MTHFR and SLCO1B1 Gene Polymorphism and Methotrexate Induced Toxicity in Children with Acute Lymphoblastic Leukemia in the Northwest of Mexico

Abstract Introduction. Acute lymphoblastic leukemia (ALL) represents approximately 52% of pediatric cancer diagnoses in Mexico and is the leading cause of death by disease among children of 5 to 14 years. The use of pharmacogenomics for the detection of germline genetic variations, which are associated with sensitivity or toxicity to chemotherapy, is one of the recent strategies to improve survival. Some mutations present in genes related to the metabolism or transport of methotrexate (MTX) have been associated with the occurrence of toxicities during treatment in pediatric acute lymphoblastic leukemia. The effect of the SNP´s rs1801131, rs1901133 in the MTHFR and rs4149058, rs4149081 in the SLCO1B1 gene have not been studied in Northwest Mexican children with acute lymphoblastic leukemia. Patients and methods. Eligible patients were infants less than 1 year to adolescents less than 18 years of age, diagnosed with B-ALL at the Specialties Children's Hospital of Chihuahua, Mexico. Patients were treated according to the locally protocols based on the St. Jude Children's Research Hospital Total XIIIB and Total XV protocols. We followed-up for two to four weeks after 24 hours high dose MTX (1 to 5 g/m 2) administration. Toxicity data were collected objectively from the patient's medical files and adverse effects were classified as a dichotomous variable yes/no. Genomic DNA was extracted with the Master Pure DNA purification kit (Epicentre Illumina® Company) from peripheral blood. Genotyping assays were performed by real-time polymerase chain reaction, using rhAMp® IDT® genotyping probes (Iowa, USA) and Quant Studio 3 Applied Biosystems Real-Time System Thermal Cycler (Thermo Fisher Scientific®). For statistical analysis association between MTX dose, presence of toxicity, and genetic polymorphisms was evaluated by the chi-square or Fisher's exact test. The effect sizes of the associations were estimated by the OR's from univariate logistic regressions and multivariate logistic regressions to account for the possible confounding effect of sex and age. Analyses were performed by using SAS System and IBM SPSS Statistics Base 22.0 software. Results. The study population demographics and clinical characteristics are summarized in Table 1. MTHFR and SLCO1B1 genotype in our patients and controls obtained from the 1000 Genomes Project database are shown in table 2. In general, a predominance of toxicity events is observed in patients heterozygous for both polymorphisms in the MTHFR gene, but not in the SLCO1B1 gene (Figure 1). Through a logistic regression analysis, we observed an association of 8% between the polymorphisms rs1801131, rs1901133, rs4149058, rs4149081 and the presence of anemia. The AC heterozygous of the rs1801131 has the strongest association with a positive coefficient (+1.1355) and when comparing AC heterozygotes with CC mutated homozygotes, an Odds Ratio (OR) of 4.64 (CI: 95%, 0.719) was observed, identifying it as a risk factor. In contrast, the homozygous AA of the same gene, presented a negative coefficient (-0.7354), thus decreasing the probability of presenting anemia in this population. The presence of neutropenia was associated in 25% with the polymorphisms rs1801131, rs1901133, rs4149058, rs4149081. The AA homozygous of rs1801131 decreased the probability of developing neutropenia (coefficient -0.7643, p=0.04) and the TC heterozygous of rs4149056 increased the probability when comparing with the wild TT homozygotes (OR of 2.91, CI: 95%, 0.496). Liver enzymes elevation was associated in 84% with the polymorphisms rs1801131, rs1901133, rs4149058, rs4149081. We found that the presence of TC heterozygote of rs4149056 decreased the probability of hepatotoxicity (coefficient -1.5718, p=0.03) and GA heterozygote of rs41419081 increased it (coefficient +3.2056, p=0.004) (Table 3). According to this statistical model, we could not analyze the association between the polymorphisms rs1801131, rs1901133, rs4149058, rs4149081 and thrombocytopenia, mucositis, febrile neutropenia or creatinine elevation. Conclusion Toxicity related to treatment is one of the most important causes of death among pediatric ALL patients in Mexico, the development of precision medicine through the identification of SNPs associated with the variability in our patients' response is an alternative to minimize methotrexate toxicity and maximize its benefit during its use. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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A Genome-Wide Analysis of Variants Influencing Methotrexate Clearance Replicates SLCO1B1.

