Objectives and background. Nowadays chronic myeloproliferative neoplasms (MPN) other than chronic myelogenous leukemia undergo renaissance of interest. It results from advances in decryption of molecular mechanisms of pathogenesis and invention of target drugs. Epidemiological information is needed to assess potential effect and additional costs of new diagnostic and therapeutic techniques. The objective of our study was to review experience of MPN diagnostic and treatment in our center for past ten years. Methods. Our institution serves as primary hematological outpatient department for a half of Saint-Petersburg city with about 2 million inhabitants. We reviewed patients' charts to obtain information about incidence, symptoms, diagnostic test results, treatment options and relationship to prognostic factors. Statistical methods included descriptive statistics, nonparametric ANOVA for frequencies comparisons and Kaplan-Meyer method with log-rank test for survival comparisons in Statistica 7.0 package. Results. Since 2004 to 2013 there were 570 newly diagnosed MPN patients (pts) in our center. This group consisted of primary myelofibrosis (PMF) (203 pts; 126 female, 77 male; median age 63 years, range 16-83 years), essential thrombocythemia (ET) (201 pts; 146 female, 55 male; median age 58 years, range 23-78 years), polycythemia vera (PV) (166 pts; 96 female, 70 male; median age 57 years, range 20-85 years). The incidence rates were stable during study period: PMF incidence varied from 0.65 to 1.35 with mean of 1.01 new patient per 100 000 inhabitants per year; ET had incidence from 0.60 to 2.1 with mean of 1.00 and PV had incidence from 0.5 to 1.15 with mean of 0.83. The most prevalent symptoms of disease were: splenomegaly (65.5%), constitutional symptoms (fever, night sweats, weight loss) (31.0%), anemia (36.3%) thrombosis (24.1%) for PMF; fatigue (33.2%), headache and dizziness (25.6%), arthralgia (21.8%), erythromelalgia (15.8%) for ET; plethora (82.5%), headache and dizziness (52.4%), fatigue (31.3%) for PV. JAK2V617F was detected in 49.7% of PMF pts, 57.8% of ET pts and in 97.7% of PV pts. Thrombosis rates according WHO IPSET-thrombosis system risks` groups of ET and PV pts were: low-risk group 3.33% (3/90), intermediate-risk group 11.1% (13/117) and 39.4% (63/160) in high-risk group with highly significant (p<0.0001) differences between risks' groups. There were 169 lethal outcomes in the analysed group (102 PMF; 31 ET; 36 PV). Ten-years overall survival rates were 49.8% in PMF pts, 84.6% in ET pts and 78.3% in PV pts. (fig.1). Overall survival in PMF was significantly influenced by risk stratification as IPSS, DIPSS and DIPSS+. Survival curves according DIPSS+ groups are presented in fig.1. Conclusions. Patients with MPN are presented in substantial number; therefore need much finance for novel therapy introduction. Risk stratification systems has high predictive value. Innovative drugs treatment results should be evaluated in comparison with historical control. Figure1 Overall survival in PMF patients according to DIPPS+ stratification groups. Figure1. Overall survival in PMF patients according to DIPPS+ stratification groups. Disclosures No relevant conflicts of interest to declare.
Objectives and background: Introduction of tyrosine kinase inhibitor (TKI) for the treatment of chronic myeloid leukemia (CML) led to favorable outcome in the majority of patients.About 70% of patients with early molecular response (BCR-ABLIS ≤ 10% at 3-months) have 5-year overall survival of 95%. Nonetheless, CML patients remain heterogeneous group and several studies in recent years were aimed to personalize treatment based on individual patients’ characteristics. One of them was the study by B. Hanfstein et al. (2014), which showed good prognostic potential of 0.35 ratio BCR-ABL level at 3 months to absolute transcript level at diagnosis[1]. In this study, GUS was used as control gene, but at present ABL is normalization gene for BCR-ABL quantification worldwide. One of the obstacles to use of baseline BCR-ABL/ABL level is a distortion of the results of its measurement (non-linearity) due to the mixture of BCR-ABL with normal ABLgene. During the first month of therapy there takes place a rapid tumor mass reduction. The aims of our study were to assess potential of ratio BCR-ABL level at 3 months to baseline and ratio BCR-ABL level at 3 months to 1 month using ABLas control gene to predict optimal response related to individual patient’s tumor characteristic. Methods: Forty-three patients (median age, 50 years; range 24-84; 17 male and 26 female) with chronic phase CML were included in the study, Sokal risk groups were low-23 / intermediate-10 / high-10; 8 patients had EUTOS high-risk. Thirty-one patients started treatment with Imatinib 400 mg/day, 11 patients started with Nilotinib 600 mg/day and 1 patient started with