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

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 > 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.

Download Full-text

Mechanisms of Adaptation to Ibrutinib in High Risk Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2018-99-116739 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 585-585 ◽

Cited By ~ 4

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.

Download Full-text

Bendamustine Replaces Chlorambucil As “Standard of Care” in the Treatment of Elderly Patients with Chronic Lymphocytic Leukemia in German Hematology Outpatient Centres

Blood ◽

10.1182/blood.v120.21.4605.4605 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4605-4605

Author(s):

Wolfgang Ulrich Knauf ◽

Wolfgang Abenhardt ◽

Arnd Nusch ◽

Renate Grugel ◽

Norbert Marschner

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Treatment Options ◽

Real Life ◽

Standard Of Care ◽

Lymphocytic Leukemia ◽

Line Treatment ◽

Clinical Registry ◽

Systemic Treatments ◽

New Treatment ◽

The Impact

Abstract Abstract 4605 Introduction With the FDA and EMA approval of Bendamustine and Rituximab new treatment options have recently become available to patients (pts) with chronic lymphocytic leukemia (CLL). Clinical registries provide insight into real-life treatment of pts. They can help to answer the question whether patients may benefit from new research findings. Methods The clinical registry on lymphoid neoplasms (TLN Registry), conducted by iOMEDICO in collaboration with the Arbeitskreis Klinische Studien (AKS) and the Kompetenznetz Maligne Lymphome (KML), prospectively collects data on the treatment of pts with lymphoid B-cell neoplasms as administered in hematology outpatient centres in Germany. Pts are followed for 5 years. A broad set of data regarding patient and tumor characteristics, comorbidities, all systemic treatments, response rates, progression-free survival and overall survival are recorded. Since May 2009, 106 sites have actively recruited a total of 2579 pts. Results From the overall sample, 420 pts received systemic 1st-line treatment for CLL. 65% of pts are male, mean age at time of primary diagnosis was 66 years (yrs) and at start of therapy 69 yrs. Tumor stage was 20% Binet A, 35% Binet B and 45% Binet C. 68% of pts (n=285) were diagnosed with at least one comorbidity, mainly hypertension (37%) or diabetes (15%); the average Charlson Comorbity Index of 0.7 indicates that overall pts have few comorbities. Rituximab is part of the 1st-line treatment in 82% (n=345) of pts with CLL. Bendamustine is part of the 1st-line treatment in 59% (n=247) of pts with CLL. It is mostly applied in combination with Rituximab (BR, 51%, n=213). Further 7% (n=28) receive Bendamustin as monotherapy. Fludarabine is part of the 1st-line treatment in 31% (n=132) of pts with CLL. It is applied in combination with Cyclophosphamide and Rituximab (FCR, 25%, n=103), as monotherapy (4%, n=15) or in combination with Cyclophosphamide (FC, 1%, n=6). Chlorambucil is part of the 1st-line treatment in 7% (n=31) of pts with CLL. It is applied as monotherapy (4%, n=15) or in combination with Rituximab (2%, n=10). Pts receiving BR, FCR or Chlorambucil differ. Pts characteristics indicate that BR and Chlorambucil are applied preferably in elderly pts (mean 70.1 (BR) vs. 75.7 (Chlorambucil) vs. 63.4 (FCR) yrs). Also, BR is given preferably in advanced stages of the disease as compared to FCR (Binet C 49% vs. 34%). The use of BR has increased from 41% in 2009 to 57% in 2011, while the use of FCR has decreased from 33% in 2009 to 17% in 2011. Of all pts with CLL in the TLN, 181 have received 2nd-line treatment. Rituximab is part of the 2nd-line treatment in 76% (n=137) of pts with CLL. Bendamustine is part of the 2nd-line treatment in 66% (n=120) of pts with CLL. It is mostly applied in combination with Rituximab (BR, 56%, n=101). Further 10% (n=18) receive Bendamustin as monotherapy. Fludarabine is part of the 2nd-line treatment in 20% (n=37) of pts with CLL. It is applied in combination with Cyclophosphamide and Rituximab (FCR, 10%, n=18), as monotherapy (5%, n=9) or in combination with Cyclophosphamide (FC, 3%, n=5). Chlorambucil is part of the 2nd-line treatment in 4% (n=7) of pts with CLL. It is mostly applied in combination with Rituximab (2%, n=4). Conclusion Rituximab and Bendamustine are the most frequently used drugs for the treatment of CLL in German hematology outpatient centres. The use or BR has significantly increased since 2009. In contrast, the use of FCR has decreased and only a minority of pts receive Chlorambucil. This indicates that in Germany Chlorambucil is no longer considered the “standard of care” for elderly pts with CLL. These data also show that results from clinical trials are quickly implemented into daily practice. The impact of these new treatment options on quality of life and survival remains to be of central interest in the future. Disclosures: Knauf: Mundipharma GmbH: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Preliminary Results of a Phase 1b Study (GO28440) Combining GDC-0199 (ABT-199) with Bendamustine/Rituximab in Patients with Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v124.21.3337.3337 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3337-3337 ◽

