Measurement of Serum microRNAs in US Veterans with Monoclonal Gammopathy of Undetermined Significance

Abstract Background Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic condition arising from clonal plasma cells and has the risk of transformation to multiple myeloma (MM). Dysregulated expression of microRNAs (miRs) has been well demonstrated in MM, but miRs are not as well characterized in MGUS. We previously found an increased risk for MGUS in Vietnam veterans exposed to Agent Orange and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Here we report the effect of age on serum levels of 13 miRs in MGUS cases and controls from that study cohort. Methods The study base population comprised 958 US veterans who participated in the 2002 follow-up of the Air Force Health Study (AFHS). A total of 49 MGUS cases were identified by using their serum stored at the AFHS 2002 follow-up (Landgren O et al. JAMA Oncology, 2015). The current study included 47 MGUS cases and 85 controls. The controls were selected from the veterans who did not have MGUS, did not have a history of tumors, and whose TCDD level was below the third quartile value among the study base. Quantitative real-time PCR (qPCR) was used to determine the serum levels of 13 miRs (let-7a, let-7i, miR-16, miR-20a, miR-21, miR-34a, miR-106b, miR-146a, miR-181a, miR-192, miR-205, miR-335 and miR-361) that were previously shown to be dysregulated in MM or other cancers . The cycle threshold (Ct) values obtained from qPCR were normalized by using spiked-in cel-miR-39 as a control. Univariate rank regression was used to examine the relationships between relative expression of each miR and age, and each miR and MGUS status (MGUS vs control); each miR-MGUS relation was also examined with adjustment for age. All miR values were analyzed in log2 units. Continuously distributed age was summarized by the median and interquartile range (IQR): age variation with MGUS status was assessed with Kruskal-Wallis test. All statistical testing was two-sided with a significance level of p<0.1. Corrections for multiple comparisons were not made. We used R for rank regression analysis and SAS Version 9.4 for Windows for all other analyses. Results Overall MGUS cases were older than controls (median, controls 66 years [IQR 61, 69] versus MGUS 67 years [IQR 64, 71], p=0.03). Rank regression analysis showed that age was significantly and negatively correlated with the serum levels of 9 (let-7a, let-7i, miR-146a, miR-361, miR-106b, miR-16, miR-20a, miR-21, and miR-335) of the 13 miRs examined in controls. Among MGUS cases, age was significantly negatively correlated with only 5 (let-7a, miR-146a, miR-106b, miR-16, and miR-20a) of the 13 miRs and positively correlated with miR-181a and miR-205 (Table 1). In the univariate analysis of the miR-MGUS relationship, the serum levels of 4 miRs (let-7a, miR-106b, miR-16, and miR-21) were significantly associated with MGUS. However, none of these miRs remained significant after adjusting for age. In both adjusted and unadjusted analyses, the miR levels were lower in MGUS cases than in controls with the exceptions of miR-205 (unadjusted) and miR-335 (adjusted). Conclusions and Discussions In this study population, serum levels of the majority of miRs tested were negatively correlated with age in controls. Most of the same miRs were similarly decreased in MGUS with age, with the exception of miR-181a and miR-205 which were positively correlated with age. miR-181a is an important regulator of apoptosis, that is altered in many cancers, and was previously shown to be elevated in plasma cells of MM and MGUS. miR-205 inhibits tumor suppressors PTEN and SMAD4, and has been shown to be increased in several cancers. Of note, based on univariate analysis, several miRs were significantly differentially expressed in MGUS, but failed to remain significant after adjusting for age effect. This finding underscores the importance of assessing the need for age adjustment when analyzing serum miR data. We are currently exploring this data set to determine whether TCDD levels had any independent effect on miR levels in this population. Note: The first two authors contributed equally. Disclosures Landgren: Pfizer: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Karyopharm: Consultancy; Takeda: Consultancy, 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.

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Analysis of Transfusion Dependency Development and Disease Evolution in Patients with MDS with 5q- and without Transfusion Needs at Diagnosis

Blood ◽

10.1182/blood.v128.22.3180.3180 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3180-3180

Author(s):

Felix Lopez-Cadenas ◽

Blanca Xicoy ◽

Silvia Rojas P ◽

Kaivers Jennifer ◽

Ulrich Germing ◽

...

Keyword(s):

Multivariate Analysis ◽

Board Of Directors ◽

Research Funding ◽

Statistical Significance ◽

Univariate Analysis ◽

Rank Test ◽

Advisory Committees ◽

Disease Evolution ◽

Free Survival

Abstract Introduction: Myelodysplastic syndrome with del5q (MDSdel5q) is the only cytogenetically defined MDS category recognized by WHO in 2001, 2008 and 2016 and is defined as a MDS with deletion on the long arm of chromosome 5 and less than 5% of blast cells in bone marrow. It is known that for patients with MDSdel5q and transfusion dependence (TD), Len (LEN) is the first choice of treatment. However, data regarding factors that may impact on the development of TD or disease evolution in patients diagnosed without TD are scanty. In our study a retrospective multicenter analysis on patients with low-int 1 MDSdel5q without TD at diagnosis has been performed in order to answer these questions. Patients and methods: We performed a multicenter collaborative research from the Spanish (RESMD) and German MDS registries. Data from 153 low risk MDSdel5q without TD at diagnosis were retrospectively analyzed. Statistical analysis: Data were summarized using median, range, and percentage. The event of TD was defined as the development of TD according to the IWG criteria (2006) and/or the beginning of a treatment which could modify disease course (LEN or ESA). Transfusion or treatment free survival (TFS), overall survival (OS) and leukemia free survival (LFS) were measured from diagnosis to TD or treatment, the first occurred (or to last follow up if none), last follow up or death from any cause and evolution to AML, respectively. TFS, OS and LFS were analyzed using the Kaplan Ð Meier method. The Log-rank test was used to compare variables and their impact on survival for univariate analysis.Multivariate analysis was performed using Cox's proportional hazards regression model. For comparison of Kaplan Meier curves the long rank test was used, with statistical significance with p<0.05. Statistical analysis was performed using SPSS 20.0. Results: Main clinical and biological characteristics were summarizing in table 1. From the total of 153 patients, finally 121 were evaluable. During the study 56 patients (46.2%) became in TD and 47 (38.8%) did not develop TD but received a modified disease course treatment. In this sense, most of the patients developed relevant anemia regarding those data (103 out of 121 patients, 85%). Median time to TD or treatment (TFS) was 20 months (1-132) from diagnosis. Secondary MDS (p=0.02), thrombocytosis (>350 109/L) (p=0.007), and neutropenia (<1.5 x 109/L) (p=0.02) were associated with poorer TFS. Thrombocytosis and neutropenia retained statistical significance in the multivariate analysis (Table 2). Among the TD patients (N=56), 42 (75%) received treatment: 28 LEN, 7 ESA and 7 other treatments. Among patients that did not develop TD (N=65), 47 (72.3%) received treatment before TD development: 16 LEN, 28 ESA and 3 other treatments. In order to know the evolution of these patients, survival analysis was performed. Median follow up was 58.9 months among alive patients and 57% of them were alive at the time of the last follow up. Estimated OS at 2 and 5 years was 94% and 64%. Regarding Univariate analysis, platelet <100 x 109/L (p=0.03), patients older than 71 years (p=0.001), and progression into AML (p=0.02) were associated with poorer OS. On the contrary, patients who had received treatment showed better OS (p<0.0001). This benefit is more evident among patients receiving LEN, median OS for patients receiving LEN, ESA/other treatments and not treated group was 137 months (CI 95%: 59,4 -215,5), 99,3 months (CI 95%: 46,6 -152) and 57,9 months (CI 95%: 38,2 -77,6), respectively, p<0.0001 (Figure 1). In the multivariate analysis, patients older than 71 years and LEN treatment retained the statistical significant impact on OS (Table 2). Twenty-eight patients (23%) progressed into AML, median time to AML was 35 months (5-122). When univariate analysis was performed, variables with adverse impact on LFS were platelets <100 x 109/L(p=0.019), neutropenia < 0.8 x 109/L (p=0.026), an additional cytogenetic abnormality (p=0.013) while treatment with LEN had a favorable impact (p=0.035). In the multivariate analysis only the presence of additional cytogenetic abnormalities retained statistical significance (Table 2). CONCLUSIONS: Most of the patients with low risk del(5q) MDS and no TD at diagnosis developed symptomatic anemia very early after diagnosis (20 months). Carefully monitoring should be stablished in order to detect this time point. Outcome of this subset of patients could improve after target therapy. Figure 1 Figure 1. Disclosures Del Cañizo: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees. Díez Campelo:celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees.

