scholarly journals Genomic Profiling in Patients with Higher-Risk Myelodysplastic Syndrome (HR-MDS) Following HMA Failure: Baseline Results from the Inspire Study (04-30)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3015-3015 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Anna Jonasova ◽  
Selina M. Luger ◽  
Aref Al-Kali ◽  
David Valcárcel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
High Risk ◽  
Board Of Directors ◽  
Primary Endpoint ◽  
Research Funding ◽  
Genomic Profiling ◽  
Advisory Committees ◽  
Ras Pathway ◽  
Ras Mutations

Background: More than 45 mutations have been identified in association with HR-MDS. In the majority of patients with MDS (80%) co-mutations are present and the prognostic contribution of each individual mutation remains elusive, especially after adjusting for clinical variables such as IPSS-R score. N-RAS and K-RAS mutations as well as regulators of the Ras pathway (e.g. PTPN11, NF1) are frequently observed (15-20%) in HR-MDS, however their clinical impact is unclear, especially in de novo MDS. Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic that has the potential to block RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways (Athuluri-Divakar 2016). Rigosertib has the potential to also inhibit wildtype upregulation of RAS. We report here genomic profiling at the time of study entry in the ongoing phase 3 randomized global study (known as INSPIRE) in patients with HR-MDS after failure of HMA therapy. Methods: INSPIRE (NCT02562443) is a global randomized Ph3 trial in pts with HR-MDS after HMA failure with an overall target enrollment of 360 pts with currently 298 pts randomized. Pts are randomized 2:1 to rigosertib or physician's choice of treatment. The primary endpoint is overall survival (OS). All pts failed to respond or progressed on HMA therapy. Key inclusion criteria includes: age < 82 years, RAEB-1, RAEB-2 or RAEB-t; intermediate risk (IR), high risk (HR) and very high risk (VHR) per IPSS-R; ≥ 1 cytopenia; duration of prior HMA ≤ 9 cycles within 12 months; last dose of HMA ≤ 6 months before enrollment; baseline blast counts between 5-29% and one of the following: progression any time after initiation of HMA treatment, intolerance to HMA, failure to achieve complete remission (CR), partial remission (PR), or hematologic improvement (HI) after six 4-week cycles of AZA or either four 4-week or four 6-week cycles of DAC, or relapse after initial CR, PR or HI. Bone marrow samples were collected at study baseline and throughout the study for mutational analysis as an exploratory endpoint. Baseline blast counts are described as % reported in bone marrow aspirate at screening. Genomic DNA was extracted from diagnostic bone marrow or peripheral blood samples and targeted capture deep sequencing of 295 genes were performed (median sequencing depth 500x) using Agilent's SureSelect custom panel. Modified Mutect and Pindel were used to identify high-confidence somatic mutations. Results: All data is presented as blinded aggregate results for both arms of the study. Baseline mutations are presented for 114 pts; 92 pts were randomized and 22 pts were screen failures. Median age is 72 years (59-81). The IPSS-R scores for the pts randomized were: Intermediate 5(5%), High 30 (32%) and VHR 56 (60%). In total 48 different mutations were identified at baseline prior to pts receiving study treatment. The most common mutations identified in pts were ASXL1 40%, STAG2 26%, TP53 24%, RUNX1 22%, SRSF2 and TET2 each 18%. Average number of mutations per pt was 3.06. At baseline, 4 pts (4%) had no mutations, 17 pts (18%) had only 1 mutation while 17 pts (18%) had between 6-8 mutations. N-RAS and K-RAS mutations occurred in 4 pts each (7% of pts) and all in the presence of other mutations. Mutations involving regulators of the Ras pathway (N-RAS, K-RAS, PTPN11, NF1) occurred in 12 (13%) of patients. Of note, 23 pts (25%) had IDH1 (6 pts) or IDH2 (17 pts) and the majority of these pts (68%) were High/VHR with an average blast count of 15% (range 5-27%) at study entry. The high proportion of IDH1/2 mutations observed is most likely due to inclusion of patients with RAEB-t. These results will be updated at the meeting with blinded baseline mutational analyses for all pts randomized into the study. Conclusion: The baseline mutational analyses from the INSPIRE study provides important initial insights into the genomic profile of pts with HMA failure, especially for the subset with VHR. Following analysis of the primary endpoint, it is anticipated that correlation of overall survival and clinical response with mutational status will be possible, including changes in mutations following therapy. Given the number of mutations involving the Ras pathway the efficacy of rigosertib in patients with this group of mutations will also be examined. Figure Disclosures Garcia-Manero: 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; Merck: Research Funding. Luger:Agios: Honoraria; Jazz: Honoraria; Kura: Research Funding; Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding; Daichi Sankyo: Honoraria; Genetech: Research Funding; Cyslacel: Research Funding; Ariad: Research Funding; Biosight: Research Funding; Celgene: Research Funding. Al-Kali:Astex Pharmaceuticals, Inc.: Research Funding. Jedrzejczak:Amgen: Consultancy, Other: travel support for hematology meetings (ASH, EBMT, EHA) ; Celgene: Other: travel support for hematology meetings (ASH, EBMT, EHA) ; Takeda: Consultancy; Novartis: Research Funding; Roche: Other: travel support for hematology meetings (ASH, EBMT, EHA) . Díez-Campelo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Cavanaugh:Onconova Therapeutics, Inc.: Employment. Woodman:Onconova Therapeutics, Inc.: Employment. Fruchtman:Onconova Therapeutics, Inc.: Employment. Takahashi:Symbio Pharmaceuticals: Consultancy.

