[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.

[CNS involvement and the feasibility of intratecal chemotherapy administration in patients with a nodal form of diffuse large B-cell lymphoma not otherwise specified. Data of prospective study].

Aim of the issue was to determine indications for intratecal chemotherapy drugs administration to prevent relapse of diffuse large B-cell lymphoma (DLBCL) with central nervous system (CNS) involvement. MATERIALS AND METHODS: Since January 2009 to December 2018 102 patients with primary nodal DLBCL over 18 years old were treated in the National Research Center for Hematology, Moscow, Russian Federation. Diagnosis were established in all cases according to histological and immunohistochemical studies which made it possible to exclude the transformation of mature B-cell lymphoma into DLBCL. RESULTS: Isolated leptomeningeal involvement of CNS in the debut of the disease was detected in 1 (0.98%) out of 102 patients with DLBCL. Focal brain tissue involvement was not detected in any patient. More than half of the patients (54%) had a high risk of disease recurrence or progression with CNS involvement: in 8 (7.8%) patients had kidney/adrenal involvement, in the same proportion - bone marrow involvement, paranasal sinuses involvement - in 5 (4.9 %), epidural space - in 7 (6.9%) and breast - in 5 (4.9%) of patients. In 82 (80%) patients, a non-GCB (postgerminal differentiation of B-cell analog) molecular subtype of DLBCL was determined. CONCLUSION: The introduction of chemotherapy drugs into the spinal canal is recommended in isolated cases of leptomeningeal involvement of CNS at the time of DLBCL onset and is carried out according to standard recommendations. Prevention of relapse with involvement of central nervous system using intratecal chemotherapy in patients with nodal form of DLBCL is not indicated due to the absence of cases with disease progression or recurrence into CNS when patients were treated with R-m-NHL-BFM-90, R-DA-EPOCH and R-CHOP protocol.

[Clinical features and diagnosis of Ph - negative myeloproliferative neoplasms occurring in conjunction with the antiphospholipid syndrome].

Thrombosis is a serious and extremely dangerous disease that has a negative impact on the quality and longevity. Antiphospholipid syndrome (APS) is a pathology characterized by recurring venous, arterial, microvasculature thrombosis, pregnancy pathology with loss of the fetus and the synthesis of antiphospholipid antibodies. A high risk of thrombotic complications is also observed in patients with myeloproliferative neoplasms (MPN). This article presents a description of three clinical cases of Ph - negative myeloproliferative diseases, occurring in conjunction with APS. In all cases, recurrent thrombosis allowed to suspect the presence of two diseases - MPN and APS.

[Nodular lymphocyte-predominant Hodgkin's lymphoma: Principles of diagnosis and treatment].

AIM: To describe the clinical and morphological features of the rare Hodgkin's lymphoma (HL) subtype--nodular lymphocyte-predominant HL (NLPHL). SUBJECTS AND METHODS: Forty-two patients were diagnosed with NLPHL in 2010 to 2014. The male to female ratio was 2.2:1; the median age was 37 years (range 17-68 years). NLPHL was diagnosed on the basis of the histological and immunohistochemical examinations of tumor biopsy specimens; disease stages were determined by standard HL studies. RESULTS: Before NLPHL was detected, 23 (55%) patients were diagnosed as having HL in 13 cases, follicular lymphoma in 2, lymphofollicular hyperplasia in 3, angioimmunoblastic lymphoma in 1, diffuse large B-cell lymphoma in 3, and B-cell lymphoma (non-HL) in 1. Long-term (3-21-year; median 8 years) persistent lymphadenopathy was observed in 16 (38%) patients. Seventeen (40.5%) patients had early (I-II) stages of the disease and 25 (59.5%) had advanced stages. B symptoms were noted in 24% of cases. There was involvement of extranodal sites (salivary gland, tonsil) in 2 patients, spleen in 14 (33%), bone marrow in 8, and bulky disease in 2. Cycles of ABVD ± rituximab ± radiotherapy (RT) were used in early-stage NLPHL; those of R-BEACOPP-14 ± RT were performed in the advanced stages of the disease or its transformation to diffuse large B-cell lymphoma with excessive T cells. CONCLUSION: When patients have a history of long-term asymptomatic lymphadenopathy, it is necessary to rule out NLPHL, for which purpose an immunohistochemical examination of a biopsy specimen and its reexamination in a laboratory having experience in diagnosing NLPHL must necessarily be done. Lower RT doses and rituximab incorporated into the cycle of treatment are indicated to reduce its toxicity and to preserve therapeutic efficiency.

