[Five year experience in ibrutinib therapy for relapsed and refractory mantle cell lymphoma in real world Russian clinical practice].

BACKGROUND: Mantle cell lymphoma (MCL) is a rare and clinically aggressive lymphoma subtype. Current approaches have greatly improved patients outcomes, but relapse is inevitable. In phase IIIII clinical trials, ibrutinib has shown significant activity in patients with relapsed or refractory (R/R) MCL. AIM: To assess efficacy and toxicity of ibrutinib monotherapy in patients with R/R MCL in routine practice outside of clinical trials. MATERIALS AND METHODS: The study enrolled patients with confirmed R/R MCL who had received at least one line of previous chemotherapy. ECOG 24, cytopenia, infectious complications, hemorrhagic syndrome were not exclusion criteria. Patients received daily oral ibrutinib 560 mg until progression or unacceptable toxicity. RESULTS: From May 2015 to September 2020 ibrutinib therapy was started in 106 patients with R/R MCL in 16 regions of Russia. The median age was 66 years; ECOG2 18%, blastoid variant (or Ki6740% or WBC50109/l) 43%. The median number of previous treatment lines was 2 (111). The ORR was 78.4% (CRR 27.4%). The median PFS was 13.6 months and OS 23.2 months. In the blastoid group the median PFS was 4.4 months vs 36.5 months in the alternative group (p0.001), the median OS 9.0 vs 41.0 (p=0.001). The median OS of patients after progression on ibrutinib was 3.2 months. The common complications are hemorrhages (63%), diarrhea (62%), myalgia and muscle cramps (60%), infections (31%), skin and nail toxicity 15%, arrhythmia 8%. None of recipients had to completely discontinue ibrutinib therapy due to complications. CONCLUSION: Ibrutinib is effective and well tolerated in routine practice of R/R MCL treatment and our results are consistent with international clinical trials. The favorable toxicity profile and the high response rate made it possible to prescribe ibrutinib in severe somatic status, cytopenia, and even in the presence of infectious complications.

[Carfilzomib, lenalidomide and dexamethasone in relapsed/refractory multiple myeloma patients: the real-life experience].

BACKGROUND: Carfilzomib, lenalidomide, and dexamethasone (KRd) have been approved for the treatment of relapsed and refractory multiple myeloma (RRMM) based on ASPIRE clinical trial. AIM: Analysis of efficacy and safety of KRd in routine clinical practice. MATERIALS AND METHODS: The prospective analysis included patients with MM who received at least one line of previous therapy. The inclusion criteria were relapse/progression; refractoriness; lack of very good partial response (VGPR) and more after the first line of therapy. Since February 2016, we used KRd like in ASPIRE trial, since October 2019, carfilzomib has been used at a dose of 56 mg/m2 on days 1, 8 and 15. Autologous hematopoietic stem cell transplantation (autoHSCT), consolidation (KRd) and maintenance therapy (Rd) were regarded as one line of therapy. RESULTS AND DISCUSSION: We evaluated 77 patients with median age at the time of diagnosis is 55 (3072) years. For 56% (n=43) of patients KRd was applied as the second line (group 1), for 44% (n=34) as the third and more (group 2). In 23/43 patients from group 1, an early change in therapy was made due to insufficient effectiveness (after 24 courses of VCD or PAD). KRd served as a "bridge" to autoHSCT in 25 (32%) patients (21 of 25 in group 1). Another 7 patients underwent collection of autoHSC (all from group 1). The overall response rate (ORR) was 80.5%, with 33.8% complete response (CR) and 26% VGPR. ORR in group 1 was 98% versus 65.6% in group 2; 24-month overall survival (OS) was 70%, progression free survival (PFS) 49.8%. In group 1, 24-month OS was 85.6% versus 50.0% in group 2, 24-month PFS was 67.8% versus 25.5% (p=0.01). CONCLUSION: Our analysis confirmed the high efficiency of KRd in the treatment of RRMM in real-life practice. Early correction of therapy with insufficient effectiveness of the first line made it possible to implement the strategy of high-dose consolidation and autoHSCT in a larger percentage of patients with MM.

[Risk - adapted intensive induction therapy, autologous stem cell transplantation, and rituximab maintenance allow to reach a high 7-year survival rate in patients with mantle cell lymphoma].

