Exploring SARS-CoV-2 infection and vaccine-induced immunity in chronic myeloid leukemia patients: insights from real-world data in Brazil and the United States.

This study investigates COVID-19 outcomes and immune response in chronic myeloid leukemia (CML) patients post-SARS-CoV-2 vaccination, comparing effectiveness of various vaccine options. Data from 118 CML patients (85 in Brazil, 33 in the US) showed similar infection rates prior (14% Brazil, 9.1% US) and post-vaccination (24.7% vs. 27.3%, respectively). In Brazil, AstraZeneca and CoronaVac were the most commonly used vaccine brands, while in the US, Moderna and Pfizer-BioNTech vaccines dominated. Despite lower seroconversion in the Brazilian cohort, all five vaccine brands analyzed prevented severe COVID-19. Patients who received mRNA and recombinant viral vector vaccines (HR: 2.20; 95%CI 1.07-4.51; p < .031) and those that had achieved at least major molecular response (HR: 1.51; 95% CI 1.01-3.31; p < .0001) showed higher seroconversion rates. Our findings suggest that CML patients can generate antibody responses regardless of the vaccine brand, thereby mitigating severe COVID-19. This effect is more pronounced in patients with well-controlled disease.

Long-Term Safety and Effectiveness of Rituximab Biosimilar RTXM83: A Retrospective Extension Study in Brazilian Patients with Diffuse Large B-Cell Lymphoma.

INTRODUCTION: RTXM83, a biosimilar of rituximab, was approved after physicochemical, functional, non-clinical, and clinical studies demonstrated their similarity; these studies included RTXM83-AC-01-11, a multicentric double-blind international prospective pivotal study. Long-term data on biosimilars can potentially elucidate their clinical robustness and facilitate their broader adoption. METHODS: In this retrospective observational study, we analyzed a dataset from a Brazilian cohort previously randomized in the RTXM83-AC-01-11 study followed by the assessment of long-term outcomes in an observational extension phase from randomization in the RTXM83-AC-01-11 study to the last recorded evaluation. Patients with diffuse large B cell lymphoma (DLBCL) received either reference rituximab (R) or RTXM83 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as adjuvant treatment. RESULTS: The median follow-up period was 77.0 months. Patients with initial DLBCL stages III and IV comprised 50% of the R-CHOP group and 40% of the biosimilar group. Five (18.5%) patients, including two RTXM83-CHOP-treated and three R-CHOP-treated individuals, experienced late adverse events (AEs) of interest. No new safety signs were established. At the final assessment, the progression-free survival (PFS) rates were 93.3% and 50.0% in the RTXM83-CHOP and R-CHOP groups, respectively. Median PFS was not achieved in the RTXM83-CHOP group, which was 40.5 months in the R-CHOP group. The overall survival (OS) rates were 100% and 66.7% in the RTXM83-CHOP and R-CHOP groups, respectively. The median OS was not reached in any group. CONCLUSION: This study demonstrated the long-term safety and effectiveness of RTXM83 in treating DLBCL; outcomes comparable to those of the reference product and potentially improved access to treatment have been indicated. However, further research with more diverse patient groups can validate these findings and advocate the broader adoption of biosimilars in cancer care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04928573. June 16, 2021, "retrospectively registered".

Production of dendritic cell vaccines using different methods with equivalent results: Implications for emerging centers

Introduction Dendritic cell (DC) vaccines have demonstrated good efficacy in preventing relapse and in increasing survival of patients affected by a variety of both solid and hematological tumors. Most protocols used to generate these cells involve the automated separation of peripheral blood monocytes from patients. This approach requires specialized equipment, which elevates the cost of this type of therapy, potentially limiting the widespread access to patients. Method: In this study, we compare the yield and quality of dendritic cells generated from monocytes and isolated by an automated method or by manual methods using gradient centrifugation. Results The results demonstrate the equivalence of the 3 methods in relation to the yield and final quality of the product, however with considerable differences between the costs of these procedures. In addition, this study also demonstrates the feasibility of the antigenic pulse with autologous tumor cell lysates, constituting a source of antigens, not only easily obtained and manipulated, but also specific to the patient's tumor. Conclusion These findings may have important implications for emerging centers interested in using this medical approach and potentially increase the access of a greater number of patients to this therapeutic option.

