scholarly journals Molecular Characterization of Leukemia Evolving from Paroxysmal Nocturnal Hemoglobinuria

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2499-2499
Author(s):  
Hassan Awada ◽  
Shafia Rahman ◽  
Cassandra M Kerr ◽  
Jibran Durrani ◽  
Vera Adema ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Incidence Rate ◽  
Molecular Characterization ◽  
Clonal Evolution ◽  
Cleveland Clinic ◽  
Clinical Manifestations ◽  
Monogenic Disease ◽  
Advisory Committees ◽  
Myeloid Malignancies ◽  
Pnh Clone

Myeloid malignancies can evolve from prior hematologic disorders, most commonly AML evolving from MDS. AA and PNH are not malignant conditions but they can evolve to myeloid malignancies with a lower frequency compared to MDS and other myeloid and myeloproliferative diseases. PNH can evolve to myeloid disorders with an incidence rate of 4-10%. Here we aim to revisit the subject of malignant evolution of PNH to myeloid disorders by analyzing the molecular background of PNH using modern NGS technologies. Clinical characteristics, demographics and mutational profiles of patients were collected at The Cleveland Clinic Foundation. In total a cohort of 243 patients evaluated for hemolytic PNH (n=83), AA (39) and AA/PNH (n=121) followed for a period of 22 years was evaluated. Inclusion criteria were: complete flow cytometric panels of PNH cells, patients without antecedent AA (pPNH, 45), patients evolving from AA with PNH clone >20% (sPNH, 38), karyotype (at diagnosis of PNH and transformation), clinical parameters including time to malignant progression, and molecular characterization resulting from NGS performed using various library preparation systems (TruSeq, TruSight, Nextera), comparison of molecular mutations with control cohorts (AA, 160; MDS, 835). The incidence rate of myeloid disorders in our PNH cohort was 3% (7/243). Among hemolytic PNH patients, 7 patients progressed to AML (n=1), MDS (n=5) or myelofibrosis (n=1). Median age was 48 yr (range, 24-80); M/F, 5/2. Median PNH clone size was 71% (range, 29-99). Three progressors were in the pPNH and 4 in the sPNH group. Time to malignant diagnosis was <1-22 yr: 4 yr for 3 patients, 5 yr for 1 patient, <1 yr for 2 patients and 22 years for 1 patient. At the time of transformation, combination of karyotypic abnormalities and molecular lesions showed that 4 cases had abnormal karyotype (+8, -7, del13q) and 5 cases carried myeloid mutations (ASXL1, BCOR, NPM1, TET2, U2AF1, WT1). Normal karyotype was seen in 3 patients with ASXL1+U2AF1, U2AF1 and BCOR+NPM1+WT. In 2 patients, del13q and -7 were associated with BCOR and TET2. In 2 others, del(13q) and +8 were the only detected aberrancies. A total of 45 somatic mutations equally distributed in the 2 groups (pPNH, 22; sPNH, 23) and with similar VAFAVG (pPNH vs. sPNH 38% vs. 33%) were found. PNH showed a higher proportion of individuals with mutations compared to AA/PNH+AA (42 vs. 22% of cases with ≥1 mutation; P=.002) with a median VAF percentage significantly higher in PNH vs. AA/PNH+AA (40 vs. 19%; P<.0001). FLT3 (n=2), JAK2 (n=1), LUC7L2 (n=1), NPM1 (n=1), SRSF2 (n=1) and ZRSR2 (n=2) were exclusively mutated in PNH with the presence of some of them (FLT3, NPM1) possibly representing an early onset of clonal evolution. BCOR/BCORL1 core was more mutated in PNH as compared to AA/PNH+AA patients (11 vs. 3%; P=.01) as did TET2 and U2AF1. This pattern of mutations had a strong similarity with that of MDS. VAF comparison between myeloid mutations and PIGA mutations showed that accessory mutations in patients with PNH were secondary hits, with PIGA mutations being the founder lesions. We then analyzed the clonal hierarchy of mutations using VAF-adjusted for X-chromosomal loci in males and inferred mutational rank (founder/ co-dominant) vs. secondary (sub-clonal). PIGA mutations were founder lesions in 70% of the cases, co-dominant in 2% and secondary in 28% suggesting that additional mutations represented mainly cooperative events without over representing PIGA. In fact, comparison of VAF and PNH clonal size showed that 70% of the hits were present in the same clone (VAFSUM >55), 17% were equivocal (possibly hits biclonal with a VAFSUM between 45-55), while 13% were more likely a result of clonal chimerism (hits present in different clones; VAFSUM <45). Clonal evolution of hemolytic PNH to MDS/AML is rare, but still occurs and it is accompanied by mutations in typical myeloid genes (BCOR, NPM1, TET2, U2AF1) which in permissive circumstances are capable to change the cell's fate favoring clonal evolution. Our results suggest that most PNH cases can carry additional mutations in the same clone and these mutations can be secondary hits, with PIGA mutations being the founder lesions. However even when mutations in myeloid genes are dominant, the phenotype of the patients is inferred by PIGA. This observation supports the nature of PNH as a monogenic disease with clinical manifestations resulting by PIGA mutations rather than by myeloid genes. Disclosures Sekeres: Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Novartis: Consultancy; Alexion: Consultancy.

scholarly journals Clonal Dynamics of Refractory Aplastic Anemia in Patients Treated with Eltrombopag

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3892-3892 ◽  
Author(s):  
Bhumika Patel ◽  
Bartlomiej P Przychodzen ◽  
Michael J. Clemente ◽  
Cassandra M. Hirsch ◽  
Caner Saygin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Somatic Mutations ◽  
Hematopoietic Cell Transplantation ◽  
Chromosomal Abnormalities ◽  
Clonal Evolution ◽  
Cleveland Clinic ◽  
Clonal Expansion ◽  
Case Control ◽  
Control Cohort ◽  
Advisory Committees

