Chromosome Abnormalities and Hematopoietic Stem Cell Transplantation in Acute Leukemias

The chapter considers specific treatment options, including allogeneic hematopoietic stem cell transplantation (allo‐HSCT) in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), in patients with some prognostically proven cytogenetic variants as monosomal ones, complex and hyperdiploid karyotypes, like chromosomal translocations t(v;11)(v;q23), t(3;3)/inv(3); t(8;21), t(9;22), etc. Important prognostic role of additional chromosome abnormalities was shown for the patients with t(8;21) and t(9;22). Hence, it is evident that allo‐HSCT in patients with poor risk cytogenetic variant must be performed as early as possible, i.e., during first complete remission

Prognosis of Elevated Serum Ferritin in Allogeneic-HCT

Introduction: Serum ferritin was demonstrated to be a useful tool to predict the risk in patients who undergo hematopoietic stem cell transplantation (HCT). Still it is not clear if its predictive value solely represents iron overload (IO) and published results are sometimes contradictory. So the objective of present study was to determine relationship between elevated pre-HCT serum ferritin levels, morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HCT) on one side, and its correlations with various risk indexes which were developed recently to predict outcomes after allo-HCT on the other side. Patients and Methods: In this retrospective study we have reviewed medical records of one hundred six consecutive patients (52 males and 54 females), with a median age of 32 years (range, 5 to 60), who underwent allo-HCT with unmanipulated grafts between Jan 2013 and Dec2014. We retrieved pre-allo-HCT serum ferritin levels and also calculated risk indexes before HCT. The incidence of complications and outcomes after allo-HCT was assessed. The median follow-up period was 12 (range, 4-27) months after allo-HCT. Results: We have determined a cuttoff ferritin level of 500 ng/mL for early complications and 737 for outcomes. We found increased incidence of number of febrile neutropenic episodes (P =0.02), number of bacterial infection episodes (P =0.009), pneumonias (P =0.039), slower period of neutrophil engraftment (P=0.032), demand for multiple red blood cell (RBC) transfusions (P =0.002) within 100 days post transplantation. A significant association was found between pre-transplant ferritin concentrations and different risk indexes; European Group for Blood and Marrow Transplantation (EBMT) risk score (P=0.001), Hematopoietic cell transplantation comorbidity index (HCT-CI) (P=0.003), Pre-transplant Assessment of Mortality (PAM) score (P=0.007) and disease risk (DR) (P =0.037). Conclusion: On the one hand we did confirmed that even moderate serum ferritin elevation is associated with increased incidence of infections, slower period to engraftment and increasing demand of RBC units transfusions, but strong correlation with pre-transplant indexes that take into account disease risk raises the question if IO is the only factor that adversely affect the outcome of HCT in patients with increased ferritin. This should be studied in prospective trials

Risk factors for outcome after allogeneic stem cell transplantation in patients with advanced phase CML

Allogeneic hematopoietic stem-cell transplantation (HSCT) remains the only curative option for patients with advanced chronic myeloid leukemia (CML). However, outcome is dismal and of short follow-up. The objective of the study was to determine long-term outcome and risk factors in patients with a history of CML Blast Crisis (BC; n = 96) or accelerated phase (n = 51) transplanted between 1990 and 2018. At transplant, patients had a median age of 39 (range 7-76) years and were in ≥CP2 (n = 70), in AP (n = 40) or in BC (n = 37) with a diagnosis-HSCT interval of median 1.9 (range 0.3-24.4) years. Overall survival (OS) amounted 34% (95% CI 22-46) and progression-free survival (PFS) 26% (95% CI 16-36) at 15 years. Adverse risk factors for OS and PFS were low CD3

A Study of Safety and Efficacy of Nivolumab and Bendamustine (NB) in Patients With Relapsed/Refractory Hodgkin Lymphoma After Nivolumab Monotherapy Failure

