ALBERT

Description: The occurrence of additional chromosomal abnormalities (ACAs) in Philadelphia chromosome (Ph’) positive cells, a phenomenon termed clonal evolution (CE), reflects an increased genetic instability of the leukemic population which progressively acquires a highly malignant phenotype. Few data are available regarding the therapeutic effects exerted by imatinib mesylate on Ph’ cells bearing ACAs. Herein, we report the activity of imatinib mesylate employed as single agent or in combination with recombinant interferon (rIFN)a2 in inducing cytogenetic and molecular responses in 14 CML patients (F:M=5:9, median age: 58 years) with CE already present at diagnosis (5) or occurring later during the course of the disease (9) as the sole sign of accelerated phase (AP) (12) or associated with other AP features (2). Overall, the analysis of ACA rate showed the presence of i(Ph’) in 4, +8 in 3, -Y in 3, variant translocation in 2 (t(9;19;22) and t(3;9;22)), -17 in 1, 17p- in 1, 3p- in 1, 22q- in 1, and additional translocations involving chromosomes other than 9 and 22 in 3 other instances. Of note, the two cases with variant translocation showed at diagnosis the classical t(9;22). The t(9;19;22) or t(3;9;22), which was documented later in the course of the disease was therefore a proven second event. Imatinib was given at 400mg po/daily in all, but 2 patients with signs of AP in addition to CE who received a daily dose of 600 mg. rIFNa2 was given at a daily dose of 1 to 3x106UI, according to patient’s tolerance. An overall cytogenetic remission rate of 64% (9/14) was documented in response to imatinib mesylate employed as single agent (6/10) or in combination with rIFNa2 (3/4). Suppression of the ACA population was documented within an interval of 3–14 months from the beginning of imatinib treatment and it was timely coincident with the occurrence of CCR in 6 patients, irrespective of the entity of the ACA population in the context of the entire Ph’ positive one. In 2 of them, a “biphasic” response to imatinib was observed. Initially, suppression of i(Ph’) and t(9;19;22) with re-emergence of the original t(9;22) hemopoiesis was documented 4 and 7 months after treatment initiation, respectively, and then CCR occurred after further 10 and 9 months of treatment, respectively. In the last patient, a mixture of non-clonal and clonal +8 Ph’ negative hemopoiesis was noted at the time when CCR was documented. All 9 CCR patients tested negative for BCR/ABL gene at FISH analysis. Six of the 9 CCR obtained a major or complete molecular remission 3–29 months from treatment initiation. In 3 additional patients, who never achieved a CCR, suppression of the secondary clones was documented. In 1 case, the clone bearing 17p- was no more detected from the 6th to the 42nd month of therapy, when a new clone showing the i(17q) was recorded. In the other 2 cases, the leukemic population bearing the 3q- and 22q- or -17 marker was suppressed 6 and 3 months after the beginning of imatinib mesylate treatment, respectively. After a median follow up of 70 months, 8 patients are still alive and in continuous CCR. Such a long follow up, along with the rate, quality and duration of the responses observed, suggest that CE does not compromise the therapeutic activity of imatinib alone or combined with rIFNa in CML.

Description: Imatinib mesylate (IM), 400 mg daily, is the standard treatment of Philadelphia-positive (Ph+) chronic myeloid leukemia (CML). Preclinical data and results of single-arm studies raised the suggestion that better results could be achieved with a higher dose. To investigate whether the systematic use of a higher dose of IM could lead to better results, 216 patients with Ph+ CML at high risk (HR) according to the Sokal index were randomly assigned to receive IM 800 mg or 400 mg daily, as front-line therapy, for at least 1 year. The CCgR rate at 1 year was 64% and 58% for the high-dose arm and for the standard-dose arm, respectively (P = .435). No differences were detectable in the CgR at 3 and 6 months, in the molecular response rate at any time, as well as in the rate of other events. Twenty-four (94%) of 25 patients who could tolerate the full 800-mg dose achieved a CCgR, and only 4 (23%) of 17 patients who could tolerate less than 350 mg achieved a CCgR. This study does not support the extensive use of high-dose IM (800 mg daily) front-line in all CML HR patients. This trial was registered at www.clinicaltrials.gov as #NCT00514488.

