Mosunetuzumab with polatuzumab vedotin in relapsed or refractory aggressive large B cell lymphoma: a phase 1b/2 trial.

Relapsed/refractory aggressive large B cell lymphoma (LBCL) remains an area of unmet need. Here we report the primary analysis of a phase 1b/2 trial of outpatient mosunetuzumab (a CD20xCD3 T-cell-engaging bispecific antibody) plus polatuzumab vedotin (an anti-CD79B antibody-drug conjugate) in relapsed/refractory LBCL. The phase 2 component is a single arm of an ongoing multi-arm trial. The primary endpoint during dose expansion was independent review committee (IRC)-assessed best overall response rate. Secondary endpoints included investigator-assessed overall response rate, complete response, duration of response, progression-free survival and overall survival. At data cutoff, 120 patients were enrolled (22 dose escalation, 98 dose expansion). The primary endpoint was met during dose expansion, with IRC-assessed best overall response rate and complete response rates of 59.2% (58/98; 95% confidence interval (CI): 48.8-69.0) and 45.9% (45/98; 95% CI: 35.8-56.3), respectively (median follow-up, 23.9 months). Median duration of complete was not reached (95% CI: 20.5-not estimable (NE)). Median progression-free survival was 11.4 months (95% CI: 6.2-18.7). Median overall survival was 23.3 months (95% CI: 14.8-NE). Across dose escalation and expansion, the most common grade 3 or higher adverse events were neutropenia (25.0%, 30/120) and fatigue (6.7%, 8/120). Any-grade cytokine release syndrome occurred in 16.7% of patients. These data demonstrate that mosunetuzumab plus polatuzumab vedotin has a favorable safety profile with highly durable responses suitable as second-line therapy in transplant-ineligible relapsed/refractory LBCL. ClinicalTrials.gov identifier: NCT03671018 .

Validation of next-generation sequencing-based chimerism testing for accurate detection and monitoring of engraftment in hematopoietic stem cell transplantation.

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is a life-saving treatment for various hematological disorders. The success of allo-HSCT depends on the engraftment of donor cells and the elimination of recipient cells monitored through chimerism testing. We aimed to validate a next-generation sequencing (NGS)-based chimerism assay for engraftment monitoring and to emphasize the importance of including the most prevalent cell subsets in proficiency testing (PT) programs. We evaluated the analytical performance of NGS-based chimerism testing (AlloSeq-HCT and CareDx) with a panel of targeted 202 informative single-nucleotide polymorphisms (SNPs) (i.e., linearity and precision, analytical sensitivity and specificity, system accuracy, and reproducibility). We further compared the performance of our NGS panel with conventional short tandem repeat (STR) analysis in unfractionated whole blood and cell-subset-enriched CD3 and CD66. Our NGS-based chimerism monitoring assay has an impressive detection limit (0.3% host DNA) for minor alleles and analytical specificity (99.9%). Pearson's correlation between NGS- and STR-based chimerism monitoring showed a linear relationship with a slope of 0.8 and r = 0.973. The concordance of allo-HSCT patients using unfractionated whole blood, CD3, and CD66 was 0.95, 0.96, and 0.54, respectively. Utilization of CD3+ cell subsets for mixed chimerism detection yielded an average of 7.3 ± 7-fold higher donor percentage detection compared to their corresponding unfractionated whole blood samples. The accuracy of the NGS assay achieved a concordance of 98.6% on blinded external quality control STR samples. The reproducibility series showed near 100% concordance with respect to inter-assay, inter-tech, inter-instrument, cell flow kits, and AlloSeq-HCT software versions. Our study provided robust validation of NGS-based chimerism testing for accurate detection and monitoring of engraftment in allo-HSCT patients. By incorporating the cell subsets (CD3 and CD66), the sensitivity and accuracy of engraftment monitoring are significantly improved, making them an essential component of any PT program. Furthermore, the implementation of NGS-based chimerism testing shows potential to streamline high-volume transplant services and improve clinical outcomes by enabling early relapse detection and guiding timely interventions.

Bortezomib, Lenalidomide and Dexamethasone Combination Induced Complete Remission in Relapsed/Refractory Plasmablastic Lymphoma: Case Report of a Potential Novel Treatment Approach.

Plasmablastic lymphoma is a rare subtype of large B-cell lymphoma characterised by an aggressive clinical course with frequent relapses and refractoriness to chemotherapy. It is usually associated with HIV, however, it can also be seen in immunocompetent patients. It has distinct pathological characteristics, such as plasmablastic morphology and lack of CD20 expression. These characteristics pose a clinical and pathological challenge. There is no standard of care established in this entity. In this case report, we described a novel bortezomib-based plasma cell targeted regimen in a HIV-negative patient refractory to chemotherapy.

