ASH 2010 meeting report—Top 10 clinically oriented abstracts in chronic myeloid leukemia
Authors: Amber Fullmer, Jorge Cortes, Hagop Kantarjian, Elias Jabbour
Journal: American Journal of Hematology (2011)

At the 2010 American Society of Hematology (ASH) annual meeting, held in Orlando, FL from December 4–7, 2010, the most current research in the biology and treatment of chronic myeloid leukemia (CML) was presented. Second generation tyrosine kinase inhibitors (TKIs) demonstrated superiority over imatinib, with rapid and durable responses in newly-diagnosed patients. Cytogenetic and molecular responses at designated time points are predictive of survival, and additional cytogenetic abnormalities do not correlate with negative outcomes. The following abstracts, all published in the November 19th, 2010 issue of Blood (volume 116, issue 21, Ref. 1), are among the most significant and clinically relevant. Nilotinib, a second generation tyrosine kinase inhibitor (TKI) with higher potency than imatinib, leads to high and rapid rates of response in newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP) [1-5]. The phase III ENESTnd (Evaluating Nilotinib Efficacy in Clinical Trials of Newly Diagnosed Philadelphia Positive CML Patients) study randomized newly diagnosed patients to receive nilotinib 300 mg twice daily (n = 282), nilotinib 400 mg twice daily (n = 281), or imatinib 400 mg daily (n = 283) [5]. Nilotinib displayed superiority over imatinib with higher rates of major molecular response (MMR) and complete cytogenetic response (CCyR), and a lower rate of progression to advanced disease reported at 12 months. Superior responses were maintained through 24 months of follow-up. MMR was significantly higher for both nilotinib 300 mg (66%) and nilotinib 400 mg (62%) compared with imatinib (40%) (P < 0.001). Complete molecular response (CMR), BCR-ABL ≤0.0032%, was also higher with nilotinib (21%, 17%, 6%, P < 0.0001). Both doses of nilotinib led to higher rates of complete cytogenetic response (CCyR) compared with imatinib (85, 82, and 74%). Fewer patients treated with nilotinib progressed to advanced forms of disease with nilotinib 300 mg (0.7%, P = 0.006) and nilotinib 400 mg (0.4%, P = 0.003) compared with imatinib (4.2%) and the estimated overall survival (OS) at 18 months was higher for nilotinib (98.5 and 99.3 vs. 96.9%). Nilotinib displays superiority in response rates with less progression to advanced disease compared with imatinib in newly diagnosed patients with CML-CP. Dasatinib, another second generation TKI, also has been shown to be superior to imatinib in the front-line setting [6, 7, 8]. With three TKIs now approved for the initial management of CML-CP, decisions on therapy require guidance from predictive factors, such as molecular markers, genetic tests, and clinical risk factors. Several questions remain unanswered with second generation TKIs as initial therapy in newly diagnosed patients. With further follow-up, the impact of these agents on survival can be determined. Furthermore, whether to discontinue therapy after achievement of deep molecular response with nilotinib or dasatinib must be evaluated. The superiority of dasatinib over imatinib in newly diagnosed patients with CML-CP has been recognized in several evaluations [6-9]. The DASISION (Dasatinib versus Imatinib Study in Treatment Naïve CML Patients) trial randomized patients with CML-CP to dasatinib 100 mg daily (n = 259) or imatinib 400 mg daily (n = 260) [8]. Higher and faster response rates with dasatinib were maintained through 18 months of follow-up. Confirmed CCyR (cCCyR), defined as CCyR on consecutive analysis at least 1 month apart, was significantly higher with dasatinib compared with imatinib (78 vs. 70%, P = 0.0366). MMR was also superior with dasatinib (57 vs. 41%, P = 0.0002) regardless of CML-risk category (low, intermediate, high), and patients treated with dasatinib were 1.84 fold more likely to reach MMR compared with imatinib (P < 0.0001). CMR was achieved in 13% of patients treated with dasatinib compared with 7% that received imatinib. Fewer patients progressed to advanced CML with dasatinib (2.3 vs. 3.5%) with similar survival estimates between study groups. Rates of progression free survival (PFS) and OS were 94.9 and 96% for dasatinib compared with 93.7 and 97.9% for imatinib at 18 months. Dasatinib was well tolerated and treatment discontinuation because of adverse events was infrequent (6%). Dasatinib was associated with less fluid retention (23 vs. 43%) and superficial edema (10 vs. 36%) than