Cited By ~ 4

Author(s):

Gilles Andre Salles ◽

Thomas E Boyd ◽

Franck Morschhauser ◽

Clemens-Martin Wendtner ◽

James Lymp ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Dose Escalation ◽

Research Funding ◽

Single Agent ◽

Previous Treatment ◽

Lymphocytic Leukemia ◽

Dose Finding ◽

Previous Exposure ◽

Phase 1B

Abstract Introduction New therapies are needed for patients (pts) with chronic lymphocytic leukemia (CLL). BCL2 is an anti-apoptotic protein that is overexpressed in CLL and may be associated with resistance to available therapies; GDC-0199 is an orally available, selective BCL2 inhibitor. The combination of bendamustine (B) and rituximab (R) has demonstrated efficacy in relapsed/refractory (R/R) and previously untreated pts with CLL and is often used in these pts. Preclinical data suggest that GDC-0199 combined with BR may show synergistic activity in CLL. Moreover, clinical data from single-agent studies of GDC-0199, and in combination with rituximab in pts with CLL, support combining GDC-0199 with BR in this population. Data presented here are from an ongoing phase 1b study that is evaluating the maximum tolerated dose of GDC-0199 when given in combination with BR, as well as the safety, tolerability, and order of administration of this combination in R/R or previously untreated pts with CLL. Methods Pts with an ECOG PS ≤1, adequate marrow, hepatic, renal and coagulation function are being enrolled in dose finding cohorts ranging from 100 to 600 mg/day of GDC-0199 using a 3+3 dose escalation design. Pts are assigned to one of two dosing schedules (Figure 1) with GDC-0199 (Schedule A) or BR (Schedule B) introduced first, both incorporating a gradual dose ramp-up of GDC-0199 to reduce the risk of tumor lysis syndrome (TLS). Prophylaxis measures to mitigate TLS include IV hydration, treatment to prevent hyperuricemia and hospitalization. After completing combination therapy, R/R pts will continue single-agent GDC-0199 until disease progression. Previously untreated pts will continue single-agent GDC-0199 for up to 18 months. Dose-limiting toxicity (DLT) data are identified after all pts in a cohort have completed ³21 days of combination treatment at the target dose of GDC-0199 and focus on treatment emergent TLS and cytopenias. Figure 1 Figure 1. Results As of May 2014, 6 pts with R/R CLL have been enrolled in the dose finding stage of the study with a median time on study of 67 (range 43-113) days. All 6 pts were enrolled on Schedule A; 3 pts were enrolled in the 100 mg GDC-0199 cohort and 3 pts were enrolled in the 200 mg cohort. Baseline characteristics of the 6 pts are as follows: median age 67 (range 52-71) years, 3 male pts, median of 2 prior CLL therapies (range 1-3, including 4 pts with previous exposure to fludarabine, cyclophosphamide and rituximab [FCR] and 1 with previous exposure to FCR and B), beta-2 microglobulin ≥3.5 mg/L in 2 pts, and unmutated IGHV in 5 pts. Prior to starting therapy, the median