Blood ◽

10.1182/blood.v120.21.2466.2466 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2466-2466 ◽

Cited By ~ 1

Author(s):

Laura B. Ramsey ◽

John C Panetta ◽

Colton Smith ◽

Wenjian Yang ◽

Yiping Fan ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Organic Anion ◽

Organic Anion Transporter ◽

High Dose ◽

Genome Wide Analysis ◽

Anion Transporter ◽

Genome Wide ◽

A Genome

Abstract Abstract 2466 High-dose methotrexate (HDMTX) is an important element of chemotherapy for acute lymphoblastic leukemia (ALL) and other malignancies. Methotrexate clearance influences cure and toxicity in children with acute lymphoblastic leukemia (ALL). HDMTX schedules and doses vary widely among treatment protocols. The Children's Oncology Group (COG) tested the efficacy of 6 courses of 2 g/m2 over 4 hours versus 1 g/m2 over 24 hours (P9904 and P9905 protocols). Patients were assigned to one of four arms for consolidation: A, 24-hour methotrexate infusion (1 g/m2) and no delayed intensification (DI); B, 4-hour methotrexate infusion (2 g/m2) with no DI; C, 24-hour methotrexate infusion with DI; D, 4-hour methotrexate infusion with DI. We estimated methotrexate clearance for 1279 patients treated on these protocols, with two plasma MTX concentrations per course, using a Bayesian pharmacokinetic modeling approach. Germline genetic variation was assessed using the Affymetrix 6.0 array, and other single nucleotide polymorphisms (SNPs) were imputed based on 1000 Genomes reference data, yielding 5.2 million SNP genotypes evaluable per patient. Average MTX clearance was highly variable, with a median (range) of 164 (65–355) and 109 (49–290) ml/min/m2 for the 24-hour and 4-hour infusions, respectively. Methotrexate clearance was lower in older children (p = 7 × 10−7), girls (p = 2.7 × 10−4), and patients who received a delayed intensification phase during consolidation (p = 0.0022). Adjusting for age, gender, race, and treatment arm, a genome-wide analysis showed that methotrexate clearance was associated with polymorphisms in SLCO1B1(p = 2.1 × 10−11), a gene that encodes for an organic anion transporter that is known to transport methotrexate. This replicates our previous findings (Trevino et al, J Clin Oncol. 2009;27(35):5972-8) that polymorphisms in SLCO1B1 influence methotrexate clearance in ALL patients treated on St. Jude protocols with three different HDMTX schedules. In a combined meta-analysis including the 1279 COG patients and 699 St. Jude patients, and adjusting for age, gender, race, and treatment arm, the association of methotrexate clearance with SLCO1B1 SNP rs4149056 yields a p-value of 3.1 × 10−19 (Figure). Even after adjustment for the rs4149056 SNP, other polymorphisms in SLCO1B1 remained significantly related to methotrexate clearance, indicating that there are multiple variants in SLCO1B1 that can influence methotrexate clearance. Validation of the association of this gene with five different treatment regimens of methotrexate solidifies the robustness of this pharmacogenomic determinant of methotrexate clearance. Disclosures: No relevant conflicts of interest to declare.

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Treatment of Acute Lymphoblastic Leukemia in Children and Adolescents with An Anthracycline Based Regimen, but without High Doses of Cytarabine and Methotrexate: Preliminary Results of the LAFAMI-LLA-2002 Protocol.

Blood ◽

10.1182/blood.v114.22.4104.4104 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4104-4104

Author(s):

Gregorio Campos-Cabrera ◽

Virgina Campos-Cabrera ◽

Jose-Luis Campos-Villagomez

Keyword(s):

Flow Cytometry ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Hospital Admissions ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

