Direct Acting Antivirals (DAA) have changed the landscape of hepatitis C virus (HCV) infection with high cure rates across genotypes. However, the use of these agents in the setting of allogeneic ...hematopoietic cell transplantation (HCT) has been limited. In this context, we report the outcome of five children (5‐12 years) with relapsed and refractory leukemia and active HCV infection (genotype 1b), who underwent urgent haploidentical HCT and were treated with Sofosbuvir and Velpatasvir (Sof‐Vel) from initiation of treatment to 24 weeks post‐HCT. All achieved complete virologic response (VR) at a median of 2 weeks, with normalization of liver enzymes. There were no adverse events related to the use of Sof‐Vel, with no major fluctuations in cyclosporine levels. Two of the patients developed chronic GVHD and one relapsed. Sof‐Vel was continued in one of them along with sirolimus without affecting drug levels. With a median follow‐up of 15 months, four patients are disease free with sustained VR. Our study shows that combination of Sof‐Vel might be effective in inducing rapid complete and sustained VR during HCT without any major untoward drug interaction.
Haploidentical transplantation with PTCY following marrow or PBSC graft has been associated with low incidence of GVHD in adults with similar data lacking in children. We report on the outcome of 25 ...patients <20 yr of age (median age 12 yr), undergoing a haploidentical PBSC transplantation for both malignant and non‐malignant disorders. Engraftment was prompt and sustained. Cumulative incidences of acute GVHD and chronic GVHD were 40.3% and 16.7%, respectively. On subgroup analysis, it was evident that acute GVHD developed in 80% of patients <10 yr compared to only 13.3% in those between 10 and 20 yr log‐rank p = 0.001, despite similar graft composition with significantly higher NRM (60% vs. 0%; p = 0.001). The FFS was 63.5%; (79% in >10 yr and 40% in <10 yr, p = 0.01). Our data suggest that PTCY‐based haploidentical PBSC transplantation is feasible in older children, but results in early and severe alloreactivity in younger children. These findings, despite being counterintuitive, could be explained by the variable metabolism of CY and oral mycophenolate in younger children indicating that PTCY‐based approach as used in adults might not be adequate for younger children.
Following a major seasonal outbreak of H1N1 influenza in 2018 September, prophylactic oseltamivir for six months was initiated in children undergoing haploidentical HCT with regular monitoring for ...influenza and other respiratory virus infections. Influenza was not detected in 22 children undergoing prophylaxis, compared to 8 H1N1 infections in 21 adults without prophylaxis (P = .01). Four children on prophylaxis were detected to have other respiratory viruses, compared to 8 in those without prophylaxis. Invasive pulmonary aspergillosis (IPA) was observed only in association with H1N1 (4/8 with H1N1 vs 0/35 without H1N1, P = .001) and was thus lower in the prophylaxis group (P = .04). The overall incidence of episodes of respiratory illness and hospital stay were also lower in those on prophylaxis (P = .001). There were no untoward side effects associated with prophylactic oseltamivir. Prophylactic oseltamivir was safe and effective in prevention of H1N1 infection and subsequent IPA in children at‐risk, early after haploidentical HCT.
We have earlier shown that early use of prophylactic G-CSF mobilized DLI resulted in improved disease-free survival following post-transplantation cyclophosphamide (PTCy) based haploidentical HSCT in ...patients with relapsed/refractory myeloid malignancies. CD56 enriched donor cell infusion following PTCy for similar cohort resulted in rapid proliferation of mature NK cells with attenuation of GVHD. However, the relapse rate was higher than that with early DLI (50% vs 21.4%). CTLA4Ig has been shown to be effective in attenuating T cell activation and induce transplantation tolerance in preclinical models. NK cells on the other hand are resistant to CTLA4Ig and in fact might demonstrate better anti-tumour effect in presence of CTLA4Ig as CD86 is a putative activation receptor. To explore this phenomenon, we employed sequential CTLA4Ig primed DLI following PTCy based haploidentical HSCT.
