Selection pressure phenomenon during treatment of chronic myeloid leukemia patients with BCR-ABL1 tyrosine kinase inhibitors: problem analysis on the basis of case report

Mimo ogromnego postępu związanego z wprowadzeniem do terapii chorych na przewlekłą białaczkę szpikową (CML) inhibitorów kinazy tyrozynowej (TKI) u około 15% pacjentów stwierdza się oporność na leczenie I linii za pomocą imatynibu (IM). Jest ona w około 40% przypadków związana z obecnością mutacji w obrębie domeny kinazowej BCR-ABL1 (KD BCR-ABL1). Część defektów jest oporna na IM, a jego stosowanie prowadzi do selekcji klonów opornych niewrażliwych także na TKI II generacji (dazatynib, nilotynib). W pracy przedstawiono przebieg choroby u pacjentki z CML w fazie przewlekłej, u której z powodu oporności na IM podjęto leczenie nilotynibem. Stosowanie leku doprowadziło do uzyskania większej odpowiedzi cytogenetycznej, a następnie jej utraty, w wyniku obecności mutacji Y253H KD BCR- -ABL1. Zmiana inhibitora II generacji na dazatynib pozwoliła uzyskać całkowitą odpowiedź hematologiczną po 3 miesiącach terapii. Niestety, wkrótce potem rozpoznano fazę akceleracji choroby i potwierdzono obecność innej mutacji F317L KD BCR-ABL1. Przebieg choroby u wspomnianej chorej był podstawą do podjęcia dyskusji dotyczącej zjawiska presji selekcyjnej związanego ze stosowaniem TKI u chorych z CML. Hematologia 2010; 1, 3: 261-266Despite a great progress related to the introduction of tyrosine kinase inhibitors (TKI) to the therapy of patients with chronic myeloid leukemia (CML), resistance to the first-line treatment with imatinib (IM) is diagnosed in about 15% of patients. In about 40% of cases it is related to the presence of mutations affecting kinase domain of BCR-ABL1 (KD BCR-ABL1). Some defects are IM-resistant and its further administration leads to the selection of resistant clones, insensitive also to the 2nd generation TKIs (dasatinib, nilotinib). This paper focuses on medical history of patient diagnosed with CML in the chronic phase in whom nilotinib treatment was started due to the appearance of IM-resistance. Administration of nilotinib allowed to obtain major cytogenetic response and, subsequently, its loss due to the emergence of Y253H mutation within KD BCR-ABL1. Substitution of the 2nd generation drug to dasatinib allowed to obtain complete hematological response after 3 months of treatment. Unfortunately, the acceleration phase of the disease and the presence of another F317L mutation of KD BCR-ABL1 were documented thereafter. Disease outcome in the presented case was the reason for undertaking a discussion about selection pressure phenomenon related to TKI administration in patients with CML. Hematologia 2010; 1, 3: 261-26

Safety and cost effectiveness of outpatient autologous hematopoietic stem cell transplantation for multiple myeloma — single-center experience of a pilot Early Discharge Program

Introduction: Multiple myeloma (MM) is the leading indication for autologous stem cell transplantation (ASCT), with over 12,000 transplants per year in Europe. Due to low toxicity, an entirely outpatient procedure or an early discharge after ASCT can be considered as alternatives to inpatient transplantation. Thus, we launched an Early Discharge Program (EDP) for patients qualified for ASCT due to MM who were under 60 years of age, without significant comorbidities, who had a caregiver available 24/7, and who lived within a 60-minute drive of our hospital. Material and methods: Patients spent 72 hours in the hospital being administered melphalan 200 mg/m2 intravenous followed by an infusion of hematopoietic stem cells. They were eventually discharged and remained under outpatient care. The program was launched in September 2019 and was temporarily halted due to the coronavirus disease 19 (COVID-19) pandemic in early 2020. Five patients were enrolled to the EDP. Results: Non-hematological toxicity was mild and manageable in an outpatient setting. Only one patient was readmitted due to exacerbation of ulcerative colitis that was probably not related to ASCT. We observed neither infections nor bleeding. Due to hematological toxicity, three of the five patients received platelet transfusion on the 6th day after ASCT as outpatients. No packed erythrocytes were transfused. The EDP demonstrated lower costs compared to an inpatient approach. Conclusions: We believe that early discharge, which is an intermediate step to full at-home transplantation due to patients’ wellbeing, reduction of infections caused by resistant microorganisms, and costs, will eventually replace a full inpatient procedure for a significant population of patients suffering from multiple myeloma and indeed other diseases

CAR-T cell therapy – toxicity and its management

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

Road to clinical implementation of CAR-T technology in Poznań

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

First observation and study of the K±→π0π0μ±νK^{\pm} \rightarrow \pi^{0} \pi^{0} \mu^{\pm} \nu decay

The NA48/2 experiment at CERN reports the first observation of the $K^{\pm} \rightarrow \pi^{0} \pi^{0} \mu^{\pm} \nu$ decay based on a sample of 2437 candidates with 15% background contamination collected in 2003-2004. The decay branching ratio in the kinematic region of the squared dilepton mass above $0.03$~GeV$^2/c^4$ is measured to be $(0.65 \pm 0.03) \times 10^{-6}$. The extrapolation to the full kinematic space, using a specific model, is found to be $(3.45 \pm 0.17) \times 10^{-6}$, in agreement with chiral perturbation theory predictions

First observation and study of the K±→π0π0μ±νK^{\pm} \rightarrow \pi^{0} \pi^{0} \mu^{\pm} \nu decay

International audienceThe NA48/2 experiment at CERN reports the first observation of the K$^{±}$ → π$^{0}$π$^{0}$μ$^{±}$ν decay based on a sample of 2437 candidates with 15% background contamination collected in 2003–2004. The decay branching ratio in the kinematic region of the squared dilepton mass above 0.03 GeV$^{2}$/c$^{4}$ is measured to be (0.65 ± 0.03) × 10$^{−6}$. The extrapolation to the full kinematic space, using a specific model, is found to be (3.45 ± 0.16) × 10$^{−6}$, in agreement with chiral perturbation theory predictions