Achievement Of Major Cytogenetic Response Research Articles

Outcome of 3q26.2/MECOM rearrangements in chronic myeloid leukemia.

To evaluate the outcomes of patients with 3q26.2/MECOM-rearranged chronic myeloid leukemia (CML). We reviewed consecutive adult patients with 3q26.2/MECOM-rearranged CML between January 1, 1998 and February 16, 2023. Rearrangements of 3q26.2/MECOM were confirmed by conventional cytogenetics, and fluorescence in situ hybridization starting in 2015. We identified 55 patients with MECOM-rearranged CML, including 23 in chronic phase (CP) or accelerated phase (AP) and 32 in blast phase (BP). Nine patients (16%) achieved a major cytogenetic response (MCyR) or deeper. At a median follow-up of 89months, median survival was 14months. The 5-year survival rate was 19% overall, 23% in CML-CP/AP, and 15% in CML-BP. In the 6-month landmark analysis, the 5-year survival rate was 41% for allogeneic stem cell transplantation (allo-SCT) recipients versus 17% for non-recipients (P = 0.050). Multivariate analysis showed that the percentage of marrow blasts and achievement of MCyR or deeper could predict survival. Outcomes of 3q26.2/MECOM-rearranged CML are poor despite the availability of multiple BCR::ABL1 tyrosine kinase inhibitors (TKIs). Third-generation TKIs in combination with novel agents and possible allo-SCT could be considered given the poor outcomes and resistance to second-generation TKIs.

Predictive factors associated with achievement of major cytogenetic response (MCyR) to omacetaxine mepesuccinate among patients with chronic phase chronic myeloid leukemia (CML-CP).

7088 Background: Omacetaxine mepesuccinate (OMA), a first-in-class cephalotaxine, is a protein synthesis inhibitor not dependent on Bcr-Abl signaling. OMA has shown clinical activity in CML patients resistant/intolerant to tyrosine kinase inhibitors (TKIs). This subanalysis of 2 phase 2 studies examines predictors of MCyR to OMA in patients failing ≥2 TKIs. Methods: OMA 1.25 mg/m2BID was given in 28-day cycles: ≤14 days for induction, ≤7 days for maintenance. MCyR was defined as ≤35% Ph+ metaphases in bone marrow. A full logistic regression model with 11 baseline parameters was examined by Hosmer and Lemeshow Goodness-of-Fit test. Results: Of 81 patients (median age 59 y; range 26-83), 16 (20%) achieved MCyR. Mean (SD) baseline body surface area (BSA) was 1.90 kg/m2(0.240). Median time since last TKI to start of study was 1.3 mo (range 0.2-28.0) and median time from diagnosis was 75.4 mo (range 7.9-234.3). The final model had 8 baseline predictors (goodness of fit of p=0.1473; Table). (Sex, 2 vs 3 TKIs, or status of any mutation were not in the final model.) Logistic regression analysis showed a significant association between MCyR and no hydroxyurea (HU) use at baseline (p=0.0118). Numerically higher MCyR rates occurred in patients with baseline CHR and BSA ≥1.94 kg/m2. Conclusions: This small sample suggests that omacetaxine may be an important option for a range of patients, regardless of Bcr-Abl T315I mutation status. Prior HU may indicate more proliferative disease. Support: Teva BPP R&D, Inc. Clinical trial information: NCT00375219, NCT00462943. [Table: see text]

Efficacy and Safety of Radotinib in Chronic Phase Chronic Myeloid Leukemia Patients with Resistance or Intolerance to BCR-ABL Tyrosine Kinase Inhibitors: Radotinib Phase 2 Clinical Trial

