Achievement Of Early Molecular Response Research Articles

Outcomes in Patients with Chronic Myeloid Leukemia in the Chronic Phase Randomized to Dasatinib or Imatinib after Suboptimal Responses to 3 Months of Imatinib Therapy: Final 5-Year Results from DASCERN

Introduction: Dasatinib has demonstrated superior responses versus imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in the chronic phase (CML-CP) (Cortes JCO 2016). Achievement of early molecular response (EMR; BCR::ABL1 ≤ 10% International Scale [IS]) at 3 months increases the probability of subsequent deep molecular response (DMR) and improves survival (Cortes JCO 2016, Hochhaus Leukemia 2016). However, ⅓ of pts treated with imatinib did not reach an EMR (Hughes Blood 2014); there are no standard treatment strategies for these pts. DASCERN (NCT01593254) is the first prospective, randomized, phase 2b trial to demonstrate the potential benefit of switching early to dasatinib in pts with no EMR after 3 months of initiating imatinib. At 12 months, pts randomized to dasatinib had significantly higher major molecular response (MMR) rates versus imatinib (29% vs 13%, primary endpoint) (Cortes Leukemia 2020). At 3 years, cumulative MMR rates were 67% and 40% with dasatinib and imatinib, respectively (Cortes EHA 2020 EP756). Switching to dasatinib did not increase the incidence of treatment-emergent adverse events (AEs). Here we report the results from the final 5-year analysis. Methods: Pts with complete hematologic response but no EMR at 3 months after initiating imatinib 400 mg were randomized 2:1 to an early switch to dasatinib (100 mg) or continue imatinib (≥ 400 mg). Pts who experienced subsequent failure with imatinib (per European LeukemiaNet 2013 recommendations at the time of the study) crossed over to dasatinib. The intent-to-treat (ITT) population included all pts randomized to each arm, irrespective of crossover status. Study endpoints included time to MMR and molecular response 4.5 (MR4.5; 4.5-log reduction in BCR::ABL1 levels; ≤ 0.0032% IS), progression-free survival (PFS), overall survival (OS), and safety. Results: At a median follow-up of 80 months (data cutoff, April 24, 2022), 174 and 86 pts with no EMR after imatinib were randomized to dasatinib and imatinib, respectively; 46 (53%) imatinib-randomized pts experienced subsequent imatinib failure and crossed over to dasatinib in a median of 9.5 months. Detailed baseline characteristics have been previously reported (Cortes EHA 2020 EP756). The median age was 37 years, and 73% of patients were Asian. All pts discontinued treatment, mainly due to study drug toxicity (26 [10%]), and other reasons (176 [68%], mostly study completion); 6 (2%) discontinued due to death. The MMR rate by 5 years in the ITT population was 77% and 44%, respectively, for pts in the dasatinib and imatinib arms. After accounting for crossover, cumulative MMR rates were 74% with dasatinib and 44% with imatinib; 65% of pts who crossed over from imatinib to dasatinib achieved MMR (Figure). Across the 5-year study period, more pts randomized to dasatinib than imatinib achieved MR4 and MR4.5 (MR4, 52% vs 31%; MR4.5, 36% vs 26%). Only 1/46 pts who later crossed over to dasatinib after imatinib failure achieved MR4.5. PFS in the ITT population was 94% in both treatment arms. PFS was numerically lower in pts who later crossed over to dasatinib after imatinib failure (90%). OS in the ITT population was similar between both arms (96% vs 95%). OS in pts who crossed over to dasatinib was 94%. Six additional deaths were reported since the 3-year follow-up. Any grade treatment-related AEs were experienced by 149 pts (87%) randomized to dasatinib, 69 (80%) randomized to imatinib, and 37 patients (80%) who crossed over to dasatinib. Treatment-related pleural effusion occurred in 31 pts (18%) randomized to dasatinib (n = 6 grade 3/4), 9 pts (20%) who crossed over to dasatinib after imatinib failure (n = 2 grade 3/4), and 0 pts who remained on imatinib (no crossover). Conclusions: At the final 5-year follow-up, sustained clinical benefit was observed from an early switch to dasatinib after suboptimal responses to 3 months of imatinib. MMR and DMR rates were higher in pts randomized to dasatinib versus imatinib. Overall, the safety profile was consistent with previous reports. These results complement the previous findings that switching to dasatinib promptly after a lack of EMR with imatinib increases the chance of achieving DMR, which may improve outcomes in pts with CML-CP. Therefore, this study further highlights the significance of achieving optimal responses early during treatment. Study support: Funded by Bristol Myers Squibb. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparison of Generic Dasatinib Versus Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia with Reference to Early Molecular Response: Results from a Single-Center, Randomized Controlled Study from India

