Accelerated Phase/blast Crisis Research Articles

Nilotinib Shows Safety and Efficacy in Older Patients (≥ 65 years) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase Comparable with That in Younger Patients with Chronic Myeloid Leukemia in Chronic Phase: Results From ENESTnd,

Abstract 3768 Background: Data from the phase 3, randomized multicenter ENESTnd trial have demonstrated the superiority of nilotinib over imatinib after 24 months (mo) of follow-up, with significantly higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR), and significantly lower rates of progression to accelerated phase/blast crisis (AP/BC). The current subanalysis evaluated the efficacy and safety of nilotinib 300 mg twice daily (Nil300) and nilotinib 400 mg twice daily (Nil400) in older (≥ 65 years [yrs] at study entry) patients (pts) with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) with a minimum follow-up of 24 mo. Methods: In ENESTnd, 846 pts stratified by Sokal risk score were randomized 1:1:1 to Nil300 (n = 282), Nil400 (n = 281), or imatinib 400 mg once daily (n = 283). Pts with impaired cardiac function or ECOG performance status > 2 were excluded. Rates of CCyR and MMR by 24 mo, progression to AP/BC on treatment, and safety were evaluated according to age group ( 60 msec from baseline in older pts and 3 in nilotinib-treated pts 500 msec did not occur in any pt treated with nilotinib on study. Periodic echocardiograms were done, and there were no decreases of > 15% in left ventricular ejection fraction from baseline in any pt treated with nilotinib on study. There were 4 cases of ischemic heart disease reported in older pts (1/35 [3%] on Nil300; 3/25 [12%] on Nil400) and 7 cases in pts Disclosures: Larson:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Bunworasate:Novartis Pharmaceutical: Research Funding. Turkina:Novartis: Consultancy, Honoraria; BMS: Honoraria. Goldberg:Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Dorlhiac-Llacer:Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding. Saglio:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hochhaus:Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Yu:Novartis: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Clark:Bristol Myers Squibb: Honoraria, Research Funding; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity9s Board of Directors or advisory committees.

Epigenetic regulation of cathepsin L expression in chronic myeloid leukaemia

The expression and significance of cathepsin L (CTSL) has been extensively studied in solid tumours. However no such information in chronic myeloid leukaemia (CML) was available. We investigated the activity and expression of this protease in peripheral blood mononuclear cells (PBMCs) of 47 adult CML patients. Thirty adults suffering from systemic diseases and 50 healthy volunteers served as controls. The mRNA levels of CTSL, its specific endogenous inhibitor cystatin C and transcriptional up-regulator vascular endothelial growth factor (VEGF) were quantitated by real-time qPCR. CTSL protease activity and its mRNA expression were significantly higher in CML chronic phase (CP) patients compared to CML accelerated phase/blast crisis (AP/BC) patients and controls (P≤ 0.001). VEGF whose expression was most pronounced in CP and declined (P≤ 0.001) in the advanced phases of the malignancy exhibited a strong positive correlation with CTSL expression (r= 0.97; P≤ 0.001). Cystatin C expression was significantly lower (P≤ 0.001) in CML and displayed inverse correlation with CTSL (r=−0.713; P≤ 0.001) activity. CTSL promoter was significantly hypomethylated in CML CP compared to CML AP/BC patients as well as controls. K562, a BC CML cell line displayed CTSL activity, expression and methylation status of CTSL promoter that was comparable to CML AP/BC patients. Treatment of these cells or PBMCs isolated from CML AP/BC patients with 5′-aza-cytidine resulted in a dramatic increase in CSTL activity and/or expression thereby demonstrating the role of promoter methylation in the stage specific expression of CTSL in CML. Differential expression of CTSL in CML at various stages of malignancy may prove useful in identification of the high-risk patients thereby facilitating better management of disease.

Nilotinib Lowers the Incidence of BCR-ABL Mutations and Improves the Molecular Response Kinetics Compared with Imatinib in Patients (Pts) with Newly Diagnosed Chronic Myeloid Leukemia (CML).