AbstractAbstract ▪695▪This icon denotes a clinically relevant abstract BackgroundRadotinib is a novel, selective Bcr-Abl tyrosine kinase inhibitor (TKI) developed by IL-YANG Pharm, South Korea. Radotinib showed a good efficacy and safety profile to chronic myeloid leukemia (CML) in preclinical and phase 1 clinical studies. To investigate the clinical efficacy and safety of radotinib 400 mg twice daily, data from CML patients treated during phase 2 clinical trial are reported. MethodsPhiladelphia chromosome (Ph+)-positive chronic phase CML (CP-CML) patients who failed or were intolerable to TKIs (imatinib and/or dasatinib and/or nilotinib) were enrolled between July 2009 and November 2011. Patients were treated with radotinib 400 mg twice daily for 12 cycles (1 cycle=4 weeks). The primary end point was an achievement of major cytogenetic response (MCyR, Ph+£35%) by 12 months. Safety parameters were also analyzed. ResultsA total of 77 CP CML patients (18 years of age or over) were enrolled from 12 sites in Korea, India, and Thailand. This analysis includes data from last enrolled patient who received at least 3 months of radotinib therapy. The median age of patients was 47 (range; 24–76) years, and 65 (84.4%) were imatinib-resistant and 12 (15.6%) were imatinib-intolerant. Four patients also had intolerance to dasatinib. With a median follow-up of 10.6 months, treatment with radotinib is ongoing in 46 patients (59.7%) and 31 patients (40.3%) discontinued the treatment including two deaths (2.6%). However, there were no CML-related deaths. Median duration of radotinib exposure was 296 (8–798) days. Overall MCyR rate was 63.6%, including 35 patients (45.4%) complete cytogenetic response and 14 patients (18.2%) partial cytogenetic response. The median time to MCyR was 2.8 months (85 days) and the median duration of MCyR was 315 (range; 5–726) days. Of patients achieving complete cytogenetic response, 37% (13/35) achieved major molecular response. Within follow-up durations, 44 patients (57.1%) required dose interruption and 41 patients (53.3%) had dose reduction. Most common grade 3/4 hematologic and laboratory adverse events (AEs) were thrombocytopenia (27.3%), neutropenia (10.4%), anemia (6.5%), and hyperbilirubinemia (31.2%). Common non-hematologic AEs were rash (29.8%), fatigue (14.3%), nausea/vomiting (14.3%), headache (13.0%), and pruritus (11.7%). The majority of AEs were easily manageable with temporal dose interruption and/or reductions. In all patients with CP-CML treated with second-line radotinib, estimated progression-free survival and overall survival rate at 12months was 84.9% (95% CI, 72.7–92.0%) and 97.4% (95% CI, 89.9–99.3% ), respectively. ConclusionRadotinib phase 2 trial confirmed the efficacy and safety of radotinib 400 mg twice daily in patients with CP-CML after failure to TKIs. Most of the AEs occurred in the early treatment period, were tolerable, and were easily controlled by dose interruption or reduction.TableSummary of patients' characteristics, efficacy, and safety profile.Total patientsN=77Age47 (24-76) yearsGendermale54 (70.1%)female23 (29.9%)Disease status at screeningImatinib resistance65 (84.4%)Resistance42 (54.5%)Resistance + intolerance20 (26.0%)Resistance + intolerance + dasatinib intolerance3 (3.9%)Imatinib intolerance12 (15.6%)Intolerance11 (14.3%)Intolerance + dasatinib intolerance1 (1.3%)Cytogenetic responseComplete cytogenetic response35 (45.5%)Partial cytogenetic response14 (18.2%)Minor cytogenetic response4 (5.2%)Minimal cytogenetic response7 (9.1%)No cytogenetic response14 (18.2%)Not applicable3 (3.9%)Dose modificationDose interruption44 (57.1%)Dose reduction41 (53.3%)Grade 3/4 hematologic adverse eventsThrombocytopenia21 (27.3%)Neutropenia8 (10.4%)Anemia5 (6.5%)The most common grade 3/4 laboratory adverse eventHyperbilirubinemia24 (31.2%)Common non-hematologic adverse events (> 10%)Rash23 (29.8%)Fatigue11 (14.3%)Nausea/vomiting11 (14.3%)Headache10 (13%)Pruritus9 (11.7%) Disclosures:Off Label Use: Radotinib, new BCR/ABL tyrosine kinase inhibitor, treatment for CML. Lee:IL-YANG Pharm.: Employment. Park:IL-YANG Pharm.: Employment. Woo:IL-YANG Pharm.: Employment. Kim:IL-YANG Pharm.: Employment. Lee:IL-YANG Pharm.: Employment. Cho:IL-YANG Pharm.: Employment. Shin:IL-YANG Pharm.: Employment. Kim:IL-YANG Pharm.: Employment. Kim:IL-YANG Pharm.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Clinical Significance of Additional Chromosomal Abnormalities In Ph-Positive and Ph-Negative Cells In Patients with Chronic Myeloid Leukemia Treated by Tyrosine Kinase Inhibitors