Head-to-head comparison of [68Ga]Ga-PSMA-11 and [18F]FDG PET/CT in multiple myeloma.

PURPOSE: The aim of this study was to compare [18F]FDG and [68Ga]Ga-PSMA-11 PET/CT image findings in patients with multiple myeloma (MM). METHODS: Twenty consecutive patients with symptomatic biopsy-proven MM were submitted to whole body [18F]FDG and [68Ga]Ga-PSMA-11 PET/CT with a time interval of 1-8 days between procedures. All lesions were counted and had their maximum SUV (SUVmax) measured. Intra-class correlation (ICC) was used to assess the agreement between [18F]FDG and [68Ga]Ga-PSMA-11 PET/CT findings. RESULTS: A total of 266 lesions were detected in 19/20 patients. [18F]FDG detected 223/266 (84%) lesions in 17 patients and [68Ga]Ga-PSMA-11 190/266 (71%) lesions in 19 patients. Both procedures did not identify any active lesion in 1 patient. Forty-three (16%) lesions were detected only by [68Ga]Ga-PSMA-11 and 76 (29%) only by [18F]FDG. Both tracers identified 147 (55%) lesions. Intralesional mismatch of FDG-PSMA uptake was identified in 25 of these 147 lesions, found in 8 different patients. Different lesions with uptake of only [18F]FDG or [68Ga]Ga-PSMA-11 in the same patient were found in 4 patients. The highest SUVmax of [18F]FDG and [68Ga]Ga-PSMA-11 had a median (min-max) SUVmax of 6.5 (2.0-37.8) and 5.5 (1.7-51.3), respectively. [18F]FDG and [68Ga]Ga-PSMA-11 respectively identified 18 and 19 soft tissue lesions. False-positive [18F]FDG findings had minimal or no uptake of [68Ga]Ga-PSMA-11. Good reliability (ICC ≥ 0.75) was found for number of lesions, number of soft tissue lesions and highest SUVmax in each patient. CONCLUSION: [18F]FDG or [68Ga]Ga-PSMA-11 alone can detect most MM lesions. Almost half of the lesions take up only one of the tracers, reflecting increased glycolysis or angiogenesis in specific lesions, and suggesting their possible complementary role in MM. The marked [68Ga]Ga-PSMA-11 uptake in some cases raises the possibility of a theranostic approach in selected patients.

Production of dendritic cell vaccines using different methods with equivalent results: Implications for emerging centers.

INTRODUCTION: Dendritic cell (DC) vaccines have demonstrated good efficacy in preventing relapse and in increasing survival of patients affected by a variety of both solid and hematological tumors. Most protocols used to generate these cells involve the automated separation of peripheral blood monocytes from patients. This approach requires specialized equipment, which elevates the cost of this type of therapy, potentially limiting the widespread access to patients. METHOD: In this study, we compare the yield and quality of dendritic cells generated from monocytes and isolated by an automated method or by manual methods using gradient centrifugation. RESULTS: The results demonstrate the equivalence of the 3 methods in relation to the yield and final quality of the product, however with considerable differences between the costs of these procedures. In addition, this study also demonstrates the feasibility of the antigenic pulse with autologous tumor cell lysates, constituting a source of antigens, not only easily obtained and manipulated, but also specific to the patient's tumor. CONCLUSION: These findings may have important implications for emerging centers interested in using this medical approach and potentially increase the access of a greater number of patients to this therapeutic option.