The study group (CTLA4Ig-DLI) had 24 patients (4-65 years; myeloid malignancies-10, Lymphoid malignancies-14) received Abatacept (CTLA4Ig) at 10 mg/kg on day -1 followed by PBSC and sequentially on days +6, +20 and +35 followed 12 hours later by DLI of 5 x 106 CD3 cells/kg containing 0.03-1 x106/kg CD56+ cells. PTCy was administered on days +3 and +4 with cyclosporine from day +5 to day +60 and subsequent rapid tapering. The outcome and immune reconstitution of the CTLA4Ig-DLI group was compared with the cohort of patients who received DLI without abatacept (n=21; DLI group)
All patients engrafted at a median of 15 days (11-20 days). The incidence of acute GVHD was 9.7% compared to 31% in the DLI group (p=0.08) and that of chronic GVHD was 28% vs 41.2% (p=0.4). Three patients required treatment for CMV infection with no non-relapse mortality (0% vs 19.9% in DLI group; p=0.03). The relapse incidence was 25.4% vs 21.4% in the DLI group (p=0.7) with an overall survival of 82% vs 70.5% at 18 months (p=0.4). In the CTLA4Ig-DLI group only 1/10 patients with myeloid malignancies relapsed compared to 5/14 in the lymphoid group. Absolute CD56+CD3- and CD56+CD16+ NK cells were significantly higher in the CTLA4Ig-DLI group at day +30 (175±162 vs 73±34; p=0.008 and 95±121 vs 32±19.1; p=0.02 )and +60 (134±107 vs 98±55; p=0.1 and 84 ±87 vs 30±10; p=0.01). The CD56+16+ NK cell population in the CTLA4Ig-DLI group had a higher expression of KIR receptors at day +30. Within the CTLA4Ig-DLI group, patients not experiencing relapse had a significantly higher CD56+16+ NK cell populations at day +30 (125±130 cells/microl vs 15 ± 8±; p=0.004) and day +60 (104±93 cells/microl vs 25± 16; p=0.006).
CTLA4Ig primed DLI resulted in greater proliferation of NK cells with mature phenotype than the DLI group with comparatively lower incidences of acute GVHD and NRM and improved relapse-free survival, particularly in those with myeloid malignancies. Higher proliferation of mature NK cells at 30 and 60 days post-transplant was associated with a lower risk of relapse following CTLA4Ig primed DLI. Thus, this novel approach enabled early institution of adoptive immunotherapy to mitigate the risk of relapse in advanced leukemia without increase in GVHD or NRM.
Display omitted
No relevant conflicts of interest to declare.
▪
Introduction : We conducted a prospective study on T cell and NK cell subset composition of the graftand the transplant outcome with single dose of subcutaneous Plerixafor(Px) to GCSF based ...mobilisation in T-replete Haploidentical Peripheral blood Stem cell transplantation with post-transplantation cyclophosphamide (PTCy) in 25 donors (G+Px group). This was compared with 26 donors who received G-CSF alone for mobilisation (G group).
Material and Methods : With the aim to collect 10 x 106/kg CD34 cells in a single apheresis, donors with peripheral CD 34 count less than 50 cells /µl in the peripheral blood on day 4 of mobilization were administered Injection Plerixafor at the dose of 0.12mcg/kg at 12 midnight in addition to routine GCSF. This was followed by PBSC harvest starting 11 hours later at 11 A.M on the next day. The rest were continued G-CSF only as per protocol.
Results: CD 34 cell countG+Px-136(range, 52-351)vs G-139 (range,72-240) cells/µl in the peripheral blood on day 5 as well as that in the graft G+Px- 2.7(range 1.1-6.0) VsG-2.3(range 0.5-5.3) X106 /ml, p=0.05 comparable between the two groups, despite a significantly lower peripheral CD34 cell count on day 4 in the pleraxifor group (G+Px-33(range, 6-47) vs G-81(58-168) cells/µl, p=0.0001). The total nucleated cell count was higher in the G- group 3.4(range 1.7-5.0) vs 3.1(range 1.15-4.73) X108/ml, p=0.05 . Despite the lower trend of CD4+ T cells 2.3(range 0.3-6.8) Vs 2.7(range 0.53-6.8) X107/ml, p=0.09 in the G-CSF group, mobilisation of Tregs was similar(7.1% vs 6.9% in G+Px group,p=0.1). There were no differences noted in the absolute number of NK cells G+Px-5.3(range 0.8-11.6) vs 5.7.(range 1.7-12.9) X106/ml, p=0.9 , or the CD56+16+/16- subsets. The time to engraftment was similar in both groups. The incidences of acute and chronic GVHD, non-relapse mortality and relapse were also similar.
Conclusion: Addition of single dose pleraxifor to G-CSF mobilisation improves CD34 recovery and does not significantly alter the T and NK cell composition of the graft, including Tregs. No adverse impact was noted on engraftment, GVHD, NRM and relapse. Our study demonstrates that pleraxifor can be safely used as an adjunct to G-CSF to boost CD34 mobilisation without impacting conventional or regulatory T cells and NK cells in the graft. The preliminary data suggests no adverse impact on transplant outcomes.
Display omitted
No relevant conflicts of interest to declare.