Clinical Significance of Additional Chromosomal Abnormalities In Ph-Positive and Ph-Negative Cells In Patients with Chronic Myeloid Leukemia Treated by Tyrosine Kinase Inhibitors

Very Long-Term Follow-up Results of Imatinib Mesylate Therapy in Chronic Phase Chronic Myeloid Leukemia After Failure of Interferon Alpha Therapy

Abstract 2749 Background:The long-term outcome of patients with chronic phase chronic myeloid leukemia treated with imatinib after failure of interferon alpha therapy has not been detailed. Patients and Methods: 368 patients were analyzed. Univariate and multivariate analyses for survival were conducted using standard statistical methods. Results: Overall, 247 patients (67%) achieved complete cytogenetic response (CCyR). Of 327 patients studied, 207(63%) achieved major molecular response (MMR), and 99 (30%) had undetectable BCR-ABL levels at some time on therapy. The estimated 10-year survival rate was 68%, progression-free survival rate 67%, and event-free survival rate 51%. By multivariate analysis, age ≥ 60 years, hemoglobin < 10g/dl, marrow basophils ≥ 5%, any peripheral blasts, and clonal evolution were independent adverse factors for survival. The estimated 7-year survival by the presence of none (n=154), 1–2 (n=190), or ≥ 3 factors (n=24) were 93%, 70%, and 25% respectively (p <0.01). Achievement of MMR, CCyR, or partial cytogenetic response at 12 months were associated with significantly better 10-year survival rate by landmark analysis (10-year survival 80–90%) vs. achieving minor cytogenetic response or complete hematologic response (10-year survival 55–65%) vs. other response (10-year survival 10%). Using landmark analysis to include imatinib response at 12 months, achievement of major cytogenetic response or better (hazard ratio 0.12; p< 0.001) and complete hematologic response or minor cytogenetic response (hazard ratio 0.36; p=0.003) were significant favorable prognostic factors. Conclusions: The estimated 10-year survival rate of 68% in patients with chronic myeloid leukemia receiving imatinib after interferon failure has improved. Disclosures:Cortes:Novartis: Consultancy; Novartis: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

Important Role of Early Therapy and Maintaining Uninterrupted Treatment In the Outcomes of Chronic Myelogenous Leukemia Patients Treated with Imatinib