Mantle cell lymphoma (MCL) is aggressive B-cell neoplasm diagnosed predominantly among older men. R-CHOP-like regimens allow to achieve high response rate, but the overall survival (OS) are disappointingly short - 3-4 years. An addition of high - dose cytarabine to the upfront therapy and autoSCT significantly improved outcomes but remain feasible largely for medically fit patients. Based on the activity and good tolerance of gemcitabine - oxaliplatin schemes in relapsed and refractory MCL patients, we developed an alternative first - line course for patients who are not eligible for R-HD-MTX-AraC. AIM: Assess toxicity and efficacy of R-DA-EPOCH/ R-HD-MTX-AraC and R-DA-EPOCH/R-GIDIOX schemes, autoSCT and R-maintenance in untreated MCL patients. MATERIALS AND METHODS: 47 untreated MCL patients from 6 centers were enrolled in prospective study between April 2008 and September 2013. All patients have stage II-V; ECOG 0-3; median age 55 years (29-64); Male/Female 76%/24%. MIPIb: 28% low, 33% intermediate and 39% high risk. Following 1st R-EPOCH patients were assigned to receive either R-DA-EPOCH/ R-HD-MTX-AraC or R-DA-EPOCH/ R-GIDIOX regimen. In the absence of renal failure, hematological toxicity grade 4 more than 3 days and severe infections patients received R-HD-MTX-AraC scheme (R 375 mg/m2 Day 0, Methotrexate 1000 mg/m2/24 hours Day 1, AraC 3000 mg/m2 q 12 hrs Days 2-3). Patients who had at least one of these complications received R-GIDIOX scheme (R 375 mg/m2 day 0, gemcitabine 800 mg/m2 days 1 and 4, ifosfamide 1000 mg/m2 days 1-5, dexamethasone 10 mg/m2 IV days 1-5, irinotecan 100 mg/m2 day 3, oxaliplatin 120 mg/m2 day 2). Subsequently these courses were alternating with R-DA-EPOCH in each arm of the protocol. Depending on the time of achieving CR patients received 6 or 8 courses, unless they progressed on therapy. Those patients who achieved PR/CR/CRu underwent autoSCT (BEAM-R). Post - transplant R-maintenance was administered for 3 years (R - 375 mg/m2 every 3 months). RESULTS: 29/47 patients were treated on R-HD-MTX-AraC arm (median 50 years; MIPIb: 35.7% low, 28.6% intermediate, 35.7% high risk) and 18/47 patients were on R-GIDIOX arm (median 60 years; MIPIb: 16.7% low, 38.9% intermediate, 44.4% high risk). In R-HD-MTX-AraC arm CR rate was 96.5%. In R-GIDIOX arm OR and CR rates were 94.4% and 77.7% respectively. Main hematological toxicity of R-GIDIOX was leukopenia gr. 4 occurred in 74.1%. With median follow - up of 76 months, the estimated 7-years OS and EFS in R-HD-MTX-AraC arm are 76% and 57% respectively. In R-GIDIOX arm the estimated 7-years OS and EFS are 59% and 44%, respectively. There are no statistical differences in EFS (p=0.47) and OS (p=0.06) between two arms. CONCLUSIONS: The use of a risk - adapted strategy allowed 95.7% of patients achieve PR/CR/CRu, performed autoSCT and begun R-maintenance therapy with rituximab. None of the patients needed a premature discontinuation of therapy because of unacceptable toxicity. The performance of autoSCT and R-maintenance apparently allowed to partially offset differences in the intensity of induction therapy and to maintain comparable results of therapy in both induction arms.

[Epidemiology of multiple myeloma in city Moscow].

AIM: To study the epidemiology of multiple myeloma in the city of Moscow and compare the results obtained with data from similar studies in other countries. MATERIALS AND METHODS: The study is based on information from a database of case histories of 3942 patients suffering from symptomatic MM, residents of the city of Moscow, which is maintained at the Hematologic Moscow City Center of S.P. Botkin Municipal Clinical Hospital. The control of the completeness of inclusion was carried out by cross - comparison with the data of the Moscow Cancer Register and the Register of Program 7 (beginning in 2019 - 12) of Highly Expensive Nosologies. The assessment was made according to data as of January 1, 2019. The calculations were carried out taking into account the data of Rosstat at the beginning of 2019 on the population of Moscow in different gender and age categories. RESULTS: Among the 3942 patients with active MM 1707 men - 43% and 2241 women - 57%, the median of the current age was 68 (28-94) years. The median time of observation of patients since the diagnosis of the disease 34 (1-423) months. The peak incidence was in the age range of more than 60 years. There were no significant differences in gender ratio in different age strata with a breakdown of 10 years. The number of cases of newly diagnosed MM per year for the period from 2009 (n=219) to 2018 (n=385) increased by 75.8%. At the same time, the demonstrated increase in the incidence rate for the described period turned out to be fair only for groups of patients over 50 years old, with the maximum increase in this indicator over the described period in the age range of 60-69 years. This is mainly due to the increase in life expectancy in Moscow in recent years. The study demonstrated that over the past 10 years, the average annual mortality rate from MM has decreased in Moscow, and as a result, its prevalence has increased. The rate of 2-year overall survival of patients with MM was 76%, 5-year - old - 49%, 10-year - old - 27%. The median overall survival of patients under the age of 65 when diagnosing the disease was 79 months, and 48 months. The distribution of patients within international classifications was consistent with international data. CONCLUSIONS: The study revealed a significant dynamic of the epidemiological situation concerning MM in Moscow. Over the past 10 years there has been an increase in the incidence of MM, as a result of an increase in the life expectancy of the population. The use of modern diagnostics and therapy of MM in real clinical practice has led to a significant reduction in mortality. Due to these factors, an increase in the prevalence of MM in Moscow has taken place, and this process will no doubt progress in the future.

