Background: Angioimmunobastic Lymphoma (AITL) and T-γδ-hepatosplenic lymphomab(HSTCL) consist two rare, aggressive T-NHL subtypes while patients with Mycosis Fungoides/Sézary (MF/SS) syndrome may have a more indolent disease course but are rarely cured with conventional therapy. AutoHSCT may offer prolonged survival in selected cases of AITL but relapses are common. Despite the significant innovation in therapeutics of hematological malignancies, little progress is made in these lymphomas management. Due to the rarety as well as to the fact that at least for AITL and MF/SS median age at diagnosis is greater than 60 years old, there is limited number of reports on allogeneic stem cell transplant outcomes and data from prospective studies are missing Aims: To describe our experience on allogeneic transplant outcomes in a small cohort of relatively young patients with AITL (3), HSTCL (3), MF/SS (8) Methods: Records of 14 patients (6 men, 8 women), who underwent consecutively allogeneic stem cell transplant from 01/01/2008 to 31/12/2019, were retrospectively studied. Survival status was censored on 15th February 2022. All had consented to the use of their data before conditioning initiation Results: Median age was 51.5, 34 and 49 years old in MF/SS, HSTCL and AITL respectively. All donor types had been used. All MF/SS had been submitted to RIC alloHSCT with FLU MEL +/-ATG and no MF/SS patient was on CR at the time of alloHCT (3 PR, 2SD, 3PD). 1 patient with AITL was in CR at the time of alloHSCT and remains alive, relapse and GVHD free 28 months after alloHSCT while 1 patient in PR at the time of alloHSCT is alive in CR, relapse/GVHD free 6 years later. 1 patient with HSTCL is alive relapse/GVHD free 12 years after HSCT. There were no early deaths before day 30 in the whole cohort, while 3 patients died before day 100 – 1 with AITL due to primary graft failure, 2 with MF/SS due to refractory disease. 2 patients with HSTCL died due to early disease relapse, 4 and 6 months post-transplant respectively, while 2 patient with MF/SS died 7 and 15 months post-transplant due to EBV positive PTLD and severe gastrointestinal PTLD complicated by CMV-colitis. At the date of data censoring 4 patients with MF/SS were alive in CR and relapse/GVHD free, while 1 patient was alive but in PR after the second relapse treated with pembrolizumab 39 months after alloHSCT Summary/Conclusion: Due to the rarity of the studied lymphoma subtypes our cohort was small and proper statistical analysis of data could not be done safely. However, it becomes clear that younger patients with MF/SS -even with relapsed/refractory disease - may benefit of prolonged survival with allogeneic stem cell transplant. For patients with HSCTL, allogeneic stem cell transplant is considered “sine qua non” for survival and cure, while fit patients with AITL should be considered candidates for alloHSCT. Immunological manipulation may contribute to relapse management.