AbstractAbstract 2300 Introduction:Imatinib mesylate (Gleevec) treatment for Chronic Myelogenous Leukemia (CML) was first introduced in Brazil in 2003, initially used as second line therapy for patients resistant or intolerant to interferon. In 2004 imatinib was adopted as front-line therapy for chronic phase (CP) and clinical experience improving since then. Close monitoring of responses achievement at scheduled time has proven to provide good predictive value for progression and event-free survival. Failure and sub-optimal responses correspond to indications for dose change or therapy switching and the identification of patients at greater risk for such events has a vital role. The aim of this study is to evaluate the impact of temporary imatinib therapy discontinuation on achievement of Major Cytogenetic Response (MCyR) and event-free survival (EFS). Materials and Methods:During the period of 1990 to 2010 a total of 185 patients from 7 CML treatment centers from Rio Grande do Sul, south Brazil, with a confirmed diagnosis of CML (Philadelphia chromosome positive [Ph+]) at CP under imatinib treatment were retrospectively analyzed. A major cytogenetic response was considered complete plus partial cytogenetic responses (Ph+ less than 35%). At least 20 metaphases were analyzed for a cytogenetic response to be evaluable. Temporary treatment discontinuation (TTD) corresponds to 20 days or more off-medication for any reason during the follow-up. Were included patients in imatinib second-line and first-line therapy. Early-imatinib treatment was considered when imatinib started before 12 months from diagnosis and late-imatinib treatment when more then 12 months lapse. EFS was measured from the start of imatinib to the date of any the following events while on therapy: death of any cause, therapy failure, any response loss, disease progression, definitive treatment discontinuation or therapy change. Descriptive statistics and Kaplan-Meier analysis (to estimate event-free survival [EFS]) were performed using SPSS software. Results:The median age at diagnosis was 48 years (range, 4–85 years) median of follow-up was 47 months (range, 7–113 months) and 55% of male sex. Preferential previous treatment was interferon in 70% of the patients and 71% were early-imatinib treatment. TTD was observed in 63/185 patients (34%) and was related to toxicities in 35/63 patients (55%), including hematological and non-hematological. Nonadherence was attributed to the remaining TTD, 28/63 patients (44%). Late-imatinib patients had significant more TTD (62%) than early-imatinib patients (26,2% [p<0,001]). Subgroup analyzes showed that was a significant TTD rate due to toxicity in the late-imatinib patients (p=0,03), but not significant due to nonadherence (p=0,37). Patients who experienced TTD had lower proportion of MCyR at 12 months: only 43% compared to 70% of patients who did not had TTD (p<0,001 [Figure 1]). Finally the TTD had a relevant negative impact on EFS in 5 years. In the group who had TTD EFS was 47,5%, compared with 73% in the group without TTD (p=0,002 Figure 2). Conclusion:In our cohort, patients with TTD were associated with lower rate of MCyR and it may be a risk factor for failure or sub-optimal responses to imatinib therapy. TTD also has a negative effect in terms of EFS in patients under imatinib treatment, possibly related to worsen cytogenetic disease control. The late onset of imatinib therapy correlates with more toxicity leading to treatment interruptions and front-line imatinib therapy should be started as soon as possible. Special attention should be given to patients who presents with side effects of any nature that could preclude the correct use of the medication. Close monitoring and early management of such adverse reactions, frequent assessment of compliance should be warrant as effort to guarantee the best chance for therapy success. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy

Clonal evolution is frequently detected in patients developing resistance to imatinib. The outcome of patients with clonal evolution treated with second generation tyrosine kinase inhibitors is not known. The authors analyzed the outcome of 177 CML patients after second tyrosine kinase inhibitor therapy. Ninety-five patients were in chronic phase, 30 had clonal evolution, 28 were in accelerated phase (AP), and 24 were in AP plus clonal evolution. Major cytogenetic response rates were 58%, 54%, 28%, and 13%; 2-year overall survival (OS) rates were 86%, 73%, 68%, and 33%; and 2-year event-free survival (EFS) rates were 69%, 67%, 31%, and 8%, respectively. The hematologic and cytogenetic response rates, OS, and EFS were no different between patients in chronic phase with clonal evolution and patients with chronic phase and no clonal evolution. However, clonal evolution had a significant adverse impact when associated with other features of AP. On multivariate analysis, clonal evolution had no independently significant effect on achieving major cytogenetic response on the second generation tyrosine kinase inhibitors. The factors predicting increasing major cytogenetic response to second generation tyrosine kinase inhibitors were prior achievement of major cytogenetic response with imatinib, higher hemoglobin levels, no splenomegaly, lower percentage of Philadelphia chromosome-positive metaphases, and no prior chemotherapy. Clonal evolution constitutes a heterogeneous entity with variable outcome with second generation tyrosine kinase inhibitors, with trisomy 8, chromosome 17, and complex abnormalities having the worst outcome, regardless of the number of metaphases involved. The molecular events behind these abnormalities and potential therapeutic approaches directed at them need to be defined.

Prognostic Factors for Progression-Free Survival in Patients with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Nilotinib Based On 24 Month Data.

