Cumulative Doses Of Vincristine Research Articles

Tooth Abnormalities and Their Age-Dependent Occurrence in Leukemia Survivors.

The multidrug nature of anticancer treatment and different treatment protocols used in the studies are likely to be a major limitation in establishing real risk factors determining the occurrence of dental abnormalities. The authors aimed to establish a relationship between the duration and the dose of chemotherapy and the number of tooth adverse effects in the group receiving the same treatment. Of the 40 anticancer therapy recipients who attended the outpatient dental clinic, 7 leukemia survivors receiving the treatment according to the ALL IC-BFM 2002 protocol were selected. The study group consisted of four females and three males aged 92 to 207 months at the time of dental examination and 29 to 91 months at leukemia diagnosis. As a result of the clinical and radiological examination, dental abnormalities such as agenesis, tooth size reduction, root abnormalities, and taurodontia were identified, and the medical records of all survivors were reviewed in terms of drugs administered, their doses, and treatment schedules. No correlation was observed between the treatment duration of an intensive therapy, the entire therapy, and the number of tooth abnormalities. No relationship was also found between the number of dental abnormalities and the cumulative dose of vincristine, L-asparaginase, methotrexate, cyclophosphamide, cytarabine, and 6-mercaptopurine. The age at the onset of antineoplastic therapy is likely to be the strongest risk factor for toxic injury during tooth development.

Vincristine and Peripheral Neuropathy in Acute Lymphoblastic Leukemia Children

Objective: Peripheral neuropathy is a common neurological side effect in acute lymphoblastic leukemia (ALL) pediatric patients, receiving vincristine treatment. This study aims to explore the frequency, clinical, and electrodiagnosis of peripheral neuropathy of ALL patients.Material and Methods: This study was a retrospective cohort study, using medical record reviews of children who, diagnosed and undergoing treatment for acute lymphoblastic leukemia, from 1st January 2018 till 31st December 2022.Results: One hundred and ninety-seven patients were diagnosed with ALL and received chemotherapy. Ten patients had clinical and electrodiagnostic studies of peripheral neuropathy. B-cell type and high- risk classification were the most common in these patients. The most common symptom was bilateral foot drop and all patients had hyporeflexia. The mean cumulative dose of vincristine was 13.35±2.12 mg/m2. The axonal neuropathy, with motor dominantly and the peroneal nerves, were the highest abnormal finding in electrodiagnosis testing.Conclusion: This report addresses the frequent and clinical of patients with peripheral neuropathy. Foot drop and hyporeflexia might be helpful in early detection of peripheral neuropathy in ALL patients.

Evaluation of vincristine-induced peripheral neuropathy in children with cancer: Turkish validity and reliability study

BackgroundThe evaluation of peripheral neuropathy in children receiving Vincristine treatment is challenging. This study examined the Turkish validity and reliability of the Total Neuropathy Score-Pediatric Vincristine (TNS-PV) measurement tool, which can measure Vincristine-induced peripheral neuropathy symptoms in children with cancer. MethodsA total of 53 children aged 5–17 years who received Vincristine treatment in two pediatric hematology-oncology centers participated in the study. Data was collected using the Total Neuropathy Score-Pediatric Vincristine (TNS-PV), the Common Terminology Criteria for Adverse Events (CTCAE), the Wong-Baker FACES Pain Scale, and the Adolescent Pediatric Pain Tool (APPT). The correlation between the TNS-PV total score and other scales and the inter-rater reliability coefficient was evaluated. FindingsOf the children, 81.1% were diagnosed with ALL and 13.2% with Ewing Sarcoma. Cronbach's alpha values of form A and B of the TNS-PV scale were 0.628 and 0.639, respectively. As the cumulative Vincristine dose increased, the children's scores on TNS-PV were higher. A moderate and significant positive correlation was found between the TNS-PV form A total score and the worst subjective symptoms a, b (A), strength, tendon reflexes, and autonomic / constipation (r = 0.441, r = 0.545, r = 0.472, r = 0.536, p < 0.01). DiscussionThe TNS-PV form B total score was found to have a moderate level, significant correlation with CTCAE sensory neuropathy score and Wong-Baker FACES Pain Scale, and a high level, significant positive correlation with CTCAE motor neuropathy score. Application to practiceThe TNS-PV is valid and reliable for measuring Vincristine-induced peripheral neuropathy in practice in Turkish children 5 years and older.

Electrophysiologic Patterns of Symptomatic Vincristine-Induced Peripheral Neuropathy in Children with Acute Lymphocytic Leukemia.

