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Dasatinib is effective for the treatment of chronic myeloid leukemia (CML) patients resistant or intolerant to imatinib. However, to date, most of the available data come from studies in which censorization was applied. One-hundred and fourteen CML patients resistant or intolerant to imatinib received dasatinib as second-line therapy outside from clinical trials. Response (hematologic, cytogenetic, and molecular), toxicities, event-free survival (EFS) and overall survival (OS) were evaluated. At 12 months, cumulative incidences of complete hematologic response, complete cytogenetic response (CCyR), and major molecular response were 94%, 51%, and 32%. Cumulative EFS and OS were 91 and 93%. Neither the dose, nor the duration, nor the response to prior imatinib affected the probability of achieving CCyR at 1 year with dasatinib (P = 0.7, 0.9, and 0.8). Moreover, we observed statistically significant better EFS and OS for patients receiving low-dose continuous therapy with dasatinib after dose reduction due to toxicity (50/70 mg/day) with respect to patients who received higher doses (100/140 mg/day) but discontinued temporarily the treatment (P = 0.04, P = 0.04). These findings show, for the first time, a possible effect for dasatinib at low doses in inducing or maintaining response (hematologic, cytogenetic, and molecular) in CML patients resistant or intolerant to Imatinib.

Chronic myeloid leukemia (CML) is a clonal hematopoietic disorder defined by the presence of the BCR-ABL1 fusion gene, which results from the translocation of the long arms of chromosomes 9 and 22 to form the Philadelphia (Ph) chromosome [1–3]. CML typically develops as an indolent disease (chronic phase, CP) and then progresses, usually via an accelerated phase, to fatal blast crisis over a median time of 3–5 years [1]. This was the natural history of the disease before tyrosine kinase inhibitors era, who had dramatically changed the scenario of CML.

Currently, first-line treatment of CP-CML patients consists of imatinib mesylate (Glivec®, Novartis, Basel, Switzerland), a selective inhibitor of BCR–ABL tyrosine kinase, which induces high rates of durable cytogenetic and molecular responses [4–6]. However, a percentage of patients stop Imatinib treatment due to the development of primary or secondary resistance to the drug [6–9]. Furthermore, another relevant reason for therapy discontinuation is represented by imatinib intolerance [6]. For patients resistant or intolerant to imatinib, treatment options actually consist of allogeneic stem-cell transplantation (allo-SCT) and second generation tyrosine-kinase inhibitors [10]. In particular, nilotinib (Tasigna®, Novartis, Basel, Switzerland) and dasatinib (Sprycel®, Bristol-Myers Squibb, New York, NY) have been shown to be highly effective and well tolerated in such categories of patients [11–17].

Dasatinib is a novel, oral, multitargeted kinase, which binds to multiple conformations (active and inactive) of the ABL kinase and potently inhibits the SFKs implicated in imatinib resistance [18, 19]. In phase 1–2 studies, dasatinib was able to induce major cytogenetic responses (MCyRs) with acceptable safety profile in patients with either early or advanced phases of imatinib-resistant or -intolerant CML and with Ph-positive acute lymphoblastic leukemia (ALL) [11, 20, 21] as well as in combination with α-interferon in Ph+ ALL [12].

However, the information so far available is to great extent limited to controlled clinical trials. The importance of real-life based studies to confirm data reported from clinical trials has been stressed by a recent paper from the Hammersmith Hospital [23], reporting their real-life-based experience in the treatment of uncensored patients with CML at a single Institution. The population of this study was not significantly different for age, performance status, organ dysfunctions, and prognostic factors to that of the IRIS study [4], and results were similar to those of the IRIS study, in terms of complete cytogenetic response (CCyR), EFS, and OS [23]. However, De Lavallade and coworkers [23] found some bias in the IRIS study regarding the definition of imatinib failure, and, consequently, they defined the EFS emerging from the IRIS study likely to be an overestimate. When failures were considered according to the Hammersmith's criteria, as in an intention-to-treat analysis, the real response rate to imatinib at 5 years was 62.7% [23]. Thus, further studies based on everyday clinical practice are indeed opportune, even for dasatinib.

