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Oral mucositis (OM) is a significant problem in patients undergoing standard or high-dose chemotherapy and/or radiotherapy for the management of haematological disorders, associated with patient morbidity and increased resource use. The OM management relies on supportive care and symptom palliation. This study evaluates the results of Polyvynilpyrrolidone-Zn gluconate and taurine (GelX� Oral Spray) in this setting. This is an observational, retrospective study, conducted on 145 paediatric and adult patients. All patients received GelX� Oral Spray as prophylaxis for OM. The research was supported by BMG Pharma S.p.A. The prevention of OM in patients treated with GelX� Oral Spray was reached in 54 patients (37.24%), 22 adults (22.22%) and 32 children (69.56%). A total number of 52 patients (35.86%) developed severe OM when GelX� was used as preventive treatment, 40 adults (40.4%) adults and 12 children (26.08%). Grade 4 OM developed in 16 patients (11.03%), 10 adults and 1 child (68.75%) had a complete remission of OM, while 3 adults and 2 children (31.25%) had partial remission. No patient had to interrupt chemo/radiotherapy due to OM. GelX� Oral Spray was considered safe, no adverse device effect or severe adverse device effect were considered related to the use of the product. This retrospective study supports prophylactic use of GelX� Oral Spray to minimize the risk of OM secondary to chemo/radiotherapy.

B-cell precursor acute lyphoblastic leukemia (ALL) is a common pediatric malignancy and patients may have significant benefits from monoclonal antibodies therapy with increased survival rates. Positive CD20 expression is identified in about half of these patients and its presence may serve as a prognostic factor in disease evolution. We performed a retrospective study including 114 patients diagnosed with B-ALL and evaluated the expression of CD20 through flow cytometry at diagnosis and on day 15. Additional immunophenotypic analyses as well as cytogenetic and molecular genetic analyses were also performed. We observed an increase in the mean fluorescence intensity (MFI) of CD20 between diagnosis—1.9 (1.2–3.26) and day 15: 6.17 (2.14–27.4), (p < 0.0001). Furthermore, we assessed that both diagnosis and day 15 CD20 MFI had an impact on RFS and OS, respectively, for cut-off values of >8.08 at diagnosis and >28.65 at day 15. In conclusion, CD20 expression appears to be a poor prognostic feature of B-ALL in pediatric patients. In this study, stratification of the outcome by the intensity of CD20 has implications concerning the allocation to rituximab-based chemotherapy and may offer new, potentially useful information for pediatric patients with B-ALL.

Introduction. Primary central nervous system lymphoma is an uncommon form of extranodal non-Hodgkin’s lymphoma, with increasing incidence, a relatively aggressive course and a poor 5-year survival. Because of its localization, the therapeutic compounds used in this disease must be able to pass through the blood-brain barrier. Chemotherapy regimens based on high-dose methotrexate are currently the standard of care for all patients who can tolerate such drugs. Autologous stem cell transplantation is indicated for malignant lymphomas in the relapsed/refractory setting. Methods. Three patients, with a median age of 60 years, range 53–64, were diagnosed with primary CNS lymphoma, and treated with ibrutinib monotherapy in the Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania, between September 2018 and November 2020 All the patients were relapsed–refractory following high-dose methotrexate chemotherapy. We present our experience using ibrutinib monotherapy-based treatment as a bridge-to-transplant option on a single-center case series and a review of the literature in this field. Results. Two of the patients were given ibrutinib as a second line therapy, both achieving complete remission and being eligible for an autologous stem cell transplantation. The third patient achieved a short remission using six cycles of systemic chemotherapy, but was started on ibrutinib monotherapy, with limited results. Conclusion. Our data is limited, and these results should be confirmed by multicentric clinical trials and should be regarded as a single-center case series, with all its limitations. Still, it brings forward a new therapeutic option for this rare subtype of malignant lymphomas, which if left untreated has a dismal prognosis.

The purpose of this study was to evaluate mobilization outcomes with biosimilar pegfilgrastim versus filgrastim in association with chemotherapy as a mobilization strategy for lymphoma patients.In the current study we included 32 lymphoma patients that received mobilization therapy and PBSC harvesting at the Bone Marrow Transplantation Department of Fundeni Clinical Institute, Bucharest, Romania between January and December 2019.Pegfilgrastim had beneficial effect when compared to filgrastim in reducing grade IV neutropenia both in the univariate and multivariate logistic models. Additionally, similar efficacy, as mobilization rate, after both filgrastim and pegfilgrastim was observed and no differences were noted between the two groups considering the need for platelet or red blood cell support.The use of biosimilar pegfilgrastim is a viable alternative to filgrastim in PBSC mobilization for lymphoma patients.