scholarly journals Overall Survival and Subgroup Analysis from a Randomized Phase III Study of Intravenous Rigosertib Versus Best Supportive Care (BSC) in Patients (pts) with Higher-Risk Myelodysplastic Syndrome (HR-MDS) after Failure of Hypomethylating Agents (HMAs)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 163-163 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Pierre Fenaux ◽  
Aref Al-Kali ◽  
Maria R. Baer ◽  
Mikkael A. Sekeres ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Board Of Directors ◽  
Primary Endpoint ◽  
Research Funding ◽  
Phase Iii ◽  
Controlled Study ◽  
Advisory Committees ◽  
Phase Iii Study ◽  
Very High

Abstract Background: No approved treatment options are available to HR-MDS pts after HMA therapy. Study 04-21 (“ONTIME” trial) was a Phase III, randomized, controlled study of the efficacy and safety of rigosertib, a novel small molecule inhibitor of PI3-kinase and PLK pathways, in a heterogeneous population of MDS pts who had relapsed after, failed to respond to, or progressed during administration of HMAs. The study was conducted at 87 sites in the United States and 5 European countries. Methods:From Dec 2010 to Aug 2013, 299 HR-MDS pts [<30% bone marrow blasts (BMBL)] who had progressed on (37% of total enrollment), failed to respond to (25%), or relapsed after (38%) HMA treatment were stratified on BMBL count and randomized 2:1 to receive rigosertib (199 pts) or BSC (100 pts). Rigosertib was administered at 1800 mg/24 hr for 72-hr as a continuous intravenous (CIV) ambulatory infusion, every 2 weeks for the first 16 weeks, and then every 4 weeks. The primary endpoint was overall survival (OS), analyzed on an intention-to-treat (ITT) basis using the Kaplan-Meier method stratified on BMBL (5% to 19% vs. 20% to 30%). The trial had a 95% power to detect a 13-wk increase in median OS from 17 wks on BSC, with a 2-sided alpha = 0.05. The following results are based on 242 deaths: 161 in the rigosertib arm and 81 in the BSC arm. Results : Overall, the 2 arms were balanced in terms of baseline characteristics, with the majority of pts being male (66%), and White (82%). Age ranged from 50-90 yrs in the rigosertib arm and 55-86 years in the BSC arm (median, 74 yrs). The majority of pts (85%) had an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. The median duration of the last HMA therapy was 8.8 months (mo) in the rigosertib arm and 10.3 mo in the BSC arm; 127 (64%) of rigosertib pts and 57% of BSC pts were classified as “primary HMA failure” (ie, they failed to respond to or progressed during HMA therapy, as defined by Prebet et al, J Clin Oncol, 2011). A 2.3-mo improvement in median OS was found in the overall (ITT) population (8.2 mo rigosertib vs. 5.9 mo BSC) (Figure 1). The ITT survival for rigosertib was similar to that noted in Phase I/II studies (35 weeks). The stratified log-rank p-value was 0.33. The stratified hazard ratio was 0.87, which was quite different from the ratio of medians (5.9/8.2 = 0.72), due to the fact that the 2 survival curves converged at 15 mo. Notably, among the 184 patients with primary HMA failure, the median OS was 8.6 mo in the rigosertib arm (N = 127) vs. 5.3 mo in the BSC arm (N = 57), HR= 0.69, p= 0.040 (Figure 2). Multivariate Cox regression, adjusting for pretreatment prognostic factors, showed little change in the treatment effect. The following subgroups were correlated with better OS: pts with failure of/progression on HMA treatment, pts with duration of HMA treatment ≤ 9 mo, pts < 75 years of age, and pts with very high risk per IPSS-R (Figure 3). Rigosertib was well tolerated, with a median dose intensity of 92%. There were no significant compliance or operations issues related to ambulatory continuous infusion. Protocol-defined dose reductions were reported in 5% of pts, with 24% experiencing dose delays of >7 days, mostly due to unrelated adverse events (AEs). No obvious differences between rigosertib and BSC were found in the incidence of AEs (rigosertib, 99%; BSC, 85%) or of ≥ Grade 3 AEs (rigosertib, 79%; BSC, 68%). In the rigosertib arm, AEs reported by ≥ 20% of pts, irrespective of severity or causality, were nausea (35%), diarrhea (33%), constipation (31%), fatigue (30%), fever (27%), anemia (22%), and peripheral edema (21%). Rigosertib had low myelotoxicity, consistent with previous clinical experience. Conclusions:Although the primary endpoint in this Phase III study of rigosertib vs BSC in pts with HR-MDS did not reach statistical significance in the ITT population, encouraging rigosertib treatment-related improvement in OS was noted in several subgroups of MDS pts, including those with “primary HMA failure and in patients in the IPSS-R Very High Risk category. CIV therapy with rigosertib had a favorable safety profile in this orphan population of elderly pts with MDS. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Fenaux: Celgene: Research Funding; Janssen: Research Funding; Novartis: Research Funding. Sekeres:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees. Roboz:Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy; Glaxo SmithKline: Consultancy; Astra Zeneca: Consultancy; Sunesis: Consultancy; Teva Oncology: Consultancy; Astex: Consultancy. Wilhelm:Onconova Therapeutics, Inc: Employment, Equity Ownership. Wilhelm:Onconova Therapeutics, Inc: Employment. Azarnia:Onconova Therapeutics, Inc: Employment. Maniar:Onconova Therapeutics, Inc: Employment.