We present here a multi-Institution retrospective study aimed to assess the efficacy and tolerability of dasatinib as second line therapy in 114 unselected CML patients not enrolled in clinical trials, resistant, or intolerant to imatinib. Patients characteristics are detailed in Table I. Disease characteristics at enrolment are detailed in Table II.

Table I. Patient Characteristics (n = 114)
CharacteristicsNo.%
Age (years)
 Median56.5 
 Range21-82 
Pts aged >60 years5040
Pts aged >70 years1915
Sex
 Male5649
 Female5851
Sokal risk group  
 Low2926
 Intermediate4540
 High4034
Time from diagnosis to switch, months
 Median61 
 Range2-243 
Time in Imatinib, months  
 Median36 
 Range1-99 
Disease characteristics
 Resistant8875
 Intolerant1615
 Resistant and intolerant1010
Bcr/Abl mutations
 Total2621
 E255K43
 M351T21.6
 E279K21.6
 F359I10.8
 A269S21.6
 F317L21.6
 T315I64.8
 Y253T10.8
 V299L10.8
 Y253H10.8
 F359V10.8
 M244V54
 V225V10.8
 K294T10.8
Table II. Baseline Disease Characteristics
 Resistant (n = 88)Intolerant (n = 16)Resistant and intolerant (n = 10)
Prior imatinib therapy   
 >600 mg/day1313
 Duration >3 years5458
Response before imatinib   
 Faliure1264
 CHR3474
 MCyR2021
 CCyR2211
Prior allogeneic stem cell transplantation311
Bcr/Abl mutations2402

To be included in the study, patients had to be diagnosed with imatinib-resistant or -intolerant CML-CP not eligible for the enrolment in clinical trials. All patients who were treated with dasatinib at the Institutions participating to the study between July 2007 and November 2008 who met this criteria were included in our analysis. Hematologic, cytogenetic and molecular response, discontinuation/dose reduction of dasatinib, event-free survival (EFS), and overall survival (OS) were evaluated. Toxicities were analyzed according to NCI-CTC version 3.0, focusing on grade III–IV toxicities.

The median follow-up for surviving patients was 12 months (range, 8–24 months); no patient was lost to follow-up. Sixty-two of 114 patients escalated imatinib from 400 to 600 mg/day and 26/62 patients from 600 to 800 mg/day before the switch to dasatinib. Median time on imatinib prior to switch was 36 months (range, 2–99 months), whereas median time on imatinib after dose escalation was 9 months (range, 1–43 months).

Patients received oral dasatinib at different doses, according to age and myelosuppression at the switch, starting at least from 100 mg/day. As a matter of fact, patients experiencing a grade III–IV toxicity discontinued dasatinib or, if possible, reduced the dose from 140 or 100 mg/day to 70 or 50 mg/day. As far as patients maintained their response or improved it even with low doses of dasatinib, we decided not to increase again dasatinib, but only to proceed with the tolerated dosage of the drug. At the time of analysis, 56 patients were receiving 50 or 70 mg/day of dasatinib, whereas 58 patients 100 or 140 mg/day. Dasatinib dose-adjustments are detailed in Table III. The median time from the start of dasatinib until dose adjustment was 29 days (range, 25–52 days). Sixty of 114 patients (53%) had to discontinue the treatment for a median time of 11 days (range, 3–29 days). Among patients who restarted dasatinib after the discontinuation, 17/60 (28%) experienced a new discontinuation, whereas 43/60 (72%) were able to proceed with 70 or 50 mg/day of dasatinib.

Table III. Dasatinib Dose Modification
Resistant88
 No modification32
 Dose increase1
 Dose reduction10
 Dose interruption45
Intolerant16
 No modification7
 Dose increase1
 Dose reduction3
 Dose interruption5
Resistant and intolerant10
 No modification1
 Dose increase0
 Dose reduction1
 Dose interruption8

One-hundred and seven patients (94%) achieved at least a complete hematologic response (CHR). During follow-up, 86 patients (75%) achieved a MCyR after a median time of 3 months (range, 3–18 months), 63 (51%) a CCyR after a median time of 6 months (range, 3–18 months), and 40 (32%) attained a major molecular response (MMolR) after a median time of 6 months (range, 3–24 months). We performed univariate and multivariate analyses to identify pretherapy prognostic factors for the achievement of CCyR. Sokal score, sex, age, prior allo-SCT, and presence of a kinase domain (KD) mutation, duration/dose of prior imatinib and best response to treatment were the variables analyzed.

