Genetic Response to Lenalidomide in the Circulating Progenitor Cell Compartment of MDS Cohort. Preliminary Results of the Multicenter German LE-MON-5 Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1721-1721
Author(s):  
Katayoon Shirneshan ◽  
Ulrich Germing ◽  
Friederike Braulke ◽  
Julie Schanz ◽  
Uwe Platzbecker ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cytogenetic Response ◽  
Response To Therapy ◽  
Fish Analysis ◽  
Trisomy 8 ◽  
Advisory Committees ◽  
Clone Size ◽  
Observation Period

Abstract Abstract 1721 Introduction: LE-MON-5 is a multicenter German phase-II study to verify the safety of monotherapy with lenalidomide (LEN) in MDS patients (pts) with IPSS low or Int-1 and isolated del(5q). We report our cytogenetic results after a monitoring period of sixteen months since start of the trial. Methods: For sequential and frequent survey of LEN-treated pts we applied FISH on enriched CD34+ stem cells from peripheral blood (CD34+ pb) every 2–3 months using a panel of 8 to 13 probes. Karyotyping and FISH on bone marrow aspirates was performed at initial screening and every six months. The median number of analyzed metaphases was 25 (4–30) and FISH analyzing was based on 200 interphase nuclei. Results: We have already screened 94 pts and could confirm isolated del(5q) in 76 (81%). Due to our cytogenetic results demonstrating additional changes in 18/94 (19%) pts, these were registered as screening failures and thus excluded from the study. Until now cytogenetic follow-up data for 40 pts is available. After a median follow-up of 9 months (2–16 months) we have observed a significant impact of LEN on the reduction of the clone size (p < 0.05) by FISH-monitoring. Based on cytogenetic remission, we have separated the cohort into three groups: Fast responders (14/40 (35%) pts) showed a very rapid cytogenetic response to therapy with >50% reduction of 5q- clone size within two months. In the second group, the slow responders, we observed >50% reduction of clone size in 9/40 (22.5%) after > two months. However, two pts showed an increase of 5q- clone after 12 and 13 months respectively after initial response in the sense of a relapse. In the third group, the non responders, (11/34 (27.5%)) we could not observe any cytogenetic response during the as yet limited observation period. In six cases (15%) we detected a reduction of the 5q- clone during follow-up, but the emergence of additional aberrations were also observed such as: 1. trisomy 8 in 6.7% of metaphases after 8 months and is reduced to 3.6% after 12 months, 2. trisomy 4 in 6.7% of metaphases after 6 months and is disappeared after 12 months, followed by emergence of trisomy 8 in 8% of interphase cells, 3. finally, two cases showed loss of Y-chromosome after 4 months in 6% and 19% of CD34+ pb cells, respectively. In CD34+ pb cells of another case, trisomy 8 was detectable after two months in 3.5% of cells. All these new secondary abnormalities occurred in cells with normal chromosomes 5 and were slightly above or below our laboratory thresholds (3 times standard variation). In only one case, a new abnormality emerged in the 5q- clone: In this case additional del(20q) occurred after 2 months in 46% of CD34+ pb cells. In this case no reduction of 5q- cells after 4 months of treatment was observed. However, FISH analysis after 6 months of treatment showed a 14% reduction for both aberrations. To date we could not identify any pts who acquired complex anomalies while treated with LEN. Conclusion: FISH analysis of CD34+ pb cells allows a reliable frequent and relevant genetic monitoring of treatment response to LEN. Our results confirm the positive and rapid effects of LEN on clones with del(5q): Thus, already after 2 months, we could observe up to 90% reduction in the 5q- clone size in 35% of pts. In general, remission rates increased with duration of therapy. We suspect that trisomy 4, 8 and Y-loss are fluctuant “mini clones” without any clinical relevance. Inclusion of additional pts and prolonged observation period will help us to better evaluate the clinical response to LEN. Disclosures: Off Label Use: lenalidomide for MDS del(5q) provided by Celgene for this clinical study. Germing:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Braulke:Celgene: Honoraria, Research Funding. Schanz:Celgene: Honoraria, Research Funding. Giagounidis:Celgene: Honoraria. Götze:Celgene: Honoraria. Haase:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Outcome of Patients with Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) with Relapse After Tyrosine Kinase Inhibitor (TKI) Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1518-1518
Author(s):  
Hun Ju Lee ◽  
Susan O'Brien ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Salvage Therapy ◽  
Research Funding ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Advisory Committees ◽  
Cns Relapse ◽  
Complete Hematologic Response

