We report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating long-term efficacy and safety ...outcomes of patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with dasatinib or imatinib.
Patients with newly diagnosed CML-CP were randomly assigned to receive dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260).
At the time of study closure, 61% and 63% of dasatinib- and imatinib-treated patients remained on initial therapy, respectively. Cumulative rates of major molecular response and molecular responses with a 4.0- or 4.5-log reduction in BCR-ABL1 transcripts from baseline by 5 years remained statistically significantly higher for dasatinib compared with imatinib. Rates for progression-free and overall survival at 5 years remained high and similar across treatment arms. In patients who achieved BCR-ABL1 ≤ 10% at 3 months (dasatinib, 84%; imatinib, 64%), improvements in progression-free and overall survival and lower rates of transformation to accelerated/blast phase were reported compared with patients with BCR-ABL1 greater than 10% at 3 months. Transformation to accelerated/blast phase occurred in 5% and 7% of patients in the dasatinib and imatinib arms, respectively. Fifteen dasatinib-treated and 19 imatinib-treated patients had BCR-ABL1 mutations identified at discontinuation. There were no new or unexpected adverse events identified in either treatment arm, and pleural effusion was the only drug-related, nonhematologic adverse event reported more frequently with dasatinib (28% v 0.8% with imatinib). First occurrences of pleural effusion were reported with dasatinib, with the highest incidence in year 1. Arterial ischemic events were uncommon in both treatment arms.
These final results from the DASISION trial continue to support dasatinib 100 mg once daily as a safe and effective first-line therapy for the long-term treatment of CML-CP.
Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I. The pivotal phase 2 Ponatinib Ph+ ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ...ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1T315I. This analysis focuses on chronic-phase CML (CP-CML) patients (n = 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ≥90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients. This trial was registered at www.clinicaltrials.gov as #NCT01207440.
•Ponatinib continued to provide deep, durable responses in heavily pretreated patients with CP-CML.•Tolerability was acceptable in this heavily pretreated population with 5 years of follow-up.
Display omitted
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The treatment of chronic myeloid leukemia (CML) achieved a great leap forward with the development of imatinib, a BCR-ABL kinase inhibitor. Alterations in the chemical structure of the inhibitor have ...produced agents that are more potent in vitro. In these studies, two new second-generation BCR-ABL kinase inhibitors, nilotinib and dasatinib, are compared with imatinib; these new drugs produce more complete responses and do so faster than imatinib. Both also appear to reduce the rate of progression to accelerated-phase and blast-phase disease.
Chronic myeloid leukemia (CML) in the chronic phase, a clonal myeloproliferative disorder, is caused by the constitutively active BCR-ABL tyrosine kinase resulting from the translocation that produces the Philadelphia (Ph) chromosome.
1
,
2
Imatinib (Gleevec, Novartis Pharmaceuticals), an inhibitor of the BCR-ABL kinase, is the standard first-line therapy for patients with chronic-phase CML.
3
–
6
Dasatinib (Sprycel, Bristol-Myers Squibb), a second-generation BCR-ABL kinase inhibitor, has been approved as a second-line treatment for patients with CML if imatinib therapy fails.
4
–
7
Dasatinib therapy induces a complete cytogenetic response in approximately 50% of patients who do not have a response to imatinib or cannot . . .
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management ...challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 40-year-old woman with a past medical history of hypertension and occasional premature ventricular contractions was found on routine blood work in June 2011 to have mild thrombocytosis, with a platelet count of 405,000. In November 2011, repeat analysis revealed a platelet count of 433,000, and by February 2012 her platelet count was 509,000. She had no evidence of leukocytosis or anemia and no symptoms of early satiety, night sweats, pruritus, or erythromelalgia. She was referred to a hematologist for evaluation of persistent isolated thrombocytosis in March 2012. Her spleen was not palpable, and a quantitative polymerase chain reaction (PCR) test for JAK2/V617F was negative. A bone marrow biopsy and aspiration revealed a mildly hypercellular marrow (70% to 80% cellularity), with an elevated myeloid:erythroid ratio of 5:1, increased megakaryocytes including micromegakaryocytes in the absence of increased blasts. Cytogenetic analysis revealed the presence of the Philadelphia chromosome translocation in 17 out of 20 metaphases. The remaining three metaphases were normal karyotype. Quantitative PCR for BCR-ABL1 yielded a value of 29.6% on the International Scale.
