Optimal Cytogenetic Response Research Articles

Experience of Generic Imatinib As a First Line Therapy for Patients with Chronic Myeloid Leukemia in a Single Reference Institution

Background: The treatment of chronic myeloid leukemia (CML) was revolutionized by the approval of Gleevec (imatinib mesylate) by the FDA in 2001. In low-middle-income countries, due to economic issues related to the high cost of this treatment, scientific governmental entities started to produce and release a generic imatinib in 2013. High quality data about the security profile and efficacy of generic imatinib treatment are still needed. Aims: We herein aimed to evaluate the 6 years follow up of CML patients treated with generic imatinib as first line therapy. Patients and Methods: We evaluated a retrospective cohort of 39 patients diagnosed with CML at a single institution, during the period between December 2001 and July 2019, that had used only generic formulation of imatinib since diagnosis; and analyzed their rate of response to treatment as a primary goal and adverse events and survival outcomes as secondary goals. Responses were evaluated according to ELN 2013. Event-free survival and overall survival were measured from starting date of treatment until: loss of molecular response or death from any cause, and until death from any cause or last seen, respectively. Results: The cohort of 39 patients treated with generic imatinib as first line therapy was composed of 23 men (59%) and 16 women (41%), with median age at diagnosis of 52 years (16-74). The median follow up time was 24 months (8-68), and the median duration of generic imatinib therapy was 19 months (5 - 68). Most of the patients were diagnosed at chronic phase (92%), with only 2 accelerated phase and 1 myeloid blast crisis. Risk stratification according to Eutos, Sokal and Hasford score was low in 92%, 67% and 80%; intermediate in 0%, 30% and 6% and high in 8%, 3% and 14%, respectively. Six different brands of generic imatinib were used (Cristalia, Instituto Vital Brasil, FURP, EMS, Fiocruz and Eurofarma); the most frequently used were Cristalia and Instituto Vital Brasil. The median number of brands used per patient was 2 (1-5). Patients received 400 mg of generic imatinib daily; the dose was increased to 600 mg in 4 patients due to sub-optimal response during follow up. The rate of hematologic response with treatment was 97% and median time to reach it was 1 month (1-7). The rate of response at 3, 6 and 12 months was 74%, 60%, and 92% for optimal cytogenetic response, and 69%, 61%, and 26% for optimal molecular response. The probability to reach deep molecular response at each year of follow up was 41% at 1st year, 52% at 2nd year, 46% at 3rd year, 50% at 4th year, 50% at 5th year, and 50% at 6th year. The probability to reach a molecular response 4.5 at each year of follow up was 10% at 1st year, 23% at 2nd year, 30% at 3rd year, 50% at 4th year, 50% at 5th year, and 50% at 6th year. Hematologic toxicities were frequent during the first three months of therapy. Reported non-hematologic adverse events were hypophosphatemia (62%), diarrhea (30%), cramps (30%), liver toxicity (28%), nausea (18%), bone pain (18%), edema (15%), rash (8%), and hypomagnesaemia (2.5%). Eight percent of patients evolved with deterioration of renal function during the treatment period, but its relationship with generic imatinib was not well established. Two patients (5%) needed a dose reduction because of adverse events. Eight (20.5%) patients switched to second line tyrosine-kinase inhibitors, five (13%) due to resistance and three (8%) due to side effects (severe hepatotoxicity, diarrhea, and rash). Three patients progressed after switching to another tyrosine kinase inhibitor. After a median follow up of 24 months, the event free survival rate was 80% and the overall survival rate was 100%. Conclusion: The rate of complete cytogenetic response, resistance, and intolerance after use of generic imatinib was not worse than the rates described in the long-term follow up of the IRIS trial (N Engl J Med 2017; 376:917-927). Deep molecular response rates seen in the cohort of patients on generic imatinib were inferior to the ones in the IRIS trial, but overall survival was not impacted. Hypophosphatemia was observed in a high percentage of patients, although it has not been reported in other cohorts on generic imatinib. Prospective randomized studies are needed to allow better conclusions regarding the comparative efficacy and safety of generic imatinib. Disclosures Figueiredo-Pontes: Novartis: Honoraria.