Platelet and extracellular vesicles in COVID-19 infection and its vaccines.

Platelets are at the crossroads between thrombosis and inflammation. When activated, platelets can shed bioactive extracellular vesicles [pEVs] that share the hemostatic potential of their parent cells and act as bioactive shuttles of their granular contents. In a viral infection, platelets are activated, and pEVs are generated with occasional virion integration. Both platelets and pEVs are engaged in a bidirectional interaction with neutrophils and other cells of the immune system and the hemostatic pathways. Severe COVID-19 infection is characterized by a stormy thromboinflammatory response with platelets and their EVs at the center stage of this reaction. This review sheds light on the interactions of platelets, pEVS and SARS-CoV-2 infection and prognostic and potential therapeutic role of pEVs. The review also describes the role of pEVs in the rare adenovirus-based COVID-19 vaccine-induced thrombosis thrombocytopenia.

Metabolism-mediated thrombotic microangiopathy and B12.

Thrombotic microangiopathies (TMAs) are a group of life-threatening conditions requiring urgent management and characterized by a clinical triad of microangiopathic hemolytic anemia, thrombocytopenia, and ischemic tissue injury. Severe vitamin B12 (Cobalamin-Cbl) deficiency or defective cobalamin metabolism, particularly defects in intracellular B12 metabolism, may lead to a TMA-like picture. The latter has been termed metabolism-mediated TMA (MM-TMA). This confusing picture is mediated partly by ineffective erythropoiesis with significant red cell fragmentation resulting in a hemolytic pattern, coupled with reduced platelet production and endothelial injury with organ damage resulting from accumulated toxic byproducts of B12 dysmetabolism. However, unlike in classic thrombotic thrombocytopenic purpura, where therapeutic plasma exchange has to be initiated promptly, cases of MM-TMA can be treated, if diagnosed properly, with adequate B12 replacement.

BeEAM conditioning regimen is a safe, efficacious and economical alternative to BEAM chemotherapy.

In many stem cell transplant centres, BCNU, etoposide, cytarabine and melphalan (BEAM) high-dose chemotherapy (HDCT) has been replaced by the more economic and available bendamustine, etoposide, cytarabine, melphalan (BeEAM) regimen. However, there is a paucity of information on the efficacy and safety of BeEAM HDCT. We describe our experience with BeEAM HDCT in terms of safety, efficacy and cost-savings. We compare overall and progression-free survival to a cohort of patients previously transplanted at our institution with the older BEAM regimen. We performed a retrospective chart review of 41 lymphoma patients undergoing BeEAM HDCT at the Royal University Hospital in Saskatoon, Saskatchewan between 2015 and 2019 to elicit regimen safety in the first 100 days post-transplant. Furthermore, we calculated overall and progression-free survival and constructed corresponding Kaplan-Meier curves, comparing the results to a historical cohort of BEAM patients (n = 86). Finally, we conducted an economic analysis using the financials available at our centre's pharmacy. With regards to BeEAM HDCT, we report a 100-day transplant-related mortality of 2.4%. Additionally, we report acceptable rates of typhlitis (27%), grade III-IV mucositis (4.9%) and grade III-IV nephrotoxicity (2.4%). In terms of overall and progression-free survival, we found no statistical difference between BeEAM and BEAM (p = 0.296; 0.762, respectively). Finally, our economic analysis revealed a net savings of $21,200 CAD per transplant when BeEAM is used in replacement of BEAM. The acceptable safety profile of BeEAM and its comparable efficacy to BEAM are encouraging for the perseverance of this cost-effective HDCT regimen.

Real World Clinical Experience of Biosimilar G-CSF (Grastofil) for Autologous Peripheral Blood Stem Cell Mobilization: Single Center Experience in Canada Following Early Adoption.

