negativity in the bone marrow. However, MALDI-TOF MS detected small abnormal serum proteins in peripheral blood and remained positive throughout the end of cycle 8. Overall, the DKRd therapy is well tolerated and it has similar toxicity profile as KRd. Grade >3 adverse events were hypotension, musculoskeletal deformity, back pain, dyspnea, lung-infection, and febrile neutropenia. So far, 5 patients underwent dose reductions of lenalidomide. CONCLUSIONS In this pre-planned interim analysis of our phase II study, we show that DKRd is a highly effective and well tolerated combination therapy for newly diagnosed multiple myeloma patients. Based on small numbers of patients who have completed the planned DKRd cycles and been evaluated by bone marrow-based MRD and peripheral-blood based assays, we show that highly sensitive protein assays may allow longitudinal MRD tracking in peripheral-blood. At the meeting, we will present updated results using longitudinal testing with MALDI TOF-MS and QTOF-MS on the entire cohort. Disclosures Landgren: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pfizer: Consultancy; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees. Lesokhin:Takeda: Consultancy, Honoraria; Janssen: Research Funding; Squibb: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Serametrix, inc.: Patents & Royalties: Royalties. Mailankody:Juno: Research Funding; Physician Education Resource: Honoraria; Takeda: Research Funding; Janssen: Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Hassoun:Oncopeptides AB: Research Funding. Shah:Amgen: Research Funding; Janssen: Research Funding. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Ho:Invivoscribe, Inc.: Honoraria. Korde:Amgen: Research Funding.

scholarly journals Treatment Patterns and Outcomes in Elderly Patients with Newly Diagnosed Multiple Myeloma: Results from the Connect® MM Registry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3129-3129
Author(s):  
Hans C. Lee ◽  
Sikander Ailawadhi ◽  
Cristina Gasparetto ◽  
Sundar Jagannath ◽  
Robert M. Rifkin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Causes Of Death ◽  
Age Groups ◽  
Treatment Patterns ◽  
Age Group ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Background: Multiple myeloma (MM) is common among the elderly, with 35% of patients (pts) diagnosed being aged ≥75 years (y). With increasing overall life expectancy, the incidence and prevalence of newly diagnosed and previously treated MM patients ≥80 y is expected to increase over time. Because elderly pts are often excluded from clinical trials, data focused on their treatment patterns and clinical outcomes are lacking. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed MM (NDMM) designed to examine real-world diagnostic patterns, treatment patterns, clinical outcomes, and health-related quality of life patient-reported outcomes. This analysis reviews treatment patterns and outcomes in elderly pts from the Connect MM Registry. Methods: Pts enrolled in the Connect MM registry at 250 community, academic, and government sites were included in this analysis. Eligible pts were adults aged ≥18 y with symptomatic MM diagnosed ≤2 months before enrollment, as defined by International Myeloma Working Group criteria; no exclusion criteria were applied. For this analysis, pts were categorized into 4 age groups: <65, 65 to 74, 75 to 84, and ≥85 y. Pts were followed from time of enrollment to the earliest of disease progression (or death), loss to follow-up, or data cutoff date of February 7, 2019. Descriptive statistics were used for baseline characteristics and treatment regimens. Survival outcomes were analyzed using Cox regression. Time to progression (TTP) analysis excluded causes of death not related to MM. Results: Of 3011 pts enrolled (median age 67 y), 132 (4%) were aged ≥85 y, and 615 (20%) were aged 75-84 y at baseline. More pts aged ≥85 y had poor prognostic factors such as ISS stage III disease and reduced hemoglobin (<10 g/dL or >2 g/dL <LLN) compared with other age groups, although no notable differences between creatinine and calcium levels were observed across age groups (Table). A lower proportion of elderly pts (75-84 and ≥85 y) received triplet regimens as frontline therapy. More elderly pts received a single novel agent, whereas use of 2 novel agents was more common in younger pts (Table). The most common frontline regimens among elderly pts were bortezomib (V) + dexamethasone (D), followed by lenalidomide (R) + D, whereas those among younger pts included RVD, followed by VD and CyBorD (Table). No pt aged ≥85 y, and 4% of pts aged 75-84 y received high-dose chemotherapy and autologous stem cell transplant (vs 61% in the <65 y and 37% in the 65-74 y age group). The most common maintenance therapy was RD in pts ≥85 y (although the use was low) and R alone in other age groups (Table). In the ≥85 y group, 27%, 10%, and 4% of pts entered 2L, 3L, and 4L treatments respectively, vs 43%, 23%, and 13% in the <65 y group. Progression-free survival was significantly shorter in the ≥85 y age group vs the 75-84 y age group (P=0.003), 65-74 y age group (P<0.001), and <65 y age group (P<0.001; Fig.1). TTP was significantly shorter in the ≥85 y group vs the <65 y group (P=0.020); however, TTP was similar among the 65-74 y, 75-84 y, and ≥85 y cohorts (Fig. 2). Overall survival was significantly shorter in the ≥85 y group vs the 75-84 y, 65-74 y, and <65 y groups (all P<0.001; Fig. 3). The mortality rate was lowest (46%) during first-line treatment (1L) in pts aged ≥85 y (mainly attributed to MM progression) and increased in 2L and 3L (47% and 54%, respectively); a similar trend was observed in the younger age groups. The main cause of death was MM progression (29% in the ≥85 y vs 16% in the <65 y group). Other notable causes of death in the ≥85 y group included cardiac failure (5% vs 2% in <65 y group) and pneumonia (5% vs 1% in <65 y group). Conclusions: In this analysis, elderly pts received similar types of frontline and maintenance regimens as younger pts, although proportions varied with decreased use of triplet regimens with age. Considering similarities in TTP across the 65-74 y, 75-84 y, and ≥85 y cohorts, these real-world data support active treatment and aggressive supportive care of elderly symptomatic pts, including with novel agents. Additionally, further clinical studies specific to elderly patients with MM should be explored. Disclosures Lee: Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ailawadhi:Janssen: Consultancy, Research Funding; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Jagannath:AbbVie: Consultancy; Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Toomey:Celgene: Consultancy. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Wagner:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Abonour:BMS: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

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