ALBERT

Description: The Journal of Organic Chemistry DOI: 10.1021/acs.joc.5b01474

Description: Background: Daratumumab is one of the most effective new myeloma drugs recently approved for relapsed/refractory multiple myeloma (MM), first in monotherapy in heavily pretreated patients, later in triplet combinations from first relapse, based on the results of the SIRIUS, POLLUX and CASTOR trials that showed good tolerability and high effectivity of daratumumab both in monotherapy and combined with lenalidomide or bortezomib. However, clinical trials are different from real world use for many reasons including less rigorous patient selection, greater flexibility with dosing and country specific funding restrictions making real world data very important for clinicians. Real world data regarding daratumumab use is currently very limited. In the Hungarian system, funding of daratumumab was initiated in December 2016, and required individual preapproved funding requests. Initially only monotherapy was reimbursed in double-refractory patients, but from 2018 triplet combination in earlier lines could start as well. Aims and Methods: The aim of this study was to evaluate the efficacy and safety of daratumumab in the real world practice. We approached all centers in Hungary where daratumumab was used, in a retrospective analysis. The scope of this study was to analyze response rate, progression free survival (PFS), treatment duration, and adverse events (AEs). Statistical analyses were performed using the SPSS (version 20.0) software package. Results: 8 centers responded with 75 patients altogether. Patients were heavily pretreated, the median number of prior lines was 3 (1-12). All patients had prior bortezomib, and most had lenalidomide (82.6%) and thalidomide (86.6%), all but one had one of the two IMiDs. 62.6% of the patients had prior autologous transplantation, with two having prior allograft, as well. Pre-daratumumab cytogenetic FISH tests of 57 patients were available, here 33/57 had high risk cytogenetics. The majority had high international staging system (ISS) score: 8, 16 and 48 were in the ISS 1, 2 and 3 groups respectively. Treatment usually continued until progression, unacceptable toxicity or death, the mean number of cycles was 6. AEs over grade 3 were uncommon, the most frequent AEs were mild infusion associated reactions (IARs, grade 1-2) and infections (Table 1). There were 7 fatal infections, other fatal AEs were absent. Infusion related toxicities were manageable in all cases. The majority of patients (41) had monotherapy with dexamethasone only, but 17 had bortezomib and another 17 lenalidomide combination. Overall response rate was assessable in 66 patients with 7 complete, 8 very good partial, 24 partial, 5 minor responses. 14 showed stable disease, 8 progressive disease. 9 patients had no formal disease reassessment due to either early death or short follow up. There was no clear connection between the number of prior lines and the quality of the response, however those who had either bortezomib or lenalidomid combinations showed better overall response rate (p=0.045). With 43 events so far the estimated PFS and OS were 151 and 260 days, but it was much better in those who showed at least a partial response (PFS 400 days, OS nor reached; Figure 1). The only other factor that significantly affected the PFS was ISS (p=0.039), we could not demonstrate a significant connection between cytogenetics, the number of prior lines, combination therapy and survival. Conclusion: Our results highlight the differences between patients treated in routine practice and those treated in clinical trials. Here treatment protocols were dictated by funding rules, and therefore similar patients were treated with doublets and triplets. The results of the POLLUX and CASTOR trials were superior in comparison to the SIRIUS study with monotherapy, but our results do not reflect this marked difference, probably due to the almost complete absence of 2nd and 3rd line patients who dominated the Pollux and Castor trials. Importantly these heavily pretreated patients tolerated daratumumab well, IARs over grade 2 were absent. Based on our results, daratumumab is an effective treatment option for relapsed/refractory MM with good safety profile. Disclosures Masszi: Janssen-Cilag: Consultancy; Takeda: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; BMS: Consultancy. Illés:Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