scholarly journals Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 804-804 ◽  
Author(s):  
Mark Bustoros ◽  
Chia-jen Liu ◽  
Kaitlen Reyes ◽  
Kalvis Hornburg ◽  
Kathleen Guimond ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Disease Progression ◽  
Board Of Directors ◽  
Rna Sequencing ◽  
Research Funding ◽  
Response Rate ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background. This study aimed to determine the progression-free survival and response rate using early therapeutic intervention in patients with high-risk smoldering multiple myeloma (SMM) using the combination of ixazomib, lenalidomide, and dexamethasone. Methods. Patients enrolled on study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al., Blood 2014. The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and Dexamethasone at days 1, 8, 15, and 22. This induction phase is followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle is defined as 28 consecutive days, and therapy is administered for a total of 24 cycles total. Bone marrow samples from all patients were obtained before starting therapy for baseline assessment, whole exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle to isolate cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Stem cell collection is planned for all eligible patients. Results. In total, 26 of the planned 56 patients were enrolled in this study from February 2017 to April 2018. The median age of the patients enrolled was 63 years (range, 41 to 73) with 12 males (46.2%). Interphase fluorescence in situ hybridization (iFISH) was successful in 18 patients. High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 11 patients (61.1%). The median number of cycles completed was 8 cycles (3-15). The most common toxicities were fatigue (69.6%), followed by rash (56.5%), and neutropenia (56.5%). The most common grade 3 adverse events were hypophosphatemia (13%), leukopenia (13%), and neutropenia (8.7%). One patient had grade 4 neutropenia during treatment. Additionally, grade 4 hyperglycemia occurred in another patient. As of this abstract date, the overall response rate (partial response or better) in participants who had at least 3 cycles of treatment was 89% (23/26), with 5 Complete Responses (CR, 19.2%), 9 very good partial responses (VGPR, 34.6%), 9 partial responses (34.6%), and 3 Minimal Responses (MR, 11.5%). None of the patients have shown progression to overt MM to date. Correlative studies including WES of plasma cells and single-cell RNA sequencing of the bone microenvironment cells are ongoing to identify the genomic and transcriptomic predictors for the differential response to therapy as well as for disease evolution. Furthermore, we are analyzing the cfDNA and CTCs of the patients at different time points to investigate their use in monitoring minimal residual disease and disease progression. Conclusion. The combination of ixazomib, lenalidomide, and dexamethasone is an effective and well-tolerated intervention in high-risk smoldering myeloma. The high response rate, convenient schedule with minimal toxicity observed to date are promising in this patient population at high risk of progression to symptomatic disease. Further studies and longer follow up for disease progression are warranted. Disclosures Bustoros: Dava Oncology: Honoraria. Munshi:OncoPep: Other: Board of director. Anderson:C4 Therapeutics: Equity Ownership; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Takeda Millennium: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Oncopep: Equity Ownership. Richardson: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; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghobrial:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy.

Effect Of Treatment With The JAK2-Selective Inhibitor Fedratinib (SAR302503) On Bone Marrow Histology In Patients With Myeloproliferative Neoplasms With Myelofibrosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2823-2823 ◽  
Author(s):  
Catriona HM Jamieson ◽  
Robert P Hasserjian ◽  
Jason Gotlib ◽  
Jorge E. Cortes ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Phase I ◽  
Board Of Directors ◽  
Clinical Benefit ◽  
Research Funding ◽  
Selective Inhibitor ◽  
Advisory Committees ◽  
Grade 3

Abstract Introduction Fedratinib, a JAK2-selective inhibitor, demonstrated clinical benefit through a reduction in splenomegaly and symptoms in patients with myelofibrosis (MF), including post-polycythemia vera MF (post-PV MF), post-essential thrombocythemia MF (post-ET MF) and primary MF (PMF), in Phase I and II studies (J Clin Oncol 2011;29:789; Haematologica 2013;98:S1113). Bone marrow fibrosis (BMF) has been associated with splenomegaly and cytopenias (Ann Hematol 2006;85:226). Hence, stabilization and/or reversal of BMF remain important therapeutic goals. This report represents an exploratory analysis of sequential BMF data from patients with MF in an open-label Phase I/II study to evaluate the long-term effects of orally administered fedratinib (TED12015; NCT00724334). Methods Patients with intermediate or high-risk MF (Mayo Prognostic Scoring System) received fedratinib therapy in consecutive cycles (1 cycle = 28 days) as long as they derived clinical benefit. Bone marrow trephine biopsies were performed at baseline and after every 6 cycles. Hematoxylin and eosin, reticulin, and Masson's trichrome staining of core biopsy slides were used to grade BMF on a scale from 0 to 3 using the 2008 WHO MF grading criteria. BMF was graded independently in a blinded fashion by 3 hematopathologists. BMF grades were established as long as at least 2 of the 3 pathologists agreed independently. Changes in BMF grade from baseline were categorized as improvement (≥1 grade reduction), stabilization (no change), or worsening (≥1 grade increase). Results Of the 43 patients enrolled in the TED12015 study, the median fedratinib dose received was 473 (range 144–683) mg/day and median treatment duration was 32.3 (range 7–61) cycles. Bone marrow biopsies at baseline and at least one other time point were available for 21/43 (49%) patients, whose baseline characteristics were: median age 61 years (range 43–85); 57% male; 38% high-risk MF by WHO 2008 criteria (Leukemia 2008; 22:14); and 90% JAK2V617F positive. A consensus grade was achieved for 96% of the samples. At baseline, 2, 10, and 9 patients had grade 1, 2, and 3 BMF, respectively. Changes in BMF grade from baseline are shown in the figure. BMF improvement with 1 grade reduction was observed in 8/18 (44%) patients at Cycle 6. By Cycle 30, 4/9 (44%) evaluable patients had BMF improvement, including 2 patients with improvement by 2 grades and 2 patients with improvement by 1 grade. Of patients with Grade 3 BMF at baseline, 6/9 (67%) exhibited 1 grade improvement at Cycle 6. Two patients had 2 grades of BMF reduction from baseline during treatment (grade 3 to 1, and grade 2 to 0, both at Cycle 12), and the latter achieved a complete clinical remission at Cycle 30 assessed by IWG-MRT response criteria. The two patients who experienced complete reversal of BMF to grade 0 (one from grade 2 and one from grade 1) had normalization of not only hemoglobin level but also white blood cell and platelet counts at Cycle 18. Conclusions These exploratory analyses suggest that a proportion of patients treated long-term with fedratinib demonstrate stable or improved BMF. The disease modifying impact of fedratinib on BMF changes will be further assessed in a randomized, placebo-controlled Phase III clinical trial (JAKARTA; NCT01437787). This study was sponsored by Sanofi. Disclosures: Jamieson: J&J, Roche: Research Funding; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Hasserjian:Sanofi, Inc: Consultancy. Gotlib:Sanofi: Travel to EHA 2012, Travel to EHA 2012 Other; Sanofi: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Research Funding. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau. Thiele:AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Consultancy; Novartis, Shire: Research Funding; AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Honoraria. Rodig:Ventana/Roche Inc.: Research Funding; Daiichi-Sankyo/Arqule Inc., Ventana/Roche Inc., Shape Pharmaceuticals Inc.: Consultancy. Patki:Sanofi: Employment. Wu:Sanofi: Employment. Wu:Sanofi: Employment. Pozdnyakova:Sanofi: Honoraria; Sanofi: Consultancy.