Impact of Imatinib Adherence on the Cytogenetic Response in Pediatric Chronic Myeloid Leukemia - Chronic Phase.

The authors aimed to study the impact of adherence to imatinib during initial 6mo on the cytogenetic response in pediatric chronic myeloid leukemia - chronic phase (CML CP). The hospital records of pediatric CML patients (age ≤18y) from 2009 through 2012, were analyzed retrospectively for the drug adherence and cytogenetic response (CyR) at 6mo. Forty eight children were analyzed, with the median age of 13y (range 5-18) and slight male preponderance (M:F- 1.18:1). Sokal scores were low, intermediate and high in 14 (29.3%), 26 (54.1%), 8 (16.6%) children respectively. Only a little more than half of the children were adherent (58%). At the end of 6mo, complete cytogenetic response (CCyR) was achieved by 78.5% of adherent children as compared to 5% of non-adherent children. Majority (80%) of the non-adherent children had only a partial cytogenetic response (PCyR). Therefore, it is concluded that most of the adherent children had optimal cytogenetic response at the end of 6mo and majority of those in the non-adherent group did not attain it.

Trough plasma imatinib levels are correlated with optimal cytogenetic responses at 6 months after treatment with standard dose of imatinib in newly diagnosed chronic myeloid leukemia

To investigate the correlation of trough imatinib mesylate (IM) levels with cytogenetic or molecular responses, we measured trough IM levels in patients with chronic myeloid leukemia, chronic phase (CML-CP), at 6 months of treatment with a standard dose of IM. Eighty-seven newly diagnosed patients with CML-CP were prospectively enrolled. Seventy-eight patients (89.7%) showed an optimal response (complete or partial cytogenetic response) at 6 months. Trough IM levels were 1378 ± 725 ng/mL. When categorized into two groups, there was a statistically significant difference in numbers of patients with optimal and suboptimal responses at 6 months (group with <1000: 80.6% vs. 19.4%; ≥1000: 94.6% vs. 5.4%; p = 0.032), and in numbers of patients with early major molecular response (early-MMR) and without MMR at 6 months (group with <1000: 3.2% vs. 96.8%; ≥1000: 21.4% vs. 78.6%; p = 0.047). In conclusion, the incidence of optimal cytogenetic response or early-MMR in patients with CML-CP treated with IM for 6 months was significantly higher in those with a trough level of ≥1000 compared with those with a level of <1000. Dose escalation of IM can be one option in patients with CML showing suboptimal response or resistance to the standard dose of IM, especially with low trough plasma IM levels (<1000 ng/mL).

Trough Plasma Imatinib Levels and ABCG2 Polymorphisms Are Correlated with Optimal Cytogenetic Responses at 6 Months After Treatment with Standard Dose of Imatinib In Newly Diagnosed CML