Novel inhibitor of hematopoietic cell kinase as a potential therapeutic agent for acute myeloid leukemia.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are characterized by risk of relapses, poor survival, unwanted side effects and high toxicity with the current therapies. In light of these facts, there are efforts to develop new drugs specific for deregulated molecules that participate in leukemia pathogenesis. Hematopoietic cell kinase (HCK), an Src kinase family member, is overexpressed on hematopoietic stem cells of MDS and de novo AML patients and involved in the oncogenic process. Thus, we investigated in vitro, ex vivo and in vivo effects of a novel chemical compound targeting HCK inhibition (iHCK-37), in combination with the most used drugs for the treatment of MDS and de novo AML, 5-Azacytidine and Cytarabine. Herein, the combination treatment with iHCK-37 and 5-Azacytidine or Cytarabine demonstrated additive effects against leukemia cells, compared to either drug alone. iHCK-37 plus 5-Azacytidine or Cytarabine treatment was able to reduce the activation of oncogenic pathways, MAPK/ERK and PI3K/AKT, leading to reduction of ERK and AKT phosphorylation, and increased BAX and decreased BCL-XL protein expression. Moreover, treatment with iHCK-37 reduced MDS and AML CD34-positive cell numbers inside a 3D-structure but did not affect normal CD34-positive cell numbers. In vivo analysis showed that leukemic mice treated with iHCK-37 had reduced ERK and AKT proteins phosphorylation levels and leukocyte numbers. In conclusion, the iHCK-37 inhibitor has anti-neoplastic activity in leukemia cells without altering apoptosis and survival rate of normal cells, suggesting on-target malignant cell killing activity as a single agent or in combination with 5-Azacytidine or Cytarabine.

Intensity of bone involvement: a quantitative 18F-FDG PET/CT evaluation for monitoring outcome of multiple myeloma.

PURPOSE: The parameter intensity of bone involvement (IBI) was recently proposed to quantitatively assess patients with multiple myeloma using 18F-fluorodeoxyglucose-PET combined with computed tomography (18F-FDG PET/CT) images. Here, we aimed to calculate IBI variation (ΔIBI) between two consecutive PET/CT of the same patient and verified its relationship with a subjective visual analysis of the images and with clinical outcome. METHODS: Consecutive whole-body 18F-FDG PET/CT performed to assess the outcomes of 29 patients diagnosed with multiple myeloma were retrospectively evaluated. ΔIBI was calculated after bone segmentation, using liver standardized uptake value as a threshold to determine metabolically active volumes in the skeleton. For each pair of consecutive PET/CTs, two nuclear medicine physicians classified visually the most recent image as PET-remission, PET-progression or PET-stable when compared to the previous examination. RESULTS: The lowest ΔIBI was -1.27 and the highest was 0.29. PET-remission was related to ΔIBI <0 (median = -0.10; -1.27 to +0.03), while PET-progression was related to ΔIBI >0 (median = 0.02; -0.07 to +0.29). ΔIBI around zero was found in images classified as PET-stable (median = 0.00; -0.08 to +0.06). Significant difference in ΔIBI was found between the three groups. Multivariate stepwise analysis showed that IBI value at diagnostic PET/CT, serum calcium and percentage of plasma cells in the bone marrow are independent prognostic factors. CONCLUSION: Delta IBI provides quantitative data for variations of 18F-FDG uptake in the bone marrow during the follow-up of the patients. In addition, higher IBI values at diagnosis are associated with a higher risk of patient's death.

Hematopoietic Cell Kinase (HCK) Is a Player of the Crosstalk Between Hematopoietic Cells and Bone Marrow Niche Through CXCL12/CXCR4 Axis.

The crosstalk between hematopoietic stem/progenitor cells (HSC), both normal and leukemic, and their neighboring bone marrow (BM) microenvironment (niche) creates a reciprocal dependency, a master regulator of biological process, and chemotherapy resistance. In acute myeloid leukemia (AML), leukemic stem/progenitor cells (LSC) anchored in the protective BM microenvironment, reprogram and transform this niche into a leukemia-supporting and chemoprotective environment. One most important player involved in this crosstalk are CXCL12, produced by the BM mesenchymal stromal cells, and its receptor CXCR4, present onto HSC. The downstream molecular mechanisms involved in CXCL12/CXCR4 axis have many targets, including the Src family members of non-receptor tyrosine kinase (SFK). We herein study the role of one SFK member, the Hematopoietic Cell Kinase (HCK), in CXCL12/CXCR4 pathway and its contribution to the AML pathogenesis. We verified that the inhibition of HCK severely impaired CXCL12-induced migration of leukemic cell lines and CD34 positive cells from AML patients bone marrow, through a disruption of the activation of CXCL12/CXCR4/PI3K/AKT and CXCL12/CXCR4/MAPK/ERK signaling, and by a decreased cytoskeleton dynamic through a lower rate of actin polymerization. We provide new insights into the key role of HCK in conferring a migratory advantage to leukemic cells thought CXCL12/CXCR4 axis. HCK represents an important protein of the main pathway involved in the crosstalk between HSC, and their surrounding milieu. Thus, HCK inhibition could represent a novel approach for the treatment of the acute myeloid leukemia.

