Improved outcomes of UM171-expanded cord blood transplantation compared with other graft sources: real-world evidence.

Cord blood (CB) transplantation is hampered by low cell dose and high nonrelapse mortality (NRM). A phase 1-2 trial of UM171-expanded CB transplants demonstrated safety and favorable preliminary efficacy. The aim of the current analysis was to retrospectively compare results of the phase 1-2 trial with those after unmanipulated CB and matched-unrelated donor (MUD) transplants. Data from recipients of CB and MUD transplants were obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Patients were directly matched for the number of previous allogeneic hematopoietic stem cell transplants (alloHCT), disease and refined Disease Risk Index. Patients were further matched by propensity score for age, comorbidity index, and performance status. Primary end points included NRM, progression-free survival (PFS), overall survival (OS), and graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) at 1 and 2 years after alloHCT. Overall, 137 patients from CIBMTR (67 CB, 70 MUD) and 22 with UM171-expanded CB were included. NRM at 1 and 2 years was lower, PFS and GRFS at 2 years and OS at 1 year were improved for UM171-expanded CBs compared with CB controls. Compared with MUD controls, UM171 recipients had lower 1- and 2-year NRM, higher 2-year PFS, and higher 1- and 2-year GRFS. Furthermore, UM171-expanded CB recipients experienced less grades 3-4 acute GVHD and chronic GVHD compared with MUD graft recipients. Compared with real-world evidence with CB and MUD alloHCT, this study suggests that UM171-expanded CB recipients may benefit from lower NRM and higher GRFS. This trial was registered at www.clinicaltrials.gov as #NCT02668315.

Impact of Implementing a Bendamustine-Based Conditioning Regimen on Outcomes of Autologous Stem Cell Transplantation in Lymphoma while Novel Cellular Therapies Emerge.

With the advent of new cellular and targeted therapies, treatment options for relapsed and refractory (r/R) lymphomas have multiplied, and the optimal approach offering the best outcomes remains a matter of passionate debate. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is still considered a treatment option for patients with chemosensitive lymphoma when cure is the expected goal. The myeloablative conditioning regimen preceding the stem cell infusion is considered the effective component of this approach. Carmustine (BCNU)-based preparative regimens, such as BEAM and BEAC, are considered the standard of care and have shown efficacy and low nonrelapse mortality (NRM). Comparative studies between conditioning regimens have failed to identify a better option. After a BCNU drug shortage in Canada followed by a steep increase in price, we elected to substitute BCNU for bendamustine (benda) in the preparative regimen. The purpose of this substitution was to improve response while preserving safety and controlling costs. From May 2015 to May 2018, a total of 131 consecutive lymphoma patients received benda-EAM conditioning. These patients were compared with 96 consecutive patients who received BCNU-based conditioning from January 2012 to May 2015. Apart from conditioning, supportive care measures were the same in the 2 groups. Patients receiving benda were older (55.7 years versus 51.1 years; P = .002). The development of grade ≥3 mucositis was more frequent with benda conditioning (39.5% versus 7.8%; P < .001) leading to a greater requirement for parenteral nutrition (48.9% versus 21.9%; P < .001). A transient creatinine increase >1.5 times the upper limit of normal (15.3% versus 4.2%; P < .008) and intensive care unit admission (6.9% versus 1.1%; P < .029) were more frequent with benda; however, there were no between-group differences in cardiac, pulmonary, or liver toxicity and NRM. With a median follow-up of 48 months for the benda group and 60 months for the BCNU group, benda was associated with significantly better progression-free survival (71% versus 61%; P = .040; hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.0 to 2.7) and overall survival (86% vs 71%; P = .0066; HR, 2.6; 95% CI, 1.3 to 5.4) compared with BCNU-based conditioning regimens. While novel therapies emerge, our study demonstrates that benda-EAM is safe and effective and should be considered a valid alternative to BCNU conditioning to improve outcomes of patients with chemosensitive r/R lymphomas undergoing ASCT.

Bortezomib Maintenance After Allogeneic Transplantation in Newly Diagnosed Myeloma Patients Results in Decreased Incidence and Severity of Chronic GVHD.

