Acute myeloid leukemia in the elderly people

The majority of patients with acute myeloid leukemia are elderly. The introduction of new more aggressive treatment regimens with allogeneic stem cell transplantation have resulted in improvement in clinical outcome of younger AML patients, but analogous improvement in older patients has not been realized. There is evidence that AML in elderly represents a biologically distinct disease that is more aggressive and less responsive to chemotherapy. The important task is to use prognostic factors and predictive modeling to distinguish patients who will benefit from intensive remission-induction approaches and allogeneic transplantation and others who should be managed with less aggressive strategies or novel agents

Characterization and prognostic factors of secondary to MDS/MPN and therapy-related AML: a single-center study

Introduction: Secondary acute myeloid leukemia (sAML) accounts for 15–30% of overall AML cases and is associated with shorter survival compared to de novo AML. The pathogenetic spectrum of sAML is heterogeneous, i.e. therapy-related AML (tAML) arises from prior cytotoxic, radiation, or immunosuppressive therapy, while myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN)-AML develops from a previous clonal disorder of hematopoiesis. Material and methods: We performed a single-center retrospective analysis of MDS/MPN-AML and tAML patients diagnosed between 2013 and 2018 in the Hematology Department of the Medical University in Lodz, Poland. Simultaneously, demographic data, clinical factors, and laboratory findings were collected. For statistical analysis, we used Cox proportional hazard models and log-rank tests. Results: The study included 110 patients with either MDS/MPN-AML (n = 78) or tAML (n = 32), with a median age of 66 years (range 31–86). The median follow-up was 3.2 months [95% confidence interval (CI): 2.5–5.3]. The median overall survival (OS) for MDS/MPN-AML patients was 4.1 months (95% CI: 2.5–7.0) and for tAML it was 2.8 months (95% CI: 1.6-5.6). In multivariate Cox regression model for OS, factors such as age at diagnosis [hazard ratio (HR) 1.03, 95% CI: 1.00–1.06], higher Eastern Cooperative Oncology Group score (HR 1.85, 95% CI: 1.08–3.15), hypoalbuminemia (HR 3.20, 95% CI: 1.95–5.24) and percentage of bone marrow blasts infiltration (HR 1.01, 95% CI: 1.00–1.03) were independent predictors of poor survival for the whole cohort. On the other hand, the intensive treatment approach was related to longer survival (HR 0.42, 95% CI: 0.21–0.82). There were no differences in OS between MDS/MPN-AML and tAML (p = 0.81). Conclusion: The poor treatment outcomes for sAML consist of a combination of low response rate and high early mortality. The positive influence of intensive chemotherapy should be highlighted, but nevertheless, optimizing treatment for thishigh-risk subpopulation remains crucial

Wtórna ostra białaczka szpikowa u chorej po skutecznym leczeniu ostrej białaczki promielocytowej

Clonal aberrations, leading to development of therapy-related myelodysplastic syndromes and secondary acute myeloid leukemias (s-AML), are present in 10% of patients treated previously for acute promyelocytic leukemia (APL). Most of them, especially monosomy 7, are associated with extremely poor prognosis. We present a case of 22-years-old female patient with APL diagnosed in 2008 who achieved complete cytogenetic and molecular remission after treatment according to PETHEMA protocol. Two years after the treatment was completed, s-AML with complex monosomal karyotype including monosomy 7 and t(3;21)(q26.2;q22) was diagnosed. Complete cytogenetic remission was achieved after 2 induction cycles and finally the allogeneic hematopoietic stem cell transplantation from HLA-matched related donor was performed. In the posttransplant period moderate chronic graft versus host disease was observed. Now, 15 months after transplantation, the patient is still in complete cytogenetic remission with 100% of donor chimerism. Presented case demonstrates diagnostic and therapeutic dilemma of s-AML in a patient with complete remission of APL.Klonalne aberracje chromosomalne, prowadzące do powstawania zespołów mielodysplastycznych rozwijających się po leczeniu lub wtórnych ostrych białaczek szpikowych (s-AML), występują u około 10% chorych leczonych w przeszłości z powodu ostrej białaczki promielocytowej (APL). Większość z nich, a w szczególności monosomia chromosomu 7, wiąże się z wybitnie niekorzystnym rokowaniem. W pracy przedstawiono przypadek 22-letniej chorej na APL rozpoznaną w 2008 roku, w całkowitej remisji cytogenetycznej i molekularnej po terapii według protokołu PETHEMA, u której 2 lata po zakończeniu leczenia APL rozpoznano s-AML ze złożonym kariotypem monoso­malnym, z obecnością między innymi monosomii chromosomu 7 i translokacji t(3;21)(q26.2;q22). Po 2 cyklach leczenia indukującego uzyskano całkowitą remisję cytogenetyczną i zakwalifikowano chorą do allogenicznego przeszczepienia krwiotwórczych komórek macierzystych od zgodnego dawcy rodzinnego. Okres okołoprzeszczepowy był powikłany przewlekłą chorobą przeszczep przeciw gospo­darzowi w stopniu umiarkowanym. Obecnie, 15 miesięcy po transplantacji, chora nadal pozostaje w całkowitej remisji cytogenetycznej ze 100-procentowym chimeryzmem donorowym. Opisany przypadek ilustruje złożony problem diagnostyczny i terapeutyczny s-APL u chorej w remisji po leczeniu APL