Obesity as a Possible Risk Factor for Progression from Monoclonal Gammopathy of Undetermined Significance Progression into Multiple Myeloma: Could Myeloma Be Prevented with Metformin Treatment?

Obesity is increasingly associated with the transformation of monoclonal gammopathy of undetermined significance (MGUS) into multiple myeloma (MM). Obesity, MGUS, and MM share common etiopathogenesis mechanisms including altered insulin axis and the action of inflammatory cytokines. Consistent with this interconnection, metformin could predominantly exert inhibition of these pathophysiological factors and thus be an attractive therapeutic option for MGUS. Despite the possible clinical significance, only a limited number of epidemiological studies have focused on obesity as a risk factor for MGUS and MM. This review describes multiple biological pathways modulated by metformin at the cellular level and their possible impacts on the biology of MGUS and its progression into MM.

Adipose tissue radiodensity: A new prognostic biomarker in people with multiple myeloma.

OBJECTIVES: Standard prognostic markers based on individual characteristics of individuals with multiple myeloma (MM) remain scarce. Body-composition features have often been associated with survival outcomes in different cancers. However, the association of adipose tissue radiodensity with MM prognosis has not yet, to our knowledge, been explored. METHODS: Computed tomography at the third lumbar vertebra was used for body-composition analysis, including adipose tissue radiodensity, in 91 people with MM. Additionally, fludeoxyglucose F 18 (18F-FDG) positron emission tomography was used to assess adipose tissue 18F-FDG uptake. Proinflammatory cytokine and adipokine levels were measured. RESULTS: Event-free survival and overall survival were both shorter in participants with high subcutaneous adipose tissue (SAT) radiodensity. Those in the highest SAT radiodensity tertile had an independently higher risk for both overall survival (hazard ratio, 4.55; 95% confidence interval, 1.26-16.44; Ptrend = 0.036) and event-free survival (hazard ratio, 3.08; 95% confidence interval, 1.02-9.27; Ptrend = 0.035). Importantly, higher SAT radiodensity was significantly correlated with increased 18F-FDG adipose tissue uptake and proinflammatory cytokine (tumor necrosis factor and interleukin-6) levels, and with decreased leptin levels. CONCLUSIONS: SAT radiodensity may serve as a biomarker to predict host-related metabolic and proinflammatory milieu, which ultimately correlates with MM prognosis.

Visceral adipose tissue glucose uptake is linked to prognosis in multiple myeloma patients: An exploratory study.

BACKGROUND & AIMS: The use of computerized tomography to opportunistically assess body composition has highlighted abnormalities such as low muscle mass and high adiposity may be hidden conditions in cancer patients. However, the role of skeletal muscle (SM), subcutaneous (SAT) and visceral (VAT) adipose tissue glucose uptake measured by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-CT on patient prognostication is unclear. METHODS: Patients with multiple myeloma (MM) with satisfactory image frame for assessing body composition and for semi-quantification of SM, SAT and VAT glucose uptakes were included. Plasmatic pro-inflammatory cytokine and adipokine levels were measured. RESULTS: High VAT mean standardized uptake value (SUV) at baseline was associated with shorter event-free survival (EFS) (hazard ratio [HR]: 7.89; 95% confidence interval [CI], 1.58-39.30; P = 0.012) and overall survival (OS) (HR, 15.24; 95% CI, 2.69-86.30; P = 0.002) among patients with newly diagnosed MM, even after adjustment for covariates. The highest tertile of VAT SUV was significantly correlated with worse MM-EFS (HR for the highest vs the lowest tertile 3.71; 95% CI, 1.22-10.56; Ptrend = 0.035) and mortality (HR, 4.41; 95% CI, 1.28-12.77; Ptrend = 0.019). Notably, patients with higher VAT SUV presented with lower VAT area, VAT index, higher SAT SUV, and higher number of individuals with visceral obesity (all P < 0.01). Additionally, we found a negative correlation between VAT mean SUV with leptin (R2 = 0.20, P = 0.003); no correlations were detected between VAT mean SUV and resistin, tumor necrosis factor (TNF) or interleukin (IL)-6. CONCLUSIONS: Functional VAT activity estimated by 18F-FDG PET-CT is a relevant prognostic factor in MM patients, specifically, a higher VAT SUV might be an early biomarker of cancer cachexia in these patients.

