Search

Simple Summary Both BR, and R-BAC are suitable induction therapies in elderly patients with mantle cell lymphoma (MCL). However, the two regimens have not been compared before. We retrospectively analysed the outcome and the safety features of elderly patients with newly diagnosed MCL, treated with BR or R-BAC between 2008 and 2019 at eight institutions. We used propensity scores to reduce selection bias, thus analysing 156 patients (53 BR, 103 R-BAC). Patients treated with R-BAC achieved higher CR rate than BR (91% vs. 60%, p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). Median overall survival (OS) was 121 months for R-BAC and 78 months for BR (p = 0.08). R-BAC was associated with significantly more pronounced grade 3–4 thrombocytopenia than BR (50% vs. 17%). This study indicates that R-BAC is associated with significantly prolonged 2-year PFS than BR in elderly patients with MCL. Abstract Background: Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed. Methods: In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score. Results: After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53–90). Median follow-up was 46 months (range 12–133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3–4 thrombocytopenia than BR (50% vs. 17%). Conclusions: This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.

The rate of complete remission (CR) with the anti-PD1 immune checkpoint inhibitors (ICI) nivolumab (N) and pembrolizumab (P) in patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) is low (20–30%), and the majority of patients eventually relapse. One strategy to improve their outcome is to combine ICI with radiotherapy (ICI-RT), taking advantage of a supposed synergistic effect. We retrospectively collected data of 12 adult patients with R/R cHL treated with ICI-RT delivered during or within 8 weeks from the start or after the end of ICI. Median age at ICI-RT was 37 years, 50% had previously received an autologous stem cell transplantation (SCT) and 92% brentuximab vedotin. RT was given concurrently, before or after ICI in 4, 1 and 7 patients. Median RT dose was 30 Gy, for a median duration of 22 days. Median number of ICI administrations was 15. Overall response and CR rate were 100% and 58%. Nine patients received subsequent SCT consolidation (7 allogeneic and 2 autologous). After a median follow-up of 18 months, 92% of patients were in CR. No major concerns about safety were reported. ICI-RT combination appears to be a feasible and highly active bridge treatment to transplant consolidation.

The use of rituximab for the treatment of immune thrombocytopenia was greeted enthusiastically: it led to up to 60% response rates, making it, nearly 20 years ago, the main alternative to splenectomy, with far fewer side effects. However, long-term follow-up data showed that only 20-30% of patients maintained the remission. No significant changes have been registered using different dose schedules and timing of administration, while the combination with other drugs seemed promising. Higher response rates have been observed in young women before the chronic phase, but apart from that, other clinical factors or biomarkers predictive of response are still lacking. In this review we examine the historical and current role of rituximab in the management of immune thrombocytopenia, 20 years after its first use for the treatment of autoimmune diseases.

Despite the improvement in understanding its pathogenesis and the introduction of novel treatment options, the management of primary immune thrombocytopenia (ITP) still remains challenging. Considering its increased incidence with aging and prolonged life-expectancy, ITP is often diagnosed in elderly patients, a subset that deserves some special precautions. Ensure the diagnosis is a crucial step, and carefully attention must be given in excluding other causes of thrombocytopenia, especially among older people that frequently suffer from many comorbidities. When it comes to treatment decision, it is worth keeping into account that the elderly have an increased risk of bleeding, thrombosis and infections, that they often require many concomitant therapies, including antiplatelet or anticoagulant agents, and that treatment-related toxicities are often increased and sometimes more dangerous that the disease itself. There are not dedicated guidelines, and only few specific studies. Steroids with or without IVIG remain the first-line treatment. Splenectomy is less effective than in youngers and burdened by an increased thrombotic and infectious risk. Rituximab is a good option in non-immunocompromised patients, but long-term remissions are few. Eltrombopag and romiplostim have a good safety and efficacy profile, and have become a prominent drug in this subset, even if they are associated with a possible increased risk of thrombosis, and long-term toxicity is unknown. Other drugs, such as dapsone and danazol, have a well-known efficacy and safety profile, and still represent a valid option among elderly patients.

