Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4558-4558

Kurzfassung: Among patients who survive over two years post-allo-HSCT, cGVHD and subsequent cancers represent a significant source of morbidity and mortality. Long-term treatment with immunosuppressive agents and cGVHD-related immune dysregulation may promote the development of subsequent cancers. The burden of subsequent cancers has not yet been described in patients with the most severe manifestations of cGVHD, who likely represent a high-risk population. 439 patients were enrolled on the prospective NIH Chronic GVHD Natural History Study from 2004 to 2019, underwent one-week evaluation by subspecialists, and were scored in accordance with 2005 NIH criteria. Follow-up data were collected by annual survey in which patients self-reported cancer diagnoses and provided consent for confirmatory medical records. Cumulative incidence was estimated for non-melanoma skin cancer (NMSC) competing with death, relapse, or cancer other than NMSC and for cancer other than NMSC competing with death or relapse using the method of Gooley. Potential predictors of subsequent cancers including demographics, transplant characteristics, and cGVHD-related factors were assessed using Gray's test in univariable analysis and Cox proportional hazards models in multivariable analysis. Patients must have been free of post-transplant relapse, NMSC (for NMSC analyses only), and cancer other than NMSC at evaluation to be included in analysis. 22 NMSC and 19 cancers other than NMSC were observed among 205 eligible patients, with cumulative incidences at 60 months of 11.2% (95% CI: 6.9-16.7) and 7.3% (95% CI 4.1-11.8), respectively. The most common cancers other than NMSC were oral squamous cell carcinoma and melanoma (n=6 each). Factors associated with NMSC in univariable analysis were older age at transplant, older age at evaluation, having received sirolimus for cGVHD, having received extracorporeal photopheresis or psoralen-ultraviolet therapy for cGVHD as well as higher CRP, higher NK cell count, and greater BMI at evaluation. Only older age at transplant (HR=2.12; 95% CI: 1.35-3.31) and higher CRP (HR=9.61; 95% CI: 1.29-71.73) remained associated in the multivariable model. Factors associated with subsequent cancers other than NMSC in univariable analysis were T-cell depletion, lymphoid malignant indication for transplant, and increasing severity of oral cGVHD by NIH score. Only lymphoid malignant indication for transplant (HR=2.58; 95% CI: 1.31-5.07) remained significant in multivariable analysis. The association of CRP with NMSC may represent an effect of cGVHD-related inflammation, with CRP previously associated with cGVHD severity. Interestingly, sirolimus was associated with increased risk of NMSC despite its purported antineoplastic effects. One study has previously reported increased risk of NMSC in allo-HSCT recipients treated with sirolimus, however, numerous studies have reported that sirolimus reduces risk of NMSC in solid organ recipients. In this study population, sirolimus was often prescribed later in patients already with refractory cGVHD and adjustment for measures of disease severity attenuated this association in multivariable modeling. The association of lymphoid indication with cancers other than NMSC may be attributable to age as patients with lymphoid malignancies were older at transplant than those with other indications. Additionally, differences in pre-transplant therapies for lymphoid vs. other indications may also contribute to this observation. Post-transplant patients with cGVHD are at high risk of developing subsequent cancers, with higher incidence of NMSC than other cancers. This study identifies potential risk groups for subsequent cancers, highlights patients who may benefit from increased surveillance, and reiterates the need for effective cGVHD therapy to mitigate risks associated with long-term immunosuppression and immune dysfunction. Disclosures Cowen: UpToDate: Other: Royalties; Elsevier: Other: Royalties.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-124020