AbstractAbstract 3431 Background:In the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Pts) trial, nilotinib demonstrated superior efficacy vs imatinib in newly diagnosed pts. Here, we examined the kinetics of molecular response and BCR-ABL mutation status in pts from ENESTnd. Methods:Pts with CML-CP were randomized to receive nilotinib 300 mg twice daily (bid) (n = 282), nilotinib 400 mg bid (n = 281), or imatinib 400 mg once daily (qd) (n = 283). BCR-ABL transcripts were quantified at baseline (BL) and every 3 months (mos); MMR was defined as ≤ 0.1% BCR-ABL on the International Scale (IS). Mutational testing of BCR-ABL was performed by direct sequencing at BL and at the occurrence of: (i) 5-fold increase in PCR levels, (ii) failure to achieve MMR at 12 mos, (iii) loss of MMR (≥ 0.1% BCR-ABLIS confirmed by a subsequent sample in association with a ≥ 5-fold rise in BCR-ABL from the lowest value achieved on study treatment), and (iv) end of treatment. Median follow-up was 18 mos. Results:During therapy, a more rapid decline in BCR-ABL levels was demonstrated in the nilotinib arms vs imatinib (Table). The median BCR-ABL levels for pts on nilotinib at 6 mos (both arms) were similar to those on imatinib at 18 mos. The median time to MMR among responders was also shorter on nilotinib (6, 8, and 10 mos in the nilotinib 300 mg bid, 400 mg bid, and imatinib arms, respectively). Loss of MMR occurred in 14 (2%) pts (6 [2%], 5 [2%], and 3 [1%] in the nilotinib 300 mg bid, 400 mg bid, and imatinib arms). Of the 14, none progressed to accelerated phase/blast crisis (AP/BC); only 1 of these pts showed a BCR-ABL mutation (M244V) in the imatinib arm, and 1 pt in the nilotinib 300 mg bid arm lost CCyR. Overall, 9 of 14 (64%) pts, including 8 of 11 on nilotinib, regained MMR within 6 mos on their assigned therapy. In 3 of these 9 pts who regained MMR, loss of MMR was concurrent with dose reduction, and MMR was regained at the time of dose re-escalation. Poor compliance may have contributed to fluctuations in BCR-ABL levels in some pts. At BL, no BCR-ABL mutations were found; 60 pts had polymorphisms which were equally distributed among the 3 arms. Mutational testing was triggered on therapy in 164, 171, and 199 pts in the nilotinib 300 mg bid, 400 mg bid, and imatinib arms, respectively, most commonly due to lack of MMR at 12 mos. Approximately twice as many BCR-ABL mutations (16 [6%]) developed in the imatinib arm vs nilotinib arms (8 [3%] and 5 [2%] for 300 mg bid and 400 mg bid), and most of these were detected within the first 12 mos. The majority of mutations in the nilotinib arms were less sensitive (Y253H, E255K, F359V) or resistant (T315I) to nilotinib, while both nilotinib-sensitive and insensitive mutations were detected in the imatinib arm (Table). The T315I mutation emerged in 5 pts: 2 on nilotinib 300 mg bid, 1 on nilotinib 400 mg bid, and 2 on imatinib; two of these 5 pts discontinued therapy. Overall, 6 of 16 pts with mutations on imatinib progressed to AP/BC vs only 1 of 13 pts on nilotinib (Table). Minimum 24 month follow-up data for all pts will be presented. Conclusions:Pts treated with nilotinib had faster and deeper molecular responses compared with imatinib. The incidence of new mutations was highest for imatinib, and most pts with mutations on nilotinib have not progressed with 18 mos of median follow-up. Loss of MMR was infrequent and was regained in the majority of cases without a change in therapy, and was not typically associated with subsequent treatment failure or the emergence of new mutations. Therefore, loss of MMR may not be an indicator for adjusting therapy, although close monitoring for further loss of response is warranted and mutation testing may be considered. Disclosures:Hochhaus:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Larson:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:Novartis: Research Funding. Goh:Novartis: Honoraria, Research Funding; Janssen Ciliag: Honoraria, Research Funding; Celgene: Honoraria; Bristol Myers Squibb: Honoraria. Dorlhiac-Llacer:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Wyeth: Research Funding. Porkka:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kurokawa:Novartis: Consultancy; Shionogi & Co., Ltd.: Consultancy. Shou:Novartis: Employment. Gallagher:Novartis Pharma AG: Employment, Equity Ownership. Haque:Novartis: Employment. Kantarjian:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Hughes:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria.

Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS)

AbstractThis study examines the prognostic significance of early molecular response using an expanded dataset in chronic myeloid leukemia patients enrolled in the International Randomized Study of Interferon and STI571 (IRIS). Serial molecular studies demonstrate decreases in BCR-ABL transcripts over time. Analyses of event-free survival (EFS) and time to progression to accelerated phase/blast crisis (AP/BC) at 7 years were based on molecular responses using the international scale (IS) at 6-, 12-, and 18-month landmarks. Patients with BCR-ABL transcripts > 10% at 6 months and > 1% at 12 months had inferior EFS and higher rate of progression to AP/BC compared with all other molecular response groups. Conversely, patients who achieved major molecular response [MMR: BCR-ABL (IS) ≤ 0.1%] by 18 months enjoyed remarkably durable responses, with no progression to AP/BC and 95% EFS at 7 years. The probability of loss of complete cytogenetic response by 7 years was only 3% for patients in MMR at 18 months versus 26% for patients with complete cytogenetic response but not MMR (P < .001). This study shows a strong association between the degree to which BCR-ABL transcript numbers are reduced by therapy and long-term clinical outcome, supporting the use of time-dependent molecular measures to determine optimal response to therapy. This study is registered at www.clinicaltrials.gov as NCT00006343.

Maintaining Imatinib ≥600 Mg Daily in the First 12 Months of Chronic Phase CML Treatment Is Associated with Superior Event-Free Survival at 5 Years.

Abstract 1125 Poster Board I-147 The Australasian Leukaemia and Lymphoma Group conducted a trial (TIDEL I) in 103 patients with newly diagnosed chronic phase CML, using imatinib 600 mg/day with dose escalation to 800 mg/day for suboptimal response. This was defined as failure to achieve (1) complete haematological response (CHR) at 3 months, (2) major cytogenetic response (MCR) at 6 months, (3) complete cytogenetic response (CCR) or molecular equivalent at 9 months, or (4) less than 0.01% (IS) BCR-ABL by RQ-PCR at 12 months. Here we report the outcomes with all surviving patients having been treated for at least 60 months. We aimed to determine whether the patient outcome at 60 months was predicted by the molecular response within the first 18 months of imatinib therapy. The outcomes for patients maintaining a dose of imatinib of ≥600 mg/day in the first 12 months was compared to those who were on a reduced dose for at least part of this time. Event-free survival (EFS) was defined as death from any cause, accelerated phase/blast crisis (AP/BC), and loss of CHR, MCR or CCR. The 103 patients included 66 males and 37 females with a median (±SD) age of 49 (±14) years. All patients had an ECOG performance status of 0-2 at enrolment. The 5-year EFS was 71%, transformation (AP/BC) free survival (TFS) was 95%, and overall survival was 87%. Of the 14 patients who died, 3 died in blast crisis, 2 from transplant-related complications, 8 from CML-unrelated causes, and the cause of death of 1 patient was unavailable. The annual rates of progression to AP/BC over 5 years were 3%, 1%, 0%, 1%, and 0%, while annual event rates were 13%, 8%, 8%, 1%, and 4%. CCR was achieved by 89% of patients by 60 months, while 72% achieved a major molecular response (MMR) by this time. In the first 12 months of treatment, 55% of patients maintained an imatinib dose of ≥600 mg/day (mean ±SD dose = 604 ±10 mg/day), while 45% were on <600 mg/day for at least part of this time (mean ±SD dose = 511 ±100 mg/day). EFS at 60 months was significantly higher in patients taking ≥600 mg/day compared with those who had been dose-reduced to <600 mg/day (89% vs 56%, P<0.001). Annual event rates for the ≥600 mg/day group were 6%, 2%, 2%, 0%, and 2%, while annual event rates for those on <600 mg/day were 14%, 16%, 16%, 8%, and 4%. By 60 months, 96% of patients who had been on ≥600 mg/day within the first 12 months had achieved CCR, while only 80% of those who had been on <600 mg/day had achieved this milestone (P<0.001). Log rank analysis of the achievement of MMR was also significant (P=0.03). Overall survival and TFS after 12 months were both similar between the dosing groups. There was no difference between the dosing groups' median age (50 vs 48 years, P=0.36) or Sokal score (1.04 vs 0.94, P=0.33) that may otherwise account for these results. The outcome was also determined for all patients dependent on the BCR-ABL levels at various assessment timepoints. Patients with a BCR-ABL level of 10% (IS) (n=8) had an event (P 1% (IS) (P<0.001). At 18 months, a level ≤0.1% (IS) (n=58) conferred an EFS of 88%, while those who had failed to attain this depth of response (n=30) had an EFS of 60%. There was a significant difference in EFS between those who had achieved an MMR at 18 months and those who had achieved a CCR, but no MMR (88% vs 67%, P=0.03). In conclusion, our data suggest that patients maintaining a dose of ≥600mg in the first 12 months of imatinib therapy are more likely to achieve CCR and MMR, and superior EFS compared to those with a lower dose. This study also confirms that achieving an MMR by 18 months is associated with improved EFS. This emphasises the value of achieving a molecular response early in the treatment course, as well as adding weight to the evidence supporting the role of molecular monitoring in CML. Disclosures Branford: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. White: Novartis and Britol-Myers Squibb: Research Funding. Seymour: Bayer Schering: Consultancy, Membership on an entity's Board of Directors or advisory committees, Travel grants; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Grants. Catalano: Roche: Honoraria, Research Funding, Travel grants. Mills: Celgene Pty Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hughes: Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding.