The efficacy and safety of thrombopoietin receptor agonists (TRAs) in older patients with primary immune thrombocytopenia (ITP) are unknown. We investigated TRA response and switch, thrombotic/hemorrhagic risk, and sustained responses off-treatment (SROTs) in 384 patients with ITP aged ≥60 years. After 3 months, 82.5% and 74.3% of eltrombopag- and romiplostim-treated patients, respectively, achieved a response; 66.7% maintained the response (median follow-up, 2.7 years). Eighty-five (22.2%) patients switched to the alternative TRA; although no cross-toxicity was observed, 83.3% of resistant patients had a response after the switch. Thirty-four major thromboses (3 fatal) and 14 major hemorrhages (none fatal) occurred in 18 and 10 patients, respectively, while on TRAs and were associated with thrombosis history (subdistribution hazard ratio, 2.04, P = .05) and platelet count

Up to 30% immune thrombocytopenia (ITP) patients achieve a sustained remission off-treatment (SROT) after discontinuation of thrombopoietin receptor agonists (TPO-RAs). Factors predictive of response are lacking. Patients aged ≥18 years with newly diagnosed or persistent ITP were treated with eltrombopag for 24 weeks. Primary end-point was SROT: the proportion of responders that were able to taper and discontinue eltrombopag maintaining the response during a period of observation (PO) of six months. Secondary end-points included the association between some immunological parameters (TPO serum levels, cytokines and lymphocyte subsets) and response. Fifty-one patients were evaluable. Primary end-point was achieved in 13/51 (25%) treated patients and 13/34 (38%) patients who started the tapering. Baseline TPO levels were not associated with response at week 24 nor with SROT. Higher baseline levels of IL-10, IL-4, TNF-α and osteopontin were negative factors predictive of response (P = 0·001, 0·008, 0·02 and 0·03 respectively). This study confirms that SROT is feasible for a proportion of ITP patients treated with eltrombopag. Some biological parameters were predictive of response.

Immune thrombocytopenia (ITP) secondary to chronic lymphoproliferative disorders (LPDs) is poorly responsive to conventional treatments. We conducted a multicenter phase 2 prospective 24-week study in 18 patients with ITP secondary to LPDs to assess the safety and efficacy of eltrombopag. Responsive patients entered an extension study for up to 5 years. For inclusion, patients should not require cytotoxic treatment and should have a platelet count30 × 109/L or have symptoms of bleeding. Eltrombopag was initiated at 50 mg/day, with a maximum of 150 mg/day. The primary end point was platelet response after 4 weeks. Median age was 70 years (range, 43-83 years), and 14 patients had chronic lymphocytic leukemia, 2 had classic Hodgkin lymphoma, and 2 had Waldenström macroglobulinemia. All patients had received previous ITP treatments. Response rate at week 4 was 78% (95% confidence interval [CI], 58%-97%), with 50% of patients having a complete response (CR) (95% CI, 43%-57%); respective results at week 24 were 59% (95% CI, 36%-82%) with 30% reaching a CR (95% CI, 8%-52%). Median exposure to eltrombopag was 16 months; median dose at week 4 was 50 mg/day (range, 25-100 mg/day), and at week 24, it was 50 mg/day (range, 25-150 mg/day). No grade2 adverse events were reported. Eltrombopag is active and well tolerated in ITP secondary to LPDs. This trial was registered at www.clinicaltrials.gov as #NCT01610180.