Allogeneic hematopoietic cell transplantation (HCT) has curative potential in myeloma but remains hampered by high rates of relapse and chronic graft-versus-host disease (GVHD). We hypothesized that bortezomib (BTZ) as maintenance therapy after allo HCT could not only decrease the incidence of relapse but also the incidence and severity of chronic GVHD. The primary endpoint of this study was to determine whether BTZ maintenance decreases the incidence and severity of chronic GVHD using National Institutes of Health (NIH) criteria. The secondary endpoints were to determine the immunosuppression burden, organ involvement and survival (overall survival, progression-free survival) in patients either receiving or not receiving BTZ. In this retrospective study, we compared the outcome of 46 myeloma patients who received BTZ after upfront tandem auto-allo HCT between 2008 and 2020 to 61 patients without maintenance. We explored the impact of BTZ maintenance on incidence and severity of chronic GVHD using the 2014 NIH criteria. At 2 years, incidences of overall (61.2% versus 83.6%; P = .001), and moderate/severe chronic GVHD (44.5% versus 77.0%; P = .001) were significantly lower in BTZ recipients who had less mouth (43% versus 67%; P = .018) and eyes (9% versus 41%; P = .001) involvement at initial diagnosis. We report a lower use of systemic steroids (45.1% versus 76.4%; P < .001), mycophenolate mofetil (15.5% versus 28.2%; P = .031) and tacrolimus (34.5% versus 70.6%; P < .001) in BTZ recipients. Probability of being alive and off systemic immunosuppressants at 3 years was 77% in BTZ recipients and 56% in controls (P = .046). To date, there is no difference in survival between both groups. In summary, BTZ maintenance improved incidence and severity of chronic GVHD and should be considered as a valid option in myeloma patients receiving upfront tandem auto-allo HCT.

Donor Age and Non-Relapse Mortality: Study of Their Association after HLA-Matched Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome.

The purpose of this retrospective study was to study the correlation between donor age (DA) and non-relapse mortality (NRM) and relapse incidence (RI) among patients treated with allogeneic hematopoietic cell transplantation (aHCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in a single Canadian center. Data from 125 consecutive patients transplanted with a matched related or unrelated donor between 2015 and 2020 were analyzed using multivariable models. After a median follow-up of 2.8 years, the cumulative incidences of NRM and relapse were 19% and 35% at 5 years. Despite being independently associated with NRM and relapse-free survival (RFS), DA was not associated with RI. The independent determinants of NRM in addition to DA were patient age and hematopoietic cell transplantation comorbidity index (HCT-CI), independently of donor kinship. The effect of DA on NRM was found to be significantly increased over the age of 50 years. DA was not associated with incidence of acute graft-versus-host disease (aGVHD) but showed an association with the occurrence of chronic GVHD (cGVHD). In conclusion, younger donors should be favored to limit NRM and increase RFS in HLA-matched aHCT. The etiological mechanisms behind the association of DA with higher NRM remain to be elucidated.

Real-World Outcomes of Autologous and Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed/Refractory Hodgkin Lymphoma in the Era of Novel Therapies: A Canadian Perspective.

Despite high cure rates with frontline therapy for Hodgkin lymphoma (HL), approximately 30% of patients will relapse or develop primary refractory disease (R/r). Autologous hematopoietic stem cell transplantation (autoHSCT) is the standard of care for R/r disease, and allogeneic HSCT (alloHSCT) is a curative option for patients in second relapse. Novel agents are being incorporated for the treatment of R/r HL, such that the optimal timing of transplantation is currently being challenged. In this rapidly evolving field, we sought to offer a Canadian perspective on the optreatment of R/r HL and demonstrate the role and effectiveness of both autoHSCT and alloHSCT for the treatment of R/r HL. This single-center retrospective study examined outcomes in 89 consecutive patients with R/r HL treated with autoHSCT between January 2007 and December 2019. A total of 17 patients underwent alloHSCT either as a tandem auto-allo approach or as salvage therapy. With a median follow-up of 5.0 years, the estimated 5-year PFS and OS for patients undergoing autoHSCT were 57.5% (95% confidence interval [CI], 45.2% to 68.0%) and 81.3% (95% CI, 70.0% to 88.8%), respectively. Corresponding values for patients who underwent alloHSCT were 76.5% (95% CI, 48.8% to 90.4%) and 82.4% (95% CI, 54.7% to 93.9%). Nonrelapse mortality at 0% at 100 days and 9.4% at 5 years post-autoHSCT and 0% and 5.9%, respectively, post-alloHSCT. The cumulative incidence of acute graft-versus-host disease (GVHD) at day +100 was 35.3% (95% CI, 17.7% to 62.3%), and that of chronic GVHD at 1 year was 23.5% (95% CI, 6.9% to 45.8%). Both autoHSCT and alloHSCT provide robust and prolonged disease control New agents should be used as a bridge to improve the curative potential of these definitive cellular therapies.