[Thrombosis of the sinus durae matris as a complication of therapy in patients with Hodgkin lymphoma].

AIM: To describe thrombosis of the sinus durae matris (TSDM) in lymphomas. SUBJECTS AND METHODS: 402 patients with Hodgkin lymphoma were treated using the BEACOPP-14 protocol in 2006 to 2013. Thrombotic events occurred in 6% of the patients, including 3 (0.8%) who developed brain magnetic resonance imaging-verified TSDM. RESULTS: TSDM developed in 3 women aged 17, 18, and 25 years during 3-6 chemotherapy cycles involving glucocorticosteroids in a dose of 80 mg/m2 on days 1-7 and an oral contraceptive used continuously for 1.5-3 months. The symptoms of thrombosis were severe headache; 2 patients had convulsive syndrome with short-term loss of consciousness. Anticoagulant therapy with intravenous heparin 20,000--24,000 U/day led to thrombus recanalization within 4-10 days. No rethromoboses were observed during a subsequent follow-up. CONCLUSION: The BEACOPP-14 treatment in young women with Hodgkin lymphoma who continuously take oral contraceptives should be combined with anticoagulant therapy, by monitoring their coagulogram.

[Tuberculosis in patients with lymphoproliferative diseases].

AIM: To study the clinical manifestations, diagnosis, and treatment of lymphoproliferative diseases (LPD) concurrent with tuberculosis. SUBJECTS AND METHODS: In 1990 to 2013, the Hematology Research Center, Ministry of Health of Russia, followed up 4422 patients with LPD. Lymphomas and leukemias were diagnosed using the universally protocols. Tuberculosis was verified by the results of a comprehensive examination involving the histological study of biopsy specimens. RESULTS: Tuberculosis was identified in 85 (2%) patients with LPD. According to the nosological entity, the tuberculosis detection rates were 3% (40/1350) in Hodgkin lymphoma (HL), 1.2% (20/1627) in aggressive lymphomas, 1.4% (16/1136) in mature cell lymphomas and chronic lymphocytic leukemia, and 2.9% (9/309) in hairy cell leukemia. In accordance with its site, pulmonary tuberculosis was 73%; extrapulmonary tuberculosis, 14%; generalized tuberculosis, 12%. In pulmonary tuberculosis, its disseminated and focal involvements were found in 71 and 18% of cases, respectively. Tuberculosis was detected in 43% of the patients with HL in remission; it occurred only in other hemoblastoses in its active phase. When tuberculosis and LPD were simultaneously found, both diseases were concurrently treated. If the chemotherapy of LPD was effective, tuberculosis was cured in all the patients. CONCLUSION: Patients with LPD are a group at increased risk for tuberculosis. The diagnosis of recurrent LPD must be histologically proven. When tuberculosis and LPD are simultaneously found, both diseases should be concurrently treated.

[The phenomenon of vascular microthrombosis in mucoperichondrium associated with plastic closure of nasal septum perforations].

The objective of the present study was to identify specific hematological features characterizing the pathophysological processes of clinical significance associated with plastic closure of nasal septum perforations. Changes of clinical, biochemical, and coagulation-related blood characteristics developing as a result of the surgical treatment of the patients with ENT pathology were analysed. It was shown that D-dimer is a specific hematological characteristic that reflects the phenomenon of postoperative vascular microthrombosis in mucoperichondrial-periosteal flaps associated with plastic closure of nasal septum perforations. Based on the results of this study, the authors recommend to prescribe low-molecular weight heparins for prophylactic purposes to the patients undergoing plastic closure of nasal septum perforations.

[Experience with outpatient treatment for thromboses and thrombophilias].

AIM: To evaluate the efficiency of diagnosis and treatment of thromboses in patients with thrombophilia in an outpatient setting. SUBJECTS AND METHODS: One hundred and seventy-two patients with different forms of thrombophilic states were examined. One hundred and thirty-two patients were found to have genetic mutations, of them 125 patients had multiple mutations. Thromboses were diagnosed in 130 patients with genetic disorders. RESULTS: The most common laboratory markers of thrombophilias were hyperhomocysteinemia (55%), sticky platelet syndrome (41%), and laboratory findings of antiphospholipid syndrome. Thrombogenic mutations, such as plasminogen activator plasminogen inhibitor-1 (73%), methylene tetrahydrofolate reductase (60%), platelet glycoprotein 1a receptors (50%), and fibrinogen (42%), were most often diagnosed. The efficiency of treatment was shown to largely depend on the duration of an initial thrombotic process. CONCLUSION: Outpatient treatment for thromboses is more economical and comfortable for patients. To avoid hospital admissions, it is necessary to time detect the disease and to start its treatment as soon as possible. The concurrent use of ultrasonography, genetic and laboratory diagnostic methods accelerates the identification and localization of the pathology, which facilitates its treatment and frequently rules out the need for patient hospitalization.