BACKGROUND AND AIM Bone marrow compensation in autoimmune hemolytic anemia (AIHA) is an emerging predictor of clinical outcome. It is measured by reticulocytosis that may be inadequate in a proportion of cases, particularly in chronic refractory ones. Moreover, reticulocytosis may be masked by constant destruction, particularly in cold forms. Recombinant erythropoietin (EPO), has been anecdotally used off-label in AIHA to improve anemia, but only case reports and small series have been described. Here we evaluate EPO efficacy and predictors of response in a multicentric cohort of primary and secondary AIHA patients. METHODS Hematological data, hemolytic markers (LDH, reticulocytes), and concomitant treatments were retrospectively and prospectively collected. Efficacy was evaluated at 15 and 30 days, and then at 3,6 and 12 months after EPO start. Response was considered as partial (PR, >2 g/dL Hb increase or >10 g/dL) or complete (CR, >12g/dL and normalization of hemolytic markers). Forty-six AIHA cases followed from June 2007 to June 2019 at 9 centers in Italy, France, Norway, Austria, Denmark, and UK were included. RESULTS Table 1 shows patients characteristics: all AIHA types (warm, cold, mixed, and DAT negative) were present, and 5 cases were secondary to a lymphoproliferative disorder (not active and without specific treatment at the time of EPO start). Bone marrow evaluation pre-EPO (N=24) showed hypercellularity in 14 cases, dyserythropoiesis in 11, and reticulin fibrosis in 3; a lymphoid infiltrate was found in 19 patients (T-cell in 6, B-cell in 10, mixed in 3), greater than 10% in the 5 secondary cases only. Forty-one cases (89%) had been previously treated, with a mean of 1.8+1 lines of therapy including steroids, rituximab, splenectomy, immunosuppressors and sutimlimab (1 case, where the drug completely abolished hemolysis). The majority (67%) started EPO due to non-response to ongoing treatment (18 steroids, 6 immunosuppressors, 1 sutimlimab) or within 3 months from rituximab course (7). At EPO initiation, 30% of cases displayed severe anemia, 71% had inadequate reticulocytosis (bone marrow responsiveness index CONCLUSIONS EPO is effective in roughly 70% of chronic refractory AIHA cases, independently from antibody thermal characteristics/isotype and underlying disease. Concomitant treatments may partially affect response evaluation, although EPO treatment has been introduced because of their partial or complete inefficacy. Further limitations are the retrospective nature of the study and a possible selection bias (i.e. most of patients had inadequate reticulocytosis). Predictors of response were severe anemia and low levels of endogenous EPO, as well as, shorter disease duration and a lower burden of previous treatments. These data suggest an early use of EPO in this setting in order to overcome inadequate bone marrow compensatory ability. Table Disclosures Fattizzo: Apellis: Consultancy. Michel:Novartis: Consultancy; Amgen: Consultancy; Rigel: Consultancy. Frederiksen:Novartis: Research Funding; Janssen Pharmaceuticals: Research Funding; Abbvie: Research Funding; Alexion: Research Funding; Gilead: Research Funding. Mauro:Gilead: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Jilma:TrueNorth a Bioverativ company, a Sanofi company: Consultancy, Research Funding. Hill:Regeneron: Honoraria; Roche: Honoraria; Ra Pharma: Honoraria; Bioverativ: Honoraria; Novartis: Honoraria; Akari: Honoraria; Alexion: Honoraria; Apellis: Honoraria. Berentsen:Mundipharma: Research Funding; Apellis, Bioverativ (a Sanofi company), Momenta Pharmaceuticals, and True North Therapeutics: Consultancy; Alexion, Apellis, and Janssen-Cilag: Honoraria. Barcellini:Agios: Other: Advisory board; Bioverativ: Other: Advisory board; Alexion: Other: Invited Speaker, Research Funding; Novartis: Other: Invited Speaker, Research Funding; Incyte: Other: Advisory board. OffLabel Disclosure: Erythropoietin (EPO) is not yet indicated for the use in autoimmune hemolytic anemia. Here we report retrospective data on a large cohort of cases treated with EPO as a support to bone marrow compensation.

REDCap is a novel workflow methodology and software solution designed for rapid development and deployment of electronic data capture tools to support clinical and translational research. We present: 1) a brief description of the REDCap metadata-driven software toolset; 2) detail concerning the capture and use of study-related metadata from scientific research teams; 3) measures of impact for REDCap; 4) details concerning a consortium network of domestic and international institutions collaborating on the project; and 5) strengths and limitations of the REDCap system. REDCap is currently supporting 286 translational research projects in a growing collaborative network including 27 active partner institutions.

Objectives To evaluate the efficacy of a salvage treatment with rituximab (RTX) in adults with primary immune thrombocytopenia (ITP), in terms of short-term response and long-term response (LTR, i.e., probability to achieve and maintain response) and to identify biological and clinical predictors of response. Methods We retrospectively evaluated the outcome of patients with primary ITP treated with standard dosage RTX (375 mg/m2 × 4) as salvage therapy in five Italian centers. One hundred and three patients, median age of 46 yr, were included. The median period of observation was 59 months. Results Response (R) and complete response (CR) were documented in 57 (55%) and 37 (36%) patients, respectively. Patients younger than 40 yr had a higher probability to achieve CR (P = 0.025). Younger women (age < 40 yr) had a significantly higher probability to achieve R and CR (P = 0.039 and P = 0.009, respectively). The estimated LTR rate was 36% and 31% after 48 and 72 months, respectively; female sex (P = 0.033) and younger age (P = 0.021) were associated with better LTR. Younger women had the highest LTR rate (P = 0.006). Response duration was associated with the obtainment of CR after RTX (CR vs. partial response, P = 0.002). Conclusions The effect of RTX salvage treatment appears higher in younger women, with LTR rate possibly approaching that of splenectomy.

