The emergence of novel immunotherapies for myelodysplastic syndrome (MDS) calls for a profound characterization of the "immunome" in the bone marrow (BM) and evaluation of prognostic impact of ...immunological changes. We performed a prospective study of 87 MDS patients who were referred to a tertiary hematological center and of 11 bone marrow donors who were not related to the study cohort. A flow cytometry panel with 48 markers including checkpoint ligands and receptors was used to study lymphoid and myeloid subpopulations in the bone marrow aspirates. The study found that both the healthy donors and the MDS patients have a high proportion of lymphocytes with PD-1 expression (41±18% and 58±25% respectively) and a high proportion of myeloid cells with PD-1L expression (31±23% and 12±7% respectively), indicating a potential physiological role of checkpoint systems in BM. At the same time, complex alterations including PD-1, CTLA-4, LAG-3 and TIM3 pathways accompanied by an increased level of T-reg and myeloid derived suppressor cell populations were identified in the BM of MDS patients. Cluster analysis showed independent prognostic significance of the checkpoint profile for overall survival (HR 1.90, 95%CI 1.01–3.56, p = 0.0471). TIM3-postive NK and CD8 effector cells along with the blast count were the key subpopulations for prognosis. An elevation of blasts in the bone marrow was associated with simultaneous expression of multiple checkpoints on myeloid cells.
Immune checkpoint inhibitors (ICI) have demonstrated high therapeutic efficacy in relapsed or refractory classical Hodgkin lymphoma (r/r cHL). Nevertheless, despite the accumulated data, the question ...of the ICI therapy duration and efficacy of nivolumab retreatment remains unresolved. In this retrospective study, in a cohort of 23 adult patients with r/r cHL who discontinued nivolumab in complete response (CR), the possibility of durable remission achievement (2-year PFS was 55.1%) was demonstrated. Retreatment with nivolumab has demonstrated efficacy with high overall response rate (ORR) and CR (67% and 33.3% respectively). At the final analysis, all patients were alive with median PFS of 16.5 months. Grade 3–4 adverse events (AEs) were reported in 36% of patients, and there was no deterioration in terms of nivolumab retreatment–associated complications.
The predictive value of graft composition and plasma biomarkers on the outcome of allogeneic HSCT is well known for conventional GVHD prophylaxis based on calcineurin inhibitors with or without ...antithymocyte globulin. Currently, there is limited data whether these results could be translated to post transplantation cyclophosphamide (PTCy). The prospective extension cohort of NCT02294552 trial enrolled 79 adult patients with acute leukemia in CR. Twenty-six received matched-related bone marrow (BM) grafts with single-agent PTCy and 53 received unrelated peripheral blood stem cell graft (PBSC) with PTCy, tacrolimus, and MMF. The grafts were studied by the flow cytometry, and plasma samples were analyzed by ELISA. In the cluster and major component analysis, we determined that transplantation from donors with high content of CD3, NKT, and CD16-CD56 + subpopulations in the PBSC grafts was associated with poor immunological recovery and compromised event-free survival (50% vs. 80%, HR 2.93, p = 0.015) both due to increased relapse incidence and non-relapse mortality. The significant independent predictor of moderate and severe chronic GVHD was the high prevalence of and iNKT, Vβ11, and double-positive cells in the PBSC grafts from young donors (HR 2.75, p = 0.0483). No patterns could be identified for BM grafts and for plasma biomarkers.
