Prognostic Value of the Hevylite Chain in MGUS Patients in a Population Study

Abstract Introduction: Studies have shown that a large monoclonal protein (MP) and immunoparesis in MGUS/SMM have predictive value of progression since they may be indirectly related to the degree of clonal expansion of bone marrow plasma cells (BMPC). A recently available assay, the Hevylite® (HLC), has allowed a more precise determination of MP and the quantification of isotype-matched immunosuppression (i.e. suppression of the monoclonal isotype but of the alternative light chain) which has shown prognostic value in some studies. In this study, we aim to evaluate the association between the alteration of the HLC parameters in MGUS patients with already known prognostic factors, but also, with less studied biomarkers such as circulating clonal plasma cells (cCPC) by Next Generation Flow (NGF) (Flores-Montero et al., Leukemia, 2017). Methods: A total of 175 MGUS patients diagnosed between October 2008 and September 2015 were included in the study. The median follow-up was 64 months (range: 1-100 months). MGUS and MGUS progression were defined according to the International Myeloma Working Group (IMWG) criteria. Clinical records were retrieved for all patients. HLC determinations were carried on a SPA+ turbidimeter analyzer and using specific reagents (Binding Site®, UK). The 6 HLCs pairs (IgGk, IgGl, IgAk, IgAl, IgMk and IgMl) were analyzed in all samples. HLC normal ranges were defined by the laboratory based on normal sera. Statistical analysis was done using IBM-SPSS-22. Results: HLC ratio was altered in 56.3% of the 111 patients with available sera (47.5% for IgG MGUS and 73.9% and 87.5% for IgA and IgM), respectively (p = 0.026). Patients with altered HLC ratio presented an MP significantly higher (Table 1) than those with normal ratio (0.62 g/dL vs 0.33 g/dL, p<0.0001; HR: 53.23 with 95% CI (2.82 / 1005.54), p=0.008); 100% of the patients had MP>1.5 g/dL (p = 0.044)). Interestingly, it also correlated with a greater frequency and a greater amount of cCPC by NGF (68.29%, p=0.001; 0.2864 /mL vs 0.0139 /mL p=0.0001). Regarding BMPC infiltration, there was a correlation between altered HLC ratios and greater percentages of infiltration of BMPC (3.72% vs. 2.43%, p = 0.001) and higher percentage of BMPC measured by multiparameter flow cytometry (MFC) (54.42% vs 24.42%, p <0.001; HR: 1.02 with 95% CI (1.01 / 1.03), p = 0.007). Patients with altered HLC ratio presented MP> 1.5 mg/dL (100%, p = 0.044), non-IgG (78,12%, p = 0.003) and ratio of altered CLL (77,77%, p = 0.011). Patients with normal HLC ratios correlated with other low risk of progression to MM parameters, such as a MP <1 g/dL (100%, p=0.0001) or <0,5 g/dL (87.8%, p=0.0001) or less than 5% of BMPC (91.3%, p=0.007).Considering the IMWG risk stratification model, 100% of the patients classified as intermediate risk (p = 0.0001) had an altered HLC ratio, while in the low risk group, ratios were evenly distributed. When considering the Spanish (GEM) model, 92% of the patients in the low risk group had normal HLC ratios (p = 0.010). Uninvolved HLC suppression >25% was observed in 15.2% of the patients. These patients presented significantly higher MP (0.91 g/dL vs 0.42 g/dL, p<0.0001; HR: 7.22 with 95% CI (1.11 / 46.83), p=0.038), greater infiltration of BMPC by MFC (70.54% vs 35.52%, p<0.0001; HR: 1.02 with 95% CI (1 / 1.04), p=0.040) and a greater amount of cCPC (0.8905 /mL vs 0.0256 /mL, p=0.030) compared to those without HLC suppression. Patients with moderate (<25%) or no suppression correlated with less aggressive parameters, such as the lower MP, <1 g/dL (95.8%, p = 0.0001) or < 0.5 g/dL (70.5%, p = 0.005). However, no significant correlation was found between the IMWG or the Spanish risk stratification models, and the frequency of HLC suppression. Conclusions: HLC abnormalities have been associated with negative prognostic factors previously established, reinforcing the idea that the HLC parameters are directly related to a greater propensity of clonal expansion, or a greater tumor load. However, the short follow-up time did not allow the confirmation of the prognostic value of HLC alterations regarding greater risk of progression to MM. A re-evaluation of the results at 10 years is foreseen. We expect to be able to access whether an evolving pattern exists for the HLC parameters mainly to investigate if the immune suppression by HLC progressively intensifies in patients closest to progressing to MM. Disclosures García Mateo: Celgene: Honoraria; Amgen: Honoraria; Binding Site: Research Funding. Mateos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Puig:Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Queizan:Janssen: Consultancy. Olivier:Celgene: Honoraria; Jassen: Honoraria.