Introduction: Granulocyte colony-stimulating factor (G-CSF) is the first line treatment for mobilization, most commonly using a regimen of daily filgrastim. The use of biosimilars can provide substantial cost savings to the health care system while delivering comparable efficacy outcomes. In 2016, the Saskatchewan Cancer Agency was a leader in Canada, instituting formulary changed from a G-CSF originator product to a cost savings alternative biosimilar for stem cell mobilization prior to autologous stem cell transplant (ASCT) and for engraftment. The purpose of this study was to investigate the clinical comparability of biosimilar G-CSF to its reference product in a real-world clinical setting and to validate use of the biosimilar in mobilization and engraftment-an indication which had been granted by extrapolation. METHODS: A retrospective chart review was completed including all patients diagnosed with a hematological malignancy between 2012 and 2018 who underwent ASCT. To assess real-world outcomes across a diverse population, successful CD34+ stem cell collection was compared between patients mobilized with originator filgrastim, Neupogen, and biosimilar filgrastim, Grastofil. Additional comparisons included the number of apheresis required, time to absolute neutrophil count (ANC) engraftment, platelet engraftment, length of hospital stay, and Plerixafor use. RESULTS: 217 patients were mobilized and transplanted during the study period. There was no statistically significant difference in success rate between patients mobilized with biosimilar filgrastim and those who had received originator G-CSF (100% vs. 92.4%, p = 0.075). Neither disease type, nor concurrent chemomobilization regimen resulted in a detectable difference between the two G-CSF products in successful stem cell harvest. Engraftment was highly similar between groups, as demonstrated by ANC recovery (11.6 days Neupogen vs. 11.6 days Grastofil), platelet recovery (14.0 days Neupogen vs. 14.2 days Grastofil), and total length of hospital stay (22.4 days Neupogen vs. 22.3 days Grastofil). No statistically significant difference in adjunctive use of Plerixafor® was observed between Neupogen and Grastofil patients (25.9% vs. 23.4%, p = 0.72). CONCLUSION: Extrapolation of indications for biosimilars is justified. This real-world evidence builds upon registrational studies to confirm that no clinically meaningful differences were detected between originator Neupogen and biosimilar Grastofil in the setting of PBSC mobilization and engraftment post ASCT. Biosimilars are as safe and effective as originator products. Implementation across all approved indications without hesitation maximizes cost savings to the provincial system, allowing for more optimal allocation of health care resources.

Vitamin B12 deficiency and metabolism-mediated thrombotic microangiopathy (MM-TMA).

Thrombotic microangiopathies (TMA) are characterized by microangiopathic hemolytic anemia, thrombocytopenia and organ damage resulting from mechanical factors, accumulation of the ultra-large von Willebrand factor multimers or complement-mediated abnormalities. Severe acquired vitamin B12 (Cobalamin - Cbl) deficiency or congenital defective Cbl metabolism could lead to a picture that mimics TMA. The later has been termed metabolism-mediated TMA (MM- TMA). This confusing picture is mediated partly by the large red cell fragmentation coupled with reduced platelet production in the absence of vitamin B12 and partly by the accumulated byproducts and metabolites that induce endothelial injury and hence organ damage. Expensive and complicated treatment for TMA is often initiated on an empiric basis, pending the results of confirmatory tests. In contrast, vitamin B12 Pseudo-TMA and MM-TMA could be treated with proper vitamin B12 supplementation. It is therefore important to identify these disorders promptly. The recent availability of a validated scoring system such as the PLASMIC score uses simple clinical and laboratory parameters. As it incorporates the mean corpuscular volume in its laboratory parameters, this helps in the identification of pseudo and MM-TMA. Perhaps some minor modification of this scoring system by changing the parameters of hemolysis to include reticulocytosis and rather than and/or other hemolytic parameters could even help refine this identification.

Recombinant Zoster Vaccine Significantly Reduces the Impact on Quality of Life Caused by Herpes Zoster in Adult Autologous Hematopoietic Stem Cell Transplant Recipients: A Randomized Placebo-Controlled Trial (ZOE-HSCT).

Herpes zoster (HZ) can have a substantial impact on quality of life (QoL). The vaccine efficacy (VE) of a recombinant zoster vaccine (RZV) was 68.2% (95% confidence interval [CI], 55.6% to 77.5%) in a phase 3 study in adult autologous hematopoietic stem cell transplant (HSCT) recipients (NCT01610414). Herein, we report the impact of RZV on patients' QoL. Autologous HSCT recipients were randomized 1:1 to receive 2 doses of RZV or placebo, given 1 to 2 months apart. QoL was measured by the Short Form Survey-36 and Euro-QoL-5 Dimension at baseline, 1 month, and 1 year postdose 2 and during suspected HZ episodes with the Zoster Brief Pain Inventory (ZBPI). The RZV impact on ZBPI burden of illness and burden of interference scores was estimated. The 2 scores were calculated from the area under the curve (days 0 to 182) of the ZBPI worst pain and ZBPI activities of daily living scores, respectively, assuming a score of 0 for patients not having a confirmed HZ episode. The ZBPI maximum worst pain score was significantly lower in the RZV than placebo group (mean: 5.8 versus 7.1, P = .011). Consequently, the VE estimates for HZ burden of illness (82.5%; 95% CI, 73.6 to 91.4) and burden of interference (82.8%; 95% CI, 73.3 to 92.3) were higher than the HZ VE estimate (ie, 68.2%). RZV showed significantly better QoL scores than placebo 1 week following rash onset among patients with confirmed HZ. In addition to reducing the risk of HZ and its complications, RZV significantly reduced the impact of HZ on patients' QoL in those who developed breakthrough disease.

