New Candidates for Biomarkers and Drug Targets of Ischemic Stroke-A First Dynamic LC-MS Human Serum Proteomic Study.

(1) Background: The aim of this dynamic-LC/MS-human-serum-proteomic-study was to identify potential proteins-candidates for biomarkers of acute ischemic stroke, their changes during acute phase of stroke and to define potential novel drug-targets. (2) Methods: A total of 32 patients (29-80 years) with acute ischemic stroke were enrolled to the study. The control group constituted 29 demographically-matched volunteers. Subjects with stroke presented clinical symptoms lasting no longer than 24 h, confirmed by neurological-examination and/or new cerebral ischemia visualized in the CT scans (computed tomography). The analysis of plasma proteome was performed using LC-MS (liquid chromatography-mass spectrometry). (3) Results: Ten proteins with significantly different serum concentrations between groups volunteers were: complement-factor-B, apolipoprotein-A-I, fibronectin, alpha-2-HS-glycoprotein, alpha-1B-glycoprotein, heat-shock-cognate-71kDa protein/heat-shock-related-70kDa-protein-2, thymidine phosphorylase-2, cytoplasmic-tryptophan-tRNA-ligase, ficolin-2, beta-Ala-His-dipeptidase. (4) Conclusions: This is the first dynamic LC-MS study performed on a clinical model which differentiates serum proteome of patients in acute phase of ischemic stroke in time series and compares to control group. Listed proteins should be considered as risk factors, markers of ischemic stroke or potential therapeutic targets. Further clinical validation might define their exact role in differential diagnostics, monitoring the course of the ischemic stroke or specifying them as novel drug targets.

Vemurafenib and Rituximab in Patients with Hairy Cell Leukemia Previously Treated with Moxetumomab Pasudotox.

The purine nucleoside analogues cladribine and pentostatin are highly-active first-line therapeutic treatments for hairy cell leukemia (HCL), resulting in complete response rates of 80% to 90%. However, HCL patients continue to relapse, and sooner or later, most require subsequent lines of treatment. This report presents the cases of four relapsed patients with classic HCL who were treated with vemurafenib (mostly at the low dose of 240 mg twice daily for 16 weeks) combined with rituximab after the failure of several lines of therapy including cladribine with or without rituximab and moxetumomab pasudotox. Two patients achieved minimal residual disease negative complete response after combined treatment with vemurafenib and rituximab, with a hematologic response ongoing after 38 months from the end of treatment in one patient and a relapse of cytopenias occurring after 13 months in the other patient. A third patient normalized her blood counts and this hematologic response, which was not evaluated in the bone marrow at the end of treatment, was lost after 18 months. The last patient died due to infection and multi-organ failure, too early to verify response to vemurafenib. Two patients who had relapsed after vemurafenib and rituximab derived meaningful clinical benefit from retreatment with the same agents, but eventually relapsed again and started indefinite therapy with dabrafenib and trametinib leading to normalization of the blood counts (despite heavy bone marrow infiltration in the only patient so far evaluable in that regard). The outcomes of these cases indicate that novel targeted agents and, in particular, vemurafenib, combined with rituximab, improve the prognosis of HCL patients, even those heavily pretreated with PNAs and moxetumomab pasudotox.

Moxetumomab pasudotox for the treatment of hairy cell leukemia.

Introduction: Cladribine and pentostatin are the drugs of choice in the treatment of hairy cell leukemia (HCL). Recently, immunotoxin moxetumomab pasudotox has been introduced to improve the prognosis in relapsed and refractory HCL. Areas covered: This review discusses the mechanism of action, safety, and efficacy of moxetumomab pasudotox in HCL patients. A literature review of the MEDLINE database for articles in English concerning immunotoxins, moxetumomab pasudotox, and hairy cell leukemia was conducted via PubMed. Publications from 2000 through December 2018 were scrutinized. The search terms used were immunotoxins and moxetumomab pasudotox in conjunction with hairy cell leukemia. Conference proceedings from the previous five years of the American Society of Hematology, European Hematology Association and American Society of Clinical Oncology were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. Results/conclusion: Moxetumomab pasudotox, a novel recombinant anti-CD22 immunotoxin, was well tolerated and active in the previous phase 1 and 3 studies in patients with HCL. The drug has been approved in 2018 by the FDA for the treatment of patients with relapsed/refractory HCL who had at least two prior systemic therapies including at least one purine nucleoside analog. Expert opinion: The use of moxetumomab pasudotox is a promising new strategy for the treatment of HCL.