Abstract Despite documented success of immunosuppressive therapy (IST) in the treatment of AA, a minority of patients remain refractory, most responses are incomplete, and use of hematopoietic cell transplantation (HCT) is limited in older patients or those with significant comorbidities. While the introduction of the cMpl agonist eltrombopag (EPG) as salvage therapy or in conjunction with IST has revolutionized treatment for refractory AA. It may be effective in improving primary response rates to IST, engaging growth factor receptors with agonistic therapeutics (such as EPG) and also has the potential to promote evolution/expansion of mutant clones, thereby increasing the rate of progression to secondary myelodysplastic syndromes (MDS), a serious complication of AA occurring in 10-20% of patients. Clonogenic somatic mutations typical of MDS in patients with AA and PNH may increase the risk of progression to MDS. DNA from marrow samples of primary refractory AA patients was subjected to analysis before and after initiation of EPG to evaluate clonal expansion or evolution using a targeted multi-amplicon deep NGS panel of all ORFs of the top 60 most commonly mutated genes in MDS. In addition to the EPG treatment group, a case control cohort matched for age and duration from AA diagnosis to last clinical follow up (who did not receive EPG), was studied. Among 210 AA patients treated at Cleveland Clinic, we identified 26 who were treated with EPG for IST-refractory AA; median duration of treatment was 56 wks. The overall response rate after 12 weeks of therapy was 58% (15/26), while 31% of patients (8/26) showed stable disease with intermittent transfusions (one of whom underwent HCT). In 3 non-responders, one developed PNH, one had refractory AA/PNH, and one progressed to AML (see below). Expansion of PNH granulocytes after EPG treatment was observed in 23% of patients (6/26). In addition, 15% (4/26) had atypical subclonal chromosomal abnormalities. Prior to EPG, at least a single somatic event was found in 31% of patients (8/26), with 2 patients harboring 2 mutations. Events included CEBPA, EZH2, BCOR/BCORL1, ASXL1, U2AF1/2, TET2, and DNMT3A mutations. Following EPG therapy, acquisition of new somatic mutations was observed in 23% of cases, including RUNX1, U2AF1, BCOR, RIT1, and CEBPA. In cases with pre-existing clones, 6 clones expanded (e.g., BCOR or ASXL1 from VAF of 8 to 21% and 9 to 29%, respectively) despite clinical hematologic response, while in 2 cases clones disappeared (e.g., U2AF2 and BCORL1). In 54% of cases (14/26), we found detectable levels of a PNH clone at the time of diagnosis. Six of those cases had PNH clonal expansion post-EPG treatment, of which two developed clinically significant PNH clonal burden requiring eculizumab therapy. In the case-control cohort, 26 AA patients who received IST but were not treated with EPG, were followed for comparable time periods, and no evidence of progression to MDS was recorded. One patient was noted to have trisomy 15 on cytogenetics at diagnosis. "MDS type" molecular mutations were present in 10 patients similar to EPG cohort. Among these patients, 3 had persistent clones of U2AF1, DNMT3A, and STAT3 over one year without acquisition of any new molecular mutations. . PNH granulocytes expanded in 50% of AA cases, decreased in 30% and stayed stable in 20%. Thus, we did not observe any difference in expansion of PNH clones between those treated and untreated with EPG (p=0.73). Unlike for PNH clones, accounting for both new evolution and expansion of preexisting molecular mutations, the frequency of these clonal events was significantly higher in the EPG treated group (p=0.009). In conclusion, we observed occasional expansion of clones with potentially leukemogenic mutations during treatment with EPG in pts with AA. While higher rates of MDS evolution were not observed in this cohort of EPG treated patients, we found that serial evaluation of somatic mutations can inform clonal evolution and can potentially be used as abiomarker for evaluation of risk for post-AA MDS. Continued use of EPG in such patients should be judicious. Disclosures Carraway: Celgene: Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Patterns of Clonal Evolution Assessed By Whole Exome Sequencing during Progression from MDS to AML Are Related to Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4309-4309
Author(s):  
María Abáigar ◽  
Jesús M Hernández-Sánchez ◽  
David Tamborero ◽  
Marta Martín-Izquierdo ◽  
María Díez-Campelo ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Clonal Evolution ◽  
Clonal Expansion ◽  
Driver Mutations ◽  
Advisory Committees ◽  
Disease Evolution ◽  
Mutational Burden ◽  
Whole Exome ◽  
Leukemic Phase