Dasatinib 100 mg/day. Median BCR-ABLIS transcript levels was 18.886% at diagnosis, range 3.390-3185.361%. In all patients BCR-ABL levels were monitored at diagnosis and at 3, 6 and 12 months of treatment, additionally 10 patients from this group had BCR-ABL levels evaluation at 1 month. The ratio of BCR-ABL levels at 3 months to baseline for each patient was calculated. In addition, we calculated ratio of BCR-ABL levels at 3 months to BCR-ABLlevels at 1 month for 10 patients. We performed ROC curve analysis to establish the best cut-off value to predict MMR achievement as optimal treatment results at 12 months. Then we compared predictive sensitivity of our ratio cut-off and early molecular response at 3 months (10% by IS). Statistical analysis was conducted with ROC analysis and Fisher exact test. Results: The ratio BCR-ABL at 3 months to baseline as 0.1 had chosen as best cut-off value (sensitivity 83.33 CI 62.6-95.3; specificity 66.67 CI 34.9-90.1) to predict MMR at 12 months. Nineteen out of 23 patients (82.6%) with ratio below than 0.1 achieved MMR at 12 months, while only 9 of 20 patients (45%) with ratio more than 0.1 had optimal response (hazard ratio = 0.2625; p=0.013). Ratio of BCR-ABL levels at 3 months to BCR-ABL levels at 1 month also showed good results with the same cut-off value – 5 out of 6 patients (83.3%) with ratio BCR-ABL at 3 months to 1 month below than 0.1 achieved MMR, while patients with ratio more than 0.1 none achieved optimal response (p=0.0238). Application of early molecular response at 3 months (10% by IS) yielded worse discrimination results: 25 of 35 (73.9%) patients with BCR-ABL ≤10% at 3 months had achieved MMR at 12 months, whereas 3 of 8 (37.5%) patients with BCR-ABL level >10% had MMR at 1 year (p=0.1036). Moreover application of our cut-off value among patients with BCR-ABL level ≤10% at 3 months allowed us to revealed additional 4 high-risk patients have not reached MMR to a 1 year of therapy. Conclusions: Our study demonstrated that the individual BCR-ABL decline rate from baseline to 3 months might be useful prognostic marker that allowed detecting more patients at risk who had no MMR at 1 year of treatment and ABL should be used as control gene. Also the study showed that the individual ratio of BCR-ABL level at 3 months to 1 month might be studied as more predictive landmark for change of TKI treatment even among these patients that have BCR-ABLlevels ≤10% at 3 months. References: 1. B. Hanfstein, V. Shlyakhto, M. Lauseker et al. Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib. Leukemia. 2014 May 6. doi: 10.1038/leu.2014.153. Disclosures No relevant conflicts of interest to declare.
Results: Serum OPG concentrations increased throughout the study period (p = 7.26x10 -5 ) while RANKL concentrations did not change (p = 0.19). The OPG:RANKL ratio exhibited a 6.2-fold increase between Days 1 and 5. CTX-1 concentrations were lower (p = 0.006) 30 minutes after the 50 U/kg FVIII infusion. CTX-1 response for each participant was assessed using linear regression throughout the time course. Spine L1-L4 Z-score (SZ) and Hip Total Z-score (HTZ) correlate with CTX-1 response (p = 3.4x10 -4 and 0.014, respectively). The mean age of participants was 25.2 ± 2.1 at time of first study visit. Participants had a mean SZ of −0.74 ± 0.34, HTZ of −0.17 ± 0.32, Hip Neck Z-score (HNZ) of −0.16 ± 0.35, and HJHS of 20 ± 5. HTZ and HNZ decreased significantly with patient age (p = 0.027 and 0.032) while SZ and HJHS did not (p = 0.18 and 0.16). Consequently, age correction was applied to BMD comparisons. Statistical comparisons between HAL, EQ-5D-3L, and BHQ answers, BMD data, and HJHS are shown in Table 1. Summary/Conclusion: This prospective study demonstrates a relationship between FVIII deficiency and bone disease in PwH. OPG acts as a decoy ligand to RANKL, inhibiting osteoclastic bone resorption. The observed increase in OPG:RANKL ratio suggests FVIII has a direct impact on this pathway. Decreased CTX-1 concentrations following factor infusion and correlations between CTX-1 response and BMD further suggests that FVIII plays a role in moderating bone remodeling. Hemophilia-associated bone and joint pathology is associated with decreased quality of life. Correlations between BMD and questionnaire responses demonstrate that poor bone and joint health is physically limiting, causes discomfort, and negatively impacts perceptions of personal well-being. Furthermore, correlations between BMD and HJHS and ISTH-BAT responses (Table 1) illustrate a relationship between bleeding management and skeletal health. PwH with lower BMD report more nose and gum bleeds, suggesting a link between FVIII replacement and skeletal health. Bleeds in the extremities were not correlated with decreased BMD or increased HJHS, but abdominal (stomach, iliopsoas) and other bleeds were. Analysis of these data is ongoing.
