The impact of the age of HLA-identical siblings on mobilization and collection of PBSCs for allogeneic hematopoietic cell transplantation: The impact of the age of HLA-identical siblings onmobilization and collection of PBSCs for allogeneichematopoietic cell transplantation

Through the recruitment of immunologic mechanisms, allogeneic hematopoeitic cell transplantation (HCT) has been establiched as a curative treatment for various hematologic diseases. The most convenient source to obtain hematopoietic progenitor cells are peripheral blood stem cells (PBSCs) which are harvested from the donor via leukapheresis after mobilization with granulocyte-colony stimulating factors. With the introduction of reduced intensity condition (RIC), the curative potential of allogeneic HCT became accessible to older and/or frail patients otherwise ineligible for HCT. However, new challenges arise as the increasing age of patients is inevitably accompanied by a comparable increase in the age of donors. Safety considerations of collecting PBSCs might attain new dimensions. Data to potential risks in elderly donors are lacking. Moreover, the impact of donor’s age on the feasibility of PBSCs collection and on the quality of the harvest in terms of stem cells (CD34+) and natural killer (NK)-cells has not been studied. It is also unknown whether PBSCs obtained from donors above 50 years would negatively influence engraftment or the incidence of graft-versus-host disease (GVHD) in the recipient. These questions were explored in a retrospective study including 167 recipients of an allogeneic HCT (52.7% after RIC) from a matched related sibling. Median donors’ age was 47 years [67 (40%) donors were > 50 years including 34 donors > 60 years]. Safety of mobilization and leukapheresis was age independent. Adequate PBSCs were collected from all donors though a higher CD34+-cell count was seen in donors 60 years contained a higher NK-cell count (p=0.003). Engraftment in the recipient occurred after a median of 12 days and was not affected by an advanced donor age. Similarly, a higher incidence of GVHD was not seen in recipients of harvests from older donors. For the first time, we show that donor’s age, even beyond 60 years, does not preclude successful collection of PBSCs from siblings, does not jeopardize the short-term safety of the donor, and is not associated with deleterious sequels for the recipient in terms of engraftment or GVHD. As NK-cells have been implicated in the suppression of GVHD, and the mediation of a graft versus leukemia effect, the impact of the higher number of NK-cells in harvests from elderly donors on relapse of hematologic malignancies in the recipient warrants further studies

Highly Elevated Serum Hepcidin in Patients with Acute Myeloid Leukemia prior to and after Allogeneic Hematopoietic Cell Transplantation: Does This Protect from Excessive Parenchymal Iron Loading?

Hepcidin is upregulated by inflammation and iron. Inherited (HFE genotype) and treatment-related factors (blood units (BU), Iron overload) affecting hepcidin (measured by C-ELISA) were studied in 42 consecutive patients with AML prior to and after allogeneic hematopoietic cell transplantation (HCT). Results. Elevated serum ferritin pre- and post-HCT was present in all patients. Median hepcidin pre- and post-HCT of 358 and 398 ng/mL, respectively, were elevated compared to controls (median 52 ng/mL) (P<.0001). Liver and renal function, prior chemotherapies, and conditioning had no impact on hepcidin. Despite higher total BU after HCT compared to pretransplantation (P<.0005), pre- and posttransplant ferritin and hepcidin were similar. BU influenced ferritin (P=.001) and hepcidin (P=.001). No correlation of pre- or posttransplant hepcidin with pretransplant ferritin was found. HFE genotype did not influence hepcidin. Conclusions. Hepcidin is elevated in AML patients pre- and post-HCT due to transfusional iron-loading suggesting that hepcidin synthesis remains intact despite chemotherapy and HCT

Highly Elevated Serum Hepcidin in Patients with Acute Myeloid Leukemia prior to and after Allogeneic Hematopoietic Cell Transplantation: Does This Protect from Excessive Parenchymal Iron Loading?

