scholarly journals Genomic Mechanisms of 17p / TP53 Loss in Primary “ultra High-risk” and Refractory Chronic Lymphocytic Leukemia: Results from the CLL2O Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2184-2184
Author(s):  
Veronica Teleanu ◽  
Jennifer Edelmann ◽  
Claudia Haferlach ◽  
Stefan Ibach ◽  
Eugen Tausch ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Lymphocytic Leukemia ◽  
Chromosome 17 ◽  
Tp53 Mutations ◽  
Ultra High Risk ◽  
Treatment Naïve ◽  
Donor Chromosome

Abstract Background: Unraveling the cytogenetic background helped to decipher the molecular basis of many hematologic cancers and to develop specific therapies. Recently, using chromosome banding analysis (CBA), jumping translocations were identified as a cause of 17p loss in multiple myeloma, providing new insights into the origin of clonal evolution and copy number alterations (CNA) (Sawyer et al, Blood 2014). In chronic lymphocytic leukemia (CLL) the genomic mechanisms leading to 17p loss are not fully understood. Aims: Characterization of underlying mechanisms of 17p loss using CBA and correlation with other clinicobiological features in “ultra high-risk” CLL. Methods: Samples from 112 patients (pts.) with refractory and/or 17p- CLL enrolled in the multicenter CLL2O trial were screened for CNAs by Affymetrix 6.0 SNP array analysis of CD19 sorted CLL cells and for chromosomal abnormalities by CBA using CpG oligonucleotide and interleukin-2 stimulation. Results: Considering both CBA and SNP data, 728 aberrations resulted in a mean of 6.5/case. 89 (79%) pts. had 17p deletion and 83 (74%) TP53 mutation. Regarding the origin of 17p/TP53 loss, 6 distinct types of rearrangements could be delineated: 1) whole arm translocations (WAT) 2) jumping translocations (JT) 3) dicentric chromosomes (DC) 4) cytogenetically balanced translocations (CBT) 5) other unbalanced translocations and 6) interstitial 17p deletions. WAT were identified in 33/112 (30%) cases and 30/33 (91%) involved chromosome 17 leading to 17p loss. Chromosomes involved ≥ 2 times in an unbalanced WAT were der(17;18)(q10;q10) (8, 24%), der(8;17)(q10;q10) (5, 15%), der(15;17)(q10;q10) (4, 12%), i(17)(q10) (4, 12 %), der(17;22)(q10;q10) (2, 6%). JT were identified in 11 (10 %) cases, 6 showing jumping WAT with 17q as donor chromosome, 1 case with breakpoints located in the pericentromeric regions of chromosome 17p11 (donor chromosome) and the receptor chromosomes 4p14 and 16p11. In 4 cases, initially a WAT involving 17q occurred and subsequently the partner chromosome “jumped off” leaving a 17p deletion behind. DC were detected in 19 pts., 8 with breakpoint in 17p11, 7/8 with TP53 mutation. Of note, all cases had the breakpoint on chromosome 17 in 17p11 indicating a fragile site affecting the pericentromeric region. Interestingly, of a total of 382 translocations observed by CBA, only 32 were CBT and except for those involving the IGH and IGK/L loci (n=6) all were random. 17p involvement in CBT was detected in 4 cases, 3 had TP53 deletion and all were TP53 mutated. Of the unbalanced translocations, der(17)t(8;17) was identified in 5 pts. simultaneously generating 8q gain. Nevertheless, breakpoints on chromosome 17p covered cytobands 17p11-13 and on chromosome 8, 8q11-22, one case having the breakpoint telomeric to the TP53 locus and no TP53 mutation, pointing to other putative candidate genes on 17p. In 36/112 (32%) cases, 17p deletion was induced by random rearrangements. Interstitial 17p deletions were identified in only 9/112 (8 %) cases. According to the inclusion criteria of the trial, 36/112 (32%) pts. had 17p deletion and were treatment-naïve while 76/112 (68%) were relapsed or refractory to fludarabine or bendamustine based therapy, 53/76 (70%) having a 17p deletion. Treatment naïve pts. had a mean of 7.36 aberrations/case and pretreated pts. 6.09/case. Focusing on WAT and JT, 18/33 (54%) pts. with WAT and 7/11 (63%) pts. with JT were pretreated whereas 57/78 (73%) pts. in the other cytogenetic subgroups had prior therapy exposure. Considering other genomic features, WAT and JT occurred almost exclusively within complex karyotypes (≥3 chromosomal aberrations), 31/33 WAT and 10/11 JT, were IGHV unmutated, 30/33 WAT and 11/11 JT and harbored TP53mutations, 29/33 WAT and 10/11 JT. Conclusions: “Ultra high-risk” CLL pts. are characterized by a high genomic complexity as compared to standard risk treatment-naïve CLL pts. (CLL8 trial with 1.8 CNAs/case). Previous genotoxic therapy had no influence on the total number of aberrations or the underlying mechanism, suggesting an intrinsic genomic instability of the tumor cells with TP53 alterations. WAT and JT emerged as nonrandom aberrations involved in 17p loss. Given the strong association of TP53 deletion with TP53 mutations of the remaining allele, one may speculate that TP53 mutations precedes TP53 deletion by disrupting the normal DNA repair mechanisms permitting incorrect recombinations. Disclosures Stilgenbauer: Amgen: Honoraria, Research Funding; Genzyme: Honoraria, Research Funding.