Background: Chronic myeloid leukemia (CML) is the commonest leukemia in adult population in India. The advent of tyrosine kinase inhibitors (TKI) targeting BCR-ABL1 fusion transcript in CML has dramatically improved survival of CML patients. Generic formulations of imatinib mesylate have been the mainstay of TKI therapy in Indian CML patients for more than a decade, due to prohibitive costs of 2nd generation TKIs and poor socio-economic status of majority of patients. However, with the availability of generic dasatinib in India since March 2021, the cost of dasatinib therapy has become comparable to that of generic imatinib treatment, thereby enabling more extensive use of dasatinib as first-line TKI therapy in CML patients in India. Achievement of early molecular response (EMR) after 3 months of first-line TKI therapy, defined as blood BCR-ABL1 transcript level ≤ 10% [international scale (IS)], has emerged as an important predictor of favorable long-term outcome in CML-CP. There is scarcity of data on efficacy & safety of generic formulations of dasatinib vis-à-vis generic imatinib in CML-CP patients in India, which the present study has attempted to explore at a tertiary care hospital in India. Objectives: The objectives of the study were to compare early molecular response (EMR) [defined as BCR-ABL1 transcript level ≤ 10%, I.S.] at 3 months of therapy with generic dasatinib versus generic imatinib in newly diagnosed CML-CP patients and to compare treatment-related adverse effects in the two groups. Methods: This randomized controlled study enrolled newly diagnosed CML-CP patients after obtaining institutional ethics committee approval & informed consent. Inclusion Criteria:Newly diagnosed patients with chronic phase CML.Age ≥ 12 years. Exclusion Criteria:Patients with de novo accelerated phase or blast phase CML.Pregnancy & lactation.Patients with pre-existing pleural effusion, grade ≥ 3 lung disease, or pulmonary arterial hypertension.Patients with angina, or grade ≥ 3 cardiac disease [as defined by the New York Heart Association (NYHA) criteria] at diagnosis.Patients with prolonged QTc interval (> 480 msec) at baseline. The EUTOS long-term survival (ELTS) risk score was calculated at diagnosis. Patients were randomized to one of the two following treatment groups: Group A: Dasatinib 100 mg p.o. once daily (60 mg/m2/day for age <18 years). Group B: Imatinib 400 mg p.o. once daily (340 mg/m2/day for age < 18 years). Follow up & monitoring of patients was done every 2 weekly till completion of 3 months of TKI therapy, followed by assessment of hematological response & molecular response as per standard criteria. Results: A total of 61 consecutive CML patients were screened between June 2021 and March 2022, out of which 54 patients with confirmed diagnosis of CML-CP were enrolled in the study and were randomized to receive generic dasatinib or generic imatinib as first-line therapy and were followed up for 3 months for EMR and complete hematological response (CHR). Four patients were lost to follow up and data was analyzed for 50 patients for whom EMR results at 3 months was available. Out of these 50 patients, 24 patients received dasatinib & 26 patients received imatinib. The median age of patients was 33 years (range 18-64 years), with male: female ratio of 1.3: 1. Achievement of CHR was documented in 96% of patients in both dasatinib & imatinib treatment arms. EMR at 3 months was achieved in overall 72% patients in study [19/24 patients (79%) in dasatinib arm & 17/26 patients (65%) in imatinib arm]. However, the difference was not statistically significant (p = 0.27). Notably, EMR rates in ELTS intermediate-risk group was 86% in dasatinib arm versus 42% in imatinib arm, and EMR rates in ELTS high-risk group was 82% in dasatinib arm versus 57% in imatinib arm (p = 0.33). The incidence of grade 3-4 adverse events was not significantly different in the two treatment groups. The patient characteristics & treatment results are summarized in Table 1 & Figure 1. Conclusion: The results of the present study suggested that generic formulations of dasatinib were well-tolerated and were associated with improved early molecular response rates compared to generic imatinib in CML-CP patients in India. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Early and Deep Molecular Responses Achieved with Frontline Asciminib in Chronic Phase CML - Interim Results from ALLG CML13 Ascend-CML

