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

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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Impact of Non-JAK2 Molecular Mutations and Cryptic SNP Lesions in Myelofibrosis Patients Treated with Ruxolitinib

Blood ◽

10.1182/blood.v124.21.3194.3194 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3194-3194

Author(s):

Jing Ai ◽

Valeria Visconte ◽

Ali Tabarroki ◽

Ahmad Zarzour ◽

Christopher Gerace ◽

...

Keyword(s):

Board Of Directors ◽

Dose Escalation ◽

Somatic Mutations ◽

Similar Response ◽

Prognostic Impact ◽

Severe Thrombocytopenia ◽

Spleen Size ◽

Advisory Committees ◽

Myeloid Neoplasm

Abstract The identification of the JAK2V617F mutation in myeloproliferative neoplasms (MPN) paved the way for the pivotal studies that led to the FDA approval of a JAK1/2 inhibitor, ruxolitinib (rux) in patients (pts) with myelofibrosis (MF). Improvement in splenomegaly and debilitating disease-related symptoms were the primary clinical responses observed with rux. Although JAK2 mutational status did not impact response/survival in MF pts, cytogenetics had an impact on prognosis. In a related myeloid neoplasm specifically myelodysplastic syndromes, molecular mutations (TET2/DNMT3A) predict for better therapeutic response to DNA methyltransferase inhibitors. We hypothesized that somatic mutations and single nucleotide polymorphism array (SNP-A) lesions are frequent in MF pts treated with rux and may affect their clinical outcomes. To further investigate the predictive and prognostic impact of SNP-A lesions and somatic mutations in MF pts in the rux era, we studied 54 MF pts who received at least 12 weeks of rux therapy (tx) using a modified dose escalation approach (Tabarroki A et al. 55th ASH; Abstract 1586). Clinical (total symptom score [TSS], spleen size), cytogenetic (metaphase cytogenetics [MC], SNP-A), hematologic and survival data were collected before and 12-weeks post rux tx. Categorical data were analyzed using X2 test. A p-value of <.05 was considered statistically significant. Sanger sequencing for genes relevant to myeloid neoplasm pathophysiology like TET2, CBL, LNK, DNMT3A, TP53, SF3B1, U2AF1, SRSF2, ASXL1, EZH2, JAK2, CALR, and IDH1/2 was performed. The median age of the cohort was 66 yrs (41-89); male/female: 28/26. The median follow-up time after initiation of tx was 17 months. The median overall follow-up of the cohort from the time of diagnosis was 35 months. Using DIPSS-plus, pts were stratified as high (24, 44%), int-2 (22, 41%) and int-1 (8, 15%) risk groups. Baseline median WBC=9.4k/μL, Hgb=10.2g/dL, PLT=212k/μl, TSS=20, and median palpable spleen size=13cm. Post-tx median WBC=9.9k/μL, Hgb=10.1g/dL, PLT=150k/μL, TSS=4, and spleen size=6cm. MC identified cytogenetic abnormalities in 24/54 (44.4%) pts. The most frequent chromosomal defects included del(20), +8, and +9. Serial MC was available for 20 pts and no cytogenetic evolution was identified. SNP-A data were available for 29 pts, of which 28 pts had SNP-A lesions. The most commonly involved chromosomes were 9 (15.1%), 20 (14.1%), and 14 (8.5%). Compared to MC analysis, additional SNP-A lesions were found in 66% of pts. Of note 39% of the pts had normal karyotypes but with pathologic SNP-A lesions; another 27% had pathologic SNP-A lesions besides the abnormal MC. Serial SNP-A analysis was available in 10 pts who while on rux tx did not develop any additional/new SNP-A lesion. There was no difference in spleen response rates or TSS between those who carried SNP-A lesions versus those who did not. Molecular analysis was possible for 34 pts. The most frequent somatic mutations observed involved JAK2 (70.6%), ASXL1 (24%), CALR (24%), SRSF2 (15%), and U2AF1 (9%). Pts with int-2 and high DIPSS plus scores were more likely to carry at least 1 mutation in any gene compared to pts with int-1 scores (int-2 vs int-1, p=.05; high vs int-1, p=.06). After a median follow-up of 35 months from diagnosis, 95% of the pts were still alive. 3 pts died from disease progression: 1 had a sole SRSF2 mutation, 1 had an SRSF2 plus CALR mutation, and 1 had a TET2 plus TP53 mutation. SRSF2 mutant pts had more severe thrombocytopenia pre-rux tx (91 vs. 203k/μL; p=.04). ASXL1 mutant pts had increased spleen sizes pre-rux (21 vs. 15cm, p=.06), but had similar response post-rux (10 vs. 8cm, p=0.6) compared to the wild-type. SRSR2 mutant pts had higher DIPSS-plus score (4.4 vs. 3; p=.05). Our study showed that MF pts treated with a rux modified dose escalation approach resulted in meaningful clinical and splenic responses regardless of molecular mutation status. Frequently found cryptic SNP-A lesions in MF pts may explain their poorer outcomes compared to pts with other MPNs. The fact that pts did not acquire additional/new SNP-A lesions during rux tx may be one of the mechanisms of improved survival in these pts. ASXL1, CALR, SRSF2 and U2AF1 were the most frequent non-JAK molecular mutations in MF pts treated with rux and were more frequent in high risk pts. Further studies are necessary to elucidate the clinical/ biological effects of these mutations in MF pts treated with rux. Disclosures Tiu: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽

10.1182/blood-2018-99-110329 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4506-4506

Author(s):

Aránzazu García Mateo ◽

Maria-Victoria Mateos ◽

Alberto Orfao ◽

Teresa Contreras Sanfeliciano ◽

Luzalba del Carmen Contreras Sanfeliciano ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Prognostic Value ◽

Plasma Cells ◽

Risk Group ◽

Clonal Expansion ◽

Low Risk ◽

Advisory Committees ◽

Risk Of Progression

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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Multiple Low Level Mutations Identifies Imatinib Resistant CML Patients At Risk of Poor Response to Second-Line Inhibitor Therapy, Irrespective of the Resistance Profile of the Mutations

Blood ◽

10.1182/blood.v118.21.111.111 ◽

2011 ◽

Vol 118 (21) ◽

pp. 111-111

Author(s):

Wendy T Parker ◽

Musei Ho ◽

Hamish S Scott ◽

Timothy P. Hughes ◽

Susan Branford

Keyword(s):

At Risk ◽

Board Of Directors ◽

Mutation Analysis ◽

Research Funding ◽

Poor Response ◽

Advisory Committees ◽

Low Level ◽

Mass Spec ◽

Imatinib Resistant

Abstract Abstract 111 Specific imatinib resistant BCR-ABL1 mutations confer clinical resistance to nilotinib (NIL; Y253H, E255K/V, T315I, F359V/C) and/or dasatinib (DAS; V299L, T315I/A, F317L/I/V/C). Therefore, mutation analysis is recommended for CML patients (pts) after imatinib failure to facilitate selection of appropriate therapy. However, around 40% of chronic phase (CP) pts without these NIL/DAS resistant mutations also fail second line inhibitor therapy. For imatinib resistant pts without these mutations at the time of commencing NIL/DAS therapy (switchover) we investigated whether sensitive mutation analysis could identity pts at risk of poor response to subsequent therapy. Switchover samples of 220 imatinib resistant pts (DAS n=131, NIL n=89) were analysed by direct sequencing (detection limit 10–20%) and sensitive, high throughput mass spectrometry (mass spec; Sequenom MassARRAY, detection limit 0.05–0.5%), which detects 31 common BCR-ABL1 mutations (approximately 89% of mutations detected in pts receiving imatinib). We previously demonstrated that mass spec could detect NIL/DAS resistant mutations at switchover in an extra 9% of pts compared to sequencing and that these low level resistant mutations were associated with subsequent failure of these inhibitors (Parker et al, JCO. 2011 In Press). Therefore, for the current analysis, pts with NIL/DAS resistant mutations detected by either method (n=45) were excluded since response is already known to be poor in these cases. In the switchover samples of the remaining 175 pts, 159 mutations were detected in 86 pts by mass spec, but just 108 mutations were detected in 89 pts by sequencing. Thirteen rare mutations detected by sequencing were not included in the mass spec assay design. Mass spec detected all other mutations detected by sequencing, plus an additional 64 low level mutations. Multiple NIL/DAS sensitive mutations (≥2 mutations) were detected at switchover in more of the 175 pts by mass spec (34/175, 19%; 2–9 mutations per pt) than sequencing (16/175, 9%; 2–3 mutations per pt), P=.009. We divided pts into 2 groups; those with multiple mutations detected by mass spec at switchover (n=34) and those with 0/1 mutation (n=141), and investigated the impact of multiple mutations on response to subsequent NIL/DAS therapy. Pts with 0 or 1 mutation, and similarly pts with 2 or >2 mutations, were grouped together, as no difference in response was observed. The median follow up for CP, accelerated phase and blast crisis pts was 17 (2–33), 18 (1–33) and 3 (1–27) mo, and the frequency of multiple mutations was 18%, 24% and 18%, respectively. During follow up, multiple mutations at switchover was associated with lower rates of complete cytogenetic response (CCyR; 21% vs 50%, P=.003, Fig 1A) and major molecular response (MMR; 6% vs 31%, P=.005, Fig 1B), and a higher incidence of acquiring new NIL/DAS resistant mutations detectable by sequencing (56% vs 25%, P=.0009, Fig 1C). At 18 mo, the failure-free survival rate (European LeukemiaNet recommendations) for CP pts with multiple mutations at switchover was 33% compared to 51% for CP pts with 0 or 1 mutation (P=.26, Fig 1D). The number of mutations detected per pt by mass spec at switchover (max of 9, 8 of 86 pts with mutations had ≥4, 9%) far exceeded the number concurrently detected by sequencing (max of 3). This suggests that mass spec detected a pool of subclonal mutants, each with a small survival advantage after imatinib therapy that was insufficient for their clonal predominance. Multiple low level mutations may be a marker of an increased propensity for subsequent selection of resistant mutations, possibly driven by genetic instability, demonstrating the advantage of a sensitive multiplex mutation assay. In conclusion, sensitive mutation analysis identified a poor-risk subgroup with multiple mutations that were not identified by sequencing. This subgroup represented 15.5% of the total cohort (34/220), who would not otherwise be classified as being at risk of poor response on the basis of their mutation status. These pts did not have NIL/DAS resistant mutations at switchover; however, they had a lower incidence of CCyR and MMR, and higher incidence of acquiring new NIL/DAS resistant mutations during NIL/DAS therapy compared to pts with 0 or 1 mutation. This poor-risk subgroup may warrant closer monitoring or experimental approaches to reduce the high risk of kinase inhibitor failure after imatinib resistance. Disclosures: Hughes: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding.