Understanding and Managing Ultra High-Risk Chronic Lymphocytic Leukemia

Hematology ◽  
2010 ◽  
Vol 2010 (1) ◽  
pp. 481-488 ◽  
Author(s):  
Stephan Stilgenbauer ◽  
Thorsten Zenz
Keyword(s):  
Clinical Trials ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Tp53 Mutation ◽  
Poor Response ◽  
Lymphocytic Leukemia ◽  
Prognostic Models ◽  
Survival Times ◽  
Treatment Approaches ◽  
Ultra High Risk

AbstractModern treatment approaches such as chemoimmunotherapy (e.g., fludarabine/cyclophosphamide/rituximab or FCR) are highly effective in the majority of chronic lymphocytic leukemia (CLL) patients. However, there remains a small but challenging subgroup of patients who show ultra high-risk genetics (17p deletion, TP53 mutation) and/or poor response to chemoimmunotherapy. The median life expectancy of these patients is below 2 to 3 years with standard regimens. Accordingly, CLL with the 17p deletion (and likely also with sole TP53 mutation) should be treated with alternative strategies. While p53 defects appear to play a central role in our understanding of this ultra high-risk group, at least half of the cases will not be predictable based on existing prognostic models. Current treatment approaches for patients with p53 defects or poor response to chemoimmunotherapy should rely on agents acting independently of p53, such as alemtuzumab, lenalidomide, flavopiridol, and a growing number of novel compounds (or combinations thereof) currently available in clinical trials. Poor survival times of patients with ultra high-risk CLL suggest that eligible patients should be offered consolidation with reduced-intensity allogeneic stem-cell transplantation or experimental approaches in clinical trials.

scholarly journals High Resolution Genomic Profiling of Primary “Ultra High Risk” and Refractory Chronic Lymphocytic Leukemia: Results from the CLL2O Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3288-3288
Author(s):  
Jennifer Edelmann ◽  
Jenny Saub ◽  
Stefan Ibach ◽  
Karlheinz Holzmann ◽  
Eugen Tausch ◽  
...  
Keyword(s):  
High Risk ◽  
Dna Damage Response ◽  
Tp53 Mutation ◽  
Lymphocytic Leukemia ◽  
Prior Therapy ◽  
Genomic Complexity ◽  
Previous Therapy ◽  
Damage Response ◽  
Ultra High Risk ◽  
Treatment Naïve

Abstract Introduction: “Ultra high-risk” chronic lymphocytic leukemia (CLL) can be defined by TP53 loss and/or mutation, and refractory or early relapsing disease after intense chemo(immuno)therapy. Since its pathogenic mechanisms are not fully understood and TP53 alteration is only found in approx. half of the cases, it was our aim to identify novel genetic alterations that might contribute to the pathogenesis of “Ultra high-risk CLL”. Methods: We screened 112 samples [36 treatment naïve patients with del(17p), 26 with del(17p) at relapse, and 50 refractory to purine analogue-based therapy] from the CLL2O trial of the GCLLSG by Affymetrix® 6.0 single nucleotide polymorphism (SNP) arrays [N=79 paired to intraindividual reference DNA, N=33 unpaired]. Results: In total, 663 copy number alterations (CNA) were detected corresponding to a mean of 5.9 CNAs per case [6.0 paired, 5.7 unpaired]. Compared to an unselected CLL cohort at time of first treatment this number was strikingly high [CLL8 trial: 1.8 CNAs per case]. The most frequent aberrations, apart from the well established ones, were: +(8)(q24.21) [15%], del(8p) [14%], del(18p) [14%], del(10)(q24.32) [12%], del(15)(q15.1) [11%], del(6)(q21) [10%], del(3)(p26.1-p25.3) [10%], del(9)(p21.3) [10%], del(3)(p21.31) [9%], +(2)(p16.1-p15) [8%], del(4)(p15.2-p15.1), del(9)(q13 q21) [8%]. The high number of CNAs per case was associated with alterations in DNA damage response (DDR) genes. Patients with both del(17p) and TP53 mutation [N=80] had a mean of 6.4 CNAs, whilst del(17p) cases without TP53 mutation had 4.7 [N=7]. Cases without TP53 alteration [N=20] had a CNA score of 4.4. Apart from TP53, we found that loss of three other components of the DDR pathway, ATM, RAD18 and SMC5, had impact on the CNA score. In particular, in del(17p) / TP53 mutated cases [N=80], the number of CNAs per case was further increased by a loss of one of the genes: ATM 8.8 CNAs per case [del(11)(q22.3), N=8]; RAD18 9.8 CNAs per case [del(3)(p26.1-p25.3), N=9]; SMC5 10.0 CNAs per case [del(9)(q13 q21), N=7]. Within the group with no TP53 alteration [N=20], cases without ATM, RAD18 or SMC5 loss [N=9] had a mean value of only 2.0 CNAs per case. Frequent occurrence of discontinuous lesions [N=168 in 71 cases] implicated a high frequency of chromothripsis. Referring to its definition of 10 switches between 2 or more copy number states, chromothripsis was found in 11 cases [10%]. With a cut point of ≥ 5 switches, 37 cases were affected [33%]. Chromothripsis further increased the mean number of CNAs per case [≥ 10 switches: 9.6 vs. 5.5 CNAs per case; ≥5 switches: 8.8 vs. 4.7 CNAs per case]. Interestingly, prior therapy was not associated with an increased number of CNAs in this cohort [7.3 CNAs per case in treatment-naïve cases, 5.4 in refractory and 6.0 in relapsed cases]. The number of prior chemotherapy lines did not have impact on genomic complexity [1 line (N=23): 5.8 CNAs; 2 (N=16): 4.6 CNAs; 3 (N=15): 4.4 CNAs; ≥ 4 (N=22): 5.7 CNAs). This did also apply to the group of del(17)(p13) / TP53 mutated cases without loss of ATM, RAD18 or SMC5 [N=62] [no previous therapy (N=22): 7.4 CNAs; 1 or 2 previous therapy lines (N=20): 4.7 CNAs; ≥ 3 (N=20): 4.6]. Neither genomic complexity (> 3 CNAs per case) nor chromothripsis had any impact on the clinical outcome. We hypothesised whether the recurrent lesions mentioned above are associated with the refractory nature of the disease. Clinical significance tests revealed that only del(9)(p21.3) encompassing the CDKN2A/CDKN2B gene locus and +(8)(q24.21) had significant impact on the clinical outcome [del(9)(p21.3): shorter OS (p=0.038), tendency to shorter PFS (p=0.12); +(8)(q24.21): shorter PFS (p=0.0016), tendency to shorter OS (p=0.064), inferior response (p=0.0079)]. Results for +(8)(q24.21) were in line with an accumulation of cases with 8q gain in the group of refractory [16%, N=8 of 50] and relapsed cases [23%, N=6 of 26]. The minimally amplified region on 8q24.21 [16.6 kb] could be delineated to a region previously linked to the enhancement of MYC expression. Conclusion: The majority of “ultra high-risk” CLL showed high genomic complexity. Alteration of genes involved in DNA damage response [TP53, ATM, RAD18, SMC5] and chromothripsis increased the number of aberrations per case, while, somewhat surprisingly, prior therapy did not. Prognostic impact of additional genomic lesions can be suggested for +(8)(q24.21) [MYC] and del(9)(p21.3) [CDKN2A/CDKN2B]. Disclosures Leblond: Roche: Honoraria, Speakers Bureau. Gribben:Celgene: Research Funding; Pharmacyclics: Honoraria; Roche: Honoraria. Stilgenbauer:Pharmacyclics, Janssen: Honoraria, Research Funding.