ATP-competitive BCR::ABL1 inhibitors are effective as frontline treatment for many Chronic Phase (CP) CML patients. However, a significant minority of patients experience treatment failure with currently available drugs, due to resistance or toxicities. Asciminib, a first-in-class drug that inhibits BCR::ABL1 by binding to its myristoyl site, is efficacious in patients who have failed 2 or more lines of treatment (Rea et al, Blood 2021). The Australasian Leukaemia Lymphoma Group (ALLG) CML13 ASCEND-CML trial aims to assess its tolerability and efficacy in the frontline setting. ALLG CML13 is a prospective open-label phase II study, enrolling 100 patients over 15 Australian and New Zealand sites. Patients commence treatment with asciminib 40mg twice a day (BID), and are assessed thereafter according to optimal 2020 ELN targets (BCR::ABL1 ≤10%, ≤1% & ≤0.1% at 3, 6, 12 months respectively); and ≤0.01% at 18 months. Patients with treatment failure (BCR::ABL1 >10% at 3 or 6 months; BCR::ABL1 >1% at 12 or 18 months) continue asciminib and add either imatinib, dasatinib or nilotinib, according to physician preference. Patients who have not failed, but have not achieved optimal response at 6, 12, or 18 months, have their asciminib dose doubled to 80mg BID. Co-primary end points are achievement of early molecular response (EMR, BCR::ABL1 ≤10% at 3 months) and major molecular response (BCR::ABL1 ≤0.1%) by 12 months. We report a protocol-specified interim analysis of EMR that allows for reporting of repeated confidence intervals. This trial received funding support from Novartis. By data cut-off at July 15, 2022, the trial remains open to recruitment with 79/100 patients registered, with a median follow-up of 10 (0-19) months. The most commonly reported grade 3/4 adverse events thus far were neutropenia, and thrombocytopenia (n=5 and 4, 5.5% and 5.2%, respectively); as well as increased lipase and amylase without clinical pancreatitis (n=6 & 2; 7.8% & 2.6%, respectively). Grade 3 increased AST/ALT, anaemia, back pain, abdominal pain and infection were each reported once. Nine patients have discontinued asciminib: 1 with persistent grade 4 cytopenia requiring HSCT, 4 with recurrent asymptomatic lipase elevations (including 1 patient who registered but had not started therapy), 1 withdrawn consent and 1 lost to follow-up. Two patients had resistance: 1 had confirmed loss of MMR at 9 months after reaching a nadir of 0.067% at 6 months, without evidence of a kinase domain or myristoyl site mutation; 1 transformed to lymphoid blast crisis at 6 months with myristoyl site mutations A337T (40%), A337V (10%) and P465S (10%), having previously achieved BCR::ABL1 of 0.37% at 3 months. The molecular analysis for EMR includes all registered patients with at least 3 months of follow-up (n=63); 1 patient missed this assessment, and 3/63 patients had withdrawn by this timepoint (all 4 scored as non-responders). EMR was achieved by 59/63 (93.7%; 99.1% CI 81.1-98.9%). By 3 months, 11 patients have already achieved MR4 or better; 29/63 patients achieved MMR (Fig 1 & 2). Three patients had asciminib dose escalation on protocol: 1 patient with BCR::ABL1 of 1.1% at 6 months, and 2 with BCR::ABL1 of 0.34% and 0.43% at 12 months; subsequent molecular results are pending. Trial interim analysis suggest asciminib to have favorable tolerability and efficacy as frontline treatment for CP-CML. The EMR rate is particularly encouraging, and is likely to translate to improved long term outcomes, with higher achievement of deep molecular responses and potentially treatment-free survival. Equally encouraging is the safety profile and early discontinuation rate. Cytopenia and lipase elevations were the most common adverse events, and appear to be ABL1 inhibitor class effects, though clinically relevant pancreatitis has not occurred. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Natural killer cell receptors and ligand variants modulate response to tyrosine kinase inhibitors in patients with chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm treated with tyrosine kinase inhibitors (TKIs). Although survival rates have improved, response to these treatments is highly heterogeneous. Variations in response rates may be due to different causes such as, treatment adherence, mutations in the BCR-ABL1 gene, clonal evolution and amplification of the BCR-ABL1 gene, but innate immune response is also considered to play a very important role and, specifically, NK cell activity through their receptors and ligands, could be determinant. The aim of this retrospective study was to explore the role of different activating and inhibiting KIR genes as well as the activating NKG2D receptor, present in NK cells, and also their respective ligands, HLA-A, -B, -C, -G, -F, MICA and MICB, in the progression of 190 patients with CML and treated at two hospitals from Barcelona between 2000 and 2019. Early molecular response (EMR), major molecular response (MMR) or MR3.0 and deep molecular response (DMR) or MR4.0 were correlated. As control samples, healthy donors from the Barcelona Blood Bank were analyzed. The presence of KIR2DL2/KIR2DS2 was associated with the achievement of EMR, MR3.0, and MR4.0. Carriers of the higher expression NKG2D variant and MICA*009:01 were also likely to achieve molecular response (MR). The most remarkable difference between CML patients and controls was a higher frequency of the lower expression NKG2D variant in CML patients. In summary, our results showed that activating NK receptor phenotypes might help to achieve MR and DMR in CML patients treated with TKIs although confirmatory studies are necessary.