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Persistent Improvement In Clinical Outcomes With Bortezomib-Thalidomide-Dexamethasone Vs Thalidomide-Dexamethasone Incorporated Into Double Autologous Transplantation For Multiple Myeloma: An Updated Analysis Of Phase 3 Gimema-MMY-3006 Study

Blood ◽

10.1182/blood.v122.21.2090.2090 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2090-2090 ◽

Cited By ~ 4

Author(s):

Michele Cavo ◽

Monica Galli ◽

Annalisa Pezzi ◽

Francesco Di Raimondo ◽

Claudia Crippa ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Low Risk ◽

Standards Of Care ◽

Consolidation Therapy ◽

Phase 3 ◽

Advisory Committees ◽

Cox Regression Analysis

Abstract Over the last years, incorporation of novel agents into autologous stem cell transplantation (ASCT) has improved markedly the outcomes of younger patients with newly diagnosed multiple myeloma (MM). Superior results with experimental treatments vs previous standards of care have been frequently reported after preliminary analyses and need to be confirmed with longer follow up. The randomized phase 3 GIMEMA-MMY-3006 study was designed to compare bortezomib-thalidomide-dexamethasone (VTD) vs thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double ASCT. Data from the initial analysis, with a median follow up of 36 months, demonstrated that patients randomized to the VTD arm enjoyed superior complete/near complete response (CR/nCR) rates after both induction and consolidation therapy, and had a significantly longer PFS compared to those prospectively assigned to the TD arm. We performed an updated analysis of the study after a median follow up of 59 months and results are herein reported. A persistent TTP and PFS benefit with incorporation of VTD into ASCT was confirmed. On an intention-to-treat analysis of 236 patients randomized to the VTD arm, median TTP was 62 months and median PFS was 57 months. The median values for 238 patients randomly assigned to the TD arm were 45 months for TTP (HR=0.64, p=0.001) and 42 months for PFS (HR=0.66, p=0.001) (Fig. 1). With the longer follow up of this analysis, an initial divergence between OS curves could be appreciated after 4 years, although the difference was not yet statistically significant at 6 years (75% for VTD vs 69% for TD). Superiority of VTD over TD for TTP and PFS was retained across prespecified subgroups of patients with high risk and low risk disease. In particular, PFS benefit with VTD was seen for patients age >60 years (HR=0.62, p=0.013) and younger than 60 years (HR=0.70, p=0.026), with ISS stage 1 (HR=0.59, p=0.009) and ISS stage 2-3 (HR=0.69, p=0.018), and for those with t(4;14) and/or del(17p) (HR=0.43, p<0.001) and with t(4;14) alone [t(4;14) positivity but lack of del(17p)] (HR=0.41, p=0.001). In comparison with patients with t(4;14) positivity who were randomized to TD, those assigned to the VTD arm had significantly longer PFS (median: 24 vs 53 months, HR=0.41, p=0.0007) (Fig. 2) and a trend towards longer OS (4-year estimates: 66% vs 81%, p=0.052). By the opposite, similar PFS curves were seen for patients in the VTD group regardless of the presence or absence of t(4;14) (Fig. 3). On multivariate Cox regression analysis, randomization to the VTD arm was an independent factor predicting for prolonged PFS (HR=0.64, P=0.001). Additional disease- and treatment-related variables independently affecting PFS included attainment of CR/nCR after both induction (HR=0.64, p=0.010) and consolidation therapy (HR=0.57, p<0.001), β2-m >3.5 mg/L (HR=1.7, p<0.001) and presence of t(4;14) and/or del(17p) (HR=2.0, p<0.001). On multivariate analysis, β2-m, cytogenetic abnormalities and attainment of CR/nCR after consolidation therapy were independently associated with OS. With an updated median follow-up of 49 months from the landmark of starting consolidation therapy, median PFS was 50 months for patients receiving VTD consolidation and 38 months for those treated with TD (HR= 0.69, P=0.015) (Fig. 4). Superior PFS with VTD vs TD consolidation therapy was observed for patients who failed CR/nCR after the second ASCT (HR=0.48, P=0.003) and was retained in both low risk and high risk subgroups. Finally, duration of OS from relapse or progression was similar between the two treatment groups (median, 42 for VTD vs 35 months for TD, p=0.47), even when bortezomib was incorporated into salvage therapy. In conclusion, this updated analysis of the GIMEMA-MMY-3006 study demonstrated: 1) a persistent PFS benefit with VTD vs TD in the overall population, as well as in subgroups of patients with high risk and low risk MM; 2) the ability of VTD, but not of TD, incorporated into double ASCT to overcome the adverse prognosis related to t(4;14); 3) the significant contribution of VTD consolidation to improved outcomes seen for patients randomized to the VTD arm; 4) the lack of more resistant relapse after exposure to VTD as induction and consolidation therapy compared to TD. A longer follow up is required to assess the OS benefit, if any, with VTD plus double ASCT. Disclosures: Cavo: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: 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; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Tacchetti:Janssen and Celgene: Honoraria. Zamagni:Celgene: Honoraria; Janssen-Cilag: Honoraria. Caravita:Celgene: Honoraria, Research Funding. Brioli:Celgene: Honoraria.

