The introduction of imatinib has significantly changed prognosis of CML patients. Despite favourable hematologic and cytogenetic response (CyR) data, patients (pts) on first line imatinib therapy may ...relapse. Thus, studies have been conducted to improve initial therapy by dose escalation or combination with other drugs. CML Study IV was designed to compare imatinib in standard dose (400 mg/d) vs high dose (800 mg/d) vs combinations with low dose cytarabine or interferon alpha. We sought to evaluate the predictive impact of early molecular response for long term event free survival (EFS). 539 pts (59% m, median age 54 years, range 16–84) randomized to imatinib based therapies by December 2005 were investigated, the median follow up was 39 mo (range, 0–69). At baseline, multiplex PCR was applied to determine the dominating BCR-ABL transcript: b2a2 (n=204), b3a2 (n=247), b2a2 and b3a2 (n=80), e1a2 (n=2), e19a2 (n=4), b3a3 (n=1) and e8a2 (n=1). Quantitative PCR from 5,419 peripheral blood samples was performed using the LightCycler technology in two central labs. PCR data were aligned to the international scale (IS) by introduction of conversion factors (Hughes et al., BLOOD 2006). Cumulative molecular response of 539 pts at 3, 6, 12, 18, and 24 mo after randomization is summarized in the Table:
Month36121824BCR-ABLISAchieved by % of pts≤10%4166818586≤1%1641657678≤ 0.1% (MMR)316375159≤0.01%13102128
For analysis of prognostic impact, events were defined as (i) loss of complete hematologic response, (ii) loss of major CyR following loss of complete CyR, (iii) accelerated phase, (iv) blast crisis, and (v) death for any reason. Pts were censored at the time of allogeneic stem cell transplantation or switch to 2nd generation tyrosine kinase inhibitors because of imatinib intolerance or resistance. The minimum molecular response levels predictive for EFS were BCR-ABLIS of 10% after 6 mo (p=0.0029), 1% after 12 mo (p<0.0001), and 0.1% (major molecular response, MMR; p=0.0016) after 18 mo of imatinib based therapies. In order to investigate the reasons for unsatisfying responses BCR-ABL kinase domain mutations were assessed in 175 pts. 30 pts (17%) harbored 35 mutations affecting 18 different aminoacids. In conclusion, prospective molecular surveillance of CML shows that early response predicts stable remissions on first line imatinib therapy. After 6 mo of treatment, PCR data start to be predictive for EFS. In pts with unsatisfactory response or molecular, cytogenetic and hematologic relapse, BCR-ABL mutations have been detected in only 17% of pts. Calculation of molecular response rates dependent on the various imatinib based therapies will be performed after stop of randomization which is expected by the end of 2009.
Allogeneic HSCT remains an important option for patients with chronic myeloid leukemia (CML) who failed imatinib. Focus has been on second line tyrosine kinase inhibitors (TKI). Little is known on ...the outcome of HSCT for such patients. In July 2002, the German CML-Study Group activated a prospective randomized trial comparing different imatinib based strategies in chronic phase CML (CP). Elective early HSCT was considered for patients (pts) with EBMT score 0–1 for those with high disease risk, and after imatinib failure. By the end of July 2008, 1197 pts were randomized. In 80 (6,5 %) pts HSCT was documented. 52 pts were male (65%), 23 were high risk pts (28%) according to the Euro score. Median age at diagnosis was 37 years (yrs) (range 16–62), median time to HSCT was 12.6 months (mo, range 3.5–54 mo). EBMT score was 0–1 in 8 (10%), 2 in 10 (12%), 3–4 in 44 (55%) and 5 in 18 pts (23%). Median follow-up after HSCT was 19 mo (range 0–59). Cumulative response rates prior to HSCT were 68% for complete hematologic response, 23% for complete cytogenetic responses, and 9% for major molecular responses. Based on the indication for HSCT three groups were defined:
early HSCT (n= 19, 23%; low EBMT score (n=9), high risk pts (n=7), patient request (n=3);HSCT after imatinib failure or intolerance in first CP (n=34, 43%) andHSCT in second CP or higher, accelerated phase or blast crisis (n=27, 34%).
14 pts died, 10 deaths were transplantation related, 4 CML related. Two pts with a molecular relapse were successfully treated with donor lymphocyte infusion in combination with TKI. Overall survival rate at two yrs for group one was 87.8%, for group two 93.8%, and for group three 49.5%. By EBMT score, survival rates were 100% for risk score 0–2, 82.2% for risk score 3–4, and 43.5% for risk score 5. Data from this prospective controlled cohort study clearly show that HSCT remains an attractive and important rescue therapy for CML patients with imatinib failure or intolerance, particularly for those with a low EBMT risk score.