Abstract Abstract 1518 Background: Treatment with TKIs has greatly improved the outcome of patients with Ph+ ALL. However, many patients treated with TKI-based therapy eventually have a relapse. The response to salvage therapy and long-term outcomes of these patients are unknown. Aims: Describe the outcomes of patients with Ph+ ALL with resistance to or relapse after frontline TKI-based chemotherapy. Methods: We analyzed the outcome of patients who were treated in clinical trials at our institution between February 2001 and July 2008 with TKI-based chemotherapy for newly diagnosed Ph+ ALL who had refractory or relapsed disease. Results: One hundred thirteen patients were treated with frontline hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone (HCVAD) plus imatinib (HCVAD+I; n=54) or HCVAD plus dasatinib (HCVAD+D; n=59). Of these, 35 (31%) experienced primary resistance (n=1) or relapse (n=34). The median age was 51 years [range (r): 20–85]; 12 patients (34%) were older than 60 years. Median follow-up was 21.1 mo (r: 4.2–56.7). Median white blood cell and platelet counts at diagnosis were 14.4 × 109/L (r: 1.2–292.9) and 48 × 109/L (r: 4–425), respectively. White blood cell count was >30 × 109/L in 13 patients (37%). Median peripheral and bone marrow blast percentages were 53% (r: 0–97%) and 80% (r: 1–98%), respectively. Twenty-two patients (63%) had received HCVAD+I and 13 (37%) HCVAD+D. Twenty-three patients (66%) had experienced first complete remission (CR1) with 1 cycle of induction. Median CR1 duration was 12 mo (r: 1.9–42). Four patients underwent allogeneic stem cell transplantation (ASCT) in CR1. ABL kinase domain mutations were investigated in 28 patients (80%) at relapse; 16 (57%) had mutations, including 5 (14%) with T315I (all had received HCVAD+D). Upon relapse, 31 patients received first salvage therapy (S1), 24 with chemotherapy [HCVAD+D, n=8; HCVAD+I, n=3; HCVAD+nilotinib (N), n=1; HCVAD+asparaginase (Asp), n=1; methotrexate, vincristine, Asp, and dexamethasone (MOAD), n=2; others, n=9]; 6 with a TKI only (I, n=2; D, n=1; N, n=1; others, n=2); and 1 with ASCT. Three patients were unfit for treatment. Median cycles of S1 were 2 (r: 1–8). Thirteen patients (42%) had second complete remission (CR2) (HCVAD+D, n=6; HCVAD+I, n=2; HCVAD+N, n=1; HCVAD+Asp, n=1; others, n=3). Median time to CR2 was 1.5 mo (r: 0.7–8.8). Five patients underwent ASCT in CR2. Median CR2 duration was 7.3 mo (r: 1.4–36.2). Complete cytogenetic response was seen in 11 patients (35%); major molecular response (BCR-ABL/ABL ratio <0.05%) in 9 (29%); and complete molecular response in 7 (22%); and complete hematologic response in 15 (48%). Times to complete cytogenetic response and complete molecular response were 1.3 mo (r: 0.7–10.6) and 3 mo (r: 1.5–8.7), respectively. Seven patients had second relapse. Fifteen patients (7 relapse, 8 refractory) received second salvage therapy (S2) with systemic chemotherapy (MOAD, n=2; phase I/single-agent TKI, n=8; others, n=5); 1 patient had solitary central nervous system (CNS) relapse treated with intrathecal cytarabine and methotrexate. CR3 was obtained in 1 patient, the patient with sole CNS relapse. Median disease-free survival (DFS) and overall survival (OS) after S1 were 6.5 mo (r: 0.5–45) and 7.3 mo (r: 1.4–36.2), respectively. At last follow-up, 2 patients (6%) were alive and 33 had died, 11 (33%) of infectious complications, 5 (15%) of organ failure, 3 (9%) of bleeding complications, 2 (6%) of graft-versus-host disease complications, 2 (6%) of CNS relapse, and 10 (30%) of other or unknown causes. Median OS after S2 was 2.1 mo (r: 1.4–2.6). In univariate analysis, age >60 years was associated with worse OS after S1 [4.2 vs. 12.7 mo; 95% confidence interval (CI) 1.8 to 6.7 vs. 7.5 to 17.9 (P=0.006)]. Complete hematologic response was associated with improved OS after S1 [15.4 vs. 4.3 mo; 95% CI 9.1 to 21.8 vs. 2.5 to 6.0 (P<0.001)]. Major molecular response was associated with improved OS after S1 [18.1 vs. 5.7 mo; 95% CI 9.3 to 26.8 vs. 3.6 to 7.8 (P=0.003)]. Choice of prior TKI (HCVAD+I vs. HCVAD+D) did not significantly influence CR and OS after relapse. Conclusion: Patients with refractory or relapsed Ph+ ALL after TKI-based therapy have poor outcome, particularly those who are older or have persistent BCR/ABL transcripts. New agents are needed to improve the outcome in this population. Disclosures: Kantarjian: BMS: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Cortes:Chemgenex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: 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 Molecular Characterization of Diffuse Large B-Cell Lymphoma Associated to Hepatitis C Virus Infection

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2402-2402
Author(s):  
Roberta Sciarra ◽  
Caterina Cristinelli ◽  
Michele Merli ◽  
Marco Lucioni ◽  
Silvia Zibellini ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Immune Regulation ◽  
Research Funding ◽  
Notch Pathway ◽  
B Cell Lymphoma ◽  
Fish Analysis ◽  
Low Grade ◽  
Advisory Committees

Abstract BACKGROUND. HCV-positive DLBCL has distinct clinical and pathologic characteristics compared to its negative counterpart: patients (pts) are usually older with more frequent splenic and extranodal involvement and elevated LDH. Differently from its clinical hallmarks, the molecular landscape of this pathological entity has been scarcely outlined. METHODS. In this bicentric study, we investigated the clinical and molecular features and outcome of 54 pts with HCV-positive DLBCL. Targeted next generation sequencing (NGS) was performed on DNA extracted from formalin-fixed paraffin-embedded tissue biopsies. A core panel probes covering coding exons from 184 genes frequently mutated in mature B cell neoplasms was designed using IDT tool and libraries were prepared using Illumina DNA-prep-with enrichment. Sequencing was performed on Illumina HiSeq 2500. Cluster analysis was performed using LymphGen tool. We also applied fluorescence in situ hybridization (FISH) for MYC, BCL2 and BCL6. RESULTS. Median age was 71 (33-84; IQR: 61.9-77). Stage was III/IV in 34 pts (63%). Extranodal sites were involved in 21 pts (38%), spleen in 20 pts (37%). LDH was higher than the upper limit in 40 pts (74%). R-IPI was good for 2 pts (4%), intermediate for 24 pts (44%), poor for 28 pts (52%). HPS score was intermediate or high in 33 of 44 assessed pts (75%). A histological low-grade component was identified in 15 pts (27%). Hans algorithm differentiated pts almost equally in GCB (26/50, 52%) and non-GCB (24/50, 48%) subtype. HCV-RNA was detectable in 52 pts (96%) and quantifiable in 43 pts (79%). Of 29 pts assessed, genotype was 1 in 9 (31%), 2 in 16 (55%), 3 in 4 pts (14%). Among 37 pts whose data were available, 11 pts (30%) received direct antiviral agents, 7 pts (19%) received interferon-containing regimen, 19 pts (51%) were not treated for HCV. Twenty-seven pts (50%) received rituximab-enriched protocols, 23 pts (43%) were treated with chemotherapy alone, 1 pt (2%) with surgery alone, 3 pts (5%) were lost to follow up. With a median follow up of 7.7 years (yrs) (IQR: 4.6-10.6), 5-yrs overall survival (OS) (95%CI) was 49.3% (34.1-62.8%) and 5-yrs progression free survival (PFS) (95%CI) was 39.5% (25.5-53.3%). Median OS and PFS were 4.9 and 3.1 yrs, respectively. FISH analysis showed lack of BCL2 (0/19) and MYC translocations (0/15). BCL6 fusions were found in 76% of pts (16/21). NGS showed mutations in 154 of the 184 analyzed genes. The informativity of the panel was 100% with all pts presenting at least one oncogenic variant. Gene mutation frequencies are presented in Fig. 1. The median mutation load (MML) was 13 mutated genes per case (2-32; IQR: 9-16). Most frequently mutated genes were the epigenetic regulators KMT2D, mutated in 23 pts (42.6%), and SETD1B, mutated in 17 pts (31.5%). FAS, PM1 and RERE were mutated in 15 pts each (27.8%). TBL1XR1, BCL11A and SGK1 were mutated in 14 (26%), 13 (24%) and 12 pts (22%), respectively. Considering genes in their specific pathway, 94% of pts harbored mutations in genes involved in epigenetic regulation (MML: 3; range 1-7; IQR: 1.25-4), 90% of pts in apoptosis-related genes (MML: 2; 1-7; IQR: 1-3) and 77% of pts in genes belonging to BCR/NFkB signaling pathway (MML: 2; 1-7; IQR: 1-3). Of note, 56% of pts carried mutations in genes related to immune regulation (MML: 1.7; 1-5; IQR: 1-2) and 25% of pts had mutations within the NOTCH pathway (MML: 1.2; range 1-2). Via the LymphGen 1.0 tool, we classified 26 pts (48%) into 4 genetic clusters: BN2 (11/26, 42%), ST2 (8/26, 31%), MCD (4/26, 15%), EZB (3/26, 12%). Twenty-eight pts (52%) were classified as "others". Among those belonging to BN2 cluster, 7 pts (64%) had a histologically confirmed transformed DLBCL. No significant differences in terms of OS and PFS were identified according to cluster subgroups. CONCLUSIONS. The prevalence of the BN2 cluster and enrichment of mutations of genes involved in NOTCH pathway seem to indicate a preferential marginal-zone origin in HCV-positive DLBCL. In addition, our data confirm the absence of BCL2 translocation in this subset of DLBCL and show a high prevalence of mutated genes within the epigenetic and immune regulation pathways in HCV-positive DLBCL, pointing out their compelling role in the pathogenesis and suggesting potential implications for molecularly targeted therapies. Figure 1 Figure 1. Disclosures Passamonti: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Arcaini: Celgene: Speakers Bureau; Gilead Sciences: Research Funding; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses.