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Tracking Daratumumab Clearance Using Mass Spectrometric Approaches: Implications on M Protein Monitoring and Reusing Daratumumab

Blood ◽

10.1182/blood-2021-153209 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2707-2707

Author(s):

Nadine Abdallah ◽

David L Murray ◽

Angela Dispenzieri ◽

Prashant Kapoor ◽

Morie A. Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Plasma Cell ◽

Research Funding ◽

Univariate Analysis ◽

M Protein ◽

Urine Protein ◽

Advisory Committees ◽

Plasma Cell Disorders

Abstract Background: MASS-FIX is a screening method for serum and urine monoclonal proteins in multiple myeloma and related plasma cell disorders, which uses immunoglobulin enrichment coupled with matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MALDI-TOF). In addition to superior sensitivity over conventional gel-based techniques, MASS-FIX can distinguish therapeutic monoclonal antibodies (MoAb) from patient's M protein. As the utilization of therapeutic MoAbs increases, it is essential to understand the persistence pattern of these therapeutic antibodies in the serum. We designed this study to evaluate the duration of daratumumab detection by MASS-FIX in the serum of treated patients. Methods: We used a prospectively maintained database at Mayo clinic to identify patients with multiple myeloma and related plasma cell disorders who were treated with a daratumumab-containing regimen anytime during their disease course and had serial MASS-FIX data available after discontinuation of daratumumab. A univariate analysis was performed to assess for factors that may impact the clearance of daratumumab. Results: We included 125 patients with plasma cell disorders who received daratumumab as first or subsequent line of treatment between March 15 th, 2016, and March 4 th, 2020. The median age was 60.2 years and 57% were male. The most common diagnoses were multiple myeloma (70%) and light chain amyloidosis (18%). Daratumumab-based treatments were initiated after a median of 28.8 (IQR: 6.4-76.3) months from initial diagnosis. The most common regimen used was daratumumab, bortezomib and dexamethasone (23%); 26% underwent transplant after daratumumab-based induction. The median duration of treatment with a daratumumab-based regimen was 208 (IQR: 99-479) days. The median follow-up from the time of daratumumab discontinuation was 457 (95% CI: 346-NR) days. By last follow up, daratumumab was not detected by MASS-FIX in 93 (74%) patients but remained detectable in 32 (26%) patients. The median time from daratumumab discontinuation to disappearance of daratumumab by MASS-FIX was 160 (IQR: 107-233) days. On univariate analysis, the presence of ≥0.5 grams of urine protein was associated with earlier disappearance of daratumumab on MASS-FIX [risk ratio (RR): 2.0, P=0.02). The median time from daratumumab discontinuation to disappearance of daratumumab on MASS-FIX was 116 (95%CI: 76-160) days in patients with urine protein ≥0.5 grams and 203 (95%CI: 162-216) days in patients with urine protein <0.5 grams (P=0.02). There was no association between the time to disappearance of daratumumab by MASS-FIX and old age ≥70 (RR: 0.9, P=0.81], male gender (RR: 0.9, P=0.60), eGFR <60 (RR: 1.0, P=0.98), daratumumab schedule (every 1/2 weeks vs >2weeks) (RR: 1.0, P=0.97), treatment duration (<200 days vs ≥200 days) ( RR: 1.0, P=0.95), or transplantation status (RR: 1.0, P=0.98). Conclusion: The therapeutic monoclonal antibody daratumumab remains detectable in the serum of treated patients by MASS-FIX for several months after discontinuation and the duration varies between individual patients. This data has implications for diagnostic and monitoring testing and may provide guidance for reuse of daratumumab in clinical trials and practice. Proteinuria is associated with earlier disappearance of daratumumab by MASS-FIX and may have implications in patients with amyloidosis and monoclonal immunoglobulin deposition disease (MIDD). Further studies are needed to identify additional factors associated with the timing of disappearance. Disclosures Murray: Mayo Clinic: Other: Has received patents for the Mass-Fix technology which has been licensed to the Binding Site with potential royalties.. Dispenzieri: Takeda: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Dingli: Alexion: Consultancy; Novartis: Research Funding; Apellis: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; GSK: Consultancy. Kumar: Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Carsgen: Research Funding; Tenebio: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

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Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years

Blood ◽

10.1182/blood.v122.21.2310.2310 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2310-2310 ◽

Cited By ~ 11

Author(s):

Christina S Lee ◽

Allison Imahiyerobo ◽

Micha Thompson ◽

Marina Izak Karaev ◽

Waleed Ghanima ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Response Rate ◽