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2019

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4241-4241

Kurzfassung: Chronic myeloid leukemia (CML) is a stem cell disease characterized by BCR-ABL1. Most patients in chronic phase (CP) CML achieve long-lasting molecular responses when treated with BCR-ABL1 tyrosine kinase inhibitors (TKI). However, resistance against TKI occurs in a subset of patients. Several molecular mechanisms, including BCR-ABL1 mutations, contribute to TKI resistance. For imatinib-resistant patients, second- and third generation TKI, including nilotinib, dasatinib, bosutinib, and ponatinib, are available. Using these drugs, it is now possible to cover most of the known BCR-ABL1 mutations, including the multi-resistant mutation T315I. Ponatinib, a third generation TKI, induces growth-inhibitory effects in drug-resistant patients even if T315I is expressed. However, not all mutant forms of BCR-ABL1 are responsive to ponatinib. Moreover, it has been described that multiple secondary mutations in BCR-ABL1, especially T315I-involving compound mutations, confer resistance against ponatinib. Furthermore, resistance against TKI may develop independent of BCR-ABL1 mutations. Therefore, drug combinations covering a broad range of targets, are currently under investigation with the aim to overcome drug resistance in advanced CML. Bardoxolone methyl (CDDO-Me) is an oleanane triterpenoid that has been described to induce ROS generation and to suppress a number of survival-related molecules, including AKT, mTOR, and STAT3. The aim of the current project was to evaluate the anti-leukemic effects of CDDO-Me in TKI-resistant CML cells. As assessed by 3H-thymidine uptake experiments, CDDO-Me was found to inhibit growth of various CML cell lines, including K562, an imatinib resistant sub-clone of K562, KU812, and imatinib-resistant KCL22 cells (IC50: 0.1-0.5 µM). These effects were accompanied by induction of apoptosis as assessed by staining for AnnexinV and propidium iodide. Furthermore, CDDO-Me was found to block the growth of Ba/F3 cells harboring the BCR-ABL1 mutations T315I, E255K, G250E, H396P, or F359V as well as Ba/F3 cells expressing TKI-resistant compound mutations, such as T315I/E255V, T315I/F311L, T315I/F359V, or T315I/G250E (IC50: 0.1-0.25 µM). The anti-proliferative effects of CDDO-Me were also confirmed in primary CML cells isolated from 13 patients with chronic phase (CP) CML (4 TKI-resistant patients, 3 with BCR-ABL1 mutations), one in blast phase (BP), and one suffering from ponatinib-resistant Ph+ ALL harboring BCR-ABL1T315I/E255K. IC50 values were comparable between samples isolated from freshly diagnosed patients (IC50: 0.1-0.5 µM) and samples isolated from heavily pre-treated patients, (IC50: 0.1-0.5 µM) suggesting that BCR-ABL1 mutations do not influence responses to this drug. In consecutive experiments, CDDO-Me was found to produce synergistic growth-inhibitory effects when combined with second- or third-generation BCR-ABL1 TKI. The combination ´CDDO-Me+ponatinib´ was found to be effective in Ba/F3 cells expressing various BCR-ABL1 mutations, including T315I-involving compound mutations. We also found that the combination ´CDDO-Me+TKI´ leads to simultaneous dephosphorylation of STAT3 and STAT5. To clarify whether this drug action contributes to the synergistic drug-interactions observed, we performed experiments with shRNA directed against STAT3 or STAT5 and the specific STAT5-inhibitor AC-3-019. Knockdown of STAT3 was found to produce synergistic effects with TKI and with AC-3-019 in K562 and KCL22 cells, whereas STAT5-knockdown sensitized CML cells against CDDO-Me, pointing to a new effective concept of dual STAT3+STAT5 inhibition. However, CDDO-Me was also found to increase expression of heme-oxygenase-1 (HO-1), a heat-shock-protein known to trigger drug resistance and cell survival in CML cells. We therefore combined CDDO-Me with the HO-1 inhibitor SMA-ZnPP, which also resulted in synergistic growth-inhibitory effects in human CML cells and BCR-ABL1+Ba/F3 cells. Moreover, SMA-ZnPP was found to sensitize KU812 cells and Ba/F3 cells expressing BCR-ABL1T315I/F311L against the combination ´CDDO-Me+TKI´. Together, combined targeting of STAT3, STAT5, and HO-1 overcomes multiple forms of TKI resistance in highly resistant CML clones expressing BCR-ABL1T315I or T315I-containing compound mutations. Whether such drug combinations are effective in vivo in TKI-resistant patients remains to be elucidated. Disclosures Hoermann: Ariad: Honoraria; Gilead: Research Funding; Amgen: Honoraria; Novartis: Honoraria. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Deininger:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI BioPharma Corp.: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Gilead: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lion:Amgen: Honoraria; Pfizer: Honoraria; Ariad: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria. Valent:Ariad: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Deciphera Pharmaceuticals: Research Funding; Amgen: Honoraria.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.4241.4241