Abstract. This single-center prospective clinical trial evaluated the combination of nivolumab plus bendamustine (NB) as a salvage regimen in classical Hodgkin lymphoma patients after failure of nivolumab monotherapy. A total of 30 patients received nivolumab (3 mg/kg) on D1,14 and bendamustine (90 mg/m2) on D1, 2 of a 28-day cycle for up to 3 cycles. The ORR was 87% with 57% CR, 30% PR. With median follow-up of 25 months, the estimated 2-year OS was 96,7% (95% CI, 90.2%–100%), PFS was 23,3% (95% CI, 8.2%–38.4%) median PFS was 10.2 months (95% CI, 7.7–14.2 months) with median DOR 6.6 months (95% CI 3.9–11.6 months). Ten patients (33.3%) experienced grade 3 to 4 AE during therapy. Infections were most common AEs of the combined therapy. NB was a highly efficient salvage regimen in relapsed/refractory cHL with a manageable toxicity profile and modest potential for achievement of long-term remission. Registered at www.clinicaltrials.gov (#NCT0334365)

Mesenchymal Stem Cells Engineering: Microcapsules-Assisted Gene Transfection and Magnetic Cell Separation

Stem cell engineeringthe manipulation and functionalization of stem cells involving genetic modificationcan significantly expand their applicability for cell therapy in humans. Toward this aim, reliable, standardized, and cost-effective methods for cell manipulation are required. Here we explore the potential of magnetic multilayer capsules to serve as a universal platform for nonviral gene transfer, stem cell magnetization, and magnetic cell separation to improve gene transfer efficiency. In particular, the following experiments were performed: (i) a study of the process of internalization of magnetic capsules into stem cells, including capsule co-localization with established markers of endo-lysosomal pathway; (ii) characterization and quantification of capsule uptake with confocal microscopy, electron microscopy, and flow cytometry; (iii) intracellular delivery of messenger RNA and separation of gene-modified cells by magnetic cell sorting (MACS); and (iv) analysis of the influence of capsules on cell proliferation potential. Importantly, based on the internalization of magnetic capsules, transfected cells became susceptible to external magnetic fields, which made it easy to enrich gene-modified cells using MACS (purity ∼95%), and also to influence their migration behavior. In summary, our results underline the high potential of magnetic capsules in stem cell functionalization, namely (i) to increase gene-transfer efficiency and (ii) to facilitate enrichment and targeting of transfected cells. Finally, we did not observe a negative impact of the capsules used on the proliferative capacity of stem cells, proving their high biocompatibility

A Phase 2 Study of Nivolumab Using a Fixed Dose of 40 mg (Nivo40) in Patients With Relapsed/Refractory Hodgkin Lymphoma

Abstract. The introduction of nivolumab has changed the landscape of relapsed/refractory classical Hodgkin lymphoma (r/r cHL) treatment. Despite its clinical importance, this therapy may remain inaccessible for a significant number of patients worldwide, especially in low-income countries, due to its high cost. The results of pharmacokinetic analysis and clinical observations suggest the potential efficacy of low dose nivolumab in r/r cHL patients. The aim of this trial was to assess the efficacy and safety of nivolumab at a fixed dose of 40 mg in patients with r/r cHL. The study included 30 patients with r/r cHL, treated with 40 mg nivolumab every 2 weeks. The median dose of nivolumab per kilogram bodyweight was 0.59 mg/kg (0.4–1 mg/kg). Median follow up was 19.2 months (range 12.7–25.4). The objective response rate was 70%, with 13 (43.3%) patients achieving a complete response. Median PFS was 18.4 months (95% CI, 11.3 to 18.5 months) with 18-month PFS of 53.6% (95% CI, 32%–71%). At the time of analysis, 96.7% of patients were alive with a median OS not reached. Severe (grade 3–5) adverse events were observed in 4 patients (13.3%). Nivolumab in a fixed dose of 40 mg was efficient in patients with r/r cHL, independent from dose per kg bodyweight. The results of this study are in good agreement with previously reported data and create a rationale for further studies aimed to define the optimal dosing regimen of nivolumab for the treatment of r/r cHL. Registered at www.clinicaltrials.gov (NCT03343665