scholarly journals TP53 Status As Well As Cytogenetic Complexity Significantly Impact on Prognosis in Myelodysplastic Syndromes with Complex (≥3 anomalies) Aberrant Karyotypes

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3007-3007
Author(s):  
Christina Ganster ◽  
Roxana Schaab ◽  
Katayoon Shirneshan ◽  
Lea Naomi Eder ◽  
Anna Mies ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Genetic Profile ◽  
Fish Analysis ◽  
Advisory Committees ◽  
Clone Size ◽  
Increased Risk ◽  
Travel Grant ◽  
The Impact ◽  
Tp53 Status

Introduction: Complex aberrant karyotypes (CK, ≥3 cytogenetic aberrations, CA) are associated with an unfavorable prognosis and an increased AML transformation rate in MDS. However, even MDS with CK (CK-MDS) are heterogeneous in terms of genetic profile and prognosis. Recently, we demonstrated that a high number of CA as well as mutations in TP53 (TP53mut) are associated with increased risk in CK-MDS (Haase et al, 2019). However, as there is a strong association between CK-MDS and TP53mut, it is still a matter of debate whether the karyotype and TP53mut are prognostically independent genetic markers. Furthermore, loss of heterozygosity (LOH) of 17p13 (TP53LOH), due to loss of genetic material or to copy number neutral LOH (CN-LOH), is also associated with a poor prognosis. We here aimed to characterize TP53mut andTP53LOH in CK-MDS and to elucidate the impact of cytogenetics, TP53mut and TP53LOH on the outcome of CK-MDS. Methods: We included 178 pts with MDS (N=138), CMML (N=5) and secondary AML after MDS (AML with myelodysplasia-related changes, N=35), all with CK. The median precentage of bone marrow (bm) blasts was 11% (range: 0-90%). The median age was 72 yrs (range: 30-95 yrs). The male:female ratio was 1.23:1. The number of CA was determined by banding analysis in all cases. The karyotype was confirmed by multicolor FISH in 134 cases. TP53LOH was verified by FISH analysis of the TP53 locus in 17p13 (146 analyses) and/or molecular karyotyping (MK, 41 analyses). In 144 cases further FISH probes in addition to TP53 were used. TP53mut was identified by NGS (54 cases) or Sanger sequencing (124 cases). Follow-up data for survival analyses were available for 127 pts with MDS and oligoblastic AML with less than 30% bm blasts. Results: The median number of CA was 7 (range: 3-46), 98/178 pts (55%) showed a TP53mut (median VAF: 34%, range: 8-93%) and 64/178 (36%) a TP53LOH (median FISH clone size: 65%, range: 6-99%), including 9 pts with a CN-LOH in 17p13. The CN-LOH was either identified by MK (5/41 pts (12%) where MK was available showed a CN-LOH, 4/5 with TP53mut) or by NGS (4/54 pts (7%) where NGS was available showed a VAF >70% and normal TP53-FISH). In total, a TP53mut and/or a TP53LOH was identified in 116/178 pts (65%). Overall survival (OS) did not significantly differ between CK-MDS with TP53mut only, TP53LOH only, and TP53mut+TP53LOH (Fig.1). Therefore, we merged TP53mut and TP53LOH to TP53altered in all further analyses. Regarding the cytogenetic characterization of pts with TP53altered, the number of CA was significantly higher in pts with TP53altered than in pts with normal TP53 (median 9 CA (range: 3-46) vs 5 CA (range: 3-24), P<0.001). Also notable was that the founder clone of pts with TP53altered included significantly more cases with del(5q) (determined by FISH, 69/92 cases, 75%) compared to pts with normal TP53 (22/52 cases, 42%, P<0.001). The number of CA as well as the TP53 status contributed significantly to OS (Fig.2). The presence of anemia (Hb <10 g/dl) at first diagnosis of the CK had the greatest impact on OS (HR: 3.95) in the multivariate model (Cox regression), followed by an altered TP53 gene (TP53mut and/or TP53LOH; HR: 3.53) and the presence of ≥5 CA (HR: 2.33). Based on these three parameters with the greatest impact on OS, we created a simple provisional prognostic system. One scoring point each was assigned to anemia (Hb <10 g/dl), TP53altered, and ≥5 CA. Regarding OS, the resulting four risk groups separated very well (Fig.4). Conclusions: The presence of ≥5 CA is associated with reduced OS in CK-MDS. A TP53mut as well as a TP53LOH both further segregate outcome. The impact of the clone size of TP53mut and TP53LOH on survival is currently being evaluated. Our data imply that the TP53 status (TP53mut and/or TP53LOH) and the complexity of the karyotype are independent prognostic markers. Based on the presence of anemia, the TP53 status (TP53mut and/or TP53LOH), and the number of CA, the individual risk of CK-MDS can be estimated more accurately. This will allow to better tailor treatment decisions for individual pts with CA. Funding (FS): 2017 SGR 288-GRC Disclosures Germing: Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding. Kaivers:Jazz Pharmaceuticals: Other: Travel Support. Kröger:Celgene: Honoraria, Research Funding; DKMS: Research Funding; JAZZ: Honoraria; Medac: Honoraria; Neovii: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Riemser: Research Funding; Sanofi-Aventis: Research Funding. Hertenstein:RS Media: Research Funding. Döhner:Daiichi: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; CTI Biopharma: Consultancy, Honoraria. Bug:Hexal: Membership on an entity's Board of Directors or advisory committees; Celgene Neovii: Other: travel grant; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Sanofi: Other: travel grants; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Nickelsen:Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