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Combining Information Regarding Chromosomal Aberrations t(4;14), Del(17p13) and the Copy Number of 1q21 with the International Staging System Classification Allows Stratification of Myeloma Patients Undergoing Autologous Stem Cell Transplantation: Results From the HOVON-65/GMMG HD4 Trial

Blood ◽

10.1182/blood.v118.21.332.332 ◽

2011 ◽

Vol 118 (21) ◽

pp. 332-332

Author(s):

Kai Neben ◽

Henk M. Lokhorst ◽

Anna Jauch ◽

Uta Bertsch ◽

Thomas Hielscher ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Prognostic Value ◽

Risk Group ◽

Staging System ◽

Risk Groups ◽

Low Risk ◽

Advisory Committees ◽

International Staging System

Abstract Abstract 332 PURPOSE : In Multiple Myeloma (MM), the combination of serum beta-2-microglobulin level with serum albumin concentration has been proposed as an outcome predictor in the International Staging System (ISS). More recently, subgroups of MM defined by genetic and cytogenetic abnormalities have been associated with unique biologic, clinical, and prognostic features. PATIENTS AND METHODS: We analyzed the prognostic value of 12 chromosomal abnormalities by fluorescent in situ hybridization (FISH) in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Patients with newly diagnosed MM were randomized to receive either three cycles of VAD (arm A; vincristine, adriamycin, dexamethasone) or PAD (arm B; bortezomib, adriamycin, dexamethasone). All patients underwent autologous stem cell transplantation (ASCT) followed by maintenance therapy with thalidomide 50 mg daily (arm A) or bortezomib 1.3 mg/m2 once every 2 weeks (arm B), respectively. In addition, a second cohort of patients was analyzed as a control group (n=462), undergoing ASCT at the University of Heidelberg between September 1994 and December 2010. RESULTS: For the entire group of patients treated within the HOVON-65/GMMG-HD4 trial, we identified 233 patients with 2 copies (67.7%), 95 patients with 3 copies (27.6%) and 16 patients (4.7%) with more than three copies of the chromosomal region 1q21. In addition to del(17p13) and t(4;14), we added +1q21 (>3 copies) to the group of high-risk aberrations, since the outcome of these patients was almost as poor as it was observed for patients with del(17p13). Subsequently, we analyzed whether combining the ISS score with information on the presence of high-risk aberrations could improve the prognostic value with regard to patients' outcome. A combination of the presence or absence of del(17p13), t(4;14), or +1q21 (>3 copies) with the ISS score allowed patients to be stratified into three distinct groups: low-risk [absence of del(17p13)/t(4;14)/+1q21 (>3 copies) and ISS I], high-risk [presence of del(17p13)/t(4;14)/+1q21 (>3 copies) and ISS II/III], and intermediate-risk (all remaining patients). Most of the patients belonged to the low- (33%) and intermediate-risk (49%) groups, whereas 18% were allocated to the high-risk group. The median PFS times for the low-, intermediate-, and high-risk groups were 41.9 months, 31.1 months (HR=1.7; p=0.0018) and 18.7 months (HR=3.6; p<0.0001), respectively. The 3yr-overall survival (OS) decreased from 94% in the low-risk group to 80% (HR=4.6; p=0.0001) and 43% (HR=12.8; p<0.0001) in the intermediate- and high-risk groups, respectively. These results were confirmed in the independent cohort of patients: From date of first ASCT, the median PFS times for the low-, intermediate-, and high-risk groups were 43.3 months, 23.0 months (HR=1.5; p=0.015) and 13.8 months (HR=2.4; p=0.0003), respectively. The 4yr-OS decreased from 84% in the low-risk group to 71% (HR=2.1; p=0.0043) and 49% (HR=3.84; p<0.0001) in the intermediate- and high-risk groups, respectively. CONCLUSION: In our series, the ISS/FISH-based score/algorithm predicted PFS and OS much better than the ISS alone. Our results with molecular cytogenetic techniques may already have implications for the risk-adapted clinical management of patients with MM particularly in younger patients. Disclosures: van de Velde: Ortho Biotech Oncology Research & Development: Employment. Sonneveld:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees.