Background: Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) is a 96-hour continuously infused regimen, aiming to improve first-line treatment of aggressive B-cell lymphoma. Prolonged exposure to chemotherapeutic drugs and dose intensification target to reduce tumor resistance, however toxicity remains a barrier for the broad use of this regimen. Aims: To reveal the experience of our Centre on the treatment of aggressive B-cell lymphoma with DA-EPOCH-R Methods: We retrospectively collected data from 54 consecutive patients treated with DA-EPOCH-R in our Department. Results: Thirty one women and 23 men with median age of 37 years (range 18-76) were diagnosed between 2013 and 2021, with a High Grade B-cell Lymphoma, HGBCL (24 cases) and Primary Mediastinal B cell Lymphoma, PMBCL (30 cases). The Ann Arbor stage was I (16 cases), II (14 cases), III (5 cases) and IV (19 cases). The majority (85%) of patients had good (0-1) ECOG performance status. All but 2 patients were HIV positive. All patients were planed to be treated with 6 cycles of DA-EPOCH-R. Ten patients changed treatment plan due to disease progression (5 patients) and toxicity (5 patients). Among patients with HGBCL, 19 achieved a complete response (CR), 3 manifested resistant disease (RD) and for 3 patients response assessment was not possible due to disease related early death. Among patients with PMBCL, 24 showed CR, 1 patient partial response and 4 patients a RD. With a median follow up of 23 months (range 1- 86), the median progression free survival (PFS) and overall survival (OS) of all patients were not reached. Comparing survival between HGBCL and PMBCL, the latter had significantly better PFS and OS. Among the 42 patients who completed 6 cycles of treatment, only 3 reached the level 5 of dose escalation, 12 the level 4, 13 the level 3, 7 the level 2 and 4 remained at the level 1. Seven cases underwent 1 step of dose increase, 14 patients 2 steps 13 patients 3 levels and 3 patients 4 levels. The administration of high dose methotrexate in 11 patients, hampered the dose escalation. In 7 subjects, level deescalation was required (1 level for 6 patients and 2 levels for 1patient). Toxicity was manifested in 51 out of 54 patients. Haematological toxicity with neutropenia was the most common side effect: grade 4 in 88%, grade 3 in 7%, grade 1 in 5%. Severe thrombocytopenia was manifested in 7 cases. All patients received erythropoietin to treat anaemia. Thirty five subjects (65%) suffered from febrile neutropenia. Fever was related to bacterial infection in 14 cases (37%) and viral infection in 7 cases (20%). Neuropathy was observed in 11% of patients, stomatitis in 24%, gastrointestinal side effects in 13% and grade 3 or greater hepatic toxicity in 11%. Eight patients died, all due to disease relapse or progression. No death was attributed to treatment toxicity. Summary/Conclusion: DA-EPOCH-R is an effective treatment for aggressive B-cell lymphoma limited by tolerability. Its administration should be confined to subgroups where the efficacy of this regimen is clearly superior.

Background: Prognosis of r/r B-NHL is detrimental. Potentially curative therapeutic approaches, such as autologous stem cell transplantation and innovative CAR-T cell therapy, require maximum disease control to achieve optimal results. Glofitamab is a new bispecific antibody, with a unique 2:1 molecular configuration resulting in superior potency compared with other CD20xCD3 bispecific antibodies with a 1:1 format. Aims: Based on these encouraging results, we included 5 heavily pretreated patients in the early access program of Glofitamab, available in our country. Methods: We collected the data of 5 consecutive patients with r/r B-NHL, who were treated with Glofitamab in our department during the last 15 months. Results: Three men and 2 women, median age of 57 years (38-62), were resistant to 4 (n = 3) and 5 (n = 2) previous lines of treatment. The underlying lymphoma was Richter’s transformation of CLL after allogeneic transplantation (alloHSCT), transformed follicular lymphoma (tFL), primary mediastinal B-cell lymphoma (PMBCL), r/r diffuse large B-cell lymphoma (DLBCL) after CAR-T therapy and gray zone lymphoma (GZL) transformed to DLBCL. The median number of Glofitamab cycles administered was 3 (2-7). All 5 patients responded early to treatment, which became apparent immediately after the first dose of 2.5 mg. The patient with Richter’s syndrome achieved metabolic remission after the 4th cycle and underwent second alloHSCT after the 7th cycle. Unfortunately, he passed away 8 months after alloHSCT due to disseminated atypical mycobacterial infection, remaining however disease free. The patient with tFL also achieved metabolic remission, but the drug was discontinued after the 7th cycle due to COVID-19 infection. He died two months after Glofitamab interruption due to disease progression and CMV encephalitis. The patient with PMBCL, responded partially after Glofitamab and had mediastinal radiotherapy as bridging therapy to CAR-T therapy. As the latter was delayed due to CMV reactivation and CMV enteritis, our patient deceased due to progressive disease. The patient with DLBCL after CAR-T therapy had initial clinical response after two Glofitamab cycles. Due to severe COVID-19, we decided to hold Glofitamab. COVID-19 and disease progression led to his death, a few weeks after COVID-19 diagnosis. Finally, the patient with transformed GZL had Glofitamab administered as bridging therapy prior to CAR-T treatment. After 3 cycles, while she was prepared to proceed to CAR-T therapy, she was diagnosed with invasive aspergillosis. She is currently been treated with antifungal agents, whereas disease is still active. Cytokine release syndrome (CRS) occurred in 3 out of 5 patients. In all cases it was grade 1-2 and manifested at the first administration of the drug, after 4, 32 and 10 hours respectively, from infusion initiation. CRS was managed with antipyretics and steroids, whereas none patient required Intensive Care Unit support. Only one patient required tocilizumab. No Immune effector cell-Associated Neurotoxicity Syndrome (ICANS) was observed. Summary/Conclusion: Glofitamab is effective in treating patients with r/r aggressive B-cell NHL. Efficacy makes it an appropriate bridging tool to autologous, alloHSCT or CAR-T therapy. Nevertheless, relapse remains a challenge for r/r disease. Adverse events, such as CRS, were generally manageable. Given the fact that it was administered to heavily pretreated patients, caution to opportunistic pathogens should be paid. Indeed, toxicity profile may be proven to be more favorable if the agent is being administered earlier in therapeutic algorithms.