Outcomes in newly diagnosed young or high-risk myeloma patients receiving tandem autologous/allogeneic transplant followed by bortezomib maintenance: a phase II study.

Despite novel drugs and autologous HCT, MM remains incurable, with short survival in patients with poor biological characteristics. Allo HCT may be curative in some patients but is hampered by high rates of toxicity and relapse. We hypothesized that bortezomib (BTZ), with its anti-myeloma and immunologic properties, could improve PFS and cGVHD after allo HCT in newly diagnosed MM patients. In this prospective phase II study, we included 39 young (≤50 years) and high-risk patients who received a tandem auto-allo HCT followed by BTZ. Patients had prospective minimal residual disease (MRD) evaluations using Next-Generation Flow cytometry prior to allo HCT, prior BTZ and every 3 months for 2 years. With a median follow-up of 48 months, we report PFS and OS at 5 years of 41% and 80%, with a non-relapse mortality of 12%. Incidences of grade II-IV aGVHD at 12 months and moderate/severe cGVHD at 2 years were 26% and 57%. In a multivariate analysis model including cytogenetics, ISS and MRD status, MRD positivity prior to allo HCT (HR 3.75, p = 0.037), prior BTZ (HR 11.3, p = 0.018) and 3 months post-BTZ initiation (HR 9.7, p = 0.001) was highly predictive of progression. Peritransplant MRD assessment thus strongly predicts disease progression.

Use of midostaurin in mixed phenotype acute leukemia with FLT3 mutation: A case series.

Mixed phenotype acute leukemia (MPAL) is a rare type of acute leukemia where blasts present phenotypes from more than one lineage. A poor prognostic has been associated with this disease, and limited data are currently available to guide the choice of therapy. Regarding FLT3-positive MPAL, only one case treated with midostaurin has been published to date. Here, we report the successful use of midostaurin to treat three FLT3-positive MPAL T/myeloid and B/myeloid patients. Midostaurin was successfully added to intensive induction (two patients) and consolidation chemotherapy (three patients) without significant adverse events requiring a dose adjustment or discontinuation. The therapy received resulted in complete remission for two patients and complete remission with an incomplete hematologic recovery for the third. All patients proceeded to HSCT and stayed in remission after an extended follow-up respectively at 28, 31, and 11 months later. These results suggest that the addition of midostaurin during induction and consolidation therapy may represent a treatment option for FLT3-positive MPAL.

Recognition of Hematopoietic Stem Cell Transplantation and Cellular Therapy Expertise to Promote Care Accessibility: A Formally Credentialed Area of Focused Competence in Canada.