Abstract Introduction: Myelodysplastic syndromes (MDS) are hematological disorders at high risk of progression to acute myeloid leukemia (AML). Although, next-generation sequencing has increased our understanding of the pathogenesis of these disorders, the dynamics of these changes and clonal evolution during progression have just begun to be understood. This study aimed to identify the genetic abnormalities and study the clonal evolution during the progression from MDS to AML. Methods: A combination of whole exome (WES) and targeted-deep sequencing was performed on 40 serial samples (20 MDS/CMML patients evolving to AML) collected at two time-points: at diagnosis (disease presentation) and at AML transformation (disease evolution). Patients were divided in two different groups: those who received no disease modifying treatment before they transformed into AML (n=13), and those treated with lenalidomide (Lena, n=2) and azacytidine (AZA, n=5) and then progressed. Initially, WES was performed on the whole cohort at the MDS stage and at the leukemic phase (after AML progression). Driver mutations were identified, after variant calling by a standardized bioinformatics pipeline, by using the novel tool "Cancer Genome Interpreter" (https://www.cancergenomeinterpreter.org). Secondly, to validate WES results, 30 paired samples of the initial cohort were analyzed with a custom capture enrichment panel of 117 genes, previously related to myeloid neoplasms. Results: A total of 121 mutations in 70 different genes were identified at the AML stage, with mostly all of them (120 mutations) already present at the MDS stage. Only 5 mutations were only detected at the MDS phase and disappeared during progression (JAK2, KRAS, RUNX1, WT1, PARN). These results suggested that the majority of the molecular lesions occurring in MDS were already present at initial presentation of the disease, at clonal or subclonal levels, and were retained during AML evolution. To study the dynamics of these mutations during the evolution from MDS/CMML to AML, we compared the variant allele frequencies (VAFs) detected at the AML stage to that at the MDS stage in each patient. We identified different dynamics: mutations that were initially present but increased (clonal expansion; STAG2) or decreased (clonal reduction; TP53) during clinical course; mutations that were newly acquired (BCOR) or disappearing (JAK2, KRAS) over time; and mutations that remained stable (SRSF2, SF3B1) during the evolution of the disease. It should be noted that mutational burden of STAG2 were found frequently increased (3/4 patients), with clonal sizes increasing more than three times at the AML transformation (26>80%, 12>93%, 23>86%). Similarly, in 4/8 patients with TET2 mutations, their VAFs were double increased (22>42%, 15>61%, 50>96%, 17>100%), in 2/8 were decreased (60>37%, 51>31%), while in the remaining 2 stayed stable (53>48%, 47>48%) at the AML stage. On the other hand, mutations in SRSF2 (n=3/4), IDH2 (n=2/3), ASXL1 (n=2/3), and SF3B1 (n=3/3) showed no changes during progression to AML. This could be explained somehow because, in leukemic phase, disappearing clones could be suppressed by the clonal expansion of other clones with other mutations. Furthermore we analyzed clonal dynamics in patients who received treatment with Lena or AZA and after that evolved to AML, and compared to non-treated patients. We observed that disappearing clones, initially present at diagnosis, were more frequent in the "evolved after AZA" group vs. non-treated (80% vs. 38%). By contrast, increasing mutations were similar between "evolved after AZA" and non-treated patients (60% vs. 61%). These mutations involved KRAS, DNMT1, SMC3, TP53 and TET2among others. Therefore AZA treatment could remove some mutated clones. However, eventual transformation to AML would occur through persistent clones that acquire a growth advantage and expand during the course of the disease. By contrast, lenalidomide did not reduce the mutational burden in the two patients studied. Conclusions: Our study showed that the progression to AML could be explained by different mutational processes, as well as by the occurrence of unique and complex changes in the clonal architecture of the disease during the evolution. Mutations in STAG2, a gene of the cohesin complex, could play an important role in the progression of the disease. [FP7/2007-2013] nº306242-NGS-PTL; BIO/SA52/14; FEHH 2015-16 (MA) Disclosures Del Cañizo: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding; Arry: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Clonal Architecture and Variant Allele Frequency Predict Clinical Outcomes and Drug Response in Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 2-2
Author(s):  
Brooks Benard ◽  
Logan Leak ◽  
Armon Azizi ◽  
Daniel Thomas ◽  
Andrew Gentles ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Clinical Outcomes ◽  
Drug Sensitivity ◽  
Clonal Evolution ◽  
High Risk Patient ◽  
Variant Allele Frequency ◽  
Clonal Heterogeneity ◽  
Advisory Committees ◽  
Clonal Architecture ◽  
Linear Evolution

Introduction: AML is an aggressive cancer that develops from the sequential accumulation and clonal expansion of somatic mutations in hematopoietic stem and progenitor cells. Recent next-generation sequencing (NGS) studies of AML have correlated mutations with clinical outcomes and response to targeted therapies. Additionally, emerging reports have suggested that increased clonal heterogeneity and mutation burden tend to correlate with worse survival outcomes. However, due to previous cohort sizes, the architecture of clonal evolution and variant allele frequency (VAF) of recurrent mutations have yet to be robustly correlated with response to therapy or with more granular risk stratification. To address previous limitations, we combined available datasets of sequenced AML to model features of clonality and determine their correlations with clinical outcomes and drug sensitivity. Methods: A systematic literature review was performed to identify cohorts of clinically annotated and genetically profiled adult AML. Studies were included if: (i) their sequencing panel targeted at least 30 of the most commonly mutated genes, (ii) censored overall survival data was reported, and (iii) data were publicly available. An additional cohort of patients profiled at Stanford was also included. Leveraging statistical learning methods and robust clonal modeling algorithms (PyClone and ClonEvol), we performed a meta-analysis of the clonal architecture of mutations, their temporal relationships, sensitivity to drugs, and correlation with outcomes in AML. Results: A total of 12 studies were aggregated into a uniformly annotated database comprising 2,987 AML patient samples profiled with an array of DNA sequencing modalities (2,884 with VAFs) and ex vivo drug screening results (nsamples = 562; ndrugs = 122); survival outcomes were available for 2,606 patients. To investigate broad features of leukemia evolution, we used clonal modeling algorithms to infer clonal architecture. Interestingly, patients exhibiting linear evolution (sequential mutations in the same clone) displayed worse outcomes compared to those with branched architecture (distinct subclonal populations). Additionally, mutational burden and clonal heterogeneity only stratified patients with branched structure. These results motivated us to understand how the temporal acquisition of mutations might further stratify outcomes. Using dynamic VAF thresholds, we identified novel high-risk patient populations for 15 recurrently mutated genes. Greater VAF was associated with statistically significant improved survival in genotypes such as GATA2mut and WT1mut and with worse outcomes for patients with NRAS and NF1 mutations. Next, we leveraged VAFs to infer the temporal ordering of individual mutations and functional mutation categories. Patients where NRAS mutations occurred before GATA2 mutations showed a significant correlation with worse outcomes. We also observed that patients in which (i) DNA methylation mutations occurred before those in tumor suppressors and (ii) splicing factor mutations occurred before RTK/RAS signaling components showed significantly shortened overall survival. These results indicate that patients with the same genotype can be stratified by the timing of mutations in the clonal evolution of their leukemia. Finally, we used linear regression between drug sensitivity and VAF to identify several mutations which predict drug sensitivity exclusively in a VAF-dependent manner. Increased WT1 VAF correlated with sensitivity to ABT-737 and elevated FLT3-TKD VAF predicted sensitivity to cabozantinib, among other clinically notable drug-gene relationships. These results suggest potential biomarkers for clinical response to emerging targeted agents. Conclusions: We show that VAF can identify novel high-risk patient populations at the individual mutation level (e.g. BCOR and NF1) and can also be leveraged to stratify outcomes based on inferring the temporal ordering of mutations (e.g. NRAS and GATA2). Our observation that patients with leukemias exhibiting branched evolution showed improved survival compared to linear evolution was also striking and warrants further experimental and clinical validation. Incorporating these results with our findings of drug sensitivity validate the clinical utility of integrating clonal analysis into the molecular evaluation and treatment of AML. Disclosures Majeti: Zenshine Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kodikaz Therapeutic Solutions Inc.: Membership on an entity's Board of Directors or advisory committees; Stanford University: Patents & Royalties: pending patent application on CD93 CAR ; Coherus BioSciences: Membership on an entity's Board of Directors or advisory committees; BeyondSpring Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc.: Divested equity in a private or publicly-traded company in the past 24 months; Gilead Sciences, Inc.: Patents & Royalties: inventor on patents related to CD47 cancer immunotherapy; CircBio Inc.: Research Funding.