Summary Purpose The primary objective of this study was to evaluate the compliance of Romanian physicians with the national therapeutic protocol and international guidelines on treatment with erythropoiesis-stimulating agents in anemic cancer patients receiving chemotherapy. The secondary objective was to assess the hemoglobin (Hb) level change due to anemia treatment and safety of darbepoetin alfa. Methods This was a single-arm, prospective, longitudinal, multicenter, observational study in patients with nonmyeloid malignancies and symptomatic chemotherapy-induced anemia treated concomitantly with darbepoetin alfa. Patients were followed for the duration of chemotherapy, but no shorter than three and no longer than eight cycles, irrespective of their exposure to darbepoetin alfa. Results In this study, 497 patients with a mean age of 60.6 years were analyzed. Most patients (80.7%) were initiated on darbepoetin alfa at a Hb of 9–11 g/dL, congruent with recommendations. The median Hb increased by 0.9 g/dL between baseline and week 12. Hb target achievement was higher among patients treated according to guidelines than those initiated at Hb

Around half of patients with Hodgkin Lymphoma (HL) who progress or relapse through first line therapy can be cured with salvage chemotherapy followed by autologous stem cell transplant (ASCT). However, this leaves approximately 50% of patients that will relapse after ASCT. The pivotal phase II SG035-00303 trial demonstrated that these patients can be successfully treated with Brentuximab Vedotin (BV), and a proportion of them can be long term free of disease without any further intervention. The objective of the current study was to investigate whether these findings were borne out in the real world via interrogation of the EBMT registry. We retrospectively analysed data for 101 patients with HL who had BV as their first treatment for relapse after ASCT from 2012 to 2019. The median age at ASCT was 34 years (range: 19-65), 60% being male and with 62% being in complete response (CR) at the time of ASCT. Carmustine, Etoposide, Cytarabine and Melphalan (BEAM) was the most common conditioning regimen, having been employed in 72% of the cases. The median time from ASCT to relapse was 10.1 months (interquartile range (IQR): 6.1-25.1). The median time on BV was 3.4 months (IQR: 2.1-5.24). BV treatment resulted in a best overall response rate (ORR) of 59% with a CR rate of 37%. At last follow-up only 2 patients remain on treatment with BV. The main reason for discontinuation of BV was progression which occurred in 37% of the patients. In 32 cases (33%) the treatment was stopped electively to proceed to a second transplant, and overall nearly a quarter (22%) completed the full treatment course. Only 5% of patients stopped due to toxicity (peripheral neuropathy 2 and neutropenia, infusion reaction and other, 1 each). Further therapy was given after BV in over half of evaluable patients (58%), with check point inhibitors (CPIs) being the most common agents used (24% of these). Nearly two thirds (64/101) of the patients received a second transplant, which were nearly all allogeneic stem cell transplant (alloSCT, 59/64), and most of these (49/59) with reduced intensity conditioning (RIC). 26% of the alloSCT recipients experienced grade II-IV acute graft versus host disease (GvHD) and 25% developed chronic GvHD. At last follow up, 62% of all patients were alive with a median follow-up of 25 months after starting BV. Of these, 27 had received a second transplant, who were mostly in CR at last follow up (26/27) and a further 22 had relapsed. There were 11 patients of the 63 still alive who continued to be responding to BV without further therapy with a median duration of response of 30 months. In conclusion BV use for relapse after ASCT was well tolerated generally, with only a minority of patients stopping treatment due to toxicity. However, although almost two thirds of the patients achieved a response, further treatment was often needed after BV, notably with CPIs and most patients were consolidated with a RIC alloSCT. These results confirm that only a minority of patients can achieve a durable remission with BV alone. Disclosures Brice: Takeda France: Consultancy, Honoraria; Millennium Takeda: Research Funding; BMS: Honoraria. Blaise:Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria. Stamatoullas:Celgene: Honoraria; Takeda: Consultancy. Robak:Takeda: Consultancy, Research Funding; UCB: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Amgen: Consultancy, Other: Travel grant; Roche: Consultancy, Other: Travel grant, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta: Research Funding; Morphosys AG: Research Funding. Wahlin:Roche and Gilead: Consultancy.