imatinib, but pleural effusion was only reported with dasatinib (12% all grades). Dasatinib demonstrates superior efficacy compared with imatinib in newly diagnosed patients with CML-CP. Large granular lymphocyte expansion during dasatinib therapy improves response rates and increases toxicity [10, 11]. The development of lymphocytosis has been associated with improvements in cytogenetic response rates in newly diagnosed patients, however, increased rates of pleural effusions also correspond [11]. As several options are available for newly diagnosed patients, consideration to comorbidities and concomitant medications is warranted before treatment initiation [12, 13]. Bosutinib, a dual Src/ABL TKI, displayed activity in patients previously treated with imatinib [14-16]. In the BELA (Bosutinib Efficacy and Safety in Chronic Myeloid Leukemia) study, patients with newly diagnosed CML-CP were randomized to bosutinib 500 mg daily (n = 250) or imatinib 400 mg daily (n = 252). After a median follow-up of 14 months, bosutinib was associated with a higher rate of CCyR and MMR compared with imatinib. In the intent to treat analysis, CCyR was higher for bosutinib (70 vs. 68%) and MMR was significantly higher (39 vs. 26%, P = 0.002). Patients that were nonevaluable were considered to be nonresponders. In evaluable patients, CCyR was reached in 78% of patients treated with bosutinib compared with 68% treated with imatinib (P = 0.02), and MMR was achieved in 43% and 28% treated with bosutinib and imatinib, respectively (P < 0.001). Adverse events reported more frequently with bosutinib were diarrhea (68% vs. 21%, P < 0.001), vomiting (32 vs. 13%, P < 0.001), pyrexia (16 vs. 9%, P = 0.022), abdominal pain (12 vs. 5%, p = 0.005), and upper abdominal pain (12 vs. 5%, P = 0.007). Bone pain, muscle cramps, and periorbital edema were more frequently reported with imatinib. Bosutinib appears to be a promising option in the armamentarium for newly diagnosed patients with CML-CP. High response rates with acceptable toxicity were reported with this new TKI. However, this study failed to meet the primary efficacy endpoint, improvement of CCyR at 12 months. Despite the efficacy of imatinib in newly-diagnosed patients with CML-CP, some patients experience treatment failure due to primary and secondary resistance [17]. Dose escalation of imatinib has been utilized as a measure to overcome resistance. In newly diagnosed patients in the TOPS (Tyrosine Kinase Inhibitor and Optimization Study) trial, initial therapy with high-dose imatinib (800 mg daily) offered no improvement in response rates at 24 months compared with standard dose imatinib (400 mg daily) [18]. In the report from the German CML-Study Group, patients were randomized to receive imatinib 800 mg daily (n = 328), imatinib 400 mg daily (n = 306), or imatinib 400 mg daily in combination with interferon (IFN) (n = 336) to determine the impact of high dose imatinib on molecular response. At 12 months, CCyR was higher with imatinib 800 mg (63%) compared with either regimen using standard dose imatinib (50%). MMR was achieved in 54.8% of patients receiving high dose imatinib compared with 30.8% of patients treated with standard dose imatinib. CMR was reached faster with high dose imatinib and was maintained over the entire study period. At 36 months, the rate of CMR was highest with imatinib 800 mg (56.8%) versus imatinib 400 mg (45.5%) and imatinib 400 mg plus IFN (40.5%). Improvements in outcome have been recognized with rapid achievement of molecular response. High-dose imatinib led to high rates of CMR that were sustained through the study period. In elderly patients, both imatinib 800 mg and 400 mg were tolerated, but 400 mg resulted in a slower response which may or may not be clinically relevant [19]. Although the exact duration of therapy for CML required to remain in remission remains to be determined, a durable CMR may eventually lead to treatment discontinuation and sustained remission. However, conflicting data argues that imatinib 800 mg lacks the benefit, with increased toxicity, to become the standard of care for newly diagnosed patients [18]. To improve response rates and overcome imatinib resistance, dose escalation of imatinib has been reported [18, 20-22]. In TIDEL-II, patients with newly diagnosed CML-CP were treated with imatinib 600 mg daily and escalated to 800 mg daily if imatinib trough levels were <1000 ng/mL at day 22 of therapy, or if classified as a nonresponder. Nonresponders were defined as those patients who did not achieve the target BCR-ABL RQ-PCR