AbstractAbstract 2272To test the correlation of trough plasma Imatinib Mesylate (IM) levels and pharmacogenomic variation with cytogenetic or molecular responses, we measured trough plasma IM levels and analyzed various genetic polymorphisms in newly diagnosed CML patients at 6 months of IM treatment and compared them with the likelihood of achieving cytogenetic complete response (CyCR) or major molecular response to standard dose of IM.Newly diagnosed 94 CML patients were prospectively enrolled in the current study. CyCR was achieved in 71 patients (75.5%). Eighty-four patients (89.4%) showed optimal response (CyCR + cytogenetic partial response CyPR) at 6 months. Trough plasma IM levels were highly variable ranging from 203 to 4980 ng/ml: mean (±SD) was 1392±78.8 ng/ml. Among 47 patients with trough plasma IM level of <1320 ng/ml, 39 patients (83.0%) showed optimal response and 8 (17.0%) suboptimal response. Among 47 patients with trough plasma IM level of ≥1320 ng/ml, 45 patients (95.7%) showed optimal response and 2 (4.3%) suboptimal response (P=0.045). Trough plasma IM level was 1346.0±78.3 ng/ml for the group with non-hematologic toxicity of grade 0 or 1 and 1969.6±365.3 for the group with grade 2–4, which was statistically significant (p=0.038).The impact of single nucleotide polymorphisms (SNPs) in cytochrome P450 (CYP) genes (CYP2D6, CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2B6, CYP2C8, CYP1A2) and transporter genes (hOCT1, hOCT2, hOCT3, ABCG2, ABCC2, SLCO1B1, ABCB1) potentially associated with IM trough level was also investigated. The AA genotype in CYP2C19*2 (681G>A) was significantly associated with higher IM trough level than dominant genotype (p=0.021), whereas transporter genes did not show any significant results. The CC genotype of ABCG2 (421C>A) gene was related with CCyR (OR 3.47, 95% CI 1.09–11.05; p=0.030).In conclusion, the incidence of optimal responses in newly diagnosed CML patients who had been treated with standard dose of IM for 6 months was significantly higher in the patient group with trough plasma IM level of ≥1320 ng/ml than the group with <1320 ng/ml, and the trough level of IM was influenced by CYP2C19 genotype. Checking trough plasma IM level together with cytogenetic and molecular data at milestone timing may guide the clinicians to adopt dose escalation or 2nd tyrosine kinase inhibitors in CML patients showing suboptimal response or resistance to standard dose of IM. Disclosures:No relevant conflicts of interest to declare.

Association Between Imatinib (IM) Transporters and Metabolizing Enzymes Genotype and Response in Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients (Pts) Is Influenced by Ethnicity.

Abstract 3283Poster Board III-1IM is the first-choice treatment in CML and allows to obtain excellent response rates. Some pts, however, experience suboptimal response or resistance, which highlights the need to find biological predictors of outcome in order to guide therapy optimization. Since blood and tissue concentrations of drugs may be influenced by variations between individuals (single nucleotide polymorphisms, SNPs) in genes encoding drug metabolizing enzymes and drug transporters, we have investigated if SNPs influencing the delivery if IM to target cells may account for differences in response. To test that hypothesis, we have genotyped a panel of SNPs known to affect the activity of the cytochrome p450 family isoforms and of the transporters that have been implicated in IM metabolism and transport in a subset of pts enrolled in the TOPS trial -; a randomized phase III study of IM 400 mg/d vs IM 800 mg/d in newly diagnosed CML (Cortes et al, ASH 2008). Included in this analysis were 18 SNPs in 7 genes: hOCT1 (ins/del, rs12208357, rs683369, rs4646277, rs4646278, rs2282143); ABCB1 (rs60023214, rs1128503, rs10245483, rs3213619, rs1128501), ABCG2 (rs2231137, rs2231142); OCTN1 (rs1050152); OATP1A2 (rs11568563); CYP3A5 (rs28365083, rs776746); CYP3A4 (rs28371759). Genotype distributions were tested for Hardy-Weinberg equilibrium (HWE). Additive models were used to assess association between individual SNPs and three response outcomes: major molecular response (MMR) at 12 months, optimal CgR and optimal response as defined by European LeukemiaNet (ELN) recommendations (Baccarani, Blood 2006). Summary measures based on SNPs from the same gene and those related functionally (uptake and efflux) were defined as the number of alleles, across the genes of interest, hypothesized to be associated with favorable response. Association of individual SNPs and summary variables with response was assessed with logistic regression models and likelihood ratio and exact tests. A total of 166 pts were genotyped, out of which 133 whites from Italy (N=21), the U.S.A. (N=66) and Australia (N=46); 22 Asian from Korea (N=17), Italy (N=1), and Australia (N=4); and 11 non-white and non-Asian from the U.S.A (N=6) and Australia (N=5). Selection of pts was based exclusively on availability of a written informed consent for correlative substudies and of a sufficient amount of archived DNA material. The response rates by 12 months among the subset of pts analyzed were 51% for MMR, 87% for optimal cytogenetic response according to ELN, and 85% for optimal response according to ELN. Our analyses have identified four monomorphic, non-informative SNP ( hOCT1: rs4646278, rs2282143; MDR1: rs1128501; and CYP3A4: rs28371759). The results have shown, when analyzing the patient population as a whole, that no association could be found between individual SNPs and any of the response variables considered. However, among whites, but not other pts, we have observed a trend of association between achievement of MMR and two SNPs in the hOCT1 and CYP3A5 genes. Namely, the wild type allele for hOCT1 rs683369 was associated with a higher response rate compared to heterozygote and homozygote mutants (60% vs 36%, p=0.057). Also, the mutant allele for CYP3A5 rs28365083 was associated with a higher response rate (p=0.058). In the subset of pts from the U.S.A, there was a evidence of association between achievement of MMR and three SNPs in the hOCT1 and MDR1 genes. Those with the wild type allele for hOCT1 ins/del had a lower MMR rate compared to those carrying at least one minor allele (48% vs 81%, p=0.08). The wild type for hOCT1 rs683369 was associated with a higher response rate compared to heterozygote and homozygote mutants (65% vs 36%, p=0.05). MDR1 rs60023214 (p=0.08) and the MDR1 gene summary measure of total number of favorable alleles among all MDR1 SNPs (p=0.08) were correlated with MMR, with improved response in the wild type group. Our study suggests for the first time a role of ethnicity in determining correlations between SNP-based molecular signature and response to treatment. If confirmed by larger studies, this suggests that ethnicity should be taken in consideration to better interpret pharmacogenetic analyses in CML and could explain the differences in results of the studies published so far. Supported by Novartis Oncology, Clinical Development, TOPS Correlative Studies Network Disclosures:White:Novartis and Britol-Myers Squibb: Research Funding. Baccarani:Novartis: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau.