scholarly journals Mechanisms of Adaptation to Ibrutinib in High Risk Chronic Lymphocytic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 585-585 ◽  
Author(s):  
Valeria Spina ◽  
Gabriela Forestieri ◽  
Antonella Zucchetto ◽  
Alessio Bruscaggin ◽  
Tamara Bittolo ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Nuclear Localization ◽  
Peripheral Blood ◽  
Research Funding ◽  
Clonal Evolution ◽  
Lymphocytic Leukemia ◽  
Adaptation Process ◽  
Over Time ◽  
Stimulation Of

Abstract Introduction. Ibrutinib inhibits the BTK molecule downstream the B-cell receptor (BCR). Though highly active in high risk chronic lymphocytic leukemia (CLL), the most typical response achievable in patients is a minimal residual disease (MRD) positive partial remission (PR) which is maintained until the development of genetically driven resistance caused by the acquisition of mutations in the BTK or PLCG2 genes. The study aims at characterizing the adaptation process allowing residual CLL cells to persist despite BTK inhibition. Methods. The IOSI-EMA-001 study (NCT02827617) is an observational study consisting in the prospective and longitudinal collection of peripheral blood samples and clinical data from high risk CLL patients treated with ibrutinib. Peripheral blood CLL cells longitudinally drawn from patients before treatment start and at fixed timepoints under ibrutinib were monitored by: i) next generation flow cytometry approaches for changes in proliferation rate, surfaceome, and pathway activation; and ii) CAPP-seq targeted deep next generation (sensitivity ~10-3) for clonal evolution. Results. The study cohort comprised 31 high risk CLL patients, including 15 treatment naïve, 16 relapsed, 80% IGHV unmutated, 42% 17p deleted and 55% TP53 mutated. Median duration of ibrutinib treatment was 45 weeks (24-72 weeks). All patients obtained a MRD positive PR that was maintained in all but one who progressed with a PLCG2 mutation (VAF 3%). Compared to baseline, under ibrutinib therapy CLL cells slowed down their proliferation, as suggested by the decreased expression of Ki-67, the reduction of the proliferating fraction (CXCR4dimCD5bright), and the increase of the resting fraction (CXCR4brightCD5dim). Compared to baseline, under ibrutinib therapy CLL cells also upregulated BCR and adhesion/homing proteins, and decreased the expression of BCR inhibitor proteins. Upon stimulation of the BCR with anti-IgM, the downstream path through pBTK and pPLCG2 was inhibited by ibrutinib, while conversely the downstream path through pAKT and pERK was still inducible throughout all the assessed timepoints. The proportion of CLL cells harboring nuclear localization of NF-kB progressively increased over time under ibrutinib. NF-kB nuclear localization was inducible throughout all the assessed timepoints by CD40L stimulation of the non-canonical NF-kB pathway, but not by anti-IgM stimulation of the BCR/canonical NF-kB pathway. Overall, 880 individual mutations were longitudinally discovered and monitored across a total of 121 sequential timepoints collected during ibrutinib treatment. Clonal evolution was observed in (67.7%) cases, a proportion rate previously documented in CLL treated with chemoimmunotherapy. Clonal evolution appeared to be heterogeneous involving different genes without a stereotypic targeting. Consistently, none of the main driver gene mutations was homogeneously selected or suppressed by ibrutinib suggesting that the biological adaptation of CLL cells under ibrutinib is not genetically driven. Clonal evolution propensity was not associated with any of the biomarkers of the disease, and it did not decrease over time under ibrutinib. Conclusions. Taken together these results suggest that residual CLL cells persisting under ibrutinib therapy adapt their phenotype by upregulating adhesion molecules, chemokine receptors and BCR molecules, and by maintaining a competence of BCR signaling through the PI3K/AKT/ERK pathway. The progressive selection of CLL cells having NF-kB in the nucleus, likely due to the BTK independent non-canonical NF-kB pathway, might explain their survival despite ibrutinib therapy. Finally, clonal evolution is not suppressed by ibrutinib chemotherapy, and despite does not seem to be directly involved in such adaptation process, may ultimately favor the acquisition of BTK and PLCG2 ibrutinib resistance mutations. Disclosures Zucca: Celltrion: Consultancy; AstraZeneca: Consultancy. Ghia:Sunesis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie, Inc: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding. Montillo:Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding. Tedeschi:Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy; AbbVie: Consultancy. Gaidano:AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Morphosys: Honoraria; Roche: Consultancy, Honoraria.

scholarly journals Prognostic Impact of NOTCH1 Hotspot Mutation in TP53-Mutated Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3283-3283
Author(s):  
Barbara Kantorova ◽  
Jitka Malcikova ◽  
Veronika Navrkalova ◽  
Jana Smardova ◽  
Kamila Brazdilova ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Tp53 Mutation ◽  
Direct Sequencing ◽  
Lymphocytic Leukemia ◽  
The Other ◽  
Wild Type ◽  
Tp53 Mutations ◽  
Time To First Treatment ◽  
Hotspot Mutation

