François Guilhot

European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013

Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, <1% at 6 months, and ≤0.1% from 12 months onward define optimal response, whereas >10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome-positive [Ph+] >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.

Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia

Imatinib mesylate is considered standard of care for first-line treatment of chronic phase chronic myeloid leukemia (CML-CP). In the phase III, randomized, open-label International Randomized Study of Interferon vs STI571 (IRIS) trial, previously untreated CML-CP patients were randomized to imatinib (n=553) or interferon-α (IFN) plus cytarabine (n=553). This 6-year update focuses on patients randomized to receive imatinib as first-line therapy for newly diagnosed CML-CP. During the sixth year of study treatment, there were no reports of disease progression to accelerated phase (AP) or blast crisis (BC). The toxicity profile was unchanged. The cumulative best complete cytogenetic response (CCyR) rate was 82%; 63% of all patients randomized to receive imatinib and still on study treatment showed CCyR at last assessment. The estimated event-free survival at 6 years was 83%, and the estimated rate of freedom from progression to AP and BC was 93%. The estimated overall survival was 88%––or 95% when only CML-related deaths were considered. This 6-year update of IRIS underscores the efficacy and safety of imatinib as first-line therapy for patients with CML.

A Phase 2 Trial of Ponatinib in Philadelphia Chromosome–Positive Leukemias

BACKGROUND Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). METHODS We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. RESULTS Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event. CONCLUSIONS Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .).

Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy.

Dasatinib, a broad-spectrum tyrosine kinase inhibitor (TKI), predominantly targets BCR-ABL and SRC oncoproteins and also inhibits off-target kinases, which may result in unexpected drug responses. We identified 22 patients with marked lymphoproliferation in blood while on dasatinib therapy. Clonality and immunophenotype were analyzed and related clinical information was collected. An abrupt lymphocytosis (peak count range 4–20 × 109/l) with large granular lymphocyte (LGL) morphology was observed after a median of 3 months from the start of therapy and it persisted throughout the therapy. Fifteen patients had a cytotoxic T-cell and seven patients had an NK-cell phenotype. All T-cell expansions were clonal. Adverse effects, such as colitis and pleuritis, were common (18 of 22 patients) and were preceded by LGL lymphocytosis. Accumulation of identical cytotoxic T cells was also detected in pleural effusion and colon biopsy samples. Responses to dasatinib were good and included complete, unexpectedly long-lasting remissions in patients with advanced leukemia. In a phase II clinical study on 46 Philadelphia chromosome-positive acute lymphoblastic leukemia, patients with lymphocytosis had superior survival compared with patients without lymphocytosis. By inhibiting immunoregulatory kinases, dasatinib may induce a reversible state of aberrant immune reactivity associated with good clinical responses and a distinct adverse effect profile.

Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi( ϕ )-LMC GROUP)

The emergence of ABL point mutations is the most frequent cause for imatinib resistance in chronic myelogenous leukemia (CML) patients and can occur during any phase of the disease; however, their clinical impact remains controversial. In this study, we retrospectively analyzed the predictive impact of 94 BCR-ABL kinase domain mutations (18 T315I, 26 P-loop, 50 in other sites) found in 89 imatinib-resistant CML patients. At imatinib onset, 64% of patients (57/89) were in chronic phase (CP), 24% (21/89) in accelerated phase (AP) and 12% (11/89) in blastic phase (BP). T315I and P-loop mutations were preferentially discovered in accelerated phase of BP CML, and other types of mutations in CP (P=0.003). With a median follow-up of 39.2 months (6.3–67.2), since imatinib initiation, overall survival (OS) was significantly worse for P-loop (28.3 months) and for T315I (12.6 months), and not reached for other mutations (P=0.0004). For CP only, multivariate analysis demonstrated a worse OS for P-loop mutations (P=0.014), and a worse progression-free survival (PFS) for T315I mutations (P=0.014). Therefore, P-loop and T315I mutations selectively impair the outcome of imatinib-resistant CML patients, in contrast to other mutations, which may benefit from dose escalation of imatinib, able to improve or stabilize disease response.

Quality of life in patients with newly diagnosed chronic phase chronic myeloid leukemia on imatinib versus interferon alfa plus low-dose cytarabine: results from the IRIS Study.