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2016

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3962-3962

Kurzfassung: Introduction Vincristine is vital in the treatment of acute lymphoblastic leukemia (ALL), but is dose-limited by the development of disabling neuropathies. Vincristine is metabolized extensively by polymorphically expressed CYP3A4/5, which contributes to its 10-fold inter-patient pharmacokinetic variability. Further, there is more recent evidence that an inherited polymorphism in the CEP72 rs924607 gene contributes to vincristine sensitivity. Hispanic children have among the lowest rates of ALL survival when compared to other ethnicities, and pharmacogenomic variability among races is postulated to contribute. This is the first study to examine specifically both CYP3A5 polymorphisms and CEP72 gene expression in correlation with vincristine neurotoxicity in a large cohort of Hispanic ALL patients. Methods Banked germline blood samples from 300 self-identified Hispanic patients with ALL treated at Texas Children's Hospital between 1990 and 2015 were interrogated for allelic discrimination of CEP72 and at the CYP3A5*3, *6, and *7 polymorphic loci using TaqMan assays. Patient medical records were electronically searched for evidence of neuropathic events. Neuropathies were categorized as motor or sensory and graded using the Modified ("Balis") Pediatric Scale of Peripheral Neuropathies. Missing administered vincristine data was imputed using the patient's known treatment protocol and date of event coupled with protocol specifics retrieved from the literature. Multivariate analysis was run modeling the influences of CYP3A5 and CEP72 genotypes on the development and time to development of greater than or equal to Grade 3 neuropathies. Descriptive statistics were used to identify the prevalence of CYP3A5 and CEP72 genotypes and the associated phenotypes in this patient population. Time to neuropathy analysis was performed using the Kaplan-Meier failure estimates and log-rank test in Stata V.12.1 (College Station, TX). Results Based on CYP3A5 polymorphisms, overall, we found that 5% of our patients were extensive metabolizers of vincristine, 33% were intermediate metabolizers, and 62% were poor metabolizers. Additionally, we found that the TT risk CEP72 genotype is a rare finding in our cohort (9.3%). Clinically, we found that 18.4% of our patients experienced greater than or equal to Grade 3 neurotoxicity. Assessing the influence of being both a CYP3A5 intermediate or poor metabolizer and having the TT risk CEP72 genotype was limited by the paucity of patients with both genotypes (n=25). However, CYP3A5 poor metabolizers experienced neurotoxicity more often than intermediate or extensive metabolizers, although we did not find a statistically significant correlation between phenotype and incidence of neurotoxicity. Additionally, we found that there was a statistically significant difference in time to development of neurotoxicity within the first 100 days of treatment between intermediate and poor CYP3A5 metabolizers (P=0.036), with poor metabolizers experiencing greater than or equal to Grade 3 neurotoxicity sooner (Figure 1). Conclusions For the first time, we show that CYP3A5 poor metabolizers experienced greater than or equal to Grade 3 neurotoxicity significantly sooner than intermediate metabolizers within the first 100 days of treatment. We found a low prevalence of the minor allele of CEP72 rs924607TT in our Hispanic cohort. However, classification of CYP3A5 metabolizers and genotypes within our Hispanic population as well as our incidence of neurotoxicity are consistent with current literature. Further testing in a larger cohort should be performed but this study reinforces the significance of CYP3A5 metabolism of vincristine in leading to significant neurotoxicity and suggests that, at least in Hispanic patients, vigilance to early development of neurotoxicity should be performed by practitioners. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.3962.3962