Influence of the Physical Training on Muscle Function and Walking Distance in Symptomatic Peripheral Arterial Disease in Elderly.

INTRODUCTION: A typical symptom of chronic lower-limb ischaemia is lower-limb pain, which occurs during walking forcing the patient to stop, intermittent claudication (IC). Exercise rehabilitation is the basic form of treatment for these patients. AIM: The aim of this study was to compare the effectiveness of three types of physical training programmes conducted over a 12-week period in patients with chronic lower-limb arterial insufficiency. MATERIALS AND METHODS: Ninety-five people qualified for the 3-month supervised motor rehabilitation programme, conducted three times a week. The respondents were assigned to three types of rehabilitation programmes using a pseudo-randomization method: Group I (TW), subjects undertaking treadmill walking training; Group II (NW), subjects undertaking Nordic walking training; Group III (RES+NW), subjects undertaking resistance and Nordic walking training. Treadmill test, 6 Minute Walk Test (6MWT), and isokinetic test were repeated after 3 months of rehabilitation, which 80 people completed. RESULTS: Combined training (RES+NW) is more effective than Nordic walking alone and supervised treadmill training alone for improving ankle force-velocity parameters (p<0.05) in patients with intermittent claudication. Each of the proposed exercise rehabilitation programmes increased walking distance of patients with intermittent claudication (p<0.05), especially in 6MWT (p=0.001). Significant relationships of force-velocity parameters are observed in the maximum distance obtained in 6MWT, both in Group III (RES + NW) and in Group II (NW) at the level of moderate and strong correlation strength, which indicates that if the lower limbs are stronger the walking distance achieved in 6MWT is longer. CONCLUSIONS: Given both the force-velocity parameters and the covered distance, the training RES + NW gives the most beneficial changes compared to training TW alone and NW alone. All types of training increased walking distance, which is an important aspect of the everyday functioning of people with IC.

Long-lasting extreme anemia during the therapy of acute lymphoblastic leukemia in a Jehovah's Witness patient.

BACKGROUND: The treatment of patients with acute leukemia, who due to their religious beliefs refuse to accept blood transfusion, is a great challenge for hematologists. CASE REPORT: We present a case of acute pre-T-lymphoblastic leukemia in a Jehovah's Witness who did not accept blood transfusion during chemotherapy. Standard induction and consolidation chemotherapy was used (according to the PALG ALL-6 regiment). RESULTS: During consolidation cycles, darbepoietin alfa, intravenous iron, and total parenteral nutrition was administered. Extreme (Hb < 5 g/dL), long-lasting (41 days) anemia was observed with the lowest Hb concentration amounting to 1.3 g/dL (lasting 7 days). CONCLUSION: We believe this to be the lowest Hb value observed, particularly one that persisted for such a long period of time and resulted in the patient surviving without consequences. The patient remains in complete remission for more than 2 years after diagnosis.

Resistant Hypertension.

Resistant hypertension is a severe medical condition which is estimated to appear in 9-18% of hypertensive patients. Due to higher cardiovascular risk, this disorder requires special diagnosis and treatment. The heterogeneous etiology, risk factors and comorbidities of resistant hypertension stand in need of sophisticated evaluation to confirm the diagnosis and select the best therapeutic options, which should consider lifestyle modifications as well as pharmacological and interventional treatment. After having excluded pseudohypertension, inappropriate blood pressure measurement and control as well as the white coat effect, suspicion of resistant hypertension requires an analysis of drugs which the hypertensive patient is treated with. According to one definition - ineffective treatment with 3 or more antihypertensive drugs including diuretics makes it possible to diagnose resistant hypertension. A multidrug therapy including angiotensin - converting enzyme inhibitors, angiotensin II receptor blockers, beta blockers, diuretics, long-acting calcium channel blockers and mineralocorticoid receptor antagonists has been demonstrated to be effective in resistant hypertension treatment. Nevertheless, optional, innovative therapies, e.g. a renal denervation or baroreflex activation, may create a novel pathway of blood pressure lowering procedures. The right diagnosis of this disease needs to eliminate the secondary causes of resistant hypertension e.g. obstructive sleep apnea, atherosclerosis and renal or hormonal disorders. This paper briefly summarizes the identification of the causes of resistant hypertension and therapeutic strategies, which may contribute to the proper diagnosis and an improvement of the long term management of resistant hypertension.