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Gene Mutations and Treatment Outcome in CLL Patients Treated with Chlorambucil (Chl) or Ofatumumab-Chl (O-Chl): Results from the Phase III Study COMPLEMENT1 (OMB110911)

Blood ◽

10.1182/blood.v124.21.1992.1992 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1992-1992 ◽

Cited By ~ 1

Author(s):

Eugen Tausch ◽

Christina Galler ◽

Richard Schlenk ◽

Peter Hillmen ◽

Fritz Offner ◽

...

Keyword(s):

Prognostic Factors ◽

Board Of Directors ◽

Research Funding ◽

Cox Regression ◽

Gene Mutations ◽

Phase Iii ◽

Response To Treatment ◽

Prognostic Impact ◽

Advisory Committees

Abstract BACKGROUND: Genomic aberrations and IGHV mutation status are established prognostic factors in CLL. With TP53, NOTCH1, SF3B1, ATM, MYD88, FBXW7, BIRC3 and POT1 recurrently mutated genes were found in CLL and were discussed to associate with disease characteristics and to affect therapy efficacy and outcome. METHODS: We assessed the incidence and impact of gene mutations in the COMPLEMENT1 trial (1st line Chl vs. O-Chl). Pretreatment samples were available from 376 patients (84.1%) and this cohort was representative of the full trial population. Mutations were analyzed by amplicon-based targeted NGS using Illumina Miseq for all coding exons (TP53, ATM, MYD88, FBXW7, BIRC3 and POT1) or hotspot exons (NOTCH1, SF3B1). Additionally, the exact variant frequency was determined. RESULTS: The incidences of gene mutations were: TP53 8.2%, NOTCH1 14.9%, SF3B1 14.1%, ATM 10.9%, MYD88 2.7%, FBXW7 3.5%, POT1 7.7%, and BIRC3 2.7%. Regarding baseline characteristics, we found significant associations: TP53mut with high ß2MG (p=0.01), 17p- (p<0.01), and unmutated IGHV (p=0.01); ATMmut with high WBC (p=0.02), and 11q- (p<0.01); MYD88mut with mutated IGHV (p=0.02); FBXW7mut with 17p- (p=0.02), and +12q (p<0.01). BIRC3mut was only present in IGHV unmutated cases (p<0.01), was more frequent in 11q- (p<0.01), +12q (p=0.05), and in cases with NOTCH1mut (p=0.05). POT1mut was more frequent in NOTCH1mut cases (p=0.02) without associations with any other baseline parameter. Regarding response to treatment, TP53mut was significantly associated with reduced ORR rate (p<0.01). CR rate was not correlated with mutations in the covered genes. At a median follow-up of 31.7 months, there were 249 (66%) events for PFS and 63 (16.8%) events for OS. O-Chl as compared to Chl resulted in significantly improved PFS (median 22.4 vs. 13.1 months, HR 0.54, p<0.01). In univariate analyses, TP53mut (HR 2.07, p<0.01), NOTCH1mut (HR 1.50, p=0.01) and SF3B1mut (HR 1.66, p=0.01) were associated with shorter PFS, whereas ATM and other candidate genes showed no association (ATMmut: HR 1.40, p=0.07). Analyzing both treatment arms separately, TP53mut had an impact on PFS with Chl and O-Chl treatment (HR 1.92, p=0.04 and HR 2.49, p<0.01). Notably, NOTCH1mut was associated with outcome in O-Chl only (HR 2.01, p<0.01 vs. HR 1.14, p=0.59) resulting in a reduced beneficial effect from the addition of Ofatumumab to Chlorambucil treatment. ATMmut and BIRC3mut mutations were only adverse prognostic factors with Chl monotherapy (ATMmut: HR 1.69, p=0.05 vs. HR 1.35, p=0.27; BIRC3mut: HR 2.84, p=0.04 vs. HR 0.99, p=0.99). OS was reduced significantly only in TP53mut cases (HR 3.69, p<0.01). Of note, none of the MYD88mut cases (n=10) had died within the follow-up period. To identify genomic factors of independent prognostic impact, we performed multivariable Cox regression analyses for PFS and OS including treatment arms, 11q-, +12q, 17p-, IGHV and all candidate gene mutations. For PFS, the following independent prognostic factors were identified: O-Chl (HR 0.46, p<0.01), 17p- (HR 3.14, p<0.01), 11q- (HR 1.57, p=0.01), unmutated IGHV (HR 1.43, p=0.02), TP53mut (HR 1.81, p=0.03), NOTCH1mut (HR 1.63, p<0.01) and SF3B1mut (HR 1.54, p=0.02). Regarding OS, only 17p- (HR 4.07, p<0.01), and unmutated IGHV (HR 1.81, p=0.05) were identified as independent adverse prognostic factors with TP53mut showing a trend (HR 2.14, p=0.10). CONCLUSION: We performed mutational analyses for the 8 most frequent mutated genes in CLL in the COMPLEMENT1 trial evaluating 1st line O-Chl against Chl. An independent prognostic impact was identified for TP53mut, NOTCH1mutand SF3B1mut regarding PFS. Notably, NOTCH1mut affected outcome mainly with O-Chl treatment, whereas ATMmut and BIRC3mut were associated with outcome with Chl monotherapy. In multivariate analysis for OS, none of the gene mutations, but the established parameters IGHV and 17p- had independent prognostic impact. Disclosures Tausch: GlaxoSmithKline: Research Funding, Travel support Other. Hillmen:GSK: Honoraria, Research Funding. Offner:GlaxoSmithKline: Honoraria, Research Funding. Janssens:GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Roche: Speakers Bureau; Mundipharma: Speakers Bureau. Mayer:Glaxo: Research Funding; Roche: Research Funding. Panagiotidis:GlaxoSmithKline: Consultancy, Honoraria. McKeown:GlaxoSmithKline: Employment. Gupta:GlaxoSmithKline: Employment. Stilgenbauer:GlaxoSmithKline: Consultancy, 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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How Are Patients (Pts) with Lower-Risk Myelodysplastic Syndromes (MDS) Treated? Impact on Clinical Evolution and Overall Survival: A Report from the Erasme Study