Description: Background: Proteasome inhibitors have a fundamental role in the treatment of multiple myeloma however there are still patients who fail to achieve a good response and have a dismal prognosis. Markers predicting the outcome of individual patients are needed to identify those who would benefit more from a different approach. Proteasome subunit beta type 1 (PSMB1) rs12717 single nucleotide polymorphism (C/G substitution resulting in a P11A change) was reported recently to be associated with greater clinical benefit in relapsed follicular lymphoma patients treated with bortezomib containing combination (Coiffier et al Clin Cancer Res 2013). To the best of our knowledge there is only one report with limited number of myeloma patients showing no association between PSMB1 P11A genotype and survival (Lichter et al Blood 2012). Aims and Methods: We analyzed the association of PSMB1 P11A polymorphism and treatment outcome of 220 consecutive myeloma patients having had first line chemotherapy in our unit. PSMB1 P11A polymorphism was tested using LightCycler melting analysis. Statistical analyses were performed using the SPSS (version 20.0) software package. Results: The distribution of presentation prognostic markers such as age, ISS and FISH were even among the three genotype groups. 149 patients had bortezomib-based chemotherapy, mainly VTD (n=76) and MPV (n=47); 63% of these patients had ASCT consolidation. 71 patients had non-bortezomib-containing induction with either thalidomide, lenalidomide or other protocols including MP and VAD; only 28% of these patients had ASCT. In a recessive model the median PFS was 727 (635-818) days in carriers of the wild type C allele either in homozygous of heterozygous form (C/C&C/G, n=188), and only 491 (366-615) days in the homozygous variant G allele carriers (G/G, n=32, p=0.01). In multivariate analysis, C allele carriers had favorable PFS compared to G/G genotype patients with a hazard ratio of 1.402 (1.093-1.799), p=0.008 besides age, ISS, FISH, bortezomib treatment and ASCT. When we analyzed separately the bortezomib-treated and non-bortezomib-treated patients the benefit in PFS was only present in the bortezomib group [Fig 1, PFS 747 (656-837) days in C/C&C/G and 448 (279-616) days in G/G patients, p=0.002], and not in patients treated without bortezomib (p=0.559). We performed statistical interaction testing which showed significant interaction between bortezomib exposure and PSMB1 P11A (p=0.035). Conclusion: PSMB1 P11A is a novel predictive marker in multiple myeloma which could help to identify patients having a suboptimal response to bortezomib who might benefit from alternative management. Disclosures No relevant conflicts of interest to declare.

Description: Due to the evolutionary conservation of the regulation of hematopoiesis, Drosophila provides an excellent model organism to study blood cell differentiation and hematopoietic stem cell (HSC) maintenance. The larvae of Drosophila melanogaster respond to immune induction with the production of special effector blood cells, the lamellocytes, which encapsulate and subsequently kill the invader. Lamellocytes differentiate as a result of a concerted action of all three hematopoietic compartments of the larva: the lymph gland, the circulating hemocytes, and the sessile tissue. Within the lymph gland, the communication of the functional zones, the maintenance of HSC fate, and the differentiation of effector blood cells are regulated by a complex network of signaling pathways. Applying gene conversion, mutational analysis, and a candidate based genetic interaction screen, we investigated the role of Headcase (Hdc), the homolog of the tumor suppressor HECA in the hematopoiesis of Drosophila. We found that naive loss-of-function hdc mutant larvae produce lamellocytes, showing that Hdc has a repressive role in effector blood cell differentiation. We demonstrate that hdc genetically interacts with the Hedgehog and the Decapentaplegic pathways in the hematopoietic niche of the lymph gland. By adding further details to the model of blood cell fate regulation in the lymph gland of the larva, our findings contribute to the better understanding of HSC maintenance.