Abstract Introduction A presence of activating mutations in NOTCH1 gene has been recently associated with reduced survival and chemo-immunotherapy resistance in chronic lymphocytic leukemia (CLL). However, a prognostic significance of the NOTCH1 mutations with respect to TP53mutation status has not been fully explained yet. Methods An examined cohort included 409 patients with CLL enriched for high risk cases; in 121 patients consecutive samples were investigated. To determine the TP53 mutation status, a functional analysis of separated alleles in yeast (FASAY, exons 4-10) combined with direct sequencing was performed; the ambiguous cases were retested using an ultra-deep next generation sequencing (MiSeq platform; Illumina). The presence of NOTCH1 hotspot mutation (c.7544_7545delCT) was analyzed using direct sequencing complemented by allele-specific PCR in the selected samples. In several patients harboring concurrent NOTCH1 and TP53 mutations, single separated cancer cells were examined using multiplex PCR followed by direct sequencing. A correlation between mutation presence and patient overall survival, time to first treatment and other molecular and cytogenetic prognostic markers was assessed using Log-rank (Mantel-cox) test and Fisher's exact test, respectively. Results The NOTCH1 and TP53 mutations were detected in 16% (65/409) and 27% (110/409) of the examined patients, respectively; a coexistence of these mutations in the same blood samples was observed in 11% (19/175) of the mutated patients. The detected increased mutation frequency attributes to more unfavorable profile of the analyzed cohort; in the TP53-mutated patients missense substitutions predominated (75% of TP53 mutations). As expected, a significantly reduced overall survival in comparison to the wild-type cases (147 months) was observed in the NOTCH1-mutated (115 months; P = 0.0018), TP53-mutated (79 months; P < 0.0001) and NOTCH1-TP53-mutated patients (101 months; P = 0.0282). Since both NOTCH1 and TP53 mutations were strongly associated with an unmutated IGHV gene status (P < 0.0001 and P = 0.0007), we reanalyzed the IGHV-unmutated patients only and interestingly, the impact of simultaneous NOTCH1 and TP53 mutation presence on patient survival was missed in this case (P = 0.1478). On the other hand, in the NOTCH1 and/or TP53-mutated patients significantly reduced time to first treatment was identified as compared to the wild-type cases (41 months vs. 25 months in NOTCH1-mutated, P = 0.0075; 17 months in TP53-mutated, P < 0.0001; and 18 months in NOTCH1-TP53-mutated patients, P = 0.0003). The similar results were observed also in the subgroup of the IGHV-unmutated patients, with the exception of patients carrying sole NOTCH1 mutation (P = 0.2969). Moreover, in the NOTCH1-TP53-mutated patients an increased frequency of del(17p)(13.1) was found in comparison to the TP53-mutated patients only (72% vs. 56%); this cytogenetic defect was not detected in the patients with sole NOTCH1 mutation. Our results might indicate, that NOTCH1 mutation could preferentially co-selected with particular, less prognostic negative type of TP53 defects. Notably, in our cohort the NOTCH1 mutation predominated in the patients harboring truncating TP53 mutations localized in a C-terminal part of the TP53 gene behind the DNA-binding domain (P = 0.0128). Moreover, in one of the NOTCH1-TP53-mutated patients the analysis of separated cancer cells revealed a simultaneous presence of NOTCH1 mutation and TP53 in-frame deletion in the same CLL cell. In contrast, in the other examined NOTCH1-TP53-mutated patient the concurrent NOTCH1 mutation and TP53 missense substitution (with presumed negative impact on patient prognosis) were found in different CLL cells. Conclusions The parallel presence of NOTCH1 hotspot mutation might be detected in a significant proportion of TP53-mutated patients and it seems to be associated with less prognostic unfavorable TP53 mutations. Nevertheless, these preliminary data should be further confirmed in a large cohort of patients. This study was supported by projects VaVPI MSMT CR CZ.1.05/1.1.00/02.0068 of CEITEC, IGA MZ CR NT13493-4/2012, NT13519-4/2012 and CZ.1.07/2.3.00/30.0009. Disclosures Brychtova: Roche: Travel grants Other. Doubek:Roche: Travel grants Other.

scholarly journals Dose-Adjusted EPOCH and Rituximab (DA-EPOCH-R) Treatment in Dual Expressor Diffuse Large B-Cell and Double/Triple Hit Lymphomas: TP53 Mutations Influence on Clinical Outcome

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4116-4116
Author(s):  
Anna Dodero ◽  
Anna Guidetti ◽  
Fabrizio Marino ◽  
Cristiana Carniti ◽  
Stefania Banfi ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Poor Prognosis ◽  
Tp53 Mutation ◽  
Advisory Committees ◽  
Tp53 Mutations ◽  
Travel Costs ◽  
Large B Cell

Introduction: Diffuse Large B-Cell Lymphoma (DLBCL) is an heterogeneous disease: 30-40% of cases have high expression of MYC and BCL2 proteins (Dual Expressor, DE) and 5-10% have chromosomal rearrangements involving MYC, BCL2 and/or BCL6 (Double-/ Triple-Hit, DH/TH). Although the optimal treatment for those high-risk lymphomas remains undefined, DA-EPOCH-R produces durable remission with acceptable toxicity (Dunleauvy K, Lancet 2018). TP53 mutation is an independent marker of poor prognosis in patients (pts) with DLBCL treated with R-CHOP therapy. However, its prognostic value in poor prognosis lymphomas, receiving intensive therapy, has not been investigated yet. Methods: A series of consecutive pts (n=87) with biopsy proven diagnosis of DE DLBCL (MYC expression ≥40% and BCL2 expression ≥ 50% of tumor cells) or DE-Single Hit (DE-SH, i.e., DE-DLBCL with a single rearrangement of either MYC, BCL2 or BCL6 oncogenes) or DE-DH/TH (MYC, BCL2 and/or BCL6 rearrangements obtained by FISH) were treated with 6 cycles of DA-EPOCH-R and central nervous system (CNS) prophylaxis consisting of two courses of high-dose intravenous Methotrexate. Additional eligibility criteria included age ≥18 years and adequate organ functions. Cell of origin (COO) was defined according to Hans algorithm [germinal center B cell like (GCB) and non GCB)]. TP3 mutations were evaluated by next generation sequencing (NGS) based on AmpliseqTM technology or Sanger sequencing and considered positive when a variant allelic frequency ≥10% was detected. Results: Eighty-seven pts were included [n=36 DE only, n=32 DE-SH (n=8 MYC, n=10 BCL2, n=14 BCL6), n=19 DE-DH/TH] with 40 patients (46%) showing a non GCB COO. Pts had a median age of 59 years (range, 24-79 years). Seventy-three pts (84%) had advanced disease and 44 (50%) an high-intermediate/high-risk score as defined by International Prognostic Index (IPI). Only 8 of 87 pts (9%) were consolidated in first clinical remission with autologous stem cell transplantation following DA-EPOCH-R. After a median follow-up of 24 months, 73 are alive (84%) and 14 died [n=12 disease (n=2 CNS disease); n=1 pneumonia; n=1 suicide]. The 2-year PFS and OS were 71% (95%CI, 60-80%) and 76% (95%CI, 61%-85%) for the entire population. For those with IPI 3-5 the PFS and OS were not significant different for DE and DE-SH pts versus DE-DH/TH pts [64% vs 57% p=0.77); 78% vs 57% p=0.12)]. The COO did not influence the outcome for DE only and DE-SH [PFS: 78% vs 71% (p=0.71); 92% vs 86% (p=0.16) for GCB vs non -GCB, respectively]. Fourty-six pts (53%;n=18 DE only, n=18 DE-SH, n=10 DE-DH/TH ) were evaluated for TP53 mutations with 11 pts (24%) carrying a clonal mutation (n=6 in DE, n=3 in DE-SH, n=2 in DE-DH/TH). The 2-year PFS and OS did not significantly change for pts DE and DE-SH TP53 wild type as compared to DE and DE-SH mutated [PFS: 84 % vs 77%, (p=0.45); OS: 87% vs 88%, (p=0.92)]. The two pts DE-DH/TH with TP53 mutation are alive and in complete remission.Conclusions: High risk DLBCL pts treated with DA-EPOCH-R have a favourable outcome independently from high IPI score, DE-SH and DE-DH/TH. Also the presence of TP53 mutations does not negatively affect the outcome of pts treated with this intensive regimen. The efficacy of DA-EPOCH-R in overcoming poor prognostic genetic features in DLBCL should be confirmed in a larger prospective clinical trial. Disclosures Rossi: Daiichi-Sankyo: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria. Carlo-Stella:Takeda: Other: Travel, accommodations; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; MSD: Honoraria; BMS: Honoraria; Genenta Science srl: Consultancy; Janssen: Other: Travel, accommodations; Servier: Consultancy, Honoraria, Other: Travel, accommodations; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy. Corradini:AbbVie: Consultancy, Honoraria, Other: Travel Costs; KiowaKirin: Honoraria; Gilead: Honoraria, Other: Travel Costs; Amgen: Honoraria; Celgene: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Travel Costs; Servier: Honoraria; BMS: Other: Travel Costs.