Blood ◽

10.1182/blood.v126.23.5239.5239 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5239-5239

Author(s):

Julia Montoro ◽

Helena Pomares ◽

Itziar Oiartzabal ◽

Teresa Bernal ◽

Edgardo Barranco ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Board Of Directors ◽

Median Time ◽

Lower Risk ◽

Low Risk ◽

Advisory Committees ◽

Very High ◽

Rbc Transfusion

Abstract Introduction: As MDS includes a wide range of heterogeneous neoplastic disorders, the therapeutic approaches for treatment of MDS vary greatly. The aim of this study was to evaluate the use of different therapies, and assess time from diagnosis to therapy initiation and pt outcomes, in an unselected Spanish population with MDS from the ERASME study. Methods : The ERASME study (CEL-SMD-2012-01) is an observational, prospective, multicenter study of pts with either MDS or chronic myelomonocytic leukemia (CMML); disease was defined using the 2008 World Health Organization (WHO) classification system. Initial pt management strategy was classified into 3 groups: active therapy (AT), such as chemotherapy and treatment with azacitidine (AZA); allogeneic hematopoietic cell transplantation (HCT), which included pts receiving other therapies before transplantation; and observation and support (OB&SP), which included red blood cell (RBC) and platelet transfusions, and growth factors. Here, we present overall survival (OS) data from a prespecified interim analysis of pts with International Prognostic Scoring System (IPSS)-defined Low- and Intermediate-1-risk (lower-risk [LR]) MDS using the Kaplan-Meiermethod. Results : A total of 207 IPSS-defined LR MDS pts (117 with Low-risk and 81 with Intermediate-1-risk MDS) were recruited from Jan 2013 to Feb 2014; median follow-up was 16.1 months (interquartile range [IQR] 11.5-19.1). Pt characteristics are described in the Table. We identified 14 pts with high-risk features (HRF) for MDS based on the presence of ≥ 1 of the following: neutropenia (n = 6; absolute neutrophil count < 0.5 × 109/L); thrombocytopenia (n = 4; platelet count < 50 × 109/L); grade 2-3 bone marrow fibrosis (n = 1); or adverse cytogenetic risk (n = 3). At baseline, 28 (14%) pts had RBC transfusion-dependence (RBC-TD), 166 (80%) were RBC transfusion-independent (RBC-TI), and 13 (6%) had missing data. Probability of RBC-TD increased over time with 41 of 166 pts having RBC-TD after 12 months. Median OS of RBC-TD versus RBC-TI pts was not reached (NR) (95% confidence interval [CI] 19.65 months-NR) versus NR (95% CI 22.93 months-NR), respectively (hazard ratio [HR] 3.2, 95% CI 1.13-9.22; P = 0.0275). At diagnosis, 117 (57%) pts (including 4 with HRF) were considered for OB, and 76 (37%) pts for SP (69 pts [5 HRF] for erythropoiesis-stimulating agents, and 7 pts [3 HRF] for RBC and platelet transfusions). Only 10 (5%) pts were considered for AT, which included AZA (n = 5; 1 HRF), lenalidomide (n = 4; 1 HRF), and alemtuzumab (n = 1). HCT was considered in 4 pts (2%; 3 with prior AZA treatment and 1 with prior chemotherapy). After 12 months, 13 (11%) of 117 OB pts switched to AT; median time to AT was 30 weeks (IQR 24.0-44.0). Of 76 pts receiving SP, 23 (30%) switched to AT; median time to AT was 23.9 weeks (IQR 16.3-39.1). Of 184 pts with Revised-IPSS (IPSS-R) scores, at 12 months' follow-up 35 had died (15 of 140 Very Low/Low-risk pts, 15 of 32 Intermediate-risk pts, and 5 of 12 High/Very High-risk pts). At 12 months, 36 of 207 (17%) LR MDS pts had died, including 6 of the 14 HRF pts. Median OS was shorter among HRF pts versus non-HRF pts (19.45 months [95% CI 5.52-NR] vs NR [95% CI NR-NR], respectively) (HR 3.5, 95% CI 1.47-8.53; P = 0.0048). Median OS for IPSS-R Very Low/Low-risk and Intermediate/High/Very High-risk pts was NR (95% CI NR-NR) and 19.45 months (95% CI 11.99-NR), respectively (HR 5.4, 95% CI 2.8-10.7; P < 0.001). Conclusions : The typical treatment of LR MDS pts in Spain consists mainly of supportive care. We observed that risk of RBC-TD increased after diagnosis. These data suggest more attention should be provided at diagnosis or during follow-up of LR MDS pts with poor prognosis, and that they should be considered for more intensive treatment. Abstract presented on behalf of the ERASME Study Investigators Group. Disclosures Off Label Use: Azacitidine was used in IPSS Intermediate-1-risk patients with MDS, and lenalidomide was used in MDS patients with del(5q) plus > 1 cytogenetic abnormality. Castellanos:SCLHH: Other: Membership; SEHH: Other: Membership. Navarro:Celgene Corporation: Employment. López:Celgene SL Unipersonal: Employment, Equity Ownership, Honoraria. Valcárcel:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: 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; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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NFE2 Mutations Impact AML Transformation and Overall Survival in Patients with Myeloproliferative Neoplasms (MPN)