lymphocyte count was 40.85 x 109 cells/L (range 2.11-169 x 109 cells/L), hemoglobin level was 101.5 g/L (range 99-134 g/L), neutrophil count was 2.54 cells/μL (range 1.81-3.8 cells/μL), and platelet count was 83.5 x 109/L (range 49-250 x 109/L). Pts were assigned to 1 of 3 TLS risk groups based on screening ALC and tumor bulk: low risk 1 pt, medium risk 4 pts, and high risk 1 pt. Cytogenetic data are available for 3 pts: 1 pt had del17p, 2 pts had del 11q, and 3 pts had del 13q. No DLTs were observed. All 6 pts have experienced adverse events (AEs, Figure 2). The most common AE was anemia with most Grade ³3 AEs being hematological toxicities (Figure 2). One serious AE of bronchitis was observed in a pt enrolled in the 100 mg GDC-0199 cohort and resolved after treatment. Two pts in the 100 mg GDC-0199 cohort discontinued BR after the 21-day DLT window secondary to treatment emergent cytopenia: 1 with neutropenia after completing 1 cycle of BR (previous treatment FCR without baseline cytopenia) and the second with thrombocytopenia after completing 3 cycles of BR (previous treatment FCR and chlorambucil with thrombocytopenia at screening). Both pts remain on single-agent GDC-0199. No TLS events (laboratory or clinical) were observed and no deaths reported. Figure 2 Figure 2. Conclusion This is the first study to evaluate the combination of GDC-0199 and BR in pts with CLL. Despite 5 pts being identified as medium or high risk for TLS, no pts developed TLS as a result of the ramp-up dosing of GDC-199 and prophylactic measures. The most frequent AEs were hematological toxicities and generally manageable; however, 2 pts had to discontinue BR (after 1 and 3 cycles) but were able to remain on GDC-0199. Dose escalation in R/R pts is continuing in order to evaluate the optimal dose/schedule with a plan to enroll previously untreated pts in the near future. Disclosures Boyd: Genentech: Research Funding; US Oncology/McKesson: Research Funding; Celgene: Consultancy. Morschhauser:Genentech: Travel grant Other; Gilead, Mundipharma, Bayer, Spectrum, Celgene: Honoraria. Wendtner:AbbVie, Genentech, Hoffman-La Roche, Mundipharma: Consultancy, Research Funding. Lymp:Genentech: Employment. Hilger:Genentech: Employment. Vosganian:Genentech: Employment. Huang:Genentech: Employment. Stilgenbauer:Genentech, Hoffman La Roche: Honoraria, Research Funding.

Download Full-text

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

Blood ◽

10.1182/blood.v124.21.2184.2184 ◽

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.

Download Full-text

Preliminary Results of a Phase 1b Study (GP28331) Combining GDC-0199 (ABT-199) and Obinutuzumab in Patients with Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v124.21.4687.4687 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4687-4687 ◽

Cited By ~ 8

Author(s):

Ian Flinn ◽

Mark Brunvand ◽

Martin JS Dyer ◽

Peter Hillman ◽

Jeffrey Jones ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Combination Therapy ◽