A Phase 1 Study of Sea-CD70 in Myeloid Malignancies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Ahmed Aribi ◽  
Anjali S Advani ◽  
William Donnellan ◽  
Amir T. Fathi ◽  
Marcello Rotta ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Immune Evasion ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Steering Committee ◽  
Advisory Board ◽  
Open Label ◽  
Advisory Committees ◽  
Myeloid Malignancies

Background SEA-CD70 is being developed in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Current treatment options are limited for patients (pts) with relapsed or refractory (r/r) MDS or r/r AML and outcomes remain poor. SEA-CD70 is an investigational humanized, non-fucosylated monoclonal antibody targeting CD70. Expression of CD70 is limited in normal tissue, but is aberrantly expressed on malignant myeloid blasts while absent from healthy hematopoietic progenitor cells. CD70 and its ligand, CD27, may play a role in malignant blast cell survival and/or tumor immune evasion. SEA-CD70 uses a novel sugar-engineered antibody (SEA) platform to produce a non-fucosylated antibody with enhanced effector function. The proposed mechanism of action of SEA-CD70 includes elimination of CD70 positive cells via enhanced antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and mediation of complement-dependent cytoxicity (CDC). Additionally, SEA-CD70 has the potential to block the interaction of CD70 with CD27, which may disrupt signals that enhance blast proliferation and survival and may modulate the immune system to limit immune evasion and increase antigen specific T cell responses. Methods SGNS70-101 is a phase 1, open-label, multicenter, dose-escalation, and cohort expansion study designed to establish the safety, tolerability, and preliminary activity of SEA-CD70 in pts with myeloid malignancies (NCT04227847). Dose escalation is ongoing. In dose escalation, pts must have r/r MDS with 5-20% blasts which has failed prior treatment with a hypomethylating agent (HMA), and have no other therapeutic options known to provide clinical benefit for MDS. After conclusion of dose escalation, monotherapy expansion cohorts will be opened for pts with MDS and for pts with AML. Primary objectives are to evaluate the safety and tolerability, and to determine the maximum tolerated dose (MTD) or recommended expansion dose of SEA-CD70. Secondary objectives are to assess antitumor activity, PK, and immunogenicity of SEA-CD70. Once dose escalation is complete and the recommended monotherapy dose is identified, combination cohorts will be considered in AML and MDS. The study is currently enrolling with sites opening in the US and EU. Disclosures Aribi: Seattle Genetics: Consultancy. Advani:OBI: Research Funding; Takeda: Research Funding; Novartis: Consultancy, Other: advisory board; Pfizer: Honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Immunogen: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Donnellan:Kite Pharma/Gilead: Research Funding; Janssen: Research Funding; Karyopharm Therapeutics: Research Funding; AstraZeneca: Research Funding; Astex Pharmaceuticals: Research Funding; Incyte: Research Funding; MedImmune: Research Funding; TCR2 Therapeutics: Research Funding; Genentech: Research Funding; PTC Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Daiichi Sankyo: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Research Funding; Bellicum Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding; Celularity: Research Funding; Forma Therapeutics: Research Funding; Forty Seven: Research Funding; Takeda: Research Funding; H3 Biomedicine: Research Funding; Ryvu Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding. Fathi:Astellas: Consultancy; Agios: Consultancy, Research Funding; Amphivena: Consultancy, Honoraria; AbbVie: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy; Jazz: Consultancy, Honoraria; Kite: Consultancy, Honoraria; NewLink Genetics: Consultancy, Honoraria; Novartis: Consultancy; PTC Therapeutics: Consultancy; Takeda: Consultancy; TrovaGene: Consultancy; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Blue Print Oncology: Consultancy; Boston Biomedical: Consultancy; Kura: Consultancy; Trillium: Consultancy; Seattle Genetics: Consultancy, Research Funding. Rotta:Merck: Speakers Bureau; Jazz Pharma: Speakers Bureau. Vachani:Blueprint: Consultancy; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Incyte: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Abbvie: Consultancy. Yang:AROG: Research Funding; Protagonist: Research Funding; Jannsen: Research Funding; AstraZeneca: Research Funding. Ho:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Garcia-Manero:Novartis: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Onconova: Research Funding; Amphivena Therapeutics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; H3 Biomedicine: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Long-Term Clinical Outcome of Patients with Acquired Aplastic Anemia In Brazil Using Cyclosporine-A (CSA) and Prednisone (PRED): 20 Years Follow-up From a Single Institution

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2234-2234
Author(s):  
Larissa A Medeiros ◽  
Samir K Nabhan ◽  
Marco Antonio Bitencourt ◽  
Michel M. Oliveira ◽  
Vaneuza A M Funke ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Overall Survival ◽  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Board Of Directors ◽  
Clonal Evolution ◽  
Severe Aplastic Anemia ◽  
Advisory Committees