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Consistent Benefit of Ruxolitinib Over Placebo in Spleen Volume Reduction and Symptom Improvement Across Subgroups and Overall Survival Advantage: Results From COMFORT-I

Blood ◽

10.1182/blood.v118.21.278.278 ◽

2011 ◽

Vol 118 (21) ◽

pp. 278-278 ◽

Cited By ~ 8

Author(s):

Srdan Verstovsek ◽

Ruben A. Mesa ◽

Jason Gotlib ◽

Richard S. Levy ◽

Vikas Gupta ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Symptom Severity ◽

Research Funding ◽

Risk Group ◽

Spleen Volume ◽

Advisory Committees ◽

Disease Subtype ◽

Baseline Hemoglobin

Abstract Abstract 278 Background: Overactive JAK-STAT signaling as a result of gain-of-function mutations (eg, JAK2V617F) and/or high circulating levels of inflammatory cytokines is considered to play a key role in the pathogenesis of myeloproliferative neoplasms. Ruxolitinib, a selective oral inhibitor of JAK1 and JAK2, demonstrated a significant reduction in spleen volume (SV) and improvements in myelofibrosis (MF)-related symptoms in a double-blind placebo-controlled trial (COMFORT-I). The objective of this analysis was to evaluate the efficacy of ruxolitinib across patient (pt) subgroups in COMFORT-I. Methods: Pts with MF were randomized to start placebo or ruxolitinib at a dose of 15 mg or 20 mg PO BID depending on baseline platelet count (100–200 ×109/L or >200 ×109/L, respectively). The dose was optimized for efficacy and safety during treatment. SV change was measured by MRI; MF symptoms were assessed using a daily diary (modified Myelofibrosis Symptom Assessment Form [MFSAF] v2.0) over 1 wk prior to dosing and throughout the 24 wks of dosing. The percent changes from baseline to wk 24 in SV and MFSAF Total Symptom Score (TSS, a measure of combined scores for abdominal discomfort, pain under ribs on left side, early satiety, itching, night sweats, and bone/muscle pain) were compared for ruxolitinib and placebo pts across the following subgroups: MF disease subtype, age, International Prognosis Scoring System (IPSS) risk group, presence/absence of JAK2V617F mutation, baseline hemoglobin, baseline spleen size (palpable spleen length), and baseline TSS. Survival was estimated by Kaplan-Meier method. Changes in SV and TSS Across Subgroups: 309 pts were randomized: 155 to ruxolitinib and 154 to placebo. Ruxolitinib demonstrated consistent benefit compared with placebo in both SV and TSS across all subgroups evaluated (Table). The impact of symptom severity on response was evaluated by baseline TSS quartiles (maximum score for TSS = 60). Ruxolitinib pts with baseline TSS of <8.5, 8.5-<16.5, 16.5-<25.5 and ≥25.5 had mean percent changes in SV of −28.0, −31.4, −31.7 and −34.8, respectively, vs +8.1 for all placebo pts combined. The mean percent change in TSS for these same subgroups was −40.5, −47.2, −48.1 and −48.2 vs +41.8 for all placebo pts combined. These data indicate that pts with modest to marked symptoms all benefit from ruxolitinib therapy in terms of both SV and TSS. Survival Analysis: 13 ruxolitinib and 24 placebo pts died during the study or during extended follow-up (median follow-up of 52 and 51 wks, respectively), representing a hazard ratio (95% CI) of 0.499 (0.254, 0.98) (p=0.0395). For ruxolitinib- and placebo-treated pts, respectively, the probability of survival (95% CI) >48 wks was 0.98 (0.92, 0.99) and 0.90 (0.81, 0.95) for pts with baseline hemoglobin values ≥10 g/dL and 0.84 (0.72, 0.91) and 0.77 (0.63, 0.86) for pts with baseline hemoglobin <10 g/dL. Conclusions: Pts receiving ruxolitinib had higher response rates than placebo based on reductions in SV and improvements in TSS at wk 24 regardless of baseline subgroup: MF disease subtype, age (≤65 or >65 y), IPSS risk group (intermediate-2 or high-risk), presence or absence of JAK2V617F mutation, hemoglobin level (≥10 g/dL or <10 g/dL), palpable spleen length (≤10 cm or >10 cm), and symptom severity (TSS quartile). In addition, the overall survival analysis suggested a benefit with ruxolitinib therapy over placebo. Disclosures: Verstovsek: Incyte: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding. Gotlib:Incyte: Consultancy, Research Funding. Levy:Incyte: Employment, Equity Ownership. Gupta:Incyte: 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. Catalano:Incyte: Honoraria; Novartis: Honoraria. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Miller:Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Winton:Incyte: Consultancy. Arcasoy:Incyte: Research Funding. Lyons:Alexion: Consultancy, Honoraria; Telik: Research Funding; Incyte: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Vaddi:Incyte: Employment. Erickson-Viitanen:Incyte: Employment. Sun:Incyte: Employment. Sandor:Incyte: Employment. Kantarjian:Incyte: Research Funding; Novartis: Consultancy, Research Funding.

