scholarly journals AHR-dependent genes and response to MTX therapy in rheumatoid arthritis patients

2021 ◽  
Author(s):  
Anna Wajda ◽  
Ewa Walczuk ◽  
Barbara Stypińska ◽  
Jakub Lach ◽  
Danat Yermakovich ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Lymphoblastic Leukemia ◽  
Mrna Level ◽  
Poor Response ◽  
Evolutionary Analysis ◽  
First Line ◽  
Aryl Hydrocarbon ◽  
First Line Therapy ◽  
Genes Expression ◽  
Ahr Gene

AbstractMethotrexate (MTX) is the first-line therapy for rheumatoid arthritis. Nevertheless, MTX resistance is quite a common issue in clinical practice. There are some premises that aryl hydrocarbon receptor (AhR) gene battery may take part in MTX metabolism. In the present retrospective study, we analyzed genes expression of AHR genes battery associated with MTX metabolism in whole blood of RA patients with good and poor response to MTX treatment. Additionally, sequencing, genotyping and bioinformatics analysis of AHR repressor gene (AHRR) c.565C > G (rs2292596) and c.1933G > C (rs34453673) have been performed. Theoretically, both changes may have an impact on H3K36me3 and H3K27me3. Evolutionary analysis revealed that rs2292596 may be possibly damaging. Allele G in rs2292596 and DAS28 seems to be associated with a higher risk of poor response to MTX treatment in RA. RA patients with poor response to MTX treatment revealed upregulated AhR and SLC19A1 mRNA level. Treatment with IL-6 inhibitor may be helpful to overcome the low-dose MTX resistance. Analysis of gene expression revealed possible another cause of poor response to MTX treatment which is different from that observed in the case of acute lymphoblastic leukemia.

Outcome of Treatment after First Relapse in Adults Patients with Acute Lymphoblastic Leukemia (ALL) Initially Treated by the LALA-94 Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1876-1876 ◽  
Author(s):  
Emmanuelle Tavernier ◽  
Jean-Michel Boiron ◽  
Francoise Huguet ◽  
Kenneth Francis Bradstock ◽  
Norbert Vey ◽  
...  
Keyword(s):  
Cord Blood ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Risk Groups ◽  
Unrelated Donor ◽  
First Line ◽  
Sibling Donor ◽  
First Line Therapy ◽  
Line Therapy ◽  
First Relapse

Abstract Introduction: More than half of adults with ALL suffer a relapse. It is generally accepted that the only curative approach at this stage is stem cell transplantation (SCT). In the LALA-94 trial, we analyzed the outcome in patients (pts) undergoing a first relapse, and evaluated the possibility to undergo SCT. Methods: Of 771 ALL pts (15–55 years (y)) who entered the trial and achieved complete remission (CR), 421 experienced a first relapse between 1994 and 2004. Except for 48 pts who died early before any chemotherapy, all other pts were given re-induction therapy with various salvage chemotherapy regimens (355 pts), autologous SCT (3 pts) with cells harvested in first CR, donor lymphocyte infusions (DLI) (1 pt) or allogeneic (allo) SCT (13 pts) from a geno-identical (7 pts) or a pheno-identical (6 pts) donor. After CR achievement with chemotherapy, pts with an HLA-identical sibling or unrelated donor were systematically assigned to allo SCT (61 pts: 33 from a related-identical donor, 27 from MUD, and one from cord blood). When possible, allo SCT was also proposed to pts refractory to re-induction chemotherapy (24 pts: 14 from a related-identical donor, 7 from MUD, and 3 from cord blood). Results: Overall, 187/421 pts (44%) achieved CR. CR proportion according to risk-groups defined in first line therapy were: 52% for standard-risk ALL, 37% for high-risk ALL, 40% for Ph+ ALL, and 36% for CNS+ ALL. There were no significant differences in CR proportion according to the first CR duration. With a median follow-up of 4.3 y, the median overall survival (OS) was 6.3 months (m). Median disease free survival (DFS) was 5.2 m with 5-y DFS at 12%. The estimated 5-y DFS rates were 11%, and 14% for T- and (Ph neg) B-lineage ALL, respectively. SCT (p<0.0001), first CR duration (p=0.03), and platelets at relapse (p=0.02) were predictors of survival in multivariate analysis. 111/421 pts (26%) had a sibling donor identified during first line therapy and available at relapse. 9 more pts had a sibling donor identified at the time of relapse. Overall allo SCT from a sibling donor could be performed in 54 pts (45% of pts with a sibling donor), and 3 pts received DLI. 40 SCT could be performed from a match unrelated donor (MUD) and 4 from cord blood. Our results showed a significantly higher survival rate at 3 y after SCT in second CR as compared to that of SCT at time of relapse (p = 0.02) or to that of SCT with active disease after failure of reinduction chemotherapy (p = 0.005). When comparing allo SCT from MUD and allo SCT from related-identical donor, survival tended to be better with MUD (3-y OS: 31% vs 21%), in relationship with a lower relapse incidence (RI) (3-y RI: 41% vs 64%) while treatment related mortality (TRM) was quiet similar (TRM at 100 days: 19% vs 35%, and 1-y TRM: 37% vs 46%). Conclusions: Our results showed a second CR in less than 50% of pts and difficulties to organize allo SCT in second CR with however a definitive advantage for pts undergoing SCT when compared to chemotherapy alone. This questions about the opportunity to perform allo SCT, when possible, systematically earlier in the evolution of the disease.

