Acid sphingomyelinase (aSMase) is involved in the generation of metabolites that function as part of the sphingolipid signaling pathway. It catalyzes the breakdown of sphingomyelin into ceramide, a ...bioactive lipid that, among other roles, is involved in regulation of apoptosis. Dry drop blood test (DBS) and colorimetric 2-step enzymatic assay were used to assess the activity of human blood aSMase, beta-galactosidase, and beta-glucosidase, these enzymes are lysosomal hydrolases that catalyze the degradation of related sphingolipids, of sphingolipid signaling molecules. Blood was collected from a group of healthy volunteers and patients that were diagnosed with multiple myeloma (MM) in various stages of the disease. Additionally, activity of those enzymes in patients diagnosed with other hematological cancers was also assessed. We found that aSMase activity in the blood of patients with MM (at the time of diagnosis) was 305.43 pmol/spot*20 h, and this value was significantly lower (
< 0.030) compared to the healthy group 441.88 pmol/spot*20 h. Our collected data suggest a possible role of aSMase in pathogenesis of MM development.
Failure to comply with treatment recommendations is very common in patients, but still poorly recognised by doctors. The current practice of using oral therapy on a large scale has been increasingly ...adopted for cancer patients. Chronic myeloid leukaemia (CML) is just such an example, where the introduction of taking new oral medications, the tyrosine kinase BCR-ABL inhibitors (TKI), has now revolutionised the treatment. The aim of our study was to assess treatment adherence in a group of Polish CML patients (a survey was conducted on 140 patient aged ≥18 years) treated with oral TKI (imatinib, dasatinib and nilotinib) taking into account the following variables: gender, age, education, place of residence, family circumstances and duration of therapy. In addition, we evaluated whether there is a relationship between how patients perceive their level of adherence to treatment recommendations with how subjectively the required dosage regimen was followed. Half the patients admitted to skipping at least one drug dose during the entire course of treatment and 39% did so within their last treatment month. Patients were also found to overestimate their own adherence assessment; around 60% of those missing at least 1 drug dose within the last treatment month believed they ‘always’ followed recommendations. The study demonstrated that adherence deteriorates over time. Furthermore, patients aged >65 years and patients suffering at least one comorbid disease had better adherence (
p
< 0.011). There were no differences in adherence among patients treated with imatinib, dasatinib and nilotinib (
p
= 0.249).
Inhibition of spleen tyrosine kinase (SYK) in tonic B-cell receptor (BCR) signal-dependent diffuse large B-cell lymphomas (DLBCLs) inhibits cellular proliferation, decreases cholesterol biosynthesis, ...and triggers apoptosis, at least in part via a mechanism involving decreased activity of phosphatidylinositol 3-kinase/AKT axis. Because forkhead box O1 (FOXO1) is a major effector of this pathway, we investigated the role of FOXO1 in toxicity of BCR pathway inhibition. Inhibition of SYK in DLBCL cells with tonic BCR signaling decreased phospho-AKT and phospho-FOXO1 levels and triggered FOXO1-driven gene expression. Introduction of constitutively active FOXO1 mutant triggered cell cycle arrest and apoptosis, indicating that increased FOXO1 activity is toxic to these DLBCL cells. Depletion of FOXO1 with short hairpin RNA led to almost complete resistance to chemical SYK inhibitor R406, demonstrating that FOXO1 is also required for R406-induced cell death. FOXO1 in these cells is also involved in regulation of expression of the critical master regulator of cholesterol biosynthesis, SREBP1. Because HRK is the key effector of SYK inhibition, we characterized a mechanism linking FOXO1 activation and HRK induction that involves caspase-dependent cleavage of HRK's transcriptional repressor DREAM. Because AKT in lymphoma cells can be regulated by other signals than BCR, we assessed the combined effects of the AKT inhibitor MK-2206 with R406 and found markedly synergistic FOXO1-dependent toxicity. In primary DLBCLs, FOXO1 expression was present in 80% of tumors, correlated with SYK activity, and was associated with longer overall survival. These results demonstrate that FOXO1 is required for SYK and AKT inhibitor-induced toxicity.
•In tonic BCR signal-dependent DLBCLs, FOXO1 is required for SYK and AKT inhibitor-induced toxicity.