Analysis of Early Events during the First Year of Tyrosine Kinase Inhibitor Therapy in Patients with Chronic Phase - Chronic Myeloid Leukemia: A “Campus CML” Study

Background Tyrosine kinase inhibitors (TKIs) revolutionized treatment of chronic myeloid leukemia (CML). However, the first months of therapy are crucial, as optimal response is defined as the achievement of molecular milestones at 3, 6 and 12 months (mo.) and as many toxicities, also causing a TKI switch, are more frequent in the 1st year.Methods To evaluate achievement of early molecular response (MR) and incidence of events leading to a TKI change during the 1st year of therapy, we retrospectively studied 1650 CP-CML patients diagnosed from 2012 and 2019 at 31 Hematology Centres and treated with frontline imatinib (IM) or second-generation (2G) TKIs dasatinib or nilotinib. Optimal MR at 3, 6 and 12 mo. were assessed according to 2020 ELN recommendations.Results Frontline TKI was IM in 926 (56.1%) and 2G-TKIs in 724 (43.9%) cases: the main clinical features at diagnosis of the entire cohort and according to frontline treatment is reported in the Table 1. Commonest comorbidities were arterial hypertension (38.7%), previous neoplasm (13.6%), diabetes (11.3%), peripheral vascular diseases (7.8%), COPD (7.5%) and ischemic heart disease (6.8%). IM-treated patients were older (p<0.001), with higher ELTS score (int/high 47.6% vs 35.6%, p<0.001) and more comorbidities (p<0.005 for all diseases).Optimal MR was achieved at 3 mo. by 1186/1430 (82.9%), at 6 mo. by 1025/1352 (75.8%) and at 12 mo. by 826/1264 patients (65.3%), respectively.Total number of patients discontinuing TKI in the 1st year was 321/1650 (19.4%), being higher with IM (237/926, 25.5%) than 2G-TKIs (84/724, 11.6%) (p<0.001). Main causes were primary resistance (8.7%, 12.3% IM vs 4.2% 2G-TKIs, p<0.001), extra-hematologic toxicity (6.4%, 8.2% IM vs 4.2% 2G-TKIs, p>0.001), hematologic toxicity (1.7%, 2.0% IM vs 1.4% 2G-TKIs, p=0.25) and progression (1.0%, 1.2% IM vs 0.8% 2G-TKIs, p=0.56). Cumulative incidence of discontinuation at 3, 6 and 12 mo. were 5.6%, 10.7% and 19.3%, respectively; values for IM and 2G-TKIs at the three timepoints were 8.1%, 15.0%, 25.5% and 2.5%, 5.3%, 11.5% (p<0.001) (Fig. 1).Conclusions This real-world study on over 1600 CML patients shows that almost 20% discontinue frontline TKI during the 1st year, mostly for primary resistance or toxicity. Discontinuation rates are higher with IM compared to 2G-TKIs, mostly at 3 mo. and are probably due to a lower attainment of early MR. The impact of older age, higher risks and heavier burden of comorbidities in IM patients should be considered and need deeper investigation. [Display omitted] DisclosuresElena: GILEAD: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; CELGENE: Other: funding for meeting participation. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Stagno: InCyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding. Iurlo: Pfizer: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Bonifacio: Novartis: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Breccia: Pfizer: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Novartis: Honoraria. Latagliata: Novartis: Honoraria; Pfizer: Honoraria; BMS Cellgene: Honoraria.

A Pharmacist-Led Oral Chemotherapy Program's Impact on Chronic Myeloid Leukemia Patient Satisfaction, Adherence, and Outcomes.

Patients with chronic myeloid leukemia (CML) can be treated with oral tyrosine kinase inhibitors (TKIs). Pharmacist-led oral chemotherapy programs (POCPs) can improve TKI adherence rates, but evaluation of patient satisfaction with such programs is rare. The purpose of this analysis was to compare the satisfaction of patients with CML taking TKIs enrolled in a POCP program with that of those not enrolled. Secondary objectives were to assess adherence rates, patient-reported value, early molecular response (EMR) rates, and major molecular response (MMR) rates. This study utilized an anonymous telephone survey of patients who had taken TKIs for at least 3 months. Molecular response was determined by chart review. Of 40 patients surveyed, 50% were enrolled in the POCP, and the POCP group had more African Americans than the non-POCP group. More patients in the POCP were satisfied with their care than in the non-POCP group (100% vs. 75%, p = .047). There were no differences in high patient-reported adherence (55% vs. 60%, p = 1.000), patient-reported value for integrated services (95% vs. 90%, p = 1.000), achievement of EMR (75% vs. 75%, p = 1.000), or MMR (85% vs. 85%, p = 1.000). Patients in the POCP received more structured clinical pharmacy services; however, both groups felt the clinical pharmacist played a major role in their care (85% vs. 90%, p = 1.000). Patients in the non-POCP group reported lower satisfaction than those enrolled resulting from fragmented care that was likely due to external specialty pharmacies. Irrespective of POCP enrollment, patients reported clinical pharmacists play a major role in their therapy and value integration of their specialty pharmacy and medical team.