Disruption of TP53 function by Point Mutations and Deletions Is Associated with An Increased Risk of Disease Progression within Previously Treated, Relapsed Chronic Lymphocytic Leukemia Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2445-2445
Author(s):  
Annika Dufour ◽  
Stefan K Bohlander ◽  
Evelyn Zellmeier ◽  
Gudrun Mellert ◽  
Karsten Spiekermann ◽  
...  
Keyword(s):  
Disease Progression ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Lymphocytic Leukemia ◽  
Dominant Negative ◽  
Tp53 Mutations ◽  
Mutational Status ◽  
Igvh Mutational Status ◽  
Binet Stage ◽  
Previously Treated

Abstract Abstract 2445 Chronic lymphocytic leukemia (CLL) patients with a deletion of the TP53 tumor supressor gene located at 17p13 have a poor prognosis in first line chemotherapy regimens. Recent studies indicated somatic TP53 mutations as a prognostic factor in CLL independent of 17p13 deletion status. We aimed to further characterize the prognostic value and the impact of TP53 mutations on progression-free survival (PFS) in the presence and absence of a 17p13 deletion in previously treated and relapsed CLL patients within an international phase III clinical study comparing Fludarabine and Cyclophosphamide with or without Rituximab (FC versus R-FC: REACH trial). We analyzed 457 patients at diagnosis for mutations in the TP53 gene using a combination of a microarray-based resequencing assay (AmpliChip p53 Test, Roche Molecular Systems, USA.) and Sanger sequencing of TP53 exons 2–10. The data were correlated with clinical and biologic markers as well as with interphase fluorescence in situ hybridization (FISH) and with PFS. Association of the clinical data with PFS was assessed by Cox proportional hazard models. To estimate the functional significance of the individual TP53 mutations we used the IARC TP53 database. TP53 mutations (n=60) were detected in 52 of 457 patients (11.4%) and included 42 missense, 4 nonsense, 8 frameshift mutations, 2 in-frame deletions and 4 mutations in splice sites. Among other clinical variables, only 17p13 deletion was associated with TP53 mutations: 27 of 52 TP53 mutated patients had a 17p13 deletion (concordance rate: 52%, Fisher's test p<0.001). Median PFS for patients with TP53 mutations (n=52, 13 months, HR=1.9 (1.4–2.7), p<0.001) was significantly shorter as compared to patients without TP53 mutations (n=480, 27 months). In a sub-group analysis, chemoimmunotherapy including Rituximab did not significantly improve the PFS of patients with TP53 mutations. Multivariate analysis including treatment arm, Binet stage, age, IGVH mutational status, 17p13 deletion and TP53 mutation status confirmed TP53 mutation status (HR-TP53=1.7 (1.1–2.6), p=0.009) as a prognostic factor for PFS independent of 17p13 deletion status (HR-17p=1.7 (1.1–2.7), p=0.024) and with a similar effect size. The other independent prognostic factors were treatment (HR=0.61 (0.48–0.76), p<0.001), Binet stage (HR=1.64 (1.3–2.1), p<0.001) and IGVH mutational status (HR=2.4 (1.85–3.1), p<0.001). To further dissect the contribution of TP53 mutation and 17p13 deletion on PFS, we considered a multivariate analysis comparing patients with both TP53 mutation and 17p13 deletion (n=28), with only 17p13 deletion (n=9), with a dominant negative TP53 mutation or multiple TP53 mutations (n=8) or with a single TP53 mutation (n=16) against patients without TP53 abnormalities (n=271), adjusted for treatment, Binet stage, age and IGVH mutational status. Patients with a predicted biallelic disruption of TP53 either by a TP53 mutation in combination with a 17p13 deletion (HR: 2.8 (1.8,4.2), p=<0.001) or patients with a dominant negative TP53 mutation as predicted by the IARC TP53 database or multiple TP53 mutations (HR=3.26 (1.5,7.1), p=0.003) had a risk similar in size and which was quite high for disease progression (the reference to calculate the risk, here and in the following, is always the group of patients without TP53 abnormalities). The risk slightly decreased for patients with only a deletion 17p13 (HR=2.2, (1.1–4.3), p=0.021). Very interestingly, single TP53 mutations showed a much lower risk for disease progression (in this case not even significant) (HR=1.61 (0.9–2.8), p=0.084) especially compared to the risk conferred by a biallelic disruption. In this large cohort of previously treated CLL patients, complete disruption of TP53 function (by a combination of a 17p13 deletion and a TP53 mutation, through dominant negative TP53 mutations or through multiple TP53 mutations) was associated with a higher risk for disease progression. Prognosis of patients with a single TP53 mutation was not significantly different from patients without TP53 aberrations. It remains to be shown whether CLL patients with a single TP53 mutation are at a higher risk of acquiring additional mutations of TP53 during disease progression. Prognostic stratification of previously treated CLL patients should include a routine molecular TP53 mutational analysis in addition to deletion analysis of the TP53 locus by FISH. Disclosures: Dufour: Roche: Research Funding. Bohlander:Roche: Research Funding. Spiekermann:Roche: Research Funding. Schneider:Roche: Research Funding. Hiddemann:Roche: Research Funding. Truong:Roche: Employment. Patten:Roche: Employment. Wu:Roche: Employment. Dmoszynska:Mundipharma:; Roche: Honoraria. Robak:Centocor Ortho Biotech Research & Development: Research Funding. Geisler:Roche: Speakers Bureau. Dornan:Genentech: Employment. Lin:Genentech: Employment. Yeh:Genentech: Employment. Weisser:Roche: Employment. Duchateau-Nguyen:Roche: Employment. Palermo:Roche: Employment.