[Efficacy of therapy of different variants of anaplastic large T-cell lymphomas].

AIM: To compare efficacy of NHL-BFM-90 and CHOP-like courses in the treatment of anaplastic large cell lymphoma (ALCL). MATERIAL AND METHODS: Twenty-two patients with ALCL participated in the study. The diagnosis was made basing on the findings of clinical, device, morphological, immunohistochemical and molecular-genetic examinations with application of a panel of monoclonal antibodies to CD30, ALK, CD3, CD4, CDS, CD7, CD34, CD15, CD68, CD20, CD45RO, CD45RA, Ki-67. 14 cases of 22 were negative by kinase of anaplastic lymphocytes (ALK-) and 8 were positive (ALK+). Mean age of ALK-ALCL patients was 39.6 +/- 4.1 years, of ALK+ALCL patients - 23.4 +/- 2.6 years. 14 patients were treated by the protocol NHL-BFM-90, 8 were initially treated with other schemes (CHOP, MACOP-B, BEACOPP and others). All 14 patients treated according to NHL-BFM-90 had ALCL stages III-IV with B-symptoms. 12 patients who completed treatment by the above protocol achieved complete remission after the forth course, 2 patients failed the treatment. Of 8 ALCL patients treated initially according to other schemes, a complete remission was achieved in 4 patients (2 had stage II). One of 4 patients with remission had recurrence. Four patients who had failed to achieve complete remission died of the disease progression. CONCLUSION: ALCL occurs more frequently in young and middle-aged patients. The disease has an aggressive course with rapid generalization. For such processes it is more preferable to use a modified protocol NHL-BFM-90.

[The modified program NHL-BFM-90 in the treatment of patients with diffuse large B-cell lymphosarcoma].

AIM: To investigate efficacy of the modified protocol NHL-BFM-90 in patients with diffuse large B-cell lymphosarcoma (DLBCLS). MATERIAL AND METHODS: A total of 13 DLBCLS patients with stage II-IV of the disease with affection of lymph nodes at the disease onset (nodal lesion) and stage II with tumor size more than 10 cm (bulky disease) received first-line treatment according to the modified program NHL-BFM-90 from 2002 to 2005. The diagnosis was made by WHO criteria. RESULTS: A complete remission was achieved in 76.9% patients. Resistance to therapy was observed in the patients with bone marrow affection. The 2.5-year overall survival was 74%, 2-year event-free survival was 75% (the events were recurrence and resistance). Follow-up continued from 5 to 47 months. CONCLUSION: The efficacy of the modified protocol NHL-BFM-90 in DLBCLS patients with stage III-IV of the "nodal" disease and stage II of the "bulky" disease was high.

[A CHOP-21 course efficacy in therapy of diffuse large B-cell lymphosarcoma].

AIM: To examine efficacy of polychemotherapy (PCT) CHOP-21 in patients with diffuse large B-cell lymphosarcoma (DLBCL). MATERIAL AND METHODS: Fifty-five DLBCL patients received first-line therapy according to CHOP-21 program in 1996-2004. The diagnosis was made by WHO criteria. RESULTS: Initially, 37 patients had lymph node lesions, 18--nonlymphatic lesions. Complete remissions were achieved in 49% (56.7% in nodal lesions, 33.3% in extranodal ones). Overall 5-year survival was 35%, event-free--25%, for patients with nodal lesions--36 and 32%, respectively, extranodal lesions--35 and 22%, respectively. Overall 5-year and event-free survival in patients with local lesions was 85 and 75%, generalized--25 and 20%, respectively. In patients with involvement of the gastrointestinal tract 3-year overall and event-free survival reached 50 and 45%. Event-free survival was not seen in patients with extranodal lesions of other locations in overall 3-year survival 45%. CONCLUSION: PCT program CHOP-21 was effective in DLBCL patients with local nodular lesions except cases with large-size tumors, invasion in the adjacent organs and tissues and isolated gastric lesion.