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2016

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4096-4096

Kurzfassung: Peripheral T-cell lymphoma (PTCL) is a group of clinically and pathologically heterogeneous non-Hodgkin lymphomas (NHL). Using gene expression profiling (GEP), we have defined molecular classifiers for PTCL subtypes reflecting their pathobiology and oncogenic pathways (Iqbal et al. 2014). We have also shown associations of specific mutations with the molecular subgroups (Wang et al. 2015). Although genomic information is increasing, the pathogenetic mechanisms of PTCLs remain largely unknown. Therefore, we analyzed copy number variation (CNV) and GEP to identify unique genetic abnormalities in the defined PTCL molecular subgroups. CNV data were generated on fresh frozen or formalin-fixed paraffin-embedded genomic DNA (n=114) on 3 Affymetrix platforms (SNP 6.0, 250K SNP, and OncoScan). Two published cohorts (PTCL-NOS, Hartmann et al. 2010; ALCL, Boi et al. 2013) were included for validation. The gene expression analysis, morphological review and clinical characteristics of these cases have been included in previous studies (Iqbal et al. 2010, 2014). Angioimmunoblastic T-cell lymphoma (AITL) represents 20% of all PTCL cases. The most recurrent CNV in AITL was chromosome (chr) 5 gain (39%), followed by chr 21 gain (21%). Interestingly, chr 21 gain co-occurred with chr 5 gain (p=0.003). No recurrent losses (≥20%) were identified among these cases. Molecularly re-classified AITL cases from morphologically classified PTCL-NOS cases showed concordant results with bonafide AITL cases. Of the commonly mutated genes, DNMT3A, IDH2, RHOA and TET2, only IDH2R172Kshowed a significant association (p=0.012) with chr 5 gain. GEP showed enrichment of gene signatures associated with oxidative phosphorylation (PGC-1α target genes) in cases with chr 5 gain. PTCL, not otherwise specified (PTCL-NOS) is the most common PTCL subtype and cannot be further sub-classified using conventional approaches; however, we have identified 2 molecular subgroups within PTCL-NOS, the GATA3 and TBX21 subgroups which are related to 2 distinct T-helper subsets (Iqbal et al. 2014), by employing GEP. Consistent with earlier observations (Hartmann et al. 2010), PTCL-NOS showed remarkably varied CNVs with nearly 50% of cases showing high CNV frequencies. When correlated with molecular subgroups, distinctive CNVs were observed in the molecular GATA3 and TBX21 subgroups. The GATA3 subgroup displayed a large assortment of CNVs. Complete or partial gain of chr 7 (57%) was the most recurrent gain in these cases. Losses affecting 17p, 10q and 9p21, encompassing tumor suppressors such as TP53 (57%), PTEN (43%) and CDKN2A (43%), were frequent in the GATA3 subgroup. The TBX21 subgroup had significantly fewer CNVs, as none were recurring (≥20%); but gains of 5p or 11p were observed in 14%. Additionally, PTCL-NOS cases with ≥10% abnormal genome had significantly poorer overall survival (p=0.012) compared to those with fewer abnormalities. This finding validates the GEP molecularly defined subgroups, as the GATA3 subgroup displayed more CNVs and has been associated with a worse prognosis compared to the TBX21 subgroup (Iqbal et al. 2014). We were able to distinguish CNVs characteristic of the different entities, including the co-occurrence of chr 5 and 21 gains specific in AITL. Gain of 1q (complete or partial) was identified in the GATA3 subgroup of PTCL-NOS and anaplastic lymphoma kinase (ALK) (-) ALCL with equal frequencies (~ 36%), but only 16% in ALK(+) ALCL. Complete or partial gain of chr 7 was also observed in ALCL, but at a considerably lower frequency than in the GATA3 subgroup. Additionally, gain of chr 18 or regions of 17q, and loss of 5q or regions on both arms of chr 9, were more frequent in the GATA3 subgroup compared to other entities. The TBX21 subgroup was primarily differentiated from the GATA3 subgroup by presence of fewer CNVs. Our analysis provides a framework for future investigations into the molecular pathogenesis of PTCL, and highlights potential candidate oncogenes and tumor suppressors deregulated by copy number aberrations. Comparative analysis revealed that certain chromosomal abnormalities are entity-specific. AITL cases with IDH2R172K also had trisomy 5 suggesting that these oncogenic events cooperate in malignant transformation. Thus, the complexity of PTCL is finally becoming clearer with the integration of high resolution molecular techniques for global genomic analysis. Disclosures No relevant conflicts of interest to declare.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.4096.4096

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2016

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 5 ( 2015-07-30), p. 604-611