Research Funding ◽

Advisory Board ◽

Lymphocytic Leukemia ◽

Phase 1B ◽

Cd20 Antibody ◽

Anti Cd20 ◽

Gradual Dose

Abstract Introduction Despite progress in chronic lymphocytic leukemia (CLL) treatment, new therapies are needed especially for relapsed/refractory (R/R) patients (pts). BCL2 is an anti-apoptotic protein expressed at high levels in all cases of CLL. GDC-0199 is an oral, highly selective BCL2 inhibitor. Clinical data for GDC-0199 have shown promising anti-CLL activity. Obinutuzumab (Gazyva®, Gazyvaro™) is a Type II, glycoengineered anti-CD20 antibody that has increased direct cell death, and enhanced antibody-dependent cell-mediated cytotoxicity. Obinutuzumab and chlorambucil have demonstrated improved progression-free survival compared to rituximab and chlorambucil in previously untreated pts with CLL. Also, preclinical data suggest that GDC-0199 combined with obinutuzumab may show synergistic activity in CLL. Collectively, these data support combining GDC-0199 and obinutuzumab for pts with CLL. We present data from an ongoing phase 1b study that is evaluating the safety and tolerability of GDC-0199 in combination with obinutuzumab in R/R or previously untreated pts with CLL. Methods Pts with an ECOG PS ≤1, adequate marrow, hepatic, renal and coagulation function are enrolled in a 3+3 study design with cohorts ranging from 100 to 600 mg/day of GDC-0199. Study eligibility is not restricted by cytogenetics or CLL risk profile. Study drug administration incorporates a gradual dose ramp-up of GDC-0199 to reduce the risk of tumor lysis syndrome (TLS), and staggering of the two agents. Pts are assigned to one of two dosing schedules (Figure 1) with GDC-0199 (Schedule A) or obinutuzumab (Schedule B) introduced first. After completing combination therapy, R/R pts continue single-agent GDC-0199 until disease progression. Adverse events (AEs) are graded according to NCI-CTCAE v.4 criteria. Dose-limiting toxicities (DLTs) are identified during the first 21 days of combination treatment and focus on potential AEs of TLS, infusion related reactions (IRRs), and cytopenias. Results As of May 2014, 9 R/R pts are on the dose finding stage of the study; 4 additional R/R pts were enrolled and discontinued following clinical TLS events in other GDC-0199 studies. No clinical TLS was observed in these 4 pts. The data presented here describe the 9 pts who continue on study treatment. Pts were assigned to 1 of 3 TLS risk groups based on screening ALC and tumor bulk: low risk 0 pts, medium risk 4 pts, and high risk 5 pts. Median time on study was 98 (range 7-252) days. No DLTs were observed in the 3 pts enrolled in the 100 mg GDC-0199 dosing cohort. Six pts were enrolled in the 200 mg GDC-0199 dosing cohort due to expansion following a DLT of laboratory TLS (characterized by asymptomatic laboratory abnormalities in potassium and phosphate) observed in 1 of the first 3 pts. Baseline characteristics include: median age 69 (range 59-80) years, 6 male pts, median of 4 prior CLL therapies (range 1-6), beta-2 microglobulin of ≥3.5 mg/L in 7 of 8 pts with available data, and IGVH mutation in 1 of 7 pts with available data. Cytogenetic data are available for 4 pts: none had del17p, 1 pt had del 11q, 1 pt had trisomy 12 and 2 pts had del 13q. The most common AEs included neutropenia (Figure 2). Dose interruptions of GDC-0199 or obinutuzumab in response to AEs were observed in 5 pts (2 pts had dose interruptions for obinutuzumab only [IRRs], and 3 pts had dose interruptions for GDC-0199 [mainly electrolyte abnormalities and cytopenias] and obinutuzumab [IRRs]); 1 pt in the 100 mg GDC-0199 dosing cohort had a dose reduction to 50 mg per day after 2 cycles of combination therapy due to ongoing neutropenia, and subsequently completed 6 cycles of combination treatment. IRRs were limited to the first infusion of obinutuzumab and were of Grade ≤2. One event of Grade 3 pneumonia required hospitalization. No treatment emergent bleeding events or deaths occurred on study. <![if !vml]><![endif]> Conclusion This is the first study combining GDC-0199 and the novel anti-CD20 antibody obinutuzumab in CLL and suggests that the combination is safely administered at the doses given. Prophylactic measures and a gradual dose ramp-up of GDC-0199 appear to reduce the incidence of TLS. Despite 9 pts being identified as medium or high risk for TLS, only 1 developed laboratory TLS, which was transient and managed. No clinical TLS was observed in these 9 pts. Dose escalation continues in R/R pts at 400 mg/day of GDC-0199. Schedule B and previously untreated pts will be enrolled in the near future. Disclosures Flinn: Genentech: Research Funding. Brunvand:Genentech: Speakers Bureau. Hillman:Roche Pharmaceuticals: Honoraria, Research Funding. Jones:Genentech: Advisory Board Other. Lymp:Genentech: Employment. Elhamy:Genentech: Employment. Vosganian:Genentech: Employment. Huang:Genentech: Employment. Kipps:Cegene, Pharacyclics, AbbVie, Genentech: Advisory Board Other, Research Funding.