Hepcidin is upregulated by inflammation and iron. Inherited (HFE genotype) and treatment-related factors (blood units (BU), Iron overload) affecting hepcidin (measured by C-ELISA) were studied in 42 consecutive patients with AML prior to and after allogeneic hematopoietic cell transplantation (HCT). Results. Elevated serum ferritin pre-and post-HCT was present in all patients. Median hepcidin pre-and post-HCT of 358 and 398 ng/mL, respectively, were elevated compared to controls (median 52 ng/mL) (P &lt; .0001). Liver and renal function, prior chemotherapies, and conditioning had no impact on hepcidin. Despite higher total BU after HCT compared to pretransplantation (P &lt; .0005), pre-and posttransplant ferritin and hepcidin were similar. BU influenced ferritin (P = .001) and hepcidin (P = .001). No correlation of pre-or posttransplant hepcidin with pretransplant ferritin was found. HFE genotype did not influence hepcidin. Conclusions. Hepcidin is elevated in AML patients pre-and post-HCT due to transfusional iron-loading suggesting that hepcidin synthesis remains intact despite chemotherapy and HCT

Analysis of predictors of response to ruxolitinib in patients with myelofibrosis in the phase 3b expanded-access JUMP study.

Data from the large, prospective, multinational, phase 3b JUMP study were analyzed to identify factors predictive of spleen and symptom responses in myelofibrosis patients receiving ruxolitinib. Factors associated with higher spleen response rates included International Prognostic Scoring System (IPSS) low/intermediate-1 risk vs intermediate-2/high risk (43.1% vs 30.6%; adjusted OR [aOR] 0.65 [95% CI 0.44-0.95]), ruxolitinib as first- vs second- or later-line therapy (40.2% vs 31.5%; aOR 0.53 [95% CI 0.38-0.75]), and a ruxolitinib total daily dose at Week 12 of20 mg/day vs ≤20 mg/day (41.3% vs 30.4%; aOR 0.47 [95% CI 0.33-0.68]). No association was seen between baseline characteristics or total daily dose at Week 12 and symptom response. Ruxolitinib led to higher spleen response rates in patients with lower IPSS risk, and when used earlier in treatment. Higher doses of ruxolitinib were associated with higher spleen response rates, but not with symptom improvement.Trial registrationINC424 for patients with primary myelofibrosis, post polycythemia myelofibrosis or post-essential thrombocythemia myelofibrosis (JUMP).2010-024473-39; NCT01493414Date of registration: 16 December 2011https://www.clinicaltrialsregister.eu/ctr-search/search?query=2010-024473-39https://clinicaltrials.gov/ct2/show/NCT01493414

Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: A snapshot of 1144 patients in the JUMP trial

JUMP is a phase 3b expanded-access trial for patients without access to ruxolitinib outside of a clinical study; it is the largest clinical trial to date in patients with myelofibrosis who have been treated with ruxolitinib. Here, we present safety and efficacy findings from an analysis of 1144 patients with intermediate- or high-risk myelofibrosis, as well as a separate analysis of 163 patients with intermediate-1-risk myelofibrosis – a population of patients not included in the phase 3 COMFORT studies. Consistent with ruxolitinib’s mechanism of action, the most common hematologic adverse events were anemia and thrombocytopenia, but these led to treatment discontinuation in only a few cases. The most common non-hematologic adverse events were primarily grade 1/2 and included diarrhea, pyrexia, fatigue, and asthenia. The rates of infections were low and primarily grade 1/2, and no new or unexpected infections were observed. The majority of patients achieved a ≥50% reduction from baseline in palpable spleen length. Improvements in symptoms were rapid, with approximately half of all patients experiencing clinically significant improvements, as assessed by various quality-of-life questionnaires. The safety and efficacy profile in intermediate-1-risk patients was consistent with that in the overall JUMP population and with that previously reported in intermediate-2- and high-risk patients. Overall, ruxolitinib provided clinically meaningful reductions in spleen length and symptoms in patients with myelofibrosis, including those with intermediate-1-risk disease, with a safety and efficacy profile consistent with that observed in the phase 3 COMFORT studies. This trial was registered as NCT01493414 at ClinicalTrials.gov

The impact of the age of HLA-identical siblings on mobilization and collection of PBSCs for allogeneic hematopoietic cell transplantation: The impact of the age of HLA-identical siblings onmobilization and collection of PBSCs for allogeneichematopoietic cell transplantation