Blood ◽

10.1182/blood-2020-136177 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-36

Author(s):

Clemence Marcault ◽

Lin-Pierre Zhao ◽

Rafael Daltro De Oliveira ◽

Juliette Soret ◽

Nicolas Gauthier ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Somatic Mutations ◽

Response To Therapy ◽

Age At Diagnosis ◽

Prognostic Impact ◽

Leukemic Transformation ◽

Advisory Committees ◽

Increased Risk

Introduction: MPN are a heterogeneous group of chronic hematological malignancies often resulting from a combination of a driver gene mutation (JAK2, MPL or CALR) and a variety of somatic mutations harboring diverse prognosis values. A subset of MPN patients carry somatic mutations in the hematopoietic transcription factor NFE2 (nuclear factor erythroid 2) resulting in a functionally enhanced truncated form of NFE2 (Jutzi JS et al., JEM, 2013). Moreover, epigenetically induced overexpression of NFE2 has recently been reported in the majority of MPN patients (Peeken JC et al., Blood, 2018). In transgenic murine models, NFE2 overexpression results in an MPN phenotype (thrombocytosis, leukocytosis, EPO-independent colony formation, characteristic bone marrow histology and expansion of stem and progenitor compartments) and has recently been shown to predispose to the acquisition of additional genetic abnormalities and subsequent leukemic transformation (Kaufmann KB et al., JEM, 2012) (Jutzi JS et al., Blood, 2019). However, clinical impact of NFE2 mutations in MPN patients remains unknown. The aim of this study was to evaluate the phenotypic characteristics and prognostic impact of NFE2 somatic mutations in a large mono-centric cohort of MPN patients. Methods: A total of 1243 consecutive patients were diagnosed with MPN according to WHO criteria and followed in our hospital between January 2011 and May 2020. This study included 707 of them in whom a next-generation sequencing (NGS) molecular analysis targeting 36 myeloid genes was performed at diagnosis and/or during follow-up. Clinical and biological characteristics at time of diagnosis and follow-up were collected from medical charts and electronic medical records. Statistical analyses were performed using the STATA software (STATA 15.0 Corporation, College Station, TX). Results: In our cohort, 411 patients presented with polycythemia vera (PV), 577 with essential thrombocythemia (ET), 184 with primary or pre-fibrotic myelofibrosis (PMF), 59 with unclassified MPN and 12 with MDS/MPN. Median age at diagnosis was 51 years [40-63]. 73.1% patients had a JAK2V617F mutation, 14.1% a CALR mutation and 3.3% a MPL mutation. Overall, 64 (9.05%) patients harbored a NFE2 mutation with a variant allelic frequency (VAF) ≥ 0.5% and 36 had a VAF ≥ 5%, the latest were considered as NFE2 mutated for the rest of the study as VAF <5% may refer to a minor clone without clinical relevance. NFE2 mutations were present in 7.3%, 5.3% and 3.6% of PV, PMF and ET patients respectively. No significant association between the presence of NFE2 mutation and clinical/molecular MPN characteristics (driver mutation, constitutional symptoms, splenomegaly, blood counts, cytogenetic and other molecular features) was observed using a logistic regression association model. Median follow-up was 103.8 months, IQR [47.2; 175.6]. In terms of response to therapy, 52.8% of patients achieved complete response, complete hematological response or clinical improvement in NFE2 mutated vs 61.7% in non-mutated patients (p= 0.026). Interestingly, presence of a NFE2 mutation (HR 9.92, 95%CI[3.21; 30.64], p< 0.001), age at diagnosis (HR 1.09, 95%CI[1.05; 1.12], p< 0.001), PMF subtype (HR 6.92, 95%CI[2.81; 17.06], p < 0.001) and high-risk mutations (ASXL1, EZH2, SRSF2, IDH1/2 and U2AF1) (HR 2.45, 95%CI[1.14; 5.28], p=0.021) were independently associated with AML/MDS transformation free survival (TFS) in a COX regression multivariate analysis (Figure A). Presence of a NFE2 mutation was also independently associated with overall survival (OS) (HR 9.37, 95%CI [4.18; 21.03], p<0.001) (Figure B). Median TFS were 216.1 months and not reached, while median OS were 144.2 months and not reached for NFE2 mutated and non-mutated patients, respectively. No difference was observed in terms of thrombo-hemorrhagic events (HR 0.73; 95%CI [0.10; 5.21], p=0.752) and secondary myelofibrosis free survivals (HR 0.67; 95%CI [0.09; 4.87], p=0.693). Conclusion: In this retrospective study we show that presence of NFE2 mutations with a VAF ≥5% is independently associated with an increased risk of leukemic transformation and shorter overall survival. These findings are in line with recently reported animal models and suggest that NFE2 mutations screening should be routinely performed in MPN patients. Disclosures Rea: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: 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; Novartis: Membership on an entity's Board of Directors or advisory committees. Benajiba:Gilead Foundation: Research Funding.