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From Mild Cytopenia to Overt MDS and AML, the Mutational Profile Predicts Progression, but Not Survival

Blood ◽

10.1182/blood-2018-99-110767 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 794-794

Author(s):

Jakob Werner Hansen ◽

Morten Munk Johansen ◽

Maj Karoline Westman ◽

Leonie Saft ◽

Lene Dissing Sjö ◽

...

Keyword(s):

At Risk ◽

Board Of Directors ◽

Bone Marrow Cells ◽

Low Risk ◽

Prognostic Impact ◽

Advisory Committees ◽

Cytogenetic Abnormalities ◽

Myeloid Neoplasm ◽

Risk Of Progression

Abstract Purpose: Recurrently mutated genes have been identified in patients with myelodysplastic syndromes (MDS) and, more recently, in patients with unexplained cytopenia. (Kwok et al. Blood 2015, Hansen et al. American Journal of Hematology 2016 and Malcovati et al. Blood 2017). In this study, we investigated the prognostic impact of these mutated genes in patients with idiopathic cytopenia and compared them to a control cohort of patients with low risk MDS. Methods: We included patients with idiopathic cytopenia after routine assessment, without cytogenetic abnormalities. For comparison, a group of low risk MDS patients without cytogenetic abnormalities, excess of blasts or ring sideroblasts were included. All samples were sequenced covering at least the 20 most recurrently mutated genes in MDS, and a subset of cases underwent a blinded morphology review by two hematopathologists. Results: Two hundred and forty nine patients, 171 with idiopathic cytopenia and 78 with low risk MDS, were included in this study. Of these, 80 (47%) and 53 (68%), respectively, had one or more detectable mutations. There was no difference in survival between the groups, however a predefined subset of "adverse mutations" (ASXL1, NRAS, SRSF2, U2AF1, TP53, RUNX1, EZH2, IDH2 and GATA2, adopted from Bejar et al. Current Opinion in Hematology 2017) was associated with inferior survival in the MDS group (p= 0.035), but not in the group with idiopathic cytopenia and at least one mutation (p= 0.43) (Figure 1). However, if an adverse mutation was present in the idiopathic cytopenia group the risk of progression to MDS or AML increased significantly (HR [CI:95%] 12.01 [1.47; 98.23], p= 0.02), after adjusting for age and sex. Thus mutational screening identified the patients with unexplained cytopenia at risk of progressing to an overt myeloid neoplasm (Figure 2). A total of 18 patients (23%) progressed to a myeloid neoplasm during follow up, of those 12 had material available at time of progression. All patients who progressed to AML (n=4) acquired a new driver mutation at time of progression, in contrast to the patients who progressed to MDS or CMML (n=8) without excess of blasts, who showed a clonal expansion or a steady variant allele frequency at the time of progression. TET2 and DNMT3A mutations were more frequent in patients with idiopathic cytopenia, and were associated with less dysplasia of bone marrow cells. A total of 109 cases with idiopathic cytopenia underwent a blinded morphology review by two independent reviewers; ten cases were concordantly reclassified to fulfill the criteria for MDS, and all of these had at least two mutations. None of these have progressed to higher risk MDS and these ten are not included in the 18 patients mentioned above, who progressed to MDS, CMML or AML during follow up. Conclusion: We here show that mutational profiling can identify patients with idiopathic cytopenia who are at risk of progression, but in contrast to low-risk MDS, the presence of adverse mutations in patients with idiopathic cytopenia do not predict inferior survival. Disclosures Hansen: Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees. Grønbæk:Janssen Pharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees.