High Dose ◽

Induction Phase ◽

Efficient Treatment

Abstract Abstract 4104 Background acute lymphoblastic leukemia (ALL) is the most common malignancy in children and adolescences, improvements in the 5 year survival rate continue to be seen since middle 80's, in the 1996 – 2004 SEER data reaching 84 % for children and young adults less than 19 years of age. In Mexico, a developing country, where the minimum salary is less than 3.5 dollars per day and more than a half of the population earn less than that and had no social security the need for an effective with high rate survival but low cost treatment is a priority. We developed a treatment based in the protocol ALL:SWOG9400; Blood 92(10)(Suppl.1): 676a (#2788) (1998) and Blood 100(11):756a (#2991) (2002) and weekly anthracycline induction intensification: protocol ALL-BMF90; Blood 84:3122-3133 (1994) and Blood 95:3310-3322 (2000); and named the LAFAMI-LLA-2002. Methods patients younger than 18 years old with ALL by bone marrow aspirate (BMA), flow cytometry and kariotype analysis; risk-based treatment assignment for children with acute lymphoblastic leukemia, (Ching-Hon Pui en J Clin Oncol 1996;14:18-24 and N Engl J Med 1998;339:605-615). Treatment with LAFAMI-LLA-2002 protocol consist in induction phase (IP) con prednisone 60 mg/m2/d for 28 days and taper to zero betwen day 29 and day 42; doxorubicine 30 mg/m2 days 1,8,15 y 22; vincristine 1.4 mg/m2 (maximum 2 mg) days 1,8,15,22,29 y 35; L-asparaginase 10,000u/m2 days 33 al 42; allopurinol 300 mg/m2 days 1 to 14; patients with high risk also receive ciclofosfamide 750 mg/m2 days 1,15 y 29; after complete IP a BMA is taken and if it is in complete remission then start CNS directed therapy with intratecal chemotherapy (IT CT) twice a week for 4 weeks, triple drug without folinic acid rescue: methotrexate 15/m2 mg, citarabine 40/m2 mg and dexametasone 8 mg; patients with positive CNS involvement and high risk patients also receive cranial irradiation (RT) 2400 cGy; maintenance initiating after IR and during IT CT with mercaptopurine 60 mg/m2/d y metotrexate 20 mg/m2 weekly during 3 years and bi monthly chemotherapy alternating one month IT CT and another month IV CT: dexametasone 40 mg/m2 days 1 to 4, ciclofosfamide 750 mg/m2 day 1, vincristine as mentioned above and citarabine 75 mg/m2 days 3 to 6 y 10 to 13; every 4 months an extra dose of doxorubicine is given with th IV CT. At the end of the treatment flow cytometry for minimal residual disease is taken and if negative go to follow up, then monthly CBC and every six months MRD by FC to complete 5 years. Echocardiograms were performed before IP and every six months until complete the end of the 5 years. Results from January 2002 to July 2009 13 patients were included, 8 male y 5 female, ages from 2 to 17 years; 12 B lineage an 1 T lineage; all with normal kariotype; 10 low risk and 3 high risk; 8 patients completed treatment and are in follow up, 4 patients are in maintenance phase, and one died from relapse during maintenance. All patients completed IP and CNS directed therapy, CR was demonstrated in all and each one. All 8 that completed treatment are in follow up and are negative in MRD, the minimum follow up is 13 months and the maximum is 35; 5 patients from this group have more than 24 months without treatment. No cardiac toxicity was seen; all had normal echocardiogram at the end and every six months after the end of treatment. Conclusions this is an efficient treatment for ALL in patients younger than 18 years, reaching until now 100% of CR in IR and CNS directed therapy; with 92.3 % of global and free event survival: similar results than in protocols using high dose cytarabine and methrotexate but without the toxicity of them; reducing financial costs and hospital admissions because it is an ambulatory treatment that can be given in almost all cities, even in developing countries. Disclosures: No relevant conflicts of interest to declare.

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Intensification of Early-Phase Therapy to Diminish the Prognostic Effect of Myeloid Antigen Expression in Infants with KMT2A-Rearranged Acute Lymphoblastic Leukemia: A Report from the JPLSG MLL-10 Trial

Blood ◽

10.1182/blood-2021-145955 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2384-2384

Author(s):

Yuki Arakawa ◽

Takashi Ishihara ◽

Takako Miyamura ◽

Takao Deguchi ◽

Masashi Sanada ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Early Phase ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Age Distribution ◽