Introduction. The substitution of brand-name drugs with cheaper generics is a modern tendency in health-care to decrease the burden on government budget and improve access to efficient treatment. Worldwide, generics have to be identical to the original drug in terms of pharmaceutical (active ingredients) and biological (pharmacokinetic) properties. Unfortunately, in Russia, as in most countries, there are no government regulations of equivalency to a brand-name product regarding dosage, strength, route of administration, quality, performance, and intended use. In Russia, since August 2012 the original Imatinib has almost fully been substituted with generics for the treatment of chronic myelogenous leukemia (CML). Aim. To assess tolerance and efficacy of Imatinib generics in terms of response durability by comparing it with that achieved previously in CML patients, who had received treatment with original Imatinib before switching to the generics. Materials and methods. Seventy-nine CML patients treated initially with original Imatinib (Novartis AG) with median treatment duration of 6.5 years (range, 0.5-11 years) were switched to generic drugs. The drugs: 1) GenericPh 100 mg, in capsules (Ph-Syntez, Russia) - 54 patients (44 with complete cytogenetic response (CCyR), including 32 with major molecular response (MMR); 2) GenericG 100 mg, in tablets (Laboratorio TUTEUR S.A.C.I.F.I.A., Argentina) - 25 patients (22 with CCyR, including 19 with MMR). In case of loss of response, besides non-compliance, we changed treatment to second-generation tyrosine kinase inhibitors (TKI2). Switching from one generic to another was made due to intolerance. We analyzed the range and frequency of adverse events (AE) and durability of responses achieved previously (hematologic, cytogenetic and molecular). IRIS data1 was used as a comparator for AE frequency during long-term Imatinib treatment. Statistical analysis included the Fisher exact test. Results. Tolerance of Imatinib generics was good with few exceptions. One patient in the GenericPh group suffered severe edema and was switched to Nilotinib with AE resolution. In the GenericG group 4/25 (16%) patients had severe gastroenterological toxicity (nausea, vomiting, abdominal distension, diarrhea) and were successfully switched to GenericPh. This might have been caused by the tablet filler (lactose) and related to concomitant lactose insufficiency in these patients. One patient had frequent infectious complications. Having stable deep molecular response, she entered the treatment free remission phase and had successful molecular response for more than two years. The frequency of other AEs is presented in Table 1. No significant differences were revealed between the generics and the original Imatinib in comparison with IRIS results. However, only 25% (20) of patients were free of any AE. No progression to AP/BC during the generics treatment was observed. Three deaths were registered (CML-related 1, blastic phase on Dasatinib treatment, the patient had only partial cytogenetic response to Imatinib and was switched to Dasatinib, with progression after 2 years on Dasatinib; cancer -1, cardiovascular disease -1). The patients who had inadequate responses to Imatinib before and after switching on generics were subsequently switched to TKI2: GenericPh - 11 patients (Nilotinib - 9 (CCyR - 8, MMR-7), Dasatinib - 2 (no CCyR with progression - 1, complete hematologic response -1)); GenericG - 3 patients (Nilotinib - 2, both with CCyR and MMR, Dasatinib - 1 -hematologic response with non-compliance). Durability of previousresponses was as follows: 4 patients lost their MMR: 3/54 (5.6%) while taking GenericPh and 1/25 (4%) - GenericG; 3 patients lost their CCyR: 2/54 (3.7%) while taking GenericPh and 1/25 (4%) - GenericG. All those patients were subsequently switched to TKI2 (3 re-achieving previous MMR and 1 demonstrating non-compliance). At the time of analysis there were still 58 (73%) patients on the generics treatment. 57 patients had CCyR and MMR, and one was not cytogenetically evaluated due to non-compliance (BCR-ABL 0.102%). Conclusion. No significant differences between the generics studied and the original Imatinib were observed in terms of their efficacy or tolerability in CML patients who were previously treated with a brand-name drug and subsequently switched to generics. Disclosures Shuvaev: Novartis pharma: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Fominykh:Novartis Pharma: Honoraria; BMS: Honoraria.
Молекулярно-генетический фенотип (носительство одной из мутаций JAK2V617F (JAK2+), MPL (MPL+), CALR (CALR1+-1-й тип, CALR2+-2-й тип), его отсутствие-тройной-негативный (ТН) статус при эссенциальной тромбоцитемии (ЭТ) рассматриваются в качестве фактора, влияющего на развитие тромбогеморрагических осложнений. Цель исследования-оценить наличие и характер взаимосвязей между молекулярно-генетическими нарушениями, клинико-лабораторными параметрами и развитием осложнений, прогнозом течения ЭТ. Методы. Проанализированы данные, полученные на этапе диагностики и последующего динамического наблюдения за 240 пациентами с ЭТ (критерии ВОЗ 2008 г.). Исследовались показатели гемограммы, результаты молекулярно-генетических методов: полиморфизма длин рестрикционных фрагментов (ПДРФ) для определения мутации JAK2V617F, полимеразной цепной реакции с последующим анализом ПДРФ (ПЦР-ПДРФ) для выявления мутаций MPL и прямого секвенирования для обнаружения CALR. Регистрировались тромботические и / или геморрагические осложнения: артериальные / венозные тромбозы, острый инфаркт миокарда (ОИМ), острое нарушение мозгового кровообращения (ОНМК) и кровотечения. Проведен анализ общей выживаемости (ОВ) у пациентов с наличием / отсутствием осложнений, различных групп риска развития тромботических осложнений по шкале риска тромбозов при ЭТ (ВОЗ-ЭТ IPSET-thrombosis).
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