Newly Diagnosed ◽

Advisory Committees ◽

Platelet Counts ◽

Best Response

Abstract Background Adults with newly-diagnosed and persistent ITP usually respond to steroid based treatments such as prednisone but relapse with tapering. One 4-day cycle of Dexamethasone (dex) at 40 mg/day in newly diagnosed ITP resulted in a lasting effect in 50% of patients (pts) in 1 study. An Italian study showed that 3 cycles of dex are better than 1 cycle. Approximately 50% of pts with chronic ITP experience a complete or partial response (CR & PR) to rituximab, yet only 20% of pts have a lasting, unmaintained response after 3 years. Mechanistically, rituximab (which depletes B cells but not plasma cells) and dexamethasone (which may be the most potent anti-plasma cell agent) are a logical combination in treatment of antibody-mediated diseases such as ITP. In 2 studies of newly-diagnosed pts, dex 40mg/day x 4 followed by rituximab was more effective than dex alone (one study added more dex half way through). In our pilot study, pts at Weill Cornell Medical College (WCMC) with all stages of ITP were treated with a combination of rituximab (R) and usually 3 cycles of dex. The outcome of this combination was retrospectively analyzed. Methods Combination of standard-dose rituximab (weekly x 4) and usually 3 4-day cycles of 28mg/m2 (max. 40mg) dex at 2-week intervals (R+3Dex) was explored in 67 pediatric and adult pts with ITP at WCMC. Patients were monitored with CBCs obtained weekly and then at less frequent intervals if a response was achieved. Best response (after 8 weeks to avoid transient effects of dex) was determined. Patients were categorized as CR (platelet count≥100x109/L) or PR (50-100x109/L). Relapse was defined as either two consecutive platelet counts <50x109/L and/or need for additional therapy. The duration of response was calculated from date of first rituximab administration to relapse or latest follow-up as of July 31st 2013. Results Overall, 50 of 67 pts treated with R+3Dex achieved a best response of either a CR (n=43) or a PR (n=7) at 8 weeks or later from start of therapy for an overall response rate of 75%. Seventy-three percent of pts received R+3Dex; variations were primarily in the timing and amount of dex given. Fifteen responders, 9 CRs and 6 PRs, relapsed at a median of 9 months. Seventy percent of the responders (or 52% of all pts treated) maintain a continuous response with platelet counts ≥ 50 x 109/L as of their last visit at a median f/u of 20 months. Kaplan Meier Analysis estimates 44% of all pts treated (Figure) and 59% of responders (Figure) maintained a best response without relapse at 67 months after initiating treatment. If only those with ITP ≤ 24 months are included, the estimated long term response rate is 59% (p=0.0017) versus only 19% for those with a duration of ITP > 24 months (Figure). Of 36 responding children and adults who had ITP ≤ 24 months, 29 continued to respond as of last follow up. Adults initially responded better than children (p=0.0019) but the long-term responses were not different (Figure). Pts achieving a CR had longer response than those achieving a PR. Adverse events related to R+Dex were usually mild-moderate, although 3 pts had serum sickness and 2 had transient colitis. IgG levels fell to below the lower limit of normal for age in 14 of 67 pts, 10 of whom had their IgG levels return to normal. In 6 of 14, IgG levels were < 400 mg/dl, some of whom received IVIG. Fifteen patients had serial BK/JC levels without ever detecting virus. Conclusions R+3Dex provides clearly superior results to rituximab alone. Notably, there was a 75% response rate overall (50/67 pts) compared to 50% with R alone. The 5 year response rate was almost 50% of all patients and 3/5 of responders. In patients who had had ITP for ≤ 2 years, the response is comparable to what has been reported with splenectomy. Specifically the results in the ≤ 2 year group suggest that R+3Dex is an effective way to induce indefinitely normal platelet counts in pts with a “short” duration of ITP. R+3Dex was tolerable although patients had difficulty with 3 cycles of dex. The 21% rate of hypogammaglobulinemia, higher than that seen with R alone, is also evidence of the mechanism of R+3Dex affecting both B cells and plasma cells. The lasting, long-lived, unmaintained responses observed in this study suggest that this combination therapeutic strategy should be further tested in a controlled trial in patients with newly diagnosed, persistent, and early chronic ITP, whether or not they have been previously treated with other agents. Disclosures: Bussel: Sysmex: Research Funding; Cangene: Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees; Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; Genzyme: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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Impact of Genomic Alterations on Outcomes in Myelofibrosis Patients Undergoing JAK1/2 Inhibitor Therapy

Blood ◽

10.1182/blood.v128.22.4263.4263 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4263-4263

Author(s):

Jay Spiegel ◽

Caroline Jane McNamara ◽

Andrea Arruda ◽

Tony Panzarella ◽

James A. Kennedy ◽

...

Keyword(s):

Treatment Failure ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Inhibitor Therapy ◽

