Background:The prognosis after frontline therapy in B‐ALL patients has improved due to monoclonal antibodies (CD20, CD19, CD22) and approximately 90% of patients achieve complete remission. In relapsed and refractory (R/R) and also in MRD+ B‐ALL outcomes are relatively poor. Disease‐free survival (DFS) in this cohort is 10–20%. Conventional chemotherapy is associated with high failure rate and significant toxicity. Immunotherapy with monoclonal antibodies and CAR‐T are the promising approaches.Aims:The aim was to evaluate the efficacy (frequency of responses, OS, DFS) and toxicity, especially neurotoxicity and cytokine‐release syndrome, of a bispecific monoclonal antibody blinatumomab in patients both children and adults with persistence of minimal residual disease (MRD+) or R/R B‐ALL.Methods:This study included 120 patients with high risk B‐ALL blinatumomab treated in 2013–2018, among them 14 pts (12%) with t (9;22), 10 (8%) with t (4;11), with MLL 11 (9%), 84 pts (70%) who were refractory to previous chemotherapy, 66 (30%) after allo‐HSCT from deferent type of donors. Children (0–18 y.o.) n = 55 (45%), and adults >18 y.o. n = 65 (54%). 63 pts (52%) had R/R ALL, 57 pts (48%) had MRD+, median days of follow up were 227 (18–720). Blinatumomab was applied as 28‐day cycles followed by a 14‐day off‐period before the start of the following cycle. Majority pts received one cycle (N = 94, 78%). In R/R ALL group dose was of 9 mcg/d during the first 7 days and afterwards 28mcg/d. Patients with weight less than 45 kg received 5 mcg/m2/d and 15mkg/m2/d accordingly. In MRD+ group dose was 15 mcg/m2/d.Results:The frequency of responses to blinatumomab was higher in MRD+ pts in comparison R/R ALL pts (85% vs 62 % p = 0.007). In MRD+ pts CR MRD− was achieved in 47 pts (82.5%), 10 pts (17.5%) were MRD+ after blinatumomab. Two‐year OS in this group was 61%. Twenty pts (34%) received allo‐HSCT. In R\R ALL pts CR MRD− was achieved in 30 pts (48%), 9 pts (14%) were MRD+ after blinatumomab, 24 pts (38%) had no hematological response. Two‐year OS in R/R ALL was 43%. Fifteen pts (24%) received allo‐HSCT. OS in CR MRD− patients who received allo‐HSCT was not significantly different in comparison with patients who received blinatumomab as a monotherapy (84% vs 71%, p = 0.08). No significant differences in DFS were observed at two years in CR MRD− pts depending status of the disease before therapy‐ MRD vs R/R (66% vs 59%, p = 0.81).Of the reported adverse events, febrile fever was the most common 91pts (76%), the other complications were neutropenia 43 (35%), thrombocytopenia 46 (38%), infection 32 (26%), neurotoxicity 29 (24%), cytokine‐release syndrome 8 (7%). All complications were reversible.Summary/Conclusion:Blinatumomab is effective option in patients with high risk B‐ALL especially in the group with MRD persistence after previous chemotherapy and facilitates effective bridging to HSCT. Blinatumomab therapy is generally well tolerated.

Background: Several treatment options are available for patients with newly-diagnosed multiple myeloma (NDMM) who are transplant ineligible. Most recently, the ongoing ALCYONE and MAIA studies demonstrated significant improvement in progression-free survival (PFS) and overall response rate (ORR) for treatment with daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) vs. VMP alone, and for treatment with daratumumab plus lenalidomide and dexamethasone (D-Rd) vs. Rd continuous alone, respectively (1,2). In the absence of randomized control trials (RCTs) vs. other relevant comparators, a network meta-analysis (NMA) is needed to support evidence-based decision making and ultimately help to optimize treatment and outcomes of patients with NDMM who are transplant ineligible (3). Aims: This NMA compares daratumumab (D)-based regimens with other relevant comparators for the frontline treatment of patients with NDMM who are ineligible for transplantation. Methods: A systematic literature review was conducted based on PubMed, EMBASE, Cochrane, the American Society of Hematology (ASH), American Society of Clinical Oncology (ASCO) and ESMO. Additional meta-analyses/reviews and ClinicalTrials.gov were further searched for potential publications that were not included in the search engines up to Dec 2018. Efficacy outcomes (i.e. the hazard ratio [HR] and 95% confidence interval [CI] for progression-free survival [PFS] and odds ratio [OR] for overall response rate [ORR]) were extracted and synthesized in an NMA. Choice of model was made on lowest deviance information criterion (DIC). Lenalidomide and dexamethasone (Rd) continuous was selected as comparator for this analysis as it was commonly included in the guidelines across regions. For PFS, HR <1 indicates the comparison is not in favor of Rd continuous whereas OR <1 is in favor of Rd continuous for ORR. Results: Random effects results for both PFS and ORR against Rd continuous are presented in Table 1. For PFS, D-based regimens are the most favorable regimens compared to all other relevant treatment options. Compared to Rd continuous, the HR of PFS of D-VMP is 0.62 (0.21–1.84) and the HR of PFS of D-Rd is 0.55 (0.30–0.99). For PFS, in addition to the D-based regimens, VMPT-VT 0.84 (0.28–2.47) and ERd 0.83 (0.22–3.04) are the only other options that are more favorable than Rd continuous, the performance of other treatment options is less favorable than Rd continuous. Similar patterns are observed with ORR.Summary/Conclusion: The NMA demonstrated favorable efficacy outcomes for D-based regimens including D-Rd and D-VMP vs. other relevant front-line options for patients with NDMM who are transplant-ineligible. A limitation of this analysis was that VRd, a regimen recommended by key treatment guidelines (4,5) for patients with NDMM who are transplant-ineligible, was not included as appropriate data on VRd treatment in this patient population was not available to enable inclusion into the current NMA.