Background: Thrombopoietin receptor-agonists (TPO-RAs), eltrombopag (ELT) and romiplostim, are effective drugs licensed for relapsed/refractory ITP, leading to 70-80% response rates. As they stimulate the Mpl receptor on megakaryocytes, increasing platelet production, their effect is expected to be dependent on their continuous administration. However, durable remissions after TPO-RAs discontinuation have been described in 10-30% of patients (pts). This evidence pointed out a possible curative role for these agents, suggesting a mode of action that goes beyond the mere increase of platelet count, and interferes with the immune dysregulation underlying the disease, which worsens as ITP becomes chronic. The aim of this prospective study is to explore the role of ELT given for a defined period of time as second-line treatment in pts with newly diagnosed (ND) or persistent (P) ITP, thus interfering with the pathogenesis of the disease at an early stage, either offering a possible curative option for pts or a steroid-sparing drug as a bridge to chronic phase (CP). Methods: Pts aged ≥18 years with ND or P ITP not responsive or in relapse after standard first-line therapy, with active disease (platelet count Results: Between 24/02/16 and 05/05/2018, 55 pts were enrolled by 10 GIMEMA Italian Centers. 3 pts didn't meet the inclusion criteria and 1 was excluded from study population because of protocol violation. Of the 51 evaluable pts, 31 (61%) were females. Median age was 65 years (range 21-90). 22 pts (44%) had ND ITP. Median baseline platelet count was 19x109/L (range 1-227). At the time of data cut-off, 10 pts were still in PT and 1 was not evaluable. Out of the remaining 40 pts, 2 were discontinued for reasons other than failure, and were excluded from response analysis. Of the 38 evaluable pts, at the end of 6 months of therapy 14 (37%) were in CR and 12 (32%) in R, with an ORR of 69%; 12 pts were non responders. All the 26 responders started the PTD. Of the 18 pts who completed the PTD, 7 maintained the response (ORR 39%), with 5 CR (28%) and 2 R (11%). At time of data cut-off, 11/26 pts have not completed yet the PO. 15/26 pts were evaluable at the end of the PO: 3 maintained the response (ORR 20%), with 1 CR and 2 R. 12 pts relapsed: 11 during the PTD and 1 during the PO. 17 pts (33%) reported a total of 58 adverse events (AEs), 8 pts (16%) reported a total of 11 grade ≥3 AEs. 4 AEs were considered treatment related, only 1 of them was grade ≥3 (deep vein thrombosis). 2 pts (3.9%) died during the study, for reasons not related to treatment. Conclusions: These preliminary data confirm the previously reported efficacy of ELT in primary ITP, with an ORR of 69%. Almost 40% of pts maintained the response at the end of PTD, which is slightly higher than expected. These data suggest that the use of ELT at an earlier phase of the disease (ND or P ITP) is a more effective approach and that 6 months of therapy is a sufficient period to think about ELT tapering and discontinuation. Long-term remission was achieved in 20% of pts, but probably this data is biased by the fact that at the time of data cut-off only a small proportion of pts completed the PO, also considering that only 1 pt lost the response during the PO. For pts who don't maintain the response, ELT can still be a steroid-sparing agent used as a bridge to CP or other treatment options. This analysis is too early to define a correlation between the response and immunological parameters (including TPO levels). Disclosures Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zaja:Amgen: Honoraria; Abbvie: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Sandoz: Honoraria.