Jak Inhibitor ◽

Jak Inhibitors ◽

Advisory Committees ◽

Number Of Patients

Abstract Introduction: The advent of next generation sequencing (NGS) has brought intense interest to the complex genetic landscape of myeloproliferative neoplasms (MPN). However, data regarding clinical outcomes in the context of novel MPN therapies such as JAK inhibitors are scarce. Limited data indicate that high molecular risk signature (HMR, presence of at least one mutation in ASXL1, EZH2, IDH1/2, SRSF2) or multiple mutations may be associated with decreased spleen response and a shorter time to discontinuation of Ruxolitinib in myelofibrosis (Patel et al, Blood 2015). Methods: All myelofibrosis patients seen in the MPN program at Princess Margaret Hospital between November 2009 and May 2016 and treated with JAK1/2 inhibitor therapy were identified. NGS molecular profiling of 54 genes (39 hotspot region; 15 complete coding region coverage) was performed on peripheral blood or bone marrow samples using the TruSight Myeloid Sequencing Panel. Reporting was restricted to well-covered, exonic nonsynonymous, intronic splice site, and known pathogenic synonymous variants. Variants with global mean allele frequency >1% were identified using multiple population databases (1000 genomes, ESP, ExAC) and excluded. The primary endpoint was time from start of JAK1/2 inhibitor therapy to treatment failure (TTF) defined as treatment discontinuation, progression to accelerated phase or leukemic transformation, spleen progression or death. Secondary endpoints included best spleen, anemia and IWG response achieved by 48 weeks of treatment and overall survival. Response was assessed according to the 2013 revised IWG-MRT criteria. Transfusion dependency was assessed as any transfusion in 12 weeks prior to treatment or being identified as transfusion dependent in medical history. Results: Of 159 patients treated with JAK1/2 inhibitors at our institution, 102 met the inclusion criteria (see Table 1). Patients were excluded if; no sample was available for analysis (19), short use of JAK inhibitor prior to transplant (9), active clinical trial (5), in accelerated phase/acute leukemia (4) and others (20). First JAK inhibitor used was ruxolitinib in 77 patients and momelotinib in 25. At least one mutation was identified in every patient. Twenty (20%) patients had one mutation, 32 (31%) had 2 mutations and 50 (49%) patients had ≥ 3 mutations. Eighty (82%) patients had the JAK2V617F mutation, 15 (15%) had mutations in CALR, 4 (4%) had MPL mutations and one patient was triple negative. One patient had mutations in both CALR and JAK2 while another had mutations in MPL and CALR. Forty-eight (47%) patients had mutations consistent with HMR profile. Mutation profile is summarized in Table 2. With median follow-up of 2.5 years, 51 (50%) patients experienced treatment failure. On univariate analysis, TTF was associated with DIPSS, pre-treatment transfusion status and Hb <100 prior to initiating JAK inhibitor therapy. However, TTF was not associated with specific driver mutations, the number of mutations or HMR profile. Exploratory analysis of genes mutated in ≥5% of the population showed EZH2 (p=0.004) and CBL (p=0.005) mutated patients had shorter TTF. Multi-variable analysis employing anemia <100 and DIPSS with either of the number of mutations or HMR profile did not show any association with TTF. There was a trend towards TTF in patients with Hb<100 (HR 2.21, 95%CI: 0.99-4.95, p=0.05). Of 102 patients, 91 were evaluable for spleen response with 43 (47%) achieving a spleen response by 48 weeks of treatment. Twelve (23%) of the 53 patients evaluated met criteria for anemia response. Neither spleen nor anemia response was associated with the use of a particular JAK inhibitor. Of the 95 patients with at least 48-week follow-up, best response while on treatment was clinical improvement and spleen response in 29 (31%) and 19 (20%) patients respectively. Conclusions: In this study of myelofibrosis patients treated with JAK inhibitors, EZH2 and CBL mutated patients had shorter TTF. We did not find any association between TTF and number of mutations or other high risk mutations such as ASXL1/SRSF2. Anemia was the only significant independent predictor of shorter TTF. Our findings highlight the need for multicenter collaborative studies on a large number of patients and cautious use of mutation profiling results in routine clinical decision making with current treatment approaches. Spiegel and McNamara are co-primary authors. Disclosures Panzarella: Cellgene: Consultancy. Schimmer:Novartis: Honoraria. Schuh:Amgen: Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kamel-Reid:BMS: Research Funding. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding.

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A Multicenter, Case-Control Study Evaluating the Characteristics and Outcome of ITP Patients Refractory to, Rituximab, Splenectomy and Both TPO Receptor Agonists

Blood ◽

10.1182/blood.v126.23.3460.3460 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3460-3460 ◽

Cited By ~ 1

Author(s):

Matthieu Mahévas ◽

Mathieu Gerfaud-Valentin ◽

Guillaume Moulis ◽

Louis Terriou ◽

Sylvain Audia ◽

...

Keyword(s):

Immunosuppressive Therapy ◽

Board Of Directors ◽

Steroid Therapy ◽

Monoclonal Gammopathy ◽

Research Funding ◽

Morbidity And Mortality ◽

Advisory Committees ◽

Receptor Agonists

Abstract Introduction: Before the emergence of new treatments, refractory immune thrombocytopenia (ITP) was defined as the failure to achieve a minimum response to splenectomy and the requirement of long-term treatments to reduce risk of significant bleeding events. These patients experience a significant morbidity and mortality rate (1). The first aim of this study was to describe the characteristics of patients with multirefractory ITP (multi-ref ITP) according to an updated definition, i.e., patients who failed to respond to splenectomy, monoclonal anti-CD20 antibodies (rituximab, RTX) and both thrombopoietin-receptor agonists (TPO-RAs), as well as to identify associated factors with this phenotype. The second aim was to examine the long-term outcome of these patients. Patients and Methods: We carried out a multicenter retrospective study in France. Inclusion criteria of patients with multi-ref ITP were failure to splenectomy, rituximab and the two marketed TPO-RAs, or presentation of an absolute contraindication to these treatments. Failure to treatment was defined according to standardized international criteria and bleeding score as described by Khellaf et al. Physicians were interviewed and patients' medical charts collected using the standardized form of the Referral Center for Adult ITP. In order to assess the variables associated with multirefractory occurrences, patients with multi-ref ITP were compared with non-multirefractory patients: for each case, 5 controls were randomly selected from the ITP clinical research database at Henri-Mondor Hospital, matched on the year of diagnosis. This database includes all ITP patients followed in the French national center for autoimmune cytopenias. Univariate and multivariate conditional logistic regression models were performed (backward procedure, α=5%). Results: Thirty-seven patients (12 men/25 women) with multi-ref ITP and 183 controls were included in the study. Patients with multi-ref ITP have presented more initial bleeding symptoms than controls (75.6% vs 52.75%, p=.012)), had more frequently secondary ITP (35% vs 8.74%, p<.001), presented more clinical/biological auto-immune abnormalities (59.46% vs 28.42%, p=0008) and had more frequently a monoclonal gammopathy of undetermined significance than controls (19% vs 2.89%, p<.001). Only 24 patients with multi-ref ITP (68.57%) achieved initial transient response to steroid therapy (CR: n=10, R: n=12), compared to 91.61% responders in controls (p<.0001). In multivariate analysis, 4 factors were found to be associated with multi-ref ITP occurrence: (1) secondary ITP (OR: 4.81, 95%CI [1.31-17.86], p=.018), (2) presence of monoclonal gammopathy (OR: 5.93, 95%CI [1.08-32.48], p<.04), (3) bleeding symptoms at diagnosis (OR: 3.54 95%CI [1.11-11.22], p=.032) and (4) no response to steroid therapy (OR: 0.38 95%CI [0.20-0.72], p= .003). After a median follow-up of 84 months (range: 12-455), patients with multi-ref ITP have received a median of 10.5 lines of treatments (range: 6-15) including splenectomy, TPO-RAs and RTX, 5 patients (14%) died (intracranial hemorrhage, n=2; sepsis, n=1; breast cancer, n=1; unknown, n=1). Throughout the course of ITP, all patients required hospitalization; 22 (60%) received platelet transfusion, and 6 red-blood cells transfusion, 9 (24%) were admitted to intensive care units, 15 (40%) presented at least one bacterial infection, and 9 experienced at least one thrombosis (arterial, n=3; venous, n=6). At the end of follow-up, 20 patients (54%) were still non responders. Nine patients achieved a complete response: one after autologous hematopoietic stem cell transplantation, 2 after chemotherapy for hematological malignancy, and 5 after a combination of immunosuppressive therapy and TPO-RA. Conclusion: Our study demonstrated that multirefractory ITP is an extremely serious condition, associated with a high morbidity and mortality. Factors significantly associated with this phenotype were secondary ITP, association with autoimmune disorders, monoclonal gammopathy and no response to steroids. Most of these patients remained non-responsive to alternative lines of rescue treatment, but some successes has been obtained with the combination of immunosuppressive therapy and TPO-RA. (1) McMillan R, Durette C. Long-term outcomes in adults with chronic ITP after splenectomy failure. Blood 2004;104(4):956-60 Disclosures Salles: Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche and Gilead Sciences: Research Funding; Celgene Corporation; Roche: Speakers Bureau. Cheze:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Michel:GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Godeau:Roche: Research Funding; Amgen: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Treatment-Free Remissions in Newly Diagnosed CP CML Patients Treated with the Combination of Nilotinib + Pegylated Interferon Alpha 2a Versus Nilotinib Alone in the National Phase III Petals Trial