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Body Mass Index and Survival of Patients with Lymphoma

Blood ◽

10.1182/blood-2020-139402 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 2-3

Author(s):

Dai Chihara ◽

Melissa C. Larson ◽

Dennis P. Robinson ◽

Carrie A. Thompson ◽

Matthew J. Maurer ◽

...

Keyword(s):

Body Mass Index ◽

At Risk ◽

Board Of Directors ◽

Body Mass ◽

Research Funding ◽

B Cell Lymphoma ◽

The United States ◽

Advisory Committees ◽

The Impact

Background: Obesity is increasing worldwide, with the highest prevalence in the United States. High or low body mass index (BMI) is a well-established risk factor for increased all-cause mortality and also has been associated with cancer-specific mortality. However, the impact of BMI on survival following diagnosis with lymphoma currently remains controversial. We leveraged a prospective cohort of lymphoma patients to assess the relationship of BMI two years prior to diagnosis (BMI-2), at diagnosis (BMI-dx), and three-years post-diagnosis (BMI+3) with lymphoma-specific survival (LSS) as the primary endpoint and with event-free survival (EFS) and overall survival (OS) as secondary endpoints. Patient and Method: Patients were prospectively enrolled at lymphoma diagnosis to the SPORE Molecular Epidemiology Resource (MER) cohort at Mayo Clinic and University of Iowa from 2002-2015. BMI-2 and BMI+3 were self-reported in patient questionnaires, while BMI-dx was extracted from the medical chart. Patients with extreme BMI (BMI <14 and BMI ≥50) were excluded from the analysis. BMI change from BMI-2 to BMI-dx and from BMI-dx to BMI+3 was categorized as no change (-5% to 5%), decrease (>-5%), and increase (>+5%). Person-time at risk was assessed from lymphoma diagnosis until death or last follow-up, except for analyses of BMI change from BMI-dx to BMI+3, which started person-time at risk when the 3-year (+/- 6 months) follow-up questionnaire was returned. Cause of death was assigned by a study clinician. For all lymphoma patients combined and in the most common subtypes, we evaluated the association of BMI at each time point and change in BMI with EFS, LSS, and OS using hazard ratios (HRs) and 95% confidence intervals (CI) from multivariable adjusted Cox models. Results: A total of 4,009 lymphoma patients (including 670 diffuse large B-cell lymphoma [DLBCL], 689 follicular lymphoma [FL] and 1018 chronic lymphocytic leukemia/small lymphocytic lymphoma [CLL/SLL] and 1,632 others) with data on BMI-dx were included. Among them, 2,955 patients had BMI-2 and 2,004 had BMI+3 and were evaluable for change in BMI. The median age of all patients at diagnosis was 61 years (range 18-92 years), and 94% of patients had ECOG performance status <2. At the time of diagnosis, 28% were normal weight (BMI 18.5-25), 1% were underweight (BMI <18.5), 39% were overweight (BMI 25-30) and 32% were obese (BMI ≥30). With a median follow-up of 108 months from diagnosis (IQR 83-143 months), 1320 deaths were observed, 48% of which were due to lymphoma. Patients with FL who were obese at BMI-2 had significantly shorter LSS (HR: 3.02, 95%CI: 1.43-6.41, p=0.004). Associations between obesity at BMI-2 and LSS were not evident for DLBCL (HR: 1.04, 95%CI: 0.62-1.76, p=0.879) or CLL/SLL (HR: 1.10, 95%CI: 0.71-1.70, p=0.668) (Table). BMI-dx was not associated with LSS in any lymphoma patients, except that DLBCL patients who were underweight at BMI-dx (n=10) experienced shorter LSS (HR: 3.52, 95%CI: 1.22-10.1, p=0.020). This correlated significantly with presence of B symptoms (p=0.004) and may signify aggressive disease. Across all subtypes, >5% decrease in BMI from BMI-2 to BMI-dx was associated with significantly shorter LSS in patients with (HR: 2.02, 95%CI: 1.65-2.48, p<0.001). However, only for FL patients, >5% increase in BMI from BMI-dx to BMI+3 also was associated with significantly shorter LSS in subsequent years (HR: 3.74, 95%CI: 1.30-10.8, p=0.014). The associations reported for LSS generally were similar for EFS and OS. Conclusions: FL patients with obesity prior to diagnosis or who experienced increasing BMI after the diagnosis had significantly shorter LSS. The impact of weight control after the diagnosis of FL patient outcomes warrants investigation. Figure Disclosures Maurer: Celgene / BMS: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Flowers:Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Denovo Biopharma: Consultancy; Celgene: Consultancy, Research Funding; BeiGene: Consultancy; Kite: Research Funding; Bayer: Consultancy; Eastern Cooperative Oncology Group: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; National Cancer Institute: Research Funding; AbbVie: Consultancy, Research Funding; V Foundation: Research Funding; TG Therapeutics: Research Funding; Burroughs Wellcome Fund: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Acerta: Research Funding; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; OptumRx: Consultancy; Gilead: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Cerhan:NanoString: Research Funding; BMS/Celgene: Research Funding.

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Prognostic Impact Of Serum Free Light Chain (sFLC) Assay In Newly Diagnosed Multiple Myeloma (MM) Treated With Bortezomib

Blood ◽

10.1182/blood.v122.21.1859.1859 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1859-1859

Author(s):

Paola Tacchetti ◽

Serena Rocchi ◽

Annalisa Pezzi ◽

Elena Zamagni ◽

Lucia Pantani ◽

...