Early Molecular Response with Generic Imatinib Therapy in Sokal/Hasford Intermediate- & High-Risk Chronic Phase Chronic Myeloid Leukemia Patients: A Single Institution Experience from India

Introduction: Chronic myeloid leukemia (CML) is the commonest adult leukemia in India. Prognostication of newly diagnosed patients of chronic phase CML (CML-CP) is done by calculating pre-treatment risk scores as per Sokal and Hasford scoring systems, and patients are categorized into low-, intermediate- & high-risk groups. According to the latest NCCN guidelines, CML-CP patients with intermediate- or high-risk Sokal or Hasford score may preferentially benefit from second generation tyrosine kinase inhibitor (TKI) treatment. The two second generation TKI drugs available in India are dasatinib & nilotinib. Unfortunately, majority of CML-CP patients in India cannot afford upfront second generation TKI therapy, and generic imatinib is the mainstay of treatment even for intermediate-risk & high-risk patients. Achievement of early molecular response (EMR), defined as BCR-ABL1 (international scale, IS) ≤ 10% after 3 months of first-line TKI therapy, has emerged as one of the most important predictors of favourable long-term outcomes in CML-CP. The present study describes the rate of EMR achievement with first-line generic imatinib therapy in Sokal & Hasford intermediate- & high-risk patients.Objectives: To study the early molecular response rates with generic imatinib therapy at 400 mg/day dose in CML-CP patients with intermediate-risk & high-risk Sokal or Hasford scores.Methods: Our study enrolled 73 newly diagnosed CML-CP patients with intermediate- or high-risk Sokal/Hasford scores between March 2016 and March 2018. All the patients hailed from poor socio-economic background with severe financial constraint, and none of them had any medical insurance. All the patients were treated with generic imatinib mesylate 400 mg/day which was available free of cost at the hospital. None of the patients could afford dasatinib or nilotinib, despite adequate counseling & information regarding the efficacy of 2nd generation TKIs. Treatment response was monitored and defined as per European LeukemiaNet 2013 recommendations. Hematological response was assessed at 3 months for achievement of complete hematologic response (CHR). Molecular response was assessed at 3 months of first-line treatment by quantitative real-time PCR for BCR-ABL1 (IS). Complete data of 65 patients who were compliant to imatinib treatment for at least 3 months were available for analysis. Eight patients were lost to follow up.Results: The median age of patients was 35 years (age range 17 - 72 years; 40 male). CHR was achieved in 92% patients (60 out of 65 patients). Early molecular response at 3 months (BCR-ABL1, IS) ≤ 10%) was documented in 68% (44 out of 65) patients. The range of BCR-ABL1 transcript level at 3 months was 0.01% - 10% in patients who achieved EMR. EMR was not achieved in about 60% of Sokal high-risk patients and 30% of Hasford high-risk patients.Conclusion: The real scenario of CML treatment in developing countries with resource-constrained settings is very much different from that in the developed countries. The response rates to generic Imatinib therapy in Sokal/Hasford intermediate-risk & high-risk CML-CP patients are not impressive. There is scope for significant improvement in treatment response with upfront 2nd generation TKI therapy in intermediate- & high-risk CML-CP patients, if the drugs can be made available at affordable costs in developing countries. DisclosuresNo relevant conflicts of interest to declare.

The hOCT1 and ABCB1 Polymorphisms Don't Condition the Efficacy and Toxicity of Nilotinib As First-Line Treatment: An Italian Multicentric Experience

