Elisabetta Abruzzese

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 .).

Contribution of ABL Kinase Domain Mutations to Imatinib Resistance in Different Subsets of Philadelphia-Positive Patients: By the GIMEMA Working Party on Chronic Myeloid Leukemia

Purpose: ABL kinase domain mutations have been implicated in the resistance to the BCR-ABL inhibitor imatinib mesylate of Philadelphia-positive (Ph+) leukemia patients. Experimental Design: Using denaturing high-performance liquid chromatography and sequencing, we screened for ABL kinase domain mutations in 370 Ph+ patients with evidence of hematologic or cytogenetic resistance to imatinib. Results: Mutations were found in 127 of 297 (43%) evaluable patients. Mutations were found in 27% of chronic-phase patients (14% treated with imatinib frontline; 31% treated with imatinib post-IFN failure), 52% of accelerated-phase patients, 75% of myeloid blast crisis patients, and 83% of lymphoid blast crisis/Ph+ acute lymphoblastic leukemia (ALL) patients. Mutations were associated in 30% of patients with primary resistance (44% hematologic and 28% cytogenetic) and in 57% of patients with acquired resistance (23% patients who lost cytogenetic response; 55% patients who lost hematologic response; and 87% patients who progressed to accelerated phase/blast crisis). P-loop and T315I mutations were particularly frequent in advanced-phase chronic myeloid leukemia and Ph+ ALL patients, and often accompanied progression from chronic phase to accelerated phase/blast crisis. Conclusions: We conclude that (a) amino acid substitutions at seven residues (M244V, G250E, Y253F/H, E255K/V, T315I, M351T, and F359V) account for 85% of all resistance-associated mutations; (b) the search for mutations is important both in case of imatinib failure and in case of loss of response at the hematologic or cytogenetic level; (c) advanced-phase chronic myeloid leukemia and Ph+ ALL patients have a higher likelihood of developing imatinib-resistant mutations; and (d) the presence of either P-loop or T315I mutations in imatinib-treated patients should warn the clinician to reconsider the therapeutic strategy.

Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell–depleting therapy with rituximab

The effects of B-cell depletion with rituximab on regulatory T cells (Tregs) have not been determined. We investigated Tregs in patients receiving rituximab for chronic idiopathic thrombocytopenic purpura (ITP). The peripheral blood Tregs, identified as CD4+FOXP3+ T cells, were measured by flow cytometry prior to and after the immunotherapy. In addition, Tregs were analyzed for their usage of the T-cell receptor (TCR) beta-variable (VB) region gene as well as their regulatory function as assessed by cell proliferation assays. Pretreatment data revealed a reduced number and a defective suppressive capacity of Tregs in ITP patients compared with control individuals. In addition, Tregs showed a polyclonal spectratype. Patients, particularly responders, showed restored numbers of Tregs as well as a restored regulatory function upon treatment with rituximab. These results indicate that patients with active ITP have a defective T regulatory cell compartment that can be modulated by a B cell-targeted therapy.

Multicenter Independent Assessment of Outcomes in Chronic Myeloid Leukemia Patients Treated With Imatinib