Cbl and TET2 Mutations Are Present in Refractory Ph+ Disorders Including Accelerated and Blast Crisis CML and ALL.

Abstract 2173Poster Board II-150Loss of heterozygosity (LOH) due to acquired uniparental disomy (UPD) is a commonly observed chromosomal lesion in myeloproliferative neoplasms (MPN) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) including chronic myelomonocytic leukemia (CMML). Most recurrent areas of LOH point towards genes harboring mutations. For example, UPD11q23.3 and UPD4q24 were found to be associated with c-Cbl and TET2 mutations, respectively. Cbl family mutations (c-Cbl and Cbl-b) have been associated with atypical MDS/MPN including CMML and juvenile myelomonocytic leukemia (JMML) as well as more advanced forms of MDS and secondary AML (sAML). Ring finger mutants of Cbl abrogate ubiquitination and thereby tumor suppressor function related to inactivation of phosphorylated receptor tyrosine kinases, Src and other phosphoproteins. TET2 mutations are present in a similar disease spectrum. The TET family of proteins is involved in conversion of methylcytosine to methylhydroxycytosine which cannot be recognized by DNMT1. Thereby, the proteins seem to counteract maintenance hypermethylation. In our screen of MDS/MPN, we found c-Cbl and Cbl-b ring finger mutations in 5/58 (9%) of CMML and AML derived from CMML, 2/39 (5%) MDS/MPNu, 4/21 (19%) JMML and 14/148 (9%) RAEB/sAML. In the same cohort, TET2 mutations were present in 37% and 14% of patients with MDS/MPN and MDS, respectively. Of note we did not find any TET2 mutations in JMML. We and others have also noted that TET2 and c-Cbl mutations were also detected in atypical chronic myeloid leukemia. While translocations resulting in BCR/ABL fusion characterize CML, we stipulated that in analogy to other chronic myeloproliferative diseases, TET2 and c-Cbl mutations may be also present in CML and contribute to phenotypic heterogeneity within BCR/ABL associated disorders. In particular, progression of CML to accelerated phase (AP) or blast crisis (BC) could be associated with acquisition of additional lesions. When 22 patients with CML chronic phase (CP) were screened, no TET2 and c-Cbl mutations were found. However, we identified 1 c-Cbl, 2 Cbl-b (6%) and 6 TET2 (12%) mutations in 51 patients with CML-AP (N=18) and CML-BC (N=33) with myeloid and lymphoid/mix 24 and 9 phenotype, respectively. These mutations were mutually exclusive. We also noted that TET2 mutations were present in 1/9 CML in BC with lymphoid phenotype. We subsequently screened Ph+ ALL cases (N=9) and found a TET2 mutation in 1 case but no Cbl family mutations. In contrast when 9 Ph- ALL cases were screened as controls, neither TET2 or Cbl mutations were found. SNP-A analysis revealed 2 cases of LOH involving chromosome 4 (UPD4q24 and del4) in a patient with lymphoid blast crisis and Ph+ ALL, respectively. However, UPD was not found in Cbl family gene regions (11q23.3 or 3q13.11). A homozygous deletion of Cbl-b region was seen in a CP patient. Cbl family mutations were associated with a more complex karyotype than TET2 mutations (67% vs. 17% cases with abnormal phenotype). Patients with Cbl family mutations were resistant to imatinib which was effective in only 2 out of 6 patients with TET2mutations. Dasatinib was effective in 2 patients with TET2 mutation. Median over all survival of progressed CML was 47, 49 and 48 months in patients with Cbl, TET2 or no mutations, respectively. In conclusion, our results indicate that Cbl family mutations can occur as secondary lesions in myeloid type aggressive CML (AP and myeloid BC), but not in lymphoid types. TET2 mutations were identified in both lymphoid BC and Ph1+ALL, as well as myeloid BC and AP. In contrast to CMML or JMML in which a vast majority of mutations are homozygous, all Cbl family mutations were heterozygous (no LOH). Similarly, all but two TET2 mutations were heterozygous (1 hemizygous in del4 and 1 homozygous case in UPD4q), suggesting that additional cooperating lesions affecting corresponding pathways may be present. These mutations likely represent secondary lesions which contribute to more either progression (CML) or more aggressive features (Ph+ ALL) and characterize disease refractory to therapy with imatinib. Disclosures:No relevant conflicts of interest to declare.