Nelarabine Alone or in Combination in High Risk Childhood / Adolescent and Young Adults (AYA) T- Cell Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3723-3723
Author(s):  
Benoit Brethon ◽  
Laetitia Morel ◽  
Arnaud Petit ◽  
Etienne Lengliné ◽  
Aurelie Cuinet ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Lymphoblastic Leukemia ◽  
First Line ◽  
Advisory Committees ◽  
Allogeneic Hsct ◽  
First Line Therapy ◽  
Line Therapy ◽  
First Relapse ◽  
Group 1

Abstract Introduction: T-cell acute lymphoblastic leukemia (T-ALL) represent 15-20% of childhood/adolescent young adults (AYA) ALL. An intensive chemotherapy is generally needed to obtain the same results than in B-lineage ALL. Day 8 Poor Prednisone Response (PPR) and early resistant disease (refractoriness after induction course or MRD level >10-3 at time point 1 (TP1) and/or TP2) remain particularly challenging as relapses are very difficult to treat especially if they occur early. Nelarabine is a water-soluble prodrug of araG (9-B-arabinofuranosylguanine) which is cytotoxic to T lymphoblasts due to the accumulation of araG nucleotides, especially araGTP, which result in inhibition of ribonucleotide reductase and inhibition of DNA synthesis. Nelarabine was shown to be effective and safe in phase II-III adult and pediatric ALL trials. We describe here a 7 consecutive years experience of nelarabine in “real life” in 3 pediatric / AYA centers. Methods: All children and AYA who received nelarabine in first line therapy or after relapse between 2006 and 2013 were reviewed retrospectively. Classical initial prognostic factors were collected: age, leucocytosis, CNS status, day 8 prednisone response, complete remission (CR) or not, minimum residual disease (MRD) level at TP1 and TP2. Eighty two % of the patients (pts) followed the French FRALLE 2000-T recommendations. Nelarabine, alone or in combination, was used in two groups of pts: group 1: pts in whom nelarabine is given in first line therapy because of high MRD level >10-3 at TP1 and/or TP2 (whatever the level at time of nelarabine infusion) and pts refractory to induction course, and group 2: pts in relapse. Group 1 and 2 are compared for MRD level after nelarabine, number of patients able to go to allogeneic HSCT and overall survival. Finally the safety profile was assessed. Results: 33 T-ALL patients received nelarabine alone (n= 22) or in combination (n= 11, most often with cyclophosphamide and etoposide) from 2006 to 2013. At initial diagnosis, median age was 11.6 y old [3-24], sex ratio 4.5 (M/F 27/6) and median leukocytosis 184.7.109/L [0.1-914]. These patients shared poor risk factors: CNS3 (n=8, 24.1%), D8 PPR (n=23, 69.7%), day 21 M3 bone marrow (n=13, 36.4%), no CR after one induction course (n=6, 18.2%) and MRD level > 10-3 at CR1 (n=15, 42.4%). Regarding group 1 (high MRD level at TP1 and/or TP2 n= 11, refractoriness to induction course n= 5), the status just before nelarabine was: 6 in CR1 with finally MRD <10-3, 5 in CR1 but MRD >10-3 and 5 refractory. Nelarabine was given alone in 12 patients and in combination in 4 patients. MRD level after nelarabine was <10-3 in 12/16 patients. Overall, 11 pts received an allogeneic HSCT and 13/16 (81%) are alive in CR1 at the time of the analysis with a median FU from first nelarabine infusion of 13.7 months [0.8-58.3]. Overall survival is 79.8%+/-10.5 at 5 years. Regarding group 2 (relapsed patients, n= 17), nelarabine was infused at the time of first relapse in 4 patients and in refractory first relapse or more than first relapse in 13 patients. Among these heavily pretreated patients, only 6 obtained a MRD level <10-3 leading to allogeneic HSCT but none of 6 survived. Only one patient survived in CR3 after a success of nelarabine alone and received other chemotherapy without allogeneic HSCT. Regarding toxicities, the only WHO grade III-IV observed side effects are cytopenias (n= 25, 75.8%). Others reported side effects are limited (grade I-II): fever of undetermined origin or infections (n= 7, 21.2%), neurological (n= 6 pts, 18.2%; some of them with more than one side effect: sensory neuropathy in 4, motor neuropathy in 2, headaches in 2, motor-facial neuropathy in 1, ataxia in 1) or muscular (n= 4, 12.1%; 2 myalgia, 1 myositis, 1 amyotrophia), liver toxicities (n= 4, 12.1%; 3 transaminase increases, 1 hyperbilirubinemia). Conclusions: In a non selected population of childhood / AYA high-risk T-ALL, nelarabine was very useful for poor risk patients in first line therapy. The majority of patients received nelarabine as a monotherapy. By contrast nelarabine mostly failed to improve the survival in heavily pretreated relapsed patients. Overall, this study conforts the use of nelarabine in first line T-ALL and high-risk features with acceptable tolerance. The evaluation of nelarabine in selected high-risk patients in a first line setting should be evaluated prospectively to confirm these results. Disclosures Baruchel: JAZZ: Membership on an entity's Board of Directors or advisory committees; ARIAD: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees.