Through the recruitment of immunologic mechanisms, allogeneic hematopoeitic cell transplantation (HCT) has been establiched as a curative treatment for various hematologic diseases. The most convenient source to obtain hematopoietic progenitor cells are peripheral blood stem cells (PBSCs) which are harvested from the donor via leukapheresis after mobilization with granulocyte-colony stimulating factors. With the introduction of reduced intensity condition (RIC), the curative potential of allogeneic HCT became accessible to older and/or frail patients otherwise ineligible for HCT. However, new challenges arise as the increasing age of patients is inevitably accompanied by a comparable increase in the age of donors. Safety considerations of collecting PBSCs might attain new dimensions. Data to potential risks in elderly donors are lacking. Moreover, the impact of donor’s age on the feasibility of PBSCs collection and on the quality of the harvest in terms of stem cells (CD34+) and natural killer (NK)-cells has not been studied. It is also unknown whether PBSCs obtained from donors above 50 years would negatively influence engraftment or the incidence of graft-versus-host disease (GVHD) in the recipient. These questions were explored in a retrospective study including 167 recipients of an allogeneic HCT (52.7% after RIC) from a matched related sibling. Median donors’ age was 47 years [67 (40%) donors were > 50 years including 34 donors > 60 years]. Safety of mobilization and leukapheresis was age independent. Adequate PBSCs were collected from all donors though a higher CD34+-cell count was seen in donors 60 years contained a higher NK-cell count (p=0.003). Engraftment in the recipient occurred after a median of 12 days and was not affected by an advanced donor age. Similarly, a higher incidence of GVHD was not seen in recipients of harvests from older donors. For the first time, we show that donor’s age, even beyond 60 years, does not preclude successful collection of PBSCs from siblings, does not jeopardize the short-term safety of the donor, and is not associated with deleterious sequels for the recipient in terms of engraftment or GVHD. As NK-cells have been implicated in the suppression of GVHD, and the mediation of a graft versus leukemia effect, the impact of the higher number of NK-cells in harvests from elderly donors on relapse of hematologic malignancies in the recipient warrants further studies

The impact of the age of HLA-identical siblings on mobilization and collection of PBSCs for allogeneic hematopoietic cell transplantation: The impact of the age of HLA-identical siblings onmobilization and collection of PBSCs for allogeneichematopoietic cell transplantation

Through the recruitment of immunologic mechanisms, allogeneic hematopoeitic cell transplantation (HCT) has been establiched as a curative treatment for various hematologic diseases. The most convenient source to obtain hematopoietic progenitor cells are peripheral blood stem cells (PBSCs) which are harvested from the donor via leukapheresis after mobilization with granulocyte-colony stimulating factors. With the introduction of reduced intensity condition (RIC), the curative potential of allogeneic HCT became accessible to older and/or frail patients otherwise ineligible for HCT. However, new challenges arise as the increasing age of patients is inevitably accompanied by a comparable increase in the age of donors. Safety considerations of collecting PBSCs might attain new dimensions. Data to potential risks in elderly donors are lacking. Moreover, the impact of donor’s age on the feasibility of PBSCs collection and on the quality of the harvest in terms of stem cells (CD34+) and natural killer (NK)-cells has not been studied. It is also unknown whether PBSCs obtained from donors above 50 years would negatively influence engraftment or the incidence of graft-versus-host disease (GVHD) in the recipient. These questions were explored in a retrospective study including 167 recipients of an allogeneic HCT (52.7% after RIC) from a matched related sibling. Median donors’ age was 47 years [67 (40%) donors were > 50 years including 34 donors > 60 years]. Safety of mobilization and leukapheresis was age independent. Adequate PBSCs were collected from all donors though a higher CD34+-cell count was seen in donors 60 years contained a higher NK-cell count (p=0.003). Engraftment in the recipient occurred after a median of 12 days and was not affected by an advanced donor age. Similarly, a higher incidence of GVHD was not seen in recipients of harvests from older donors. For the first time, we show that donor’s age, even beyond 60 years, does not preclude successful collection of PBSCs from siblings, does not jeopardize the short-term safety of the donor, and is not associated with deleterious sequels for the recipient in terms of engraftment or GVHD. As NK-cells have been implicated in the suppression of GVHD, and the mediation of a graft versus leukemia effect, the impact of the higher number of NK-cells in harvests from elderly donors on relapse of hematologic malignancies in the recipient warrants further studies