Acute lymphocytic leukemia is one of the most common cancers in children. Multi-drug chemotherapy is used for treatment, and the representative drug is vincristine. Although various side effects may occur due to vincristine, the association with peripheral neuropathy is high compared to that of other drugs. This study focused on children under the age of 18 years of age with ALL who received chemotherapy containing vincristine. We retrospectively analyzed the results of a nerve conduction study and a cumulative dose of vincristine in 30 children diagnosed with peripheral neuropathy. The average cumulative dose until diagnosis of vincristine-induced peripheral neuropathy was 14.99 ± 1.21 mg/m2, and motor nerves were predominantly involved. Additionally, a marked decrease in average amplitude was also observed in motor nerves. In addition, when the relationship between the incidence of peripheral neuropathy and the cumulative dose was analyzed through the survival curve, about 50% of children developed peripheral neuropathy at a dose of 15.5 ± 1.77 mg/m2. Based on the electrophysiological characteristics of pediatric vincristine-induced peripheral neuropathy, as well as the relationship between the incidence rate and the cumulative dose, it is possible to observe more closely the vincristine-induced peripheral neuropathy occurrence in children with ALL at an appropriate time.

Total Neuropathy Scale Pediatric Vincristine to detect vincristine induced peripheral neuropathy in children with Acute Lymphoblastic Leukemia

Objective: To analyze the Total Neuropathy Scale Pediatric Vincristine (TNS-PV) score as a vincristine induced peripheral neuropathy (VIPN) diagnostic tool. Methodology: This observational analytic study was conducted in Outpatient Pediatric Hematology Oncology Dr. Soetomo Hospital. The inclusion criteria were Acute Lymphoblastic Leukemia (ALL) children aged 4-18 years that had undergone chemotherapy treatment, received a cumulative dose of vincristine &gt;12 mg/m2, had no muscle weakness and signed informed consent. The TNS-PV instrument were used to assess VIPN and nerve conduction studies (NCS) was used as the gold standard. Results: A total of 54 children were enrolled, two refused to sign the informed consent. About 60% were male children, 76.9% aged &lt;10 years old, and 94% were ALL-L1. The TNS-PV had an area under the curve (AUC) of 0.638 (95% CI 0.531-0.834) with cut off value of 3.5. It had a sensitivity 87.9%; specificity 42.1%, positive predictive value 72.5%; negative predictive value (NPV) 66.6% and OR (Odds ratio) 5,273. Conclusion: TNS-PV score cannot replace NCS as the gold standard, but TNS-PV can be an alternative tool for diagnosing VIPN.

Cardiac function in childhood cancer survivors treated with vincristine: Echocardiographic results from the DCCSS LATER 2 CARD study

BackgroundAnthracyclines and radiotherapy involving the heart region are cardiotoxic, but the potential cardiotoxicity of vincristine remains unknown. We assessed cardiac function in vincristine-treated >5-year childhood cancer survivors (CCS). Methods and resultsWe cross-sectionally compared echocardiograms of 101 vincristine-treated CCS (median age 35 years [range: 17–53], median vincristine dose 63 mg/m2) from the national Dutch Childhood Cancer Survivor Study, LATER cohort, to 101 age- and sex-matched controls. CCS treated with anthracyclines, radiotherapy involving the heart region, cyclophosphamide or ifosfamide were excluded. Twelve CCS (14%) versus four controls (4%; p 0.034) had a decreased left ventricular ejection fraction (LVEF; men <52%, women <54%). Mean LVEF was 58.4% versus 59.7% (p 0.050). Global longitudinal strain (GLS) was abnormal in nineteen (24%) CCS versus eight controls (9%; p 0.011). Mean GLS was 19.0% versus 20.1% (p 0.001). No ≥grade 2 diastolic dysfunction was detected. In multivariable logistic regression analysis CCS had higher risk of abnormal GLS (OR 3.55, p 0.012), but not abnormal LVEF (OR 3.07, p 0.065), than controls. Blood pressure and smoking history contributed to variation in LVEF, whereas obesity and diastolic blood pressure contributed to variation in GLS. Cumulative vincristine dose was not associated with either abnormal LVEF or abnormal GLS in multivariable models corrected for age and sex (OR per 50 mg/m2: 0.88, p 0.85 and 1.14, p 0.82, respectively). ConclusionsVincristine-treated long-term CCS showed an abnormal GLS more frequently than controls. Their risk for future clinical cardiac events and the role of risk factor modification should be further elucidated.

Cardiovascular Toxicity Induced by Chronic Vincristine Treatment.