Description: Background: imatinib mesylate (IM) is the drug of choice for the front-line treatment of Ph+ CML, at a dose of 400 mg daily (M. Baccarani et al Blood2006;108:1809–1820). Several biological and clinical observations suggest that increasing the dose may improve the results. The cytogenetic response to IM 400 mg daily is significantly related with Sokal relative risk. High risk patients could benefit of a dose increase front-line. Aim: to compare the effects of 400 mg and 800 mg daily in previously untreated, early chronic phase patients, high Sokal risk. The primary efficacy variable of the study is the complete cytogenetic response (CCgR) rate after 12 months, on an intention-to-treat analysis. Patients and Methods: this is a multicentric international study running in Italy, Sweden, Denmark, Finland, Norway, Turkey and Israel, approved by the local Ethic Committees, conducted according to Helsinki Declaration and Good Clinical Practice. 215 patients with confirmed Ph+ CML previously untreated, high risk according to Sokal formulation (J. Sokal et al Blood1984;63:789–799) were enrolled over a 3-year period and were randomized (1:1) to receive IM 400 or 800 mg daily. Cytogenetic response was assessed by conventional cytogenetics and FISH analysis after 3, 6 and 12 months. Molecular response was evaluated every three months. Results: as of August 2007, 137 patients are evaluable for CCgR rate at 12 months (primary efficacy variable). Patients in CCgR at that time were 78/137 (57%). Treatment failures during the study (no complete hematologic response or 100% Ph+ at 6 months, or loss of response) were 24/137 (17%), patients off-treatment for protocol violations or refusal were 10/137 (7%), patients off-treatment for toxicity were 7/137 (5%). Conclusions: the results of this preliminary analysis show that the CCgR rate at 12 months is overall 57%, in line with the results of the IRIS trial (imatinib 400 mg daily - T. Hughes et al, NEJM 2003, 349;15: 1423–1432) in the same risk category (69% all risks, 49% high Sokal risk). At the time of writing is too early to analyze the results by arm: a second analysis will be performed in November (datalock, October 31) and the results will be presented on site.

Description: Achieving a molecular response after imatinib treatment is considered today the gold standard on Ph+ CML therapy. However, only a restrict group of patients is able to achieve a complete molecular response (CMR). Based on a mathematic model, it has been suggested that imatinb reduces the rate at which differentiated cells are produced from leukaemic stem cells, with no significant effect in reduction of Ph+ stem cells (Michor F et al, Nature 2005). So, cure of the disease is still considered to be restricted to allogeneic bone marrow transplant. Clinical data obtained in patients who stop treatment can be of great value in evaluating the degree of suppression of the neoplastic clone. We report 6 cases of patients with CML in complete cytogenetic remission (CCyR) who interrupted imatinib treatment. Stop was due in 5 cases to some degree of toxicity whereas one male patient decided to stop for personal reasons. All patients were in chronic phase and previously achieved a CCyR within 12 months after imatinib start; major molecular remission (MMR) was observed in 5 cases, and 4 of them also showed a CMR in at least one occasion. After discontinuation, three patients had a molecular or cytogenetic relapse in a period of 3 to 6 months. In these cases, CMR was never reached, or in one case it was delayed in time, being observed after 3 years of treatment, and not confirmed in all subsequent samples. All patients responded again to imatinib treatment. Three other patients did not relapse and are PCR-negative with a follow-up of 18, 22 and 39 months respectively. One of them received imatinib for cytogenetic relapse after IFN + ARA-C, whereas two patients were treated with Peg-IFN and imatinib front-line; Peg-IFN was stopped for toxicity in both cases. At imatinib stop, they all were in sustained complete molecular remission, as defined by undetectable BCR-ABL transcript at RT- and RQ-PCR both on BM and PB samples, in multiple serial samples. In these three patients, CCyR was reached whithin 3 months of imatinib therapy and CMR was achieved after 1 year, 6 months, and 9 months respectively, and never lost. The median duration of treatment before discontinuation was 45,5 months, while the median time of PCR negativity on imatinib was 39 months. In most reported cases, imatinib discontinuation results in relapse after few months (Cortes J et al, Blood 2004; Michor F et al, Nature 2005; Mauro MJ et al, Leuk Res 2004). However, both time of treatment and duration of molecular response were relatively short in these reports. Recently, 12 patients who stopped treatment when in CMR for more than two years have been published (Rousselot P et al, Blood 2007): 6 of them relapsed early whereas 6 remain in CMR after a median follow-up of 18 months. We describe 3 cases who are persistently PCR-negative after imatinib discontinuation, with a median follow-up of 26 months; all of them were characterized by a rapid clearance of leukemic cells after start of imatinib, which allowed to obtain a stable CMR within the first 12 months of treatment. Less than 5% of early CP patients on imatinib achieve CMR in the first year (Brandford S et al, Blood 2006). These data suggest that kinetics of molecular response achievement may predict prolonged response after imatinib discontinuation, possibly reflecting a decline in leukemic stem cell compartement.