Intriguingly, we did not find any association between the dose of prior imatinib (400, 600, or 800 mg/day, with or without dose escalation) and the probability of achieving CCyR at 1 year with dasatinib (P = 0.7). Furthermore, we did not find any association between the duration of the previous treatment with imatinib and the probability of achieving CCyR at 1 year with dasatinib (P = 0.9). Finally, we did not observe any association between best response to imatinib and probability of achieving CCyR after 1 year with dasatinib (P = 0.8).

Fifty-nine patients performed KD mutations analysis at time of switching from imatinib to dasatinib, and 24/59 (41%) showed a KD mutation. Types of KD mutation at study entry are listed in Table I. As expected, patients without KD mutation had a significantly superior EFS at 12 months (P = 0.0002, data not shown). Interestingly, patients developing the T315I or F317L KD mutation did not significantly underperform with respect to patients with other KD mutations (P = 0.08, data not shown).

Seven patients resistant to imatinib died after progression of disease to overt blast-crisis. Cumulative EFS and OS at 12 months were 91 and 93%, respectively. The achievement of CHR, MCyR, CCyR, and MMolR significantly influenced EFS and OS both in univariate and multivariate analysis. The most relevant data emerging from the multivariate statistical analysis are listed on Table IV.

Table IV. Multivariate Analysis
 DFSOS
Age0.50.5
Imatinib dose0.950.9
Imatinib duration0.40.1
Imatinib duration pre switch0.40.4
Dasatinib dose intensity (no discontinuation vs. any discontinuation of therapy)0.040.04
Dasa dose post discontinuation (140 vs. 100 vs. 70)0.40.6
CHR duration0.0060.002
MCyR duration0.040.02
CCyR duration0.0080.004
MMR duration0.0030.001

Grade III–IV toxicities are detailed in Table V. The commonest grade III/IV adverse events were thrombocytopenia and neutropenia occurring in 19% and 19% of patients, respectively. Only 3% of the patients suffered from a grade III–IV pleural effusion or dyspnoea. The incidences of thrombocytopenia and neutropenia were significantly lower with respect to clinical trials, maybe due to the fact that the vast majority of patients received less than 140 mg/day of dasatinib [21].

Table V. Grade III–IV WHO Toxicities (n = 114)
ToxicityNo.%
Thrombocytopenia2419.3
Neutropenia2419.3
Leucopenia1713.7
Anemia1613
Asthenia64.8
Pleural effusion43
Dyspnea43
Fatigue43
Diarrhea32.4
Pericardial effusion10.8
Nausea10.8
Bone pain10.8
Congestive heart failure10.8
Muscle aches10.8
Bleeding10.8
Weight loss10.8
Deep vein thrombosis10.8
Oral mucositis10.8
Periobital edema10.8

Finally, we observed statistically significant better EFS and OS for patients receiving low-dose continuous therapy with dasatinib after dose reduction due to toxicity (50/70 mg/day) with respect to patients who received higher doses (100/140 mg/day) but discontinued temporarily the treatment (P = 0.04, P = 0.04). In this regard, a recent paper by Shah, Sawyers and coworkers demonstrated that a transient but potent BCR-ABL inhibition is sufficient to commit CML cells irreversibly to apoptosis [24]. This biological observation [24], coupled with the demonstration that the clinical benefit of dasatinib is indeed equivalent when dosed once daily [25], supports our clinical hypothesis that a transient, potent, and clinical inhibition of BCR-ABL might be ensured in vivo even by a low dose of dasatinib, namely 50 or 70 mg.

In conclusion, our data confirm that dasatinib is well tolerated and highly effective in overcoming resistance and intolerance to imatinib even for real-life patients treated outside from clinical trials. In fact, our population was not selected, and, even if the median age (56 years) was in line with median age found in clinical trials, it represents a setting in which all events were recorded without any censorization.

