Chronic lymphocytic leukemia treatment based on the results of recent clinical trials

Przewlekła białaczka limfatyczna wiąże się z akumulacją dojrzałych, spoczynkowych komórek limfoidalnych o niskim wskaźniku mitotycznym. Powoduje to stosunkowo niewielką wrażliwość na większość stosowanych klasycznych cytostatyków. Strategie terapeutyczne stosowane w przewlekłej białaczce limfatycznej są zróżnicowane i uzależnione głównie od zaawansowania klinicznego i dynamiki procesu chorobowego. U wielu pacjentów charakteryzujących się niskim stopniem zaawansowania choroby przyjmuje się postawę wyczekującą do czasu progresji. Do leków stosowanych w przypadku progresywnej postaci przewlekłej białaczki limfatycznej należą środki alkilujące, analogi nukleozydów purynowych (PNA), a także przeciwciała monoklonalne przeciw antygenowi CD20 (rituksimab) oraz przeciw antygenowi CD52 (alemtuzumab). W badaniach randomizowanych wykazano, że u pacjentów otrzymujących PNA występuje większy odsetek odpowiedzi na leczenie niż u chorych, u których stosowano leki alkilujące. Za pomocą PNA częściej uzyskuje się również całkowite remisje oraz wydłużenie okresu wolnego od nawrotu choroby. Przeciwciała monoklonalne, zwłaszcza alemtuzumab, są skuteczne u pacjentów z nawrotem przewlekłej białaczki limfatycznej oraz w przypadku oporności na PNA. Rituksimab jest bardziej skuteczny, jeśli jest stosowany łącznie z PNA.Chronic lymphocytic leukemia is characterized by accumulation of mature, resting lymphocytes with low mitotic index. Therapeutic strategies employed in chronic lymphocytic leukemia depend on stage of the disease and its tendency to progression. Patients with stable disease are often observed only for many years without treatment. Chemotherapeutic armamentarium consists of alkylating agents, purine nucleoside analogs and monoclonal antibodies against CD20 antigen (rituximab) and against CD52 (alemtuzumab). Randomized trials have shown higher response rates including complete response rates and prolongation of disease free survival in case of purine nucleoside analogs as compared with alkylating agents. Monoclonal antibodies especially alemtuzumab are highly active in relapsed or refractory to standard treatment cases. Combination of rituximab with PNA enhances its efficacy

Selected factors influencing angiogenesis and hematopoietic niche

Angiogenesis is the vital, multistage process in which new blood vessels are created by sprouting from pre-existing vessels. It takes part in carcinogenesis and contributes to progression, metastases, and dissemination of neoplastic disease. In the bone marrow, angiogenesis influences the hematopoietic stem cells (HSC) proliferation, differentiation, and maintenance of normal hematopoiesis under both physiological and stress conditions. The bone marrow niche contains different types of cells, including macrophages, osteoblasts, mesenchymal stem cells, endothelial progenitors, and endothelial cells. All of these interact and form a unique microenvironment necessary for the appropriate function, and preservation of HSC in the quiescent state, and take a major part in the process of mobilization to peripheral blood and homing after transplantation. Cytokines active in the hematopoietic niche as well as miRNAs regulating hemato- poiesis, and angiogenesis have a significant influence on processes occurring in the bone marrow. The aim of this review was to present selected proteins, and molecules associated with angiogenesis as well as bone marrow niche processes: VEGF, ANGPT1, ANGPT2, MMP-9, SDF-1, miRNA-15a, miRNA-16, miRNA-126, miRNA-146a, and miRNA-223