Vincristine is an effective anticancer agent for treating leukemias, lymphomas, and other solid tumors. Vincristine’s better-known severe side effects include bone marrow depression, hyponatremia, peripheral neuropathy, and gastrointestinal distress. In recent years, cardiovascular damage also has been described during vincristine treatments. However, the vascular toxicity induced by vincristine is little studied. The aim of the present is to evaluate whether these alterations remain after the suspension of chemotherapy treatment (sequelae) and the possible mechanisms involved in this vascular damage. Adult male Wistar rats were used. The animals were divided into four treatment groups: two groups of saline (0.9% NaCl; saline, sequelae saline) and two groups of vincristine (100 μg/kg; vincristine, sequelae vincristine). Saline or vincristine was administered intraperitoneally in two cycles of 5 days each, leaving a rest period between cycles of 2 days. The final cumulative vincristine dose administered was 1 mg/kg. Sequelae groups correspond to 2 weeks after stopping treatment with the antitumor agent. At the end of the different experimental protocols, cardiac and vascular functions were analyzed. Alterations in the expression of different proteins in the cardiovascular tissues were also investigated. Chronic treatment with vincristine did not produce significant changes in basal cardiac function but provoked significant endothelial dysfunction in the aorta and a significant decrease in the mesenteric contractile function. These cardiovascular functional alterations disappeared 2 weeks after the suspension of chemotherapy treatment. Vincristine treatment caused a significant increase in the expression of tumor necrosis factor-alpha (TNFα), endothelial and inducible nitric oxide synthases (eNOS and iNOS), and connexin 43 in cardiac tissue. In the aorta, the chronic treatment with vincristine caused a slight non-significant increase in TNFα expression, a significant increase in eNOS and iNOS, and a significant decrease in connexin 43. After 2 weeks of vincristine treatment (sequelae group), the expression of TNFα increased and eNOS and iNOS expressions disappeared, but a significant decrease in the expression of connexin 43 was still observed in the aorta. In mesenteric arteries, similar data to those found in the aorta were observed. In conclusion, chronic treatment with vincristine causes functional alterations in the vascular function of both conductance and resistance vessels and changes in the expressions of TNFα, eNOS, iNOS, and connexin 43 in cardiovascular tissues, implicating direct toxicity during its treatment. These functional alterations are transitory and disappear after the suspension of its treatment.

Patient and Therapy-Related Factors Affecting the Toxicity of Pegylated-Asparaginase for the Treatment of Adult Acute Lymphoblastic Leukemia

The application of pediatric regimens in the treatment of adult acute lymphoblastic leukemia (ALL) has led to a significant improvement in patients outcome. However, concerns about the feasibility of more intensive therapies and of the use of pegylated L-Asparaginase (PEG-ASP) in adult patients have emerged. Some patient-related risk factors as high BMI or hepatic steatosis have been already identified as risk factors for the development of PEG-ASP related toxicity, but few data are available on the toxic effectof PEG-ASP when combined with other drugs.The aim of the present study was to evaluate the incidence of PEG-ASP related adverse events in a cohort of adult ALL patients in order to identify potential patient and therapy-related risk factors contributing to toxicity.Since 2013, 21 adult ALL patients received PEG-ASP therapy in our institution. Median age was 44 (range 19-76); 12 patients were treated in frontline setting (7 according to a full pediatric protocol) whereas 9 patients received therapy for relapsed/refractory leukemia. We retrospectively analyzed each single course which included PEG-ASP administration as an independent event, accounting 41episodes. Patients' features (age, BMI, disease status) and concomitant therapies were accurately analyzed as factors potentially affecting PEG-ASP toxicity. The incidence of major thrombotic/bleeding complications and grade III/IV hepatic or pancreatic toxicity was analyzed; toxicity grading and management of PEG-ASP related complications were performed according to guidelines recently published by Stock et al.No grade III/IV pancreatic, thrombotic or hemorrhagic adverse events were recorded. Five patients experienced grade III hepatic toxicity and in 3 cases grade IV toxicity was observed. All 3 patients experienced unexplained severe weight gain and painful epathomegaly, a clinical picture resembling sinusoidal occlusive disease, and ultrasonography showed the onset of acute liver steatosis. All of them had received concomitant therapy with idarubicin, vincristine and vancomycin.In univariate analysis, the incidence of grade III/IV hepatic toxicity was significantly higher when concomitant chemotherapy with at least 2 mg/sqm cumulative dose of vincristine (p 0.044, HR 4.75) or at least 16 mg/sqm cumulative dose of idarubicine (p 0.046, HR1.45) were administered. Steroids therapy determined a borderline increase in toxicity risk (p 0.068, HR 1.688). No increase in toxicity was observed with any dosing of daunorubicin, cyclophosphamide, cytarabine, methotrexate and 6-mercaptopurine. Among concomitant antibiotic therapies, vancomycin administration seemed to increase the incidence of grade III/IV hepato-toxicy (p 0.02, HR 1.863). No significant increase was observed with carbapenems and azoles (Tab I). Older age (>45), receiving PEG-ASP with active leukemia or a high BMI (>25) were not related with an increased incidence of grade III/IV hepato-toxicity (Tab I). Notably, none of the patients undergoing full pediatric induction (who received the highest doses of PEG-ASP), regardless of age (ranging from 21 to 55), experienced grade III/IV hepatotoxicity. Multivariate logistic regression analysis disclosed that concomitant administration of idarubicin, vincristine or vancomycin were independent predictors of grade III/IV hepatotoxicity (p 0.004, 0.027 and 0.042, respectively, Tab. I).Our data show that the toxicity profile of PEG-ASP in adult patients is manageable. However, serious warnings emerge from our experience. Concomitant drugs and their timing of administration may play a crucial role contributing to PEG-ASP hepatic toxicity. In order to attempt to reduce toxicity, anthracyclines with shorter half-life, i.e. daunorubicin instead of idarubicin, should be used. A particular attention should be paid when administration of concomitant antibiotic therapy is required. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pediatric-Inspired Protocol Improved Overall Survival in Young Adult Aged 18-30 Years Old with Philadelphia-Negative Acute Lymphoblastic Leukemia Compared to the Standard Adult Hypercvad Protocol