[Opportunities of delayed densitometry of "late (fixed) contrast" as a test for tumors in residual mediastinal lesion in primary mediastinal lymphosarcoma after polychemotherapy]. / Vozmozhnosti sposoba otsrochennoi densitometrii "pozdnego (fiksirovannogo) kontrasta", primeniaemogo v kachestve testa opukholi v ostatochnom obrazovanii sredosteniia pri pervichnykh mediastinal'nykh limfosarkomakh posle okonchaniia polikhimioterapii.

AIM: To clarify the potential of delayed densitometry of late (fixed) contrast in differentiation between tumor and fibrosis in residual mediastinal lesion (RML). MATERIAL AND METHODS: Computed tomography (computed tomograph of the third generation COMATOM CR-3 made in Germany, SIEMENS) has examined 12 patients with mediastinal lymphosarcomas after polychemotherapy. All of them had a RML 3 to 6 cm in diameter. RESULTS: CT has detected 8 cases of the tumor and 4 cases of fibrosis. The criteria of the tumor were the following: increased RML density shortly after the contrast medium introduction and 30 min after urographine introduction (p < 0.01); RML density 30 min after introduction of contrast medium was higher than above the aorta (p < 0.01). Fibrosis in RML was stated if RML density before, at the high of concentration and after introduction of the contrast medium was the same (p > 0.01); aortic density was significantly higher of RML density at the height of the contrast (p < 0.01). CONCLUSION: The above method differentiates the tumor with fibrosis in RML with maximal probability. This facilitates further choice of therapeutic policy in secondary resistant form of primary mediastinal lymphosarcoma.

[Plasmapheresis in combine therapy of hypercoagulation syndrome in hematogenic thrombophilia]. / Plazmaferez v kompleksnoi terapii giperkoaguliatsionnogo sindroma pri gematogennykh trombofiliiakh.

AIM: To specify indications to plasmapheresis (PA) and to assess its efficiency in patients with hypercoagulatory syndrome in hematogenic thrombophilia (HT). MATERIAL AND METHODS: 18 patients (11 males, 7 females, age 26-50 years) with various forms of HT received standard antiaggregation, anticoagulatory therapy plus therapeutic PA. By PA technique the patients were divided into two groups. RESULTS: A positive trend in clinical, instrumental and laboratory indices was observed in all the patients. CONCLUSION: Therapeutic PA in hypercoagulation syndrome in HT patients leads to fast normalization of the clinical picture and reestablishment of patency of thrombus-affected vessels.

[The 1st results of the combined therapy of recurrent and refractory forms of lymphogranulomatosis (polychemotherapy, radiation therapy and the removal of the residual mediastinal formation)]. / Pervye rezul'taty kombinirovannoi terapii retsidivnykh i refrakternykh form limfogranulematoza (polikhimioterapiia, luchevaia terapiia, udalenie ostatochnogo mediastinal'nogo obrazovaniia).

AIM: To achieve a maximal complete remission rate in patients with recurrent and refractory Hodgkin's disease. To find out a group of patients in whom surgical removal of the residual mediastinal mass would be most effective. MATERIAL AND METHODS: 46 patients with Hodgkin's disease received Dexa-BEAM chemotherapy followed by radiotherapy. Surgical removal of the residual mediastinal mass was made in 12 patients. RESULTS: Second-line Dexa-BEAM therapy produced a 50% complete remission rate. Overall survival was 45.5%, the disease-free survival--43.5%. Removed mediastinal masses were indicative of Hodgkin's disease in 7 cases and fibrosis in 4 cases. CONCLUSION: Dexa-BEAM is an effective program in the treatment of recurrent and refractory Hodgkin's disease. Surgical removal of the residual mediastinal mass with radiotherapy and high-dose chemotherapy improves prognosis in very unfavorable, primary progressive form of Hodgkin's disease.

[Protection of reproduction function in women with Hodgkin's disease in the course of polychemotherapy]. / Sokhranenie reproduktivnoi funktsii pri provedenii polikhimioterapii u zhenshchin, stradaiushchikh limfogranulomatozom.

AIM: To evaluate efficiency of estrogen-gestagen treatment for protection of the ovaries during polychemotherapy. MATERIALS AND METHODS: Ultrasonography of the pelvic organs, radioimmunoassay of LH, FSH, prolactin, E2, testosterone were performed in 95 women of child-bearing age with different stages of Hodgkin's disease. RESULTS: Cytostatic therapy of Hodgkin's disease had ovariotoxic effects and led to amenorrhea in 83% of the examinees. Regular estrogen-gestagen treatment protected ovaries in 86% of the patients. CONCLUSION: It is recommended for women to take estrogen-gestagen drugs to protect ovaries during polychemotherapy of Hodgkin's disease.