Peripheral arterial disease decreases muscle torque and functional walking capacity in elderly.

OBJECTIVES: The aim of this study is to compare values of force-velocity and functional walking capacity in elderly patients with intermittent claudication with respect to the control group. MATERIALS AND METHODS: The study involved 135 individuals: 85-peripheral arterial disease (PAD) group diagnosed with stage II chronic lower limb ischemia, according to Fontaine's classification, and 50-control group. The studies included an assessment of walking capacity using a six-minute walk test (6MWT) and measurement of force-velocity parameters (peak torque-PTQ, total work-TW, average power-AVGP) of the lower limbs obtained by means of a functional dynamometry under isokinetic conditions. RESULTS: The peripheral arterial disease group is characterized by significantly lower values of force-velocity parameters compared to the control group (p<0.005). Walking capacity in this group is significantly reduced due to significant differences in the distance covered (p<0.0001), walking speed (p<0.01), and its intensity (p<0.01). Further, a positive correlation was found between the maximum distance specified in the six-minute walk test and lower limb muscle strength in the isokinetic test. CONCLUSIONS: Mean values of all force-velocity parameters and walk distance were significantly higher in the control group than in the peripheral arterial disease group. In the PAD group, in both men and women, the value of the agonist/antagonist ratio of both lower limbs are lower in men and women comparing to the control group. A rehabilitation program for patients with intermittent claudication must consider exercises improving strength, exercise capacity, and endurance in patients with PAD.

The relationship between selected VDR, HFE and ALAD gene polymorphisms and several basic toxicological parameters among persons occupationally exposed to lead.

UNLABELLED: The aim of this study was to find a relationship between polymorphisms of ALAD rs1805313, rs222808, rs1139488, VDR FokI and HFE C282Y and H63D and basic toxicological parameters (lead and ZnPP blood concentration) in people occupationally exposed to lead. We collected data of 101 workers (age 25-63 years) directly exposed to lead. The toxicological lab tests included blood lead, cadmium and ZnPP concentration measurement and arsenic urine concentration measurement. Workers were genotyped for ALAD (rs1805313, rs222808, rs1139488), HFE (C282Y, H63D) and VDR (FokI). Individuals with the lead exposure and coexisting F allel in the locus Fok-I of VDR gene are suspected of higher zinc protoporphyrins concentrations. Workers exposed to the lead with the Y allel in the locus C282Y of the HFE gene are predisposed to lower ZnPP levels and individuals with coexisting H allel in the locus H63D HFE gene are predisposed to lower Pb-B levels. The T allel in the locus rs1805313 of the ALAD gene determines lower Pb-B and ZnPP levels in lead-exposed individuals. The heterozigosity of the locus rs2228083 of the ALAD gene has a strong predilection to higher Pb-B levels. The carriage of the C allel in the locus rs1139488 of the ALAD gene might determine higher Pb-B levels and the heterozigosity of the locus rs1139488 of the ALAD gene might result in higher ZnPP levels. CONCLUSION: The study revealed relationship between VDR, HFE and ALAD genes polymorphism and basic toxicological parameters in occupationally exposed workers.

Endothelial dysfunction in young healthy men is associated with aspirin resistance.