Kurzfassung: CDKN2A and TP53 deletions remain of bad prognostic value in younger MCL patients treated according to the current standard of care. CDKN2A and TP53 deletions have independent deleterious effects and should be considered for treatment decisions in addition to MIPI and Ki-67 index.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2015-02-628792

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2015

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1187-1187

Kurzfassung: Background: Allogeneic HCT is a potentially curative procedure for many hematologic malignancies, but is associated with several complications. Acute GvHD is a condition that affects 35-50% of allogeneic HCT recipients, typically occurs within 100 days after transplant, and can be life-threatening. Existing treatments are poorly tolerated and frequently ineffective. While the clinical consequences of acute GvHD are understood, the economic burden of the condition has not been well characterized. Methods: Using a large US healthcare claims database (Truven MarketScan® Commercial Claims and Encounters Database), patients aged ≥2 years old were identified who underwent allogeneic HCT between October 2009 and March 2013. Patients without continuous health plan enrollment or evidence of hematologic malignancy in the 6-month period prior to the "Index Admission" (hospital admission during which HCT was performed) were excluded. Patients were followed from the first day of the Index Admission until death, plan disenrollment, or one year; whichever occurred first ("Follow-Up"). Patients were classified into two cohorts: "Acute GvHD" based on ICD-9 CM diagnosis codes within first 100 days of Follow Up, or "No Acute GvHD". Total healthcare costs (inpatient care, outpatient care, outpatient pharmacy) and hospital length of stay (LOS) at discharge from Index Admission, the 100th day of Follow-Up, and the 365th day of Follow-Up were determined. Reimbursed amounts (plan payment plus patient liability) were used as a proxy for healthcare costs. Total healthcare costs and LOS between the two cohorts were compared for each of the three evaluation periods using Student's t-tests (unadjusted analyses), and analyses of covariance (ANCOVA; adjusting for differences in age, sex, plan type, geography, year of Index Admission, type of malignancy, Charlson Comorbidity Index score, and pre-admission healthcare cost). Results: 1,635 patients underwent HCT and met all selection criteria (mean age was 48 years, 56% were men, acute myeloid leukemia was the most common malignancy); 42% met the criteria for inclusion in the Acute GvHD cohort. Univariate mean total healthcare costs for the Acute GvHD cohort (vs No Acute GvHD) were $36,651 greater during Index Admission, $83,322 greater at the 100th day of Follow-Up, and $123,220 greater at the end of the 1-year Follow-Up (all p 〈 0.01); additional mean LOS (days) were 5.7 during Index Admission, 14.0 at the 100th day of Follow-Up, and 17.4 at the end of the 1-year Follow-Up (all p 〈 0.01) [Table 1]. Multivariate-adjusted mean total healthcare costs were $24,292 greater during Index Admission (p=0.02), $73,622 greater at the 100th day of Follow-Up (p 〈 0.01), and $114,698 greater at the end of the 1-year Follow-Up (p 〈 0.01); additional LOS was 5.2 during the Index Admission, 14.1 at the end of the 100th day of Follow-Up, and 17.9 at the end of the 1-year Follow-Up (all p 〈 0.01) [Table 2]. Conclusions: Over the one-year period following allogeneic HCT, patients who develop Acute GvHD experience over $100,000 more in total healthcare costs-and nearly three additional weeks in hospital-relative to those who do not. While healthcare claims appear to represent a good source with which to assess the impact of complications of HCT, confirmation with prospective clinical studies is recommended. Given that nearly one-half of patients develop Acute GvHD, our findings suggest that therapeutic strategies that prevent this complication may confer substantial savings to the healthcare system. Disclosures Grubb: Fate Therapeutics: Employment, Equity Ownership. Huse:Evidera: Employment; Fate Therapeutics: Consultancy. Alam:Evidera: Employment; Fate Therapeutics: Consultancy. Dychter:Fate Therapeutics: Employment, Equity Ownership. Wingard:Merck: Consultancy; Ansun: Consultancy; Fate Therapeutics: Consultancy; Gilead: Consultancy; Astellas: Consultancy. Berger:Evidera: Employment; Fate Therapeutics: Consultancy.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.1187.1187

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2016

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Blood, American Society of Hematology, Vol. 129, No. 13 ( 2017-03-30), p. 1831-1839

