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The only proven cure for Shwachman–Diamond syndrome (SDS) bone marrow failure is allogeneic hematopoietic stem cell transplantation (HSCT). However HSCT with donors other than HLA-identical siblings is associated with high mortality and unfavorable prognosis. This paper presents the first experience of HSCT treatment of SDS using an unaffected HLA-identical sibling produced through preimplantation genetic diagnosis (PGD). The patient was a 6-year-old blood transfusion-dependent SDS baby girl with secondary myelodysplastic syndrome, for whom no HLA-identical donor was available. As a result of PGD, two unaffected HLA matched embryos were identified; one of them was randomly selected for transfer, resulting in a clinical pregnancy and birth of an apparently healthy child. The patient underwent allogeneic transplantation of cord blood hematopoietic stem cells, together with bone marrow from this sibling, resulting in complete hemopoietic recovery. The patient was no longer transfusion-dependent and had normal blood values 160 days after transplantation.

AIM: To evaluate the efficiency of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloblastic leukemia in first remission depending on the regimens of conditioning, the source of a graft, and the characteristics of a donor and a recipient/MATERIAL AND METHODS: In 66 treated patients, including from partially HLA-mismatched relatives (n=4), the efficiency of allo-HSCT from related donors (n=26) and unrelated donors (n=40), were compared. According to cytogenetic findings, 7 (11%), 31 (47%), and 10 (15%) patients belonged to low-, intermediate-, and high-risk groups, respectively/RESULTS: Five-year overall survival (OS) and mortality associated with transplantation were 56 and 22% for allo-HSCT from related donors, 68 and 23% for that from HLA-matched donors, and 71 and 25% for that from partially HLA-mismatched donors, respectively (p=0.8 and p=0.7). The relapse risk after allo-HSCT from unrelated donors was significantly lower than after that from related donors (13 and 35%, respectively; p=0.8). Univariate analysis showed that the OS rates depended on the cytogenetic risk group (OS was 24 and 64% in the high- and intermediate-risk groups, respectively (p=0.027). The relapse risk in chronic graft-versus-host reaction (GVHR) and in grade 3 acute GVHR (p=0.01) was shown to be less than that in grades 1-2 acute GVHR (p=0.06)/CONCLUSION: OS rates after allo-HSCT from related and unrelated donors were comparable and unrelated to the source of a graft, the regimen of conditioning, and other characteristics of a donor and a recipient.

To evaluate the efficiency of extracorporeal photopheresis (ECP) in the treatment of patients with refractory chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT).The study included 49 patients aged 2 to 55 years. Allo-HSCT was carried out in 38 (79%) patients with acute leukemias, 5 (10%) with chronic leukemias, 4 (8%) with myelodysplastic syndrome/myeloproliferative disease, and 2 (3%) with other hematologic diseases. The patients included in the study had glucocorticosteroid (GCS)-refractory disseminated cGVHD or a history of severe complications from GCS therapy.When evaluating the efficiency of therapy, its response was recorded in 37 (77%) cases; the best results were obtained in patients with hepatic (82%), mucosal (76%), and skin (74%) lesions. The mean severity according to the cGVHD Working Group, National Institutes of Health, and a platelet level of more than 100.10(9)/1 were defined as factors improving a therapy response. In the patients receiving ECP, the overall survival was 70%. The latter was higher in the group of patients who had responded to ECP therapy without involving the gastrointestinal tract in the cGVHD process and in those receiving a combination of ECP and other immunosuppressive drugs.ECP is an effective treatment for patients with refractory cGVHD, it may be used in those with a history of severe complications from GCS therapy. ECP allows the dose of GCS to be reduced to the point of complete discontinuation.

