Strategies to reduce relapse risk in patients undergoing allogeneic stem cell transplantation for acute myeloid leukaemia

Allogeneic stem cell transplantation is a centrally important curative strategy in adults with acute myeloid leukaemia; however, relapse occurs in a significant proportion of patients and remains the leading cause of treatment failure. The prognosis for patients who relapse post‐transplant remains poor, and the development of new strategies with the ability to reduce disease recurrence without increasing transplant toxicity remains a priority. In this review, within the context of our understanding of disease biology and the graft‐versus‐leukaemia (GVL) effect, we will discuss established, evolving and novel approaches for increasing remission rates, decreasing measurable residual disease pretransplant, future methods to augment the GVL effect and the opportunities for post‐transplant maintenance. Future progress depends upon the development of innovative trials and networks, which will ensure the rapid assessment of emerging therapies in prospective clinical trials

Donor-derived mycosis fungoides following reduced intensity haematopoietic stem cell transplantation from a matched unrelated donor

A 46-year-old woman with a history of dasatinib-resistant chronic myeloid leukaemia, clonal evolution and monosomy 7 underwent reduced intensity conditioned in vivo T-cell-depleted allogeneic haematopoietic stem cell transplantation (HSCT) from a matched unrelated donor. Following the transplantation, she developed recurrent cutaneous graft versus host disease (GvHD), which required treatment with systemic immunosuppression and electrocorporeal photophoresis. Concurrently, she developed a lichenoid rash with granulomatous features suggestive of cutaneous sarcoidosis. Additional treatment with hydroxychloroquine was initially successful, but 2 months later, she developed erythroderma with palpable lymphadenopathy. Repeated histological analysis established a diagnosis of folliculotropic mycosis fungoides stage IVA2, and the malignant clone was confirmed to be of donor origin. A positive response to brentuximab has been shown. This is the first reported case of primary mycosis fungoides after matched unrelated donor HSCT, and in a patient still undergoing treatment for GvHD

Early inflammatory markers as prognostic indicators following allogeneic stem cell transplantation

Allogeneic stem cell transplantation is used widely in the treatment of hematopoietic malignancy although graft versus host disease and relapse remain major complications. We measured the serum protein expression of 92 inflammation-related markers from 49 patients at Day 0 (D0) and 154 patients at Day 14 (D14) following transplantation and related values to subsequent clinical outcomes. Low levels of 7 proteins at D0 were linked to GvHD whilst high levels of 7 proteins were associated with relapse. The concentration of 38 proteins increased over 14 days and higher inflammatory response at D14 was strongly correlated with patient age. A marked increment in protein concentration during this period associated with GvHD but reduced risk of disease relapse, indicating a link with alloreactive immunity. In contrast, patients who demonstrated low dynamic elevation of inflammatory markers during the first 14 days were at increased risk of subsequent disease relapse. Multivariate time-to-event analysis revealed that high CCL23 at D14 was associative of AGvHD, CXCL10 with reduced rate of relapse, and high PD-L1 with reduced overall survival. This work identifies a dynamic pattern of inflammatory biomarkers in the very early post-transplantation period and reveals early protein markers that may help to guide patient management.</p

Early inflammatory markers as prognostic indicators following allogeneic stem cell transplantation

Allogeneic stem cell transplantation is used widely in the treatment of hematopoietic malignancy although graft versus host disease and relapse remain major complications. We measured the serum protein expression of 92 inflammation-related markers from 49 patients at Day 0 (D0) and 154 patients at Day 14 (D14) following transplantation and related values to subsequent clinical outcomes. Low levels of 7 proteins at D0 were linked to GvHD whilst high levels of 7 proteins were associated with relapse. The concentration of 38 proteins increased over 14 days and higher inflammatory response at D14 was strongly correlated with patient age. A marked increment in protein concentration during this period associated with GvHD but reduced risk of disease relapse, indicating a link with alloreactive immunity. In contrast, patients who demonstrated low dynamic elevation of inflammatory markers during the first 14 days were at increased risk of subsequent disease relapse. Multivariate time-to-event analysis revealed that high CCL23 at D14 was associative of AGvHD, CXCL10 with reduced rate of relapse, and high PD-L1 with reduced overall survival. This work identifies a dynamic pattern of inflammatory biomarkers in the very early post-transplantation period and reveals early protein markers that may help to guide patient management

Brief cycling intervals incrementally increase the number of hematopoietic stem and progenitor cells in human peripheral blood