Transplant-associated thrombotic microangiopathy: Diagnostic challenges and management strategies.

Transplant-associated thrombotic microangiopathy (TA-TMA) is one of the early endothelial complications post Hematopoietic Stem Cell Transplant (HSCT). Several mechanisms during HSCT can contribute to systemic capillary endothelial damage which can lead to TA-TMA among other complications as capillary leak syndrome or engraftment syndrome. Early diagnosis of TA-TMA contributes a challenge due to overlapping clinical manifestations and the absence of specific diagnostic criteria. Incidence is greatly variable between 1-76% according to risk factors of patients and the definition used to confirm the diagnosis. The mortality rates in patients who develop severe TA-TMA are in excess of 80%. Early treatment improves the outcome. This review outlines the diagnostic challenges and therapeutic options for TA-TMA.

Reflections on multiple strategies to reduce transfusion in cancer patients: A joint narrative.

Transfusion of red blood cells, platelets and plasma is widely used in the management of anemia and coagulopathy in cancer patients undergoing surgery, chemotherapy, and radiation. The decision to transfuse should not be made lightly as exposure to transfused blood, whether from an allogeneic or even autologous source, is not without risk and the long-term effect of blood transfusion on cancer outcomes remains questionable. Recognition of anemia associated with nutritional deficiency should be promptly corrected while avoiding the use of erythropoiesis stimulating agents. Minimizing blood loss and the prompt control of bleeding, coupled with a restrictive transfusion strategy, seem to be a reasonable approach that does not appear to be associated with long-term sequelae. Limiting platelet transfusion to patients with severe hypo-proliferative thrombocytopenia, and implementation of local hemostatic measures, together with the use of fractionated coagulation factor concentrates, as an alternative to frozen plasma transfusion, may reduce the exposure of cancer patients to potentially harmful thrombogenic and pro-inflammatory cellular microparticles. This joint narrative highlights current opinions for minimizing blood usage in patients with cancer.

Transfusion challenges in hematology oncology and hematopoietic stem cell transplant - Literature review and local experience.

Transfusion medicine plays a vital role in the supportive care of patients receiving therapy for hematology, oncology and hematopoietic stem cell transplants (HSCT). With advances in therapy with more intensive chemotherapy or radiotherapy, patients usually develop cytopenias and need frequent transfusion support with packed red blood cells, granulocyte transfusion or platelets to support them until they recover from the effect of therapy. HSCT poses unique challenges for transfusion medicine, since transplant recipients may require substantial transfusion support due to cytopenias associated with toxic medications, decreased marrow reserve, infection or their malignancy. Transfusion support has many complications, mainly immune mediated and infectious complications. Jehovah's Witness patients deny transfusions of blood products as a therapeutic option and, consequently, management of their disease with chemotherapy and stem cell transplant after myeloablative therapy is quite challenging. This review describes the challenges of transfusion support in managing hemato-oncology and stem cell transplant patients and highlights a local experience in transplanting two Jehovah's Witness patients.

Platelet microparticles and cancer: An intimate cross-talk.

Blood cell-derived microparticles (MP), in general, and platelet MPs (PMPs), in particular, have emerged as important contributors, as well as markers, of the delicate balance between health and disease. They may, on one hand, have beneficial effects by supporting tissue repair and regeneration, as well as hemostasis, but may, on the other hand, be a pro-coagulant promoter leading to the thrombotic events seen in the context of cancer. PMPs can act as a direct tumor growth enhancer through the release of potent growth factors in the tumor micro-environment. Tumor engraftment can also be stimulated by the pro-angiogenic potentials of platelet growth factors released by PMPs. PMPs, by their pro-inflammatory and immunomodulatory functions, can also exert an indirect role in the metastatic multistep process by helping malignant cells to escape from immunological surveillance. The possible detrimental effect of transfusions in cancer patients has been debated for several years and the role played by PMPs present in blood products is receiving specific attention, considering their propensity to trigger thrombosis and support tumors. The intimate PMP-tumors crosstalk may therefore result in pro-thrombotic states and a physiological state favorable to tumor growth, tethering and dissemination. Laboratory and experimental studies are needed to better unveil the contribution of PMPs as coagulation promoters, as well as potential markers and targets to treat cancer.

A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial.