Paroxysmal nocturnal haemoglobinuria (PNH) clones are frequently detected in patients with aplastic anaemia (AA). To evaluate the prognostic role of PNH clone presence we conducted a prospective study in 125 AA patients treated with combined immunosuppressive therapy (IST). Seventy-four patients (59%) had a PNH clone (PNH+ patients) at diagnosis, with a median clone size of 0·60% in granulocytes and 0·15% in red blood cells. The response rate at 6 months was higher in PNH+ patients than that in PNH- patients, both after first- and second-line IST: 68% vs. 45%, P = 0·0164 and 53% vs. 13%, P = 0·0502 respectively. Moreover, 42% of PNH+ patients achieved complete remission compared with only 16% of PNH- patients (P = 0·0029). In multivariate logistic regression analysis, PNH clone presence (odds ratio 2·56, P = 0·0180) and baseline absolute reticulocyte count (ARC) ≥30 × 10(9) /l (odds ratio 5·19, P = 0·0011) were independent predictors of response to treatment. Stratification according to PNH positivity and ARC ≥30 × 10(9) /l showed significant distinctions for cumulative incidence of response, overall and failure-free survival. The results of this prospective study confirmed the favourable prognostic value of PNH clone presence in the setting of IST for AA.

To study the incidence and risk factors of bacterial infections and the efficiency of empirical antibacterial therapy in patients in the early period after allogeneic hematopoietic stem cell transplantation (allo-HSCT).The study included 155 patients who had undergone allo-HSCT. Myeloablative conditioning was used in 39% of the patients. All the patients with neutropenia (NP) received antibiotic prophylaxis with fluoroquinolones until recovery of white blood cell counts or before systemic antibiotic therapy. Antibiotic therapy and a change of antibiotics were considered effective in achieving persistent apyrexia and positive clinical changes.The incidence of febrile neutropenia (FNP) in the patients after allo-HSCT was 63%. The duration of grade 4 leukopenia did not depend on the conditioning regimen. Neutropenic fever was noted in 68% of the patients with NP lasting longer 10 days. In shorter-duration NP, the rate of fever was 52%. Among the patients with mucositis, the frequency of FNP episodes was significantly higher (69% versus 52%; p=0.02). The diverse spectrum of isolated bacteria was represented as gram-positive cocci in 45% of cases; Klebsiella pneumoniae and Enterobacter cloacae were more common among gram-negative ones (24%). The efficiency of empirical antibiotic therapy was 57% (25% for monotherapy, 53% for combined treatment regimens); the early mortality was 2%.Infection-related FNP is noted in 68% of the patients in the early posttransplantation period and the risk factors of its development are NP duration, oral colonization with pathogens, and the absence of invasive mycosis after allo-HSCT. Antibacterial prophylaxis significantly decreases the incidence of bacterial complications. Empirical monotherapy with third- or fourth-generation cephalosporins and carbapenems against infections in a transplantation patient is as effective as their combination with aminoglycosides.Цель исследования. Изучить частоту развития, факторы риска бактериальных инфекций и эффективность эмпирической антибактериальной терапии у пациентов в раннем периоде после трансплантации аллогенных гемопоэтических стволовых клеток (алло-ТГСК). Материалы и методы. В исследование включили 155 пациентов, которым выполнена алло-ТГСК. Миелоаблативное кондиционирование использовано у 39% пациентов. Всем пациентам в периоде нейтропении (НП) проводили медикаментозную антибактериальную профилактику фторхинолонами до восстановления количества лейкоцитов или до начала системной антибиотикотерапии. Антибактериальную терапию и смену антибактериальных препаратов считали эффективными при достижении стойкой апирексии и положительной клинической динамике. Результаты. Частота развития фебрильной нейтропении (ФНП) среди пациентов после алло-ТГСК составила 63%. Продолжительность лейкопении IV степени не зависела от режима кондиционирования. В группе пациентов с продолжительностью НП более 10 дней нейтропеническая лихорадка отмечена в 68% случаев. При сокращении срока НП частота лихорадки составила 52%. Среди пациентов с мукозитом частота эпизодов ФНП оказалась достоверно выше (69% против 52%; p=0,02). Разнообразный спектр выделенных бактерий в 45% случаев представлен грамположительными кокками; среди грамотрицательных (24%) чаще встречались Klebsiella pneumoniae, Enterobacter cloacae. Эффективность эмпирической антибиотикотерапии составила 57% (монотерапии 25%, комбинированных схем 53%); ранняя летальность - 2%. Заключение. ФНП, связанная с инфекциями, отмечена в раннем посттрансплантационном периоде у 68% больных, а факторами риска ее развития являются продолжительность периода НП, колонизация полости рта патогенной микрофлорой, отсутствие инвазивного микоза при алло-ТГСК. Антибактериальная профилактика достоверно снижает частоту развития бактериальных осложнений. Эмпирическая монотерапия инфекции у трансплантационного больного цефалоспоринами III-IV поколения и карбапенемами так же эффективна, как их комбинация с аминогликозидами.