Background:Immune checkpoint inhibitors (ICI) may allow to achieve a durable remission in patients with resistant or refractory (r/r) classical Hodgkin lymphoma. The population of patients who discontinued therapy due to various causes is increasing. In case of relapse after the ICI treatment the optimal treatment is not yet defined. One of the possible options is the retreatment of the patient with ICI. To date there is lack of information regarding the retreatment of patients with relapse after ICI cessation.Aims:To determine the effectiveness of nivolumab therapy in patients with r/r Hodgkin lymphoma with relapse of disease after achievement of complete remission with ICI and cessation of therapy.Methods:This analysis included 20 patients (5 male/15 female) with median age 32 (20–47) years with r/r classical Hodgkin lymphoma who were treated with nivolumab (3 mg/kg every 14 days) and achieved CR. After nivolumab therapy was stopped the patients received no other treatment before the disease progression. Response was assessed by positron‐emission tomography/computed tomography (PET/CT) using LYRIC criteria every 3 months. After relapse of the disease the patients were retreated with nivolumab monotherapy or in combination with chemotherapy. Median follow‐up after the retreatment initiation was 10 (6–14) months.Results:In 20 patients previously treated with nivolumab the median number of cycles was 25 (18–30). CR was achieved after median of 6 (6–18) cycles. The median duration of therapy after CR achievement was 7 (1–15) months. Median follow‐up after therapy discontinuation was 23 (13–24) months. At the moment of analysis, all patients were alive.Eight (40%) out of 20 patients relapsed after therapy discontinuation. In 4 out of 8 patients relapse was confirmed by biopsy. Median time before the relapse was 11(5–20) month. All patients had undergone the retreatment with nivolumab: 7 were treated with monotherapy and 1‐ in combination with chemotherapy. Doses of nivolumab were 3 mg/kg in 5 patients, 1,5; 1,0 and 0,5 mg/kg in one patient each. Six patients were evaluated for response: CR (n = 3), PR (n = 1), indeterminate response type 2 (n = 2). The best response was achieved after median of 6 (6–12) cycles.It is worth noting that 3 patients had adverse events after retreatment with nivolumab. Two of these patients did not have any complications during initial nivolumab treatment. Adverse events included pyrexia, thrombocytopenia and pneumonitis. In last case therapy was discontinued before resolution of complication, but the patient achieved complete remission before therapy cessation.Summary/Conclusion:This analysis demonstrates that patients with relapse after nivolumab discontinuation sustained sensitivity to nivolumab and achieved a response during retreatment with nivolumab monotherapy or with chemotherapy combination. Further research is required to determine response rate and durability of response.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is effective treatment in high risk hematological malignancies.Nevertheless, the relapse rates after allo-HSCT range from 10% to 70%.There are no optimal strategy of the relapse therapy after allo-HSCT.Possible therapeutic options include re-induction chemotherapy, immunoadoptive therapy (DLI), target drugs, immunotherapy (CAR-T) and second allo-HSCT.The presented study is a retrospective single-institution experience of second allo-HSCT in the patients (pts) with acute leukemia relapses or graft failure in high-risk cases.The aim of our study was to analyze the outcomes after second allo-HSCT in 50 children with hematological malignancies, i.e., ALL (n=24), AML (n=15), MPDs/MDS (n=11). ResultsForty-four patients achieved engraftment, with median neutrophil engraftment time of 21 days (12 to 41).Remission was achieved in 44 pts (88%).Median follow-up period was 3 years 7 months.Overall survival (OS), according to Kaplan-Meier method, was 48% in the whole group.Relapse-free survival (RFS) was 60%.The fiveyear OS in ALL group was 46.2%; in AML group, 53.3%; in MPDs/MDS, 44.4%.Causes of death were as follows: relapse/progression in 65% (n=17), transplant-related mortality (TRM), in 18% (n=9; 95%CI, 8.8%-29.8%);cumulative relapse rate was 34% (95% CI, 21.6%-48%). ConclusionSecond allo-HSCT is an effective treatment option in cases of relapse after 1 st allo-HSCT.The patients that achieved remission or even blast cytoreduction prior to 2 nd allo-HSCT had better outcome.Clinical manifestations of acute and chronic GVHD can significantly improve the OS.Results of 2 nd allo-HSCT were comparable when using RIC or MAC conditioning regimens.Posttransplant therapy is required to improve results after 2 nd HSCT.