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The introduction of nivolumab has changed the landscape of relapsed/refractory classical Hodgkin lymphoma (r/r cHL) treatment. Despite its ...clinical importance, this therapy may remain inaccessible for a significant number of patients worldwide, especially in low‐income countries, due to its high cost. The results of pharmacokinetic analysis and clinical observations suggest the potential efficacy of low dose nivolumab in r/r cHL patients. The aim of this trial was to assess the efficacy and safety of nivolumab at a fixed dose of 40 mg in patients with r/r cHL. The study included 30 patients with r/r cHL, treated with 40 mg nivolumab every 2 weeks. The median dose of nivolumab per kilogram bodyweight was 0.59 mg/kg (0.4–1 mg/kg). Median follow up was 19.2 months (range 12.7–25.4). The objective response rate was 70%, with 13 (43.3%) patients achieving a complete response. Median PFS was 18.4 months (95% CI, 11.3 to 18.5 months) with 18‐month PFS of 53.6% (95% CI, 32%–71%). At the time of analysis, 96.7% of patients were alive with a median OS not reached. Severe (grade 3–5) adverse events were observed in 4 patients (13.3%). Nivolumab in a fixed dose of 40 mg was efficient in patients with r/r cHL, independent from dose per kg bodyweight. The results of this study are in good agreement with previously reported data and create a rationale for further studies aimed to define the optimal dosing regimen of nivolumab for the treatment of r/r cHL. Registered at www.clinicaltrials.gov (NCT03343665)
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This single‐center prospective clinical trial evaluated the combination of nivolumab plus bendamustine (NB) as a salvage regimen in classical ...Hodgkin lymphoma patients after failure of nivolumab monotherapy. A total of 30 patients received nivolumab (3 mg/kg) on D1,14 and bendamustine (90 mg/m2) on D1, 2 of a 28‐day cycle for up to 3 cycles. The ORR was 87% with 57% CR, 30% PR. With median follow‐up of 25 months, the estimated 2‐year OS was 96,7% (95% CI, 90.2%–100%), PFS was 23,3% (95% CI, 8.2%–38.4%) median PFS was 10.2 months (95% CI, 7.7–14.2 months) with median DOR 6.6 months (95% CI 3.9–11.6 months). Ten patients (33.3%) experienced grade 3 to 4 AE during therapy. Infections were most common AEs of the combined therapy. NB was a highly efficient salvage regimen in relapsed/refractory cHL with a manageable toxicity profile and modest potential for achievement of long‐term remission. Registered at www.clinicaltrials.gov (#NCT0334365).
Introduction
Although a number of studies were published on the efficacy of post‐transplantation cyclophosphamide (PTCy) for graft‐versus‐host disease (GVHD) prophylaxis, no large studies ...prospectively evaluated this strategy in related, unrelated, and haploidentical grafts.
Methods
In this study, GVHD prophylaxis for 57 matched bone marrow (MBM) grafts consisted of single‐agent PTCy, for 88 matched PBSC grafts (MPBSC) consisted of PTCy, tacrolimus, and mycophenolate mofetil (MMF) 30 mg/kg, and for 55 mismatched grafts (MMGs) consisted of PTCy, tacrolimus and MMF 45 mg/kg.
Results
The study met the primary endpoint to demonstrate equivalent rates of acute GVHD grade II‐IV (11%, 17%,19%, P = .46), III‐IV (7%, 2%, 6%, P = .41), and moderate and severe chronic GVHD (22%, 11%, 15%, P = .23). There was also no differences in non‐relapse mortality (11% vs 15% vs 17%, P = .75), overall survival (63% vs 71% vs 56%, P = .72), event‐free‐survival (51% vs 66% vs 48%, P = .32) for MBM, MPBSC, and MMG groups, respectively. Toxicity was comparable between groups except higher incidence of nephrotoxicity in combination arms (P = .0005) and higher incidence of graft failures in MMG group (P = .004).
Conclusion
The suggested risk‐adapted PTCy‐based prophylaxis is feasible and is associated with low GVHD incidence and mortality in all types of grafts. The study was registered on clinicaltrials.gov (NCT02294552).
Background. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for patients with acute myeloid leukemia (AML). The conditioning regimen administered for this ...patient based on busulfan combined with cyclophosphamide (BuCy), fludarabine (BuFlu) or some other agents. Comparisons of myeloablative conditioning (MAC) versus reduced intensity conditioning (RIC) have demonstrated a various results between relapse and toxicity in a few reports. We supposed, that dose intensity of busulfan across regimens may affect treatment outcomes.