Long-term benefits of imatinib (IM) for patients newly diagnosed with chronic myelogenous leukemia in chronic phase (CML-CP): The 5-year update from the IRIS study

6506 Background: IM was proven to be superior to IFN+Ara-C for newly diagnosed patients (pts) with CML-CP (O’ Brien et al, NEJM 2003). 1,106 pts were randomized between June 2000 and Jan 2001 to either IM 400 mg or IFN+Ara-C with 553 pts to each treatment. This abstract is based on data collected up to 54 months after last patient had been recruited on IM. 60-months (5-year) data will be available for presentation. Methods: Evaluations included complete hematologic response (CHR), complete/partial cytogenetic response (CCyR/PCyR - defined as 0% / 1–35% Ph+ metaphases respectively), major cytogenetic response (MCyR=CCyR+ PCyR), major molecular response (MMR) - defined as ≥ 3 log reduction of BCR-ABL transcript levels from the standardized baseline, time to progression - defined as loss of CHR/MCyR, evolution to accelerated phase/blast crisis (AP/BC), or death due to any cause during treatment, and overall survival. Results: With a median follow-up of 54-months, 72% of the 553 randomized pts remain on initial IM treatment (5% of pts discontinued due to adverse events, 9.5% due to unsatisfactory therapeutic effect and 11% due to other reasons another 2.5% crossed over to IFN+Ara-C). Overall, the cumulative best response rates of CHR, MCyR and CCyR are 97%, 88% and 82%, respectively. The overall estimated survival was 90% (93% when censored at bone marrow transplant). An estimated 84% of pts have not progressed on treatment and 93% of pts were free from progression to AP/BC. The annual rate of progression to AP/BC of &lt; 1% in the fourth year was lower than each of the first three years (1.5, 2.8, and 1.6%, respectively). Of the pts with MCyR at 12 months (n=436), an estimated 96% were free of progression to AP/BC at 54 months whereas it was only 81% for the 73 pts who did not achieve a MCyR at 12 months (p&lt; 0.001). No patient with a MMR within 12 months progressed to AP/BC within 54 months. Conclusions: This analysis confirms the high rates and durability of responses to IM. Encouragingly, the rate of progression in the fourth year was lower than in each of the preceding three years. Results further demonstrate the beneficial effect of cytogenetic and molecular responses on long-term outcomes. [Table: see text]

Beneficial Effects of Cytogenetic and Molecular Response on Long-Term Outcome in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib (IM): Update from the IRIS Study.