[Acute and chronic renal failure in patients with myeloma]. / Ostraia i khronicheskaia pochechnaia nedostatochnost' u bol'nykh mielomnoi bolezn'iu.

AIM: To analyze causes of reversible and irreversible renal failure in myeloma patients, lethal outcomes, treatment policy. MATERIALS AND METHODS: 43 myeloma patients with renal failure entered the trial. The replacement therapy consisted of hemodialysis, hemofiltration, hemodiafiltration. All the patients received full-dose polychemotherapy according to the programs M-2 and VAD. RESULTS: 69% of the patients retained normal renal function. 23% of the patients died. Partial recovery of renal function was observed in 1 patient who had to undergo dialysis once in 10-12 days. The patients survived from 5 days to 36 months (mean 20.6 months). The main causes of death in renal failure were sepsis (38%) and hemorrhagic stroke (14%).

[Coagulation system in patients with blood malignancies treated with estrogens in the course of cytostatic therapy]. / Sostoianie svertyvaiushchei sistemy krovi u patsientok s onkogematologicheskimi zabolevaniiami, prinimaiushchikh éstrogengestagennye preparaty v period provedeniia tsitostaticheskoi terapii.

AIM: To evaluate the effect of estrogen gestagenic drugs (EGD) on blood coagulation in patients with blood malignancies treated by polychemotherapy. MATERIALS AND METHODS: 32 females of reproductive age treated with ovarioprotector marvelon during cytostatic therapy. The following indices were determined: activated partial thrombin time, prothrombin index of the ethanol test, fibrinogen and antithrombin III levels, factor XIIa dependent time of fibrinolysis, thrombin time. Dopplerography of the lower limb vessels was carried out. RESULTS: No significant alterations in coagulograms of the patients treated with cytostatics in combination with EGD were recorded. CONCLUSION: It is safe to use EGD as ovarioprotectors in females with hematological malignancies in hypercoagulation.

[The factors of hereditary predisposition to lymphogranulomatosis]. / Faktory nasledstvennoi predraspolozhennosti k limfogranulematozu.

AIM: To determine genetic factors of predisposition marked HLA with reference to serological and molecular characteristics. MATERIALS AND METHODS: Four groups of patients were included in the study: 51 patients with lymphogranulomatosis (LGM), 33 healthy relatives of these patients, 37 patients with chronic myeloid leukemia (CML), 24 healthy relatives of these CML patients. 224 donors served control. HLA-antigens were identified with the lymphocytoxic test and PSR-MSSR. Results of typing of class II antigens were taken into consideration in coincidence of serological and DNA typing. The significance of the differences was estimated according to the chi-square criterion. RESULTS: Differences in frequency of distribution of HLA-antigens (subloci A and B) were not found. Antigen CW7 was present in 70, DR5 in 60, DR6 in 50% of LGM patients. This frequency was much higher than in control groups. Carriers of CW7 are at 7 times higher risk to develop LGM. Among LGM patients the number of homozygous individuals is higher than in healthy ones (50 and 15.6%) while the number of individuals with a complete set of HLA-A.B antigens is significantly less. CONCLUSION: Genetic predisposition to LGM is predetermined by HLA antigens CW7, DR5, DR6. Genes HLA-DR1 and HLA-DR7 protect carriers from factors provoking LGM. Common HLA genes in the parents predispose their children to LGM. Insufficiency of the phenotype is a factor predisposing to LGM.

[The prevention of reproductive disorders occurring during the chemotherapy of women of child-bearing age suffering from Hodgkin's disease]. / Profilaktika reproduktivnykh narushenii, voznikaiushchikh v protsesse khimioterapii u zhenshchin detorodnogo vozrasta, stradaiushchikh bolezn'iu Khodzhkina.

A menstrual function was studied in 24 females treated by drugs for advanced stages of Hodgkin's disease. 17 of them received oral contraceptives for preventing gonadotoxic effect of cytostatic agents (the study group). 7 women did not use contraceptives (the control group). After chemotherapy menstrual cycle was normal in 88.2% of patients of the study group, whereas in 71.4% of controls artificial menopause developed. Oral contraceptives can be recommended to protect the ovaries in the course of chemotherapy.