Description: Nilotinib has a higher binding affinity and selectivity for BCR-ABL with respect to imatinib and is an effective treatment of chronic myeloid leukemia (CML) after imatinib failure. In a phase 2 study, 73 early chronic-phase, untreated, Ph+ CML patients, received nilotinib at a dose of 400 mg twice daily. The primary endpoint was the complete cytogenetic response (CCgR) rate at 1 year. With a median follow-up of 15 months, the CCgR rate at 1 year was 96%, and the major molecular response rate 85%. Responses were rapid, with 78% CCgR and 52% major molecular response at 3 months. During the first year, the treatment was interrupted at least once in 38 patients (52%). The mean daily dose ranged between 600 and 800 mg in 74% of patients, 400 and 599 mg in 18% of patients, and was less than 400 mg in 8% of patients. Dose interruptions were mainly due to nonhematologic and biochemical side effects. Myelosuppression was irrelevant. One patient progressed to blastic crisis after 6 months; one went off-treatment for lipase increase grade 4 (no pancreatitis). Nilotinib is safe and very active in early chronic-phase CML. These data support a role for nilotinib for the frontline treatment of CML. This study was registered at ClinicalTrials.gov as NCT00481052.

Description: Imatinib mesylate has become the treatment of choice for chronic myeloid leukemia (CML): the standard dose for chronic- phase (CP) CML is 400 mg daily. Response rates are different according to Sokal score, being significantly lower in intermediate and high Sokal risk patients. Phase 1 and 2 trials have shown a dose-response effect and high-dose imatinib trials in early CP CML showed better results compared with standard dose. Our study is the first prospective trial planned to evaluate the efficacy and tolerability of high-dose imatinib in previously untreated intermediate Sokal risk CML patients. Seventy-eight patients were treated with 400 mg imatinib twice daily: complete cytogenetic response (CCgR) rates at 12 and 24 months were 88% and 91%; moreover, at 12 and 24 months 56% and 73% of CCgR patients achieved a major molecular response. The incidence of adverse events was slightly higher than reported by the most important standard-dose trials. With a median follow-up of 24 months, 3 patients progressed to advanced phase. In intermediate Sokal risk newly diagnosed CML patients, high-dose imatinib induced rapid and high response rates, apparently faster than those documented in the International Randomized Study of IFN and Imatinib for the same risk category. These clinical trials are registered at www.clinicaltrials.gov as no. NCT00510926.