Abstract Abstract 3298 Poster Board III-186 Background Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor, approved for the treatment of patients with Ph+ CML in CP or AP who are resistant or intolerant to imatinib therapy. After 24 months (mos) of follow-up of imatinib-resistant and -intolerant patients treated with nilotinib in the pivotal phase II study, achievement of major cytogenetic response (MCyR) was demonstrated in 59% of patients and complete cytogenetic response rates (CCyR) in 44% of patients. The purpose of the analysis was to identify baseline disease factors or time-dependent response endpoints that predict for progression-free survival (PFS). Methods Imatinib-resistant and -intolerant CML-CP patients (N = 321) were treated with nilotinib 400 mg twice daily. A Cox regression model was performed on 21 baseline disease factors or response endpoints. The effect of these factors on PFS was evaluated. Progression was defined as death or discontinuation due to disease progression or progression to accelerated phase or blastic phases. Q-PCR data for BCR-ABL were not included. Patients with T315I mutation at study entry were excluded (n=6). Results Ten factors were included in the multivariate analysis that were all identified as significant factors in the initial univariate analysis (at a significance level of 0.05): minor CyR (≤ 65% Ph+ metaphases) at or before 6 mos, MCyR at or before 12 mos, baseline complete hematologic response (CHR), highest prior imatinib dose (&lt; 600 mg/day), absence of baseline mutations, absence of mutations with low sensitivity (E255K/V, Y253H, F359C/V), intolerance to imatinib (vs resistance), baseline hemoglobin (Hb; continuous variable), baseline basophilia (continuous variable), and baseline percent Philadelphia positive (Ph+) metaphases (continuous variable). One other marginally significant factor was included in the multivariate analysis (prior response to CML therapy). Following the multivariate analysis of these 11 factors, only 4 were found to be independently significant, including: MCyR at or before 12 mos (hazard ratio, HR = 0.359, P &lt; 0.0001); baseline hemoglobin ' 120 g/L (HR = 0.985, P = .0291); baseline basophils &lt; 4% (HR = 1.070, P = .0128) and the presence of baseline mutations with low sensitivity to nilotinib (E255K/V, Y253H, F359C/V) (HR = 6.097, P = &lt;.0001). The four binary factors (baseline basophilia ≥ 4%, baseline Hb &lt; 120 g/L, low sensitivity mutations and MCyR at or within 12 mos nilotinib therapy) were then combined to create a single prognostic score with values between 0 (best) and 4 (worst). Based on these scores, patients were stratified into 5 prognostic subsets with the best group having none of the 3 unfavorable disease risk factors and had MCyR at 12 mos while patients in the worst group had all of the 3 unfavorable disease risk factors and no MCyR at 12 mos. The 24 mo PFS rates for patients based on prognostic scores are shown in Table 1. As expected, PFS rates decreased with increasing risk scores. When only considering patients with at least 12 months follow-up the respective 24 mo PFS rates are 90%, 79%, 67%, and 37% (no patients with prognostic score of 4), for patients with prognostic scores of 0, 1, 2, and 3, respectively. The multivariate analysis did not find that at least minor CyR or PCyR responses at or within 6 mos of initiation of nilotinib significantly influenced 24 mo PFS compared to these other factors. Conclusion The preliminary results of this multivariate analysis of 21 disease or response factors identified 4 factors that predict for PFS in imatinib-resistant and -intolerant patients receiving nilotinib therapy in this large dataset. The achievement of MCyR by 12 mos, lack of baseline mutations with low sensitivity to nilotinib, baseline Hb &gt; 120 g/L, and baseline basophilia (&lt; 4%) were all associated with the most favorable PFS on nilotinib therapy. These results suggest that even in the presence of poor disease characteristics, nilotinib therapy provides patients with clinical benefit as measured by PFS. This developed risk model may be useful to determine the benefit of continued nilotinib therapy versus allogeneic transplant. Disclosures Jabbour: Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Giles:Novartis: Consultancy, Research Funding; BMS: Research Funding; Merck: Research Funding; Clavis: Research Funding. Bhalla:Novartis: Honoraria, Research Funding; Merck: Honoraria. Pinilla-Ibarz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Larson:Novartis: Consultancy, Honoraria, Research Funding. Gattermann:Novartis, Celgene: Honoraria, Participation in Advisory Boards on deferasirox clinical trials, Research Funding. Ottmann:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Wang:Novartis: Employment. Woodman:Novartis: Employment. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. le Coutre:Novartis: Honoraria, Research Funding; BMS: Honoraria. Cortes:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Wyeth: Honoraria, Research Funding, Speakers Bureau.