Blood ◽

10.1182/blood-2021-146412 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2553-2553

Author(s):

Franck E. Nicolini ◽

Gabriel Etienne ◽

Francoise Huguet ◽

Agnès Guerci-Bresler ◽

Aude Charbonnier ◽

...

Keyword(s):

Board Of Directors ◽

Primary Endpoint ◽

Research Funding ◽

Statistical Difference ◽

Univariate Analysis ◽

Phase Iii ◽

Newly Diagnosed ◽

Advisory Committees ◽

Obstructive Sleep

Abstract Aims: Combining 2GTKI+pegylated IFN-a (Peg-IFN) represents an attractive approach for first-line treatment of CP CML, while providing somewhat light additional AEs, it induces high rates of deep molecular responses. We evaluated nilotinib (NIL) alone versus NIL+Peg-IFN in newly diagnosed CP-CML patients (pts) in a randomised phase III trial (PETALs, EudraCT 2013-004974-82) and analysed here the proportion of patients reaching Treatment-Free Remission (TFR) and outcome. Methods: Newly diagnosed CP CML pts ≤65 years, without vascular history were randomized 1:1 to get NIL 300 mg BID alone [M0 to M72 (unless TFR), arm A] vs Peg-IFN alone for 30 days (M-1→M0) 30 mg/wk, prior to NIL 300 mg BID + Peg-IFN 30 mg/wk 2 wks, upgraded to 45 mg/wk thereafter, for up to 2 y (M0 to M24, arm B) followed by NIL alone until M72 unless TFR. The primary endpoint was the rate of MR4.5 by M12, and after amendment, the trial was extended to 72 months follow-up in order to add, as a secondary endpoint, the TFR rate in pts reaching MR4.5 ≥2 y. The trigger for treatment resumption was loss of MMR. All molecular assessments were centralised until M36, and in case of TFR, MR4.5 was centrally confirmed at M0 TFR, and further molecular follow-up was then performed locally. All molecular quantifications are expressed as BCR-ABL1/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control in the central lab and in the local labs all involved to the pluri-annual French external quality controls. Results are analysed in intention-to-treat. Results: As previously reported, 200 pts were randomized (99 in A, 101 in B), 130 M and 35 F in each arm, median age of 46 (18-66) y. The median follow-up (FU) since diagnosis is now 47.5 (33.77-62.39) Mo. and the median FU since discontinuation is 9.86 (5.8-23) Mo. in arm A and 15.57 (12.62-22.77) Mo. in arm B. Sokal and ELTS scores were high in 25% and 2.5%, intermediate in 33% and 16.5% and low in 42% and 81% pts respectively, equally balanced. All pts harboured a "Major" BCR transcript. We have previously shown that by M12, the rate of MR4.5 was 15.9% vs 21.5% (primary endpoint met, p=0.049) and that the overall cumulative incidence of MR4.5 was somewhat superior in arm B (54.6 [43.7-65.5] %) vs A (44 [31.5-54] %), p=0.05. Two pts died, one from myeloid blast crisis before TFR (arm A), one from a solid tumour (arm A). Overall, 40 pts (20%) reached the TFR criteria, 21 in arm A with a median FU of 9.86 (5.8-23) Mo. and 19 in arm B with a median FU since Nilo cessation of 15.57 (12.62-22.77) Mo, partly related to slightly different time for obtaining sustained MR4.5 in favour of arm B (16 vs 13 Mo.). For these 40 pts reaching TFR criteria, there was no statistical difference in terms of age at diagnosis and age at TFR, gender, Sokal, ELTS, FU since diagnosis, undetectability at cessation, BCR-ABL1 levels at 3 Mo. after cessation between the 2 arms. The survival without loss of MMR after cessation is illustrated in Figure 1. It looks superior in arm B over arm A, but did not reach statistical difference (p=0.445), but the FU is very short after cessation yet, especially in arm A. Once NIL was resumed in the pts that failed TFR, all pts recovered MMR within 6 Mo., with no difference between arms (p=1.00). In univariate analysis, we did not identify significant factor impacting on the TFR success (age at cessation, sex, undetectability at cessation, Sokal, ELTS) except the BCR-ABL1 value at M3-TFR (undetectable versus detectable, HR 7.15 [2.06-24.75], p=0.002), and the duration of MR4.5 before discontinuation (HR 1.11 [1.03-1.19], p=0.004). During this TFR phase 7 SAEs were reported in arm A (2 pregnancies, 1 obstructive sleep apnea, 1 fever episode, 1 carotid stenosis and 1 femoral stenosis in the same patient at 2 Mo. after cessation, 1 lung carcinoid tumor) and 2 in arm B (1 persistent atrial fibrillation, 1 cholecystectomy). Conclusions: The combination of NIL + Peg-IFN induces higher MR4.5 rates by M36 in newly diagnosed CP CML pts that may translate in higher successful TFR rates, however a longer follow-up is needed to see consistent significant differences. Updated data will be presented. Figure 1 Figure 1. Disclosures Nicolini: Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Etienne: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Guerci-Bresler: Novartis: Speakers Bureau; Incyte: Speakers Bureau. Charbonnier: Incyte: Speakers Bureau; Novartis: Speakers Bureau. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Deconinck: Stemline Therapetutics: Membership on an entity's Board of Directors or advisory committees; Imunogen: Membership on an entity's Board of Directors or advisory committees; Chugai: Research Funding; Novartis: Research Funding; Pfizer: Other: Travel Grants, Research Funding; Abbevie: Research Funding. Rea: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Introducing a Predictive Score for Successful Treatment Free Remission in Chronic Myeloid Leukemia (CML)