99mTc-sestamibi SPECT/CT and 18F-FDG-PET/CT have similar performance but different imaging patterns in newly diagnosed multiple myeloma.

PURPOSE: F-fluorodeoxiglucose (F-FDG)-PET/CT has been widely used to evaluate multiple myeloma. Tc-sestamibi (MIBI) scintigraphy has also been proposed for assessing multiple myeloma, but its use with state-of-the-art single-photon emission computed tomography/computed tomography (SPECT/CT) technology has not been fully evaluated.This study aimed to compare these two imaging modalities in multiple myeloma staging. MATERIALS AND METHODS: Sixty-two patients with recently diagnosed multiple myeloma were submitted to whole-body F-FDG-PET/CT and whole-body MIBI scans plus SPECT/CT of the chest and abdomen/pelvis. Number of focal lesions, contiguous soft tissue involvement (CSTI), extramedullary lesions (EMLs) and diffuse bone marrow (BM) involvement were recorded. RESULTS: PET/CT was positive in 59 patients (95%) and MIBI SPECT/CT in 58 (93%) (P = 0.69). MIBI detected more diffuse bone marrow involvement than PET/CT (respectively 78 vs. 58% of the patients), while PET/CT demonstrated more focal lesions than MIBI SPECT/CT (81 vs. 54% of the patients) (P = 0.002). PET/CT detected EMLs in four subjects and MIBI in one subject. CSTI was found in 28 (45%) and 23 (37%) patients on PET/CT and MIBI images, respectively (P = 0.36). Three patients with lytic lesions and no FDG uptake were MIBI positive, and two subjects with lytic lesions without MIBI uptake were FDG positive. CONCLUSION: MIBI SPECT/CT performs similarly to F-FDG-PET/CT in identifying sites of active disease in multiple myeloma staging. MIBI is more efficient than FDG for detecting the diffuse involvement of bone marrow but less efficient for detecting focal lesions. Some patients presented a 'mismatch' pattern of FDG/MIBI uptake.

Computed tomography-based skeletal segmentation for quantitative PET metrics of bone involvement in multiple myeloma.

PURPOSE: Quantifications in nuclear medicine are occasionally limited by the lack of standardization for defining volumes of interest (VOIs) on functional images. In the present article, we propose the use of computed tomography (CT)-based skeletal segmentation to determine anatomically the VOI in order to calculate quantitative parameters of fluorine 18 fluorodeoxyglucose (F-FDG) PET/CT images from patients with multiple myeloma. METHODS: We evaluated 101 whole-body F-FDG PET/CTs of 58 patients with multiple myeloma. An initial subjective visual analysis of the PET images was used to classify the bone involvement as negative/mild, moderate, or marked. Then, a fully automated CT-based segmentation of the skeleton was performed on PET images. The maximum, mean, and SD of the standardized uptake values (SUVmax, SUVmean, and SDSUV) were calculated for bone tissue and compared with the visual analysis. RESULTS: Forty-five (44.5%), 32 (31.7%), and 24 (23.8%) PET images were, respectively, classified as negative/mild, moderate, or marked bone involvement. All quantitative parameters were significantly related to the visual assessment of bone involvement. This association was stronger for the SUVmean [odds ratio (OR): 10.52 (95% confidence interval (CI), 5.68-19.48); P < 0.0001] and for the SDSUV [OR: 5.58 (95% CI, 3.31-9.42); P < 0.001) than for the SUVmax [OR: 1.01 (95% CI, 1.003-1.022); P = 0.003]. CONCLUSION: CT-based skeletal segmentation allows for automated and therefore reproducible calculation of PET quantitative parameters of bone involvement in patients with multiple myeloma. Using this method, the SUVmean and its respective SD correlated better with the visual analysis of F-FDG PET images than SUVmax. Its value in staging and evaluating therapy response needs to be evaluated.