Background: IM was proven to be superior to IFN+Ara-C for newly diagnosed pts with CML-CP (O'Brien et al, NEJM 2003). At 42-months of follow-up, 75% of the 553 pts randomized to IM remain on treatment. Of the 553 pts randomized to IFN+Ara-C only 4% are still on IFN+Ara-C. This update analysis is focused on IM pts.Methods: Evaluation included complete hematologic response (CHR), major/complete cytogenetic response (MCyR/CCyR) - defined as 0-35% Ph+ and 0% Ph+ metaphases respectively, major molecular response (MMR) - defined as ≥3 log reduction of bcr-abl transcripts from the standardized baseline, time to progression - defined as loss of CHR/MCyR or evolution to accelerated phase/blast crisis (AP/BC) or death due to any cause, time to AP/BC - defined as evolution to AP/BC or death due to CML, and overall survival.Results: With an average duration of 38 months of IM treatment, the best observed rates of CHR, MCyR and CCyR are 96%, 88% and 81%, respectively. Although the majority of MCyRs were achieved within the first 3 to 9 months, some pts achieved a MCyR and some even a CCyR after more than one year of treatment (Figure 1). The estimated MMR rate at 12 months is 40%. [Display omitted] The estimated progression-free rate at 42 months is 84%; additionally 94% are estimated free of progression to AP/BC (97% of the pts with CCyR and 73% of the pts without CCyR during study, p<0.001). The risk of relapse remains low with no apparent increased risk over time. The yearly hazard for progression to AP/BC is about 2% in each of the 4 years.The overall estimated survival at 42 months is 91% (considering all deaths). The estimated survival was lowest in pts with high risk Sokal score (84%) as compared to 91% in the intermediate risk pts and 94% in the low risk pts (p<0.001). Similarly, the best observed CCyR in the high, intermediate, and low risk groups were 69%, 80% and 88% respectively (p=0.002). In the subset of pts with CCyR the estimated survival at 42 months was 92%, 93% and 97% in the high to low risk groups (p=0.30), indicating that once pts achieve a CCyR, their survival is not significantly different between the Sokal risk groups.Of the 509 pts who were still on treatment at 12 months and had achieved a MCyR by then (n=436), the rate without progression to AP/BC at 42 months was 97% whereas it was only 83% for the 73 pts who did not achieve a MCyR at 12 months (p<0.001). The estimated survival rates at 42 months were 95% and 83% in these two response groups, respectively (p<0.001).Furthermore, for pts who had achieved a MMR at 12 months, the probability of remaining free from progression to AP/BC was 100% at 42 months compared to 95% for pts in CCyR but not in MMR, and 91% for pts not in CCyR at 12 months (p=0.0013). Conclusions: The follow-up confirms the beneficial effect of cytogenetic and molecular responses on long-term outcomes with IM. These results will be further updated using data cut-off of 31-July 2005 to reflect additional 12-months of data (i.e., 54-month follow-up).

Allogeneic Peripheral Blood Stem Cell vs. Bone Marrow Transplantation for Patients with Chronic Myeloid Leukemia: Results of an Individual Patient Data Meta-Analysis.