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.

Efficacy, Safety, and Confirmation of the Recommended Phase 2 Dose of Ruxolitinib Plus Panobinostat in Patients with Intermediate or High-Risk Myelofibrosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 711-711 ◽  
Author(s):  
Jean-Jacques Kiladjian ◽  
Florian H Heidel ◽  
Alessandro M. Vannucchi ◽  
Vincent Ribrag ◽  
Francesco Passamonti ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Spleen Volume ◽  
Bone Marrow Fibrosis ◽  
Advisory Committees ◽  
Expansion Phase ◽  
Marrow Fibrosis

Abstract Background: Myelofibrosis (MF) is a clonal neoplastic disease resulting in bone marrow fibrosis, splenomegaly, and debilitating constitutional symptoms. The Janus kinase (JAK) pathway is often dysregulated in MF, and agents targeting this pathway have demonstrated efficacy in this disease. Ruxolitinib (RUX), a potent JAK1/JAK2 inhibitor, demonstrated superiority in spleen volume reduction, symptom improvement, and survival compared with the control arm in the phase III COMFORT-I and COMFORT-II studies. Panobinostat (PAN), a potent pan-deacetylase inhibitor (pan-DACi), inhibits JAK signaling through disruption of the interaction of JAK2 with the protein chaperone heat shock protein 90. In phase I/II studies, PAN has shown splenomegaly reduction and improvement of bone marrow fibrosis. The combination of RUX and PAN demonstrated synergistic anti-MF activity in preclinical studies. These preliminary results led to the initiation of a phase Ib study evaluating the combination of RUX and PAN in patients (pts) with MF. The updated results from the expansion phase of this trial are presented here. Methods: Eligible pts had intermediate-1, -2, or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF by International Prognostic Scoring System criteria, with palpable splenomegaly (≥ 5 cm below the costal margin). The primary objective was determination of the maximum tolerated dose (MTD) and/or recommended phase II dose (RPIID). Secondary objectives included safety, efficacy, and pharmacokinetics. Exploratory endpoints included assessment of improvement in bone marrow fibrosis and reduction of JAK2 V617F allele burden. The treatment schedule was RUX (5-15 mg) twice daily (bid) every day and PAN (10-25 mg) once daily 3 times per week (tiw; days 2, 4, and 6) every other week (qow) in a 28-day cycle. Following dose escalation and identification of the potential RPIID, additional pts were enrolled into the expansion phase and treated at this dose. Results: As of March 14, 2014, a total of 61 pts were enrolled (38 escalation phase and 23 expansion phase). The median duration of exposure to PAN and to RUX was 24.6 weeks and 24.0 weeks, respectively, for pts treated in the expansion phase. Three DLTs were observed in the escalation phase (grade 4 thrombocytopenia [n = 2], grade 3 nausea [n = 1]). No MTD was reached. The RPIID was confirmed to be RUX 15 mg bid and PAN 25 mg tiw qow in May 2014. Among the 34 pts treated at the RPIID, grade 3/4 adverse events (AEs) regardless of causality included anemia (32%), thrombocytopenia (24%), diarrhea (12%), asthenia (9%), and fatigue (9%). AEs led to discontinuation in 6% of pts treated at the RPIID. Two pts treated at the RPIID died due to causes unrelated to study treatment (1 due to myocardial infarction and 1 due to progression of myelofibrosis). Among the pts treated at the RPIID, 79% showed a >50% decrease in palpable spleen length, with 100% decrease (non-palpable spleen) being observed in 53% of pts. Additionally, 48% of pts treated at the RPIID in the expansion phase achieved ≥35% reduction in spleen volume (Figure). These results are similar to those observed for spleen volume response at 24 weeks among pts who received single-agent RUX on the phase III COMFORT-I (41.9%) and COMFORT-II (32%) studies. Conclusions: The combination of the JAK1/JAK2 inhibitor RUX and the pan-DACi PAN was well tolerated and resulted in high rates of reductions in splenomegaly in pts with intermediate- and high-risk MF. Although a relatively larger proportion of patients experienced spleen volume reductions at week 24 as compared to the COMFORT studies, the smaller sample size, shorter follow up times and potential differences in the patient populations preclude definitive comparisons. Similar to COMFORT-I and II trials, hematological AEs, specifically anemia and thrombocytopenia, were the most common AEs observed in pts treated with the combination therapy. Pts continue to be treated in the expansion phase at the RPIID. Updated safety, efficacy, and exploratory analyses on bone marrow fibrosis, JAK V617F allele burden, and biomarkers, including cytokines, will be presented. Figure Change in Spleen Volume in Expansion Phase Figure. Change in Spleen Volume in Expansion Phase Disclosures Kiladjian: Novartis: Honoraria, Research Funding, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Honoraria, Research Funding. Heidel:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ribrag:Celgene: Consultancy; Pharmamar: Consultancy; Epizyme: Research Funding; Bayer: Consultancy, Research Funding; Servier: Consultancy, Honoraria, Research Funding. Conneally:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kindler:Novartis: Consultancy. Acharyya:Novartis: Employment. Gopalakrishna:Novartis: Employment. Ide:Novartis: Employment, Equity Ownership. Loechner:Novartis: Employment. Mu:Novartis: Employment. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Gilead: Honoraria; SBio: Consultancy; Shire: Speakers Bureau.