Proposal for a Quantitative 18F-FDG PET/CT Metabolic Parameter to Assess the Intensity of Bone Involvement in Multiple Myeloma.

Many efforts have been made to standardize the interpretation of 18F-FDG PET/CT in multiple myeloma (MM) with qualitative visual analysis or with quantitative metabolic parameters using various methods for lesion segmentation of PET images. The aim of this study was to propose a quantitative method for bone and bone marrow evaluation of 18F-FDG PET/CT considering the extent and intensity of bone 18F-FDG uptake: Intensity of Bone Involvement (IBI). Whole body 18F-FDG PET/CT of 59 consecutive MM patients were evaluated. Compact bone tissue was segmented in PET images using a global threshold for HU of the registered CT image. A whole skeleton mask was created and the percentage of its volume with 18F-FDG uptake above hepatic uptake was calculated (Percentage of Bone Involvement - PBI). IBI was defined by multiplying PBI by mean SUV above hepatic uptake. IBI was compared with visual analysis performed by two experienced nuclear medicine physicians. IBI calculation was feasible in all images (range:0.00-1.35). Visual analysis categorized PET exams into three groups (negative/mild, moderate and marked bone involvement), that had different ranges of IBI (multi comparison analysis, p < 0.0001). There was an inverse correlation between the patients' hemoglobin values and IBI (r = -0.248;p = 0.02). IBI score is an objective measure of bone and bone marrow involvement in MM, allowing the categorization of patients in different degrees of aggressiveness of the bone disease. The next step is to validate IBI in a larger group of patients, before and after treatment and in a multicentre setting.

BRD4 Inhibition Enhances Azacitidine Efficacy in Acute Myeloid Leukemia and Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell-based disorders characterized by ineffective hematopoiesis, increased genomic instability and a tendency to progress toward acute myeloid leukemia (AML). MDS and AML cells present genetic and epigenetic abnormalities and, due to the heterogeneity of these molecular alterations, the current treatment options remain unsatisfactory. Hypomethylating agents (HMA), especially azacitidine, are the mainstay of treatment for high-risk MDS patients and HMA are used in treating elderly AML. The aim of this study was to investigate the potential role of the epigenetic reader bromodomain-containing protein-4 (BRD4) in MDS and AML patients. We identified the upregulation of the short variant BRD4 in MDS and AML patients, which was associated with a worse outcome of MDS. Furthermore, the inhibition of BRD4 in vitro with JQ1 or shRNA induced leukemia cell apoptosis, especially when combined to azacitidine, and triggered the activation of the DNA damage response pathway. JQ1 and AZD6738 (a specific ATR inhibitor) also synergized to induce apoptosis in leukemia cells. Our results indicate that the BRD4-dependent transcriptional program is a defective pathway in MDS and AML pathogenesis and its inhibition induces apoptosis of leukemia cells, which is enhanced in combination with HMA or an ATR inhibitor.

Up-regulation of SPINT2/HAI-2 by Azacytidine in bone marrow mesenchymal stromal cells affects leukemic stem cell survival and adhesion.

The role of tumour microenvironment in neoplasm initiation and malignant evolution has been increasingly recognized. However, the bone marrow mesenchymal stromal cell (BMMSC) contribution to disease progression remains poorly explored. We previously reported that the expression of serine protease inhibitor kunitz-type2 (SPINT2/HAI-2), an inhibitor of hepatocyte growth factor (HGF) activation, is significantly lower in BMMSC from myelodysplastic syndromes (MDS) patients compared to healthy donors (HD). Thus, to investigate whether this loss of expression was due to SPINT2/HAI-2 methylation, BMMSC from MDS and de novo acute myeloid leukaemia (de novo AML) patients were treated with 5-Azacitidine (Aza), a DNA methyltransferase inhibitor. In MDS- and de novo AML-BMMSC, Aza treatment resulted in a pronounced SPINT2/HAI-2 levels up-regulation. Moreover, Aza treatment of HD-BMMSC did not improve SPINT2/HAI-2 levels. To understand the role of SPINT2/HAI-2 down-regulation in BMMSC physiology, SPINT2/HAI-2 expression was inhibited by lentivirus. SPINT2 underexpression resulted in an increased production of HGF by HS-5 stromal cells and improved survival of CD34+ de novo AML cells. We also observed an increased adhesion of de novo AML hematopoietic cells to SPINT2/HAI-2 silenced cells. Interestingly, BMMSC isolated from MDS and de novo AML patients had increased expression of the integrins CD49b, CD49d, and CD49e. Thus, SPINT2/HAI-2 may contribute to functional and morphological abnormalities of the microenvironment niche and to stem/progenitor cancer cell progression. Hence, down-regulation in SPINT2/HAI-2 gene expression, due to methylation in MDS-BMMSC and de novo AML-BMMSC, provides novel insights into the pathogenic role of the leukemic bone marrow microenvironment.