The Stem Cell Trialist’s Collaborative Group. An individual-patient data meta-analysis using data from 9 randomized trials enrolling 1,111 patients (pts.) to compare allogeneic peripheral blood stem cell transplantation (PBSCT) with bone marrow transplantation (BMT) has recently been completed (Hematology J2004;5:s89). Here, we report the results of this analysis for patients suffering from CML in 1st chronic phase (CP1) (n=422) or accelerated phase/blast crisis (AP/BC) (n=50). Overall survival at five years (70%) was not significantly different in patients who were transplanted with peripheral blood (PB) as compared to bone marrow (BM) cells if all pts. [absolute difference (AD) 3.3 %, p=0.16] or pts. in CP1 [AD 1.1 %, p=0.72] were considered. However, pts. transplanted for AP or BC survived significantly longer following PBSCT than BMT [AP 40 %, p=0.015]. The difference between two subgroups was significant (test of interaction chi²=4.3;p=0.04). Disease-free survival (DFS) was significantly better after PBSCT for all pts. [AD 15.2 %, p=0.004], for pts. in CP1 [AD 11.5 %, p=0.069], and AP/BC [AD 30.3 %, p=0.009]. Test of interaction between two subgroups was chi²=4.3;p=0.07. Relapse rates for all pts. [AD 18.6 %, p=0.00005] and pts. in CP1 [AP 17.0 %, p=0.0002] were significantly lower after PBSCT; no statistical difference was found for pts. in AP/BC most likely due to small patient numbers. Extensive chronic GVHD occurred more often after PBSCT [AD 20%, p&lt;0.00001 ) than after BMT.Treatment-related mortality (TRM) at 5 yrs was 27% for all pts and 26% for patients in CP phase with no significant differences between pts. transplanted with PB instead of BM.TRM was higher in the BMT arm (62% vs. 22%, p=0.02) for pts. in AP/BC. The difference between two subgroups was statistically significant (chi²=5.5;p=0.02). Pts. with CML in AP/BC should be offered a transplant with G-CSF mobilized PB. For pts. in CP1 the decision to use PB or BM needs to value the higher risk of attracting extensive cGVHD against the lower risk of relapse after PBSCT. Further follow up will be necessary to see if the difference in relapse rates after BMT as compared to PBSCT continues to increase over time.

ABL Mutations in Late-Chronic Phase Chronic Myeloid Leukemia Patients with Cytogenetic Refractoriness to Imatinib Are Associated with a Greater Likelihood of Progression to Blast Crisis and Shorter Survival. on behalf of the GIMEMA Working Party on Chronic Myeloid Leukemia.

Using a novel denaturing-high performance liquid chromatography (D-HPLC)-based screening method, we investigated the frequency and prognostic relevance of ABL mutations in 47 CML patients who never achieved a major cytogenetic response in 12 months of Imatinib therapy. Seven patients were enrolled in the CML/011/STI571 trial (early-CP patients treated with Imatinib 400 mg/d and peghilated-interferon) while the remaining 40 were enrolled in the CML/002/STI571 trial (late-CP patients resistant/refractory to α-interferon, treated with Imatinib 400 mg/d). For each patient, a longitudinal analysis was done on all the available samples collected from Imatinib start up to the twelfth month of therapy. A nested RT-PCR was set up and, for each sample, two fragments of 393 and 482 bp spanning the ABL kinase domain were analysed. Two out of 7 (29%) early-CP patients had mutations, resulting in both cases in novel aminoacid substitutions (F311I, E355D). Mutations were already detectable at 6 and 9 months, respectively, from Imatinib start. Nineteen out of 40 (48%) late-CP patients had mutations. Eleven patients showed mutations falling in close proximity (M244V) or within (G250E, Y253F, Y253H, E255K, E255V) the P-loop. Eight patients showed mutations outside the P-loop (F311L, F317L, M351, E355G, F359V, H396R and a silent mutation at codon 298). Mutations were already detectable after a median of 3 months (range, 1–6) from onset therapy. At the time of mutation detection, all patients but four had sustained hematologic response. Presence of a missense mutation was significantly associated with a greater likelihood of subsequent progression to accelerated phase/blast crisis (AP/BC)(P=0.0002) and shorter survival (P=0.001). Patients with mutations falling in close proximity or within the P-loop had a particularly poor outcome in terms of time to progression to AP/BC with respect to the remaining mutated patients (P=0.03). Our results indicate that: i) ABL kinase domain mutations may be found also in the setting of early-CP CML patients, even though they are not the predominant mechanisms of resistance; ii) as many as 50% of late-CP patients who fail to achieve cytogenetic control of the disease in the first 6 months of therapy already have evidence of a mutation by D-HPLC analysis; iii) within cytogenetic nonresponders, presence of ABL mutations may identify a subset of patients with particularly poor prognosis. Thus, irrespective of the hematologic response, regular monitoring for emerging mutations in the first months of Imatinib administration may play a crucial role in detecting patients for whom a revision of the therapeutic strategy should be considered.