Hematopoietic stem cell transplantation (HSCT) and cellular therapy (CT) exploit the therapeutic potential of manipulated or unmanipulated hematopoietic cells to treat diseases. While initially dedicated to the treatment of hematologic malignancies and disorders, the use of these therapies in several diseases and cancers is currently under investigation. Indications are currently booming. In the midst of this expansion, both the American Society for Transplantation and Cellular Therapy (ASTCT) and the European Society for Blood and Marrow Transplantation (EBMT) have highlighted the global shortage of hematologists adequately trained in this field of high expertise. This shortage in transplant physicians and cellular therapists can significantly impact patients' access to cell-based therapy. To address this unmet need and attract aspiring hematologists to the field of cellular therapy, as well as to standardize training, anticipating this trend, a Canadian national task force aiming to develop a structured academic program in HSCT and CT was created. Workshops were organized to identify and establish the fundamentals of the practice in HSCT and CT. These workshops followed a rigorous process in developing the competency-based training program established by the Royal College. The program begins with the development of the main tasks associated with the practice of the discipline and the evidence that trainees must provide to demonstrate that they can perform these tasks independently (the competence portfolio). It continues with the development of training requirements that summarize the knowledge, skills, and aptitudes required to perform these tasks, followed by specific exposure during training (milestones) essential to demonstrate the acquisition of these skills. HSCT and CT together is now formally recognized as an Area of Focused Competence (AFC) by the Royal College of Physicians and Surgeons of Canada, a national organization that provides oversight of the medical education of specialists in Canada. AFCs are areas of specialty medicine that address a legitimate societal and patient population need previously unmet by the system of primary and subspecialty disciplines. The AFC designation for HSCT and CT provides a standardized curriculum, training experience, and accreditation process to attract young hematologists and promote expertise and quality care to meet the needs of both patients and society. A critical number of highly qualified hematologists will ensure continuing expansion of accessibility to HSCT and CT.

UM171-Expanded Cord Blood Transplants Support Robust T Cell Reconstitution with Low Rates of Severe Infections.

Rapid T cell reconstitution following hematopoietic stem cell transplantation (HSCT) is essential for protection against infections and has been associated with lower incidence of chronic graft-versus-host disease (cGVHD), relapse, and transplant-related mortality (TRM). While cord blood (CB) transplants are associated with lower rates of cGVHD and relapse, their low stem cell content results in slower immune reconstitution and higher risk of graft failure, severe infections, and TRM. Recently, results of a phase I/II trial revealed that single UM171-expanded CB transplant allowed the use of smaller CB units without compromising engraftment (www.clinicaltrials.gov, NCT02668315). We assessed T cell reconstitution in patients who underwent transplantation with UM171-expanded CB grafts and retrospectively compared it to that of patients receiving unmanipulated CB transplants. While median T cell dose infused was at least 2 to 3 times lower than that of unmanipulated CB, numbers and phenotype of T cells at 3, 6, and 12 months post-transplant were similar between the 2 cohorts. T cell receptor sequencing analyses revealed that UM171 patients had greater T cell diversity and higher numbers of clonotypes at 12 months post-transplant. This was associated with higher counts of naive T cells and recent thymic emigrants, suggesting active thymopoiesis and correlating with the demonstration that UM171 expands common lymphoid progenitors in vitro. UM171 patients also showed rapid virus-specific T cell reactivity and significantly reduced incidence of severe infections. These results suggest that UM171 patients benefit from rapid T cell reconstitution, which likely contributes to the absence of moderate/severe cGVHD, infection-related mortality, and late TRM observed in this cohort.

Newly diagnosed multiple myeloma patients treated with tandem auto-allogeneic stem cell transplant have better overall survival with similar outcomes at time of relapse compared to patients who received autologous transplant only.

BACKGROUND: Long-term survival in patients progressing after tandem autologous-allogeneic stem cell transplant (SCT) has been reported, suggesting a persistent graft-vs-myeloma (GvM) effect even after post-transplant progression. METHODS: In order to confirm this observation, we updated the results of our previously published cohort of 92 newly diagnosed myeloma patients who received tandem transplant and compared them with 81 contemporary patients who received autologous transplant only. RESULTS: With a median follow-up of 13.1 and 10.2 years, respectively, median overall survival (OS) in the tandem group has not been reached, compared with 6.1 years after auto-SCT (P ≤ .001). Disease progression occurred less frequently after tandem transplant, with an estimated 10-year cumulative incidence of 49% vs 76% (P ≤ .001). Cumulative incidence of extensive chronic graft-vs-host disease (cGVHD) was high at 83%, with modest benefits on OS (60% vs 49%, P = .550) but sharp improvement of progression-free survival (PFS; 55% vs 10%, P = .002) at 10 years associated with development of cGVHD. After first progression, median OS was 5.8 years in tandem and 5.2 years in the auto-group (P = .062); median PFS was also similar. CONCLUSION: Despite confirmation of better outcomes after upfront tandem transplant, our data do not support persistence of a strong, clinically significant graft-vs-myeloma effect after first progression, emphasizing the need to better characterize the GvM effect.