Blood ◽

10.1182/blood-2019-131500 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 26-26 ◽

Cited By ~ 4

Author(s):

Simone Claudiani ◽

Silvia Metelli ◽

Rafiee Kamvar ◽

Richard Szydlo ◽

Afzal Khan ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cox Model ◽

Univariate Analysis ◽

Age At Diagnosis ◽

Predictive Score ◽

Rank Test ◽

Advisory Committees ◽

Tki Resistance

Background: Treatment free remission (TFR) is now a realistic goal of treatment for CML. Approximately 50% of patients (pts) who discontinue tyrosine kinase inhibitors (TKI) after achieving deep molecular responses (DMR) are able to remain off treatment without losing major molecular response (MR3). Data from the largest available TKI stopping trial, EURO-SKI, showed that the most important variable associated with prolonged TFR is the duration of DMR. However, to date no clinical tool exists to guide clinicians and patients in predicting the likelihood of success of TFR attempt. Methods: We performed a retrospective analysis of clinical data from 172 pts with CML in whom treatment was discontinued in 6 hospital centres in order to identify factors associated with TFR. Data analysis started with a training set (TS) derived from pts treated at a single centre which was then validated on a validation set (VS) derived from the 5 other centres. Eligibility criteria included diagnosis of CML in chronic phase, a minimum duration of treatment with TKI of 3 years and discontinuation of TKI after achievement of confirmed ≥MR4. Patients diagnosed in accelerated phase CML and/or who underwent prior allogeneic stem cell transplant were excluded. Kaplan-Meier method was used for univariate analysis, with log-rank test for group comparison. A Cox proportional hazards model was employed with the purpose of choosing the most influential prognostic predictors on the probability of TFR in MR3 (pTFR3) and TFR in MR4 (pTFR4) on the TS. Variables with a p-value ≤0.1 entered in the multivariate analysis (MVA). Proportional hazard assumptions were tested for the final model. A prognostic TFR score was built from the combination of the predictors identified by the Cox model and validated on the VS. Results: The TS included 118 pts, while the VS 54 pts (Table 1). In the TS, the 2-year pTFR3 was 67.4% (95% CI 66.5-68.3%) and the 2-y pTFR4 was 56.8% (95% CI, 55.9-57.7%). The median time to MR3 loss was 3.8 months (range 1-31), and for MR4 loss was 3.2 months (range 0.8-24.5). After loss of MR4, the 1-year probability of MR3 loss was 77% (95% CI, 70.8-73.2%). However, 10 pts (8.5%) resumed TKI after MR4 loss and were not evaluable for time to loss of MR3. In univariate analysis, the variables most significantly associated with higher pTFR3 and pTFR4 were age at diagnosis >40 years (p=0.029 and p=0.002), absence of previous TKI resistance (p=0.003 and p= 0.068), longer duration of MR4 (p=0.003 and p<0.0001) and ≥MR4.5 at stopping (p=0.026 and p= 0.004). Variables entered into the MVA were age at diagnosis, BCR-ABL1 transcript type, Sokal score, dose of TKI at stopping, previous TKI resistance, duration of MR4 at stopping, depth of response at stopping. The Cox model suggested the inclusion of the following variables, for both pTFR3 and pTFR4: duration of MR4, previous TKI resistance, age at diagnosis and transcript type. Using these variables we developed a predictive score (Figure 1a), which was able to identify a good risk population (2-y pTFR3 81.8%, 2-y pTFR4 80%); intermediate (66.6% and 61.5%) and poor risk (42.3% and 30.8%) (overall log-rank test p=0.00092 and p <0.0001 for pTFR3 and pTFR4, respectively)(Figure 1b). The score was tested on the VS of 54 pts. In this population, the overall 2-y pTFR3 and pTFR4 were 61.3% (95% CI, 59.8-62.7%) and 42.6% (95% CI, 41.2-44%), respectively. Despite the small sample size, our score was still able to predict different 2-y TFR probabilities (Figure 1c) in the three risk groups. Of the pts who lost MR3 in the TS (n=39), 37 regained ≥MR3 after resuming TKI; 1 patient did not restart TKI and died from an unrelated cause; 1 patient had only 2 months follow-up after TKI resumption. In the VS, 15 of 21 pts losing MR3 achieved ≥MR3 again after TKI resumption; 3 pts had a follow-up <3 months after MR3 loss, 2 were lost to follow-up and 1 had not yet re-gained MR3 6 months after restarting TKI. In both cohorts no case of disease progression had occurred at last follow-up. Conclusions:This retrospective study confirms the safety of TFR attempt and identifies variables strongly associated with prolonged TFR. The resulting predictive score presented here, if validated in larger patient cohorts, might help in tailoring the choice of TKI discontinuation to the individual patient. Also, most pts who lose MR4 inevitably lose MR3, suggesting the importance of a more intense monitoring strategy in this subgroup. Disclosures Claudiani: Pfizer: Honoraria; Incyte: Honoraria. Byrne:Ariad/Incyte: Honoraria, Speakers Bureau. Rothwell:Incyte: Speakers Bureau; Novartis: Honoraria, Other: advisory board; Pfizer: Speakers Bureau. Copland:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Cyclacel: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Clark:Ariad/Incyte: Honoraria; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Milojkovic:BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Apperley:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Validation of the International Prognostic Score for Thrombosis in Essential Thrombocythemia (IPSET) in Patients with Pre-Fibrotic Primary Myelofibrosis

Blood ◽

10.1182/blood-2019-124302 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1657-1657

Author(s):

Paola Guglielmelli ◽

Alessandra Carobbio ◽

Elisa Rumi ◽

Valerio De Stefano ◽

Lara Mannelli ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Incidence Rate ◽

