Chimeric antigen receptors (CARs) are genetically engineered receptors that provide specific properties to an immune effector cell and these receptors gain the specificity of a monoclonal antibody targeted against specific tumor cells. T cells with engineered CARs acquire potent immunological properties and redirect the immune system in order to eliminate malignant cells. First-engineered T cells with chimeric molecule (CAR-T cells) were developed in 1989–1993 by Israeli immunologists Zelig Eshhar and Gideon Gross. The first clinical application of CAR-T cells was done in the University of Pennsylvania and Children’s Hospital in Philadelphia by the immunologist Carl June and hematologist David Porter to patients with chronic lymphocytic leukemia in 2011 and together with the pediatrician Stephan Grupp to patients with acute lymphoblastic leukemia (ALL) in 2012. The US Food and Drug Administration Agency (FDA) in 2017 and the European Medicines Agency (EMA) in 2018 have licensed two products of CAR-T cells: tisagenlecleucel for the use in children and young adults up to 25 years of age with B-cell ALL who do not respond to treatment or have relapsed two or more times and tisagenlecleucel and axicabtagene ciloleucel for the use in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Current progress in CAR technology includes the use in other hematological malignancies, solid tumors, the use of dual CAR-T cells and chimeric antigen receptor natural killer cells (CAR-NK cells).
Chimeric antigen receptor T-cell (CAR-T) therapy is an effective new treatment for hematologic malignancies. Two anti-CD19 CAR-T products, namely axicabtagene ciloleucel and tisagenlecleucel, have been approved for the management of relapsed/refractory large B-cell lymphoma after two lines of systemic therapy. Additionally, tisagenlecleucel is indicated for refractory acute lymphoblastic leukemia in pediatric patients and young adults up to 25 years of age. CAR-T cells are undoubtedly a major breakthrough therapy in hematooncology resulting in up to 90% response rate with durable remissions in population with refractory high-risk disease. However, there are serious side effects resulting from CAR-T therapy, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Manifestations of CRS mostly include fever, hypotension, hypoxia, and end organ dysfunction. Neurologic toxicities are diverse and include encephalopathy, cognitive defects, dysphasia, seizures, and cerebral edema. Since the symptoms are potentially severe, practitioners need to familiarize themselves with the unique toxicities associated with these therapies. In this article, we present a practical guideline for diagnosis, grading and management of CRS and CAR-T neurotoxicity. In addition, infectious complications and late toxicities including prolonged cytopenias and hypogammaglobulinemia are discussed.
Graft-versus-host disease (GVHD) is a common and serious complication after allogeneic stem cell transplantation (allo-SCT). However, a similar syndrome has been reported after autologous stem cell transplantation (ASCT) as well.
A 61-year-old female diagnosed with immunoglobulin (Ig) G lambda multiple myeloma completed 10 cycles of bortezomib, thalidomide, and dexamethasone (VTD) and 2 cycles of cyclophosphamide, thalidomide, and dexamethasone (CTD). High-dose of melphalan (200 mg/kg) was given as conditioning, followed by an infusion of 2.5 × 106 CD34+ cells/kg. Three months later, she received her second ASCT. On Day +25 after tandem ASCT, the patient developed a maculopapular, itchy skin rash, which covered her face, trunk, and limbs. A skin biopsy was in line with the diagnosis of GVHD. The other organs were not involved. Treatment with systemic and local corticosteroids (CSs) resulted in the improvement of skin lesions, but the CSs were slowly tapered due to toxicity. In the following weeks, she developed symptoms of liver and gut involvement, which were resistant to steroids. The introduction of other immunosuppressive agents failed to achieve a response. As a consequence, she had cytomegalovirus (CMV) reactivation, as well as pancytopenia, and eventually, she died of infectious complications.
GVHD after ASCT remains a rare but life-threatening complication with poor prognosis.