A Pivotal Phase 2 Trial of Ponatinib in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I BCR-ABL Mutation: 12-Month Follow-up of the PACE Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 163-163 ◽  
Author(s):  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Javier Pinilla-Ibarz ◽  
Philipp le Coutre ◽  
Ron Paquette ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Primary Endpoint ◽  
Research Funding ◽  
Treatment Options ◽  
Response Rates ◽  
Cytogenetic Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Abstract 163 Background: Despite progress in Ph+ leukemia therapy, patients who experience failure of tyrosine kinase inhibitors (TKIs) and those with the T315I BCR-ABL mutation have limited treatment options. Ponatinib is an oral TKI developed using computational and structure-based design with optimal binding to the BCR-ABL active site. At clinically achievable concentrations, ponatinib demonstrated potent in vitro activity against native BCR-ABL and all BCR-ABL mutants tested, including T315I. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with Ph+ leukemia were evaluated in a phase 2, international, open-label clinical trial. Methods: 449 patients resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation confirmed at entry were enrolled and assigned to 1 of 6 cohorts: chronic phase (CP)-CML R/I (N=203), CP-CML T315I (N=64), accelerated phase (AP)-CML R/I (N=65), AP-CML T315I (N=18), blast phase (BP)-CML/Ph+ALL R/I (N=48), BP-CML/Ph+ALL T315I (N=46). Five patients (3 CP-CML, 2 AP-CML) without confirmed T315I and not R/I to dasatinib or nilotinib were treated, but not assigned to a cohort; they were included in safety analyses. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 months for CP-CML and major hematologic response (MaHR) at any time within 6 months for advanced Ph+ leukemia. The trial is ongoing. Data as of 23 July 2012 are reported: median follow-up 11 (0.1 to 21) months; minimum follow-up 9 months. Results: Median age was 59 (18–94) yrs; 53% were male. Median time from diagnosis to ponatinib was 6 (0.3–28) yrs. Patients were heavily pretreated: 96% received prior imatinib, 84% dasatinib, 65% nilotinib; median number of prior TKIs was 3, with 53% exposed to all 3 approved TKIs. In patients previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance and 12% were purely intolerant to dasatinib or nilotinib. Best prior response to most recent dasatinib or nilotinib was 26% MCyR or better in CP-CML, and 23% MaHR or better in advanced Ph+ leukemia. Frequent BCR-ABL mutations confirmed at entry were: 29% T315I, 8% F317L, 4% E255K, 4% F359V, 3% G250E. No mutations were detected in 44%. The primary endpoint response rates (see Table) in each cohort exceeded the prespecified statistical criteria for success. In CP-CML and AP-CML R/I (the 3 largest cohorts), 95% CIs exceeded the prespecified response rate. Median time to response (for responders) was 84 days in CP-CML, 112 days in AP-CML, 55 days in BP-CML/Ph+ALL. Responses were durable; the estimated (Kaplan-Meier) probability of responders maintaining the primary endpoint at 1 yr was 91% in CP-CML, 42% in AP-CML, 35% in BP-CML/Ph+ALL. In CP-CML, 46% had complete cytogenetic response and molecular response rates were 32% MMR, 20% MR4, and 12% MR4.5. Response rates were higher in patients exposed to fewer prior TKIs and those with shorter disease duration. Similar response rates were observed in patients with and without BCR-ABL mutations. In CP-CML, response rates were higher in those with T315I; however, a post hoc analysis found that presence of T315I was not a predictor of response. Instead, the difference in response rate was explained by T315I patients' younger age, shorter duration of leukemia, and exposure to less prior therapy. At the time of analysis, 52% of patients remained on therapy (66% CP-CML). The most frequent reasons for discontinuation were progression (18%) and AEs (12%). The most common drug-related AEs were thrombocytopenia (36%), rash (33%), and dry skin (31%). Pancreatitis was the most common drug-related SAE (5%); however, it occurred early and was managed with dose modification (1 patient discontinued due to pancreatitis). Conclusions: Ponatinib has substantial activity and is generally well tolerated in these heavily pretreated Ph+ leukemia patients who have limited available treatment options. Data with a minimum follow-up of 12 months will be presented. Disclosures: Cortes: Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Kim:Novartis, BMS, Pfizer, ARIAD, Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis, Bristol-Myers Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Deciphera: Research Funding; ARIAD: Research Funding; Celgene: Research Funding; Millenium: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BMS: 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, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:BMS, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, Novartis, Bristol Myers Squibb, Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, BMS, Pfizer, MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:ARIAD: Consultancy, Research Funding; Briston-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Novartis: Consultancy, Research Funding; BMS: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding.

Update On Imatinib-Resistant Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) On Nilotinib Therapy at 24 Months: Clinical Response, Safety, and Long-Term Outcomes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1129-1129 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Francis J. Giles ◽  
Kapil N. Bhalla ◽  
Javier Pinilla-Ibarz ◽  
Richard A. Larson ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cytogenetic Response ◽  
Study Entry ◽  
Advisory Committees ◽  
Transcript Levels ◽  
Imatinib Resistant ◽  
Efficacy Parameters