Background. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disorder, characterized by intravascular hemolysis, cytopenia and thrombosis. Diagnostic errors with delayed diagnosis of PNH are often due to the variety of the clinical presentation and the lack of awareness of the doctors of this rare disease. Aim. The aim of the study was to characterize the spectrum of clinical manifestations and the complexity of diagnosis of classical PNH. Materials & Methods. The study included 150 patients with classical PNH. The inclusion criteria were: 1) clinical and laboratory signs of intravascular hemolysis; 2) verifi cation of the diagnosis using standard fl ow cytometry; 3) absence of aplastic anemia, myelodysplastic syndrome and primary myelofi brosis. Results. The study population consisted of 89 (59 %) women and 61 (41 %) men. Median age was 34 years (13–72 years). The time before the diagnosis ranged from 0 to 455 months (median 33 months). The median size of the PNH clone among granulocytes and erythrocytes was 95 % and 41 %, respectively. The median of the lactate dehydrogenase was 7.2 times the upper limit of normal (ULN). Cytopenia occurred in 65 % of patients, including a combination of thrombocytopenia and neutropenia in 29 % of cases. Weakness and fatigue (99 %), hemoglobinuria (57 %), pain (52 %), icterus (46 %), dysphagia (37 %) and infection/fever (23 %) were the most common symptoms on the onset of the disease. Before the diagnosis of PNH, thrombosis or acute kidney injury was found in 22 % and 12 % of patients, respectively. Only 22 % of patients were initially diagnosed with PNH. In the remaining patients, the primary diagnosis was incorrect. Conclusion. The clinical manifestation of PNH is characterised by the presence of hemoglobinuria, cytopenia and early thrombosis in 57 %, 65 % and 22 % of patients, respectively. Errors of the primary diagnosis reach 78 % and lead to 334 А.Д. Кулагин и др. КЛИНИЧЕСКАЯ ОНКОГЕМАТОЛОГИЯ Заключение. Клиническая манифестация классической ПНГ характеризуется наличием гемоглобинурии, цитопении и ранних тромбозов у 57, 65 и 22 % пациентов соответственно. Ошибки первичного диагноза достигают 78 % и приводят к неадекватному предшествующему лечению. Результаты исследования подчеркивают необходимость мультидисциплинарного взаимодействия и строгого соблюдения алгоритмов диагностики классической ПНГ в группах риска, согласно современным рекомендациям. Ключевые слова: классическая пароксизмальная ночная гемоглобинурия, клон ПНГ, цитопения, клиническая манифестация, ошибки диагностики. Получено: 20 февраля 2017 г. Принято в печать: 8 мая 2017 г. Для переписки: Александр Дмитриевич Кулагин, д-р мед. наук, проф., ул. Льва Толстого, д. 6/8, Санкт-Петербург, Российская Федерация, 197022; тел.: +7(812)338-62-36; e-mail: kulagingem@rambler.ru Для цитирования: Кулагин А.Д., Климова О.У., Добронравов А.В. и др. Клиническая манифестация и ошибки диагностики классической пароксизмальной ночной гемоглобинурии: анализ 150 наблюдений. Клиническая онкогематология. 2017;10(3):333–41. DOI: 10.21320/2500-2139-2017-10-3-333-341

There is a growing evidence of safety and efficacy of post-transplantation cyclophosphamide (PTCy) in related and haploidentical bone marrow (BM) transplantations, but the data regarding unrelated and peripheral blood stem cell (PBSC) transplants is limited. Hence, we conducted a prospective trial of risk-adapted graft-versus-host disease (GVHD) prophylaxis with PTCy that included different types of donors and graft sources.