Single UM171-expanded cord blood transplant can cure severe idiopathic aplastic anemia in absence of suitable donors.

Haplo-identical donors have been increasingly used as an alternative source of stem cells in patients with severe aplastic anemia in need of an allogeneic transplantation but lack a matched donor. Single cord blood (CB) transplant also offers a curative option for this disease, but few adult patients have been reported due to low number of progenitor cells leading to prolonged cytopenias and a high risk of infections. CB stem cell expansion may theoretically solve these pitfalls but has not been used previously in non-malignant diseases, likely due to fear of graft rejection and lack of availability of expanded CBs outside clinical trials. We report the first case of an adult patient with severe aplastic anemia who was successfully transplanted with a UM171-expanded CB graft. After a conditioning of rabbit antithymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation, a UM171 expanded graft of 3.29 × 106 CD34 + cells/kg (a 51-fold increase) was infused. Full donor chimerism was observed on day + 14, with neutrophil and platelet engraftment on days + 23 and + 27. There was no severe infection or graft-vs-host disease. UM171-expanded grafts offer a valuable option for patients with aplastic anemia in need of transplantation but have no suitable donor.

Evaluation of the Impact of Autologous Hematopoietic Stem Cell Transplantation on the Quality of Life of Older Patients with Lymphoma.

High-dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplantation (AHSCT) improves survival in patients with chemosensitive non-Hodgkin lymphoma (NHL). Determination of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) has contributed to improve patient selection while allowing for prediction of nonrelapse mortality. We previously demonstrated the efficacy and safety of AHSCT in a cohort of older patients with chemosensitive NHL. Quality of life following AHSCT still has not been widely evaluated. The goal of this study was to assess the long-term quality of life of elderly patients surviving AHSCT. This single-center, Research and Ethics Committee-approved study investigated QoL in survivors of AHSCT for the treatment of NHL in a cohort of older patients. Inclusion criteria were defined as patients age ≥60 years who underwent AHSCT for NHL between January 1, 2008, and January 1, 2015, at our center. Fifty-nine patients from the original cohort of 90 survived at a median of 50 months post-AHSCT. Forty-seven (79.7%) of those patients agreed to complete the QoL assessment questionnaires after the transplantation and are included in this report. All patients provided signed informed consent. We used the EQ-5D instrument to assess mobility, self-care, usual activities, pain/discomfort, and anxiety/depression and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) questionnaire to assess physical, social/family, emotional, and functional well-being and BMT-specific concerns. With both tools, a higher score indicates better QoL. Fifteen percent of patients were in relapse at the time of the QoL assessment. In the EQ-5D, few patients (9%) reported severe impairment, which requires significant negative effects in 4 or 5 domains. Lower Karnofsky Performance Status (KPS) score at the time of transplantation was negatively correlated with mobility (P= .001), self-care (P= .001), and usual activities (P= .007) dysfunction. Anxiety was significant for patients in relapsed after transplantation (P= .002). FACT-BMT questionnaire results demonstrated that physical, social, and emotional well-being were all well preserved after the transplantation, whereas functional well-being was more variable among patients. Relapse was associated with impaired functional well-being (P= .007) and lower total FACT-BMT score (P= .014). Other comparators, including the conditioning regimen, sex, age subgroups (<65 or ≥65 years), HCT-CI score, and disease status at transplantation, did not impact any of these outcomes. This study demonstrates that physical, social, and functional well-being are preserved in older patients following AHSCT. Low KPS score before AHSCT is a predictor of disability at distance from AHSCT. Relapse following AHSCT remains the most significant impediment to maintaining a good QoL. Innovative interventions to improve performance status before transplantation and measures to prevent relapse thereafter should be investigated to improve survival and QoL.

Hematopoietic stem cell transplantation using single UM171-expanded cord blood: a single-arm, phase 1-2 safety and feasibility study.