Background: The anti-CD52 monoclonal antibody alemtuzumab (Alem) induces a rapid-onset, profound and long-lasting depletion of lymphocytes: B cells recover within 12 months, while T cell recovery is still incomplete after 30 months. Alem is used as induction therapy for solid organ transplantations, including renal. Autoimmune complications following Alem include thyroid disorders (20-30%), immune thrombocytopenia (ITP) (2-3%), and autoimmune hemolytic anemia (AIHA) and autoimmune nephropathies (< 1%). Methods: we retrospectively analyzed 41 patients (pts) attending the Haematology Clinic at Hammersmith Hospital (HH), who developed autoimmune cytopenias (ITP or AIHA) after an Alem-induced renal transplant. The autoimmune cytopenia was defined as a rapid onset of isolated thrombocytopenia and/or anemia without other explanation. For ITP, complete response (CR) and response (R) were defined according to IWG standard criteria (Rodeghiero,Blood,2009). For AIHA, CR was defined as a stable Hb level >120 g/L, no transfusion requirement and no signs of hemolysis; partial response (PR) as a rise in Hb levels >20 g/L, without transfusion requirement. The study aim is to report clinical features and treatment outcomes of these 41 pts. Results: Between 1/11/05 and 14/12/16, 1431 pts received an Alem-induced renal transplant at HH. 34 (2.3%) developed ITP and 7 (0.48%) AIHA; 28 (68%) pts were males. Median age at renal transplant was 48 (range 20-69) years. The cytopenia developed a median of 35 months (range 6-161) after Alem administration. Median lowest platelet count was 5.5x109/L (range 0-41) and median nadir of hemoglobin (Hb) was 58 g/L (range 35-65). ITP pts: 2 pts achieved spontaneous CR. Of the remaining 32, 91% received steroids, IVIG or both as first line therapy, with an overall response rate (ORR) of 62%. 10 pts (31%) maintained the response without any further treatment. 22 pts required second line therapy, 11 required ≥ 3 lines of treatment. Treatments included: thrombopoietin receptor agonists (TPO-RA), rituximab (RTX), MMF and/or a combination. TPO-RA were used 15 times, with an ORR of 80%, a relapse rate of 33% and a median duration of response (DOR) of 22 months (range 3-48); 10/12 pts (83%) who responded to TPO-RA, discontinued treatment after a median of 64 days (range 7 - 528): 6 maintained the response after discontinuation. RTX was used 10 times, with an ORR of 90%, a relapse rate of 22% and a median DOR of 27 months (range 3 - 83). A combination of RTX and TPO-RA was used 7 times, with an ORR of 71%, a relapse rate of 40% and a median duration of response (DOR) of 5 months (range 2-44); the 5 responders discontinued treatment after a median of 49 days (range 14-462): 3/5 maintained their response. After a median follow-up of 38 months (range 3-96), all ITP pts maintained a response (91% CR and 9% R); 4 were still on treatment (2 TPO-RA and 2 MMF). AIHA pts: 6 of 7 (86%) pts with AIHA received first line steroids +/- IVIG with an ORR of 67%. 4 pts needed second line therapy: all received RTX with an ORR of 50%. 2 pts needed ≥ 3 lines of therapy. After a median follow-up of 68 months (range 27-102) all AIHA pts maintained a response (57% CR and 43% PR), without any ongoing treatment. Adverse events: 33 pts (80%) experienced 1 or more adverse events (AEs): 25 cardiovascular (including 14 thrombosis), 21 infections (16 grade ≥3), 5 steroid-induced diabetes, 3 graft failures, 10 malignancies (6 solid tumors and 4 PTLD). 6 of the ITP pts also developed AIHA (Evans syndrome). 3 ITP pts died. Conclusions: ITP and AIHA represent important complications of Alem-induced renal transplant. Response rates after first-line therapy for ITP were comparable to primary ITP (30%). However, long-term response rate, sustained response to RTX and the proportion of pts able to continue in remission after discontinuing TPO-RA are higher than seen with primary ITP. Recovery from cytopenias may occur in conjunction with T cell reconstitution post Alem (this is under investigation). The large majority of AEs were related to multifactorial heavy immunosuppression and increased thrombotic risk distinguishing this group of pts. Hence for ITP and AIHA, steroids should be limited, as they are curative in only a few pts and burdened by many side effects. Both RTX and a short course of TPO-RA appear valid options, but the choice should be driven by the individual balance between thrombotic and infectious risks versus persistence of cytopenias. Disclosures Cooper: Amgen, Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.