Research Funding ◽

Risk Model ◽

Univariate Analysis ◽

Thrombotic Event ◽

Advisory Committees ◽

Thrombotic Risk

Introduction. Prefibrotic myelofibrosis (pre-PMF) is a unique entity in the 2016 WHO classification of myeloproliferative neoplasms with distinct clinical phenotype and outcome [Guglielmelli P, Blood 2017]. Compared to essential thrombocythemia (ET), pre-PMF is characterized by more pronounced disease manifestations, adverse mutation profile and worse outcome. Previous studies [Rumi E, Oncotarget 2017] showed that patients (pts) with pre-PMF present a risk of vascular events similar to ET. However, no studies performed a comprehensive assessment of risk factors for thrombosis in pre-PMF. The current study aimed to identify risk factors for thrombosis and bleeding in a large series of pre-PMF pts and explore the effectiveness of contemporary prognostic models developed specifically for ET. Patients and Methods. The study included 382 pre-PMF pts, diagnosed by 2016 WHO criteria, referred by 4 Italian Centers. Previously published methods were used to genotype JAK2, MPL, CALR, EZH2, ASXL1, IDH1/2 and SRSF2; a high molecular risk (HMR) category was defined according to Vannucchi A, [Leukemia 2013]. Thrombosis‐free survival (TFS) was determined from diagnosis to the first thrombotic event. Pts were grouped according to the conventional risk stratification system [Barbui T, JCO 2011], IPSET‐thrombosis [Barbui T, Blood 2012] and revised IPSET‐thrombosis [Barbui T, BCJ 2015]. Cox-regression model was used for univariate analysis. Harrell's concordance (C) statistic was calculated to measure the incremental accuracy of multivariable models sequentially adjusted for new predictors of thrombotic risk. A P <0.05 was considered statistically significant. Results. At diagnosis, 65 pts (17%) experienced major thrombotic events which included 35 (9%) arterial and 31 (8%) venous thromboses. With a median follow-up of 6.9 y (range 0.08-32.6), 56 (15%) pts developed an arterial or venous thrombotic event, with a total incidence rate of 1.99% pts/year (pt-y); 30 (8%) were arterial and 28 (7%) venous events with incidence rate of 1.00% pt-y and 0.95% pt-y, respectively. Splanchnic vein thrombosis (SVT) represented the most frequent venous events before/at diagnosis (26%). During the follow-up, 16% and 8% of pts experienced myelofibrotic or leukemic progression, and 105 (27%) died, with incidence rate of 2.05% pt-y, 0.95% pt-y and 3.41% pt-y, respectively. In univariate analysis, factors significant for arterial thrombosis after diagnosis were age >65y (HR 2.88; P=0.005), WBC>10x109/L (HR 2.43; P=0.026), presence of >1 generic CV risk factor (HR 2.16; P=0.047), JAK2V617F (HR 3.35; P=0.027) and HMR status (HR 13.1; P=0.027). Conversely, only history of previous thrombosis (HR 3.06; P=0.005) and previous venous event (HR 5.53; P<0.0001) retained significance for predicting venous thrombosis. Pts were effectively stratified according to IPSET and conventional risk model. The risk of thrombosis in IPSET low-, intermediate-, and high-risk categories was 0.67%, 2.05% and 2.95% pt-y, and 1.47% pt-y and 2.71% pt-y in 2-tiered thrombotic risk model. (Figure 1); in revised-IPSET, 0.54%, 2.23%, 2.44% and 2.69 %pt-y in the very low, low, intermediate- and high-risk category. When WBC>10x109/L or HMR variables were incorporated into IPSET model, the C-statistic increased significantly for the prediction of arterial events: from baseline value of 0.68 to 0.74 adding WBC and 0.91 HMR status. The proportion of pts who experienced major bleeding was 3% prior/at diagnosis,and 7% during follow-up, with total incidence rate of 0.94% pt-y. In univariate analysis, predictors for major bleeding during follow-up were age >75y (HR 3.34; P=0.011), WBC>13x109/L (HR 2.33; P=0.035), presence of >1 generic CV risk factor (HR 2.41; P=0.035), particularly hypertension (HR 2.63; P=0.016) and grade-1 fibrosis (HR 2.28; P=0.05). High platelet count and treatment, including antiplatelet and anticoagulant drugs, did not reach statistical significance. Conclusions. Overall, this study identified independent risk factors for major thrombosis and bleeding in pre-PMF. Of interest, we report that HMR status predicted for arterial thrombosis during the follow-up. Pre-PMF pts showed remarkably high rate of venous thrombosis, mostly represented by SVT. The 3-tiered IPSET prognostic model for thrombosis reliably predicted occurrence of thrombotic events in pre-PMF and should be considered as standard reference. Figure 1 Disclosures Rumi: novartis: Honoraria, Research Funding. Thiele:Shire: Research Funding; Incyte: Consultancy, Honoraria, Other: Remuneration, Research Funding; Sanofi: Consultancy, Honoraria, Other: Remuneration; Novartis: Consultancy, Honoraria, Other: Remuneration, Research Funding; AOP Orphan Pharmaceuticals: Consultancy, Research Funding. Vannucchi:Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Presence of Chip-Mutated Autologous Hematopoietic Cells in Mobilized Peripheral Blood Products Is Associated with Shorter Progression-Free Survival after Autologous Transplants for Multiple Myeloma

Blood ◽

10.1182/blood-2019-127335 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 515-515

Author(s):

Ehsan Malek ◽

Petra Martin ◽

Paolo F Caimi ◽

Benjamin K. Tomlinson ◽

Michael Caldwell ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Progression Free Survival ◽