Keyword(s):

Partial Response ◽

Board Of Directors ◽

Median Time ◽

Light Chain ◽

Complete Response ◽

Lower Probability ◽

Prognostic Impact ◽

Newly Diagnosed ◽

Advisory Committees

Abstract Introduction sFLC assay is an important advance in the diagnosis and monitoring of MM, however data on prognostic significance are still limited. Methods We performed a retrospective analysis aimed to investigate the role of sFLC assay as predictor of outcomes in newly diagnosed MM patients (pts) treated up-front with bortezomib based regimens. sFLC assay (Freelite; The Binding Site, Birmingham, UK) was performed by BN II nephelometer (Date Behring, Deerfield, IL, USA). sFLC-k, sFLC-l and sFLC k/l ratio were serially measured at baseline, during treatment and follow-up. sFLC k/l ratios were classified as normal (0.26-1.65) or abnormal (<0.26 or >1.65) according to the IMWG criteria. An involved sFLC level >=100 mg/L, defined by the IMWG criteria as the level to identify a sFLC evaluable disease, was categorized as high. Results We analyzed 110 pts who received first-line bortezomib-based treatments: 67% incorporated into autotransplantation and 33% combined with conventional chemoterapy. The median age was 63 years, 47 pts (43%) were female and 63 (57%) were male. Fifty-eight pts (53%) had IgG heavy chains, 25 (23%) IgA, 1 (1%) IgM and 1 (1%) IgD; 23 pts (21%) had light chain only disease, and 2 pts (2%) had nonsecretory MM. Overall, the involved light chain was kappa in 69 pts (64%), lambda in 36 (33%) and both in 2 (2%), whereas 3 pts (3%) had no detectable light chains. An abnormal sFLC k/l ratio was detected in 91 pts (83%) at baseline, whereas 76 pts (69%) had an involved sFLC >=100 mg/L. The median involved k and l concentrations were 720 and 479 mg/L, respectively. Baseline sFLC >=100 mg/L correlated with higher frequency of Bence Jones isotype (p=0.041), higher beta-2-microglobulin (b2M) (p=0.011), lower hemoglobin concentration (p=0.003) and higher frequency of del(13q) (p=0.016). No correlation was found between high baseline sFLC and other parameters including ISS stage, LDH, bone marrow infiltration, and presence of t(4;14) or del(17p). IMWG response was: 43% stringent complete response (sCR), 11% complete response (CR), 18% very good partial response (VGPR) and 15% partial response (PR). Overall, 83 pts (75%) achieved a normalization of sFLC k/l ratio during treatment. With a median follow-up of 26 months (mos), 36 pts progressed and 17 died. The median time to progression (TTP), progression free survival (PFS) and overall survival (OS) were 46, 46 and 75 mos, respectively. In comparison with a baseline sFLC <100 mg/L, sFLC >=100 mg/L was associated with a reduced rate of sCR/CR (71% vs 48%, p=0.028), a lower probability to normalize sFLC k/l ratio (94% vs 67%, p=0.002) and a shorter median TTP (not reached vs 36 mos, p=0.047) and PFS (not reached vs 35 mos, p=0.034), whereas the OS was similar in the two groups (65 vs 75 mos, p=0.16). By the opposite, pts who achieved a normalization of sFLC k/l ratio during treatment had an extended TTP (53 vs 20 mos, p<0.0001), PFS (53 vs 18 mos, p<0.0001) and OS (not reached vs 75 mos, p=0.0026) in comparison with those who failed this objective. Of the 36 pts who relapsed or progressed, 28 could be assessed for sFLC at relapse. Eleven pts (39%) showed a sFLC escape, defined as an increase of sFLC with no associated increase of intact M protein concentration, that preceded the conventional relapse by a median time of 4 mos. No difference was observed between pts with or without sFLC escape, in terms of time to start second line therapy (1 vs 2 mos, p=0.38) and OS post relapse (p=0.86), whereas sFLC >=100 mg/L at relapse was associated with earlier start of salvage therapy, compared with sFLC <100 mg/L (1 vs 4 mos, p=0.006). A multivariate analysis including age, treatment, b2M, albumin, ISS stage, sFLC and cytogenetic abnormalities identified non-transplant regiments (p<0.001), IIS 3 (p=0.032) and sFLC >=100 mg/L (p=0.047) as variables independently associated with a reduced probability to normalize sFLC k/l ratio. By Cox regression analysis, the normalization of sFLC k/l ratio was an independent factor predicting for extended TTP and PFS (p=0.022 and p=0.001) together with ISS 1-2 (p=0.042 and p=0.007). Conclusions High sFLC at baseline was associated with more aggressive disease characterized by a lower probability to achieve sCR/CR and shorter TTP and PFS. Moreover, high sFLC at relapse predicted for short-lasting asymptomatic phase. By opposite, the achievement of normal sFLC k/l ratio during treatment resulted a considerable prognostic indicator of longer TTP and PFS. Disclosures: Tacchetti: Janssen: Honoraria; Celgene: Honoraria. Zamagni:Janssen-Cilag: Honoraria; Celgene: Honoraria. Brioli:Celgene: Honoraria. Martinelli:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; Ariad: Consultancy. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: 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; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

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