Introduction. Drug transporters, such as ABCB1, hOCT1, and ABCG2, control both intracellular and systemic plasma concentrations of BCR-ABL1 inhibitors. Our group previously reported that the hOCT1 c.480C>G polymorphism significantly correlated with higher rates of adverse events and shorter event-free survival (EFS) of patients receiving imatinib. Even if nilotinib has less affinity than imatinib for the transmembrane transporters, no definitive data about the possible role of their polymorphisms are available from the "real life".Methods. Through an approach similar to the one previously used for imatinib, we investigated any possible influence of ABCB1 and hOCT1 polymorphisms on the nilotinib efficacy and toxicity in a series of 78 CML patients receiving nilotinib as first-line therapy in 8 Italian Centers from June 2012 to June 2016. Lack of CCyR at 12 months, stop of treatment for any cause, loss of MR3 or CCyR, appearance of mutations were computed as events in the EFS assessment. The following polymorphisms were tested by real-time PCR: hOCT1: rs683369[c.480C>G]; ABCB1: rs1128503 [c.1236C>T], rs2032582[c.2677G>T/A], and rs1045642[c.3435C>T].Results. Forty-six patients were male and 32 female; the median age was 47 years (range, 18-79); Sokal score was low in 44%, intermediate in 37%, and high in 19% of cases; EUTOS was high in 30%. Efficacy: 97% of patients were in CHR and 82% in early molecular response (EMR) at 3 months; 85% achieved the CCyR at 6 months, and 88% the MR3 with a median time of 6.1 months; 78% achieved a deep molecular response (DMR), with 14% of MR5, with a median time of 26 months.With a median follow-up of 36 months, no patient lost CCyR and 9% lost MR3. All patients are still alive; 23% of patients stopped nilotinib (one third of them because of failure), and half of them reduced to<600 mg/day at least once; 3-year EFS was 90%.Patients were grouped according to the absence or the presence of at least one polymorphic allele (heterozygous or polymorphic homozygous): concerning c.3435C>T SNP, 56% of patients were heterozigous and 22% omozigous polymorphic; for the c1236 C>T SNP, 54% of patients were heterozigous and 12% omozigous polymorphic; finally, for the hOCT1 c.480 C>G, 41% of patients were heterozigous and 10% omozigous polymorphic.We found that ABCB1 and hOCT1 polymorphisms did not condition the achievement of CHR, CCyR, or MR3. Nevertheless, polymorphism of ABCB1 (c.3435C>T) was associated with a higher probability of achieving DMR (90% vs 65%; p=0.04).A longer 3-year EFS was conditioned by the achievement of EMR (90% vs 75%; p=0.012) and of MR3 (90% vs 65%: p=0.04). We found that polymorphic or wild-type status of transporters did not impact on EFS.Toxicities were observed in 41% of cases, with 40% of grade 3 or 4; ABCB1 and hOCT1 polymorphisms did not condition toxicities or nilotinib discontinuation.Conclusions. Our previous studies showed that polymorphic hOCT1 negatively conditioned CCyR and EFS during imatinib treatment, and that the combination of ABCB1 and hOCT1 polymorphisms were related to higher levels of toxicity.On the contrary, the present study demonstrated that the same polymorphisms did not condition toxicity when patients received nilotinib as first-line treatment. About efficacy, even if in a multicentric "real life" setting, it resulted superimposable to that reported in literature. We found that hOCT1 polymorphism did not have any impact on the quality of response; on the contrary, the ABCB1 c.3435C>T polymorphism (that induces a lower efflux from the leukemic cell and lower intestinal and renal excretion) was associated to a high rate of deep molecular response.On the basis of these results, we demonstrated that hOCT1 and ABCB1 polymorphisms, differently from the imatinib setting, are not relevant in patients receiving nilotinib, and that patients polymorphic for ABCB1 can even receive an advantage on DMR. DisclosuresSaglio:Ariad: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy.

Comparison of ABL1 and Gusb Reference Genes in the qRT-PCR Analysis of Halving Time and Early Molecular Response to TKI Therapy in Patients with Chronic Myeloid Leukemia

Objectives and background: Early molecular response (EMR) to tyrosine kinase inhibitors (TKI) therapy defined as BCR-ABL1 transcript level ≤ 10% at 3 months is a well-established predictive factor in CML patients. Recently, several study groups presented the concept of BCR-ABL1 decline velocity or "halving time" as a new predictive factor for optimal TKI treatment response. Different reference genes were used in the quantitative RT-PCR (qRT-PCR) analysis to calculate halving time and EMR rate, potentially influencing results of these analyses. The aim of the study was to compare ABL1 and beta-glucuronidase (GUSB) as reference genes used for calculation of halving time and EMR rate in chronic phase CML patients (pts) treated with imatinib 400 mg/d in the clinical settings.Methods: A total of 52 chronic phase CML pts with blood samples collected at baseline and at 3 months of imatinib therapy were investigated. Transcript levels of BCR-ABL1 were determined by qRT-PCR with the use of ABL1 and GUSB as control genes for each patient. Halving time for BCR-ABL1 transcripts was calculated using baseline transcript levels, transcript levels at 3 months of treatment, and number of days between these two points according to methodology reported elswhere1. Using receiver operating characteristic (ROC) analysis, the optimal halving time thresholds for achievement of EMR for each control gene were determined. Optimal thresholds along the ROC curves were calculated using the Youden index.Results: 40 of 52 (76.9%) and 44 of 52 (84.6%) pts achieved EMR with BCR-ABL1 transcripts levels calculated with GUSB and ABL1 as control genes, respectively (p=0.55). In 4 pts there was no BCR-ABL1 transcript reduction from baseline at 3 month using GUSB as a control gene resulting with negative halving times. The GUSB based halving times of these 4 patients were imputed to the longest positive halving time (8530 days) calculated for the patient with the smallest BCR-ABL1 decline. Transcript reduction occurred in all pts when ABL1 was used as a control gene. ROC curve analysis resulted in the optimal halving time thresholds for achievement of EMR of 39 days (area under the curve [AUC ] 0.96, ;95% CI 0.9-1.0, ) and 31 days (AUC 0.95; 95% CI 0.87-1.0, ) for GUSB and ABL1 control gene, respectively.Discussion and Conclusions: Lack of linearity in qRT-PCR analysis observed in blood samples collected in CML patients at diagnosis, with high amount of BCR-ABL1 and wild type ABL1 transcripts could affect the accuracy of early kinetics decline of BCR-ABL1 transcript calculations when ABL1 is used as a reference gene. The analysis with the use of GUSB as a control gene is not biased by this phenomenon. In this study, a non - statistically significant differences in the rate of EMR achieved at 3 months of imatinib therapy and halving time were observed. Analyses performed in our study with ABL1 and GUSB as reference genes suggest that both GUSB and ABL1 are able to identify relevant cut-offs for EMR achievement and could be used for halving time calculation.Reference:Branford S, Yeung DT, Parker WT, et al. Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood 2014 Jul 24;124(4):511-8 DisclosuresZawada:Novartis: Speakers Bureau. Czekalska:Novartis: Speakers Bureau. Sacha:Pfizer: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria.