scholarly journals Prognostic Significance of Bone Marrow Cellularity in the Outcome of Patients with Myelodysplastic Syndromes Treated with Azacyitidine: A Retrospective Analysis from the Hellenic MDS Study Group

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5417-5417
Author(s):  
Elena E. Solomou ◽  
Alexandra Kourakli ◽  
Anna Vardi ◽  
Ioannis Kotsianidis ◽  
Panagiotis Zikos ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Hypomethylating Agents ◽  
Advisory Committees ◽  
Female Ratio ◽  
Bone Marrow Cellularity ◽  
Marrow Cellularity ◽  
Male To Female

Introduction: Clinical trials in patients with high risk myelodysplastic syndromes (MDS) have shown that these patients benefit from the available hypomethylating agents 5-azacytidine and decitabine. The majority of these patients display hypercellular bone marrow, but a small proportion despite the excess of blasts, exhibit marrow hypocellularity (<30% cellularity). Data are limited for the efficacy and safety of treatment with hypomethylating agents in this patient subgroup. In the present study we examined the effect of bone marrow cellularity in the overall survival in patients with MDS treated with azacitidine. Patients & Methods: This is a retrospective multicenter study from the Hellenic National MDS Registry (EAKMYS) on behalf of the Hellenic MDS Study Group. Between 1.1.2009 and 31.12.2018 a total of 1161 MDS patients who have received treatment with azacytidine have been registered. Complete patient information and follow-up were available for 989 patients, and all these have been included in the final analysis. Statistical analysis was performed and overall survival (OS) was evaluated, using Kaplan-Meier estimates (GraphPad Prism software, CA). A p value less than 0.05 was considered statistically significant. Results: Forty nine patients had a hypocellular bone marrow (hMDS), representing the 4.95% of the whole patient population. Of these patients 39 were men (5.3% of all men included in the study) and 10 were women representing the 2.98% of all women enrolled (male to female ratio 3.9). In the non-hypoplastic group, 750 were men and 358 were women (male to female ratio 2.09). The median age at diagnosis for the hMDS group was 70.8 years, compared to 72.8 years in the non-hypoplastic group. The IPSS-R prognostic risk categorization included 15 hMDS patients in the low group, 9 in the intermediate, 14 in the high and 11 in the very high risk group. Twenty-six patients (53%) of the hMDS group had bone marrow blasts between 10 and 20%, and the remaining 23 (47%) had 5-10% blasts. The patients with hMDS received an average of 10 cycles of azacytidine treatment during the follow-up period (range 2-29 cycles). The outcomes tested were overall survival and progression to AML. The median overall survival of patients with hMDS, following azacytidine treatment start, was not significantly different from the median survival of patients with non-hypoplastic MDS [20 months versus 16 months in the non-hypoplastic group (95% CI of ratio: 0.839 to 1.863). The survival curves were not significantly different between the hMDS and non-hypoplastic MDS group (p=0.32, Figure 1). Progression to AML was also evaluated. Eleven (22.4 %) hMDS patients showed disease progression to AML. Patients with hMDS had significantly prolonged estimated median time to AML transformation, compared to the non-hypoplastic MDS population (31.7 versus 22 months respectively, p<0.001). There were not any major safety issues among patients with hMDS, despite the increased RBC and Platelet transfusion needs. The infectious episodes and the hospitalization courses did not differ significantly between the hMDS and the non-hypoplastic group. Discussion and Conclusive remarks: In this retrospective study, in which a large number of MDS patients was analyzed, we showed that bone marrow cellularity does not affect the outcome in patients treated with azacyitidine. Patients with hMDS show statistically significant slower AML progression compared to non-hypoplastic MDS. Bone marrow cellularity should not be a contraindication for using hypomethylating agents as a therapeutic option, and this type of treatment can be used safely, when indicated, also in patients with hMDS. Disclosures Pappa: Amgen: Research Funding; Gilead: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Vassilakopoulos:Merck: Honoraria; Takeda Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis Pharmaceuticals: 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; Astellas: Honoraria; Winmedica: Honoraria; Servier: Membership on an entity's Board of Directors or advisory committees. Symeonidis:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Progression Risk-Based Classification of Asymptomatic Waldenström Macroglobulinemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 150-150
Author(s):  
Mark Bustoros ◽  
Romanos Sklavenitis-Pistofidis ◽  
Chia-jen Liu ◽  
Efstathios Kastritis ◽  
Geoffrey Fell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Proportional Hazards ◽  
Risk Group ◽  
Advisory Committees ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Risk Of Progression