Abstract Abstract 2234 Introduction/Background: Immunosuppressive therapy is the best alternative for patients with severe aplastic anemia (SAA) without matched sibling donor or with age > 40 years. Since 1988, an alternative protocol was developed with cyclosporine (CSA) and prednisone (PRED) due to irregularity in distribution of anti-thymocyte globulin (ATG) in Brazil. This study aims to show the results of this treatment on the quality of response, overall survival and development of clonal evolution. Materials and methods: 384 patients diagnosed with SAA (Camitta and Bacigalupo criteria) were evaluable by medical records review from 12/1988 to 12/2008. The immunosuppressive therapy consisted of CSA: 12mg/kg/day BID from day (D)1- D8, then 7mg/kg/day BID until 1 year. After that CSA was progressively tapered (5% each month) and ultimately stopped usually by two years. CSA levels were kept between 200–400ng/ml. PRED: 2mg/kg/day from D1-D14 then 1mg/kg/day from D15- D45. From that day on PRED dose was tapered 20% each week. Sulfamethoxazole-trimethoprim and fluconazole were used for prophylaxis against Pneumocystis jiroveci (P carinni) and fungal diseases, respectively. Treatment response was defined as Table 1. Treatment evaluation was performed at 6 weeks, 3, 6 and 12 months and then yearly. At diagnosis: median age was 21 years (2-75), disease duration 95 days (2-4749), and median number of transfusions were 12 (0-200). Etiology was idiopathic in 78%. In peripheral blood, median hemoglobin was 7.4g/dL, granulocytes 580/uL, platelets 12.000/uL and reticulocyte 0.5% (corrected value). 60% of the patients had not been treated previously. Results: Overall survival was 61% ± 3 with a median follow-up of 7 years (range: 2 months - 23 years). Response to treatment: 51% had some degree of response, with good quality of life and transfusions independent (143 patients with complete response and 53 partial response). 36 patients had no response and there were 96 deaths. Fifty six patients have lost follow-up. Most patients achieved response between 3 and 6 months of therapy. In multivariate analysis the number of neutrophils ≥ 200/uL (p = 0.009), platelets ≥ 12.000/uL (p = 0.018), reticulocyte ≥ 0.5% (p <0.001) and starting treatment after 1997 (p = 0.002) had an impact on overall survival. Patients with 15 or more previous transfusions (p = 0.006) and age ≥ 40 years (p = 0.003) had lower survival. Overall survival was 63% ± 4 and 42% ± 6 for for patients with severe disease and very severe aplastic anemia (p <0.001). The subgroup analysis of patients under 10 years old had similar results. Among patients with response, thirty-four remained dependent of CSA. Cumulative incidence of relapse was 28% ± 4 within a median of 4.4 years. Hypertension, gingival hypertrophy and diabetes mellitus were common, but easily controlled. The rate of clonal evolution among this cohort was 7.81% (16 patients developed Paroxysmal Nocturnal Hemoglobinuria, 9 Myelodysplastic Syndrome and 5 Acute Myeloid Leukemia). Conclusion: This study, with a long follow-up, has demonstrated that the overall survival using CSA and PRED is similar to that reported with ATG therapy. Even patients with partial responses had achieved good quality of life, free from transfusions and infections. Survival was influenced by the neutrophils, platelet counts, reticulocyte, number of transfusions, age at diagnosis, and therapy started after 1997. The incidence of clonal evolution was lower when compared to reported trials with ATG + CSA. Disclosures: Oliveira: Alexion: Speakers Bureau. Funke: Novartis, Bristol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pasquini: Novartis, Bristol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

ENESTnd Update: Continued Superiority of Nilotinib Versus Imatinib In Patients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 207-207 ◽  
Author(s):  
Timothy P. Hughes ◽  
Andreas Hochhaus ◽  
Giuseppe Saglio ◽  
Dong-Wook Kim ◽  
Saengsuree Jootar ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Clonal Evolution ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Free Survival ◽  
Superior Efficacy ◽  
Rate Of Progression

Abstract Abstract 207 Background: Results from the phase 3, international, randomized ENESTnd trial have demonstrated the superior efficacy of nilotinib over imatinib with significantly higher rates of major molecular response (MMR), complete cytogenetic response (CCyR), and with significantly lower rates of progression to AP/BC on treatment. Here, we present data with a median follow-up of 18 months. Methods: 846 CML-CP patients were randomized to nilotinib 300 mg twice daily (bid) (n=282), nilotinib 400 mg bid (n=281), and imatinib 400 mg once daily (n=283). Primary endpoint was MMR (≤ 0.1% BCR-ABLIS) rate “at” 12 months, as previously presented. Key secondary endpoint was durable MMR at 24 months. Other endpoints assessed at 24 months include progression to AP/BC (with and without clonal evolution), event-free survival, progression-free survival, and overall survival (OS). Results: With a median follow-up of 18 months, the overall best MMR rate was superior for nilotinib 300 mg bid (66%, P < .0001) and nilotinib 400 mg bid (62%, P < .0001) compared with imatinib (40%). Superior rates of MMR were observed in both nilotinib arms compared with the imatinib arm across all Sokal risk groups (Table). The overall best rate of BCR-ABLIS ≤ 0.0032% (equivalent to complete molecular response, CMR) was superior for nilotinib 300 mg bid (21%, P < .0001) and nilotinib 400 mg bid (17%, P < .0001) compared with imatinib (6%). The overall best CCyR rate was superior for nilotinib 300 mg bid (85%, P < .001) and nilotinib 400 mg bid (82%, P=.017) compared with imatinib (74%). The superior efficacy of nilotinib was further demonstrated using the 2009 European LeukemiaNet (ELN) 12-month milestone in which fewer patients had suboptimal response or treatment failure on nilotinib 300 mg bid (2%, 3%) and nilotinib 400 mg bid (2%, 2%) vs imatinib (11%, 8%). Rates of progression to AP/BC on treatment were significantly lower for nilotinib 300 mg bid (0.7%, P=.006) and nilotinib 400 mg bid (0.4%, P=.003) compared with imatinib (4.2%). The rate of progression on treatment was also significantly lower for nilotinib when including clonal evolution as a criteria for progression (Table). There were fewer CML-related deaths on nilotinib 300 mg bid (n=2), and 400 mg bid (n=1) vs imatinib (n=8). Estimated OS rate (including data from follow-up after discontinuation) at 18 months was higher for nilotinib 300 mg bid (98.5%, P=.28) and nilotinib 400 mg bid (99.3%, P=.03) vs imatinib (96.9%). Both drugs were well-tolerated. Discontinuations due to adverse events or laboratory abnormalities were lowest for nilotinib 300 mg bid (7%) compared with nilotinib 400 mg bid (12%) and imatinib (9%). With longer follow up there has been minimal change in the occurrence of AEs. Minimum 24-month follow-up data for all patients will be presented. Conclusions: With longer follow-up, nilotinib was associated with a significantly lower rate of progression to AP/BC on treatment and lower rates of suboptimal response or treatment failure vs imatinib. Nilotinib resulted in fewer CML-related deaths and a higher OS rate vs imatinib. Nilotinib induced superior rates of MMR, CMR, and CCyR vs imatinib in patients with newly diagnosed CML-CP. Taken together, these data support nilotinib as a new standard of care for patients with newly diagnosed CML. Disclosures: Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Meyers Squibb: Honoraria, Research Funding; Ariad: Honoraria. Hochhaus:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. le Coutre:Novartis: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Reiffers:Novartis: Research Funding. Pasquini:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Clark:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Honoraria, Research Funding. Gallagher:Novartis Pharma AG: Employment, Equity Ownership. Hoenekopp:Novartis Pharma AG: Employment. Haque:Novartis: Employment. Larson:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