IntroductionPeripheral blood stem cell (PBSC) donation is the primary procedure used to collect hematopoietic stem and progenitor cells (HSPCs) for hematopoietic stem cell transplantation. Single bouts of exercise transiently enrich peripheral blood with HSPCs and cytolytic natural killer cells (CD56dim), which are important in preventing post-transplant complications. To provide a rationale to investigate the utility of exercise in a PBSC donation setting (≈3 h), this study aimed to establish whether interval cycling increased peripheral blood HSPC and CD56dim concentrations to a greater degree than continuous cycling.MethodsIn a randomised crossover study design, eleven males (mean ± SD: age 25 ± 7 years) undertook bouts of moderate intensity continuous exercise [MICE, 30 min, 65%–70% maximum heart rate (HRmax)], high-volume high intensity interval exercise (HV-HIIE, 4 × 4 min, 80%–85% HRmax) and low-volume HIIE (LV-HIIE, 4 × 2 min, 90%–95% HRmax). The cumulative impact of each interval on circulating HSPC (CD34+CD45dimSSClow) and CD56dim concentrations (cells/µL), and the bone marrow homing potential of HSPCs (expression of CXCR-4 and VLA-4) were determined.ResultsThere was an increase in HSPC concentration after two intervals of LV-HIIE (Rest: 1.84 ± 1.55 vs. Interval 2: 2.94 ± 1.34, P = 0.01) and three intervals of HV-HIIE only (Rest: 2.05 ± 0.86 vs. Interval 3: 2.51 ± 1.05, P = 0.04). The concentration of all leukocyte subsets increased after each trial, with this greatest for CD56dim NK cells, and in HIIE vs. MICE (LV-HIIE: 4.77 ± 2.82, HV-HIIE: 4.65 ± 2.06, MICE: 2.44 ± 0.77, P &lt; 0.0001). These patterns were observed for concentration, not frequency of CXCR-4+ and VLA-4+ HSPCs, which was unaltered. There was a marginal decrease in VLA-4, but not CXCR-4 expression on exercise-mobilised HSPCs after all trials (P &lt; 0.0001).DiscussionThe results of the present study indicate that HIIE caused a more marked increase in HSPC and CD56dim NK cell concentrations than MICE, with mobilised HSPCs maintaining their bone marrow homing phenotype. LV-HIIE evoked an increase in HSPC concentration after just 2 × 2-minute intervals. The feasibility and clinical utility of interval cycling in a PBSC donation context should therefore be evaluated

Brief cycling intervals incrementally increase the number of hematopoietic stem and progenitor cells in human peripheral blood

Introduction: Peripheral blood stem cell (PBSC) donation is the primary procedure used to collect hematopoietic stem and progenitor cells (HSPCs) for hematopoietic stem cell transplantation. Single bouts of exercise transiently enrich peripheral blood with HSPCs and cytolytic natural killer cells (CD56dim), which are important in preventing post-transplant complications. To provide a rationale to investigate the utility of exercise in a PBSC donation setting (≈3 h), this study aimed to establish whether interval cycling increased peripheral blood HSPC and CD56dim concentrations to a greater degree than continuous cycling. Methods: In a randomised crossover study design, eleven males (mean ± SD: age 25 ± 7 years) undertook bouts of moderate intensity continuous exercise [MICE, 30 min, 65%–70% maximum heart rate (HRmax)], high-volume high intensity interval exercise (HV-HIIE, 4 × 4 min, 80%–85% HRmax) and low-volume HIIE (LV-HIIE, 4 × 2 min, 90%–95% HRmax). The cumulative impact of each interval on circulating HSPC (CD34+CD45dimSSClow) and CD56dim concentrations (cells/µL), and the bone marrow homing potential of HSPCs (expression of CXCR-4 and VLA-4) were determined. Results: There was an increase in HSPC concentration after two intervals of LV-HIIE (Rest: 1.84 ± 1.55 vs. Interval 2: 2.94 ± 1.34, P = 0.01) and three intervals of HV-HIIE only (Rest: 2.05 ± 0.86 vs. Interval 3: 2.51 ± 1.05, P = 0.04). The concentration of all leukocyte subsets increased after each trial, with this greatest for CD56dim NK cells, and in HIIE vs. MICE (LV-HIIE: 4.77 ± 2.82, HV-HIIE: 4.65 ± 2.06, MICE: 2.44 ± 0.77, P &lt; 0.0001). These patterns were observed for concentration, not frequency of CXCR-4+ and VLA-4+ HSPCs, which was unaltered. There was a marginal decrease in VLA-4, but not CXCR-4 expression on exercise-mobilised HSPCs after all trials (P &lt; 0.0001). Discussion: The results of the present study indicate that HIIE caused a more marked increase in HSPC and CD56dim NK cell concentrations than MICE, with mobilised HSPCs maintaining their bone marrow homing phenotype. LV-HIIE evoked an increase in HSPC concentration after just 2 × 2-minute intervals. The feasibility and clinical utility of interval cycling in a PBSC donation context should therefore be evaluated

Helminth Communities of Owls (Strigiformes) Indicate Strong Biological and Ecological Differences from Birds of Prey (Accipitriformes and Falconiformes) in Southern Italy

We compared the helminth communities of 5 owl species from Calabria (Italy) and evaluated the effect of phylogenetic and ecological factors on community structure. Two host taxonomic scales were considered, i.e., owl species, and owls vs. birds of prey. The latter scale was dealt with by comparing the data here obtained with that of birds of prey from the same locality and with those published previously on owls and birds of prey from Galicia (Spain). A total of 19 helminth taxa were found in owls from Calabria. Statistical comparison showed only marginal differences between scops owls (Otus scops) and little owls (Athene noctua) and tawny owls (Strix aluco). It would indicate that all owl species are exposed to a common pool of 'owl generalist' helminth taxa, with quantitative differences being determined by differences in diet within a range of prey relatively narrow. In contrast, birds of prey from the same region exhibited strong differences because they feed on different and wider spectra of prey. In Calabria, owls can be separated as a whole from birds of prey with regard to the structure of their helminth communities while in Galicia helminths of owls represent a subset of those of birds of prey. This difference is related to the occurrence in Calabria, but not Galicia, of a pool of 'owl specialist' species. The wide geographical occurrence of these taxa suggest that local conditions may determine fundamental differences in the composition of local communities. Finally, in both Calabria and Galicia, helminth communities from owls were species-poor compared to those from sympatric birds of prey. However, birds of prey appear to share a greater pool of specific helmith taxa derived from cospeciation processes, and a greater potential exchange of parasites between them than with owls because of phylogenetic closeness