Hodgkin lymphoma is a highly curable malignant hemopathy, using chemotherapy, radiotherapy, target therapies and hematopoietic stem cell transplantation. Current research in this field focuses on identifying prognostic factors associated with the pathogenic characteristics of the tumoral process, enabling the therapy to be adjusted to each patient’s degree of risk. The identification of biomarkers associated with the tumoral process is extremely important because these molecules can be targets for new biological therapies.

BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas.METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152.FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2-not evaluable) in the A+CHP group and 20·8 months (12·7-47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54-0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group.INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile.FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.

Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by a wide range of genetic defects. Cytogenetics, molecular and genomic technologies have proved to be helpful for deciphering the mutational landscape of AML and impacted clinical practice. Forty-eight new AML patients were investigated with an integrated approach, including classical and molecular cytogenetics, array-based comparative genomic hybridization and targeted next generation sequencing (NGS). Various genetic defects were identified in all the patients using our strategy. Targeted NGS revealed known pathogenic mutations as well as rare or unreported variants with deleterious predictions. The mutational screening of the normal karyotype (NK) group identified clinically relevant variants in 86.2% of the patients, in the abnormal cytogenetics group, the mutation detection rate was 87.5%. Overall, the highest mutation prevalence was observed for the NPM1 gene, followed by DNMT3A, FLT3 and NRAS. An unexpected co-occurrence of KMT2A translocation and DNMT3A-R882 was identified, alterations of these genes, which are involved in epigenetic regulation, are considered to be mutually exclusive. A microarray analysis detected CNVs in 25% of the NK AML patients. In patients with complex karyotypes, the microarray analysis made a significant contribution toward the accurate characterization of chromosomal defects. In summary, our results show that the integration of multiple investigative strategies increases the detection yield of genetic defects with potential clinical relevance.

Acquired von Willebrand disease (AvWD) represents a rare, potentially severe and most likely underdiagnosed category of hemorrhagic syndromes determined by quantitative, qualitative or functional, nonhereditary, alterations of von Willebrand factor (vWF) that occur in the context of various underlying diseases. It is diagnosed mainly in adults, without any personal or familial history of bleeding. The etiopathogeny of AvWD is complex, marked by the intervention of multiple mechanisms, occuring in the evolution of neoplasia, autoimmune disorders, cardiovascular diseases and other conditions. The clinical and laboratory manifestations are similar to the congenital form with mucocutaneous hemorrhage in patients without bleeding history and demonstration of quantitative and/or functional anomalies of vWF. Treatment has two major objectives: control of bleeding and therapy of the underlying condition. As a practical illustration of the theoretical aspects we present 3 clinical cases of AvWD diagnosed in the Colţea Hospital Department of Hematology during the last 10 years.

Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive mature T-cell malignancy caused by the human T lymphoma virus I (HTLV-I) affecting 3&ndash, 5% of HTLV-1 carriers and is usually diagnosed in endemic regions. Romania is a region with high prevalence of HTLV-1 infection and ATLL and with low median age at diagnosis for aggressive types. We performed a retrospective analysis of post-transplant outcome in the first Romanian patients with ATLL receiving hematopoietic stem cell allotransplant. The study population included eight patients (three males, five females), with median age of 39.5 (range 26&ndash, 57), with acute (one case) and lymphoma type (seven cases) that received peripheral stem cells (PBSC) from matched related (MRD) and unrelated donors (MUD) after reduced intensity conditioning. Graft versus host disease (GVHD) developed in six patients. Relapse occurred in four cases (50%) at a median time of 5-months post-transplant. Six patients died: four cases with disease-related deaths and two patients with GVHD-related deaths. The median survival post-transplant was 19.5 months (range 2.3&ndash, 44.2 months). The post-transplant survival at 1-year was 62.5%, at 2-years 50%, and at 3-years 37.5%. In our opinion allogeneic transplant improves outcome in aggressive type ATLL.