Abstract Abstract 1129 Poster Board I-151 Background Nilotinib is a selective and potent BCR-ABL inhibitor, developed through structure-based drug design, indicated for the treatment of Philadelphia chromosome positive (Ph+) CML patients in CP or accelerated phase (AP) resistant or intolerant to prior therapy including imatinib. Recently, 24-month follow-up data from the pivotal nilotinib 2101 study demonstrated achievement of rapid and durable cytogenetic responses in the majority of patients and an excellent overall survival (OS) rate of 87%. The current update focuses on the major molecular response (BCR-ABL transcript levels ≤ 0.1% according to the international scale; MMR) of patients treated with nilotinib. Methods Imatinib-resistant and -intolerant CML-CP patients (n=321) were treated with nilotinib 400 mg twice daily and followed for at least 24 months. In this report, the efficacy parameters studied were: rate of MMR, rate of major and complete cytogenetic response (MCyR, CCyR), time to and duration of response, time to progression (TTP), and OS. Efficacy parameters were also analyzed based on the presence or absence of a CHR at study entry. Results The median duration of exposure to nilotinib was 18.7 months (< 1.0–36.5), with 62% of patients on therapy for at least 12 months and 42% on therapy for ≥ 24 months. Median dose intensity of nilotinib was 788.5 mg/day, very close to planned dosing. Overall, 58% of patients required dose interruption (defined conservatively ≥ 1 day of interruption regardless of reason) with a median cumulative duration of interruption of 20 days (4% of days of exposure). Importantly, 73% of patients that required treatment interruptions resumed treatment after interruption at the planned dose. The achievement of MMR in imatinib-resistant and -intolerant CML-CP patients who had BCR-ABL transcript levels available post-baseline (n=294) were included in this efficacy analysis (Table). Of these patients, 105/294 (36%) entered the study with a CHR and 189/294 (64%) did not have a CHR at study entry. The overall MMR rate was 28%; MMR was higher in patients with CHR at study entry (38% vs. 22%). Overall, CCyR was achieved in 46% of patients, among whom 56% achieved MMR. Median time to MMR was 5.6 months. Overall, 77% and 84% of responding patients maintained MCyR and CCyR at 24 months, respectively. Overall (n=321), the estimated rate of progression-free survival (PFS), defined as progression to AP/BC or discontinuation due to progression or death, at 24 months was 64%, however, only 9 patients (3%) progressed to AP/BC based on actual laboratory values. PFS rate at 24 months was higher for patients with baseline CHR (77%) compared with patients without CHR at study entry (56%). OS at 24 months is 87% for the entire patient population. The safety profile of nilotinib remains unchanged at 24 months of follow-up. The majority of first episodes of grade 3/4 bilirubin and lipase elevations occurred within the first month of therapy and were brief in duration (median duration 15 days). The incidences of hepatic and pancreatic disorders on nilotinib were 1.3 and 1.7 per 100-patient years of therapy and no cumulative risk of hepatic and pancreatic events was observed in this population with longer follow-up. Importantly, discontinuations due to hepatobiliary adverse events were uncommon (n=2; < 1.0%). Conclusions Nilotinib therapy led to the achievement of MMR in a majority of patients with CCyR, and in 38% of patients with CHR at study entry. Furthermore, the response and outcomes of patients treated with nilotinib was higher in patients with CHR at baseline suggesting that patients with imatinib resistance and intolerance who lost cytogenetic response but not hematologic response have a more favorable response compared to those patients who have lost hematologic response when switched to nilotinib. Overall, the safety profile of nilotinib remains well-tolerated with long-term follow-up. At 24 months, nilotinib therapy remains an effective and tolerable therapy for patients with imatinib-resistant or -intolerant CML. Disclosures Kantarjian: Novartis: Research Funding. Giles:Novartis: Consultancy, Research Funding; BMS: Research Funding; Merck: Research Funding; Clavis: Research Funding. Bhalla:Novartis: Honoraria, Research Funding; Merck: Honoraria. Pinilla-Ibarz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Larson:Novartis: Consultancy, Honoraria, Research Funding. Gattermann:Novartis, Celgene: Honoraria, Participation in Advisory Boards on deferasirox clinical trials, Research Funding. Ottmann:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Radich:Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Martinelli:Novartis: Research Funding. Kim: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; Wyeth: Research Funding. Shou:Novartis: Employment. Gallagher:Novartis: Employment, Equity Ownership. Wang:Novartis: Employment. Cortes-Franco:Novartis: Honoraria, Research Funding, Speakers Bureau; Wyeth: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. le Coutre:Novartis: Honoraria, Research Funding; BMS: Honoraria.

Monitoring By Chromosome Banding Analysis (CBA) and FISH Of Circulating CD34+ Cells In Low-Risk MDS Patients Treated In The Le-Mon-5 Study With Lenalidomide Monotherapy Reveals 82% Cytogenetic Responders With Different Response – , Evolutionary -, and Remission Patterns and No Increased Karyotype Evolution (KE)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2783-2783 ◽  
Author(s):  
Katayoon Shirneshan ◽  
Uwe Platzbecker ◽  
Florian Nolte ◽  
Aristoteles Giagounidis ◽  
Katharina Götze ◽  
...  
Keyword(s):  
Research Funding ◽  
Chromosome Banding ◽  
Karyotype Evolution ◽  
Cytogenetic Response ◽  
Fish Analysis ◽  
Clone Size ◽  
Banding Analysis ◽  
Cytogenetic Remission ◽  
Time Point

Abstract Introduction Besides a more reliable and frequent measurement of cytogenetic response, it was our aim to find out whether lenalidomide treatment in patients with IPSS low- or intermediate I-risk MDS can foster karyotype evolution (KE) and thus increase the risk of leukemic transformation. Thus, it is an important goal of the Le-Mon-5 study to examine the cytogenetic course under treatment with lenalidomide. In this study, only lower risk MDS patients with an isolated del(5q) are included. Methods We performed a rigid initial pretreatment screening of bone marrow (bm) aspirates by chromosome banding (CBA) as well as FISH-analysis to ensure an isolated del(5q). For initial screening as well as frequent cytogenetic follow-up every two to three months (FISH analysis of immunomagnetically enriched CD34+ peripheral blood cells (PBC) = CD34+ pb FISH), we used panels of 8 to 13 FISH probes covering the most common aberrations in MDS (Braulke et al. Leuk Res, 2010, 2013). Using this method we intended a reliable surveillance of cytogenetic changes occurring during therapy. Complete cytogenetic remission (CCyR) was defined as: no metaphases with del(5q) and abnormal FISH result below the laboratory threshold (5% EGR1-loss in CD34+ PBC) and partial cytogenetic remission (PCyR) was defined as: >50% reduction of clone size, also including cases with a CCyR at only one time point and those with either only CBA-CCyR or FISH-CCyR. Results From the initially screened 145 MDS patients, 84 could be included in the study according to the study inclusion criteria. Currently, follow-up data (at least 2 different time points) are available for 67 patients. An ongoing (>1 time point) CCyR was observed in 22 (33%) patients after a median follow-up of 18 (6-33) months. Thirty-three patients (49%) had a PCyR. Considering only CD34+ pb FISH results 31 (46%) patients showed a complete molecular-cytogenetic remission. A cytogenetic response was observed after a median of 6 (2-12) months after initiation of therapy for a median duration of 10 (2-25) months. In twelve patients (18%) the size of the del(5q) clone did not change. The median del(5q)-clone size at start of therapy was 60% in responders. After 10 cycles maximum clone size reduction was achieved (n=26) (median: 2.6%; range: 0% - 33.6%), after 24 months of observation clone size in responders (n=22) still was reduced to a median of 10.8% (range: 0.5% -76%) (Figure 1). In 10 of 67 patients (15%) a KE occurred in the del(5q) clone after a median time of 18 months (6-42). This is not increased compared to the rate of spontaneous KE (13%) in a representative MDS cohort (n=729) studied recently by our group by banding analysis (Cevik et al. DGHO 2013, accepted for oral presentation). Remarkably, in one patient a KE with loss of a p53 allele and a 20q- deletion resolved after the 8th cycle of lenalidomide and after the 10th cycle a complete cytogenetic remission was achieved (Figure 2). In two additional cases, the del(5q) clone was completely eliminated, however a new cell clone with independent abnormalities (t(3;3)(q21;q26), second case: inv(11)(p15q23)del(11)(q13q22)) emerged under lenalidomide. There is a growing body of evidence that these clones were preexistent initially but below the cytogenetic detection level and were possibly suppressed by the del(5q) clone until its cytogenetic remission. Conclusions Our interim results show that: Disclosures: Platzbecker: Celgene: Honoraria. Nolte:Celgene: Honoraria, Research Funding. Giagounidis:Celgene: Honoraria. Götze:Celgene Corp: Honoraria. Schlenk:Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Chugai: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Ambit: Honoraria. Bug:Celgene: Honoraria, Research Funding. Germing:Celgene: Honoraria. Haase:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Application of a Short Tandem Repeat Based PCR Assay for Chronological Monitoring of Myelodysplastic Syndrome (MDS) Patients with Deletion of Chromosome 5q Following Lenalidomide Treatment