Background:Pediatric acute lymphoblastic leukemia (ALL) have excellent overall survival (OS) compared to adult ALL even in the young adult group. The difference in OS was thought to be due to the difference in treatment protocol with the pediatric-inspired protocol being more intensive and with minimal residual disease (MRD) driven. Strong data has emerged over the past decade from different ALL study groups from Europe and North America to support the use of pediatric-inspired protocol for young adult up to age 30-40 years.HyperCVAD protocol, designed by MD Anderson group in early 90s, has been our standard treatment for adult ALL including young adult since year 2000. Over the past decade, a locally designed pediatric-inspired and MRD driven protocol - known as MASPORE Protocol was used with increasing frequency for those age 30 years and below. MASPORE protocol has higher cumulative dose of vincristine and methotrexate, and use of L-Asparaginase compared to HyperCVAD.In this retrospective study, we aimed to evaluate the safety, tolerability and efficacy of MASPORE protocol in relation to the standard adult ALL protocol - HyperCVAD in young adult aged 18-30 years who were diagnosed with Philadelphia-negative (Ph-) ALL.Method:Patients aged 18 to 30 years old with Ph- ALL who had received HyperCVAD or MASPORE regimen were retrospectively identified via our institution database. Clinical data, toxicity profile, and treatment outcome were collected, compared and analyzed.High risk disease was defined as high white blood cell (WBC) (>30x109/L for B-ALL, and >100x109/L for T-ALL), failure to achieve complete remission (CR) after induction, failure to achieve MRD target at 4 weeks and 8 weeks (in MASPORE group), hypodiploidy, t(9;22), t(4;11) and other MLL-gene rearrangement. An intensified chemotherapy regimen would be given to those high-risk disease in MASPORE regimen, while HyperCVAD regimen has a fixed intensity irrespective of risk.Results:A total of 30 consecutive Ph- ALL patients aged between 18 to 30 years old who were treated with HyperCVAD or MASPORE protocol were included in the analysis. 16 were treated with MASPORE protocol while 14 were treated with HyperCVAD protocol. The median age was 22 years old (Range: 18 - 29 years old). Median follow-up for MASPORE was 37.0 months and HyperCVAD was 85.0 months. HyperCVAD-treated patients were mainly from year 2004 to 2011, while more than 80% of MASPORE patients were treated after year 2013.18 patients had B-ALL, 11 with T-ALL and 1 with mixed phenotypes. 2 patients (1 in each group) had high cytogenetic risk. Median WBC was 14.1 (range: 1.9-287) and 10.1 (range: 1.2-242) for HyperCVAD and MASPORE respectively.All patients achieved CR at the end of induction with no early death (within 60 days of induction). Overall relapse rate was 33.3% with lower relapse rate observed in in MASPORE (18.8%) compared to 50.0% in HyperCVAD. (p-value: 0.07). 4 in HyperCVAD and 3 in MASPORE received allo-SCT subsequently.Median OS in MASPORE was not reached. Median OS for HyperCVAD was 26.3 months (95% CI: 3.6-49.1 months). Overall survival at 3 years were 84.0% and 46.2% in the MASPORE and HyperCVAD, respectively, p=0.038 (Figure 1).Median Leukemia Free Survival (LFS) in MASPORE was not reached. Median LFS in HyperCVAD was 12.5 months (95% CI: 4.2-20.8 months). LFS at 3 years were 75.8% and 38.5% in the MASPORE and HyperCVAD respectively, p=0.089 (Figure 2).6 patients in MASPORE had thrombotic events (3 with cerebral venous thrombosis and 3 with deep vein thrombosis (DVT)) while only 1 patient had DVT in HyperCVAD group. 11 patients in MASPORE group had at least 1 episode of grade 3 or more transaminitis, compared to 3 patients in HyperCVAD. 7 patients in HyperCVAD group had at least one episode of bacteremia during the course of treatment compared to 4 patients in the MASPORE group. Two treatment-related death were observed, both from HyperCVAD group.ConclusionsMASPORE protocol was well tolerated albeit higher rate of thrombotic events and transaminitis which most likely related to L-asparaginase, but with lower incidence of bacteremia and treatment related death. It showed a superior overall survival compared to HyperCVAD protocol and a trend towards improved leukemia free survival. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