Cytogenetic and molecular responses and outcome in chronic myelogenous leukemia

Response rates in chronic myeloid leukemia (CML) are now reported based on the cumulative incidence of a single-time best response. The study aim was to examine the significance of different response criteria for CML on imatinib therapy. In all, 276 patients with chronic phase CML on imatinib therapy were analyzed. Cytogenetic and molecular responses were coded as to single best response and response at specific intervals of treatment. The cumulative incidence of complete cytogenetic response (CGCR) with imatinib was 91%; however, the incidence of CGCR at 48 months into therapy was only 78%. Similarly, the incidence of major molecular responses (best cumulative vs landmark at 48 months) were 74% versus 62%, and of undetectable BCR-ABL transcripts 38% versus 24%. There was a strong association between achievement of major cytogenetic response (Philadelphia chromosome [Ph]-positivity <or=35%) at 6 months to 12 months and survival as well as progression-free survival (PFS). Achievement of major molecular response (vs lesser molecular response) in patients in complete cytogenetic response was not associated with significant differences in survival, but showed some association with PFS. Durable CGCR and major molecular responses (documented continuously for >or=12 months) were associated with longer PFS duration but not with survival duration differences. Of interest, major molecular responses documented at least twice were noted in 71% of patients on imatinib therapy; undetectable BCR-ABL transcripts documented at least twice were noted in 34%. Achievement and durability of CGCR and of major and complete molecular responses at landmark times predict outcome in CML, and may help in comparing the efficacy of different treatments.

Long-Term Significance of Achieving a Major Cytogenetic Response (MCyR) without a Complete Hematologic Response (CHR) among Patients (pts) with Chronic Myeloid Leukemia (CML) in Advanced Phase Treated with Second Generation Tyrosine Kinase Inhibitors (TKI).

The BCR-ABL TKI, dasatinib (D) and nilotinib (N), are effective in Philadelphia chromosome-positive (Ph+) leukemias, including all stages of imatinib-resistant CML and Ph+ ALL. For both dasatinib and nilotinib, the reported rates of MCyR are higher than the rates of CHR; that is, some pts achieve MCyR but may have cytopenias that make their hematologic response less than a CHR; this has been attributed to myelosuppression induced by TKI. At present it is not known whether pts with MCyR who do not have CHR have a similar outcome as those with a CHR. We studied 135 pts with accelerated (AP; n=84) or blast phase (BP; n=47) CML or Ph+ ALL (n=4) treated with D (59) or N (76) for imatinib resistance, to see whether the presence of cytopenias at the time of best response affected the prognosis. The median age was 55 yrs (range, 15 to 98) and 62 were female. 56 (41%) had bcr/abl mutations at the start of therapy. Overall 36 pts (27%) achieved MCyR. All the 36 pts who achieved a MCyR after treatment with N or D had received imatinib for an average time of 34 mos (range 4–78) and 24/36 pts had obtained a MCyR under imatinib. They started the new TKI 66 mos after first diagnosis (12–336). 2-yr survival rates for pts that achieved MCyR was 72% compared to 35% for those without MCyR (p<0.001). There was a trend for an inferior survival for those not having a concomitant CHR at the time of MCyR compared to those with CHR (2-yr survival 58% vs 82%; p=0.11). The rates of CHR and MCyR were 68% and 29%, respectively in AP; 32% and 21% in BP, and 50% and 50% in Ph+ ALL. Among pts in AP, 17/24 (70%) who achieved a MCyR, had a CHR at the time of best cytogenetic response; 6 of these 17 (35%) pts eventually failed (lost response or transformed), compared to 3/7 (43%) of those with no CHR at the time of MCyR (p=0.28). The results are similar when analyzing separately pts treated with N or D. 2-yr survival was 88% and 66% for those with and without concomitant CHR (p=0.29). Among the 10 pts in BP that achieved a MCyR, 5 had a CHR at the time of best cytogenetic response. Three (60%) of these pts eventually failed (lost response), compared to 4 failures among the 5 pts with no CHR at the time of MCyR (p=1.0). Survival rates at 2 yrs were 60% and 40% for those with and without concomitant CHR (p=0.29). Among the 2 patients with ALL that achieved MCyR, one had comcomitant CHR (treated with N) and the other did not have CHR (D); both of them failed. Of the 18 pts who failed after having achieved an MCyR, 7 had a mutation before starting treatment with a 2nd TKI (A433T, G250E, E355G, E459K, M244V, M315T, F317L), and 6 developed a new mutation after treatment (F317L, F311I, Y253H, G476C, E255K, H359V). Five of them occurred in pts with a concomitant CHR and 1 without a CHR. These results suggest that achievement of MCyR with residual cytopenias (ie, without a concomitant CHR) may not have the same favorable outcome as that of MCyR with concomitant CHR. Whether this is related to pt- or disease-related characteristics remains to be determined.