Pharmacogenomic Factors Such as the Expression of Imatinib Transporters (OCT-1, ABCB-1 and ABCG-2) at Diagnosis, OCT-1 SNPs, and Steady-State Imatinib and Desmethyl-Imatinib Trough Plasma Levels in De Novo Chronic Phase Chronic Myelogenous Leukemia, May Influence Disease Response to Imatinib

The treatment of chronic myelogenous leukemia (CML) with imatinib mesylate (IM) has dramatically improved the prognosis of this disease, notably for chronic phase (CP) patients. However, a significant proportion of CP patients may progress along the years and it is important to identify early markers of poor response in order to offer to such patients the best alternative treatment. It has been demonstrated recently that the activity of some membrane transporters such as the organic cation transporter 1 (OCT-1), and ATP-binding cassette transporters (ABCB-1 and ABCG-2) may modify IM intracellular concentrations within leukemic cells and influence disease response and survival. In this study, we enrolled 76 CP CML patients (47M, 29F) at diagnosis and we measured in 66 patients on peripheral blood (PB) samples with RQ-PCR, the levels of OCT-1, ABCB-1 and ABCG-2 and analyse the impact on disease response and steady-state plasmatic IM and desmethyl-IM trough concentrations. The transporter data generated were normalised using a pool of peripheral blood samples from 10 healthy blood donors. Additionally, OCT-1 SNPs in exons 1 to 9 have been analysed in 41 patients out of 76. Median age at diagnosis was 50.3 (18.1–81.8) years, Sokal score was high for 16 (21%), intermediate for 34 (45%) and low for 23 (30%) patients and unknown for 3 (4%), Hasford score was high for 5 (7%), intermediate for 29 (38%), low for 30 (39%), and unknown 12 (16%). IM alone was initiated at 400 mg/day for 50 patients, 600 mg/day for 3 patients, IM was associated to monthly subcutaneous courses of 14 days Cytarabine in 13 patients and to Peg-IFN-a in 10 patients the first year of treatment. Heighty eight percent of patients were in optimal cytogenetic response (PCyR) at 6 months. Seven percent, 33%, 39%, 46%, 59% and 63% of patients were in major molecular response [MMR, BCR-ABL/ABL (IS) <0.1%] at 3, 6, 9, 12, 18 and 24 months respectively. Univariate analysis demonstrated a significant correlation (p=0.04) between ABCG-2 RQ-PCR levels at diagnosis and the proportion of patients in MMR at 6 months, between ABCB-1 levels and MMR at 12 months (p<0.01), and between OCT-1 levels and MMR at 24 months. A conditional logistic-regression model was used to analyse associations between molecular responses and transporter RQ-PCR levels, age, gender, Sokal and Hasford scores, and showed that only ABCB-1 levels were a favourable factor on the MMR rate at 12 months (HR= 2.62, 95%CI= 2.32–6.10). Logrank test did not find any significant impact of transporters levels, IM and desmethyl-IM trough concentrations, on disease progression. More extensive statistical analysis will be presented. OCT-1 SNPs analysis identified 3 patients with polymporphisms reported to decrease the enzymatic activity of OCT-1 (exon 1) and 1 patient with a polymorphism reported to fully abolish OCT-1 activity (exon 1). However, these 4 patients showed optimal cytogenetic and molecular responses, suggesting the involvement of other mechanisms in the regulation of the response to IM. Ten patients were identified with OCT-1 polymorphisms (in exons 2, 3 and 7) reported not to influence the enzymatic activity of this protein. In conclusion, the activity of these transporters (as assessed by RQ-PCR) may have some impact on the molecular response of CP CML to front-line IM therapy, however, the interrelationships between the different transporters in conjunction with other factors (drug-drug interactions, genetic background…) do not contribute to clearly distinguish one transporter more than another as a key prognostic factor for IM-molecular disease control.