Assessment of the Aryl Hydrocarbon Receptor Gene as a Therapeutic Target in Childhood T-Lineage Acute Lymphoblastic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 536-536
Author(s):  
Marrit Meier ◽  
Monique L. den Boer ◽  
Mathilde J.C. Broekhuis ◽  
Ronald W. Stam ◽  
Elisabeth R. van Wering ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Aryl Hydrocarbon Receptor ◽  
Therapeutic Target ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Mrna Levels ◽  
Childhood All ◽  
Aryl Hydrocarbon ◽  
Fold Induction ◽  
Ahr Gene

Abstract T-lineage ALL is an unfavorable subtype of childhood ALL and is associated with in-vitro resistance to drugs. Therefore the identification of novel genes that may serve as targets to modulate drug resistance is desirable. We compared the gene expression profile of 28 pediatric T-ALL patients being either sensitive (DNRS) or resistant (DNRR) to daunorubicin. The aryl hydrocarbon receptor (AHR) gene appeared to be highly discriminating between DNRS and DNRR T-ALL patients. AHR is known to mediate signal transduction in response to xenobiotics by activating the transcription of xenobiotic-responsive genes such as CYP1A1 and CYP1A2. Expression analysis by real-time quantitative PCR confirmed that basal AHR mRNA levels in ALL cells derived from patients is correlated with DNR resistance (Rs=0.41, P=0.02). Exposure to DNR of the REH cell line expressing a low AHR level led to a 40-fold induction of AHR mRNA. In two other cell lines (i.e. HL60 and SEMK-2) expressing high levels of AHR the upregulation was only 1.4-fold. In REH, the 40-fold induction of AHR after DNR exposure was inhibited by 40% after pre-exposure to the AHR inhibitors salicylamide (SAL) and geldanamycin (GA). Pre-incubation of leukemic cells of T-ALL patients with SAL or GA prior to DNR exposure had a synergistic effect on DNR sensitivity. In addition, transfection of SEMK-2 cells with AHR-specific siRNA resulted in the reduction of AHR expression by 80% after 24 h and had also a synergistic effect on DNR induced cell kill up to 96 hours after siRNA treatment. We conclude that a high expression of the AHR gene is involved in DNR resistance in childhood T-ALL and that AHR may serve as a very attractive new therapeutic target.