Background. Prognosis of acute myeloid leukemia (AML) with complex aberrant karyotype (CAK) is poor. These patients (pts) are often refractory to both chemotherapy and allogeneic HSCT (alloHSCT). At diagnosis the proportion of these pts is about 6-8 %, but their frequency essentially increases in relapses after chemotherapy and alloHSCT. Mechanism of CAK development and its effect on relapses have been studied insufficiently. Material and methods. Serial cytogenetic assays, including multicolor FISH, were performed on bone marrow cells from 99 patients with post-transplant relapses (PTR) AML (n=61) and ALL (n=38). Median ages for AML and ALL pts at HSCT were 23 and 17 years (range, 2-60 and 0.8-51 years), respectively. Results. Aberrant karyotypes were found in 90 % AML and 97 % ALL pts, respectively (Table 1). Of note, the proportion of CAK in general group of ALL patients, as well as in that with more 4 chromosomal abnormalities was significantly higher, compared to AML (66% vs. 36%, P=0.003 and 61% vs. 33%, P=0.006, respectively). Table 1. Frequency and characteristics CAKs in AML and ALL patients with the PTRs Leukemia type AML ALL P Patients, n 61 38 Karyotype, n (%) Normal 6 (10 %) 1 (3 %) NS Abnormal 55 (90 %) 37 (97 %) NS Complex karyotype, n (%) 22 (36 %) 25 (66 %) 0.003 3 abnormalities 2 (3 %) 2 (5 %) NS ³4 abnormalities 20 (33 %) 23 (61%) 0.006 NS - not significant The above difference in frequency of CAK in ALL and AML might be explained by higher frequency of myeloablative conditioning regimes in the ALL group, compared to AML (55% vs. 36 %, respectively; P=0.09). Of notice also, that fraction of CAK with 4 and more chromosomal abnormality in the group of children from 1 to 18 years was significantly higher in patients with ALL, as compared with AML (60% vs. 30%, respectively; P=0.03). Furthermore, a similar tendency was revealed also in the group of patients aged 19-40 years (difference insignificant; P=0.08) (Table 2). Table 2. The incidence of CAKs with ³4 chromosomal abnormalities in PTRs in different age groups. Patients, n (%) Age (years) AML ALL P 1-18 7/23 (30 %) 15/25 (60 %) 0.03 19-40 8/25 (32 %) 7/11 (64 %) 0.08 41-60 5/13 (39 %) 1/2 (50 %) 0.5 Finally, our data demonstrate, the proportion of CAK to be significantly higher in PTR of ALL pts compared with those of AML, when they were transplanted in active disease phase (70% vs. 32%; P=0.007; Table 3). Table 3. The incidence of CAKs with ³4 chromosomal abnormalities in PTRs, depending on the clinical status at alloHSCT. Patients, n (%) P Clinical status at HSCT AML ALL CR 1 3/13 (23 %) 2/7 (29 %) 0.6 CR ³2 6/14 (43 %) 7/11 (64 %) 0.2 Active disease 11/34 (32 %) 14/20 (70 %) 0.007 Discussion. Our study shows that number of karyotype abnormalities in acute leukemia with CAK+ is closely associated with previous chemotherapy and/or conditioning regimes. Despite it, only alloHSCT gives a hope for treatment of these pts. In order to improve overall results of treatment several modifications of alloHSCT and post-transplant treatment have been recently suggested. The main of them, called as early alloHSCT, includes modified FLAMSA-RIC conditioning regime, alloHSCT before obtaining results of standard courses chemotherapy followed by DLI in escalating doses at post-transplant period (Schmid et al., 2012). If such a possibility for early alloHSCT is lost, another variant of PTR prevention may be used. The latter can include the same DLI, hypomethylating agents, ATRA etc. As for PTR prevention in CAK+ ALL it may be different from AML. In our opinion, in these pts should be treated at the first with such target agents as tyrosine-kinase inhibitors, rituximab, ATRA etc. Conclusion. According to our data, the frequency of CAK in PTRs is high not only in AML, but ALL too. Mechanisms of CAK formation as well as treatment of CAK+ leukemia began to elucidate. In our opinion, the leading place in this treatment is to be given an early alloHSCT. Reference. Schmid C., et al. Early allo-SCT for AML with a complex aberrant karyotype – results from prospective pilot study. Bone Marrow Transplantation 2012; 47: 46-53. Disclosures No relevant conflicts of interest to declare.