BACKGROUND: Benefits of cord blood transplantation include low rates of relapse and chronic graft-versus-host disease (GVHD). However, the use of cord blood is rapidly declining because of the high incidence of infections, severe acute GVHD, and transplant-related mortality. UM171, a haematopoietic stem cell self-renewal agonist, has been shown to expand cord blood stem cells and enhance multilineage blood cell reconstitution in mice. We aimed to investigate the safety and feasibility of single UM171-expanded cord blood transplantation in patients with haematological malignancies who do not have a suitable HLA-matched donor. METHODS: This single-arm, open-label, phase 1-2 safety and feasibility study was done at two hospitals in Canada. The study had two parts. In part 1, patients received two cord blood units (one expanded with UM171 and one unmanipulated cord blood) until UM171-expanded cord blood demonstrated engraftment. Once engraftment was documented we initiated part 2, reported here, in which patients received a single UM171-expanded cord blood unit with a dose de-escalation design to determine the minimal cord blood unit cell dose that achieved prompt engraftment. Eligible patients were aged 3-64 years, weighed 12 kg or more, had a haematological malignancy with an indication for allogeneic hematopoietic stem cell transplant and did not have a suitable HLA-matched donor, and a had a Karnofsky performance status score of 70% or more. Five clinical sites were planned to participate in the study; however, only two study sites opened, both of which only treated adult patients, thus no paediatric patients (aged <18 years) were recruited. Patients aged younger than 50 years without comorbidities received a myeloablative conditioning regimen (cyclophosphamide 120 mg/kg, fludarabine 75 mg/m2, and 12 Gy total body irradiation) and patients aged older than 50 years and those with comorbidities received a less myeloablative conditioning regimen (cyclophosphamide 50 mg/kg, thiotepa 10 mg/kg, fludarabine 150 mg/m2, and 4 Gy total body irradiation). Patients were infused with the 7-day UM171-expanded CD34-positive cells and the lymphocyte-containing CD34-negative fraction. The primary endpoints were feasibility of UM171 expansion, safety of the transplant, kinetics of hematopoietic reconstitution (time to neutrophil and platelet engraftment) of UM171-expanded cord blood, and minimal pre-expansion cord blood unit cell dose that achieved prompt engraftment. We analysed feasibility in all enrolled patients and all other primary outcomes were analysed per protocol, in all patients who received single UM171-expanded cord blood transplantation. This trial has been completed and was registered with ClinicalTrials.gov, NCT02668315. FINDINGS: Between Feb 17, 2016, and Nov 11, 2018, we enrolled 27 patients, four of whom received two cord blood units for safety purposes in part 1 of the study. 23 patients were subsequently enrolled in part 2 to receive a single UM171-expanded cord blood transplant and 22 patients received a single UM171-expanded cord blood transplantation. At data cutoff (Dec 31, 2018), median follow-up was 18 months (IQR 12-22). The minimal cord blood unit cell dose at thaw that achieved prompt engraftment as a single cord transplant after UM171 expansion was 0·52 × 105 CD34-positive cells. We successfully expanded 26 (96%) of 27 cord blood units with UM171. Among the 22 patients who received single UM171-expanded cord blood transplantation, median time to engraftment of 100 neutrophils per µL was 9·5 days (IQR 8-12), median time to engraftment of 500 neutrophils per µL was 18 days (12·5-20·0), and no graft failure occurred. Median time to platelet recovery was 42 days (IQR 35-47). The most common non-haematological adverse events were grade 3 febrile neutropenia (16 [73%] of 22 patients) and bacteraemia (nine [41%]). No unexpected adverse events were observed. One (5%) of 22 patients died due to treatment-related diffuse alveolar haemorrhage. INTERPRETATION: Our preliminary findings suggest that UM171 cord blood stem cell expansion is feasible, safe, and allows for the use of small single cords without compromising engraftment. UM171-expanded cord blood might have the potential to overcome the disadvantages of other cord blood transplants while maintaining the benefits of low risk of chronic GVHD and relapse, and warrants further investigation in randomised trials. FUNDING: Canadian Institutes of Health Research, Canadian Cancer Society and Stem Cell Network.

Allodepleted T-cell immunotherapy after haploidentical haematopoietic stem cell transplantation without severe acute graft-versus-host disease (GVHD) in the absence of GVHD prophylaxis.