The most frequent and severe complications after chimeric antigen receptor T-cells (CAR-T cells) therapy include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH), tumor lysis syndrome (TLS), followed by B-cell aplasia and hypogammaglobulinemia. With these immunologically related events, cytokine storm and immunosuppression, there is a high risk of sepsis and infectious complications. The objective of this review was to present current knowledge on incidence, risk factors, clinical characteristics, and outcome of infections in patients following CAR-T cells therapy, as well as to present current recommendations on prophylaxis of infections after CAR-T cells therapy. Comparable to hematopoietic cell transplantation setting, specific pre- and post-CAR-T cells infusion phases can be determined as early (from 0 to +30 days), intermediate (from +31 to +100 days), and late (beyond day +100). These phases are characterized by CAR-T cells therapy-related factors and immune system defects contributing to an increased risk of infections. It is recommended that in case of active infection, CAR-T cells infusion should be delayed until infection has been successfully treated. After CAR-T cells therapy, prophylaxis should be implemented (anti-bacterial, anti-viral, anti-fungal, anti-pneumocystis), as well as treatment of neutropenia and immunoglobulin replacement should be considered. No recommendations so far can be given on revaccinations after CAR-T cells therapy.
Quality assurance and safety of hematopoietic stem cells (HSC) with special emphasis on bacterial and fungal contamination is the prerequisite for any transplantation procedure. The aim was to determine the incidence rate of such contamination during processing of transplantation material with regard to HSC source: peripheral blood stem cell (PBSC), bone marrow (BM), or cord blood (CB). Analysis involved autologous and allogenic products dedicated for patients and comprised in all 4135 donations, including 112 BM (2.70%), 3787 PBSC (91.60%), and 236 CB (5.70%) processed in cell bank over the period 1996–2016. Aerobic and anaerobic contamination was determined.
Analysis of the 20-year data revealed 42 contaminated products: 25 PBSC (0.66% of tested units) and 17 CB (7.20% of tested units). No microbial contamination of BM products was detected. Overall percentage of contaminated products was 1.01%, mostly with Staphylococcus epidermidis (61.36%). Bacterial contamination rate at cell bank is relatively low and processing in a closed system does not seem as crucial as might be expected. This is particularly true for BM components. Equally important are evaluation of donor’s medical status and condition of the puncture site for collection of source material. Implementation of appropriate sample collection procedures should help minimize the risk of false-positive results due to environmental contamination.
The International Prognostic Index and its modifications are used to estimate prognosis in non-Hodgkin lymphoma. However, the outcome is often different in patients with similar index scores.
The aim of this study was to elaborate a prognostic model for patients with mature B-cell non-Hodgkin lymphoma using a combination of predictive markers.
Material and methods
The study included 45 patients with mature B-cell non-Hodgkin lymphoma. Before the administration of treatment, clinical and laboratory parameters were measured. After the 35-month follow-up period, overall survival was studied in relation to the data obtained at initial examination.
We revealed nine adverse predictive markers for overall survival of enrolled patients: Eastern Cooperative Oncology Group (ECOG) performance status >1; erythrocyte sedimentation rate >30 mm/h; levels of hemoglobin <120 g/L, fibrinogen ≥6 g/L, interleukin-6 ≥2 pg/mL, tumor necrosis factor ≥1.45 pg/mL, soluble fibrin monomer complexes >4 mg/dL, high-density lipoprotein cholesterol <1.03 mmol/L in men, and <1.29 mmol/L in women; and short activated partial thromboplastin time. A prognostic model for the estimation of the risk of death within the ensuing 1.5–2 years in patients with non-Hodgkin lymphoma was constructed.
Markers of inflammation, anemia, hypercoagulability, dyslipidemia, and poor ECOG status are associated with worse survival in patients with mature B-cell non-Hodgkin lymphoma.