Cytogenetic studies in patients on imatinib

In the management of chronic myeloid leukemia (CML), cytogenetic response (CgR) has been recognized as an important prognostic factor and is used in predicting patient outcome. Imatinib (Gleevec) (formerly STI571), a potent inhibitor of BCR-ABL, is very effective in inducing CgRs in chronic-phase CML patients, even in late chronic-phase patients in whom interferon (IFN) was unsuccessful. This review describes the intrinsic value of a CgR following different forms of nontransplant treatment options for CML. Achievement of major CgR is predictive of prolonged survival with imatinib. In addition, patient prognostic risk score (Sokal or Euro risk score) affects patient outcome. Low-risk patients survive longer than non-low-risk patients given the same CgR. Preliminary results from studies with imatinib are superior and CgR remains an important surrogate marker of survival in the imatinib era. Semin Hematol 40(suppl 2):56-61. © 2003 Elsevier Inc. All rights reserved.

Comments on the Hammersmith policy

In the management of chronic myeloid leukemia (CML), cytogenetic response (CgR) has been recognized as an important prognostic factor and is used in predicting patient outcome. Imatinib (Gleevec) (formerly STI571), a potent inhibitor of BCR-ABL, is very effective in inducing CgRs in chronic-phase CML patients, even in late chronic-phase patients in whom interferon (IFN) was unsuccessful. This review describes the intrinsic value of a CgR following different forms of nontransplant treatment options for CML. Achievement of major CgR is predictive of prolonged survival with imatinib. In addition, patient prognostic risk score (Sokal or Euro risk score) affects patient outcome. Low-risk patients survive longer than non-low-risk patients given the same CgR. Preliminary results from studies with imatinib are superior and CgR remains an important surrogate marker of survival in the imatinib era. Semin Hematol 40(suppl 2):56-61. © 2003 Elsevier Inc. All rights reserved.

The cytogenetic response as a surrogate marker of survival

In the management of chronic myeloid leukemia (CML), cytogenetic response (CgR) has been recognized as an important prognostic factor and is used in predicting patient outcome. Imatinib (Gleevec) (formerly STI571), a potent inhibitor of BCR-ABL, is very effective in inducing CgRs in chronic-phase CML patients, even in late chronic-phase patients in whom interferon (IFN) was unsuccessful. This review describes the intrinsic value of a CgR following different forms of nontransplant treatment options for CML. Achievement of major CgR is predictive of prolonged survival with imatinib. In addition, patient prognostic risk score (Sokal or Euro risk score) affects patient outcome. Low-risk patients survive longer than non-low-risk patients given the same CgR. Preliminary results from studies with imatinib are superior and CgR remains an important surrogate marker of survival in the imatinib era. Semin Hematol 40(suppl 2):56-61. © 2003 Elsevier Inc. All rights reserved.