Introduction: Mantle Cell Lymphoma (MCL) is an indolent B-cell non Hodgkin Lymphoma (NHL) with a worse outcome compared to other low grade NHL. The prognosis of the disease is dictated by various biologic and clinical factors. Although MCL is chemosensitive in newly diagnosed patients, soon it relapses. A significant improvement of its outcome has been achieved by the administration of Rituximab (R) based regimens and the intensification of first line treatment by high dose Cytarabine and autologous stem cell transplantation. Methods: To reveal the experience of our Centre on the diagnosis, treatment and outcome of this difficult to treat lymphoma, we collected data from 51 consecutive patients, diagnosed at our department between 1999 and 2020. Results: Thirty nine (39) men and 12 women with median age 68 years (range 33-88) were diagnosed with MCL. All but one had typical histology. One patient manifested the blastoid variant. Ki67 was available for 39 biopsy: In 57% specimens Ki67 was >30% and in 43% Ki67 was ≤30%. In 84% of cases the performance status at diagnosis was good (PS 0-1) and only 16% showed PS 2-4. The majority of patients (90%) had advanced stage disease (III-IV). High MIPI score was observed in 59%, intermediate in 18% and low in 22%. Elevated lactate dehydrogenase was observed in 58% of cases. Nineteen patients received R - Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone (R-CHOP), 11 an intensified regimen, 14 patients R -Bendamustin, 5 patients R - Chlorambucil and 2 subjects had no treatment. Response to treatment showed as follow: Complete Response (CR) 52%, Partial Response (PR) 36%, Stable disease (SD) 2% and Progressive Disease (PD) 10%. Among patients who received an intensified treatment, 9 underwent an autologous transplantation. Twenty two patients with responsive disease beneficed of R maintenance. Over a median follow up of 62.8 months (range 0.3 - 262), the median overall survival (OS) was 165 months (range 0.3 - 262). Twenty three out of 44 (52%) patients with responsive disease, relapsed. The median progression free survival (PFS) was 59 months (range 6 - 140). Sixteen out of 23 (69%) patients achieved a 2nd response. The treatments administered were: R-CHOP (6 patients), R-Bendamustin (6 patients), platinum based regimens (3 patients), Ibrutinib (5 patients), corticosteroids (2 patients), R - Chlorambucil (1 patient). The median PFS and OS after the 1st relapse were 26.4 months (range 6.9 - 165) and 27 months (range 0.2 - 233) respectively. Response to 1st line treatment (p 0.0001), lower MIPI score (p 0.001) and intensified regimen (p 0.0004) were correlated with a better survival. Conclusions: Increasing the percentage of 1st complete response by intensifying the 1st line treatment could improve the survival of patients with MCL. Keywords: Indolent non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Usually, after double umbilical cord blood transplantation (DUCBT), only 1 of the transplanted units persists in the long term. The characteristics of the winning cord blood unit (W-CBU) that determine unit dominance and how they influence the outcomes of DUCBT remain unclear. We retrospectively analyzed 347 patients with acute leukemia transplanted with a DUCBT (694 CBU) from 2005 to 2013 who had documented neutrophil engraftment and a W-CBU identified by chimerism analysis, to identify unit characteristics impacting on dominance. Median age at DUCBT was 40 years and median follow-up was 35 months. Among W-CBUs, 41% were ≥5/6 HLA matched to the recipient and 59% were ≤4/6. Multivariate analysis indicated that ≤4/6 HLA-matched W-CBUs led to lower leukemia-free survival (44% versus 56%; hazard ratio [HR], 1.5; P = .032) and overall survival (49% versus 62%; HR, 1.5; P = .028), increased nonrelapse mortality (26% versus 18%; HR, 1.9; P = .027), and acute graft-versus-host disease (46% versus 35%; HR, 1.7; P = .013). We were unable to predict unit dominance, but we demonstrated that outcomes were strongly influenced by the degree of HLA mismatch between W-CBU and recipient. Therefore, selection of both units with the lower number of HLA mismatches with the recipient is indicated.