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2891-2891 ◽  
Author(s):  
Johann-Christoph Jann ◽  
Daniel Nowak ◽  
Florian Nolte ◽  
Stephanie Fey ◽  
Verena Nowak ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Genomic Dna ◽  
Research Funding ◽  
Cytogenetic Response ◽  
Pcr Assay ◽  
Advisory Committees ◽  
Clone Size ◽  
Quantitative Correlation ◽  
Str Loci ◽  
Chromosome 5Q

Abstract Introduction Deletion of chromosome 5q (del(5q)) defines a distinct clinical subtype of myelodysplastic syndromes (MDS) and qualifies patients to specific treatment with Lenalidomide (LEN). Therefore, detection and monitoring of this deletion is an important element in routine clinical diagnostics for determining molecular response. Current methodologies for performing these analyses consist of cytogenetics, fluorescence in situ hybridization (FISH) or microarrays. All of these methods have downsides due to the high demands to the input material, i.e. viable cells or necessity for large amounts of high quality genomic DNA (gDNA). To perform quantitative assessment of cytogenetic lesions in low quantity or residual material we here present the establishment of a PCR-based assay for interrogation of del(5q) in MDS, based on the allelic loss at heterozygous short tandem repeat (STR) loci within deleted regions. Methods Genomic DNA was isolated from bone marrow (BM) and peripheral blood (PB) of n=86 MDS del(5q) patients. 49 non-del(5q) MDS patients were used as controls. Serial chronological BM samples (n=95) following treatment with LEN from n=40 del(5q) patients, who were enrolled in the LEMON-5 trial from the German MDS study group, were analysed. Using 10ng DNA, 12 fluorochrome-labelled PCR amplicons of STR loci located between chromosomal bands 5q21 and 5q31 were amplified in a single optimized multiplex-PCR reaction. Subsequently, amplicon fragment analysis was carried out via capillary electrophoresis and allele size quantification of heterozygous STR loci was performed. Finally, the degree of skewing in the allelic ratios of all informative STR markers was averaged and translated into an allelic burden of del(5q). Results Paired quantitative correlation of clone sizes using STR-PCR and interphase FISH was carried out in n=34 samples and revealed highly concordant results with r²=0.924. The diagnostic accuracy of the PCR assay was evaluated by receiver operating characteristic (ROC) analysis and revealed an area under the curve of 0.989 (sensitivity and specificity of 0.977 and 0.948, respectively). Prior to treatment with LEN, clone sizes as determined by STR-PCR were heterogeneous (mean: 57%, range: 11-91%). During follow-up analysis, while cytogenetic analyses failed (e.g. metaphase failure) in 7/40 (18%) cases, our STR-PCR assay successfully generated estimates of del(5q) cell burden in all available samples. Upon LEN treatment, n=12 patients achieved major cytogenetic remission (absence of del(5q)-positive metaphases). The mean clone size carrying del(5q) determined by STR-PCR in that group was 7% (range 3 - 10%) and significantly increased compared with n=15 patients who reached minor cytogenetic response (defined as 50% reduced aberrant metaphases, mean 13%, range 5 - 39%, p=0.025). Intriguingly none of n=6 patients without cytogenetic response achieved a del(5q) clone size of less than 35% as determined by STR-PCR (mean 46%, range 35 - 66%), highlighting the correlation of PCR based follow-up analysis with currently used cytogenetic methods for response evaluation. Finally in n=93 matched PB and BM samples a correlation of del(5q)-frequency in BM versus PB showed r²=0.81. Moreover, in 96% of samples in which the BM still showed clone sizes >10%, we reliably detected del(5q) in corresponding PB cells with a robust sensitivity of 5% deleted cells. Discussion We present a highly adaptable tool for precise measurement of large chromosomal deletions, requiring only minute amounts of genomic DNA. It shows a very good quantitative correlation with established methods and good diagnostic accuracy. Most importantly, this PCR based assay does not require dividing cells so it can be performed from PB, which shows a sufficient correlation with clone sizes in BM and rarely involves the risk of underrepresentation of del(5q)-clones in PB, possibly allowing the use of PB as a regular specimen for clone size monitoring. Thus, especially in the context of serially monitored patients this assay represents an alternative method for less invasive tracking of cytogenetically aberrant clones. Disclosures Platzbecker: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Boehringer: Research Funding. Schlenk:Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Teva: Honoraria, Research Funding; Arog: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Bug:TEVA Oncology, Astellas: Other: Travel Grant; NordMedica, Boehringer Ingelheim, Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene, Novartis: Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

scholarly journals Multicenter Phase II Trial Addressing Lenalidomide Maintenance in Patients with Relapsed Diffuse Large B-Cell Lymphoma (rDLBCL) Who Are Not Eligible for Autologous Stem Cell Transplantation (ASCT): Efficacy and Safety Results after a Median Follow-up of Five Years

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1688-1688
Author(s):  
Andres JM Ferreri ◽  
Marianna Sassone ◽  
Francesco Zaja ◽  
Alessandro Re ◽  
Michele Spina ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Salvage Therapy ◽  
Research Funding ◽  
Progressive Disease ◽  
De Novo ◽  
Phase Ii Trial ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Observation Period