Even if considered a cumulative and not a proliferative CD5+ B-cell neoplasm, chronic lymphocytic leukemia (CLL) has a proliferation rate higher than that recognized earlier, especially in the lymphoid tissues. Some patients with CLL develop a clinical syndrome entitled Richter syndrome (RS). Understanding CLL genetics and epigenetics may help to elucidate the molecular basics of the clinical heterogeneity of this type of malignancy. In the present project we aimed to identify a microRNA species that can predict the evolution of therapy-resistant CLL towards RS. In the first phase of our study, microRNA-19b was identified as a possible target, and in the second phase, we transfected three different CLL cell lines with microRNA-19b mimic and inhibitor and assessed the potential role on leukemia cells in vitro. The mechanism by which miR-19b acts were identified as the upregulation of Ki67 and downregulation of p53. This was further supported through RT-PCR and western blotting on CLL cell lines, as well as by next generation sequencing on two patients diagnosed with CLL that evolved into RS.

Introduction Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm triggered by HTLV1 infection. According to the Japanese studies, the median onset of disease is around age 60 (Yamada Y et al. Br J of Haematol 2001, Kamiunten A et al. Hematol Oncol 2018). The aggressive forms exhibit a poor prognosis, due to intrinsic or acquired chemotherapy resistance and severe immunosuppression. Combination chemotherapy can improve the response rates, and consolidation with allogenic hematopoietic stem cell transplantation (allo-HSCT) prolongs complete remission (CR) (Yamada Y et al. Br J of Haematol 2001, Kamiunten A et al. Hematol Oncol 2018). The overall survival (OS) rates at 1 and 2 years after transplantation were reported to be 34% and respectively 27% (Kamiunten A et al. Hematol Oncol 2018). Romania is one of the regions with the highest prevalence of HTLV1 infection (5.33 at 10.000 donors in 2003-2008, Leperche S et al. Vox Sang 2009), therefore the prevalence of ATL is also higher. Methods A prospective observational study was performed on all patients with aggressive forms of ATL, diagnosed in Bucharest between April 2010 and January 2019, respectively 56 patients. Patients under 18 years of age and with chronic or smoldering type were excluded. The goal of this study was to better describe the disease characteristics and to discover novel factors that influence response and survival. All patients were assessed in collaboration with Necker Hospital, Paris, France, as reference center. Clinical and lab data were collected, the treatment was administered at investigator choice using CHOP/CHOP-like, Hyper-CVAD and LSG15 regimens, and allo-HSCT was offered to all eligible patients as soon as CR was obtained. Statistical analyses were performed using IBM SPSS Statistics 25. For survival analysis we used Kaplan-Meier estimate. The ROC curve was used to set cutoff values. The statistical significance was calculated using Chi-squared test and Fisher's exact test. Results In this study we analyzed a total of 56 ATL patients (M:F=1:1.3), with a median age of 42.5 years, all having aggressive types. Within this group, 33.9% had hypercalcemia and 73.2% elevated LDH (64.3% >2xN). Most used chemotherapy regimens were: CHOP/CHOP-like (60.7%), followed by LSG15 (23.2%) and Hyper-CVAD (7.1%); antiretroviral therapy (51.8%) and allo-HSCT (12.5%) were also used. LSG15 regimen is not fully applicable in our country due to unavailability of Ranimustine and Vindesine, therefore a small proportion of patients received this treatment. In multivariate analysis, factors showing significant association with lower rate of CR were: age >40.5 years, leukocytosis with a cut-off of 8950/μl, hypercalcemia >9.5 mg/dl, high LDH >512 U/L. LSG15 was associated with a higher CR rate (50%) compared to CHOP/CHOP-like (22.7%) and Hyper-CVAD (33.3%), although not statistically significant. Median OS was 6.5 months (5.1 - acute type, 8.0 - lymphomatous type), versus 3.5 months in acute type and 9.5 months in lymphomatous type in previous data in our center. Early death rate (< 1 month) was found in 8.9% (n=5) of patients. Factors associated with early death were: acute type (n=4), leukocytosis (n=5), hypercalcemia (n=4), high LDH (n=5), extranodal involvement (n=4). Patients who obtained CR (n=9) had a better survival that those who did not (median OS 40.7 vs 5.1 months, p=0.000) (Fig a); undergoing allo-HSCT also significantly increased OS (median OS not reached vs 6.1 months, p=0.003) (Fig b). Among patients who underwent allo-HSCT, OS at 1 year and 2 years after the allo-HSCT were 57.1% and 42.9%, respectively. Three patients died, all less than 1 year after transplantation. Conclusions Median age at diagnosis in our group was lower (42.5 years) versus the Japanese studies (Yamada Y et al. Br J of Haematol 2001, Kamiunten A et al. Hematol Oncol 2018). This might reflect an origin of infection in the 1980s in Romania, where other outbreaks occurred by horizontal transmission in that period, including an outbreak of HIV-1 (Patrascu I V et al, Lancet 1990). Future in-depth studies of this cohort might better correlate age of infection, HTLV1 subtype and latency to ATL. The best predictors of better survival were obtaining CR and receiving allo-HSCT. Among the treatments we used, LSG15 regimen had higher rate of CR. Survival after transplantation was higher in our group compared to the Japanese studies (Kamiunten A et al. Hematol Oncol 2018). Disclosures Constantinescu: AgenDix GmbH: Other: Co-Founder, MyeloPro Research and Diagnostics; AlsaTech: Other: Co-Founde; Wiley & Sons: Other: Editor in Chief, Journal of Cellular and Molecular Medicine; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hermine:Celgene: Research Funding; AB science: Consultancy, Equity Ownership, Honoraria, Research Funding; Novartis: Research Funding.