Kurzfassung: Brain tumor patients have a very high risk of VTE. Podoplanin expression by primary brain tumors induces platelet aggregation and is associated with hypercoagulability and a high risk of VTE.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2016-06-720714

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2017

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Blood, American Society of Hematology, Vol. 133, No. 5 ( 2019-01-31), p. 436-445

Kurzfassung: Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-09-875732

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2019

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1571-1571

Kurzfassung: Chronic myelogenous leukemia (CML) is a bone marrow-derived hematopoietic neoplasm in which BCR/ABL1 acts as a major driver of proliferation, differentiation and survival of leukemic cells. In a majority of all patients with CML, leukemic cells can be kept under control by BCR/ABL1 tyrosine kinase inhibitors (TKI), including imatinib, nilotinib, dasatinib, bosutinib, and ponatinib. Nevertheless, resistance or intolerance against one or more of these TKI may occur. Therefore, current research is focusing on novel potential drug targets in CML. A promising class of targets may be epigenetic regulators of cell growth, such as members of the bromodomain and extra-terminal domain (BET) family. The epigenetic reader and BET family member BRD4 has recently been identified as a novel potential drug target in acute myeloid leukemia (AML). However, so far, little is known about the expression and function of BRD4 in CML cells. The aims of the present study were to determine the expression of BRD4 and its downstream target MYC in CML cells and to explore whether BRD4 can serve as a novel drug target in this disease. As determined by qPCR, primary CML cells (chronic phase patients, n=7) as well as the CML cell lines KU812 and K562 expressed BRD4 mRNA. In addition, both CML cell lines stained positive for BRD4 in our immunocytochemistry staining experiments. In one patient with accelerated phase CML, putative leukemic (CD34+/CD38-) stem cells were sorted to near homogeneity and found to express BRD4 mRNA by qPCR. In order to examine the functional role of BRD4 in CML cells, a BRD4-specific shRNA was applied. In these experiments, the shRNA-induced knockdown of BRD4 in KU812 cells and K562 resulted in reduced growth compared to a control shRNA. Furthermore, the BRD4-targeting drug JQ1 was found to inhibit 3H-thymidine uptake and thus proliferation in KU812 cells in a dose-dependent manner (IC50: 0.25-0.75 µM). In addition, we were able to show that JQ1 inhibits growth of primary CML cells with variable IC50 values (0.1-5 µM). However, no substantial growth-inhibitory effects of JQ1 were seen in K562 cells (IC50: 〉 5 µM). As determined by Annexin V/PI staining, JQ1 induced apoptosis in KU812 cells whereas no apoptosis-inducing effect of JQ1 was observed in K562 cells. Nevertheless, we were able to show that both CML cell lines as well as primary CML cells express MYC mRNA, and treatment of KU812 cells or K562 cells with JQ1 resulted in a decreased expression of MYC mRNA and MYC protein. Next, we analyzed whether MYC expression in CML cells can be blocked by BCR/ABL1 TKI. We found that imatinib, nilotinib, dasatinib, and ponatinib decrease MYC mRNA- and MYC protein expression in KU812 and K562 cells. Finally, we found that JQ1 cooperates with imatinib, nilotinib, ponatinib and dasatinib in inhibiting the proliferation of KU812 and K562 cells. Together, our data show that BRD4 serves as a potential new target in CML cells, and that the BRD4 blocker JQ1 cooperates with BCR/ABL1 TKI in inducing growth-inhibition. Whether BRD4 inhibition is a pharmacologically meaningful approach in patients with TKI-resistant CML remains to be determined in clinical trials. Disclosures Sperr: Ariad: Consultancy; Celgene: Consultancy. Zuber:Mirimus Inc.: Consultancy, Other: Stock holder; Boehringer Ingelheim: Research Funding. Valent:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Celgene: Honoraria.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.1571.1571