Screening Patients with Myelodysplastic Syndrome and Aplastic Anemia for Paroxysmal Nocturnal Hemoglobinuria Clones: A Retrospective Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3426-3426 ◽  
Author(s):  
Andrew Shih ◽  
Ian H. Chin-Yee ◽  
Ben Hedley ◽  
Mike Keeney ◽  
Richard A. Wells ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Retrospective Study ◽  
Aplastic Anemia ◽  
Board Of Directors ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Bone Marrow Failure ◽  
Cell Surface Expression ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Pnh Clone

Abstract Abstract 3426 Introduction: Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare disorder due to a somatic mutation in the hematopoietic stem cell. The introduction of highly sensitive flow cytometric and aerolysin testing have shown the presence of PNH clones in patients with a variety of other hematological disorders such as aplastic anemia (AA) and myelodysplasic syndrome (MDS). It is hypothesized that patients with these disorders and PNH clones may share an immunologic basis for marrow failure with relative protection of the PNH clone, due to their lack of cell surface expression of immune accessory proteins. This is supported by the literature showing responsiveness in AA and MDS to immunosuppressive treatments. Preliminary results from a recent multicenter trial, EXPLORE, notes that PNH clones can be seen in 70% of AA and 55% of MDS patients, and therefore there may be utility in the general screening of all patients with bone marrow failure (BMF) syndromes. Furthermore, it has been suggested that the presence of PNH cells in MDS is a predictive biomarker that is clinically important for response to immunosuppressive therapy. Methods: Our retrospective cohort study in a tertiary care center used a high sensitivity RBC and FLAER assay to detect PNH clones as small as 0.01%. Of all patients screened with this method, those with bone marrow biopsy and aspirate proven MDS, AA, or other BMF syndromes (defined as unexplained cytopenias) were analysed. Results from PNH assays were compared to other clinical and laboratory parameters such as LDH. Results: Overall, 102 patients were initially screened over a 12 month period at our center. 30 patients were excluded as they did not have biopsy or aspirate proven MDS, AA, or other BMF syndromes. Of the remaining 72 patients, four patients were found to have PNH clones, where 2/51 had MDS (both RCMD, IPSS 0) [3.92%] and 2/4 had AA [50%]. The PNH clone sizes of these four patients were 0.01%, 0.01%, 0.02%, and 1.7%. None of the MDS patients with known recurrent karyotypic abnormalities had PNH clones present. Only one of the four patients had a markedly increased serum LDH level. Conclusions: Our retrospective study indicates much lower incidence of PNH clones in MDS patients or any patients with BMF syndromes when compared to the preliminary data from the EXPLORE trial. There is also significant disagreement in other smaller cohorts in regards to the incidence of PNH in AA and MDS. Screening for PNH clones in patients with bone marrow failure needs further study before adoption of widespread use. Disclosures: Keeney: Alexion Pharmaceuticals Canada Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wells:Alexion Pharmaceuticals Canada Inc: Honoraria. Sutherland:Alexion Pharmaceuticals Canada Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Lost and Gain of t(4;14) and t(11;14) in Multiple Myeloma Patients Between Relapse and diagnosis: An Illustration of Clonal Dynamic During Disease Course. an IFM Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 196-196 ◽  
Author(s):  
Benjamin Hebraud ◽  
Denis Caillot ◽  
Jill Corre ◽  
Gerald Marit ◽  
Cyrille Hulin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Plasma Cells ◽  
Clonal Evolution ◽  
Genomic Analysis ◽  
Clonal Diversity ◽  
Large Cohort ◽  
Fish Analysis ◽  
Disease Course ◽  
Advisory Committees ◽  
Tumor Types