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Hypomethylating Agent and Venetoclax Combination Yields Comparable Outcomes to CPX-351 in Newly Diagnosed Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-130379 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3895-3895

Author(s):

Hannah Asghari ◽

Dasom Lee ◽

Yehuda E. Deutsch ◽

Onyee Chan ◽

Najla Al Ali ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Risk Group ◽

Newly Diagnosed ◽

Advisory Committees ◽

Acute Myeloid

Background The therapeutic landscape for acute myeloid leukemia (AML) has become complex with recent drug approvals. CPX-351 has become standard-of-care for patients (pts) with therapy-related AML and AML with myelodysplasia-related changes. Moreover, earlier phase studies combining hypomethylating agents (HMA) and Venetoclax (HMA+Ven) in the frontline setting for elderly patients have demonstrated high response rates and improved survival. Given the overlapping indications, yet lack of comparative outcome data between these therapeutic regimens, treatment decisions have become challenging in the frontline setting. Therefore, we compared the outcomes of newly diagnosed AML pts receiving HMA+Ven vs. CPX-351. Methods We retrospectively annotated 119 pts that received frontline treatment with HMA+Ven and CPX-351 at Moffitt Cancer Center and Memorial Healthcare System between 2013 and 2019. Pts were divided in two cohorts: HMA+Ven (Cohort A) or CPX-351(Cohort B). Via comprehensive chart review of each patient that received HMA+Ven, we further classified a subgroup of pts meeting criteria to receive CPX-351 as CPX-351eligible. Clinical and molecular data were abstracted for each patient in accordance with IRB requirements. Overall response rate (ORR) was the combined total of complete remission (CR), complete remission with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Fisher's Exact method was used to determine significance. Kaplan-Meier analysis was performed to estimate median overall survival (mOS) with log-rank test to determine significance. All p-values are two-sided. Results Out of 119 total pts, 41 pts received HMA+Ven (Cohort A) and 78 pts received CPX-351 (Cohort B) with baseline characteristics outlined in Table 1. Among 111 response evaluable pts, ORR was 64.1% in Cohort A, including 28.2% with CR and 28.2% with CRi (Table 2). ORR was 50.0% in Cohort B, comprised of CR in 29.2% and CRi in 18.1%. There was no difference in ORR between Cohort A and Cohort B (64.1% vs. 50%, p 0.17). A significantly greater fraction of pts in Cohort B underwent allogeneic stem cell transplant (allo-SCT) (24.4% vs. 2.4%, p=0.004). ORR was higher in pts with European LeukemiaNet (ELN)-defined favorable/intermediate (fav/int) risk compared to adverse risk group in Cohort A (100% vs. 58.3%, p=0.03), however there was no difference in Cohort B (52.6% vs. 49.1%, p=1.0). ORR was similar among adverse risk groups in both cohorts (58.3% in Cohort A vs. 49.1% in Cohort B, p=0.47). Among responders, median time to best response was significantly longer in Cohort A (61.0 days vs. 40.5 days, p<0.0001). Median duration of response was not reached (NR) in both cohorts. Impact of somatic mutations on ORR is represented in Figure 3. Median follow-up was 6.5 months (mo) in Cohort A and 13.0mo in Cohort B. Median OS was similar in both cohorts (A vs. B, 13.8mo vs. 11.1mo, p=0.82) (Figure 1). Among responders, mOS was NR in Cohort A and 18.2mo in Cohort B (p=0.88) (Figure 2). Compared to Cohort B, mOS was superior for pts with fav/int risk disease in Cohort A (14.2mo (B) vs. NR (A), p=0.045) and not different for adverse risk group (11.1mo (B) vs. 7.3mo (A), p=0.2). Prior HMA exposure was 26.8% in Cohort A and 29.5% in Cohort B for an antecedent hematologic malignancy, however it did not impact mOS (p=0.86) or ORR (p=0.7). Early mortality rates for Cohort A and B were similar at day 30 (2.4% vs. 0%) and day 60 (4.9% vs. 3.8%). Rate of relapse was similar between cohorts A and B (16.0% vs. 30.6%, p=0.24). We then compared the outcomes of pts in Cohort B to CPX-351eligible arm from Cohort A (n=14). ORR and mOS were similar in Cohort B and CPX-351 eligible arm (ORR: 50% vs. 50%, p=1.0; mOS 11.1mo vs. 13.8mo, p=0.43). Only 1 patient (7.1%) of the CPX-351eligible arm underwent allo-SCT. Conclusion Our study demonstrates that HMA+Ven results in comparable response rates and survival outcomes to patients receiving CPX-351 when used as an initial remission therapy for patients with newly diagnosed AML, however the median follow up for patients receiving HMA+Ven was short. Survival did not appear to be impacted by a significantly greater proportion of patients proceeding to allo-SCT in the CPX-351 arm. Overall, HMA+Ven may represent a reasonable frontline remission therapeutic choice in patients with AML and a randomized trial would seem justified. Disclosures Kuykendall: Abbvie: Honoraria; Janssen: Consultancy; Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:celgene: Consultancy; Agios: Consultancy; pfizer: Consultancy; DSI: Consultancy; JAZZ: Speakers Bureau; JAZZ: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Astellas: 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; Pfizer: Consultancy; Celgene: Speakers Bureau; Jazz: Speakers Bureau. Talati:Agios: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Honoraria; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria.