Description: Background. Myeloma patients reaped immense benefit from the introduction of new classes of drugs over the last decades. This improvement, however, was much less marked in patients with translocation 11;14 [t(11;14)], a group in which immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) - the two most important pillars of current myeloma care - are less effective. This subgroup of patients used to be known for their relatively slow pace of progression often experiencing long plateau phases following autologous stem cell transplantation (ASCT), whereas at the same time t(11;14) is also disproportionately prevalent in difficult to treat clinical entities such as plasma cell leukemia or AL amyloidosis. Venetoclax, a selective bcl-2 inhibitor first approved for CLL was investigated for the treatment of relapsed myeloma patients and although it failed to show benefit for myeloma patients as a whole, t(11;14) patients showed exceptional responses, thus paving the way towards the first genetically targeted treatment in myeloma. As a result, its off label use is on the rise, even though clinicians have to face unanswered questions regarding the right dosage and therapy length, as well as the potential for adverse events (AEs), especially infections. Real world data could help elucidate its optimal use, but is as of yet very limited. Aims and methods. We addressed all Hungarian centers treating myeloma to evaluate the efficacy and safety of venetoclax, collecting data about the treatment duration, AEs, dose modifications and treatment discontinuations, and analysed response rates as well as progression free survival (PFS). Results. 33 patients were reported from 7 Hungarian sites. After the initial analyses, we identified two distinct rationales for venetoclax treatment. 22 patients were relapsed and heavily pretreated with an average of 4.5 prior lines; here venetoclax was chosen as ultimum refugium. In this group, combination partners were bortezomib-dexamethasone (VelDex) in 14 patients, 5 had dexamethasone only, one VRd, one DRd and one Kd. Considering the highly pretreated nature of this group, the overall response rate was a remarkably high 95% with 40.9% partial, 31.8% very good partial, and 22.7% complete responses. Treatment mostly continued until progression. The median PFS and OS calculated from venetoclax initiation were 299 and 437 days. The most common AEs were cytopenias and infections reported in 8 and 6 patients with 1 fatal infection. In the second group, 11 patients received venetoclax after a suboptimal initial response (6 PR, 4 SD, 1 PD) to their first line IMiD+PI combination with the goal of further tumor elimination preceding ASCT. Remarkably, although the length of venetoclax treatment was short - median 2 cycles -, all 11 patients deepened their response to at least VGPR and 7 to CR. 9 patients had ASCT converting 2 further VGPRs into CR, so at the end of the planned protocol 10 of the 11 patients had CR. Venetoclax was combined with VelDex in 9 and VTD in 2 cases, the one year PFS and OS were 91 and 100%, with no venetoclax related AEs reported. An important aspect of our analysis was the question of venetoclax dosing, as the appropriate dose in this indication is not yet clear. Reflecting this uncertainty, as well as funding difficulties with this off-label drug, only one patient received 800 mg dose as seen in the Bellini trial; one received 600 mg daily, with all others taking 400 mg or less. To counteract this lower daily dose available, some centers employed a combination with clarithromycin, a strong CYP3A inhibitor known to increase venetoclax serum levels two- to threefold. Where available, serum venetoclax levels were monitored to ensure serum levels comparable to regular dosing. Another point to emphasize is that 5 patients in the relapsed, and another 2 in the frontline group had deletion 17p, usually resulting in refractoriness to standard treatments. Among these patients however, 5 reached VGPR, 1 PR, and only one progressed on venetoclax treatment. Some responses proved lasting especially in the frontline group. Conclusion. Our results highlight the importance of targeted treatments in multiple myeloma. We experienced lasting responses in quadruple-refractory patients. In the newly diagnosed group where the depth of pre-ASCT response has a big impact on PFS, venetoclax may have a role converting suboptimal responses into CRs by eliminating residual disease. Figure Disclosures Illés: Takeda, Seattle Genetics: Research Funding; Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Celgene, Janssen, Novartis,Roche, Takeda: Consultancy; Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria. OffLabel Disclosure: venetoclax use in t(11;14) myeloma which is not yet licensed

Description: Nomadic groups of conquering Hungarians played a predominant role in Hungarian prehistory, but genetic data are available only from the immigrant elite strata. Most of the 10–11th century remains in the Carpathian Basin belong to common people, whose origin and relation to the immigrant elite have been widely debated. Mitogenome sequences were obtained from 202 individuals with next generation sequencing combined with hybridization capture. Median joining networks were used for phylogenetic analysis. The commoner population was compared to 87 ancient Eurasian populations with sequence-based (Fst) and haplogroup-based population genetic methods. The haplogroup composition of the commoner population markedly differs from that of the elite, and, in contrast to the elite, commoners cluster with European populations. Alongside this, detectable sub-haplogroup sharing indicates admixture between the elite and the commoners. The majority of the 10–11th century commoners most likely represent local populations of the Carpathian Basin, which admixed with the eastern immigrant groups (which included conquering Hungarians).