Abstract Abstract 196 Until recent data, MM concept implies that all clones are linearly related to each other and homogenous in their mutational landscape. However, studies are now contradicting this model and reveal a more complex clonal architecture of Darwinian-like somatic evolution, where tumor progression proceeds in a branching rather than in a linear manner, leading to substantial clonal diversity and coexistence of wide genetic heterogeneity. By use of serial genomic analysis at different points during the disease course of MM patients, Keats et al. found the existence of 3 temporal tumor types, which can either be genetically stable, linearly evolving, or heterogeneous clonal mixtures with shifting predominant clones. In order to confirm these data we study on a large cohort of MM patients the emergence or disappearence by FISH analysis of t(4;14) and t(11;14) between diagnosis and relapse. We selected 444 patients from the IFM cell collection for whom we had a FISH analysis at diagnosis and relapse. Among them, 342 were evaluable for proceeding to FISH analysis. Upon receipt, bone marrow plasma cells were sorted using nanobeads and an anti-CD138 antibody (RoboSep, Stem Cell Technologies). After immuno-magnetic sorting, the plasma cell suspension purity was verified, and only samples with at least 90% of plasma cells were kept. Cells were then fixed in Carnoy's fixative. To test plasma cells for the t(4;14) and t(11;14), we did use specific IGH-FGFR3 and IGH-CCND1 fusion probes (Abbott Molecular). Hybridizations were performed according to the manufacturer's instructions. For analysis, at least 100 plasma cells with correct signals were scored using a Zeiss epifluorescence microscope. Our population baseline data presents usual characteristics: median age at diagnosis was 57 years (36y to 82y), diagnosis was made between 18/05/2000 and 19/08/2008. Relapse occurred between 11/08/2000 and 04/02/2009, with a median PFS of 26.6 months. The t(4;14) was present at diagnosis in 16.7% of the patients (38/232), and 11% (36/322) at relapse; Chi2 test did not find statistical difference between incidence at diagnosis and relapse (p=0.12). The t(11;14) was present in 24.6% of patients at diagnosis (48/195) but only 10.7% (20/187) at relapse (p=0.002). The purpose of our study was to explore clonal evolution during myeloma course. The t(4;14) translocation appeared (negative at diagnosis and positive at relapse) in 13 patients (n=218; 5.96%). On the contrary, t(4;14) disappeared in 11 cases (5.04%, n=218). In the same way, t(11;14) appeared for only 2 patients (1.42%, n=141) and disappeared in six cases (4.25%, n=141). Interestingly, we did not see switch between emergence and disappearance of the two translocations; no patient changed his cytogenetic status for one translocation to the other one. This phenomenon represents an important percentage of patients: for t(4;14), 11% of patients changed their status and 5.67% for t(11;14). Our data are in link with a study by Keats et al. who identified an evolution of aCGH data on a cohort of 28 patients showing changes over time for all their patients. Even if our data did not identify one of the three temporal tumor types described by Keats, the diversity of our findings (gain or loss of t(11;14) or t(4;14) between diagnosis and relapse) is an illustration on a large cohort of the clonal diversity and evolution of MM. Conclusion: this study describes for the first time on a large cohort of patients an aspect of subclonal evolution of MM. We identified a change of cytogenetic status for 11% of t(4–14) and 5,67% of t(11–14). These data illustrate the subclonal evolution of MM and underline the importance to perform novel cytogenetic analysis during disease course because treatment may be influenced by clonal expansion. Disclosures: Hulin: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Kolb:janssen: Honoraria; celgene: Honoraria. Facon:onyx: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees.

Consolidation with Vtd Significantly Improves the Complete Remission (CR) Rate Following Vtd Induction and Single Autologous Stem Cell Transplantation (auto) in Multiple Myeloma (MM).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3096-3096
Author(s):  
Xavier Leleu ◽  
Benjamin Hebraud ◽  
Guillemette Fouquet ◽  
Murielle Roussel ◽  
Denis Caillot ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Incidence Rate ◽  
Relapse Rate ◽  
Research Funding ◽  
The Other ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Advisory Committees ◽  
Induction Regimen

Abstract Abstract 3096 Background. Several studies have demonstrated the impact of VTd on response rates and PFS either as induction or consolidation regimen. However there are limitations to these studies, especially that no data is available regarding the role of VTd consolidation in the context of bortezomib-triple based VTd induction regimen followed by a single auto. At completion of therapy, the response rate (ORR, PR and better) was 89%, VGPR+CR rate 74%, CR rate 29%, relapse rate and median PFS was 53% and 26 months (median F-up 32 months) in the VTd arm of the phase 3 IFM2007-02 trial conducted for newly diagnosed MM (Moreau et al, Blood 2012). In this study, only a minority of patients had received a consolidation or maintenance. On the other hand, Cavo et al. (Blood 2012) reported 97.5%, 92%, 61%, 39% 3-year progression and 62% estimated 5-year PFS (F-up 43 months) respectively in the VTd arm. VTd was given as induction before and consolidation after double auto in this upfront GIMEMA phase 3 trial (Cavo et al, Lancet 2010). We aimed to assess the efficacy and safety of VTd as consolidation therapy in the context of VTd as induction regimen followed by a single auto (VTd-auto-VTd regimen). Method. This study has included a first group of 121 newly diagnosed MM from 2009 to 2011 across 9 IFM centers. Patients were to be eligible for auto upfront, aged less than 65 and treated with VTd-auto-VTd regimen. The second cohort included MM treated with VTd-auto without consolidation from the IFM2007-02 trial (n=76). A third cohort comprised MM that received upfront a triplet Vd-based combination induction (VCd, VRd) -auto without consolidation (n = 40). Results. In the whole study, the median age was 56 years, the sex ratio was 1,49, 50% had ISS 2 and 3, 22% had adverse FISH [t(4;14); del17p] (similar in the 3 groups). Overall, the ORR was identical in the 3 cohorts at completion of therapy, 104 (86%), 72 (94%) and 32 (80%) for the cohort 1 to 3, respectively. Nevertheless, the CR rate was significantly greater in patients that received a consolidation (cohort 1), as compared to the cohorts 2 and 3 that did not receive any consolidation, 59 (53%) vs. 26 (34%) and 13 (32.5%), respectively (p=0.0001). Interestingly, the CR rates were identical at the end of the induction in the 3 cohorts, 13%, 15% and 22.5%, respectively. With a median follow-up of 25 months, the incidence rate of relapse was significantly greater in the cohort 2 and 3 versus 1, further demonstrating the importance of the consolidation, 25 (21%), 42 (55%) and 13 (32.5%) patients (p=0.0001), respectively; and 9 (8%), 6 (8%) and 8 (20%) had died in cohorts 1 to 3 (p=0.07). The median (95%CI) PFS was not reached in cohort 1, and was 32 (28;36) months and 30 (26;33) months in cohort 2 and 3, respectively. Importantly, 54.5%, 32% and 32% of patients were free of relapse at 32 months in the 3 cohorts, respectively. Similar data were obtained for TTP. The median (95%CI) OS was not significantly different in cohorts 1 to 3, although not reached for the first 2 cohorts and 38 (33;43) months for the 3rdcohort. The 3-year survival was 84%, 91% and 76%, respectively (p=ns). A longer follow up will certainly demonstrate greater survival end points benefit in favor for consolidation. The safety profile of the cohort that contained a consolidation was superimposable to that of the remaining 2 cohorts without consolidation. The incidence rate of hematological EIs of grade 3 and 4 was 4%, 6% and 8% in the 3 cohorts (p=ns), respectively. The incidence rate of neuropathy grade 1–2 and 3–4 was 5% and 2% in the cohort 1 with consolidation, but only 1% occurred during the consolidation. This data compares favorably to the 3% reported in the cohort 2 (Moreau et al. Blood 2012). We have also observed 9 (9%) thromboembolic events (TE), 8 of venous type and 1 arterial. None of them happened during the consolidation, and again, this incidence rate if superimposable to that reported in the IFM2007-02 vTd cohort. Conclusion. This study showed an impressive increase in CR rate in relation to the consolidation that translated into a lower relapse rate. This study also demonstrated that the VTd regimen, used both as induction and consolidation, in the context of a single auto upfront in MM, significantly contributed to improve clinical outcomes with an acceptable toxicity profile. VTd-auto-VTd compared very favorably to the other upfront protocols, and may become in the near future a standard of care in newly diagnosed patients with Myeloma. Disclosures: Leleu: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; Onyx: Honoraria, Speakers Bureau; LeoPharma: Honoraria, Speakers Bureau. Off Label Use: Pomalidomide. Roussel:celgene: Honoraria; janssen: Honoraria. Facon:onyx: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees.