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Progression Risk-Based Classification of Asymptomatic Waldenström Macroglobulinemia

Blood ◽

10.1182/blood-2018-99-114324 ◽

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.

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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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Long-Term Outcome of Total Therapy Regimens: Impact of Molecular Subgroups

Blood ◽

10.1182/blood-2019-131870 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3309-3309

Author(s):

Frits van Rhee ◽

Maurizio Zangari ◽

Carolina D. Schinke ◽

Guido J. Tricot ◽

Doug Steward ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Low Risk ◽

Event Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Cure Fraction ◽

Research Grant

Introduction. Our TT regimens for newly diagnosed multiple myeloma (MM) incorporate novel agents into a sequential treatment program comprising induction, tandem autologous stem cell transplantation and consolidation followed by 3 years of maintenance. Herein, we report the very long-term results in a large cohort of 1986 patients treated on successive TT protocols, the most mature of which (TT1, 2, and 3a) have a median follow-up ranging from 12.8 to 23.1 yrs. Methods. TT1 (1990) was followed by TT2 (1998), which introduced Thalidomide (T) in a randomized fashion. TT3 used bortezomib (V) throughout, with TT3a (2003) and 3b (2006) having different maintenance. TT3a used in year 1 of maintenance V, T and dexamethasone (D) and in years 2 and 3 TD. TT3b introduced lenalidomide (R) during maintenance for 3 years together with V and D. TT4 (2009) only enrolled patients with GEP-defined low risk disease and randomized patients to a standard arm or light arm using a similar regimen as TT3b. TT5 (2009) was specifically designed for patients who have a high 70-gene score and employed a dose dense treatment approach. Finally, TT6 (2009) accrued previously treated, patients irrespective of GEP-defined risk using a treatment schema similar to that used in TT5. Gene expression profiling was used to assign molecular classifications. These include HY (hyperdiploidy), LB (gene expression patterns frequently seen in patients with fewer focal bone lesions), MF (spikes in MAF and MAFB expression), MS (hyperactivation of MMSET +/- FGFR3), PR (over-expression of proliferation-related genes), and CD-1 or CD-2 (different forms of aberrant CCND1 and CCND3 expression). A mixed parametric cure model was used to estimate the proportion of patients with long-term, event-free survival, or the "cure fraction." When using progression free survival (PFS) in the model, the cure fraction is the percent of patients who are likely to never experience relapse based on trends in the survival times that have been observed. When using complete remission duration (CRD) in the model, the model estimates the cure fraction among patients who achieved complete response. Results. The median follow-up on the entire cohort patients was 11.6 years (range: 0.0-27.6) The median overall survival was 9.2 years, with 79.3% and 48.0% having an event-free survival greater than 3 and 10 years, respectively. Overall, patients with GEP70 low risk MM had estimated PFS and CRD cure fractions of 20.1% and 32.7%, respectively. GEP70 high risk MM patients fared much worse with estimated cure fractions of only 8.2 and 11.0%. The estimated PFS- and-CRD based cure fractions increased over time with successive protocols (PFS-cure: 6.0% in TT1 to 27.7% in TT4; CRD-cure: 9.3 to 49.8%). These cure fractions were consistent with the early plateau in the PFS and CRD curves seen at 9 years in TT4 patients. The highest cure fractions were seen in the CD-1 molecular group (34.9 and 40.3%) with intermediate outcomes in the HY (20.1 and 30.0%) and MS (22.8 and 33.5%) groups (Table 1). Surprisingly, low cure fractions were observed in the LB (1.1 and 13.5%) and CD-2 groups (13.5 and 26.4%). CD-1, LB and CD-2 groups had similar 5-yr PFS rates of 60, 60 and 63% respectively, but a steady low rate of relapse was observed in the CD-2 and especially the LB group. These findings were confirmed in a 5-yr landmark analysis showing high PFS and CRD cure fractions in the CD-1 group of 62.7 and 72.3% respectively contrasting to much lower cure fractions in the CD-2 (47.2 and 49.2%) and LB (30.8 and 45.0%) groups. Conclusions. We report excellent long-term outcomes in patients with GEP70 low risk MM and cure fractions in the range of 20-30%. Patients with LB and CD-2 subgroups have lower overall cure rates, despites similar initial 5-yr PFS rates compared to the superior performing CD-1 group, which can be explained by the occurrence of late relapses. Table 1 Disclosures van Rhee: EUSA: Consultancy; Adicet Bio: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy; Kite Pharma: Consultancy; Karyopharm Therapeutics: Consultancy; Castleman Disease Collaborative Network: Consultancy. Walker:Celgene: Research Funding. Davies:Janssen, Celgene: Other: Research Grant, Research Funding; Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. OffLabel Disclosure: anti-CD38 monoclonal antibody targeting myeloma

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Prognostic and Biologic Significance of Long Non-Coding RNA (lncRNA) Profiling in Cytogenetically Abnormal Acute Myeloid Leukemia (CA-AML)

Blood ◽

10.1182/blood-2018-99-114035 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2767-2767

Author(s):

Dimitrios Papaioannou ◽

Deedra Nicolet ◽

Xiaoqing Rong-Mullins ◽

Krzysztof Mrózek ◽

Jessica Kohlschmidt ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Risk Group ◽