Abstract Background: Lenalidomide (LENA) maintenance is associated with significantly improved outcome in patients (pts) with chemosensitive relapse of DLBCL not eligible for ASCT or experiencing relapse after ASCT. Preliminary results of a multicentre phase II trial (NCT00799513), reported after a median follow-up of 25 months, showed a 1-yr PFS of 70 ± 7% and a 1-yr OS of 81 ± 6%, with good tolerability (Ferreri AJM, et al. Lancet Haematol 2017). However, LENA was ongoing in 41% of pts at time of analysis, and late side effects and events after maintenance completion remained to be defined. Herein, we report efficacy and safety results of the trial after a median follow-up of 56 (range 27-100) months. Methods: HIV-neg pts (age ≥18 ys) with de novo or transformed DLBCL and relapsed disease responsive to conventional rituximab-containing salvage therapy were registered and treated with LENA 25 mg/day for 21 days out of 28, until lymphoma progression or unacceptable toxicity. A protocol amendment in 2015 allowed physicians to interrupt maintenance after a minimum duration of two years. Primary endpoint was 1-year PFS. Simon's two-stage optimal design was used. To demonstrate a 1-yr PFS improvement from 30% (P0) to 50% (P1), 47 pts (one-sided; α 5%; β 80%) were needed. Maintenance would be considered effective if ≥19 pts were progression-free survivors at 1 yr. Cell of origin was assessed by NanoString Technology (n=23) and Hans algorithm (n=39). Results: Between 3/2009 and 12/2015, we recruited 48 pts; 46 of them were assessable (median age 72 ys; range 34-86); 36 pts had de novo DLBCL, 10 had transformed DLBCL. All pts were previously treated with anthracycline- and rituximab-based combination, plus ASCT in 6 pts. Thirty-three pts were enrolled at 1st relapse; salvage therapy contained high doses of cytarabine or ifosfamide in two-thirds of cases, and response was complete in 26 pts and partial in 20. Most pts had unfavourable features: IPI ≥2 in 38 (83%) pts, advanced stage in 35 (76%), extranodal disease in 29 (63%), high LDH level in 21 (46%); 28 (61%) pts were older than 70 ys. Sixteen pts received ≥2 years of LENA (5 received >2 ys), 30 pts interrupted treatment due to progressive disease (PD; n= 17), toxicity (9) or pt refusal (4) (Table). LENA was well tolerated after an average of 18 courses/pt (range 3-82). With the exception of neutropenia, grade-4 toxicities occurred in <1% of courses. Infections were rare, and well controlled with oral antibiotics (grade 1-2 in 9 courses; grade 3 in 3). LENA dose reduction was indicated in 25 pts (transient in 21), and was due to neutropenia (13), rash (7), diarrhoea (3), or neurotoxicity (2). Three (6%) pts died of toxicity during maintenance (intestinal infarction, meningitis and sudden death) and two pts died due to myelodysplastic syndrome (Table). Grade 4-5 toxicity and SAEs were equally distributed according to maintenance duration (Table). At one year from trial registration, 31 pts were still progression free, which was significantly higher than the pre-determined efficacy threshold (n≥19). During the whole observation period, there were 24 events: progressive disease in 21 pts and death of toxicity in 3, with a 1-yr (primary endpoint) and 5-yr PFS of 67 ± 7% and 50 ± 7%, respectively. The duration of response to LENA was longer than response duration after the prior treatment line in 28 (61%) pts, and was twice as long in 21 (46%) of them. Twenty-six pts were disease-free at the last LENA course (Table), 22 of them remain relapse free after a median observation period from maintenance completion of 26 (8-92) months; 3 of the 4 relapses occurred in pts who received <1 yr of LENA (refusal or SAEs). The benefit of LENA was observed both in pts with de novo or transformed DLBCL. According to the Hans' algorithm, the 4-yr PFS was 50 ± 11% for GCB-DLBCL and 42 ± 11% for nonGCB-DLBCL (p= 0.58). Results using the Nanostring technique were consistent with the Hans' algorithm. Overall, 28 (61%) pts are alive, with a 1- and 5-yr OS of 80 ± 6% and 60 ± 8%, respectively. Conclusions: Long-term results of this trial soundly promotes the use of LENA maintenance in pts with chemosensitive relapse of DLBCL not eligible for ASCT or experiencing relapse after ASCT. LENA was well tolerated in this elderly population, without higher toxicity rates in pts treated for ≥2 years, and with enhanced survival figures. These results warrant further investigation of immunomodulatory drugs as maintenance in these high-risk pts. Table. Table. Disclosures Ferreri: Celgene: Research Funding. Zaja:Abbvie: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria; Janssen: Honoraria; Sandoz: Honoraria. Di Rocco:Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Rusconi:Celgene: Research Funding.

scholarly journals Spirit 2: An NCRI Randomised Study Comparing Dasatinib with Imatinib in Patients with Newly Diagnosed CML

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 517-517 ◽  
Author(s):  
Stephen G O'Brien ◽  
Corinne Hedgley ◽  
Sarah Adams ◽  
Letizia Foroni ◽  
Jane F. Apperley ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Blast Crisis ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
The Difference

Abstract Objective. SPIRIT 2 is the largest phase 3 prospective randomized open-label trial comparing imatinib 400mg with dasatinib 100mg daily: this is the first presentation of data comparing the two arms. Methods. 814 patients were recruited at 144 hospitals between August 2008 and March 2013. 812 started study medication (406 in each arm). The primary endpoint is event-free survival at 5 years. A key secondary endpoint is the rate of achievement of a BCR-ABL/ABL ratio of &lt;0.1%IS (major molecular response (MMR), 3 log reduction or MR3). Results. Discontinuations. With a median follow up of 34 months a total of 289/812 (35.6%) patients have discontinued study medication. 118/812 (14.5%) patients have discontinued due to non-haematological toxicity: imatinib 47/406 (11.6%); dasatinib 71/406 (17.5%). 40 patients discontinued due to sub optimal response as assessed by the treating physician: imatinib 37/406 (9.1%); dasatinib 3/406 (0.7%). Side effects. Patients receiving imatinib experienced GI toxicity more often than patients receiving dasatinib; fatigue, rash and headache were more common with dasatinib. A higher rate of grade 3/4 thrombocytopenia was observed in the dasatinib arm: imatinib 17/406 (4.2%); dasatinib 52/406 (12.8%). Pleural effusions occurred in 78/406 (19.2%) patients on dasatinib; 13 of 78 (16.7%) patients required drainage. Arterial cardiovascular events (excluding hypertension) were experienced by 10/812 (1.2%) patients: imatinib 2/406 (0.5%; myocardial infarction (MI) x2); dasatinib 8/406 (2.0%; MI x1; angina/acute coronary syndrome x5; peripheral arterial disease x2). Hypertension was observed in 10/812 (1.2%) patients: imatinib 3/406 (0.7%); dasatinib 7/406 (1.7%). Venous CV events occurred in 7/812 (0.9%) patients: imatinib 3/406 (0.7%); dasatinib 4/406 (1.0%).Efficacy.For both PCR and cytogenetic analyses patients that had discontinued their allocated therapy or that did not have a 12 month sample were analysed as not having achieved MR3/CCR. The MR3 (PCR &lt;0.1% IS) rate at 12 months in all treated patients is significantly different (p&lt;0.001) between the two treatment arms: imatinib 173/406 (42.6%); dasatinib 236/406 (58.1%). The MR3 rate at 12 months in patients treated with dasatinib is 51/78 (65.4%) in those with a pleural effusion and 185/328 (56.4%) in those without (p=0.148, NS).The complete cytogenetic response (CCR) rate at 12 months is: imatinib 163/406 (40.1%); dasatinib 207/406 (51.0%). The difference between the two treatment arms is statistically significant (p=0.002) but caution is required in interpreting these data as there were missing analyses in 367 of 812 (45.2%) patients: imatinib 191 of 406 (47.0%), dasatinib 176 of 406 (43.3%). The difference in major cytogenetic response (MCR) rate between the two treatment arms at 12 months is not statistically significant: imatinib 200/406 (49.3%); dasatinib 218/406 (53.7%), p=0.206.Disease progression and deaths. 16 patients have progressed to either accelerated phase or blast crisis and 13 of those progressions were within the first year. Accelerated phase: imatinib 3/406 (0.7%); dasatinib 2/406 (0.5%). Blast crisis: imatinib 7/406 (1.7%); dasatinib 4/406 (1.0%). Conclusions. Dasatinib-treated patients have a higher rate of molecular response at 1 year but, with a median of 34 months follow up, there is no significant difference in rates of disease progression or overall survival. More patients abandoned imatinib than dasatinib due to investigator concerns about sub optimal responses. Further follow up is required to evaluate whether there will be differences in event free survival at five years. Disclosures O'Brien: Ariad: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Hedgley:BMS: Research Funding; ARIAD: Research Funding. Adams:BMS: Research Funding. Apperley:Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Speakers Bureau; 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. Holyoake:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: 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. Byrne:BMS: Honoraria; Novartis: Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy. Osborne:ARIAD: Research Funding. Copland:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria. Clark:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Honoraria, Research Funding.