[Therapy for Burkitt's lymphoma according to the BL-M-04 protocol: 12-year experience].

AIM: To evaluate the efficiency and toxicity of the intensive Burkitt's lymphoma (BL) therapy protocol BL-M-04. SUBJECTS AND METHODS: A total of 70 patients diagnosed with BL, including 45 men and 25 women whose age was 15 to 62 years (median age 31 years), were followed up in 2003 to 2014. Stage I (according to S. Murphy) was diagnosed in 4 (5.7%) patients; II in 9 (12.9%), III in 25 (35.7%), IV in 11 (15.7%), and Burkitt's leukemia in 21 (30%). There were tumor involvements of the bone marrow and central nervous system in 23 (32.9%) and 15 (21.4%) patients, respectively. B symptoms were detected in 56 (80%) patients; enhanced lactate dehydrogenase (LDH) activity was found in 50 (78.1%) out of 64 patients; moreover, in 34 (56.2%) out of 64 patients, LDH activity was more than twice as high as the reference values. The median LDH activity was 2398 (238-20,300) U/I. Acute renal failure at disease onset was identified in 17 (24.2%) patients; chemotherapy was initiated in 8 patients during renal replacement therapy. The treatment was performed using the BL-M-04±R protocol (4 successive blocks of A-C-A-C±R). Six blocks of A-C-A-C-A-C with rituximab has been carried out in patients with bone marrow involvement since 2011. RESULTS: Sixty-two (89%) patients achieved complete remission. At this time, 6 patients died from therapy complications during remission induction; 2 patients were observed to have disease progression; 3 developed disease recurrence (2 patients had early recurrence; 1 patient developed recurrence 2 years after treatment). Five-year overall survival (OS) was 85%; 5-year relapse-free survival (RFS) was 95%. The Cox multivariate regression analysis revealed that Burkitt's leukemia and bone marrow involvement were independent factors that influenced OS and RFS. The poor somatic status (3-4 ECOC scores versus 0-2 scores) proved to be statistically significant for OS rather than RFS. CONCLUSION: Despite the optimistic results obtained by our study group, there is a need to further improve BL treatment protocols and to elaborate novel approaches to therapy particularly for older patients and patients with Burkitt's leukemia.

[Study of functional interhemispheric asymmetry in children in the context of electrophysiological markers and the efficiency of neurological rehabilitation]. / Issledovanie funktsional'noi mezhpolusharnoi asimmetrii mozga detei v aspekte ee élektrofiziologicheskikh markerov i éffektivnosti neiroreabilitatsii.

The paper presents neurological findings of children and adolescents, which included the determination of the individual profile of cerebral asymmetry by 3 spheres: motor, sensory, and mental, as well as electrophysiological measurement. To develop biology teaching methods by taking into account the individual profile of pupils' brain asymmetry is an aim of this study.

[Psychophysiological health aspects of population living in radiation-contaminated territories]. / Psikhofiziologicheskie aspekty zdorov'ia naseleniia radiatsionno zagriaznennykh territorii.

A combined psychophysiologic study of 100 individuals living in territories contaminated by radionuclides and 60 people from ecologically clean region. There were no significant differences in the incidence of neurotic disorders between people from these regions (61.2 and 65.3%, respectively). The highest sensitivity to small radiation doses was observed at rather young age (20-40 years). It was found that a considerable role in the development of borderline psychic disorders belongs to both somatic disturbances due to low-dose radiation and psychogenic effects. A combined action of psychogenic and somatogenic factors aggravated symptoms of neurotic disorders and promoted widening of a range of psychic disturbances. Some part of the population from the contaminated territories tended to the development of cerebro-vascular psychoorganic pathology resultant from a breakdown of the reserves of the adaptation. Now the stress factor of radionuclides exposure is not so important as social and economic problems.