Download Full-text

Identification of Baseline Characteristics That Predict Good Outcome of Allogeneic Hematopoietic Cell Transplantation in Young Chronic Lymphocytic Leukemia Patients - a Retrospective Analysis from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

Blood ◽

10.1182/blood.v128.22.522.522 ◽

2016 ◽

Vol 128 (22) ◽

pp. 522-522

Author(s):

Michel van Gelder ◽

Dimitris Ziagkos ◽

Liesbeth C de Wreede ◽

Anja van Biezen ◽

Peter Dreger ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Kinase Inhibitors ◽

Lymphocytic Leukemia ◽

Unrelated Donor ◽

Advisory Committees ◽

Matched Sibling

Abstract Patients with relapsed/refractory chronic lymphocytic leukemia (CLL) have excellent responses with kinase or BCL2 inhibitors, but patients with high risk cytogenetics (del(17p) and/or del(11q)) do not seem to achieve long-term disease control. Allogeneic hematopoietic stem cell transplantation (alloHCT) can result in sustained progression-free survival. As non-relapse mortality (NRM) after alloHCT is partly age-dependent, alloHCT is preferably considered in younger high cytogenetic risk CLL patients, but data of early NRM and longer-term PFS lack for this age group. We focused in this study on younger allo-transplanted CLL patients (<50 years) in an EBMT registry cohort with additional data collection (n=197, median follow-up 90.4 months). The most important prognostic factor for 2-year NRM in multivariate analysis was the donor HLA match: HR 2.5, 95% CI: 1.1-5.4 for an HLA-matched unrelated donor, and HR 4.0, 95% CI: 1.4-11.6 for an HLA-mismatched unrelated donor, both versus a matched sibling (Table 1). Predictors for poor 8-year PFS were "no remission at the time of alloHCT" (HR 1.7 (95% CI: 1.1-2.5)) and partially HLA-mismatched unrelated donor (HR 2.8 (95% CI: 1.5-5.2))(Table 2). High risk cytogenetics did not have a significant impact on 8-year PFS. Based on the regression model, a reference patient was created with high risk cytogenetics (del(17p) and/or del(11q)) and "good transplant" characteristics (remission at the time of alloHCT and HLA- and sex-matched sibling donor). The predicted two-year NRM for this patient was 12.1% (95% CI: 2.5%-21.7%)(Figure A) and 8-year PFS 53.5% (95% CI: 38.0%-69.0%)(Figure B). Such a low predicted NRM may keep up with the 9% "real-world" reported 1-year NRM of ibrutinib and the 8-year PFS compares favorably to outcomes after using kinase inhibitors or venetoclax. Taking into account the amount of uncertainty for predicting survival after alloHCT but also for the sequential administration of kinase inhibitors and venetoclax, alloHCT still remains a valid option for younger high cytogenetic risk refractory/relapsed CLL patients with a 10/10 HLA-allele matched donor. Figure. Figure. Disclosures Dreger: Novartis: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy; Gilead: Consultancy; Roche: Consultancy. Gramatzki:Janssen: Other: Travel/Accommodation/Expenses, Research Funding. Delgado:Janssen: Consultancy, Honoraria; Novartis/GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Infinity: Research Funding. Schoenland:Jansen: Honoraria, Other: financial support of conference participation, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schetelig:Sanofi: Honoraria.

Download Full-text