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2015

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2884-2884

Kurzfassung: Background: Hypomethylating agents, especially AZA, have become the reference treatment of higher risk MDS, but the median survival of about 2 years obtained with AZA remains modest, and must be further improved. In addition, AZA yields only about 30% of marrow responses (including CR+PR+marrow CR). Intensive chemotherapy combining Idarubicin (IDA) and AraC yields 30 to 50 % CR in higher risk MDS (Beran and all, cancer 2001) and IDA, as single agent, induces about 30% CR in elderly AML patients (Carella, haematologica 1990). We designed a phase I/II study evaluating the safety and efficacy of the combination of AZA and IDA (1 day during each AZA cycle) in higher risk MDS patients (NCT01305135). Methods: Main Inclusion criteria were: (1) IPSS int-2 or high MDS, or CMML with WBC 〈 13 G/l and marrow blasts 〉 10%, or AML with 20-30% marrow blasts (2) Age ≥ 18 years (3) Performance Status (PS) 〈 =2 (4) no prior treatment, except ESAs. Patients received AZA 75 mg/m2/d SC x7d every 4 weeks combined, on day 8 of each cycle (for the first 9 cycles), with IDA 5 mg/m2 (IV) in a first cohort of 10 patients, escalated to 10 mg/m2 IV in a second cohort of 10 patients, followed by an extension study in 21 patients with the IDA 10 mg/m2 schedule. The primary endpoint of the study was response after 6 cycles according to IWG 2006 criteria. Results: Between Dec 2010 and Jan 2014, 41 patients (from 13 centers) were enrolled, including 13 women and 28 men with a median age of 74 years [IQR 70; 76]. At inclusion, WHO classification was RCMD in 1 pt, CMML in 2 pts, RAEB-1 in 10 pts, RAEB-2 in 13 pts, AML in 12 pts and unclassified MDS in 3 pts. Median marrow blast % was 9.5 [IQR: 6-19.9] and karyotype according to IPSS was favorable in 12 (29%), intermediate in 9 (22%) and unfavorable in 18 pts (44%) (2 cytogenetic failures). IPSS was int-2 and high in 56% and 44%, respectively. PS was 0 in 39%, 1 in 55% and 2 in 6% pts. 10 patients received 5 mg/m2 of idarubicin (cohort 1) and 31 received 10 mg/m2 (cohort 2). 375 cycles of AZA were administered (219 of them with AZA+IDA, as IDA was used only for the first 9 cycles), with a median number of 6 cycles/patient (median 6 in the IDA 5 mg/m2 cohort and 4 in the 10 mg/m2 cohort (p=0.9). Of the 41 patients enrolled, 20(48.8%, 95%CI: 32.9-64.9) achieved response (6 CR, 7 PR, 4 mCR and 3 stable disease with HI) with no difference between the two cohorts (50% vs 48%) and a marrow response rate (CR + PR + mCR) of 41,5%. Thirteen of the 22 patients with abnormal karyotype were evaluable for cytogenetic response: 5 achieved cytogenetic response (4 complete, 1 partial), 1 in cohort 1 and 4 in cohort 2. With a median follow up of 14 months, 9 of the 20 responders had relapsed. Median response duration was 11 months [3.2-42.7], with no difference between the two cohorts. Median OS was 14.3 months [IC95%: 12.5; NA] and 2y OS was 24.8%, with no significant difference between the 2 cohorts (p=0.43). By univariate analysis no baseline parameter including gender, karyotype, marrow blast %, IPSS and IDA dosage (5 or 10 mg/m2), had any significant impact on response or survival. 45 SAEs were reported in 26 patients, including febrile neutropenia (n=25), bleeding (n=7) and 2 non-clinically significant reductions in left ventricular ejection fraction (1 transient, and 1 persisting without symptoms). The number of infections per cycle [9/85 (10%) in the IDA 5 mg/m2 arm and 38/281 (14%) in the IDA 10 mg/m2 arm] and the number of bleeding events (9% vs 17%) did not significantly differ between the two cohorts. Conclusion: In our experience, Idarubicin (on day 8 of each cycle) can be combined to Azacitidine without any additional toxicity. The marrow response rate obtained with the combination (41.5%) may be higher than with AZA alone. We are currently comparing in higher risk MDS patients this AZA-IDA combination versus AZA alone (and other combinations of AZA with other drugs) in a prospective randomized GFM trial. Disclosures Sebert: Celgene: Research Funding. Fenaux:Celgene: Research Funding.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.2884.2884

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2015

ZDB Id: 1468538-3

ZDB Id: 80069-7