Central Nervous System Involvement ◽

High Dose ◽

Pediatric Leukemia ◽

Hematopoietic Stem ◽

Significant Difference

Abstract Background KMT2A-rearranged acute lymphoblastic leukemia (KMT2A-r ALL) is a rare and dismal disease in infants. Despite restriction of the indication of allogeneic hematopoietic stem cell transplantation to the high-risk group (patients aged <180 days with KMT2A-r ALL or central nervous system involvement), adoption of an Interfant-06-based induction therapy with stricter age-related dosing followed by COG AALL0631-based post-remission chemotherapy with additional administration of high-dose cytarabine in the early intensification phase led to rapid clearance of minimal residual disease (MRD) in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) MLL-10 trial. The MLL-10 trial demonstrated an improved outcome of 66.2% in 3-year event-free survival (EFS) among infants with KMT2A-r ALL (Tomizawa D. Blood 2021). As the Interfant-06 study showed an association between the expression levels of myeloid markers (MM) and poor MRD clearance at end of induction (EOI) and a high relapse rate (Stutterheim J, J Clin Oncol.2021), we analyzed the significance of MM expression in the MLL-10 cohort and its association with prognosis. Methods We analyzed and compared the MM expression (defined as at least one positive marker [with a positive blast subset ≥ 10%] among CD117, CD13, CD33, and CD65/CD15) by using flow cytometry (FCM) in infants with KMT2A-r ALL who were registered in the JPLSG MLL-10 trial. We also compared the results of immunoglobulin/T-cell receptor (Ig/TCR) gene-based polymerase chain reaction (PCR)-MRD analyses or 4-color FCM-MRD assay between the MM-positive and MM-negative groups at EOI and end of early consolidation. The Ig/TCR-MRD results were classified as negative if <5 × 10 −4 and positive if ≥5 × 10 −4, while the FCM-MRD results were classified as negative if <0.01% and positive if ≥0.01%. We prioritized PCR-MRD and used FCM-MRD when we could not make a primer for PCR-MRD. The presence of MRD was not used as a basis for choosing the appropriate therapy. Results and Discussion Among the patients with KMT2A-rALL, 74 were included in this study, excluding one who was not evaluated with FCM at diagnosis. Of these patients, 42 were MM-positive and 32 were MM-negative. The 3-year EFS rates of the MM-positive and MM-negative patients were 62.3% (95% confidence interval [CI], 45.5-75.3) and 70.0% (95% CI, 50.3-83.1), respectively (p = 0.61). Their 3-year overall survival rates were 80.6% (95% CI, 65.0-89.8) and 87.5% (95% CI, 70.0-95.1), respectively (p = 0.74). The numbers of MM-positive and MM-negative patients according to age group are summarized in Table 1, and the difference in age distribution between the two groups was not significant. The MRD statuses of the patients at EOI in the two groups are also summarized in Table 1. No significant difference in MRD clearance was found between the MM-positive and MM-negative groups. Conclusion In this study, we found no significant difference in survival rate between the MM-positive and MM-negative groups. The MM expression was not a prognostic marker in the infants with KMT2A-r ALL in the MLL-10 cohort. We believe that rapid MRD clearance in the early phase of treatment with enhanced chemotherapy would have the greatest contribution to the improvement of prognosis. In this study, the MM-positive patients from the MLL-10 cohort might have benefited from early-phase treatment intensification in terms of MRD clearance. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Safety and Immunogenicity of High Dose Trivalent Inactivated Influenza Vaccine in Pediatric Patients with Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v120.21.3531.3531 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3531-3531

Author(s):

Meghann Pine McManus ◽

Haydar Frangoul ◽

Jonathan McCullers ◽

Wenli Wang ◽

Steve Ampath ◽

...

Keyword(s):

Immune Response ◽

Acute Lymphoblastic Leukemia ◽

Influenza Vaccine ◽

Pediatric Patients ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Vaccine Antigen ◽

