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Considering the high relapse rates of AML after allogeneic hematopoietic stem cell transplant, research aims to improve post-transplant surveillance. To determine the value of peripheral blood (PB) for post-transplant minimal residual disease monitoring, we compared 38 PB and bone marrow (BM) sample pairs in 25 stem cell recipients with NPM1-mutated AML (12 males, 13 females, ages 21-73 years). NPM1A mutation levels and chimerism ratios were determined in non-separated BM/PB. We observed congruent results in 28/38 (74%). In 14/38 sample pairs (37%), BM and PB were negative for the NPM1A mutation. Fourteen sample pairs were positive in BM and PB, albeit at higher mutation levels in the BM in 11 cases (4- to 278-fold). Results were discordant in 10 cases (26%), with weakly positive mutation levels in the BM but negative levels in the PB. Cases with ≥0.2% NPM1A mutation level in BM were always positive in PB. Chimerism was concordant in BM and PB in 21/34 (62%) of sample pairs. In conclusion, MRD monitoring with qPCR for the NPM1 mutation and chimerism from non-separated PB contributes to surveillance in patients with AML in the post-transplant period, but even with highly sensitive qPCR there is a risk of failure to detect the mutation in PB.

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The aim of this study was to evaluate efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute lymphoblastic leukemia (ALL), and to specify significant factors affecting clinical outcomes. Patients and methods. The study included 354 ALL patients aged 1 to 61 years who underwent allo-HSCT over a period of 1995 to 2015. Before HSCT, 24% of patients were in the 1st remission, 26%-in 2nd remission, 17%, in the ≥ 3rd remission; 34% of patients had active disease. Results. Overall survival (OS) was 47% when HSCT was performed in remission status versus 18% in patients transplanted in active disease state (p <.0001). Appropriate relapse incidence (RI) comprised 26% and 50%, respectively (P <.0001). Five-year OS was similar in children and adults (48% and 47% respectively, p>0.2). Pre-transplant remission state showed certain correlations with OS in pediatric and adult transplant patients, i.e., 79% vs 60% for HSCT in 1st remission; 40% vs 43% in 2nd remission, and 33% vs 23% for the patients treated in ≥ 3rd remission. ALL RI in children and adults were also comparable for HSCT carried out in 1st remission (21% vs 32%), 2nd remission (33% vs 17%), and 17% vs 23% for HSCT performed in ≥3rd remission (p>0.2). Most ALL patients underwent myeloablative conditioning regimen (MAC) before allo-HSCT (n=89). OS in MAC group was 53% versus 40% among patients who underwent reduced-intensity conditioning (RIC) regimens (n=70, p=0.04). The conditioning regimen intensity did not correlate with the RI after allo-HSCT (24% and 30% (MAC vs RIC respectively), p=0.09). Non-relapse mortality (NRM) did not significantly differ for children and adults (32% vs 37%, p>0.2), being dependent on the disease state: 21% vs 25% after HSCT in the 1st remission; 31% and 43%, when treated in the 2nd remission, and 50% vs 61% if transplanted in ≥3rd remission. Conclusion. Allo-HSCT from an HLA-matched related or unrelated donor is indicated in patients with high-risk ALL in first remission and in all the patients in the second remission.

Background: Anticomplement C5 therapy with eculizumab is the standard of treatment of patients (pts) with active hemolytic PNH. However, there are few data on long-term complement inhibition efficacy and current PNH prognosis from real-world clinical practice. Objectives: The aim of this study was to evaluate long-term eculizumab efficacy and PNH outcomes in the large cohort in Russia. Methods: As of August 1, 2018, a total of 354 pts with hemolytic PNH were observed in the I.P. Pavlov First St. Petersburg State Medical University in cooperation with the local hematological service in 75 regions of Russia (n=344), as well as in Belarus, Kazakhstan, Kyrgyzstan, Ukraine, Tajikistan (n=10) (Table 1). The analysis was conducted in the whole cohort and separately in the prospective phase after November 2011 with the eculizumab availability in Russia. We analyzed indications and access to anticomplement C5 therapy according to National guidelines (2014), frequency and causes of discontinuation of therapy, cumulative incidence of independence from transfusions with allo-HSCT as competing risk, frequency of breakthrough hemolysis (BTH) and intensive extravascular hemolysis, overall survival (OS) and causes of mortality. Results: According to the current National guidelines (2014), 323 pts had at least one indication for therapy with eculizumab: thrombosis (n=89, 25 %), transfusion-dependent hemolytic anemia (n=261, 74 %), acute kidney injury (AKI, n=69, 19 %), chronic kidney disease (CKD, n=244/304, 80 %) including CKD stage ≥ 2 (n=66/304, 22 %), pulmonary hypertension (n=66/265, 25 %) and pregnancy (n=22). Due to differences in regional support for rare diseases, only 204 (63%) pts had access to therapy with eculizumab. In addition, 19 pts received novel anti-C5 agent in clinical trial and were excluded from analysis. Allogeneic HSCT was performed in 24 pts, including 2 cases of MDS/AML evolved from AA/PNH and 17 cases of severe AA/PNH with eculizumab bridging in the prospective phase. With the median duration of eculizumab therapy of 3.4 years (0.2-6.1) the independence from RBC transfusions (TI) was achieved in 109 of 154 initially transfused pts (71 %) with a cumulative incidence of 61 % (95 % CI, 52-68) and 69 % (95 % CI, 60-76) after 12 and 24 months of therapy respectively. The median hemoglobin level at last follow-up were 6.6 (4.0-9.7), 10.5 (range, 7.1-15.4) and 12.1 g/dl (8.9-14.0) in patients who did not reach the TI, who reached the TI and were never transfused, respectively (p =0.0001). BTH was documented in 36 of 184 evaluated pts (20 %), including 16 and 20 cases with and without obvious triggers respectively. Intensive extravascular hemolysis with bilirubin level > 2xULN persisted in 31 % pts. Temporary or permanent discontinuation of eculizumab treatment occurred in 58 pts due to death (n=11), allogeneic BMT (n=17), spontaneous clone reduction (n = 4), absence of new indications 6 months after delivery (n=4), and terminating access to treatment (n=22). All pts of the latter group developed a relapse of intensive intravascular hemolysis, which in 3 cases was complicated by AKI (n=1), stroke (n=1) and myocardial infarction (n=1). OS was assessed in the prospective phase after 2011. A total of 24/203 (12 %) pts died which resulted in 5-year OS of 87% (CI 95 %, 81-92). Treatment with eculizumab significantly improved OS (Fig.1). The 5-year OS rate was 91% (CI 95 %, 85-98) in pts treated with eculizumab and 74 % (CI 95 %, 63-85) in never-treated pts (p=0.0003). There were significant differences in the causes of death between pts receiving and not receiving eculizumab: related to thrombosis 1/7 (14 %) vs 9/17 (53 %), AA and MDS 4/7 (57%) vs 5/17 (29 %). Conclusions: The results of the study show both the high efficacy and limitations of treatment with eculizumab for PNH in real-world practice. Prospectively confirmed significant improvement of the overall survival on eculizumab stress the need for faster and wider access to costly therapy. Nevertherless, a number of limitations, including BTH and extravascular hemolysis, lack of control of bone marrow failure and further clonal evolution, determine the relevance of next-generation complement inhibitors and risk-adjusted allogeneic HSCT as a curative option. Disclosures Kulagin: Alexion Pharmaceuticals, Inc: Consultancy, Honoraria.