Abstract Background. Waldenström macroglobulinemia (WM) is a low-grade non-Hodgkin's lymphoplasmacytic lymphoma associated with overproduction of monoclonal IgM protein. It is preceded by an asymptomatic stage, called Smoldering Waldenström Macroglobulinemia (SWM), associated with a high risk of progression to overt disease. Current understanding of progression risk in SWM is based on a few small studies, and it is still unclear how to distinguish the asymptomatic patients who will progress from those who will not. Patients and Methods. We obtained clinical data of all WM patients who had been diagnosed and followed up at Dana-Farber Cancer Institute from 1982 to the end of 2014. Only patients with asymptomatic disease at the time of diagnosis were included in this study to identify risk factors for disease progression. Patients who received chemotherapy for a second cancer, before or after asymptomatic WM diagnosis (n =24), were excluded as chemotherapy might have affected the natural course of disease. Patients who progressed to or were diagnosed later with other types of B-cell lymphoproliferative disorders or Amyloidosis (n =71) and patients with myeloproliferative disorders or thalassemia (n = 4) were all excluded from our cohort. Furthermore, we excluded patients with no morphologic evidence of lymphoplasmacytic infiltration in the bone marrow biopsy (n =37), those without a bone marrow biopsy done at time of diagnosis (n =21), and those who were treated for peripheral neuropathy alone (n =13). Progression was defined based on the Consensus Panel recommendations of the Second International Workshop on WM. Survival analysis was performed using the Kaplan-Meier method and differences between the curves were tested by log-rank test. Effects of potential risk factors on progression rates was examined using Cox proportional-hazards models, with hazard ratios (HRs) and associated 95% confidence intervals (CIs). Results. A total of 439 patients were included in the study. During the 35-year study period and a median follow up of 7.8 years, 317 patients (72.2%) progressed to symptomatic WM. The median time to progression was 3.9 (95% CI 3.2-4.6) years. In the multivariate analysis, IgM ≥ 4,500 mg/dL (adjusted HR 4.65; 95% CI 2.52-8.58; p < 0.001), BM lymphoplasmacytic infiltration ≥ 70% (adjusted HR 2.56; 95% CI 1.69-3.87; p < 0.001), β2-microglobulin ≥ 4.0 mg/dL (adjusted HR 2.31; 95% CI 1.19-4.49; p = 0.014), and albumin < 3.5 g/dL (adjusted HR 2.78; 95% CI 1.52-5.09; p = 0.001) were all identified as independent predictors of disease progression, suggesting those thresholds could be clinically useful for determining high-risk patients. On the other hand, given the continuous nature of these variables, we built a proportional hazards model based on four variables (Bone marrow infiltration percentage, serum IgM, albumin, β2-microglobulin). The model divided the cohort into 3 distinct risk groups: a high-risk group with a median time to progression (TTP) of 1.9 years (95% CI 1.64-2.13), an intermediate-risk group with median TTP of 4.6 years (95% CI 4.31-5.15), and a low-risk group with a median TTP of 8.1 years (95% CI 7.33-8.13)(See Figure). To enhance its clinical applicability, we made the model available as user interface through a webpage and mobile application, where clinicians can enter an individual SWM patient's lab values and get information regarding their risk group and estimated individual risk of progression to symptomatic WM. Conclusion. We have assembled the largest cohort of SWM patients to date, which allowed us to identify four independent predictors of progression to overt disease: BM infiltration ≥ 70%, IgM ≥ 4,500 mg/dL, b2m ≥ 4.0 mg/dL and albumin < 3.5 g/dL. Using those variables in a proportional hazards model, we developed a robust, flexible classification system based on risk of progression to symptomatic WM. This system stratifies SWM patients into low-, intermediate- and high-risk groups and thus has the potential to inform patient monitoring and care. Most importantly, it can help identify high-risk patients who might benefit from early intervention in this rare malignancy. Figure 1. Figure 1. Disclosures Bustoros: Dava Oncology: Honoraria. Kastritis:Takeda: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: 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. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Treon:Johnson & Johnson: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Research Funding; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Castillo:Genentech: Consultancy; Millennium: Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Dimopoulos:Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Ghobrial:BMS: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Celgene: Consultancy.

scholarly journals Bortezomib, Lenalidomide and Dexamethasone (VRD) Followed By Autologous Stem Cell Transplant for Newly Diagnosed Multiple Myeloma; The Mayo Clinic Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2147-2147
Author(s):  
M Hasib Sidiqi ◽  
Mohammed A Aljama ◽  
Angela Dispenzieri ◽  
Eli Muchtar ◽  
Francis K. Buadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
High Risk ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Mayo Clinic ◽  
Research Funding ◽  
Advisory Committees ◽  
Post Transplant ◽  
Standard Risk