Cytomegalovirus (CMV), the beta-human herpesvirus type 5 (HHV-5), is a major cause of morbidity in immunocompromised hosts, especially recipients of allogeneic hematopoietic cell transplantation (HCT) or solid organ transplantation. The standard-of-care approach to CMV prevention based on CMV surveillance-guided preemptive therapy is being challenged by the recent approval of letermovir (LMV) for primary prophylaxis. Real-word clinical data show dramatic improvement in the reduction of risk of CMV infection and any CMV viremia in all studies performed so far. LMV is the drug that is breaking the paradigm of preemptive therapy with shift to prophylaxis. A summary of reported data presented in 2019 annual meetings of American Society of Transplantation and Cellular Therapy (ASTCT), European Society for Blood and Marrow Transplantation (EBMT) and American Society of Hematology (ASH), as well as already published results, is presented in this review. A total number of 401 adult high-risk patients on primary prophylaxis after HCT were reported in 11 studies up to January 1, 2020. It was shown that fewer patients in the LMV arms had any CMV reactivation or need for CMV treatment compared with the any other prophylactic or preemptive approaches. In conclusion, LMV is much highly effective than CMV-guided preemptive therapy in preventing CMV infection and CMV disease. The use of LMV in prophylaxis results in an improvement in overall survival during the first 24 and 48 weeks. LMV has a favorable safety profile, as it does not cause myelotoxicity. Current guidelines of European Conference on Infections in Leukemia (ECIL7) recommend LMV for the use in prophylaxis of CMV infection in patients after allogeneic hematopoietic cell transplant.
The objective of this paper is to present the process of the national and international accreditation leading to the establishment of the first certified chimeric antigen receptor T (CAR-T) Cell Unit in Poland on the basis of the Department of Hematology and Bone Marrow Transplantation in Poznan University of Medical Sciences and first successful CAR-T therapy in Poland. During 12 months from the initial decision to establish the CAR-T Cell Unit to the application of CAR-T cell treatment in the first patient, the center had to undergo the multidisciplinary external and internal training, as well as the adaptation of multiple procedures within the Transplant Unit and Stem Cell Bank. In order to get accreditation for the implementation of CAR-T cell therapy, an initial training of the team involved in handling cellular products and patient care was organized and updated as a continuous process. The Department fulfilled the site-selection international criteria. The first patient diagnosed for refractory/relapsed DLBCL was qualified, and finally CAR-T cells were administered with successful clinical outcome.
Systemic mastocytosis (SM) with an associated hematological neoplasm (SM-AHN) constitutes about 40% of all patients with SM. AHN commonly includes myeloid neoplasms and chronic myelomonocytic leukemia (CMML) is seen in about 30% of these patients.
A 67-year-old male presented to hematologist with fatigue and significant weight loss. Abdominal ultrasound and computed tomography (CT) detected hepatosplenomegaly, abdominal lymphadenopathy, and ascites. He was anemic with leukocytosis and eosinophilia. Trephine biopsy showed > 30% of spindle-shaped mast cells. The KITD816V mutation was present. Serum tryptase level was elevated to 62 ng/mL. The patient was diagnosed with aggressive SM and received six cycles of cladribine with partial response. Three years later, he developed severe anemia. Eosinophilia and monocytosis (5.6 × 109/L) were demonstrated in blood film. Hepatosplenomegaly and abdominal lymphadenopathy were also present. Trephine biopsy did not demonstrate the presence of spindle-shaped mast cells, but dysplasia in erythroid and myeloid lineages was evident. The histological result of lymph node biopsy as well as blood and bone marrow findings were in line with CMML. He received hydroxyurea, but he transformed soon into fatal acute monocytic leukemia.
The prognosis of SM-AHN depends on AHN component. Leukemic transformation of AHN component may occur in a proportion of patients.
Triplet induction regimens are standard of care for newly diagnosed transplant eligible multiple myeloma patients. The combinations of bortezomib and dexamethasone with either cyclophosphamide (VCD) or thalidomide (VTD) are widely used. There are no data available on the impact of the two regimens on stem cell harvest by using G-CSF only mobilization. In this study, we retrospectively analyzed data from our national registry. The outcome measures were mobilization failure, CD34+ cell counts on collection day, number of apheresis procedures, and the number of collected cells. Overall, 72 patients were treated with either VCD or VTD. The mobilization failure rates were 7% and 9% (p = 0.771) and the total number of collected stem cells were 7.0 × 106 and 6.7 × 106 per kg body weight (p = 0.710) for VCD and VTD, respectively. We found no statistically significant difference between the treatment groups in the outcome measures. The addition of thalidomide to bortezomib and dexamethasone (VTD) does not adversely affect stem cell harvest in patients mobilized with G-CSF only.