Outcomes Continue to Be Favorable for De Novo Philadelphia Chromosome Negative B-Lymphoblastic Leukemia (ALL) After Therapy with Hyper-CVAD (with or without Rituximab) Regimen

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3572-3572 ◽  
Author(s):  
Deborah A. Thomas ◽  
Hagop M. Kantarjian ◽  
Jeffrey L. Jorgensen ◽  
Stefan Faderl ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Performance Status ◽  
Poor Performance ◽  
Poor Performance Status ◽  
First Line ◽  
Historical Experience ◽  
First Line Therapy ◽  
Line Therapy ◽  
Cd20 Expression ◽  
Consolidation Phase

Abstract Abstract 3572 The hyper-CVAD regimen [Kantarjian, JCO 18: 547, 2000; Kantarjian, Cancer 101: 2788, 2004] includes intensive cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternating with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone) interrupted by early and late intensifications. The regimen was modified in 1999 to include use of laminar air flow rooms during the induction phase for patients (pts) aged 60 years or older. Therapeutic modifications included rituximab 375 mg/m2 (Days 1 & 11 of hyper-CVAD, Days 1 & 8 of MTX-cytarabine for 8 total doses) for CD20 expression > 20% to counteract increased propensity for relapse [Thomas D, Blood 113: 6330, 2009], early anthracycline intensification with liposomal daunorubicin-cytarabine from 1999–2000 only [omitted thereafter owing to lack of benefit, Thomas D, Cancer 116: 4580, 2010], augmentation of CNS prophylaxis, and extension of maintenance POMP therapy from 24 to 30 months with additional early and late intensifications [details in Thomas D, JCO 28: 3830, 2010]. Overall, 216 pts with Ph negative B-lymphoblastic leukemia have been treated with the modified hyper-CVAD regimens. Median age was 46 years (range, 16–84). For the CD20 positive B-lymphoblastic subset treated with hyper-CVAD and rituximab 3-yr rates of CR duration (CRD) and survival (OS) were 66% and 57%. In the younger (age < 60 years) CD20-positive subset, rates of CRD and OS were superior compared with standard hyper-CVAD (69% v 38%; P <.001% and 71% v 47%, P =.003). Historical experience in 37 adolescent and young adult (AYA) subset aged 15 – 30 yrs with CD20 positive B-lymphoblastic leukemia (prior to shift to augmented BFM regimen as first line therapy) showed that the addition of rituximab improved 3-yr CRD rates from 26% to 60% (P =.001) and 3-yr OS rates from 47% to 70% (P =.05) compared with standard hyper-CVAD without rituximab. There were no significant differences in outcome for this AYA subset by regimen (standard or modified) for the CD20 negative groups (all 3-yr rates > 70%). Elderly pts aged 60 year or older with CD20 positive B-lymphoblastic leukemia treated with hyper-CVAD and rituximab, in contrast to the Burkitt experience, had outcomes which were similar to the historical experience with standard hyper-CVAD (rates of CRD 59% v 50%, P = NS and OS 23% v 32%, P = NS, respectively), despite high rates of negativity for minimal residual disease (MRD) by multiparameter flow cytometry (MFC) at CR, related mainly to deaths in CR during consolidation. MRD positivity by MFC after induction therapy with hyper-CVAD and rituximab was associated with a higher relapse rate and lower 3-yr CR duration rates compared with MRD negative status at the time of CR. Additional doses of rituximab were added to consolidation (Day 1 of cycles 5 – 8) and maintenance chemotherapy in order to potentially improve outcomes for the MRD positive subset. Upfront dose reductions of cyclophosphamide, doxorubicin, vincristine, dexamethasone and methotrexate have been implemented for all cycles of induction-consolidation phase for older age and/or poor performance status with reduction in rate of deaths in CR noted. Incorporation of pegylated asparginase (one dose of 2000 Units/m2 with capping per cycle, 1000 Units/m2 if older or poor performance status) during the induction-consolidation phase (“augmented hyper-CVAD”) was piloted as first line therapy in 19 pts aged 30 – 59 years of age, then omitted owing to excessive toxicity. Incorporation of rituximab into first line intensive chemotherapy such as the hyper-CVAD regimen appears beneficial for younger pts, prompting investigation of second generation anti-CD20 monoclonal antibodies such as ofatumumab and hyper-CVAD (regardless of CD20 expression owing to data showing upregulation of CD20 expression) for the younger subsets and inotuzumab (with or without rituximab) and “mini-hyper-CVAD” for the elderly group. Multivariate analysis of outcomes by risk groups (age/MRD status/CD20 expression) and the impact of the early/late intensifications during maintenance chemotherapy will be presented. Disclosures: O'Brien: Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Erwinia Asparaginase Safety and Feasibility during Therapy for Acute Lymphoblastic Leukemia in Adult Patients with Pegaspargase Hypersensitivity or Severe Toxicity

