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.

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.

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.

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.

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.