HSCT in 1st CPearly HSCTHSCT for failure and intolerance in 1st CPTotalHSCT in advanced phasesN19345327Euro scorehigh68149intermediate312157low10142411% male63566078Median age (range)35 (16–56)38 (21–56)37 (16–56)37 (18–62)Median time to HSCT (Range) (months)8.5 (4.8–23.6)17,5 (5.0– 53.7)12.6 (4.8 53.7)12.0 (3.5–54.1)EBMT score0–15380254913–4926359>=501117Best responseCHR11/1828/3439/5214/26CCyR3/1710/3313/504/22MMR2/173/315/482/19Response at HSCTBC00024AP0003CP1934530HR1119300Ccyr2240MMR0000Transplant sourceSibling1010209Unrelated9243318Conditioning therapystandard14213517reduced3694other2796SourcePB13263922BM68145Dead22410TRM2246CML0004Probability of survival at 2 years after HSCT87.8%93.8%91.4%49.5%
In spite of favorable response and survival results for the majority of CML patients on imatinib therapy, in a substantial minority imatinib fails or shows suboptimal responses. A treatment ...optimization study was therefore designed to compare in a randomized fashion standard imatinib vs. imatinib + interferon alpha (IFN) vs. imatinib + low dose araC vs. imatinib after IFN (for low- and intermediate-risk patients) or vs. imatinib 800 mg (for high-risk patients). Inclusion criteria were newly diagnosed BCR/ABL positive CML in chronic phase. In July 2005, randomization to the arms imatinib + araC and imatinib after IFN was discontinued and recruitment for imatinib 800 mg was expanded to low- and intermediate-risk patients. Primary goals are: rates of hematologic, cytogenetic and molecular remissions, duration of chronic phase, overall survival, adverse events and analysis of subsequent allografting. Since its activation in 7/2002, 1203 patients have been randomized. The current evaluation represents the first of three designed, statistically adjusted interim analyses of 710 patients randomized by the end of 2005 with a followup of at least 2 years. Analysis was according to intention to treat. 666 patients (545 with primary imatinib, 121 with primary IFN) were evaluable for hematologic, 621 for cytogenetic, and 631 for molecular responses. Median age was 53 years, 60% were male, median values were for Hb 12.5 g/dl, WBC 71.2/nl and platelets 384/nl, 35% had low, 53% intermediate and 12% high risk (Euro score). Median observation time was 3.5 years. Median duration of IFN pretreatment was <4 months. At 1 year, the cumulative incidence of complete hematologic remission (CHR) was 82.3% and 74.4%, of major cytogenetic remission (MCR) 65.6% and 40.6%, of complete cytogenetic remission (CCR) 52% and 19.7%, and of major molecular remission (MMR) 33.2% and 4.7% for primary imatinib and IFN therapies, respectively. At 3 years, the cumulative incidence of CHR was 96.4% and 93.8%, of MCR 89.5% and 89.1%, of CCR 85.2% and 78.5%, and of MMR 79% and 63% for primary imatinib and IFN therapies, respectively. 5-year-survival probability of all patients currently exceeds 90% (94% for imatinib-, 91% for IFN-based therapy, Figure 1). Event free survival after two years (no progression, no death, CCR within the first 18 months, no loss of CHR or MCR) was 80.3%. 36 patients died, 51 patients were transplanted in first chronic phase, and 80 patients progressed, 43 of which were switched to alternative treatments (16 to new drugs, 18 to transplantation, 9 received both). Type and severity of adverse events (AE) did not significantly differ from those reported previously. Hematologic AEs (leukopenia, thrombocytopenia) were most frequent in the imatinib 800 mg arm. Nonhematologic AEs (gastrointestinal) were most frequent in the combination arms and with imatinib 800 mg. In no case recruitment had to be changed due to superiority or inferiority of any arm. This applies also to the high dose imatinib arm where earlier response might translate into better survival. In conclusion, this first interim analysis shows favorable survival and long term response rates. Imatinib in combination with, or after, IFN or with low dose araC are feasible and equally safe treatment alternatives. More definite information will be provided by the next interim evaluation after recruitment has been terminated.
Display omitted
Provider: - Institution: - Data provided by Europeana Collections- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain ...Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