Hematologic remission and cytogenetic improvement after treatment of stable‐phase chronic myelogenous leukemia with continuous infusion of low‐dose cytarabine

Prolonged exposure to low concentrations of cytarabine preferentially inhibits in vitro growth of neoplastic myeloid progenitors from patients with chronic myelogenous leukemia (CML) compared to that of normal myeloid progenitors. Continuous infusions of cytarabine in doses of 15-30 mg/m2/day were therefore administered for extended periods to patients with CML in stable phase to determine if this treatment could achieve selective cytoreduction of Philadelphia chromosome (Ph)-positive cells. Five patients demonstrating > 90% Ph-positive metaphases before treatment received a total of 43 cycles of cytarabine infusional therapy. Cytarabine was administered on an outpatient basis using a portable, battery-operated syringe pump until the total leukocyte count reached 2500/microliters or the platelet count reached 75,000/microliters. A new cycle was begun when the total leukocyte count exceeded 4,000/microliters and the platelet count exceeded 100,000/microliters. The median duration of cytarabine administration per cycle was 29 days (range 15-72 days). Leukocytosis was readily controlled by low-dose cytarabine therapy in all patients. All five patients experienced complete hematologic responses during cytarabine therapy. The fraction of Ph-positive metaphases in the marrow of the five patients was reduced to 0, 10%, 43%, 72%, and 84%, respectively, during therapy. The median time to achieve optimal cytogenetic response was 4.8 months (range 2.8-8.6 months). One patient demonstrated a complete cytogenetic response after three cycles of cytarabine. Another patient demonstrated persistent cytogenetic improvement during 20 cycles of cytarabine, with a median 38% Ph-positive marrow metaphases (range 10-53%) over 32 months. Cytarabine therapy was generally well-tolerated, but was discontinued in one patient because of persistent asymptomatic elevations in hepatic enzymes, which resolved within 2 months after discontinuing therapy. There were no episodes of fever during neutropenia, and platelet transfusions were not required. However, symptomatic anemia requiring transfusion of red cells occurred during most cycles of treatment. In summary, treatment of CML with low-dose cytarabine can induce prolonged cytogenetic improvement in some patients with acceptable toxicity. Further evaluation is needed to ascertain the effect of this treatment on duration of stable phase and overall survival.