Metformin and blood cancers.

Type 2 diabetes mellitus and cancer are correlated with changes in insulin signaling, a pathway that is frequently upregulated in neoplastic tissue but impaired in tissues that are classically targeted by insulin in type 2 diabetes mellitus. Many antidiabetes treatments, particularly metformin, enhance insulin signaling, but this pathway can be inhibited by specific cancer treatments. The modulation of cancer growth by metformin and of insulin sensitivity by anticancer drugs is so common that this phenomenon is being studied in hundreds of clinical trials on cancer. Many meta-analyses have consistently shown a moderate but direct effect of body mass index on the incidence of multiple myeloma and lymphoma and the elevated risk of leukemia in adults. Moreover, new epidemiological and preclinical studies indicate metformin as a therapeutic agent in patients with leukemia, lymphomas, and multiple myeloma. In this article, we review current findings on the anticancer activities of metformin and the underlying mechanisms from preclinical and ongoing studies in hematologic malignancies.

Lithium, a classic drug in psychiatry, improves nilotinib-mediated antileukemic effects.

Although Tyrosine kinase inhibitors (TKIs) that target Bcr-Abl play a key role in Chronic Myeloid Leukemia (CML) therapy, they do not eradicate CML-initiating cells, which lead to the emergence of drug resistance. Here we used the lithium, a GSK-3 inhibitor, to attempt to potentiate the effects of nilotinib against leukemia cells. For this purpose, a K562 leukemia cell line and bone marrow cells from untreated Chronic Myeloid Leukemia (CML) patients, prior to any exposure to TKIs, were used as a model. Our results demonstrated that the combination of lithium + nilotinib (L + N) induced K562-cell death and cleaved caspase-3 when compared to lithium or nilotinib alone, accompanied by GSK-3ß phosphorylation and Bcr-Abl oncoprotein levels reduction. Interestingly, these events were related to autophagy induction, expressed by increased LC3II protein levels in the group treated with L + N. Furthermore, the clonogenic capacity of progenitor cells from CML patients was drastically reduced by L + N, as well as lithium and nilotinib when used separately. The number of cell aggregates (clusters), were increased by all treatments (L + N, lithium, and nilotinib). This pioneering research has demonstrated that lithium might be of therapeutic value when targeting Bcr-Abl cells with nilotinib because it triggers cell death in addition to exerting classical antiproliferative effects, opening new perspectives for novel target and therapeutic approaches to eradicate CML.

Metformin and blood cancers

Type 2 diabetes mellitus and cancer are correlated with changes in insulin signaling, a pathway that is frequently upregulated in neoplastic tissue but impaired in tissues that are classically targeted by insulin in type 2 diabetes mellitus. Many antidiabetes treatments, particularly metformin, enhance insulin signaling, but this pathway can be inhibited by specific cancer treatments. The modulation of cancer growth by metformin and of insulin sensitivity by anticancer drugs is so common that this phenomenon is being studied in hundreds of clinical trials on cancer. Many meta-analyses have consistently shown a moderate but direct effect of body mass index on the incidence of multiple myeloma and lymphoma and the elevated risk of leukemia in adults. Moreover, new epidemiological and preclinical studies indicate metformin as a therapeutic agent in patients with leukemia, lymphomas, and multiple myeloma. In this article, we review current findings on the anticancer activities of metformin and the underlying mechanisms from preclinical and ongoing studies in hematologic malignancies.