RISK FACTORS OF VINCRISTINE-INDUCED PERIPHERAL NEUROPATHY IN ACUTE LYMPHOBLASTIC LEUKAEMIA CHILDREN.

Objective : This study analysed Vincristine-induced peripheral neuropathy (VIPN) risk factors in Acute Lymphoblastic Leukaemia (ALL) children. Method : This cross-sectional study design was performed at Dr. Soetomo Hospital, Surabaya, Indonesia, from August to October 2019. It included ALL children, aged 4-18 years, undergoing the 2013 or 2018 ALL Indonesian Protocol of Chemotherapy, with a cumulative vincristine dose ≥ 12 mg / m2. VIPN diagnosis is based on complaints, the Total Neuropathy Score Pediatric Vincristine (TNS-PV), and nerve conduction studies (NCS). The examined risk factors were sex, age, ALL classification, nutritional status, impaired liver function, and cumulative vincristine dose. Results : There were 52 ALL children : median age 7 years, 59.6% boys, 59.6% ALL standard risk, 44.2% experienced impaired liver function at initial ALL diagnosis. Based on a single parameter for diagnosis, 26.9% had VIPN based on complaints, 76.9% had it based on the TNS-PV, and 100% had it based on NCS. VIPN was diagnosed in 25% of children, with predominantly motor impairment and located in lower extremities. Impaired liver function is a risk factor for VIPN in ALL children (p = 0.046, prevalence ratio (PR) 2.84). Conclusion : Impaired liver function is a significant risk factor for VIPN in ALL children. J. Med. Invest. 68 : 232-237, August, 2021.

Association of CEP72 rs924607 with vincristine-induced peripheral neuropathy (PN) in patients with diffuse large B-cell lymphoma on CALGB 50303 (Alliance).

e13535 Background: Pediatric patients (pts) receiving long-term vincristine treatment for acute lymphoblastic leukemia (ALL) who carry two variant alleles of CEP72 rs924607 experience more severe peripheral neuropathy (PN) at lower cumulative vincristine doses. The objective of this retrospective pharmacogenetic analysis was to determine if pts homozygous for rs924607 have increased PN risk when receiving short-term vincristine treatment for diffuse large B-cell lymphoma (DLBCL). Methods: Caucasian pts with DLBCL randomized to either of two vincristine-containing regimens (R-CHOP or DA-EPOCH-R) on the CALGB 50303 (Alliance) trial were genotyped for germline rs924607 via TaqMan. Vincristine was administered intravenously 1.4 mg/m2 (2 mg cap) on day 1 of each R-CHOP cycle (1.4 mg/m2/cycle) or 0.4 mg/m2/day (no cap) on days 1-4 of each DA-EPOCH-R cycle (1.6 mg/m2/cycle). Dosing was repeated every 21 days for 6 treatment cycles, for a maximum cumulative vincristine dose of 8.4 (R-CHOP) or 9.6 (DA-EPOCH-R) mg/m2 over 18 weeks. The primary analysis compared risk of NCI CTCAE grade 3 or higher PN in rs924607 homozygous variant pts versus wild-type allele carriers using multivariable Cox proportional hazards regression adjusted for treatment received (R-CHOP vs. DA-EPOCH-R), age (continuous), and sex (male vs. female). A secondary analysis was conducted only in pts assigned to the DA-EPOCH-R arm. Results: Of 307 pts included in the analysis, 32 (10.4%) experienced grade 3+ PN. PN occurrence was nominally lower in homozygous pts (5/59 = 8.5%) than wild-type carriers (27/248 = 10.9%). In the primary analysis, homozygous pts did not experience PN earlier in treatment (Hazard ratio (HR) = 1.04, (95% confidence interval: 0.39-2.75), one-sided p-value = 0.47). There was no significant difference between groups in dose-at-PN occurrence (homozygous (n = 5): 8.81 mg/m2 vs. wild-type carrier (n = 27):6.74 mg/m2, p &gt; 0.05). The secondary analysis in pts on the DA-EPOCH-R arm (n = 147), in which the majority of PN events occurred (n = 27/32 = 84%), homozygous pts (n = 26) did not have significantly increased PN risk (HR = 1.30, p = 0.56). Conclusions: This retrospective analysis of the prospective CALGB 50303 trial did not find that pts homozygous for CEP72 rs924607 had increased PN risk during short-term vincristine treatment for DLBCL. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org . ClinicalTrials.gov Id: NCT00118209.