Ibrutinib In Combination With Rituximab (iR) Is Well Tolerated and Induces a High Rate Of Durable Remissions In Patients With High-Risk Chronic Lymphocytic Leukemia (CLL): New, Updated Results Of a Phase II Trial In 40 Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 675-675 ◽  
Author(s):  
Jan A. Burger ◽  
Michael J. Keating ◽  
William G. Wierda ◽  
Julia Hoellenriegel ◽  
Ghayathri Jeyakumar ◽  
...  
Keyword(s):  
High Risk ◽  
Subdural Hematoma ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Single Agent ◽  
Infectious Complications ◽  
Lymphocytic Leukemia ◽  
High Rate ◽  
Grade 3

Abstract The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is a promising new targeted therapy for patients with mature B cell malignancies, especially CLL and mantle cell lymphoma (MCL). Single agent ibrutinib induces an overall response rate (ORR) of 71% in relapsed CLL, based on the Phase 1/2 experience. To accelerate and improve responses to ibrutinib in high-risk CLL, ibrutinib was combined with rituximab; we update this Phase 2 single-center clinical trial with a median follow-up of 14 months. Methods Patients were treated with ibrutinib 420 mg PO daily continuously throughout the study Rituximab (375 mg/m2) was administered weekly for the first four weeks (cycle 1), then monthly until cycle 6.at which point patients continued on ibrutinib monotherapy. Study inclusion required high-risk disease (del17p or TP53 mutation [treated or untreated]), PFS < 36 months after frontline chemo-immunotherapy, or relapsed CLL with del11q. Results Characteristics of the 40 patients enrolled included median age of 65 (range 35–82) with a median of 2 prior therapies. There were14 female and 26 male patients. 20 patients had del17p or TP53 mutation (4 without prior therapy), and 13 patients had del11q. 32 patients had unmutated IGHV, only one patient mutated IGHV, the remaining patients had inconclusive IGHV results. The median β2 microglobulin was 4.2 mg/L (2.2 – 12.3), At a median follow up of 14 months, 32 of 40 patients continue on therapy (16 out of 20 with del17p or TP53 mutation) without disease progression. 39 patients were evaluable for response assessment per 2008 IWCLL guidelines; 34 (87%) achieved partial remission (PR), and three (8%) complete remission (CR), accounting for an ORR of 95%. One CR was negative for MRD by flow cytometry, The ORR in the 20 patients with del17p or TP53 mutation was 90% (16 PR, 2 CR). Among the 8 patients that came off study, 3 patient died from unrelated infectious complications (2 cases of sepsis, 1 case of pneumonia), and 1 died from unrelated respiratory and cardiovascular failure. Two patients came off study because of possibly ibrutinib-related toxicity (one subdural hematoma, one grade 3 mucositis), one patient had progressive disease, and one proceeded to stem cell transplantation. Treatment generally was well tolerated, with infectious complications (6 cases of pneumonia and 3 cases of upper respiratory infections) being the most common complication. There were two Grade 3, possibly related AEs: mucositis (n=1), and peripheral neuropathy (n=1). Milder toxicities included Grade 1-2 bruising (n=7), Grade 1 subdural hematoma (n=1), fatigue (n=2), bone pain, myalgias, and arthralgia (n=5), or diarrhea (n=1). Questionnaires revealed significantly improved overall health and quality of life (QOL) after 6 months, based on the EORTC-QOL-v.3 questionnaire, which coincided with a significant weight gain at 3 and 6 months. Conclusion Ibrutinib in combination with rituximab is a safe, well tolerated regimen for high-risk CLL patients, which induces high rates of durable responses. Responses were associated with significant improvements in QOL. Compared to ibrutinib monotherapy, the redistribution lymphocytosis resolves more rapidly and completely (see Figure), and consequently the ORR is higher. Whether the addition of rituximab to ibrutinib therapy translates into longer progression-free and overall survival will be addressed in an upcoming larger, randomized trial of ibrutinib versus iR in relapsed/refractory CLL. Disclosures: Burger: Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: Ibrutinib (PCI-32765) for treatment of high-risk CLL patients. O'Brien:Pharmacyclics: Research Funding.