Abstract 1953 Objective. Graft-vs-host disease (GVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) causing significant morbidity and transplant-associated mortality. Acute GVHD (aGVHD) has been observed in approximately 60% of HLA-identical sibling transplants and up to 80% of unrelated donor grafts. Chronic GVHD (cGVHD) occurs in 50–70% of patients and frequently requires long-term systemic immunosuppressive treatment. Corticosteroids are considered to be the gold standard of first-line therapy for GVHD. Patients not responding to steroids have a dismal prognosis, being at risk of lifethreatening infections and severe organ toxicities. Extracorporeal photopheresis (ECP) has objective activity in the treatment of both acute and chronic steroid-refractory GVHD patients. Methods. The study included 82 patients (pts) after allo-HSCT, 34 with aGVHD and 48 with cGVHD. The age was from 2 to 55 y.o. (median 22 y.o.). Treatment aGVHD included tacrolimus or cyclosporine A basic immunosuppressive therapy with steroids (2 mg/kg) as a first line ± MAB. ECP combined with first line or used as third line, after MAB. Therapy cGVHD also included steroids (1 mg/kg) as a first line, imatinib or MMF used as a second line. ECP combined with first or second line therapy. Group aGVHD included: unrelated-HSCT – 20 pts, related-HSCT – 7 pts, haplo-HSCT – 7 pts; grade of aGVHD: II – 16 pts, III – 6 pts, IV – 12 pts; organs involvement: skin – 31 pts, GIT – 14 pts, liver – 7 pts. Group cGVHD included: unrelated-HCT – 26 pts, related-HCT – 12 pts, haplo-HCT – 10 pts; steroid-depended forms – 26 pts, steroid-refractory – 12 pts, steroid-intolerance – 10 pts; severity of cGVHD: moderate cGVHD – 15 pts, severe cGVHD – 33 pts; organs involvement: skin – 44 pts, mucosa – 27 pts, GIT – 11 pts, liver – 9 pts, lungs – 10pts. Infection complications (IC): for aGVHD group – total frequency - 73%, n=25 (bacterial – 53%, n=18, reactivation CMV – 61%, n=21, invasive fungal infection – 29%, n=10), the most frequent – lung infection and urinary tract infection. For cGVHD group: total frequency – 73%, n=35 (bacterial – 60%, n=29, reactivation CMV – 41%, n=20, invasive fungal infection – 56%, n=20), the most frequent – invasive pulmonary aspergillosis. Results. Response to therapy was observed in 23 pts (67%) with aGVHD and in 36 cases with cGVHD (75%). Factors affecting the achievement of response were severity of GVHD: II grade aGVHD vs III, IV – 93% vs 44%, (p=0,015); «moderate GVHD» vs «severe chronic» - 94% vs 77%, (p=0,024) and confirmed infection in pts with cGVHD (69% vs 93% in pts without infection, p=0,045). Probability of overall survival (OS) at 3 years was 54% for aGVHD, and 71% for cGVHD. Factors affecting to OS were achievement of response (70% vs 16 for aGVHD, p=0,001; 88% vs 33% for cGVHD, p=0,000), severity of aGVHD (77% for II grade vs 37% for III, IV). Evaluating the effectiveness of various schemes of immunosuppressive therapy for aGVHD we did not reveal significant differences for achievement response or OS between combination of ECP and first line therapy and using ECP after MAB, but IC were more common in last group (60% vs 100%, p=0,078). For group with cGVHD, pts treated only by combination steroid and ECP had a worse response then scheme including ECP and imatinib or MMF: 82% vs 65%, p=0,088%, OS pts receiving imatinib was better (85% vs 61%, p=0,041); frequency of IC was similar. Conclusion. ECP is effective for steroid-resistance forms of GVHD. It shows the best results in cases of II grade aGVHD and moderate cGVHD. The use of MAB doesn't influence frequency of treatment response or OS, but it increases incindence of IC. As concerns cGVHD, better results are documented in combination of ECP and imatinib or MMF. Disclosures: No relevant conflicts of interest to declare.