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4915-4915
Author(s):  
Troy Z Horvat ◽  
Joshua J Pecoraro ◽  
Ryan J Daley ◽  
Larry W Buie ◽  
Dan Douer
Keyword(s):  
Adverse Effects ◽  
Lymphoblastic Leukemia ◽  
First Line ◽  
Second Line Therapy ◽  
First Line Therapy ◽  
Line Therapy ◽  
First Remission ◽  
Erwinia Asparaginase ◽  
Grade 3

Abstract Introduction: Severe pegaspargase hypersensitivity during first-line therapy for acute lymphoblastic leukemia (ALL) occurs in 1.8-5.9% of patients (Oncaspar [package insert]; Douer D, et al. J Clin Oncol 2014;32:905-911). Erwinia asparaginase is the preferred therapeutic alternative as it retains excellent activity in patients with Escherichia coli asparaginase or pegaspargase antibodies (Willer A, et al. Blood 2011;118:5774-82; Plourde PV, et al. Pediatr Blood Cancer 2014;61:1232-38; Salzer WL, et al. Blood 2013;122:507-14; Zalewska-Szewczyk B, et al. Clin Exp Med 2009;9:113-16). Furthermore, pegaspargase desensitization may not prevent recurrence of severe allergy (Sahiner UM, et al. Pediatr Int 2013;55:531-33). The risk for allergy and other common asparaginase-related adverse effects exists with Erwinia asparaginase, however most data is from pediatric reports. The aim of this study was to assess the safety and feasibility of using Erwinia asparaginase in adult ALL patients with previous pegaspargase hypersensitivity or intolerance. Methods: This is a single-center retrospective analysis of eight adult ALL patients who received Erwinia asparaginase after intolerance to pegaspargase between November 2011 and July 2015. Toxicities were graded using the Common Terminology Criteria for Adverse Events version 4.0. The Memorial Sloan Kettering Investigational Review Board granted an exemption from IRB review. Results: The eight patients received a total of 29 cycles (median 3 cycles each, range 1-6) as part of various pediatric-inspired chemotherapy regimens. Each cycle consisted of Erwinia asparaginase 25,000 units/m2 intramuscularly every 48 hours (either including or excluding weekends). Corticosteroid premedication was given with 52 of 170 total Erwinia asparaginase doses. The median age was 33 years (range 23-72), 7 (87.5%) were males, 75% had B-cell ALL, and 25% had T-cell ALL. Seven patients received Erwinia asparaginase while in first complete remission (CR1) and only one as part of second-line therapy. Patients received a median of 2 prior doses of pegaspargase (range 1-4) before switching to Erwinia asparaginase for either grade 3/4 anaphylaxis (n=6), urticaria/pruritus (n=1), or grade 4 hyperbilirubinemia (n=1). Six patients received all intended cycles, 1 patient was lost to follow up after 1 cycle, and 1 patient was still receiving treatment at the time of analysis. No hypersensitivity reactions occurred and no patient developed arterial or venous thrombosis. Laboratory adverse effects are reported in table 1. One patient died from disease (the 1 patient that received Erwinia asparaginase as part of second-line therapy), 1 patient died in a motor vehicle accident while in first remission, and six patients are still alive and in first remission at 7.5-29.6 months from diagnosis. No morphologic relapses have occurred in patients in first remission (n=7) at a follow up of 4.9-26.4 months after switching to Erwinia asparaginase. Conclusions: Replacing pegaspargase with Erwinia asparaginase after hypersensitivity allowed all patients to continue asparaginase therapy without hypersensitivity. Adverse effects with Erwinia asparaginase were limited to laboratory abnormalities of minimal clinical consequence. In contrast to the known high rate of hepatoxicity in adults treated with pegaspargase, no high grade liver toxicity was seen. In light of the critical role of asparaginase in ALL therapy, our preliminary observations suggest that asparagine depletion with Erwinia asparaginase can proceed as scheduled despite pegaspargase intolerance. Within our small cohort undergoing first-line therapy, relapse did not occur after transitioning to this therapeutic alternative. Table 1. Laboratory abnormalities by grade Grade 1 Grade 2 Grade 3 Grade 4 AST 7 0 0 0 ALT 7 2 0 0 TBILI 1 0 0 0 Amylase 2 0 0 0 Lipase 1 1 0 0 Triglycerides 3 4 3 1 Fibrinogen 2 6 1 0 Total 23 13 4 1 *Laboratory abnormalities were counted per event, not per patient Disclosures Douer: Gilead: Consultancy.

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