BackgroundThe efficacy of umbilical cord blood transplantation (UCBT) as treatment for acute myeloid leukaemia (AML) relies on immune-mediated graft-versus-leukaemia effects. Previous studies have suggested a strong association between graft-versus-host disease (GVHD) occurrence and graft-versus-leukaemia effects after allogeneic hematopoietic cell transplantation. MethodsHere, we evaluated the kinetics of relapse rate in correlation with GVHD occurrence after UCBT. The kinetics of relapse rate over time in correlation to GVHD occurrence were assessed by calculating the relapse rate per patient-year within sequential 90-day intervals. The impact of GVHD on relapse and mortality was further studied in multivariate Cox models handling GVHD as a time-dependent covariate. ResultsThe study included data from 1068 patients given single (n=567) or double (n=501) UCBT. The proportion of patients with grade II, III and IV acute GVHD was 20%, 7% and 4%, respectively. At 2years, the cumulative incidence of chronic GVHD was 42%, the cumulative incidence of relapse was 32%, and overall survival was 32% as well. Relapse rates declined gradually over time during the first 30months after transplantation. There was a possible suggestion that grade II-IV acute (HR=0.8, P=0.1) and chronic (HR=0.65, P=0.1) GVHD decreased relapse risk. However, grade II-IV acute GVHD significantly increased early (the first 18months after UCBT) mortality (HR=1.3, P=0.02), whilst chronic GVHD increased each early (HR=2.7, P<0.001) and late (HR=4.9, P<0.001) mortality after UCBT. ConclusionsThe occurrence of grade II-IV acute or chronic GVHD each increases overall mortality after UCBT for AML mitigating the possible graft-versus-leukemia effect of GVHD.

Conference: 42nd Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation, Valencia, SPAIN, APR 03-06, 2016

Hematopoietic stem cell transplantation for T-cell large granular lymphocyte leukemia: a retrospective study of the European Society for Blood and Marrow Transplantation

Outcomes after unmanipulated haploidentical stem cell transplantation (Haplo) and after unrelated cord blood transplantation (UCBT) are encouraging and have become alternative options to treat patients with high-risk acute leukemia without human leukocyte antigen (HLA) matched donor. We compared outcomes after UCBT and Haplo in adults with de novo acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Median follow-up was 24 months. Analysis was performed separately for patients with AML, n =918 (Haplo=360, UCBT=558) and ALL, n =528 (Haplo=158 and UCBT=370). UCBT was associated with delayed engraftment and higher graft failure in both AML and ALL recipients. In multivariate analysis, UCBT was associated with lower incidence of chronic graft-vs-host disease both in the AML group (hazard ratio (HR)=0.63, P =0.008) and in the ALL group (HR=0.58, P =0.01). Not statistically significant differences were observed between Haplo and UCBT for relapse incidence (HR=0.95, P =0.76 for AML and HR=0.82, P =0.31 for ALL), non-relapse mortality (HR=1.16, P =0.47 for AML and HR=1.23, P =0.23 for ALL) and leukemia-free survival (HR 0.78, P =0.78 for AML and HR=1.00, P =0.84 for ALL). There were no statistically differences on main outcomes after unmanipulated Haplo and UCBT, and both approaches are valid for acute leukemia patients lacking a HLA matched donor. Both strategies expand the donor pool for patients in need.