PURPOSE Quality of life (QOL) outcomes in patients with chronic myeloid leukemia (CML) were evaluated in an international phase III study. PATIENTS AND METHODS Newly diagnosed patients with chronic phase CML were randomly assigned to imatinib or interferon alfa plus subcutaneous low-dose cytarabine (IFN+LDAC). Cross-over to the other treatment was permitted because of intolerance or lack of efficacy. Patients completed cancer-specific QOL (Functional Assessment of Cancer Therapy-Biologic Response Modifiers) and utility (Euro QoL-5D) questionnaires at baseline and during treatment (n = 1,049). The primary QOL end point was the Trial Outcome Index (TOI; a measure of physical function and well-being). Secondary end points included social and family well-being (SFWB), emotional well-being (EWB), and the utility score. Primary analyses were intention to treat with secondary analyses accounting for cross-over. RESULTS Patients receiving IFN+LDAC experienced a large decline in the TOI, whereas those receiving imatinib maintained their baseline level. Treatment differences at each visit were significant (P <.001) and clinically relevant in favor of imatinib. Mean SFWB, EWB, and utility scores were also significantly better for those patients taking imatinib. Patients who crossed over to imatinib experienced a large increase in TOI; significant (P <.001) differences were observed between patients who did and did not cross over in favor of imatinib. CONCLUSION Imatinib offers clear QOL advantages compared with IFN+LDAC as first-line treatment of chronic phase CML. In addition, patients who cross over to imatinib from IFN+LDAC experience a significant improvement in QOL compared with patients who continue to take IFN+LDAC.

Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia

Imatinib is the current standard of care in the treatment of chronic myeloid leukemia (CML), inducing durable responses and prolonged progression-free survival. However, plasma exposure to the drug from a given dosing regimen can vary widely among patients. Reasons for this may include incomplete adherence, intrinsic variations in the metabolism of imatinib, and drug–drug interactions. Data from two recent studies have shown a correlation between imatinib trough plasma concentration and clinical response, leading to suggestions that maintaining imatinib blood concentrations above ∼1000 ng/ml might be associated with improved outcomes. In patients who do not respond as well as expected to initial imatinib treatment, measurement of trough plasma concentration could assist with decisions about whether to increase the dose. Blood-level testing may also be helpful in other clinical scenarios: for example, when poor adherence is suspected, adverse reactions are unusually severe, or there is a possible drug–drug interaction. Further work is required to confirm prospectively the link between imatinib plasma concentrations and response, and to define effective trough concentrations in different patient populations. However, based on the current data, imatinib blood-level testing seems to be a useful aid when making clinical decisions in CML.

On the use of lonafarnib in myelodysplastic syndrome and chronic myelomonocytic leukemia

Lonafarnib is an orally bio-available farnesyltransferase inhibitor that prevents farnesylation of specific target proteins including Ras. In a multicenter study, 67 patients with advanced myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) were treated with a continuous oral dose of 200–300 mg of lonafarnib and were evaluated for hematologic, pathologic and pharmacodynamic response. The median age of patients was 70 years (range 44–86). There were 32 patients with MDS (RAEB-20 and RAEB-t-12) and 35 with CMML. Overall 16 (24%) of the patients responded with two patients achieving a complete remission and one a partial response. Responses were seen in 6/32 and 10/35 patients with MDS and CMML, respectively. Of the 19 patients who were platelet transfusion-dependent prior to treatment, 5 (26%) became transfusion-free for a median duration of 185 days. A decrease in the farnesylation of the HDJ-2 protein measured in patient-derived cells was observed in the majority of patients during treatment with lonafarnib, but no clear correlation between changes in farnesylation and clinical effect could be made. Gastrointestinal toxicity was significant with 19% of patients discontinuing therapy due to diarrhea, nausea and/or anorexia. Lonafarnib has demonstrable activity in patients with advanced MDS and CMML.

Unexpected occurrence of second malignancies in patients treated with interferon followed by imatinib mesylate for chronic myelogenous leukemia

Unexpected occurrence of second malignancies in patients treated with interferon followed by imatinib mesylate for chronic myelogenous leukemia

Prior treatment with the tyrosine kinase inhibitors dasatinib and nilotinib allows stem cell transplantation (SCT) in a less advanced disease phase and does not increase SCT Toxicity in patients with chronic myelogenous leukemia and philadelphia positive acute lymphoblastic leukemia

Prior treatment with the tyrosine kinase inhibitors dasatinib and nilotinib allows stem cell transplantation (SCT) in a less advanced disease phase and does not increase SCT Toxicity in patients with chronic myelogenous leukemia and philadelphia positive acute lymphoblastic leukemia