Bosutinib As Therapy for Chronic Phase Chronic Myeloid Leukemia Following Resistance or Intolerance to Imatinib: 36-Month Minimum Follow-up Update

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3779-3779 ◽  
Author(s):  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Dong-Wook Kim ◽  
Anna G Turkina ◽  
Zhi-Xiang Shen ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Baseline Assessment ◽  
Advisory Committees ◽  
Abl Kinase ◽  
Grade 3

Abstract Abstract 3779 Bosutinib (BOS) is an oral, dual Src/Abl kinase inhibitor with minimal inhibitory activity against PDGFR or c-KIT. This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following imatinib resistance (IM-R) or intolerance (IM-I). Pts aged ≥18 y with IM-R (n = 195) or IM-I (n = 91) CP CML received oral BOS 500 mg/d. Of 286 pts, 53% were male, median age was 53 y (range, 18–91 y), and median time from CML diagnosis was 3.7 y (range, 0.1–15.1 y). Median treatment duration was 24.6 mo (range, 0.2–72.3 mo); median BOS dose intensity was 443 mg/d (range, 61–600 mg/d); 12% of pts received dose escalation to BOS 600 mg/d. Minimum time from last enrolled pt's first dose was 38 mo; 42% of pts are still receiving BOS. A confirmed complete hematologic response (CHR) was attained/maintained by 167/194 (86%) IM-R and 77/91 (85%) IM-I pts with a valid baseline assessment; Kaplan-Meier (KM)–estimated probabilities of maintaining a CHR at 3 y were 65% and 83%. A major cytogenetic response (MCyR) was attained/maintained by 106/182 (58%) IM-R and 49/82 (60%) IM-I pts with a valid baseline assessment. A complete cytogenetic response (CCyR) was attained/maintained by 88/182 (48%) and 42/82 (51%) evaluable pts. Among evaluable pts without a CCyR at baseline, 101/177 (57%) IM-R and 39/71 (55%) IM-I pts achieved a MCyR including 83 (47%) IM-R and 33 (47%) IM-I pts who achieved a CCyR. The KM-estimated probability of maintaining a MCyR at 3 y was 71% for IM-R and 88% for IM-I pts. Of 210 pts with baseline mutation status assessed, 78 (37%) pts had 42 unique Bcr-Abl kinase domain mutations (P loop, 9% of pts; non-P loop, 30% of pts), including 9 (4%) pts with the T315I mutation. Responses to BOS were seen across different Bcr-Abl baseline mutations, including those associated with resistance to other TKIs, but were low (22% for both CHR and MCyR) among pts with T315I. When pts with T315I at baseline were excluded, response rates for the remaining pts with ≥1 mutation were 93% for CHR and 62% for MCyR. Eighteen of 68 pts evaluated at baseline and treatment discontinuation had ≥1 new Bcr-Abl mutation (T315I, n = 8; V299L, n = 3; E255V, E450A, E450G, G250E, K378E, L273M, and M244V, n = 1 each); 15 of these 18 pts had discontinued due to disease progression or lack of efficacy. On-treatment transformation to accelerated or blast phase CML occurred in 10 (5%) IM-R and 2 (2%) IM-I pts. KM-estimated on-treatment progression-free survival (PFS) at 3 y was 72% for IM-R pts and 89% for IM-I pts. KM-estimated overall survival (OS) at 2 y was 88% for IM-R and 98% for IM-I pts (3-y OS not provided as results may be unreliable since per study protocol pts were followed for OS for only 2 y after BOS discontinuation). There were 34 (12%) deaths on study, with 5 deaths occurring within 30 d of the last BOS dose. Most deaths were due to disease progression (n = 17 [6%]) or an adverse event (AE) unrelated to BOS (n = 12 [4%]); only 1 treatment-related death occurred (due to febrile neutropenia 78 d after the last BOS dose in the IM-R group). Four additional deaths were due to unknown causes ≥136 d after the last BOS dose. The most frequent non-hematologic treatment-emergent AEs (TEAEs; all grades/grade 3/4) were diarrhea (85%/10%), nausea (46%/1%), vomiting (37%/4%), rash (36%/9%), pyrexia (26%/1%), abdominal pain (25%/1%), and fatigue (25%/1%). Diarrhea was predominantly grade 1/2 in severity, had an early onset (median time to first event of 2 d [range, 1–1,330 d]), and was typically transient (median event duration of 1 d [range, 1–830 d]). Grade 3/4 on-treatment hematologic and non-hematologic lab abnormalities in ≥10% of pts included thrombocytopenia (25%), neutropenia (18%), lymphocytopenia (16%), anemia (14%), hypermagnesemia (11%), alanine transaminase elevation (11%), and hypophosphatemia (10%). Toxicities were manageable with medications and/or BOS dose modification; 45% of IM-R and 57% of IM-I pts had ≥1 dose reduction, and 66% of IM-R and 84% of IM-I pts had ≥1 dose interruption. AEs led to BOS discontinuation in 32 (16%) IM-R and 37 (41%) IM-I pts; the most common reason was thrombocytopenia. Overall, the rates of TEAEs and BOS discontinuation due to AEs showed little increase from the prior 24-mo analysis. In conclusion, BOS therapy continues to demonstrate durable efficacy and manageable toxicity in pts with CP CML following IM-R or IM-I after a minimum of 36 mo of follow-up, emphasizing the therapeutic potential of BOS in this population. Disclosures: Cortes: Novartis, Bristol Myer Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding. Kantarjian:Pfizer Inc: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Turkina: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, Speakers Bureau. Brümmendorf:Bristol Myer Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Patent on the use of imatinib and hypusination: Patents & Royalties. Schafhausen:Bristol Myers Squibb, Novartis, Pfizer: Consultancy, Honoraria. Porkka:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Besson:Pfizer Inc: Employment. Gambacorti-Passerini:Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy.

Sign in / Sign up

Export Citation Format

Share Document