The aim of this study was to investigate the relation between endothelial dysfunction and aspirin response in a young healthy population (102 men aged 18-40). Initial concentrations of the NO pathway metabolites (ADMA, l-arginine, SDMA), cardiovascular risk markers, oxidative stress markers (MDA, thiol index), sICAM1, sVCAM1, PAI-1, sE-selectin, sP-selectin, VEGF, thromboxane B2, 6-keto-PGF1α and arachidonate-induced platelet aggregation (to separate aspirin resistant from sensitive group) were measured. Flow-mediated-vasodilation (FMD) was measured before and after intravenous infusion of 16.0 g of l-arginine. Measurements were repeated following aspirin administration (75 mg/24 h) for 4 days. Both groups were homogenous regarding demographic and biochemical characteristics reflecting cardiovascular risk. Aspirin resistant subjects were characterized by lower baseline FMD and higher FMD following aspirin and l-arginine treatment, as compared to aspirin sensitive control. MDA and nitrotyrosine were greater, whereas thiol index was lower in aspirin resistant men. The sICAM1, sVCAM1, PAI-1, sE-selectin, sP-selectin and VEGF levels were similar in the analyzed groups. Thromboxane in aspirin resistant subjects was greater both at baseline and following aspirin therapy. However, a significant decrease following aspirin treatment was present in both groups. Aspirin resistance in young men is associated with endothelial dysfunction, which could be due to oxidative stress resulting from lipid peroxidation.

The role of chemokines in hypertension.

Hypertension is a major risk factor for cardiovascular disease, which is a serious health problem in the highly industrialized countries. In more than 95% of the cases, the etiology of hypertension remains unknown. A key role in the etiology of hypertension is played by endothelial dysfunction and the inflammatory reaction in the vascular wall, in which the low molecular weight proteins so called chemokines are involved. The chemokines involved in the pathogenesis of hypertension include monocyte chemoattractant protein-1, MCP-1, CCL2, interferon-inducible protein (IP-10; CXCL10), interleukin-8 (IL-8; CXCL8), RANTES (CCL5), fractalkine (CX3CL1) and their receptors CCR2, CCR5, CXCR1, CXCR2, CXCR3 and CX3CR1. The mechanisms involving chemokines and their receptors in the pathogenesis of hypertension are complex and not fully understood. They include the impact of the migration of macrophages and monocytes to the vascular wall, endothelial dysfunction, effects on nitric oxide and endothelin-1 and smooth muscle cell proliferation. Chemokines are also involved in the pathogenesis of complications of hypertension, such as atherosclerosis, myocardial and renal fibrosis. In Poland, only about 26% of patients are effectively treated with antihypertensive drugs. The use of new therapeutic methods based on the inhibition of the inflammatory process in the vascular wall, including the impact on the function of chemokines and their receptors, could improve the effectiveness of the treatment of hypertension.

Toward personalized therapy for chronic lymphocytic leukemia: DSC and cDNA microarray assessment of two cases.

The differences in clinical course of chronic lymphocytic leukemia could have an impact on variations in a patient's response to therapy. Our published results revealed that thermal transition (95 ± 5°C) in differential scanning calorimetry profiles appear to be characteristic for the advanced stage of CLL. Moreover, a decrease/loss of this transition in nuclei from leukemic cells exposed to drugs ex vivo could indicate their diverse efficacy. It seems that the lack of changes in thermal profile could predict patient's drug resistance. In this study, we demonstrate the results obtained after drug treatment of leukemic cells by calorimetry, apoptosis-related parameters involved in expression of genes using cDNA microarray and western blot. These data were compared with the patients' clinical parameters before and after RCC therapy (rituximab + cladribine + cyclophosphamide). The complementary analysis of studied cases with opposite clinical response (CR or NR) revealed a strong relationship between clinical data, differences in thermal scans and apoptosis-related gene expression. We quantified expression of eight of apoptosis-related 89 genes, i.e., NOXA, PUMA, APAF1, ESRRBL1, CASP3, BCL2, BCL2A1 and MCL1. Particular differences in NOXA and BCL2 expression were revealed. NOXA expression in cells of patients who achieved a complete response to RCC therapy was 0.44 times higher in comparison to control ones. Interestingly, in the case of patients who did not respond to immunotherapy, NOXA expression was highly downregulated (RQ = 4.39) as compared with untreated cells. These results were confirmed by distinct cell viability, protein expression as well as by differences in calorimetry profiles.

Changes in the apoptotic gene expression profile in CLL patients treated with rituximab combined with cladribine and cyclophosphamide-preliminary results.

The study was aimed to investigate modifications of apoptotic gene expression profile by microarray technique in 10 patients with chronic lymphocytic leukemia by treatment with rituximab, cladribine and cyclophosphamide (RCC) according to IGHV mutational status. The TaqMan Low Density Array for 96 gene transcripts was used. Those modifications followed two distinctive patterns largely overlapping the IGHV mutational status. In the IGHV-mutated group, the expression of many proapoptotic genes increased after treatment as compared to initial value. Our results suggest that RCC drugs may act through influence on the expression of some apoptosis-involved genes dependently on the IGVH mutational status.

Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies.

Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as well as the identification of "CLL-biased" features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm. We document that CLL may be subdivided into 2 distinct categories: one with stereotyped and the other with nonstereotyped BCRs, at an approximate ratio of 1:2, and provide evidence suggesting a different ontogeny for these 2 categories. We also show that subset-defining sequence patterns in CLL differ from those underlying BCR stereotypy in other B-cell malignancies. Notably, 19 major subsets contained from 20 to 213 sequences each, collectively accounting for 943 sequences or one-eighth of the cohort. Hence, this compartmentalized examination of VH sequences may pave the way toward a molecular classification of CLL with implications for targeted therapeutic interventions, applicable to a significant number of patients assigned to the same subset.

General population low-count CLL-like MBL persists over time without clinical progression, although carrying the same cytogenetic abnormalities of CLL.

Monoclonal B-cell lymphocytosis (MBL) is classified as chronic lymphocytic leukemia (CLL)-like, atypical CLL, and CD5(-) MBL. The number of B cells per microliter divides CLL-like MBL into MBL associated with lymphocytosis (usually detected in a clinical setting) and low-count MBL detected in the general population (usually identified during population screening). After a median follow-up of 34 months we reevaluated 76 low-count MBLs with 5-color flow cytometry: 90% of CLL-like MBL but only 44.4% atypical CLL and 66.7% CD5(-) MBL persisted over time. Population-screening CLL-like MBL had no relevant cell count change, and none developed an overt leukemia. In 50% of the cases FISH showed CLL-related chromosomal abnormalities, including monoallelic or biallelic 13q deletions (43.8%), trisomy 12 (1 case), and 17p deletions (2 cases). The analysis of the T-cell receptor ß (TRBV) chains repertoire showed the presence of monoclonal T-cell clones, especially among CD4(high)CD8(low), CD8(high)CD4(low) T cells. TRBV2 and TRBV8 were the most frequently expressed genes. This study indicates that (1) the risk of progression into CLL for low-count population-screening CLL-like MBL is exceedingly rare and definitely lower than that of clinical MBL and (2) chromosomal abnormalities occur early in the natural history and are possibly associated with the appearance of the typical phenotype.

Rapamycin, the mTOR kinase inhibitor, sensitizes acute myeloid leukemia cells, HL-60 cells, to the cytotoxic effect of arabinozide cytarabine.

The mammalian target of rapamycin (mTOR) kinase is a key regulator of cell growth and proliferation. Overexpression of the mTOR signaling pathway has been described in several tumor cells, including the majority of acute myeloid leukemia (AML) cases. The anti-tumor efficacy of mTOR inhibitors was shown in several preclinical and clinical studies. In AML, however, the potential antineoplastic effect of mTOR inhibitors has received little attention thus far. In this in-vitro study of the human AML cell line, HL-60, we aimed to assess the antileukemic activity of rapamycin (RAPA), an mTOR inhibitor, alone and in combination with cytarabine (Ara-C). The study showed that RAPA in concentrations of 1-10 nmol/l arrested the cell cycle progression of Hl-60 cells in the G1 phase, without evident cytotoxic effect. This effect was associated with significant inhibition of cyclin E expression. At concentrations higher than 10 nmol/l, RAPA exerted a significant proapoptotic effect, with the collapse of mitochondrial potential and caspase-3 activation. The most prominent proapoptotic effect was observed for a combination of 1 nmol/l of RAPA and 50 nmol/l of Ara-C, especially when Ara-C was added at a 24-h interval after RAPA. In conclusion, these data indicate that RAPA might be effective in the treatment of acute leukemia patients, especially in combination with Ara-C, the drug routinely used in AML treatment. On the basis of these results, attempts to combine classical induction chemotherapy with an inhibitor of the mTOR kinase in AML treatment could be warranted.

Cladribine combined with cyclophosphamide and mitoxantrone is an active salvage therapy in advanced non-Hodgkin's lymphoma.