High Risk Group ◽

Low Risk ◽

Group Status ◽

Advisory Committees ◽

Expression Levels ◽

Pathway Analyses

Abstract Introduction: Aberrant expression levels of lncRNAs have been shown to independently associate with outcome of younger and older patients (pts) with cytogenetically normal AML. However, the prognostic and biologic significance of lncRNA expression in CA-AML pts have not been extensively studied. Methods: We performed whole transcriptome profiling (RNA-seq) in 469 pts with de novo CA-AML. Cytogenetic analyses were performed in institutional laboratories and the results were reviewed centrally. All pts were treated on frontline Cancer and Leukemia Group B (CALGB)/Alliance protocols. Results: To evaluate the prognostic significance of lncRNA expression in CA-AML, we analyzed RNA-seq data of 469 pts by applying a machine learning algorithm-based approach. As CA-AML pts constitute a heterogeneous group, we first determined which other clinical and molecular parameters were prognostic [i.e., associated with event-free survival (EFS)] in our dataset. Among the parameters tested, the European LeukemiaNet (ELN) Risk Group status and age group [i.e., younger than 60 years (y) or aged 60 y and older] significantly associated with clinical outcome of CA-AML pts. Next, we individually identified each lncRNA that associated with EFS while adjusting for ELN Risk Group and age group. We conducted random forest analyses to select the prognostic lncRNAs, whose combined expression levels could generate an effective outcome predictor for CA-AML pts. For each step of the random forest analyses, a bootstrap technique was applied; a simple random sample of pts was drawn which served as the training set and the out-of-sample pts were used as the independent validation set. We identified 55 prognostic lncRNAs and used their expression levels to separate our CA-AML cohort into a lncRNA low-risk (n=161) and a lncRNA high-risk (n=308) group. With regard to clinical characteristics, pts in the lncRNA low-risk group were younger (P<.001) and had lower platelet counts (P<.001) and higher white blood cell counts (P=.01) than pts in the lncRNA high-risk group. Concerning cytogenetic abnormalities, pts in the low-risk group more often had core-binding factor translocations or inversions (P<.001) and less often complex karyotypes (P<.001) than pts in the high-risk group. Pts in the lncRNA low-risk group had higher complete remission (CR) rates than pts in the high-risk group (91% vs 48%, P<.001). LncRNA low-risk group status also associated with longer disease-free survival (DFS; 5-y rates 49% vs 12%, P<.001), overall survival (OS; 5-y rates: 58% vs 14%, P<.001) and EFS (5-y rates: 45% vs 6%, P<.001). With regard to the accuracy of outcome prediction, the lncRNA risk classification had a C-index of 0.73, which compares favorably with other prognostic classifiers of AML pts. In multivariable analyses, lncRNA low-risk status was an