High Dose ◽

Children With Cancer ◽

Significant Difference

Abstract Abstract 3531 Background: Influenza is an important cause of morbidity and mortality worldwide. Most deaths outside the elderly population are seen in other high risk groups, such as immunocompromised individuals. Compared to the general population, children with cancer have a higher frequency of influenza infections, have symptoms lasting twice as long and are more likely to require hospitalization, all of which may lead to delays in their chemotherapy. It is recommended that children with cancer receive a yearly trivalent influenza vaccine (TIV) and studies show that children with acute lymphoblastic leukemia (ALL) do mount an immune response to the TIV, although they often have lower titers and seroresponse rates compared to healthy controls. Recently, a high dose (HD) TIV was found to provide a statistically significant increase in the level of antibody response in elderly patients compared to the standard dose (SD) TIV. We hypothesized that the HD TIV would be well tolerated and more immunogenic compared to the SD TIV in pediatric patients with ALL. Methods: This was a randomized, double-blind, phase I safety and immunogenicity trial comparing HD to SD TIV in children with ALL aged 3–17 years, at least one month into chemotherapy and in 1stcomplete remission. Subjects were randomized 2:1 to receive either 0.5mL of HD (60ug per antigen) or SD (15ug per antigen) 2010–11 or 2011–12 TIV. Local and systemic reactions were collected for 7 days after each vaccination. HAI titers to influenza virus antigens as well as complete blood count, quantitative CD4, CD8, CD19 and serum IgG levels were measured before and 28–35 days after vaccination. In year 1, no blood was drawn before dose 2 if a second dose was required. Results: 50 subjects were enrolled (20 in year 1, 30 in year 2). Mean age was 8.25 years (range 4.7 – 12.3 years) and 62% were male. The majority of patients (78%) were in the maintenance phase of therapy. 34 subjects received the HD TIV and 16 subjects received the SD TIV (mean age 7.8 vs. 9.3 years), with 11 subjects receiving 2 doses (9 in HD and 2 in SD groups). The only significant difference noted between the HD and SD TIV group was mean total CD19 count (29 vs. 56, p=0.027). There were no significant differences reported in local or systemic symptoms, except fatigue/malaise and headaches were reported more frequently in the SD TIV group (p=0.008 and p=0.03, respectively). No severe adverse events were attributed to vaccination. The immune response measured by a ≥ 4-fold rise in titers for each vaccine antigen were similar in both the HD and SD TIV groups after 1 or 2 vaccines, respectively (A/California: p=0.12, p=0.46; A/Perth: p=0.35, p=0.34; B/Brisbane: p=0.42, p=0.89). Please see refer to tables 1 and 2 for further immunogenicity results. Conclusion: No differences were noted between the HD and SD TIV groups for solicited systemic and local reactions. The immune response appeared similar in both vaccine groups. A phase 3 trial is planned to determine the immunogenicity of HD versus SD TIV in the pediatric ALL population. Disclosures: No relevant conflicts of interest to declare.

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Should We Use a Desensitization Protocol In Acute Lymphoblastic Leukemia Patients With Silent Inactivation Of Pegasparaginase?

Blood ◽

10.1182/blood.v122.21.1434.1434 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1434-1434

Author(s):

Wing H. Tong ◽

Rob Pieters ◽

Wim J Tissing ◽

Inge M. van der Sluis

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Real Time ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Significant Proportion ◽