Investigating fine motor deficits during maintenance therapy in children with acute lymphoblastic leukemia.

Children diagnosed with acute lymphoblastic leukemia (ALL) in their early childhood are more susceptible to neuromuscular and musculoskeletal impairments. This cross-sectional study was designed to address different types of fine motor impairments in Egyptian children diagnosed with ALL. Fifty-four children treated for ALL in maintenance phase aged from four to seven years were compared with an age- and sex-matched control group. Fine motor performance was assessed using the total fine motor form of the Bruininks-Oseretsky Test of Motor Proficiency-second edition (BOT-2). Sex- and age-specific norms of BOT-2 were used to calculate scale and standard scores in both groups. Children with ALL had significantly impaired fine motor skills in all subtests and composites of BOT-2 compared with the typically developing group (P<0.00001). Cumulative doses of vincristine, methotrexate, and dexamethasone revealed no significant correlation with any BOT-2 measure. Males performed significantly better than females in all BOT-2 scores except for the fine motor integration subtest and the total fine motor control composite as no significant differences were observed. The protocol risk stratum, duration of maintenance treatment, and the age at assessment did not significantly affect the BOT-2 measures. About 67% of children with ALL on maintenance treatment experienced fine motor difficulties. Periodic evaluation along the course of chemotherapy could identify specific impaired fine motor domains providing the base for a successful rehabilitation program.

Gene Expression of ABCG1, ABCG2, and ABCB1 and Their Role in Iranian Pediatric Patients with Acute Lymphoblastic Leukemia’s Recurrence

Background: Expression of ATB-binding cassette (ABC) transporters could be correlated with drug resistance and treatment failures like recurrence in pediatric patients with acute lymphoblastic leukemia (ALL). The relation of ABC gene expression and relapse in ALL is still unclear. This might be important especially in regions with a high rate of relapse. Objectives: This study aimed to evaluate the role of ABCG1, ABCG2, and ABCB1 gene expression in the recurrence of Iranian pediatric patients with ALL. Methods: Iranian pediatric patients with confirmed ALL were enrolled in this study as two groups; relapsed ALL and a control group consisting of 3 years relapse-free survival (RFS). Real Time-PCR was done with GAPDH for expressing ABCG1, ABCG2, and ABCB1 transporter genes. Cumulative doses of VCR (vincristine), DNR (daunorubicin), and L-ASP (L-asparaginase) were calculated for each patient. The gathered data were analyzed with SPSS version 22 and REST 2009 software. Results: Total of 39 samples (23 cases; 16 controls) were enrolled during 26 months. High expression of ABCG1 (P value = 0.0068), ABCG2 (P value = 0.0120) and low expression of ABCB1 (P value = 0.0029) related with conferring increased risk of relapse in the patients. The mean relative folds of expressions were 2.3, 1.8, and 1.07 for ABCG1, ABCG2, and ABCB1, respectively. In addition achieved expression pattern was related to high doses of VCR, DNR, and L-ASP. Conclusions: Designed expression pattern have the predictive value for estimating of conferring relapse in Iranian pediatric patients with diagnosed ALL.

Small-fiber neuropathy and pain sensitization in survivors of pediatric acute lymphoblastic leukemia.