Expression of interferon-α (IFN-α) receptor 2c at diagnosis is associated with cytogenetic response in IFN-α–treated chronic myeloid leukemia

For the management of chronic myeloid leukemia (CML), prediction or early determination of the response to interferon-alpha (IFN-alpha) treatment is important for identifying nonresponder patients to whom alternative therapy may be proposed. In this study, the levels of expression of both BCR-ABL and subunit 2c of IFN-alpha receptor (IFN-alphaR2c) genes were analyzed at diagnosis in 74 patients with chronic phase CML treated with an IFN-alpha monotherapy. By using blood samples, real-time quantitative polymerase chain reaction was performed to quantify BCR-ABL, IFN-alphaR2c, and G6PDH mRNA as external control. The results were compared with hematologic and cytogenetic responses to IFN-alpha. A wide variation in the BCR-ABL/G6PDH ratio was observed at diagnosis (median, 6.68%; range, 0.18%-41.31%), but no significant association with response to IFN-alpha was observed. In contrast, the variation of IFN-alphaR2c/G6PDH ratio at diagnosis was significantly associated with the achievement of major cytogenetic response (MCR; 34% or lower Ph(+) metaphases). Median values of IFN-alphaR2c/G6PDH ratio for patients achieving MCR and for those who did not achieve it were 110.75% (range, 9.47%-612.30%) and 64.42% (range, 5.96%-425.40%), respectively (P =.037). In addition, this novel molecular factor, combined with the achievement of complete hematologic response at 3 months, makes it possible to predict MCR achievement with high probability by Kaplan-Meier analysis (91% +/- 17% at 24 months; P =.0001). (Blood. 2001;97:3568-3573)

Early treatment decisions with interferon-alfa therapy in early chronic-phase chronic myelogenous leukemia.

To determine, in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) on interferon alfa (IFNalpha), whether combining pretreatment characteristics and early response profiles would distinguish patients with differential benefits that would allow better decisions on subsequent therapy. A total of 274 patients treated from 1982 through 1990 with IFNalpha regimens were analyzed. A second group of 137 patients treated with IFNalpha and low-dose cytarabine (ara-C) between 1990 and 1994 was later used to confirm the guidelines derived from the original study group analysis. Patients' pretreatment factors and response to IFNalpha therapy at 3, 6, and 12 months were analyzed in relation to subsequent achievement of major cytogenetic response. After univariate analysis of prognostic factors, a multivariate analysis selected, at 6 months, independent pretreatment factors that added to the response status in predicting subsequent outcome. The results were then applied at the 3- and 12-month periods and confirmed in the subsequent population. Response to IFNalpha therapy at 3, 6, and 12 months was a significant predictor of later major cytogenetic response. The presence of splenomegaly > or = 5 cm below the costal margin (BCM) or thrombocytosis > or = 700 x 10(9)/L pretreatment added significant independent prediction to response. At 6 months, patients with a partial hematologic response (PHR) or resistant disease had a less than 10% chance of achieving a later major cytogenetic response, as were those in complete hematologic response (CHR) and who had pretreatment splenomegaly and thrombocytosis. Applying the model at 3 months showed that only patients with < or = PHR and pretreatment splenomegaly or thrombocytosis at 3 months had such a low major cytogenetic response rate. Finally, at 12 months, patients with CHR still had a 15% to 25% chance of having a major cytogenetic response later if they did not have pretreatment splenomegaly and thrombocytosis. This analysis allows better selection of patients with Ph-positive CML on IFNalpha therapy for continuation of IFNalpha versus changing therapy early in the course of CML. For treatment programs that choose to change patients to other investigational therapies (eg, intensive chemotherapy and/or autologous stem-cell transplantation [SCT]), baseline outcome expectations are provided for patients continued on IFNalpha therapy, against which the results of new approaches can be compared.