Monitoring Program ◽

Activity Levels ◽

Activity Measurements ◽

Asparaginase Activity ◽

Erwinia Asparaginase

Abstract Purpose Previous studies have shown that children with silent inactivation of asparaginase had poorer outcomes as they were not switched to another asparaginase preparation that retained its activity. Recently, a case report was published that described the successful use of desensitization courses in a patient with severe hypersensitivity reaction to asparaginase. We analyzed whether continuation of asparaginase in case of silent inactivation may result in desensitization, disappearance of asparaginase antibodies (AAA) and recovery of asparaginase activity levels in children with newly diagnosed acute lymphoblastic leukemia (ALL). Patients and Methods Children who received intensified PEGasparaginase or Erwinia asparaginase for 30 weeks according to the intensification phase of the Dutch Childhood Oncology Group-ALL-10 medium-risk protocol were studied. All children had received native E.coli asparaginase in induction and all asparaginase preparations were administered intravenously in one hour. AAA against native E.coli asparaginase (Coli-AAA), PEGasparaginase (PEG-AAA), and Erwinia asparaginase (Erwinia-AAA) and PEGasparaginase and Erwiniaasparaginase activity levels were analyzed in serum. Results 7/89 patients had silent inactivation of PEGasparaginase. Two were detected by real-time asparaginase activity measurements and were switched to Erwinia asparaginase. Five patients continued PEGasparaginase because no real-time asparaginase measurements were available at the starting phase of our drug monitoring program. Those patients with silent inactivation were, therefore, not recognized in time. PEGasparaginase activity levels recovered in all 5 patients after 2-7 PEGasparaginase infusions. In all 5 patients, Coli-AAA were present at start of the intensification phase which declined over time coinciding with the rise of PEGasparaginase activity levels. PEG-AAA were absent at the start of intensification but also increased after 1-2 doses of PEGasparaginase, and declined thereafter also coinciding with recovery of the PEGasparaginase activity levels. 29% of the PEGasparaginase patients without an allergy and without silent inactivation were positive for Coli-AAA. Also in this group, the Coli-AAA gradually decreased to undetectable levels after 5 PEGasparaginase courses. In a different cohort of 59 patients treated with Erwinia asparaginase, there were no cases of silent inactivation and two developed allergic reactions. In 50% of the non-allergic patients, the Erwinia-AAA were absent at start of therapy, gradually increased and decreased to absent baseline values during 30 weeks of Erwiniaasparaginase therapy. Conclusion This unintended desensitization program applied in five patients with silent inactivation of PEGasparaginase leads to recovery of PEGasparaginase activity levels. However, this takes an unpredictable and sometimes long time period. Therefore, we do not advise such desensitization approaches, but recommend switching to Erwinia asparaginase. A significant proportion of patients treated for prolonged period with PEGasparaginase or Erwinia asparaginase develops antibodies without influencing asparaginase activity levels that disappear with continued use of the same asparaginase product. Disclosures: No relevant conflicts of interest to declare.

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

Journal of Clinical Oncology ◽

10.1200/jco.2012.46.2309 ◽

2013 ◽

Vol 31 (6) ◽

pp. 676-683 ◽

Cited By ~ 114

Author(s):

Susan O'Brien ◽

Gary Schiller ◽

John Lister ◽

Lloyd Damon ◽

Stuart Goldberg ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Hematopoietic Cell Transplantation ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Chemotherapy Resistance ◽

High Dose ◽

Rapid Progression ◽

Target Tissue ◽

Vincristine Sulfate ◽

Pivotal Phase

Purpose 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). Patients and Methods 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/m2, 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). Results 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%). Conclusion 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.

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MTHFR 677T-1298C haplotype in acute lymphoblastic leukemia: Impact on methotrexate therapy

Journal of Oncology Pharmacy Practice ◽

10.1177/10781552211017193 ◽

2021 ◽

pp. 107815522110171

Author(s):

Rim Frikha ◽

Moez Elloumi ◽

Tarek Rebai ◽

Hassen Kamoun

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Methylenetetrahydrofolate Reductase ◽

Fragment Length Polymorphism ◽

Lymphoblastic Leukemia ◽

Allelic Frequency ◽

Mthfr Gene ◽

Methotrexate Therapy ◽

Wild Type ◽

Functional Variants ◽

Toxicity Score

Introduction Functional variants of the Methylenetetrahydrofolate reductase ( MTHFR) gene, the C677T and A1298C, have largely investigated in pharmacogenomics of Methotrexate (MTX) in acute lymphoblastic leukemia (ALL), yet the conclusions are inconsistent. In addition; most of these studies do not analyze haplotypes. Here, we investigate the MTHFR 677/1298 genotypes and the 677-1298 haplotype and characterize the MTX response in Northern African ALL patients. Methods Genomic DNA was extracted from whole venous from a total of 28 patients with ALL. Genotyping were carried out with restriction fragment length polymorphism (RFLP). A toxicity score (TS) is calculated for each patient and correlate to the haplotype. Results The allelic frequency of MTHFR 677T-1298C haplotype was 10.7% in ALL patients. According to the toxicity’s score (TS) there was no significant differences between haplotype groups (p = 0.79): TS was higher with wild type of MTHFR (TS = 3.43; SEM ± 0.85) followed by combined genotype (677T-1298C) (TS = 2.67; SEM ± 0.88) and isolated variant (C677T or A1298C) (TS = 2.64; SEM ± 0.92). Conclusion Despite the limitation of this study; our results suggest that the MTHFR 677T-1298C haplotype is common in ALL and may be a promising HD-MTX chemotherapy-related adverse effects biomarker.

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