Newly Diagnosed Multiple Myeloma (MM) Patients Treated With Lenalidomide Induction and Maintenance Show a Low Incidence Of Second Primary Malignancies (SPMs)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2074-2074
Author(s):  
Annamaria Brioli ◽  
Charlotte Pawlyn ◽  
Walter Gregory ◽  
Samantha Hinsley ◽  
Samantha Marshall ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Incidence Rate ◽  
Maintenance Treatment ◽  
New Drugs ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Non Invasive ◽  
To Receive

Abstract Introduction New drugs have significantly improved the outcome of MM patients (pts) increasing both progression free survival (PFS) and overall survival (OS). Among new drugs lenalidomide (LEN) due to its oral availability and favourable toxicity profile is an attractive option both as an induction and as a maintenance treatment, with different studies demonstrating its effectiveness. Long term therapy with LEN, however, has been associated with an increased risk of developing SPMs. Aims We are conducting a large phase III study to evaluate the use of LEN as induction and/or as maintenance therapy. The primary end points of the study are OS and PFS. Secondary end points are response and toxicity. Methods Pts are treated following an intensive or a non intensive pathway based on their eligibility for high dose Melphalan (HDM) and stem cell transplantation (ASCT) and are randomised to receive induction therapy with cyclophosphamide and dexamethasone combined with either LEN (CRD) or thalidomide (CTD). Pts failing to achieve an optimal response are randomised to receive additional therapy with cyclophosphamide, dexamethasone and bortezomib (CVD) or no extra therapy. Pts with minimal or no response will automatically receive further therapy with CVD. A randomisation between LEN maintenance and no maintenance is also performed. Data on the occurrence of SPMs are being routinely collected as part of safety assessment during all protocol phases and follow up. Analyses were performed on treatment actually received. Results As per cut off of the 23rd July, 2371 pts have undergone the induction randomisation, of which 2368 are eligible for the safety analysis; 794 pts entered maintenance randomisation. The median follow up is 1.36 years from initiation of the study and 1.06 years from maintenance randomisation. Localised skin cancer other than melanoma were considered as non-invasive SPMs. At the time of the present analysis 17 SPMs have been reported with a cumulative incidence rate of 0.7% (cumulative rate of 0.6% for invasive SPMs and 0.1% for non-invasive SPMs); four additional patients, reported as having a SPM, were excluded, after central review of the data, either due to a previous history of malignancy or because of the evidence of a pre-existing tumour other than MM at the time of study entry. The median age at the time of SPMs development is 72 years (range 61-92), and the median time from trial entry to development of SPMs is 11 months (range 2.1-27.0). The most common SPMs reported were squamous cell carcinoma (4 pts, 2 invasive and 2 non invasive), breast cancer (3 pts), colon cancer (2 pts) and prostate cancer (2 pts). No haematological SPM has so far been reported. One patient, treated according to the intensive arm with LEN both as induction and maintenance, was reported as having a suspect myelodysplasia (MDS) due to anaemia and thrombocytopenia 2.7 months after entering the maintenance randomisation. No clear histological sign of MDS was found and the values improved after stopping maintenance treatment; these data fit with treatment related toxicity and not with the development of a MDS, and the patient was excluded from this analysis. Ten out of 17 SPMs developed during maintenance treatment or follow up phase, with 7 patients having received LEN maintenance. Median time from maintenance randomisation to SPMs development is 7 months (range 2-20.6 months). The remaining 7 were diagnosed during or immediately after induction. About half of the patients (8/17) were randomised to receive LEN induction; 3 patients received LEN both as induction and as maintenance. Interestingly only one of those 3 pts had been treated according to the intensive arm. With a median follow up of 1.36 years the estimated incidence rate at 1 and 2 years are 0.70% (95% CI .40-1.22)and 1.17% (95% CI .70-1.96) respectively (Figure 1). Conclusions Our data do not confirm previous findings of an excess risk of SPMs in association with the use of LEN and HDM in presenting patients, with 12/17 pts developing SPMs treated on the non intensive pathway that does not contain HDM. Most importantly only 0.4% of the patients enrolled within the intensive pathway developed a SPM, with only 2 of them receiving LEN maintenance. Longer follow up will help to further elucidate the risk of LEN associated SPMs. On behalf of the NCRI Haemato-Oncology subgroup Disclosures: Brioli: Celgene: Honoraria. Off Label Use: The presentation include the use of Lenalidomide as induction and as maintenance treatment for newly diagnosed multiple myeloma patients. Cook:Janssen: Honoraria, Research Funding, Speakers Bureau. Cavo: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; Millenium: 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; Bristol-Meyer Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Morgan:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millenium: Consultancy, 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; Merck: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Johnson and Johnson: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

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