Abstract We retrospectively reviewed all patients receiving bortezomib, lenalidomide and dexamethasone induction followed by autologous stem cell transplantation (ASCT) within 12 months of diagnosis for multiple myeloma at the Mayo Clinic. 243 patients treated between January 2010 and April of 2017 were included in the study. Median age was 61 (interquartile range, 55-67) with 62% of patients being male. High risk cytogenetic abnormalities (HRA) were present in 34% of patients. 166 (68%) patients received some form of maintenance/other therapy post transplant (no maintenance (NM, n=77), lenalidomide maintenance (LM, n=108), bortezomib maintenance (BM, n=39) and other therapy (OT, n=19)). Overall response rate was 99% with complete response (CR) rate of 42% and 62% at day 100 and time of best response post transplant respectively. The four cohorts categorized by post transplant therapy were well matched for age, gender and ISS stage. HRA were more common amongst patients receiving bortezomib maintenance or other therapy post transplant (NM 18% vs LM 22% vs BM 68% vs OT 79%, p<0.0001). Two year and five year overall survival rates were 90% and 67% respectively with an estimated median overall survival (OS) and progression free survival (PFS) of 96 months and 28 months respectively for the whole cohort. OS was not significantly different when stratified by post-transplant therapy (Median OS 96 months for NM vs not reached for LM vs 62 months for BM vs not reached for OT, p=0.61), however post-transplant therapy was predictive of PFS (median PFS 23 months for NM vs 34 months for LM vs 28 months for BM vs 76 months for OT, p=0.01). High risk cytogenetics was associated with a worse OS but not PFS when compared to patients with standard risk (median OS: not reached for standard risk vs 60 months for HRA, p=0.0006; median PFS: 27 months for standard risk vs 22 months for HRA, p=0.70). In patients that did not receive maintenance therapy presence of HRA was a strong predictor of OS and PFS (median OS: not reached for standard risk vs 36 months for HRA, p<0.0001; median PFS: 24 months for standard risk vs 7 months for HRA, p<0.0001). Patients receiving maintenance therapy appeared to have a similar PFS and OS irrespective of cytogenetics (median OS: not reached for standard risk vs 62 months for HRA, p=0.14; median PFS: 35 months for standard risk vs 34 months for HRA, p=0.79).On multivariable analysis ISS stage III and achieving CR/stringent CR predicted PFS whilst the only independent predictors of OS were presence of HRA and achieving CR/stringent CR. The combination of bortezomib, lenalidomide and dexamethasone followed by ASCT is a highly effective regimen producing deep and durable responses in many patients. Maintenance therapy in this cohort may overcome the poor prognostic impact of high risk cytogenetic abnormalities. Table Table. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Kumar:KITE: 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; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gertz:Abbvie: Consultancy; Apellis: Consultancy; annexon: Consultancy; Medscape: Consultancy; celgene: Consultancy; Prothena: Honoraria; spectrum: Consultancy, Honoraria; Amgen: Consultancy; janssen: Consultancy; Ionis: Honoraria; Teva: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Physicians Education Resource: Consultancy.

scholarly journals The Combination of Frailty and ISS Scores Identifies a Simple Prognostic Index for Overall Survival in Elderly Patients Treated with Novel Agents-Based Induction Therapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4740-4740
Author(s):  
Alessandra Larocca ◽  
Sara Bringhen ◽  
Roman Hajek ◽  
Maria Teresa Petrucci ◽  
Massimo Offidani ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Dose Intensity ◽  
Staging System ◽  
Advisory Committees ◽  
Frail Patients ◽  
International Staging System ◽  
Frailty Score

Abstract Background: Several biological parameters define patients with multiple myeloma (MM) at high-risk of progression or death. The well-known International Staging System (ISS), as well as age per se, are insufficient to explain differences of overall survival (OS) in patients over 65 years, who are 2/3 of newly diagnosed (ND) MM patients. We have recently showed that a frailty score combining age, functional status (Activity of Daily Living and Instrumental Activity of Daily living scores) and comorbidities (Charlson index) defines 3 categories of patients - fit, intermediate-fitness, frail - with significantly differences in OS and progression-free survival (Larocca A, et al. Blood 2013 122:687). Here we assess the causes of the different mortality in intermediate-fitness and frail groups compared to fit ones and present a final prognostic score based on the combination of ISS and frailty scores. Methods: NDMM patients over 65 years enrolled in 3 clinical trials, receiving either lenalidomide, bortezomib or carfilzomib were included in the analysis. Details on treatment regimens and results of these studies have previously been reported (Palumbo A, et al. Blood 2013 122:536; Larocca A, et al. Blood 2013 122:539, Bringhen S et al. Blood 2014 Jul 3;124(1):63-9). The cumulative incidences of discontinuation and toxicities were calculated using the Fine & Gray model. The frailty score was combined with ISS with the CHi-squared Automatic Interaction Detector method used as an iterative decision tree. Results: 869 patients (median age 74 years) were included in the analysis; 260 (30%) were frail, 269 (31%) intermediated-fitness and 340 (39%) fit. The 3-year OS was 57% in frail, 76% in intermediated-fitness and 84% in fit patients. Overall, 143 patients (16%) died, 70 (27%) frail, 39 (14%) intermediate-fitness and 34 (10%) fit. The causes of death were: disease progression [35 (13%) in frail, 22 (8%) in intermediate-fitness and 18 (5%) in fit patients] and toxicity [21 (8%), 10 (4%) and 11 (3%), respectively]. The higher risk of death for progression was related with the lower dose-intensity due to the higher rate of drug discontinuation and/or dose reduction. The average dose intensity was lower in frail (74%, p=0.0006) and intermediate-fitness patients (80%, p=0.07) compared with fit patients (85%). The cumulative incidence of drug discontinuation for any cause, excluding progression and death, was higher in frail (25%; HR 2.21, p<0.001) and intermediate-fitness (22%; HR: 1.41, p=0.052) patients compared with fit ones (17%). The most frequent reasons for toxicity-related death were cardiac events [11 (4%) in frail patients, 2 (1%) in intermediate-fitness, 3 (1%) in fit] and infections [8 (3%), 2 (1%) and 2 (1%), respectively]. When we combined the frailty score with the ISS, 6 groups of patients and 4 risk categories were identified: fit patients with ISS I at low risk (15%; 3-year OS: 94%), fit patients with ISS stage II or III and intermediate-fitness patients with ISS I, II or III at intermediate risk (55%; 3-year OS: 75-77%.), frail patients with ISS stage I or II at high risk (19%; 3-year OS: 61%) and frail patients with ISS stage III at very-high risk (11%, 3-year OS: 55%) (Figure 1). Conclusion: The inferior survival observed among intermediate-fitness and in frail patients as compared to fit ones, is related to a higher rate of toxic deaths and disease progression, due to a lower dose intensity. The combination of the frailty score, evaluating the patient's status, and the standard ISS, taking into account the biological characteristics of the disease, can predict survival and enhances the single predictive values of the scores, thus representing a valuable tool for treatment-decision in the clinical practice. Figure 1. Overall survival of patients classified into 6 categories according to the recursive partitioning analysis by combining the frailty score and the International Staging System. Figure 1. Overall survival of patients classified into 6 categories according to the recursive partitioning analysis by combining the frailty score and the International Staging System. Disclosures Larocca: Janssen Cilag: Honoraria; Celgene: Honoraria. Off Label Use: Use off-label of lenalidomide (immunomodulatory drug), carfilzomib (proteasome inhibitor), subcutaneous bortezomib (proteasome inhibitor) in terms of schedule used and combination.. Bringhen:Onyx: Consultancy; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria. Hajek:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Offidani:Celgene: Honoraria; Janssen: Honoraria. Maracci:Mundipharma: Honoraria. Gay:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Marasca:Janssen: Honoraria; Celgene: Honoraria. Giuliani:Celgene: Research Funding. Musto:Janssen: Honoraria; Celgene: Honoraria. Boccadoro:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: 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. Sonneveld:Millenium: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Palumbo:Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Array BioPharma: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria.