Introduction: Adult T lymphoma (ATL) is a rare and aggressive disease shown to be consistently caused by the human T lymphoma virus I (HTLV-I). It generally occurs in Japan and Africa, with a low incidence in Europe. Romania is an exception to this rule, presenting an endemic representation of ATL. Aim: The aim of this study was to present our experience with allogeneic stem cell transplantation (alloSCT) for ATL. Methods: The current study was a retrospective analysis of the ATL cases that received alloSCT in the Fundeni Clinical Institute. The patients were included between January 2016 to April 2019. Results: A total of 7 patients were included in the present study, out of which 2 (28%) presented the acute form, while the rest presented the lymphomatous form. Four (57%) patients presented extranodal involvement, with 3 of those (75%), showing skin involvement. Of note, all patients presenting skin involvement also had bone marrow involvement. Thus, skin involvement was associated with a more advanced disease. Graft versus host disease (GvHD) was present in 4 (57%) patients, two of which were acute GvHD and two, chronic GvHD. Interestingly, the two patients that relapsed presented either acute or chronic GvHD, showing that the graft versus lymphoma (GVL) effect that can be observed in other lymphoma types is not observed in this cohort. Another noticeable observation is the fact that 4 out of the 6 patients tested for HTLV-I at 6 months post alloSCT presented a positive HTLV-I viral load. This event occurred, although, at 30 days, all patients presented 100% donor chimerism and the donor samples were negative for HTLV-I. This shows a possible imperfect jump of the HTLV-I from the recipient to the donor T lymphocytes or the possibility of a reinfection. Three (43%) patients presented a response less than complete remission (CR) after the first line of therapy, two of which progressed to death. The two deaths occurred at 14 and 15 months from the diagnosis, with the other follow-up periods in the cohort being higher than 26 months with the exception of one patient that had a follow-up of 6.8 moths from diagnosis. These two aforementioned patients were also the only ones to relapse thus far. Conclusion: For ATL, alloSCT represents a viable and potentially curative approach when used in chemosensitive disease. This being said, there are clear differences from other lymphomas, ATL having to be considered separately. Disclosures Tanase: Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol Myers: Consultancy. Hermine:Novartis: Research Funding; Celgene: Research Funding; AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding.

Immunophenotyping of B-cell lymphoproliferative disorders is indispensable, especially in disorders with CD19(+) CD5(+) B lymphocytes, where we have to make the distinction between low grade neoplasia, such as chronic lymphocytic leukemia with CD23(+) malignant lymphocytes, and aggressive neoplasia such as mantle cell lymphoma with CD23(-) malignant lymphocytes. We found some cases of CD19(+) CD5(+) lymphoproliferative disorders that do not meet all criteria for diagnosis of chronic lymphocytic leukemia or mantle cell lymphoma. For instance, we found cases with a low or no expression of CD23, asociated with absence of expression of FMC7 and surface immunoglobulins. These cases could be classified as "borderline" CD19(+) CD5(+) B cell lymphoproliferative disorders, with an intermediate neoplasic grade.