Early Molecular Response (EMR) with Frontline Treatment Is a Significant Predictor of Long-Term BCR-ABL Transcript Levels in Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia (CML) in Chronic Phase

▪Background: An emerging goal of tyrosine kinase inhibitor (TKI) therapy for patients with CML is to achieve sustained deep molecular response. Several factors, such as efficacy and tolerability of therapy and patient or disease characteristics, may impact treatment success. In this study, the correlation between specified prognostic factors and predicted molecular response levels after 1 year of treatment with nilotinib (NIL) 300 mg twice daily or imatinib (IM) 400 mg once daily was evaluated.Methods: Datafrom the ENESTnd trial comparing frontline treatment with NIL vs IM, in which BCR-ABL1 transcript levels were assessed every 3 months by real-time quantitative polymerase chain reaction on the International Scale (IS), were used to develop a statistical regression model to predict the BCR-ABL1IS category of a patient at any time point after 1 year of therapy. Potential predictors investigated were treatment, EMR status (BCR-ABL1IS ≤ 10% at 3 months), gender, age, Sokal risk score, BCR-ABL1IS categories from the previous 2 assessments, and the proportion of previous BCR-ABL1IS observations at or below MR4. BCR-ABL1IS transcript levels for patients in the NIL and IM arms of ENESTnd were stratified into 5 clinically relevant categories: ≤ 0.0032% (MR4.5), > 0.0032% to ≤ 0.01% (MR4), > 0.01% to ≤ 0.1%, > 0.1% to ≤ 10%, and > 10%. The model was specified to be a second-order Markov chain (to accommodate previous BCR-ABL1IS transcript levels) with ordinal prediction values (for ordered BCR-ABL1IS categorical outcomes).Results: Overall, 522 patients (NIL, n = 258; IM, n = 264) were included in the model, which contributed 5950 usable observations of BCR-ABL1IS transcript levels with corresponding values from the 2 prior assessments. Achievement of EMR (P = .0007), proportion of previous BCR-ABL1IS observations at or below MR4 (P < .0001), and BCR-ABL1IS categories from the previous 2 assessments (both P< .0001) were significant predictors of BCR-ABL1IS category at any time after 1 year of treatment. In our model, neither Sokal risk score nor type of therapy was a significant predictor of BCR-ABL1IS category due to their high correlations with other factors included in the model and which are measured on treatment. For example, more patients in the NIL arm than in the IM arm achieved EMR (91% vs 67%, respectively), which accounted for a lack of model statistical significance for treatment type. Model predictions had good agreement with the observed trial data (Figure).Conclusion: Patients with CML who achieve EMR after initiating frontline TKI therapy have improved long-term treatment responses and survival outcomes. Our model also demonstrates that achievement of EMR is significantly associated with BCR-ABL1IS transcript levels after 1 year. These results add to the growing body of evidence that early response to TKI treatment should be carefully considered to ensure optimal long-term treatment success. [Display omitted] DisclosuresSaglio:Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis Pharmaceutical Corporation: Consultancy, Honoraria. Snedecor:Pharmerit International: Employment, Other: Institution received payment to conduct this study. Ji:Novartis Pharmaceuticals: Research Funding. Tai:Pharmerit International: Employment. Ray:Novartis Pharmaceutical Corporation/Rutgers University: Other: I am currently a fellow with Rutgers University, conducting my "field" experience at Novartis.. Mendelson:Novartis Pharmaceutical Corporation: Employment, Equity Ownership. Buchbinder:Novartis Pharmaceutical Corporation: Employment, Equity Ownership. Edrich:Novartis Pharma AG: Employment. Mahon:Novartis: Consultancy, Honoraria; Pfizer: Consultancy; ARIAD: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria.