The purine nucleoside analogs (PNA) form an important group of cytotoxic drugs active in the treatment of neoplastic and autoimmune diseases. Three of them, fludarabine (FA), cladribine (2- ...chlorodeoxyadenosine, 2-CdA) and pentostatin (2-deoxycoformycin, DCF) have established clinical activity in hematological malignancies and have been approved by FDA. These drugs are also investigated in some autoimmune diosorders. Recently four novel PNA: clofarabine (CAFdA), nelarabine, immucillin H (BCX-1777, forodesine) and 8-chloroadenosine (8-Cl-Ado) have been synthesized and introduced into clinical trials. All these drugs have chemical structure similar to adenosine or guanosine, however, the mechanism of their action is different. FA, 2-CdA and CAFdA mainly require phosphorylation by deoxynucleoside salvage pathways. The cytotoxic effect exerts the triphosphate metabolites, which are incorporated into DNA, and finally lead to programmed cell death. In contrast, DCF does not need to be phosphorylated and results in an increase of plasma deoxyadenosine (dAdo) levels and intracellular deoxyadenosine triphosphate (dATP). Nelarabine is an arabinosylguanine (ara-G) prodrug, which after conversion to ara-G is phosphorylated to ara-G triphosphate (ara-GTP). Accumulation of ara-GTP finally leads to apoptosis. Forodesine is a purine nucleoside phosphatase (PNP) inhibitor which blocks intracellular deoxyguanine (dGuo) cleaving to guanine (Guo), but instead converts it to deoxyguanosine triphosphate (dGTP), and similarly to other PNA resulting in apoptosis. 8-chloroadenosine (8-Cl-Ado) is a ribonucleoside analog. The mechanism of its action is quite different from other PNA and remains poorly understood. However, it is known that the drug inhibits RNA synthesis, but not DNA . These agents have significant cytotoxic activity against lymphoid and myeloid malignant cells. Moreover, they have deleterious effects on the normal resting lymphocytes. They result in prolonged lymphocyte depletion especially in the CD4 subset of T-cells. Several clinical trials have demonstrated that PNA used alone or in combination with other cytotoxic drugs or monoclonal antibodies shows good efficacy and acceptable toxicity profile in the treatment of lymphoid malignancies. 2-CdA and DCF are drugs of choice in the treatment of hairy cell leukemia. FA and 2-CdA have significant clinical activity in low-grade non-Hodgkins lymphoma and chronic lymphocytic leukemia. 2-CdA exhibits some activity in progressive multiple sclerosis and other autoimmune disorders. This review will summarize current knowledge concerning the mechanism of action, pharmacological properties, clinical activity and toxicity of PNA accepted for use in clinical practice as well as new agents available for clinical trials.
Acute myeloid leukemia (AML) in older unfit patients is a therapeutic challenge for clinical hematologists. We evaluated the efficacy and safety of a novel low-intensity regimen consisting of ...low-dose cytarabine and cladribine (LD-AC+cladribine) in first-line treatment of elderly (≥60 years) AML patients not eligible for intensive chemotherapy (IC) who had either the Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 or the hematopoietic cell transplantation comorbidity index (HCT-CI) score ≥3. The induction phase included two cycles of LD-AC+cladribine. Patients who achieved at least partial remission (PR) received maintenance treatment with LD-AC alone. Overall, 117 patients with a median age of 70 years were enrolled. Adverse cytogenetics, ECOG PS ≥2 and HCT-CI score ≥3 was observed in 43.5%, 60%, and 58% of patients, respectively. The response rate (≥PR) was 54% (complete remission CR, 32%; CR with incomplete hematologic recovery CRi, 5%). A median overall survival (OS) was 21 and 8.8 months in CR/CRi and PR group, respectively. Advanced age (≥75 years) and adverse cytogenetics had a negative impact on OS. The 56-day mortality rate was 20.5%. In conclusion, LD-AC+cladribine is a beneficial therapeutic option with a predictable safety profile in elderly AML patients not eligible for IC.
The risk of HBV reactivation is important in lymphoma patients receiving immunosuppressive chemotherapy containing steroids or anti-CD20 antibodies. We aimed to establish the prevalence of HBV Ag and ...anti-HBc serologic positive results in patients with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) in Poland before anti-CD20 therapy initiation; to assess the frequency of insufficient HBV screening; and to assess the association between inadequate HBV screening and diagnosis according to the WHO classification and age or gender.
We retrospectively collected data from 805 patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia treated in 2016-2018.
We found a positive result of HBsAg in 13 (1.16%), and a negative result in 633 (78.64%) patients. The test was not done in 159 (19.75%) patients. In the HBsAg negative subgroup of 633 patients, we found that the anti-HBc was positive in 52 (8.22%), negative in 303 (47.87%) and not done in 278 patients. In 136 out of 805 (16.9%) patients diagnostics tests were not performed before therapy initiation. We found that age is significantly associated (
= 0.0002) with the lack of HBV infection screening, and in CLL this risk is significantly (
= 0.024) higher (by 49%) compared with other WHO diagnosis subgroups.
In Polish lymphoma patients the incidence of positive HBsAg and/or anti-HBc results is consistent with the prevalence in the United States or Australia. The adherence to appropriate HBV screening guidelines in Polish centers is not sufficient. We should intensify educational strategies in the global oncohematologic medical community.
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