Comparison of prediction models for two different peripheral stem cell collection protocols in autologous patients. How to avoid errors in calculating total blood volume to process?

Introduction: Calculating accurate blood volume to process is a critical practice in apheresis planning; therefore, researchers try to develop dedicated prediction models. In this analysis, we have attempted to compare three algorithms for two different apheresis collection protocols. Methods: In a retrospective study, we have analyzed 137 apheresis procedures performed on 100 autologous patients. Apheresis procedures were performed with the Spectra Optia apheresis device with two protocols: mononuclear cell collection (MNC) and continuous mononuclear cell collection (cMNC). Three algorithms: a model based on mean collection efficiency (CE2), a linear regression model, and a power regression model were validated by plotting collected CD34+ cell dose versus predicted CD34+ cell dose. Results: All models showed high predictability for MNC procedure, a high correlation of predicted CD34+ yield and actual CD34+ yield (R2 = 0.9547; 0.9487; 0.9474 for CE2-based model, linear and power regression model, respectively). In contrast, alteration between models for the cMNC procedure was greater (R2 = 0.8049, 0.7970, and 0.8169) with a higher number of overpredictions. Further analysis revealed that for low CD34+ precounts blood volume to process, calculated with the three models, differ significantly up to fivefold times. Conclusions: Utilizing regression models may lead to calculation errors, which can affect undercollection, repetition of apheresis, or even mobilization failure. Contrary to regression models, the model based on mean CE2 gave the most accurate prediction both for MNC and cMNC procedures. Although new prediction algorithms are created, this simple formula remains a reliable tool that promotes careful planning of apheresis, thus improving patient safety

The role of neuronal apoptosis inhibitory protein (NAIP) in acute myeloid leukemia patients

Acute myeloid leukemia (AML) is a heterogeneous, highly malignant neoplasm. Apoptosis is a complex process executed by caspases and suppressed by the inhibitor of apoptosis (IAP) family. Neuronal apoptosis inhibitory protein (NAIP), IAP’s member, may play an exceptional role in the mechanisms of tumors’ resistance to chemotherapy. The aims of the study were to assess the expression of NAIP in leukemic blasts of AML patients using flow cytometry and to evaluate its influence on disease outcome. NAIP expression was found in 106 out of 108 patients. A higher complete response rate was associated with a low expression of NAIP, age < 60 yo, and white blood cell count < 20 G/L ( = 0.009, = 0.033, and = 0.076, respectively) in univariate analyses and a low NAIP expression and age < 60 yo ( = 0.025 and = 0.013, respectively) in multivariate analyses. Longer overall survival (OS) in the univariate analysis was influenced by a low NAIP expression, age < 60 yo, and intensive chemotherapy ( = 0.033, < 0.001, and < 0.001, respectively). In the intensively treated group, better OS was observed in patients with age < 60 yo, AML, and a low NAIP expression ( = 0.03, = 0.024, and = 0.07, respectively). In multivariate analysis, longer OS was associated with age < 60 yo ( = 0.009) and AML ( = 0.007). In conclusion, we suggest that NAIP might play an adverse role in response to chemotherapy

Rola midostauryny w leczeniu ostrej białaczki szpikowej z towarzyszącą mutacją FLT3