Chemotherapy-induced Peripheral Neuropathy (CIPN) of large-fibers affects up to 20% of survivors of pediatric acute lymphoblastic leukemia (ALL). We aimed to describe small-fiber toxicity and pain sensitization in this group. In a cross-sectional, bicentric study we assessed 46 survivors of pediatric ALL (Mean age: 5.7±3.5years at diagnosis, median 2.5 years after therapy; males: 28). ≥6 years of age, ≥3 months after last administration of Vincristine, and cumulative dose of Vincristine 12mg/m2. We used a reduced version of the Pediatric-modified Total Neuropathy Score (Ped-mTNS) as bedside test and Quantitative Sensory Testing (QST) for assessment ofsmall- and large-fiber neuropathy as well as pain sensitization. We employed Nerve Conduction Studies (NCS) as the most accurate tool for detecting large-fiber neuropathy. Fifteen survivors (33%) had abnormal rPed-mTNS values (≥4 points) and 5 survivors (11%) reported pain. In QST, the survivor group showed significant (p<0.001) inferior large-fiber function and pain sensitization when compared to healthy matched peers. We identified deficits of vibration in 33 (72%) and tactile hypoesthesia in 29 (63%), hyperalgesia to blunt pressure in 19 (41%), increased mechanical pain sensitivity in 12 (26%) and allodynia in 16 (35%) of 46 survivors. Only 7 survivors (15%) had pathologic NCS. QST is a sensitive tool that revealed signs of large-fiber neuropathy in two thirds, small-fiber neuropathy and pain sensitization in one third of survivors. Prospective studies using QST in pediatric oncology may help to elucidate the pathophysiology of small-fiber neuropathy and pain sensitization as well as their relevance for quality of survival.

Age-related toxicity in patients with rhabdomyosarcoma: a report from the children's oncology group.

On the Fourth Intergroup Rhabdomyosarcoma study, older children experienced excessive neurotoxicity, whereas younger children had increased myelosuppression. The purpose of this study was to determine whether the same pattern of toxicity was seen on the successor study when use of growth factor was required and dosing of chemotherapy was different by performing a retrospective cohort analysis on patients treated on Children's Oncology Group protocol D9803. Toxicity data were analyzed by stratifying children into 4 age groups. The frequency of grade 3/4 neurotoxicity, myelosuppression, infection, and mucositis was predicted for each age group. The cumulative doses of vincristine and cyclophosphamide administered were measured as percent of protocol-prescribed dose. Adolescents (aged 15+) were more likely to experience neurotoxicity compared with younger patients (odds ratio, 3.6; P<0.0001). There was no difference in myelosuppression, infection, or mucositis. The mean percent protocol-prescribed doses administered for vincristine and cyclophosphamide did not differ much by age group. Adolescents experienced more neurotoxicity with vincristine compared with younger patients. No differences in other toxicities were observed between age groups. As adolescents received at least 85% of protocol-prescribed doses of vincristine, it is difficult to attribute the poorer survival in this age group to inadequate protocol-delivered therapy.

Ptosis unilatéral induit par la vincristine : à propos d’un cas et revue de la littérature

We report the case of a 31-month-old girl, treated by the ifosfamide-vincristine-actinomycin chemotherapy protocol for vaginal rhabdomyosarcoma, who developed a unilateral left ptosis on day 36 of chemotherapy, i.e. 7 days after the fifth vincristine dose (1.5mg/m(2) or 0.90 mg). The cumulative vincristine dose was thus 4.50mg. The remainder of the neurological and systemic examinations were unremarkable. Laboratory testing and thoracic-cervical-cranial CT were normal. Other causes of ptosis were excluded. The ptosis decreased a few days after the infusion of vincristine and re-increased just after a new dose. It finally resolved upon lowering the dose of vincristine. According to our observations, the role of vincristine in the pathogenesis of this ptosis appears "likely". In such cases, maintenance of treatment is possible with adjustment of vincristine doses, but requires regular follow-up.

High-Dose Vincristine Sulfate Liposome Injection for Advanced, Relapsed, and Refractory Adult Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia

Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) -negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT). Sixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m(2), without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi). The CR/CRi rate was 20% and overall response rate was 35%. VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single- and multiagent reinduction therapies. Median CR/CRi duration was 23 weeks (range, 5 to 66 weeks); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. VSLI was generally well tolerated and associated with a low 30-day mortality rate (12%). High-dose VSLI monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to standard VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR.