Abstract The outcome of hyperacute grade 3–4 steroid-refractory graft-versus-host-disease (SR-GVHD) remains dismal despite a plethora of agents being tried alone or in combination. Following T ...replete haploidentical transplantation with post-transplantation cyclophosphamide on 75 patients, 10 patients (13%) aged 2–20 years, developed hyperacute SR-GVHD. We report on the outcome of two different regimens for treatment of SR-GVHD on the outcome of these patients. Five patients were treated in Regimen A consisting of anti-thymocyte globulin, Etanercept and Basiliximab. The next 5 patients were treated combining T cell costimulation blockade with Abatacept along with Etanercept and Basiliximab. The overall response at days 29 and 56 were 40% and 0% with Regimen A and100% and 40% with Regimen B. The major cause of treatment failure was progression of GVHD and opportunistic infections. Two of the patients achieving a complete remission on Regimen B are long term disease free survivors off immunosuppression. Our study demonstrates the dismal outcome of early onset SR-GVHD in children following T replete haploidentical transplantation. However, the combination of Abatacept with anticytokine agents seems to produce encouraging early response and might warrant further investigation.
Haploidentical (haplo) hematopoietic cell transplantation (HCT) for nonmalignant disease (NMD) carries inherent challenges of both alloreactivity and graft failure. Building on promising results from ...pilot studies in which abatacept was combined with post-transplantation cyclophosphamide (PTCy) and sirolimus (AbaCyS) in younger NMD patients undergoing haplo-HCT, we present the long-term outcomes of this protocol. On the back of uniform disease-specific conditioning regimens containing antithymocyte globulin 4.5 mg/kg from day -9 to day -7, GVHD prophylaxis with AbaCyS consisted of abatacept administered on days 0, +5, +20, +35, and monthly until 180 days with PTCy and sirolimus. The patients were followed up with longitudinal assessment of immune reconstitution, growth, and reproductive development and quality of life (QoL) analyses. Among 40 patients (aplastic anemia, n = 24; hemoglobinopathies, n = 14; and primary immunodeficiencies, n = 2) with a median age of 10 years (range, 2 to 25 years), 95% achieved sustained engraftment. Post-transplantation hemophagocytic syndrome was detected in 3 patients, leading to graft failure in 2 cases. The incidence of acute graft-versus-host disease (GVHD) was 2.6%, and that of chronic GVHD (cGVHD) was 14.3%. Cytomegalovirus, adenovirus, and Epstein-Barr virus infections were observed in 45%, 5%, and 0% respectively. Rates of nonrelapse mortality, overall survival, event-free survival, and GVHD-free, event-free survival were 5%, 95%, 90%, and 82%, respectively, at a median follow-up of 4.6 years. Absence of cGVHD correlated with younger patient age and early sustained recovery of regulatory T cells and mature natural killer cells, which in turn was associated with improved QoL and lack of late infections. The AbaCyS protocol was associated with excellent long-term survival, with attenuation of both early and late alloreactivity in >80% of younger patients undergoing haplo-HCT for NMD. This study sheds light on predispositions to cGVHD and its impact on QoL, warranting further optimization of this approach.
In a pilot study, 75 patients with Primary Refractory (PRef) AML without matched family donors were offered post-transplantation cyclophosphamide (PTCY) based haploidentical peripheral blood stem ...cell (PBSC) transplantation. Twenty-seven patients (36%) opted for haploidentical transplantation with or without further chemotherapy. There was no difference in the patient or disease characteristics amongst patients undergoing transplantation or not. The conditioning regimen comprised of FluCyMel (n=5), FluBuMel (n=17) and FluTreoTBI (n=5). MMF was tapered between days 14 and 21 posttransplant in the absence of GVHD and cyclosporine A was tapered between days 60 and 90. The progression free survival at a median follow-up of 25 months was 36.6% and 0% in the transplant and the non-transplant group (p=0.0001). Prompt engraftment was noted at a median of 14 days irrespective of disease status or conditioning regimens. Cumulative incidences of acute graft-versus-host disease (GVHD) and chronic GVHD were 26.6% and 8% respectively. The overall incidence of infections remained low, with CMV reactivation and invasive aspergillosis occurring in 9 and 2 patients respectively. CMV disease was diagnosed in 2 patients. Non-relapse mortality at 1 year was 16.7%. The incidence of disease progression was 54%. Factors positively impacting progression free survival were < 15% marrow blasts at transplant and a Natural Killer Cell Ligand Mismatch (NKLMM) donor. NKLMM, Haplotype or B scores had no impact on CMV infection or GVHD. However, Bx Haplotype was associated with lower NRM (5%, 95%CI-1-9) compared to 48.6% (95%CI 28.2-69.0) in AA Haplotype (p=0.01). Disease status did not impact the overall survival (p=0.11) in the HSCT cohort. In fact, NKLMM donors with B haplotype had the greatest impact on overall survival in both the HSCT cohort (71.4%, 95%CI 54.3-88.5%) compared to 20% (95%CI 8.8-31.2, p=0.01) in those without the same. Our data suggests PTCY based Haploidentical PBSC transplantation is feasible in patients with PRef AML and donor NKLMM might improve progression free survival, provided the conditioning protocol and the post-grafting therapy offer the optimum platform for alloreactivity of NK cells.
No relevant conflicts of interest to declare.
PDF