Azacytidine and Vorinostat in Patients with Chronic Lymphocytic Leukemia (CLL) Diagnosed with Therapy-Related Myelodysplastic Syndromes/Acute Myeloid Leukemia (t-MDS/AML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5627-5627
Author(s):  
Yesid Alvarado ◽  
Michael J Keating ◽  
Susan O'Brien ◽  
Hagop M. Kantarjian ◽  
William G. Wierda ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Median Time ◽  
Stable Disease ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Bone Marrow Involvement ◽  
Lymphocytic Leukemia ◽  
Cycle Number ◽  
Prognostic Features

Abstract Background: There is evidence of a leukemogenic effect of purine analogues, mainly when combined with DNA-damaging agents. Various series report an approximately 5% rate of t-MDS/AML in patients treated with a fludarabine-based regimen. Patients are generally old, and old age is associated with worse outcomes. To date, there is no established standard therapy recommendation for this group of patients, and results of prospective treatment evaluations are scarce. Aim: To determine the characteristics and treatment outcomes of patients with CLL and t-MDS/AML. Methods: We analyzed a group of 6 patients with newly diagnosed t-MDS/AML who were treated in our institution from September 2011 to July 2014. Patients were enrolled in a phase II trial of azacitidine (75 mg/m2 IV daily x 5 days) in combination with vorinostat (200 mg orally three times daily x 5 days) (Arm A) or azacitidine alone (Arm B), with courses repeated every 3-8 weeks. This trial was designed to uniformly treat patients not eligible for other leukemia protocols due to comorbidities. Results: At baseline, all patients had an underlying diagnosis of CLL that was in remission or minimally active. The median percentage of CLL bone marrow involvement was 10% (range 0-60%), and ALC was 0.9 K/uL (range 0.2-9.79). The median number of prior CLL treatments was 2 (range 0-3). All patients had previously received fludarabine-based regimens. The median time from chemotherapy to t-MDS/AML diagnosis was 10 years (range 4-10). All patients were male, and the median age was 72 years (range 52-72). All patients had 3-line cytopenia, with median WBC 2.3 K/uL (range 0.8-8.9), ANC 0.55 K/uL (range 0-1.22), hemoglobin 9.6 G/DL (range 8.3-10.4), platelets 39 K/uL (range 6-80), and bone marrow blast percentage of 5% (range 1-18%). The karyotype was complex in all patients. Molecular studies showed that 3 patients had TP53 gene mutations. Five patients received treatment in Arm A, and only 1 patient was randomized to Arm B. Patients received a median of 4 cycles (range 2-7) and remained in the study for a median time of 216 days (range 86-329) before progression. None of the patients achieved remission, but stable disease was observed in 5 out of 6 patients. At the time of this analysis, 4 patients are dead and 2 are still alive: one discontinued treatment because of prolonged myelosuppression and is receiving best supportive care, and the other is recovering from cycle number 4 of treatment. The median survival in the group from the time of treatment initiation was 10.1 months and from the time of study discontinuation was 3.1 months. Further therapy was attempted in 3 patients without response. Conclusion: This is a group of patients with poor prognostic features. Azacytidine and vorinostat have been previously reported to be a safe combination (Garcia-Manero et al. ASH 2010, abstract 604) and may constitute a reasonable treatment alternative. Further prospective studies involving larger numbers of patients are required. Abstract 5627. Table 1: Baseline Patient Characteristics. Patient Age WBC K/uL Hb G/DL Plt K/uL BM Blast % CLL BM % Cytogenetic Molecular Prior CLL Treatments Treatment Arm Best Response 1 52 11 9.6 6 18 60 -3,-4,-5q,-6,-7, -7p,-12, +16 TP53 mutation 1.FCR x 62. Rituximab + Lenalidomide A NR 2 74 1 10 41 3 10 -3p,-5q,-7,-15,-17,-19 TP53 mutation 1. FCR x 42. FCR x 53. BR x 2 A SD 3 68 2.2 9.4 27 6 30 +7,-7p,t(7,21) Negative 1. FCR x 62. FCR x 4 B SD 4 73 2.3 9.7 39 6 0 +2,-5q,+8,-17,-18,+19,+20,-Y Negative 1. FCR x 6 A SD 5 71 0.8 8.3 39 4 0 +2,+4,t(5;17),+6,-7,-9, +13, +15,-16,-17,+18,+19,-20,+21 Negative 1. FR x 12. BR x43. MEDI-551 A SD 6 74 2.4 10.4 80 1 10 t(1;3),inv3,-5q,-18 TP53 mutation 1. R-CHOP x 62. BR x 13. FCR x 4 A SD WBC: White blood cells, Hb: hemoglobin, Plt: Platelets, BM: Bone Marrow, CLL: Chronic Lymphocytic Leukemia, F: Fludarabine, C: Cyclophosphamide, R: Rituximab, B: Bendamustine, MEDI-551: anti-CD19 antibody, NR: no response, SD: stable disease. Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding.

BCR-Assosiated Kinase Inhibition in Relapsed/Refractory Chronic Lymphocytic Leukemia. Real World Experiences of a German Regional Clinical Register

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-11
Author(s):  
Dietrich Kaempfe ◽  
Roshanak Bob ◽  
Joerg Brenn ◽  
Thomas Haverkamp ◽  
Agnes Knopp ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Real Life ◽  
Treatment Protocol ◽  
Lymphocytic Leukemia ◽  
Clinical Registry ◽  
Kinase Inhibition ◽  
Ample Evidence ◽  
Co Morbidity