BACKGROUND Imatinib slows development of chronic myeloid leukemia (CML). However, available information on morbidity and mortality is largely based on sponsored trials, whereas independent long-term field studies are lacking. PATIENTS AND METHODS Consecutive CML patients who started imatinib treatment before 2005 and who were in complete cytogenetic remission (CCyR) after 2 years (± 3 months) were eligible for enrollment in the independent multicenter Imatinib Long-Term (Side) Effects (ILTE) study. Incidence of the first serious and nonserious adverse events and loss of CCyR were estimated according to the Kaplan-Meier method and compared with the standard log-rank test. Attainment of negative Philadelphia chromosome hematopoiesis was assessed with cytogenetics and quantitative polymerase chain reaction. Cumulative incidence of death related or unrelated to CML progression was estimated, accounting for competing risks, according to the Kalbleisch-Prentice method. Standardized incidence ratios were calculated based on population rates specific for sex and age classes. Confidence intervals were calculated by the exact method based on the χ(2) distribution. All statistical tests were two-sided. RESULTS A total of 832 patients who were treated for a median of 5.8 years were enrolled. There were 139 recorded serious adverse events, of which 19.4% were imatinib-related. A total of 830 nonserious adverse events were observed in 53% of patients; 560 (68%) were imatinib-related. The most frequent were muscle cramps, asthenia, edema, skin fragility, diarrhea, tendon, or ligament lesions. Nineteen patients (2.3%) discontinued imatinib because of drug-related toxic effects. Forty-five patients lost CCyR, at a rate of 1.4 per 100 person-years. Durable (>1 year) negative Philadelphia chromosome hematopoiesis was attained by 179 patients. Twenty deaths were observed, with a 4.8% mortality incidence rate (standardized incidence ratio = 0.7; 95% confidence interval = 0.40 to 1.10, P = .08), with only six (30%) associated with CML progression. CONCLUSIONS In this study, CML-related deaths were uncommon in CML patients who were in CCyR 2 years after starting imatinib, and survival was not statistically significantly different from that of the general population.

Omitting Radiotherapy in Early Positron Emission Tomography–Negative Stage I/II Hodgkin Lymphoma Is Associated With an Increased Risk of Early Relapse: Clinical Results of the Preplanned Interim Analysis of the Randomized EORTC/LYSA/FIL H10 Trial

PURPOSE Combined-modality treatment is standard treatment for patients with clinical stage I/II Hodgkin lymphoma (HL). We hypothesized that an early positron emission tomography (PET) scan could be used to adapt treatment. Therefore, we started the randomized EORTC/LYSA/FIL Intergroup H10 trial evaluating whether involved-node radiotherapy (IN-RT) could be omitted without compromising progression-free survival in patients attaining a negative early PET scan after two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) as compared with standard combined-modality treatment. PATIENTS AND METHODS Patients age 15 to 70 years with untreated clinical stage I/II HL were eligible. Here we report the clinical outcome of the preplanned interim futility analysis scheduled to occur after documentation of 34 events in the early PET-negative group. Because testing for futility in this noninferiority trial corresponds to testing the hypothesis of no difference, a one-sided superiority test was conducted. RESULTS The analysis included 1,137 patients. In the favorable subgroup, 85.8% had a negative early PET scan (standard arm, one event v experimental arm, nine events). In the unfavorable subgroup, 74.8% had a negative early PET scan (standard arm, seven events v experimental arm, 16 events). The independent data monitoring committee concluded it was unlikely that we would show noninferiority in the final results for the experimental arm and advised stopping random assignment for early PET-negative patients. CONCLUSION On the basis of this analysis, combined-modality treatment resulted in fewer early progressions in clinical stage I/II HL, although early outcome was excellent in both arms. The final analysis will reveal whether this finding is maintained over time.

Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study

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.

Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial.

PURPOSE Patients with chronic myelogenous leukemia in accelerated phase (CML-AP) that is resistant or intolerant to imatinib have limited therapeutic options. Dasatinib, a potent inhibitor of BCR-ABL and SRC-family kinases, has efficacy in patients with CML-AP who have experienced treatment failure with imatinib. We now report follow-up data from the full patient cohort of 174 patients enrolled onto a phase II trial to provide a more complete assessment of the efficacy and safety of dasatinib in this population. PATIENTS AND METHODS Patients with imatinib-resistant (n = 161) or -intolerant (n = 13) CML-AP received dasatinib 70 mg orally twice daily. Results At a median follow-up of 14.1 months (treatment duration, 0.1 to 21.7 months), major and complete hematologic responses were attained by 64% and 45% of patients, respectively, and major and complete cytogenetic responses were achieved in 39% and 32% of patients, respectively. Responses were achieved irrespective of imatinib status (resistant or intolerant), prior stem-cell transplantation, or the presence of prior BCR-ABL mutation. The 12-month progression-free survival and overall survival rates were 66% and 82%, respectively. Dasatinib was generally well tolerated; the most frequent nonhematologic severe treatment-related adverse event was diarrhea (52%; grade 3 to 4, 8%). Cytopenias were common, including grade 3 to 4 neutropenia (76%) and thrombocytopenia (82%). Pleural effusion occurred in 27% of patients (grade 3 to 4, 5%). CONCLUSION Dasatinib is effective in patients with CML-AP after imatinib treatment failure.

Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors.

Dasatinib and nilotinib are tyrosine kinase inhibitors (TKIs) developed to overcome imatinib resistance in Philadelphia-positive leukemias. To assess how Bcr-Abl kinase domain mutation status evolves during sequential therapy with these TKIs and which mutations may further develop and impair their efficacy, we monitored the mutation status of 95 imatinib-resistant patients before and during treatment with dasatinib and/or nilotinib as second or third TKI. We found that 83% of cases of relapse after an initial response are associated with emergence of newly acquired mutations. However, the spectra of mutants conferring resistance to dasatinib or nilotinib are small and nonoverlapping, except for T315I. Patients already harboring mutations had higher likelihood of relapse associated with development of further mutations compared with patients who did not harbor mutations (23 of 51 vs 8 of 44, respectively, for patients who relapsed on second TKI; 13 of 20 vs 1 of 6, respectively, for patients who relapsed on third TKI).

Severe peripheral arterial disease during nilotinib therapy

(36.4%) had a history of nicotine abuse, seven (63.6%) had arterial hypertension, three (27.3%) had diabetes mellitus, five (45.5%) had dyslipidemia, three (27.3%) were obese, six (54.5%) were male, and seven (63.6%) were older than 60 years (all cardiovascular risk factors). All 11 PAD patients had at least a cytogenetic remission while on nilotinib. One patient with hyper eosinophilic syndrome and one patient with CML received nilotinib as first-line treatment. Previous treatments for the remaining patients were hydroxyurea (nine patients), interferon alpha (seven patients), imatinib (nine patients), dasatinib (one patient), or another agent (four patients). In these 11 patients, the mean time from CML diagnosis to initiation of nilotinib was 347 weeks (range = 8–651 weeks) and the mean time from initiation of nilotinib to the first PAD event was 105.1 weeks (range = 16–212 weeks) (Table 1). In all cases, the lower limbs were affected; in nine patients, the femoral superficial artery was involved. These patients were treated with angioplasty (eight patients), stent implantation (eight patients), and/or amputation (four patients).

Nilotinib is active in chronic and accelerated phase chronic myeloid leukemia following failure of imatinib and dasatinib therapy

Nilotinib is a highly selective Bcr–Abl inhibitor approved for imatinib-resistant chronic myeloid leukemia (CML). Nilotinib and dasatinib, a multi-targeted kinase inhibitor also approved for second-line therapy in CML, have different patterns of kinase selectivity, pharmacokinetics, and cell uptake and efflux properties, and thus patients may respond to one following failure of the other. An international phase II study of nilotinib was conducted in CML patients (39 chronic phase (CP), 21 accelerated phase (AP)) after failure of both imatinib and dasatinib. Median times from diagnosis of CP or AP to nilotinib therapy were 89 and 83 months, respectively. Complete hematological response and major cytogenetic response (MCyR) rates in CP were 79% and 43%, respectively. Of 17 evaluable patients with CML-AP, 5 (29%) had a confirmed hematological response and 2 (12%) a MCyR. The median time to progression has not yet been reached in CP patients. At 18 months 59% of patients were progression-free. Median overall survival for both populations has not been reached, and the estimated 18-month survival rate in CML-CP was 86% and that at 12 months for CML-AP was 80%. Nilotinib is an effective therapy in CML-CP and -AP following failure of both imatinib and dasatinib therapy.