We conducted a randomized, controlled trial comparing thalidomide-prednisone as maintenance therapy with observation in 332 patients who had undergone autologous stem cell transplantation with melphalan 200 mg/m2. The primary end point was overall survival (OS); secondary end points were myeloma-specific progression-free survival,progression-free survival, incidence of venous thromboembolism, and health-related quality of life (HRQoL). With a median follow-up of 4.1 years, no differences in OS between thalidomide-prednisone and observation were detected (respective 4-year estimates of 68% vs 60%, respectively; hazard ratio = 0.77; P = .18); thalidomide-prednisone was associated with superior myeloma-specific progression-free survival and progression-free survival (for both outcomes, the 4-year estimates were 32% vs 14%; hazard ratio = 0.56; P < .0001) and more frequent venous thromboembolism (7.3% vs none; P = .0004). Median survival after first disease recurrence was 27.7 months with thalidomide-prednisone and 34.1 months in the observation group. Nine second malignancies were observed with thalidomide-prednisone versus 6 in the observation group. Those allocated to thalidomide-prednisone reported worse HRQoL with respect to cognitive function, dyspnea, constipation, thirst, leg swelling, numbness, dry mouth, and balance problems. We conclude that maintenance therapy with thalidomide-prednisone after autologous stem cell transplantation improves the duration of disease control, but is associated with worsening of patient-reported HRQoL and no detectable OS benefit.

Graft-versus-host disease prophylaxis with tacrolimus and mycophenolate mofetil in HLA-matched nonmyeloablative transplant recipients is associated with very low incidence of GVHD and nonrelapse mortality.

Incidence of grade II-IV acute graft-versus-host disease (aGVHD) in nonmyeloablative (NMA) transplant recipients remains high. To date, the ideal prophylaxis regimen, which minimizes aGVHD and chronic GVHD (cGVHD), but does not abrogate graft-versus-tumor (GVT) response, has not been described. Because tacrolimus is more potent than cyclosporine (CSA), and because mycophenolate mofetil (MMF) is an effective immunosuppressant that does not lead to mucositis, we hypothesized that a combination of these 2 oral agents may be an effective GVHD prophylactic strategy. We, therefore, designed an outpatient prospective cohort study with a conditioning regimen consisting of fludarabine (Flu) 30 mg/m2 daily and cyclophosphamide (Cy) 300 mg/m2 daily for 5 days followed by infusion of blood stem cells. Tacrolimus 3mg twice a day was started on day (D) -8, adjusted to achieve levels 10-15 nmol/L, continued until D +50 and then tapered by D +100 or +180 according to estimated risk of relapse. MMF 1000 mg twice a day was started on D +1 and discontinued on D +50. To date, 131 patients (males/females: 75/56) with a median age of 54 years have received a 6/6 matched sibling transplant using this protocol. Indication for NMA transplant included age >55 years (24%), expected increased risk of toxicity (28%), or participation in a multiple myeloma (MM) sequential protocol (48%). Most common diagnoses included MM (N = 62), non-Hodgkin lymphoma (NHL, N = 46), and acute leukemia (N = 10). Following infusion of 6.8 x 10(6) CD34+ cells/kg (range: 0.30-22.3), neutrophil and lymphocyte engraftment occurred in 95% of patients by D +180. The estimated cumulative incidence of classical grade I-IV aGVHD by D +120 was 11.6% (95% confidence interval [CI]: 7.1-18.5). No grade IV aGVHD was observed. In addition, 15 patients (12%: CI: 7.4-19.2; median D +140) developed an overlap syndrome consisting of clinical and histologic features of both aGVHD and cGVHD simultaneously. The estimated cumulative incidence of extensive cGVHD was 76.1% (95% CI: 67.4-83.9) at 2 years, with clinical features at presentation similar to other reported series. In patients developing extensive cGVHD, the probability of remaining on immunosuppression at 5 years was 34.8% (95% CI: 16.4-57.3). With a median follow-up of 982 days, the estimated probabilities of nonrelapse mortality (NRM) and overall survival (OS) were 15.5% (95% CI: 9.0-26.1) and 62.7% (95% CI: 51.4-72.1). The cumulative incidence of relapse was 30% at 7 years. Following NMA transplant, disease-free survival (DFS) was highest in recipients with follicular NHL (79.8%: 95% CI: 57.6-91.2) and lowest in large cell NHLs (34.3%: 95% CI: 1.6-75.9). From this large group of patients treated with a uniform conditioning and GVHD prophylaxis regimen, we conclude that aGVHD prophylaxis with early use of tacrolimus and MMF is safe, effective, and associated with low NRM. Future strategies will need to focus on decreasing the incidence of extensive cGVHD without increasing the risk of relapse.