Vincristine‐induced unilateral ptosis

AbstractPurpose To report the ocurrence of an unilateral ptosis in a 2‐year‐old girl treated by vincristine for a vaginal rhabdomyosarcoma.Methods Our young patient developed a vaginal rhabdomyosarcoma and had been treated by chemotherapy (Ifosfamide‐Vincristine‐Actinomycine) when an unilateral ptosis occurred 7 days after the fifth vincristine dose (1.5 mg/m2). At that time, cumulative vincristine dose was 4.50 mg. Neither oculomotor dysfunction nor anisocoria were present. Neurological and systemic examinations were otherwise unremarkable. Laboratory testing and thoracic‐cervical‐cranial scan were normal. Other causes of ptosis were excluded. Despite vincristine dose was reduced by a third, ptosis slightly increased after the 2 subsequent injections but decreased between cures. Ptosis disappeared at day 78 and no recurrence was noticed after the treatment continuation at the same dose.Results Neurotoxicity is a well‐known complication of vincaalkaloids. Bilateral ptosis is relatively common but reported cases of vincristine‐induced unilateral ptosis are infrequent. In our young patient, occurrence of the ptosis during treatment, increase during new infusions of vincristine and exclusion of other aetiologies are forceful arguments to consider the role of vincristine in this side effect. The use of pyridoxine or pyridostigmine were suggested to treat vincristine‐induced cranial neuropathies but to date, the benefit remains unproved. Adaptation of treatment regimen must be done. In our case dose reduction allowed disappearance of the ptosis.Conclusion Even if unilateral ptosis is rare among vincristine‐induced neurological complications, ophthalmologists must be aware of this diagnosis.

Neuromuscular impairments in adult survivors of childhood acute lymphoblastic leukemia: associations with physical performance and chemotherapy doses.

Treatment regimens for childhood acute lymphoblastic leukemia (ALL) contain neurotoxic agents that may interfere with neuromuscular health. In this study, the authors examined associations between neuromuscular impairments and physical function and between neuromuscular impairments and doses of vincristine and intrathecal methotrexate used to treat leukemia among survivors of childhood ALL. ALL survivors >10 years from diagnosis participated in neuromuscular performance testing. Treatment data were abstracted from medical records. Regression models were used to evaluate associations between treatment factors, neuromuscular impairments, and physical performance. Among 415 survivors (median age, 35 years; age range, 21-52 years), balance, mobility, and 6-minute walk (6MW) distances were 1.3 standard deviations below age-specific and sex-specific values in 15.4%, 3.6%, and 46.5% of participants, respectively. Impairments included absent Achilles tendon reflexes (39.5%), active dorsiflexion range of motion (ROM) <5 degrees (33.5%), and impaired knee extension strength (30.1%). In adjusted models (including cranial radiation), survivors who received cumulative intrathecal methotrexate doses ≥215 mg/m(2) were 3.4 times more likely (95% confidence interval, 1.2-9.8 times more likely) to have impaired ROM than survivors who received no intrathecal methotrexate, and survivors who received cumulative vincristine doses ≥39 mg/m(2) were 1.5 times more likely (95% CI, 1.0-2.5 times more likely) to have impaired ROM than survivors who received lower cumulative doses of vincristine. Higher intrathecal methotrexate doses were associated with reduced knee extension strength and 6MW distances. Neuromuscular impairments were prevalent in childhood ALL survivors and interfered with physical performance. Higher cumulative doses of vincristine and/or intrathecal methotrexate were associated with long-term neuromuscular impairments, which have implications on future function as these survivors age.

Neuropathic pain during treatment for childhood acute lymphoblastic leukemia

Improved cure rates for childhood acute lymphoblastic leukemia (ALL) over the past 2 decades have allowed greater attention to patients' quality of life. Neuropathic pain (NP) is an unpleasant side effect of chemotherapeutic agents for leukemia, especially vincristine. We retrospectively reviewed the records of 498 patients treated on a single protocol for ALL to investigate the risk factors, the incidence, and the use of therapeutic and prophylactic gabapentin treatment for NP. White non-Hispanic race was the only patient variable predictive of NP. One hundred and seventy-four of 498 patients (34.9%) experienced 207 episodes of NP; 16% (28 of 174) patients experienced at least one recurrence of pain after the initial episode. No statistical significance was found in the relation between the severity (grade) of the NP episode and the cumulative dose of vincristine (P = 0.45) or the vincristine dose that immediately preceded the diagnosis (1.5 mg/m(2) versus 2.0 mg/m(2) [correction made here after initial online publication], P = 0.59). Of 180 episodes with treatment data, 62.2% (112) and 37.8% (68) were treated with gabapentin or opioids, respectively. The selection of treatment with gabapentin or opioids was not influenced by the pain intensity score at the time of diagnosis of NP (P = 0.91). The mean gabapentin dose used for 112 episodes was 15.5 mg/kg/day (SD 7.9). We found no evidence that gabapentin prevented recurrence of NP. Our results highlight the need for prospective randomized studies to elucidate the value of gabapentin regimen for prevention or treatment of vincristine-related pain during treatment of childhood leukemia.