Graft-versus-host disease (GVHD) is a major cause of transplant-related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and presents a challenge in haploidentical HSCT. GVHD may be prevented by ex vivo graft T-cell depletion or in vivo depletion of proliferating lymphocytes. However, both approaches pose significant risks, particularly infections and relapse, compromising survival. A photodepletion strategy to eliminate alloreactive T cells from mismatched donor lymphocyte infusions (enabling administration without immunosuppression), was used to develop ATIR101, an adjunctive therapy for use after haploidentical HSCT. In this phase I dose-finding study, 19 adults (median age: 54 years) with high-risk haematological malignancies were treated with T-cell-depleted human leucocyte antigen-haploidentical myeloablative HSCT followed by ATIR101 at doses of 1 × 104 -5 × 106  CD3+  cells/kg (median 31 days post-transplant). No patient received post-transplant immunosuppression or developed grade III/IV acute GVHD, demonstrating the feasibility of ATIR101 infusion for evaluation in two subsequent phase 2 studies. Additionally, we report long-term follow -up of patients treated with ATIR101 in this study. At 1 year, all 9 patients receiving doses of 0·3-2 × 106  CD3+  cells/kg ATIR101 remained free of serious infections and after more than 8 years, TRM was 0%, relapse-related mortality was 33% and overall survival was 67% in these patients.

Outcome of autologous hematopoietic stem cell transplant in older patients with B cell lymphoma when selected for fitness and chemosensitive disease.

BACKGROUND: Autologous hematopoietic stem cell transplantation (AHSCT) in the older population is associated with an increased risk of morbidity and mortality. Determination of the hematopoietic cell transplant comorbidity index (HCT-CI) has contributed to improve patient selection while allowing prediction of their non-relapse mortality (NRM). The goal of this study was to identify factors influencing both safety and efficacy of AHSCT in an older non-Hodgkin lymphoma (NHL) population to better select those who will benefit from this intervention in the Canadian context of a single-payer government healthcare program. METHODS: This single center, retrospective study, examined clinical outcomes in 90 consecutive older patients (≥60 years old) with B-cell NHL treated with AHSCT between 2008 and 2014. FINDINGS: Median age was 63 (60-69) at time of transplantation. The HCT-CI risk score was low, intermediate and high in 34%, 40% and 26% of patients, respectively. NRM was 1% at 100 days and one-year post transplant and not influenced by age. At a median follow-up of 52 months, median progression-free survival (PFS) was 56 months while median overall survival (OS) was still not reached. Stable and progressive disease status at time of transplantation were associated with a lower PFS (HR 2.94) and OS (HR 3.91). BEAC conditioning and a graft cell dose 5 × 106 CD34+/kg led to faster recovery, decreased toxicity and resource consumption. INTERPRETATION: In the older population, AHSCT is safe and optimal when restricted to fit chemosensitive patients.

Platelet phenotype changes associated with breast cancer and its treatment.

Platelets and their granular contents influence both angiogenesis and breast cancer progression. This study was performed to assess the effect of breast cancer and its treatment on platelet biology and the response to inhibition of the platelet P2Y12 receptor. Receptor-specific platelet activation and inhibition was studied for three platelet-associated proteins important in cancer angiogenesis and progression, vascular endothelial growth factor (VEGF), thrombospondin1 (TSP1), and transforming growth factor beta 1 (TGF-ß1). Twenty-four women with active breast cancer and 10 healthy controls not receiving antiplatelet therapy participated in the study. Ex vivo activation of platelets in whole blood was accomplished using PAR1AP, PAR4AP, convulxin, and ADP. Platelet inhibition was accomplished using the P2Y12 receptor antagonist cangrelor (the in vitro equivalent of clopidogrel). VEGF, TSP1, and TGF-ß1 were measured using standard ELISA. Platelet activation by ADP, PAR1, PAR4, and collagen receptors increased VEGF, TSP1, and TGF-ß1 secretion in patients with breast cancer. Agonist-induced release of VEGF was greater in cancer patients as compared to healthy controls (p = 0.02 for ADP, p < 0.001 for PAR1AP, PAR4AP, and convulxin) despite a decrease in the efficiency of VEGF secretion in patients with breast cancer. These differences were not observed for TSP1 and TGF-ß1 secretion. P2Y12 receptor inhibition decreased VEGF, TSP1, and TGF-ß1 secretion. In patients with cancer, cangrelor inhibited TSP1 release to a greater extent than VEGF and TGF-ß1 release. In patients with breast cancer, the magnitude of platelet inhibition achieved by cangrelor was greater than that achieved with healthy controls for all agonists and platelet proteins studied. While platelets are known to influence progression of breast cancer, our results show that breast cancer and its treatment influence the platelet phenotype by increasing the secretion of pro-angiogenic proteins following platelet activation, modulating the efficiency of platelet protein release as well as increasing the response to antiplatelet therapy.