scholarly journals Utilizing Organ-Sparing Marrow Irradiation to Condition Patients Prior to Allogeneic Hematopoietic Cell Transplant with High-Risk Hematologic Malignancies: Results of a Pilot Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2856-2856
Author(s):  
Sumithira Vasu ◽  
Meghan Kromer ◽  
Qiuhong Zhao ◽  
Hannah Choe ◽  
Karilyn Larkin ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Cell Transplant ◽  
Advisory Committees ◽  
High Incidence ◽  
Grade Ii

Abstract Background: Total body irradiation (TBI) has long been incorporated as part of the conditioning regimen prior to hematopoietic stem cell transplant (HSCT). While the myeloablative TBI conditioning is associated with a lower relapse rate in high risk diseases such as Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Acute Lymphoblastic Leukemia (ALL), it is also associated with substantial toxicities, and increased NRM so use of this regimen is limited to young patients with excellent performance status. In this study, we used a linac-based volumetric modulated arc therapy (VMAT) technique to deliver standard myeloablative radiation to high risk body sites while sparing radiation sensitive organs (Organ Sparing Marrow Targeted Irradiation, OSMI). We hypothesized that this technique would be feasible and safe in patients who are older or who have higher transplant specific comorbidity index (HCT-CI), typically ineligible for standard TBI conditioning. Methods: This is a single-arm prospective study. Patients from age 18-75 with high risk AML, MDS or ALL were eligible. There are 3 cohorts: (1) age 18-50 with HCT-CI of 3/4; (2) age 51-65 with HCT-CI of ≤ 3; and (3) age 66-75 with HCT-CI of ≤ 2. Patients receive OSMI to a total dose of 1200 cGy delivered twice daily for 6 fractions for a total of 7200 cGy. Clinical tumor volume includes total skeletal bone marrow and any sanctuary or high-risk areas. Graft-versus-host disease (GVHD) prophylaxis originally was tacrolimus and methotrexate. Given high incidence of bacterial infections related to mucositis, prophylaxis was changed to tacrolimus and sirolimus without methotrexate. All patients received Keratinocyte growth factor for prevention of mucositis. The primary objective was to assess feasibility and tolerability of OSMI based HSCT as defined by transplant-related mortality (TRM) at day 30 (D30) as well as rate of grade II/III organ toxicity (defined by Bearman Regimen-Related Toxicities Scale) attributable to conditioning occurring within 30 days. Results: Patient demographics for the 24 patients are shown in Table 1. Median age of recipients was 56.5 years. No graft failures were observed. The most common grade II or III Bearman toxicities include mucositis (grade 2: n=4), and diarrhea (grade 2: n=4). Clinical outcomes are shown in Figure 2. With a median follow-up of 3.3 years, overall survival (OS) and relapse-free survival (RFS) at 2 years was 78% and 74% respectively. Among the 5 patients who were not in complete remission at the time of transplant, 2-year OS and RFS rate was 40%. Incidence of Grades II-IV acute GVHD was 79% and Grades III-IV GVHD was 30%. Relapse incidence was 4% at 2 years. Incidence of Thrombotic microangiopathy by day 100 (TMA) as defined by Jodele's criteria was 17%. Incidence of chronic GVHD was 45% and severe chronic GVHD was 16%. One year non-relapse mortality was 22%, likely due to higher incidence of GVHD. Conclusions: Selected patients who are older or with higher HCT-CI, who are typically not candidates for standard TBI conditioning, were able to receive a radiation-based myeloablative conditioning regimen with 2 year overall survival rates of 78%. We observed a high incidence of TMA, possibly related to use of tacrolimus and sirolimus as GVHD prophylaxis, and a high incidence of Grade II-IV acute GVHD. Low incidence of relapse was observed. OSMI-based conditioning was feasible in this cohort with median age of 56 years and was associated with low rates of relapse and favorable 2 year overall survival. Figure 1 Figure 1. Disclosures Vasu: Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Jaglowski: Novartis: Consultancy, Research Funding; Takeda: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. de Lima: Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding.

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