The goal of this retrospective study was to evaluate the impact dose of busulfan to overall survival (OS), transplant-related mortality (TRM), relapse-free survival (RFS), toxicity, the incidence of primary graft failure and acute graft-versus-host disease (GVHD) in transplantation in children and adolescents with AML.
Material and methods. We analyzed 110 AML pediatric patients with the median age 9 y.o. (range 1-19), who underwent first allo-HSCT with busulfan based (per os and IV) conditioning in R.M. Gorbacheva Memorial Institute from 2002 to 2018. Patients were divided into 3 groups: Bu1 - patients, who received busulfan at the dose 8-10 mg/kg, n=34 (31%), in Bu2 - dose of busulfan was 12 mg/kg, n= 35 (32%), in Bu3 - dose of busulfan was >12 mg/kg, n= 41 (37%). In Bu1 busulfan was combined with Flu in 31 pts (91%) and Cy in 3 (9%); in Bu2 - with Flu in 12 (34%) , Cy in 7 (20%) and other agents in 16 (46%); in Bu3 - with Cy in 32 (78%), with Flu in 7 (17%) and other agents in 2 pts (5%) (p < 0.001). Patients in Bu2 received more Cy based GVHD prophylaxis regimens (69% vs 44% in Bu1, vs 29% in Bu3, p = 0.003) and more HAPLO grafts (51% vs 29% in Bu1, vs 15% in Bu3, p = 0.003). The complete remission at the HSCT was observed in 79 % in Bu1, 49% in Bu2, 61% in Bu3 p=0,02. Probabilities of OS, RFS, TRM were estimated by using the Kaplan-Meier method. Incidence of toxicity, acute GVHD and primary graft failure - by using Mann - Whitney U-test.
Results. Transplant engraftment was achieved in 95 (86%) of patients. Graft failure occurs in the 5 patients of Bu1 group (15%), in the 6 pts of Bu2 (17%) and in the 4 pts of Bu3 (10%), p=0,7. Median follow-up was 2 years for Bu1 and Bu3, 1 year for Bu2. OS was similar (Bu1=59% vs Bu2=60% vs Bu3=51%), p=0,7. OS of pts with CR before HSCT was 70% in Bu1, 82% in Bu2, 60% in Bu3, p=0,3 and 14%, 39%, 38% for pts with progression disease (PD), respectively, p=0,5. RFS was 74% in Bu1, 82% in Bu2, 64% in Bu3 at CR, p=0,4; 43%, 39% and 38% in pts with progression, respectively, p=0,9. Median of RFS were also similar for the pts in PD, (4 months in Bu1, 5 months in Bu2 and Bu3), p=0,9 and not achieved for pts at CR. Drug related toxicity grade 3-4 experienced in 35% pts in Bu1, 29% in Bu2, in 54% in Bu3, p=0,04. Mucositis and toxic hepatitis were the most common adverse events. Sinusoidal obstruction syndrome (SOS) experienced in 8 pts from different group: 4 from Bu2 (11%), 3 from Bu3 (7%) and only 1pts from Bu1 (3%) with previously treated of gemtuzumab ozogamicin, p=0,4. The most pts with SOS (3/5) had PD at the HSCT. Cumulative incidence of acute GVHD grade 2 (15% vs 14% vs 10%, p=0,8) were not different. Acute GVHD grade 3-4 was observed a bit more often in Bu3 (34%), than in Bu1 (18%) and Bu2 (17%), p=0,09. TRM up to +100 days was also higher in Bu3 (15%), than in Bu2 (6%) and Bu1 (0%), p=0,05.
Conclusions. The transplant results of children with similar disease status of AML, received conditioning with various dose of busulfan, were not associated with significant differences in overall outcomes. The higher dose busulfan may increase incidence of toxicity grade 3-4 (p=0,04) and acute GVHD grade 3-4 (p=0,09) with increasing of early TRM (p=0,05).
Moiseev:Celgene: Consultancy, Other: Travel grants; Novartis: Consultancy, Honoraria, Other: Travel grants, Speakers Bureau; Pfizer: Other: Travel grants; MSD: Other: Travel grants; BMS: Other: Travel grants; Takeda: Other: Travel grants.
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