Description: Abstract 2211 Poster Board II-188 Dasatinib is a 2nd generation tyrosine-kinase inhibitor active in CML patients resistant or intolerant to Imatinib; at present there is no data on its toxicity and efficacy in unselected elderly patients. To highlight this issue, 97 patients treated with Dasatinib when aged 〉 60 years were retrospectively evaluated from 16 Italian Centers on a “real-life” basis, including all patients treated at each Center independently from enrolment or not in controlled clinical trials.There were 52 males and 45 females, median age at Dasatinib start was 69.5 years (IR 65.0 – 73.3), Sokal Risk at diagnosis was low in 26 patients, intermediate in 37, high in 15 and not valuable in 19. Forthy-five patients (46.4%) were primarily resistant, 11 (11.4%) were intolerant and 41 (42.2%) had secondary resistance to Imatinib; all patients were in CP when Dasatinib was started. Median time from diagnosis to Dasatinib treatment was 85.0 months (IR 44.8 – 120.0); 53/97 patients (54.6%) had been pretreated with IFN ± Ara-C before Imatinib, all patients received Imatinib at standard dose (400 mg/day) followed in 50/97 (51.5%) by increased dose (600 – 800 mg/day) with an overall median period of Imatinib treatment of 48.6 months (IR 26.9 – 67.0). In addition, 28/97 patients (28.8%) received other 2nd line treatment (10 Nilotinib, 14 HU +/- other drugs, 3 Imatinib + HU or IFN and 1 allogeneic transplant) before Dasatinib. Starting dose of Dasatinib was 140 mg/day in 47 patients, 100 mg/day in 44 patients and ≥ 50 mg/day in 6 patients, respectively. After a median period of treatment of 15.6 months (IR 7.6 – 23.0) all patients were evaluable for toxicity; on the whole, grade 3 – 4 hematological and extra-hematological toxicities were reported in 36/97 (37.1%) and 27/97 (27.8%) patients, respectively. A grade 3 – 4 hematological toxicity occurred in 25/47 (53.1%) patients receiving 140 mg as compared to 10/44 (22.7%) patients receiving 100 mg (p

Description: Abstract 2205 Poster Board II-182 Nilotinib is an effective and registered treatment of chronic myeloid leukemia (CML) after imatinib failure. Its efficacy as frontline treatment has been explored in phase 2 trials from MDACC and Italian GIMEMA , whose results have been presented recently (Cortes ASH Rosti, EHA). Here we present a detailed analysis of the safety profile of nilotinib 800 mg daily in the CML early chronic phase (ECP) setting. Briefly, 73 ECP patients (median age 51 yrs, range 18-83 yrs, 21/73 – 29% - ≥ 65 yrs at enrolment) received nilotinib at a dose of 400 mg BID. With a median follow-up of 15 months (range 12-24 months), the CCgR rate at 1 yr was 96%, and the major molecular response (MMolR) rate 85%. During the first 365 days, the treatment was interrupted at least once in 38 patients (52%; overall, 86 interruptions), with a median cumulative duration of drug interruption of 19 days (5.2% of 365 days) per patient (range 3-169 days); 35 pts (48%) received the full prescribed dose. The proportion of patients with ≥ 1 interruption decreased during the first and second quarter and second half (37%, 25% and 22% respectively). The mean daily dose was 600-800 mg, 400-599 mg, and less than 400 mg in 74%, 18% and 8% of patients, respectively. Four AEs (≥ grade 2) accounted for the great majority of dose interruptions: bilirubin increase (38%, no gr. 4), skin rash and/or pruritus (37%, no gr. 4), asymptomatic amylase and/or lipase increase (16%, gr. 4: 4%) (no pancreatitis), transaminases increase (19%, no gr. 4). Notably, only 3 events of peripheral edema/fluid retention have been recorded so far (2 gr 1, 1 gr. 2). No pleural or pericardial effusion. Only one pt permanently discontinued nilotinib for recurrent amylase and lipase increase gr. 3-4 after 7 months on nilotinib, without pancreatitis (normal ECO scan and MRI): the pt. is on imatinib 400 mg daily from 12 months, maintaining the CCyR but loosing MMolR on imatinib. The transient hyperglicemia (gr. 2 and 3: 6%) did not lead to any treatment discontinuation. The hematopoietic toxicity (grade 3-4) was negligible: only 5 events (3 neutropenias and 2 thrombocytopenias) in 5 pts (7%) (all within 3 months from treatment start: 431/438 q2weeks scheduled blood counts evaluable). Nilotinib 800 mg daily is feasible, safe and very effective in ECP CML (ClinicalTrials Gov.NCT00481052). ACKNOWLEDGEMENTS: The Italian Association Against Leukemia-lymphoma and myeloma (BolognAIL), The Fondazione del Monte di Bologna e Ravenna, The Italian Ministery of Education (PRIN 2005, No. 20050 63732_003, and PRIN 2007, No 2007F7 AE7B_002), The University of Bologna, The European Union (European LeukemiaNet). Disclosures: No relevant conflicts of interest to declare.