Hematopoietic Cell ◽

Advisory Committees ◽

Free Survival ◽

Whole Exome ◽

High Risk Disease

Multiple Myeloma (MM) remains a cancer of terminally-differentiated plasma cells that reside predominantly within the bone marrow. Malignant plasma cells are nurtured by a permissive microenvironment that favors tumor progression, drug resistance and disease relapse. Recurrent somatic mutations in hematopoietic stem cells, the source of major components in bone marrow niche, lead to age-associated clonal hematopoiesis of indetermined potential (CHIP) and has been associated with inferior survivals among individuals without malignant hematologic disorders. It is possible that these mutations in non-MM cells would affect remission time after transplant. We performed whole exome sequencing to identify CHIP-associated mutations within the autograft utilized to rescue hematopoiesis after high dose melphalan and autologous hematopoietic cell transplant (HCT). We then correlated the presence of CHIP with the outcome of MM patients (pts) following autologous HCT. Methods. MM pts (N=101) that underwent HCT between 2006 and 2017 were studied. DNA was extracted from 1 ml of cryopreserved mobilized hematopoietic cell product. Targeted sequencing was then performed using Tempus xE whole exome platform (Tempus, Chicago, IL) with variable allele frequency (VAF) ≥0.1. Progression-free survival (PFS) and overall survival (OS) were defined as the time from transplantation until event of interest, with censoring at time of last follow up. Cox regression was used for time-to-event outcomes; hazard ratios (HR) and 95% confidence intervals (CI) were reported. P-values were two-sided and those <0.05 were considered statistically significant. Results. The median age was 60.1 years at the time of HCT. 58 pts were male and 43 female; 29 pts were African-American, 1 Asian/Indian and 71 were Caucasian. Seventy five (75%) and 42 (43%) pts had prior exposure to lenalidomide or cyclophosphamide, respectively. Thirty two pts (32%) underwent hematopoietic cell mobilization with GCS-F and plerixafor, 38 pts (38%) with cyclophosphamide and 31 pts (31%) with GCS-F alone. Forty seven pts (47%) had at least one CHIP-associated mutation. The median number of CD34+ yield in the first day was 6.7 x 10e6/kg for pts with CHIP mutations and 5.64 x 10e6/kg for pts without any CHIP mutation (p = 0.4). The presence or absence of CHIP mutations did not impact the yield of CD34+ stem cells collected (Fig. 1). The majority of mutations were either missense variants or mRNA splicing variations (Fig. 2), most commonly SF3B1, ASXL1, TET2 and ASXL2. CHIP mutations were associated with increased age (p= 0.021), but there was no association with prior history of previous cancer, smoking, cytogenetically-defined high risk disease, pre-HCT hemoglobin level or red blood cell mean corpuscular volume. There was also no significant difference between the transplant course between the two groups in terms of neutrophil and platelet engraftment or length of hospital stay. Median follow up was 32 months. During follow up 3 pts develop MDS/AML (2 pts in the CHIP group and one in no CHIP group). Coronary artery disease was the cause of death in one patient in CHIP cohort versus none in the CHIP negative cohort. Myeloma progression was the major cause of death in CHIP and No CHIP cohorts (66% vs. 60%, p=0.48). Median PFS was 19 months in CHIP cohort vs. 39 months in No CHIP group (HR: 0.62, 95% CI: 0.51-0.92, p= 0.001). Median OS has not been reached in the No CHIP group while it was 56 months in CHIP group (HR: 0.78, 95% CI: 0.62-1.04, P=0.09). In multivariate analysis, presence of CHIP remained a significant predictor of worse PFS after adjusting for age, maintenance therapy, high risk disease, performance status, triplet vs. doublet pre-SCT therapy, melphalan dose and MM genetic risk. (Table 2). Conclusion: Here we showed high frequency of large clonal hematopoiesis clones (i.e., VAF ≥0.1) in autograft of MM pts. The presence of this mutations does not impact stem cell yield or transplant course, however it impacts PFS independent of age and other unfavorable factors. Our data highlights high frequency of SF3B1; the role of this mutant in modulating apoptotic factors in myeloma microenvironment should be investigated. Disclosures Malek: Celgene: Consultancy; Amgen: Speakers Bureau; Adaptive: Consultancy; Janssen: Speakers Bureau; Medpacto: Research Funding; Sanofi: Consultancy; Takeda: Consultancy. Caimi:ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Fate Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Caldwell:Tempus Inc.: Employment.

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Impact of sFLC Ratio on Outcome in Patients with MM: Validating the Utility of sFLC in Response Definition

Blood ◽

10.1182/blood-2019-131835 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3080-3080

Author(s):

Nadine Abdallah ◽

S. Vincent Rajkumar ◽

Dragan Jevremovic ◽

Prashant Kapoor ◽

Angela Dispenzieri ◽

...

Keyword(s):

Flow Cytometry ◽

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Complete Response ◽

Light Chains ◽

Advisory Committees ◽

Normal Ratio ◽

Abnormal Ratio

Background: The treatment of Multiple Myeloma (MM) has evolved significantly in the past decade with the introduction of novel agents and drug combinations, thus enhancing treatment efficacy and allowing more patients to achieve complete response (CR). This has created a need to identify surrogates for depth of treatment response. Serum free light chain (sFLC) ratio normalization has been shown to be prognostic for progression free survival as well as overall survival in patients achieving a complete response to therapy. Consequently, it has been incorporated as a defining feature for stringent CR, along with lack of clonal plasma cells by immunohistochemistry (IHC) or low sensitivity flow cytometry. The routine use of multiparametric flow cytometry with higher sensitivity to detect residual disease than IHC or the older 4-color flow cytometry, has raised the question as to whether sFLC ratio is still a valid indicator of response depth. Moreover, in nearly half of the patients with an abnormal sFLC ratio after treatment, the abnormality is secondary to suppression of one or both serum light chains. Therefore, we designed a retrospective study to address these issues. Patients and Methods: This is a retrospective study using the Multiple Myeloma Database at Mayo Clinic, Rochester. We included patients who, after any line of therapy, had negative serum and urine immunofixation and absence of clonal bone marrow plasma cells by flow cytometry (PC-PRO), which has a sensitivity of >10-4. Simultaneous sFLC data was also extracted. Patients were grouped into three categories based on their sFLC ratios: 1) normal ratio (normal), 2) abnormal ratio due to suppression of the uninvolved light chain (LC), involved LC, or both (Abn-suppressed) and 3) abnormal ratio due to elevation of the involved LC (Abn-inv elevated). The primary endpoint was the median time to next treatment (TTNT), defined as the time from sample collection to the time of initiation of the subsequent therapy or time of last follow up if a subsequent line of treatment was not initiated. Results: The cohort consisted of 510 patients. 285 (56%) were males and 225 (44%) females. Median age was 61 years (IQR: 55-67). Median Follow-up was 41 months. The last treatments administered prior to data collection included stem cell transplant (SCT) (with or without maintenance) in 290 (57%) patients, and non-SCT regimens in the others. The sFLC ratio was normal in 337 (66%) and abnormal in 173 (34%) patients. Among the patients with abnormal sFLC ratios, 81 had elevated involved LC, 25 had suppression of the involved LC, 45 had suppression of the uninvolved LC and 22 had suppression of both LCs. We first examined the TTNT for the three groups and found that the TTNT was identical for those with a normal ratio and those with an abnormal ratio due to suppression of one or both light chains (Figure 1). So, we combined these two groups (Normal-Abn suppressed) and compared their outcomes to the patients with abnormal sFLC ratio due to elevated involved LC. The Abn-inv elevated group had a shorter TTNT as shown in Figure 2 (log-rank 0.06, Wilcoxon <0.01). The Abn-inv elevated group also had decreased overall survival compared to the other group (log-rank: 0.05, Wilcoxon: 0.01) (Figure 3). Conclusion: This study provides 2 important observations. First, patients with an abnormal ratio due to suppression of one or both LCs have outcomes similar to those with a normal ratio, suggesting a need to clarify the current definition of stringent CR. Second, the study suggests an important prognostic value for an abnormal sFLC ratio due to elevated involved LC, suggesting this as an important surrogate for depth of response. Disclosures Kapoor: Janssen: Research Funding; Takeda: Honoraria, Research Funding; Cellectar: Consultancy; Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Spectrum: Honoraria, Research Funding. Lacy:Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Leung:Takeda: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

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