These findings show, for the first time, a possible effect for dasatinib, even at low doses, in inducing or maintaining responses (hematologic, cytogenetic, and molecular) in real-life CML patients resistant or intolerant to Imatinib. Further studies are warranted to confirm our findings to demonstrate the efficacy of front-line low-dose continuous dasatinib therapy in patients potentially not eligible to receive dasatinib at standard doses.

Methods

CP and CHR were defined by conventional criteria [5]. Cytogenetic analysis was performed by standard chromosome banding analysis of marrow metaphases, and cytogenetic response was rated according to the European LeukemiaNet guidelines [5]. Molecular response was assessed with a standardized methodology on peripheral blood cells by a standardized quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) method on an ABI PRISM 7700 Sequence Detector (Perkin Elmer, Faster City, CA) [23]. Major molecular response (MMolR) was defined as a ratio BCR-ABL:ABL less than 0.1% on the International Scale (IS), whereas undetectable BCR-ABL transcript levels required a ratio BCR-ABL:ABL less than 0.01% on the IS [26]. All the results (CCyR, MMolR and undetectable BCR-ABL transcript levels rates) were calculated based on all enrolled patients, according to the intention-to-treat principle.

Imatinib resistance was defined as failure to achieve CHR after 3 months, cytogenetic response after 6 months, MCyR after 12 months, or loss of a hematologic or cytogenetic response at any time during treatment with imatinib [16]. Entry criteria for imatinib intolerance included patients with intolerance symptoms, but who also had never achieved a MCyR with imatinib [16]. Intolerance symptoms were defined as any nonhematologic toxicity of grade 3 or higher severity, or of grade 2 or higher severity lasting more than 1 month or recurring more than three times despite dose reduction and maximal supportive care [16]. The definition of intolerance also included hematologic toxicity of grade 4 severity persisting for more than 7 days [16]. Patients were seen on a monthly basis. Cytogenetic analysis and RT-PCR were performed every 3 months.

Fifty-nine of 114 patients were analyzed for the presence of Bcr-Abl KD mutations at the time of IM failure, before starting subsequent dasatinib treatment. Mutation analysis was performed by denaturing high-performance liquid chromatography [26].

OS was calculated by the product-limits method of Kaplan–Meier from the date of first dasatinib dose to the date of death or last contact, whichever came first. EFS was calculated from the date of first dasatinib dose to the date of dasatinib discontinuation, CCgR loss, progression to AP/BC or to death, whichever came first. AP and BC were identified as previously reported [5].

Univariate analyses to identify prognostic factors for OS, EFS, cytogenetic response, and cytogenetic relapse were carried out using the log-rank test. Variables found to be significant were entered into a proportional hazards regression model (Cox regression model). The limit of significance for all analyses was defined as P < 0.05; two-sided tests were used in all calculations.

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Giuseppe Visani g.visani@ospedalesansalvatore.it*, Massimo Breccia†, Antonella Gozzini‡, Giorgina Specchia§, Enrico Montefusco¶, Enrica Morra**, Mario Annunziata††, Andrea Camera‡‡, Francesco Cavazzini§§, Fabio Stagno¶¶, Patrizia Pregno11, Emilio Usala12, Valeria Santini‡, Pier Paolo Piccaluga13, Alessandro Isidori*, * Hematology and Stem Cell Transplant Center, San Salvatore Hospital, Pesaro, Italy, † Department of Biotechnologies and Hematology, University “La Sapienza”, Rome, Italy, ‡ Hematology Unit, AOU Careggi, Universitàdegli Studi di Firenze, Florence, Italy, § Hematology, University of Bari Medical School, Bari, Italy, ¶ Hematology, University “La Sapienza”, Rome, Italy, ** Hematology, Niguarda Ca'Granda Hospital, Milano, Italy, †† Division of Hematology and Stem Cell Transplantation Unit, Cardarelli Hospital, Naples, Italy, ‡‡ Hematology, Università Federico II, Naples, Italy, §§ Section of Haematology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Italy, ¶¶ Institute of Hematology, University of Catania, Italy, 11 Hematology, Molinette Hospital, Torino University, Italy, 12 Hematology, Armando Businco Hospital, Cagliari, Italy, 13 Hemolymphopathology, Bologna, Italy.