The aim of this study was to determine the feasibility, efficacy and toxicity of the combined therapy consisting of cladribine (2-CdA), mitoxantrone and cyclophosphamide (CMC regimen) in patients with refractory or relapsed non-Hodgkin's lymphoma (NHL). Thirty six patients, 14 with mantle cell lymphoma (MCL), 10 with diffuse large B-cell lymphoma (DLBCL), 5 with follicular lymphoma (FL), 3 with small lymphocytic lymphoma (SLL), and 4 with T-cell lymphoma were enrolled to the study. The CMC protocol consisted of 2-CdA at a dose of 0.12 mg/kg in a 2-hour infusion on days 1 through 3, mitoxantrone 10 mg/m(2) i.v. on day 1 and cyclophosphamide 650 mg/m(2) i.v. on day 1. The CMC courses were repeated at intervals of 4 weeks. Thirty three patients were available for evaluation of response. Overall response rate (OR) was 58% (95% CI, 41--75%). Seven patients (21%; 95% CI, 7--35%) achieved a complete response (CR) and 12 patients (36%; 95% CI, 20--52%) achieved a partial response (PR). Seven of 19 patients with CR/PR are still in remission with a median follow-up of 3 months (range, 2-17 months). The median failure-free survival (FFS) was 5 months (range, 2-17 months). The median overall survival (OS) for the entire group was 9 months (range, 0.1-7 months). There was a significant difference in OS between responders and nonresponders after CMC therapy (log rank test, P = 0.015). When different disease status before CMC treatment was considered, a trend toward longer survival of recurrent patients was observed (log rank test, P = 0.08). Grade 3-4 neutropenia developed in 14 (39%) patients, and 16 episodes (15%) of grade 3-4 infections were observed. Grade 3-4 thrombocytopenia or anemia was seen in 9 patients (25%) and 10 patients (28%), respectively. The results of our study show that the CMC regimen is effective salvage therapy with acceptable toxicity in heavily pretreated patients with NHL including MCL and DLBCL.

No influence of 3435C>T ABCB1 (MDR1) gene polymorphism on risk of adult acute myeloid leukemia and P-glycoprotein expression in blast cells.

Inherited differences in xenobiotic transport and metabolism may play an important role in the development of adult acute myeloid leukemia (AML) and response to the chemotherapy. An ATP-binding cassette (ABC) family transporter P-glycoprotein (P-gp or ABCB1), encoded by ABCB1 (MDR1) gene, is involved in the protection against xenobiotics and multi-drug resistance. The aim of this study was to investigate the potential involvement of the ABCB1 gene exon 26 3435C>T single nucleotide polymorphism (SNP) in the genetic susceptibility to AML and regulation of P-gp expression and activity in AML cells. A total of 180 adult AML patients and 180 sex-matched controls were genotyped using PCR-RFLP method. Moreover, in 40 AML patients ABCB1 gene expression was studied by real-time RT-PCR and P-gp expression and activity were assessed by flow cytometry assays. The prevalence of 3435C>T ABCB1 polymorphism was similar in patient and control cohorts (P = 0.16). Furthermore, the carriers of different ABCB1 genotypes did not differ significantly according to ABCB1 gene expression (P = 0.99), P-gp expression (P = 0.42) and P-gp activity (P = 0.83) in leukemic cells. The authors conclude that isolated 3435C>T ABCB1 SNP is not a major factor of the genetic susceptibility to adult AML, and that genotyping of this polymorphism does not allow predicting P-gp expression or activity in AML cells.

Multi-drug transporter MDR1 gene polymorphism and prognosis in adult acute lymphoblastic leukemia.

P-glycoprotein (P-gp), a membrane transporter encoded by MDR1 gene, influences pharmacokinetics of anti-cancer drugs and contributes to multi-drug resistance phenotype in adult acute lymphoblastic leukemia (ALL). In this study, we explored prognostic and functional role of single nucleotide polymorphism C3435T in MDR1 gene in 44 adult Caucasian patients with ALL. We found that the outcome of chemotherapy as well as MDR1 gene expression, P-gp expression and P-gp activity in isolated ALL blast cells were comparable among the patients carrying different MDR1 genotypes. Our results suggest that C3435T polymorphism in MDR1 gene is not a major prognosticator in adult ALL.