Distinct predictive factors influence on achievement of early molecular response by frontline imatinib in chronic phase chronic myeloid leukemia

To explore the factors for achieving early molecular responses (EMR; BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months) by imatinib (IM), baseline characteristics including individual BCR-ABL1 transcript level, dose intensity, and IM trough level on day 29 were analyzed in 286 chronic phase chronic myeloid leukemia patients. Distinct predictive factors for achieving EMR at 3 months and 6 months were noted. Blast count at diagnosis and IM trough level on day 29 were significantly associated with an achievement of 3-month EMR. Early decline of BCR-ABL1 transcript, low Sokal risk, and mean daily dose (≥350mg/day) by 6 months were associated with an achievement of 6-month EMR. Understanding the predictive factors for EMR may provide additional information to guide clinical decisions on the changing therapies at each landmark.

European Treatment and Outcome Study (Eutos) Score Predicts Early Molecular Response to Imatinib Therapy in Chronic Phase Chronic Myeloid Leukemia Patients (Cp-Cml)

rd month using quantitative RT-PCR. Results were expressed as BCR-ABL/ABL ratio. Early molecular response (EMR) was defined as a transcript level ≤ 10%. Univariate and multivariate analysis (Linear regression) was performed to identify potential factors associated with the achievement of EMR. Univariate analysis (Linear regression) with RQPCR value at 3 rd month as dependent variable in relation to the other continuous variables was performed. Variables showing statistically significant association with the outcome (EMR at 3 rd month) at p < 0.05 were considered as candidate variables for inclusion in the multivariate model. Multivariate analysis (linear regression) was performed with the potential candidate variables as the co-variates. SPSS software version 17.0 was used for analysis. Results: The study population included 68 newly diagnosed patients of CP-CML, of which 55.88% (38) were males. The median age at diagnosis in our cohort was 46 years. According to Sokal risk stratification 55.88% (38), 33.82% (23) and10.29% (07) were in high, intermediate and low risk respectively. As per Hasford risk stratification score 25% (17), 61.76% (42), and 13.24% (09) were in high,intermediate and low risk respectively. EUTOS score stratified 58.82% (40) of patients as high risk and 41.18% (28) as low risk. 69.12% (47) of patients had b3a2 transcript and 30.88% (21) had b2a2 transcripts. 32.35% (22) achieved EMR at 3 rd month. In univariate analysis, spleen size (p= <0.001),pretreatment basophil percentage(p= <0.001),WBC count at 3 rd month (p = 0.006),percentage of Ph+ metaphases at 3 rd month(p = 0.009) and EUTOS score (p = < 0.001) significantly predicted the achievement of EMR. In multivariate analysis spleen size(p = 0.01), pretreatment basophil percentage(p = < 0.001) and EUTOS score (p = < 0.001) significantly predicted the achievement of EMR. Conclusions: EUTOS score at diagnosis predicts early molecular response to imatinib therapy at 3 rd month.

Second-Line Therapy for Patients With Chronic Myeloid Leukemia Resistant to First-Line Imatinib

The treatment of chronic myeloid leukemia (CML) with BCR-ABL1 tyrosine kinase inhibitors (TKIs) is highly effective in reducing disease burden and prolonging overall survival in the majority of patients. Up to one-third of patients who initiate first-line TKI therapy with imatinib, however, experience resistance to treatment, presenting as a lack or loss of response or as disease progression. Sokal or Hasford risk score at baseline and achievement of early molecular response to treatment may help identify patients at risk for resistance to first-line TKI therapy and poor prognosis. Approximately half of the patients with resistance to TKI treatment have mutations in the BCR-ABL1 kinase domain. Mutation status can be informative and should be considered alongside other factors, including patient history and drug safety profile, in second-line treatment choice. Factors present at the time of initiation of second-line TKI therapy, such as response to initial therapy, as well as achievement of molecular response within the first 6 months of second-line TKI therapy, have value in predicting response and survival outcomes. Given the expanding number of therapeutic options currently approved (FDA), an understanding of the clinical data supporting each of the options for second-line treatment would enable clinicians to develop treatment plans based on the best evidence-based information. This review estimates the incidence rate of TKI resistance that might be expected in the first-line setting, outlines practical approaches to determine TKI resistance, and discusses the factors that clinicians should consider when making a second-line treatment choice.

ENESTnd Update: Nilotinib (NIL) Vs Imatinib (IM) In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) and The Impact Of Early Molecular Response (EMR) and Sokal Risk At Diagnosis On Long-Term Outcomes

ENESTnd Update: Nilotinib (NIL) Vs Imatinib (IM) In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) and The Impact Of Early Molecular Response (EMR) and Sokal Risk At Diagnosis On Long-Term Outcomes