values of ≤10%, 1%, and 0.1% IS by 3, 6, and 12 months, respectively. Patients who did not meet molecular endpoints within 3 months of dose escalation, experienced loss of response with imatinib, or were intolerant to high-dose imatinib, were switched to nilotinib 400 mg twice daily. Of 105 patients enrolled on study, 21 switched to nilotinib (7 for suboptimal response and 14 for intolerance), of which 95% remained in CCyR. Of nineteen patients not in MMR at time of nilotinib initiation, 75% of patients intolerant to imatinib and 14% with suboptimal response to imatinib reached MMR. The European LeukemiaNet recommendations for patients with suboptimal response are dose escalation and/or a switch to second generation tyrosine kinase inhibitors. This study has failed to show an improvement in the rate of major molecular response after a switch to nilotinib and therefore such a switch should not be recommended outside clinical trial. Furthermore, the achievement of a complete cytogenetic response remains the major surrogate of outcome in CML. Achievement of early CCyR has been recognized as a predictive outcome for survival [23]. In newly diagnosed patients with CML-CP treated at MD Anderson Cancer Center in a Phase II study with imatinib 400 mg daily (n = 73), imatinib 400 mg twice daily (n = 208), or second generation (2nd) TKI (n = 154), high rates of CCyR correlated with improvements in survival. Patients treated with imatinib 400 mg, imatinib 800 mg, and 2nd TKI achieved CCyR rates of 87, 91, and 96%, respectively. MMR was reported for 77% of patients treated with imatinib 400 mg, 87% with imatinib 800 mg, and 89% with 2nd TKI. Event free survival (EFS) and OS at 3 years were as follows: 85 and 93% with imatinib 400 mg, 92 and 97% with imatinib 800 mg, and 97 and 100% with 2nd TKI. Of patients that experienced CCyR at 3, 6, and 12 months (65, 83, and 89%), EFS (98, 97, and 98 vs. 83%, 72, and 67%) and OS at 3 years (99, 99, and 99 vs. 95, 90, and 94%) were higher as compared with patients that did not experience CCyR at the respective time points. If CCyR was achieved, type of therapy did not impact the rates of EFS or OS. These studies from MD Anderson demonstrate that achievement of early CCyR at 12 months remains a major determinant of outcome regardless of treatment used. Second generation TKIs induce high rates of CCyR that could translate into survival improvements. Finally, in this study, investigators have shown that the achievement of CCyR is predictive of outcome regardless of molecular response. The impact of early achievement of CCyR on EFS and OS in patients treated with CML-CP that failed imatinib was assessed at MD Anderson Cancer Center [24]. Patients were treated with dasatinib (n = 78) or nilotinib (n = 45) and experienced complete hematologic rates (CHR) of 87 and 84%, respectively. Major cytogenetic response (MCyR) was achieved with dasatinib in 64% of patients and nilotinib in 62% (P = 0.85), with CCyR reported for 60 and 56%, respectively (P = 0.75). At 3, 6, and 12 months, the rates of CCyR for patients treated with dasatinib and nilotinib were 32, 41, and 48% (P = 0.13) and 36, 36, and 35% (P = 0.99), respectively. Three year EFS and OS were 53 and 84%, respectively. In the univariate analysis, age over 55 years, lack of cytogenetic response to imatinib, ≥90% Philadelphia-positive metaphases at the start of 2nd TKI, and lack of 3-month CCyR were predictive of poor EFS. Age over 55 years, increasing marrow blasts, lack of cytogenetic response to imatinib, and lack of 3-month CCyR were predictive for poor OS. In multivariate analysis, only lack of 3-month CCyR was recognized as an independent factor for poor EFS (HR = 4.5, P < 0.001) and lower probability of survival (HR = 5.4, P = 0.03). For patients with and without CCyR at 3 months, EFS at 3 years was 74% and 43%, whereas 3 year OS was 98 and 79%, respectively. Factors associated with achievement of CCyR at 3 months included high hemoglobin level, previous cytogenetic response to imatinib, ≤90% Philadelphia positive metaphases at the start of therapy, and increasing marrow blasts in the univariate analysis. In subsequent multivariate analysis, hemoglobin <12 g/dL and >90% Philadelphia positive metaphases at start of therapy were independent poor predictive factors for 3-month CCyR. This study does help clinicians select salvage therapy at the time of imatinib failure. Patients with anemia or high disease burden who did not achieve any cytogenetic response with imatinib therapy will have a lower likelihood of reaching CCyR with