Background: The advent of B-cell-receptor associated kinase inhibition (BCR-KI) inaugurated a novel therapeutic principle in chronic lymphocytic leukemia (CLL). First-in-class Ibrutinib (Ib) and Idelalisib (Id) received marketing authorization from the EMA for the treatment of relapsed/refractory (r/r) CLL in 2012 and 2014, respectively. In spite of ample evidence from trials, real life data are scarce. Methods: Our clinical registry has been previously described in detail [https://doi.org/10.1182/blood-2018-99-110618]. It comprises of 168 unselected CLL patients (pts.), who were observed between 10/2014 and 08/2020. 65 of them required treatment during this period: 39 x 1st line only and 26 x &gt; 2nd line. 18 of these 26 r/r CLL pts were treated either with Ib (11 x) or Id (7 x). Treatment was started according to iwCLL guidelines. The type of BCR-KI was chosen based on an individual's performance status, previous treatment and co-morbidity. Median 1st line-treatment (as a rule immunochemotherapy) started 27.5 months (m) after diagnosis (range: 0.5 m to 87.5 m). Time from 1st line therapy to BCR-KI treatment ('Ctx effected time') was 13.0 to 128.1 m (median 50.5 m), in total (18 pts.) 1052.5 m, i.e. 87.7 years (y). 17 of 18 pts. had received Rituximab (R) as part of a pre-BCR-treatment protocol. Estimated charges per month are 9.000 € in Id + R, 7.000 € in R + chemotherapy (ctx, i.e. Fludara or Bendamustin mostly) and 4.500 € in Ib or Id mono or R + Chlorambucil (Clb) respectively. Results: Patients described herein differed according to age at start of BCR-KI (44.4 to 86.8 y, median 76.0 y), sex (10 m, 8 f), types and lines (1 to 6, median 2) of prior treatment. Indications for BCR-KI were increasing tumor burden (17 x, 1 x combined with pleural effusion) and persistent hemolysis (1 x). Genetic high risk features comprised of at least one of the following: IGHV unmutated status, mutation and/or deletion of TP53 gene, deletion of 11q, and complexe karyotype. These features were present in 17 of 18 pts. (median 3 features). In particular, unmutated IGHV was found in 13/18 r/r pts who received BCR-KI (total cohort of r/r pts, 21/26). Overall response rate was 78% (Ib 8/11; Id 6/7). Time to next therapy or death (`KI effected time`) varies from 1.1 m to 69.1 m - in total 286.9 m until now. 4 pts. continued BCR-KI from 30 to 67 months. This was always the longest period of unchanged therapy in these 4 pts. Shorter `KI effected time` in the other 14 pts. was associated with higher treatment line and treatment interruptions. 2 responding pts. (without side effects) stopped BCR-KI and stayed in ongoing hematological remission for 11 and 25 months after cessation of treatment. Adverse drug reactions occurred in 6 pts. (Ib 4 x, Id 2 x). 5 pts. died on BCR-KI, but there was no therapy related death. Approximate costs per month in Germany are 1700 € in `Ctx effected time` (1.800.000 € per 1052,9 m) and 4.700 € in `KI effected time` (1.350.000 € per 286,9 m). Of note, one pt. on Id showed clinical progression associated with genetic evolution after 67 months of BCR-KI. He promptly responded to venetoclax. Discussion: In real live many r/r CLL pts. are elderly and present a broad spectrum of different clinical features. A clinical registry can reflect this and may add to our knowledge from multicenter studies. Remarkably almost all of our unselected r/r CLL pts. revealed genetic high risk features, in particular unmutated IGHV status, making them ideal candidates for targeted treatment strategies. These strategies take advantage of the fact that BCR-KI has been demonstrated to be well tolerated and effective in elderly and pre-treated pts. Undoubtedly BCR-KI increases the total costs of therapy, but affords a prolongation of overall survival. Remaining open questions include optimal treatment sequences, combination partners for BCR-KI as well as thorough analysis in the quality of molecular remissions. Disclosures Böttcher: Janssen: Honoraria, Research Funding; Celgene: Research Funding; AbbVie: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Novartis: Honoraria.

Lenalidomide-Dependent Activation of the Phosphatidylinositol 3-kinase-δ Pathway Is Antagonized by CAL-101 In Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1821-1821
Author(s):  
Sarah E.M. Herman ◽  
Rosa Lapalombella ◽  
Jeffrey A. Jones ◽  
Leslie Andritsos ◽  
Amber L. Gordon ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Cell Activation ◽  
Specific Inhibitor ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Cytokine Release ◽  
Treatment Naïve ◽  
Previously Treated

Abstract Abstract 1821 Lenalidomide is an oral immune-modulating agent that has been shown to have clinical activity in patients with treatment-naive and previously treated chronic lymphocytic leukemia (CLL). In CLL, a disease-specific phenomenon of drug-induced tumor flare is often observed that results in lymph node enlargement, rash, and cytokine release. We and others have attributed both lenalidomide-induced tumor flare and cytokine release in part to CLL cell activation, with concomitant increase in surface co-stimulatory molecules including CD154. The potential consequences of such activation by lenalidomide in CLL are multiple. In symptomatic, previously untreated CLL, activation of tumor cells by lenalidomide likely contributes to reversal of hypogammaglobulinemia in a subset of patients. Additionally, activation of CLL cells increases their capacity for antigen presentation, potentially facilitating a clinically beneficial development of tumor-specific antibodies toward antigens such as ROR1. In patients with previously treated CLL, lenalidomide therapy does not reverse hypogammaglobulinemia. However, treatment has been documented to increase serum b-FGF and VEGF levels, which correlates with lack of response. Previous work demonstrates that CLL cells predominately utilize the PI3K p110δ isoform for activation following CD154 signaling. Given our prior findings of prominent lenalidomide induction of CD40-CD154 signaling in vitro and in vivo, we focused initially on molecular interrogation of isoforms responsible for this in CLL cells. Utilizing primary CLL cells, we demonstrated that inhibition of PI3K-δ signaling by CAL-101, a clinically relevant PI3K-δ isoform-specific inhibitor, abrogated lenalidomide-induced activation of CLL cells by directly reducing PI3K enzymatic activity and also reducing phosphorylation of the downstream PI3K target AKT. Parallel studies with siRNA targeted to the p110δ isoform of PI3K demonstrated antagonism of lenalidomide-induced AKT phosphorylation. Furthermore, we found that inhibition of PI3K-δ by CAL-101 at therapeutically relevant concentrations (1 μM) prevented up-regulation of CD40, CD154, and CD86 by lenalidomide and also antagonized production of IgM by normal B-cells co-cultured with CLL cells. Collectively, these data demonstrate the importance of PI3K-δ signaling in modulating the pharmacological effects of lenalidomide in CLL cell activation including up-regulation of CD40, CD154, CD86 and active CLL cell co-stimulation of normal B-cells. Our findings suggest that clinical evaluation of combination strategies of lenalidomide and CAL-101 in treatment-naive patients with CLL should be performed with careful pharmacodynamic monitoring of immune modulation and signaling to best preserve the clinical benefits of both drugs. This work is supported by the Leukemia and Lymphoma Society, D. Warren Brown Foundation, and The OSU Leukemia SPORE grant funded by the NCI. CAL-101 was provided by Calistoga Pharmaceuticals, Inc. Disclosures: Jones: Glaxo Smith-Kline: Consultancy; Abbott: Research Funding. Lannutti:Calistoga Pharmaceutical Inc.: Employment. Byrd:Calistoga Pharmaceutical Inc.: Equity Ownership. Johnson:Calistoga Pharmaceutical Inc.: Research Funding.

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