Efficacy of a short course of complex lymphedema therapy or graduated compression stocking therapy in the treatment of post-thrombotic syndrome.

Treatment options for established post-thrombotic syndrome (PTS) are limited. Complex lymphedema therapy (CLT), a non-invasive treatment that improves lymphatic flow, may have the potential to improve PTS. We conducted a single-center, investigator-blind, randomized controlled trial of 31 patients with a clinically established diagnosis of PTS and compared the efficacy of graduated compression stockings alone (30-40 mmHg) with CLT, a treatment that includes compression stockings, exercise, patient education, skin care and lymphatic drainage. Primary outcomes were the 1- and 3-month changes in PTS severity by the Villalta score and disease-specific quality of life using the VEINES-QOL (Venous Insufficiency Epidemiological and Economic Study Quality of Life) questionnaire. Analysis was by intent-to-treat. We found from a baseline average score of 9.9 points, CLT reduced mean PTS severity scores by -2.4 points (p=0.02) at the 1-month and -2.3 points (p=0.05) at the 3-month follow-up. Score reductions with stockings only were similar at -2.1 (p=0.03) and -3.3 points (p=0.03) at 1 and 3 months. The differences in score between treatments were not significant. Neither treatment significantly changed the VEINES-QOL score except in patients with severe disease. Patients with moderate to severe PTS derived the greatest benefit from either therapy and the two therapies differentially impacted PTS signs and symptoms. We found a short course of lymphedema therapy and compression stockings offer similar benefit in patients with PTS; however, larger studies are needed to further explore the potential use of CLT in PTS, particularly in patients with more severe disease. ClinicalTrials.gov Identifier: NCT00633971.

The effect of P2Y-mediated platelet activation on the release of VEGF and endostatin from platelets.

Vascular endothelial growth factor (VEGF) and endostatin are key protein modulators of angiogenesis found within platelets. The platelet activation pathways that control angiogenic protein release are incompletely elucidated. The differential release of pro-angiogenic and anti-angiogenic proteins from the platelet has been demonstrated for proteinase activated receptors (PARs). Given the ability of tumors to secrete ADP and the availability of ADP receptor antagonists clinically, we determined the influence of adenosine diphosphate (ADP) and the ADP receptors, P2Y(1) and P2Y(12), on platelet release of the angiogenic stimulator protein, VEGF, and the angiogenic inhibitor protein, endostatin. Minimally altered whole blood (WB) and platelet rich plasma (PRP) from healthy volunteers was stimulated with ADP alone (12.5 uM), in combination with a P2Y(1) antagonist (MRS2179) or a P2Y(12) antagonist (cangrelor). VEGF and endostatin protein concentrations were assessed by an ELISA assay. We report that maximally stimulating concentrations of ADP significantly increased VEGF release from platelets in both PRP and WB by 36+/-12% 36+/-12% 54+/-18% 36 +/- 12% (p < 0.05) respectively as compared to control. Both P2Y(1) and P2Y(12) receptor antagonism inhibited this release. Conversely, endostatin levels did not change following ADP stimulation in PRP, while a 4.7% (p = 0.03) increase was observed in WB. As compared to thrombin receptor activation, ADP activation was a weaker stimulus for VEGF release. We found that activation of platelets by ADP results in an increase in soluble VEGF concentrations with minimal effects on endostatin concentrations, suggesting ADP release in the tumor microenvironment may be, on balance, proangiogenic. P2Y receptor antagonism abrogates ADP mediated proangiogenic protein release and thus may represent a potential pharmacologic strategy for regulating platelet mediated angiogenesis.