Acute myeloid leukemia (AML) is a highly heterogeneous disease. Mutation with internal tandem duplication of fms-like tyrosine kinase-3 (FLT3-ITD) is one of the two most common driver mu­tations in AML, the presence of which is associated with a poor outcome. Midostaurin (Mido) is a multi-targeted tyrosine kinase inhibitor that potently inhibits kinase FLT3, other kinases including platelet-derived growth factor receptors α (PDGFR-α) and b (PDGFR-β), tyrosine-protein kinase Src, KIT receptor tyrosine kinase, and vascular endothelial growth factor receptor (VEGFR). Mido is the first targeted therapy to demonstrate improved outcome, and as such it represents a game-changer. The RATIFY study demonstrated significant improvements in overall survival, and in event-free survival, when Mido was added to standard chemotherapy in patients with newly diagnosed FLT3-mutated AML. This paper reviews the current clinical evidence regarding Mido and its use in the induction and treatment of relapsed or refractory disease, and maintenance setting.Ostra białaczka szpikowa (AML) jest chorobą wysoce heterogenną. Wewnętrzna tandemowa duplikacja kinazy tyrozynowej 3 podobnej do fms (FLT3-ITD) jest jedną z dwóch najczęstszych mutacji kierujących w AML, której obecność wiąże się ze złym rokowaniem. Midostaurin (Mido) jest nieselektywnym inhibitorem kinaz tyrozynowych, który silnie hamuje kinazę FLT3 oraz inne kinazy w tym m.in. receptory płytkowego czynnika wzrostu α (PDGFR-α) i β (PDGFR-β), kinazę tyrozynowo-białkową Src, kinazę tyrozynową KIT i receptor czynnika wzrostu śródbłonka naczyniowego (VEGFR). Mido jest pierwszym lekiem celowanym, który poprawił wyniki leczenia w AML-FLT3 i zmienił praktykę kliniczną. Badanie RATIFY wykazało, że dołączenie Mido do standardowej chemioterapii wydłuża znamiennie całkowite przeżycie i przeżycie wolne od zdarzeń u chorych z nowo zdiagnozowaną AML z mutacją FLT3. Mido w skojarzeniu z intensywną chemioterapią jest obecnie standardem leczenia w tej grupie chorych. Praca jest przeglądem aktualnych dowodów klinicznych dotyczących midostaurynu i jej zastosowania w leczeniu indukującym, leczeniu nawrotowej/opornej AML oraz w leczeniu podtrzymującym

Assessment of colonization and infection epidemiology in patients undergoing autologous hematopoietic stem cell transplantation: a single-center study

Introduction: Infections are one of the main causes of early death after autologous hematopoietic stem cell transplantation (auto-HSCT). Material and methods: We present a single-center retrospective analysis of colonization and infection epidemiology in 115 patients with median age 63 years (range 21–72), who underwent auto-HSCT in 2017 or 2018 in the course of multiple myeloma [79.1% (n = 91)], Hodgkin lymphoma [18.3% (n = 21)] and non-Hodgkin lymphoma [2.6% (n = 3)]. Results: Colonization was observed in 40.9% of patients before auto-HSCT, the most common location being the urinary tract — 54.3%. Multi-drug resistant bacteria (MDR) accounted for 20.9% of positive colonization cultures before auto-HSCT. In the post-transplantation period, infections occurred in 77.4% of patients after auto-HSCT. Bacteremia was observed in 43.5% of patients and it was mostly caused by methicillin-resistant coagulase-negative Staphylococcus epidermidis (MRCNSE) — 27.6%. Infection of the skin near the central vascular catheter was found in 18.3% of patients, urinary tract infections in 11.3%, and gastrointestinal infections in 20.9%. MDR pathogens accounted for 65.2%. The most common of these was methicillin-resistant coagulase-negative Staphylococcus (MRCNS) — 73.9%. Fungal and viral infections were reported in 21.7% and 7%, respectively. The median duration of empirical and targeted antibiotic therapy was 5 (range 1–20) and 7 (range 4–31) days, respectively. Death due to septic shock occurred in 2/115 (1.7%) patients during the neutropenia period. Conclusions: Evaluation of the epidemiology of colonization and infection in patients undergoing auto-HSCT can be an effective tool in providing control and therapy for infections in HSCT recipients. Such knowledge is also essential in monitoring potential pathogen transmission and helping to improve local infection management standards

Targeting Apoptosis in AML: Where Do We Stand?

More than 97% of patients with acute myeloid leukemia (AML) demonstrate genetic mutations leading to excessive proliferation combined with the evasion of regulated cell death (RCD). The most prominent and well-defined form of RCD is apoptosis, which serves as a defense mechanism against the emergence of cancer cells. Apoptosis is regulated in part by the BCL-2 family of pro- and anti-apoptotic proteins, whose balance can significantly determine cell survival. Apoptosis evasion plays a key role in tumorigenesis and drug resistance, and thus in the development and progression of AML. Research on the structural and biochemical aspects of apoptosis proteins and their regulators offers promise for new classes of targeted therapies and strategies for therapeutic intervention. This review provides a comprehensive overview of current AML treatment options related to the mechanism of apoptosis, particularly its mitochondrial pathway, and other promising concepts such as neddylation. It pays particular attention to clinically-relevant aspects of current and future AML treatment approaches, highlighting the molecular basis of individual therapies