independent marker for higher CR rates, as well as for longer DFS, OS and EFS (P<.001 in all comparisons), after adjusting for other covariates. Finally, we examined the prognostic value of the lncRNA risk classification within the Favorable and Intermediate ELN Groups of our dataset, for which lncRNA risk groups had adequate pt numbers. Among pts in ELN Favorable Group, lncRNA low-risk pts (n=128) had higher CR rates (P=.003) and longer DFS (P<.001), OS (P<.001) and EFS (P<.001) than lncRNA high-risk pts (n=32). Similarly, in the ELN Intermediate Group (n=85), lncRNA low-risk group status (n=28) associated with higher CR rates (P=.01), longer OS (P=.01) and EFS (P=.005) and a trend for longer DFS (P=.08). To gain biological insights, we examined the molecular pathways regulated by the 55 prognostic lncRNAs. To minimize the confounding effects of differences in the concurrent cytogenetic abnormalities, we restricted these analyses to the ELN Favorable Group. We identified approximately 900 transcripts that were differentially expressed between lncRNA low- and high-risk pts. DAVID pathway analyses showed enrichment of genes involved in the processes of phosphorylation, acetylation and RNA-binding. Ingenuity pathway analyses of up-stream regulators identified aberrant activity of homeobox genes such as MEIS1, HOXA9 and HOXA10 in the lncRNA low-risk group and other transcription factors such as MYC, FOSB and JUN in the high-risk group. Conclusion: We conclude that lncRNA profiling provides meaningful prognostic and biologic information in CA-AML pts. Disclosures Kolitz: Magellan Health: Consultancy, Honoraria. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Stone:Cornerstone: Consultancy; Astellas: Consultancy; Orsenix: Consultancy; Merck: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Novartis: Consultancy, Research Funding; Arog: Consultancy, Research Funding; Fujifilm: Consultancy; Ono: Consultancy; Jazz: Consultancy; Sumitomo: Consultancy; Pfizer: Consultancy; Otsuka: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Amgen: Consultancy; AbbVie: Consultancy; Agios: Consultancy, Research Funding. Uy:Curis: Consultancy; GlycoMimetics: Consultancy. Wang:Amgen: Consultancy; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau. Stock:Jazz Pharmaceuticals: Consultancy.

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

Blood ◽

10.1182/blood-2018-99-114821 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5576-5576

Author(s):

Weixin Wang ◽

Youn K Shim ◽

Joel E Michalek ◽

Emily Barber ◽

Layla M Saleh ◽

...

Keyword(s):

Board Of Directors ◽

Monoclonal Gammopathy ◽

Research Funding ◽

Plasma Cells ◽

Univariate Analysis ◽

Serum Levels ◽

Advisory Committees ◽

Rank Regression ◽

Study Base

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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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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