a second TKI, with less than optimal EFS and OS and therefore, these patients should be offered additional options. Identifying risk factors for imatinib failure can aid in determination of best TKI for initial therapy [25]. Lack of molecular response is predictive of poor outcomes. In the German CML-Study IV, 289 patients were evaluable after receiving imatinib or imatinib combinations for initial therapy. Treatment failure at 12 and 18 months was identified in 20 and 29 patients, respectively. Patients with BCR-ABL levels over 10% after 3 months of imatinib had a significantly higher occurrence of treatment failure and progression to advanced disease or death. Compared with patients with BCR-ABL levels <10%, the rate of treatment failure at 12 months (2.5% vs. 17.4%, P < 0.001), 18 months (5.8% vs. 20.7%, P = 0.0003), and disease progression and/or death (2.7% vs. 8.1%, P = 0.156) was higher for patients with BCR-ABL levels >10%. Data that addresses the management of patients with suboptimal response is lacking. The limitation of this study is the validity of PCR BCR-ABL ratio prior to the achievement of CCyR. Since testing for BCR-ABL becomes more accurate with less disease present, validation of this study is important. The impact on prognosis of patients with t(9:22) and additional chromosomal abnormalities has yet to be determined [26]. In the German CML-Study IV, cytogenetic analysis was performed on patients with CML-CP treated with imatinib or imatinib based combinations. Of 1028 patients, 88% had no variant of t(9;22) or any additional chromosomal aberrations. Twelve percent of patients displayed cytogenetic findings at diagnosis, 5.1% had variants of t(9;22), 3.2% lacked the Y chromosome, and 3.7% had other numerical or structural aberrations. One cytogenetic finding was reported for 10.2%, whereas 1.8% of patients had 2 more or more. Of the patients with variants of t(9;22), 86% had one additional chromosomal abnormality and 13.5% had 2 or more. Chromosomes 10, 18, 20, 21, X or Y were not involved. No difference in time to CCyR or OS was found for patients without variant t(9;22) and additional chromosomal aberrations, with variant t(9;22), with variant t(9;22) and additional chromosomal aberrations other than −Y, and with additional chromosomal aberrations other than −Y and variant t(9;22). Additional chromosome abnormalities have no impact on prognosis. A separate study evaluated chromosomal abnormalities in Philadelphia negative metaphases after treatment with a 2nd TKI (dasatinib, nilotinib, bosutinib) for initial therapy or following imatinib failure [27]. Cytogenetic abnormalities in Philadelphia-negative cells are transient and lack clinical significance. These abnormalities may indicate the emergence of an MDS clone, therefore monitoring is indicated. The use of imatinib as targeted therapy dramatically changed the management of CML and resulted in durable responses and long-term survival. The Swedish Cancer Registry grouped patients diagnosed with CML into 5 calendar periods: 1973–1979, 1980–1986, 1987–1993, 1994–2000, and 2001–2008. Reflective of the initiation of imatinib in clinical trials in 2000 and the approval of imatinib in 2001, survival improved within the last 2 calendar periods (1994–2000, 2001–2008). Five year relative survival ratios for patients diagnosed from 2001–2008 were 0.91 for patients aged <50 years), 0.87 (50–59 years), 0.82 (60–69 years), 0.75 (70–79 years), and 0.25 (>79 years). Higher mortality was reported in males and in patients diagnosed at an older age. TKIs have improved survival in patients with CML with a projected survival of beyond 25 years. Sustained improvement with the availability of second generation TKIs as front-line therapy, particularly with the ENESTnd trial, showed follow up at 18 months that will trend toward survival improvement. The earlier use of advanced generation TKIs in the front-line setting improves response rates compared with the standard of care, imatinib. Both nilotinib and dasatinib have produced high and rapid responses, now sustained through 18 months. As several TKIs are approved for newly diagnosed patients with CML-CP, guidance for treatment decisions will rely on predictive factors to select patients likely to fail therapy with imatinib. Early achievement of molecular response and cytogenetic response predicts for long term survival benefit. Cytogenetic abnormalities require monitoring, but rarely impact clinical outcome. Deeper molecular responses achieved with more potent TKIs may eventually lead to a CML cure.