Niedokrwistość aplastyczna związana z zapaleniem wątroby

W pracy przedstawiono rzadką postać nabytej niedokrwistości aplastycznej (AA), anemię aplastyczną związaną z uszkodzeniem wątroby ( – HAAA). Choroba dotyczy młodych mężczyzn bez wcześniejszego wywiadu chorób przewlekłych. Najczęściej stwierdza się zapalenie wątroby przebiegające ze wzrostem enzymów wątrobowych, zazwyczaj również z hiperbilirubinemią. Po około 2-3 miesiącach od objawów zapalenia wątroby u chorych rozwija się niedokrwistość aplastyczna. U większości z tych pacjentów badania wirusologiczne są negatywne. Podejrzewa się zakażenie wirusami zapalenia wątroby trudnymi do identyfikacji, innymi niż wirusy A, B, C czy G. Efekty leczenia immunosupresyjnego oraz transplantacji komórek macierzystych hematopoezy są porównywalne w HAAA, jak w AA bez cech uszkodzenia wątroby

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 Complement Activating Collectins and Associated Serine Proteases in Patients With Hematological Malignancies, Receiving High-Dose Chemotherapy, and Autologous Hematopoietic Stem Cell Transplantations (Auto-HSCT)

We conducted a prospective study of 312 patients (194 with multiple myeloma, 118 with lymphomas) receiving high-dose conditioning chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT). Polymorphisms of MBL2 and MASP2 genes were investigated and serial measurements of serum concentrations of mannose-binding lectin (MBL), CL-LK collectin and MASP-2 as well as activities of MBL-MASP-1 and MBL-MASP-2 complex were made. Serum samples were taken before conditioning chemotherapy, before HSCT and once weekly after (totally 4-5 samples); in minority of subjects also 1 and/or 3 months post transplantation. The results were compared with data from 267 healthy controls and analyzed in relation to clinical data to explore possible associations with cancer and with chemotherapy-induced medical complications. We found a higher frequency of MBL deficiency-associated genotypes (LXA/O or O/O) among multiple myeloma patients compared with controls. It was however not associated with hospital infections or post-HSCT recovery of leukocytes, but seemed to be associated with the most severe infections during follow-up. Paradoxically, high MBL serum levels were a risk factor for prolonged fever and some infections. The first possible association of MBL2 gene 3′-untranslated region polymorphism with cancer (lymphoma) in Caucasians was noted. Heterozygosity for MASP2 gene +359 A>G mutation was relatively frequent in lymphoma patients who experienced bacteremia during hospital stay. The median concentration of CL-LK was higher in myeloma patients compared with healthy subjects. Chemotherapy induced marked increases in serum MBL and MASP-2 concentrations, prolonged for several weeks and relatively slighter decline in CL-LK level within 1 week. Conflicting findings on the influence of MBL on infections following chemotherapy of myeloma and lymphoma have been reported. Here we found no evidence for an association between MBL deficiency and infection during the short period of neutropenia following conditioning treatment before HSCT. However, we noted a possible protective effect of MBL during follow-up, and suspected that to be fully effective when able to act in combination with phagocytic cells after their recovery

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

SIRT1-SIRT7 Expression in Patients with Lymphoproliferative Disorders Undergoing Hematopoietic Stem Cell Mobilization

Sirtuins are involved in the fate of hematopoietic stem cells (HSCs), including their metabolism, stress response, differentiation, migration, and apoptosis. The aim of this study was to explore SIRT1-7 expression during HSC mobilization. The study included 50 patients with lymphoproliferative disorders (39 multiple myeloma, 11 lymphoma). Samples were taken before mobilization (day 0) and on the day of first apheresis (day A). The sirtuin expression was evaluated by the Droplet Digital PCR (ddPCR) method. A significant increase of the SIRT1, SIRT2, SIRT3, SIRT5, SIRT6, and SIRT7 levels measured at day A as compared to baseline was observed. The study revealed a positive correlation between SIRT5, SIRT6, and SIRT7 expression and the CD34+ peak value in peripheral blood and the number of CD34+ cells collected on day A. Patients from the SIRT7 “high expressors” group collected more CD34+ cells on day A than “low expressors”. Upregulated expressions of SIRT3 and SIRT7 on the day of first apheresis were observed in patients in complete remission status (CR) as compared to the non-CR group. Our results suggest that the investigated sirtuins may influence the HSC migration and hematopoietic landscape during mobilization. SIRT5, SIRT6, and SIRT7 may be associated with the efficacy of HSC mobilization