Description: Sokal risk formulation was elaborated 25 years ago, based on very simple factors (age, spleen size, platelet count, and percentage of myeloblasts in the peripheral blood), based on patients treated with conventional chemotherapy. In spite of that, Sokal risk score is still the major prognostic factor for response to treatment with the tyrosine kinase inhibitor, Imatinib mesylate (IM). Since several preclinical, pharmacokinetic and clinical studies suggested that the therapeutic efficacy of IM may be concentration/dose–dependent, we assigned prospectively 217 adult patients with Ph pos CML, Sokal high risk (SHR), to be treated front line with IM 400 mg or 800 mg (Clin.Trials Gov. NCT00514488), comparing the cytogenetic and the molecular response rates at 3, 6, and 12 months. Cytogenetic response was evaluated by chromosome banding analysis (CBA) of marrow metaphases, and by FISH analysis of marrow cells in case of insufficient metaphase number. Molecular response was evaluated by RT-Q-PCR (PB), according to the international scale. The results are shown in Table 1. No difference between the two arms was significant at any time point. In the 400 mg arm, the median daily dose of IM was 400 mg, with 87% of patients receiving 350 to 400 mg. In the 800 mg arm, the median daily dose of IM was 720 mg, with 63% of patients receiving 600 to 800 mg. The CCgR rate was 86%, vs 66% in the patients who received a median daily dose of 600 to 800 or less than 600 mg daily, respectively (p=0.013). With a median follow up of 31 months (range 1–49 months), progression-free and overall survival are higher than 90% in both arms. Based on an intention-to-treat analysis, this study did not show a significant benefit of 800 mg over 400 mg in SHR patients, but the patients who could comply with the high dose had a better cytogenetic outcome. 3 months 6 months 12 months 400 800 400 800 400 800 (1)Refusal, or lost to follow-up, or protocol violations (2)Failure was defined according to the ELN recommendations (Baccarani et al, Blood2006;108:1809–1920) (3)No Ph pos metaphases out of at least 20 marrow cell metaphases, by CBA, or 〈 1% BCR-ABL positivity out of at least 200 marrow cells, by FISH (4)BCR-ABL:ABL 〈 0.10 and 〈 0.005 by RT-Q-PCR, converted to the International Scale. No. of pts 109 108 109 108 109 108 Dropouts(1) 4% 4% 5% 7% 5% 8% D/C adverse events 1% 2% 4% 4% 4% 7% Failure(2) 1% 1% 9% 10% 16% 15% CCgR(3) 19% 25% 49% 52% 58% 64% MolR〉3.0 log(4) 7% 12% 25% 31% 33% 40% MolR〉4.5 log(4) 1% 2% 3% 9% 10% 19% Transcript level (median) 2.085 1.122 0.378 0.108 0.084 0.036 Table 1: Summary of cytogenetic and molecular results. All percentages are calculated based on all randomized patients, according to the intention-to-treat principle. p-values are 〉 0.10 for all comparisons.

Description: Patients with Philadelphia (Ph) chromosome–positive acute lymphoblastic leukemia (ALL) have a rapid disease course and a poor prognosis. Dasatinib, a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, has previously induced responses in patients with imatinib-resistant or -intolerant Ph-positive ALL. We present the interim results of a phase 2 study designed to further assess the efficacy, safety, and tolerability of dasatinib 140 mg in this patient population (n = 36). With a minimum follow-up of 8 months, treatment with dasatinib resulted in substantial hematologic and cytogenetic response rates. Major hematologic responses were achieved in 42% (15/36) of patients, 67% of whom remained progression-free. Complete cytogenetic responses were attained by 58% (21/36) of patients. The presence of BCR-ABL mutations conferring imatinib resistance did not preclude a response to dasatinib. Dasatinib was also tolerable, with 6% (2/36) of patients discontinuing therapy as a result of study-drug toxicity. Most adverse events (AEs) were grade 1 or 2; febrile neutropenia was the most frequent severe AE, but this and other cytopenias were manageable with dose reduction. Dasatinib represents a safe and effective treatment option and an important therapeutic advance for patients with Ph-positive ALL. This trial was registered at www.clinicaltrials.gov as #CA180015.