FLT3 internal tandem duplication (FLT3-ITD) mutations account for ~25% of adult acute myeloid leukemia cases and are associated with poor prognosis. Venetoclax, a selective BCL-2 inhibitor, has ...limited monotherapy activity in relapsed/refractory acute myeloid leukemia with no responses observed in a small subset of FLT3-ITD+ patients. Further, FLT3-ITD mutations emerged at relapse following venetoclax monotherapy and combination therapy suggesting a potential mechanism of resistance. Therefore, we investigated the convergence of FLT3-ITD signaling on the BCL-2 family proteins and determined combination activity of venetoclax and FLT3-ITD inhibition in preclinical models. In vivo, venetoclax combined with quizartinib, a potent FLT3 inhibitor, showed greater anti-tumor efficacy and prolonged survival compared to monotherapies. In a patient-derived FLT3-ITD+ xenograft model, cotreatment with venetoclax and quizartinib at clinically relevant doses had greater anti-tumor activity in the tumor microenvironment compared to quizartinib or venetoclax alone. Use of selective BCL-2 family inhibitors further identified a role for BCL-2, BCL-XL and MCL-1 in mediating survival in FLT3-ITD+ cells in vivo and highlighted the need to target all three proteins for greatest anti-tumor activity. Assessment of these combinations in vitro revealed synergistic combination activity for quizartinib and venetoclax but not for quizartinib combined with BCL-XL or MCL-1 inhibition. FLT3-ITD inhibition was shown to indirectly target both BCL-XL and MCL-1 through modulation of protein expression, thereby priming cells toward BCL-2 dependence for survival. These data demonstrate that FLT3-ITD inhibition combined with venetoclax has impressive anti-tumor activity in FLT3-ITD+ acute myeloid leukemia preclinical models and provides strong mechanistic rational for clinical studies.
Genomic studies have revealed significant branching heterogeneity in cancer. Studies of resistance to tyrosine kinase inhibitor therapy have not fully reflected this heterogeneity because resistance ...in individual patients has been ascribed to largely mutually exclusive on-target or off-target mechanisms in which tumors either retain dependency on the target oncogene or subvert it through a parallel pathway. Using targeted sequencing from single cells and colonies from patient samples, we demonstrate tremendous clonal diversity in the majority of acute myeloid leukemia (AML) patients with activating FLT3 internal tandem duplication mutations at the time of acquired resistance to the FLT3 inhibitor quizartinib. These findings establish that clinical resistance to quizartinib is highly complex and reflects the underlying clonal heterogeneity of AML.
•Polyclonal mechanisms of resistance, demonstrated by single-cell analysis, occur in the majority of AML patients who relapse on quizartinib.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ponatinib was developed to overcome resistance to the tyrosine kinase inhibitors used to treat leukemias that are positive for the Philadelphia chromosome. In a phase 1 study, ponatinib was ...associated with dramatic antitumor effects, with pancreatitis as a dose-limiting toxicity.
The fusion protein product of the Philadelphia chromosome (Ph), BCR-ABL, is a constitutively active tyrosine kinase that gives rise to chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia (Ph-positive ALL).
1
,
2
Three tyrosine kinase inhibitors targeting the BCR-ABL protein (imatinib, nilotinib, and dasatinib) have been approved for the treatment of patients with newly diagnosed chronic-phase CML.
3
–
5
Resistance to tyrosine kinase inhibitors is the major reason for the failure of therapy in patients with Ph-positive disease. Primary or secondary resistance to imatinib occurs in approximately 20 to 30% of patients with newly diagnosed chronic-phase CML.
3
,
6
Second-generation . . .
Type II kinase inhibitors bind in the “DFG-out” kinase conformation and are generally considered to be more potent and selective than type I inhibitors, which target a DFG-in conformation. Nine type ...II inhibitors are currently clinically approved, with more undergoing clinical development. Resistance-conferring secondary mutations emerged with the first series of type II inhibitors, most commonly at residues within the kinase activation loop and at the “gatekeeper” position. Recently, new inhibitors have been developed to overcome such mutations; however, mutations activating other pathways (and/or other targets) have subsequently emerged on occasion. Here, we systematically summarize the secondary mutations that confer resistance to type II inhibitors, the structural basis for resistance, newer inhibitors designed to overcome resistance, as well as the challenges and opportunities for the development of new inhibitors to overcome secondary kinase domain mutations.
Old age and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukaemia are associated with early relapse and poor survival. Quizartinib is an ...oral, highly potent, and selective next-generation FLT3 inhibitor with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. We aimed to assess the efficacy and safety of single-agent quizartinib in patients with relapsed or refractory acute myeloid leukaemia.
We did an open-label, multicentre, single-arm, phase 2 trial at 76 hospitals and cancer centres in the USA, Europe, and Canada. We enrolled patients with morphologically documented primary acute myeloid leukaemia or acute myeloid leukaemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 into two predefined, independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukaemia within 1 year after first-line therapy (cohort 1), and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or haemopoietic stem cell transplantation (cohort 2). Patients with an FLT3-ITD allelic frequency of more than 10% were considered as FLT3-ITD positive, whereas all other patients were considered as FLT3-ITD negative. Patients received quizartinib once daily as an oral solution; the initial 17 patients received 200 mg per day but the QTcF interval was prolonged for more than 60 ms above baseline in some of these patients. Subsequently, doses were amended for all patients to 135 mg per day for men and 90 mg per day for women. The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete haematological recovery) and the proportion of patients who achieved a complete remission. Efficacy and safety analyses included all patients who received at least one dose of quizartinib (ie, the intention-to-treat population). Patients with a locally assessed post-treatment bone marrow aspirate or biopsy were included in efficacy analyses by response; all other patients were considered to have an unknown response. This study is registered with ClinicalTrials.gov, number NCT00989261, and with the European Clinical Trials Database, EudraCT 2009-013093-41, and is completed.
Between Nov 19, 2009, and Oct 31, 2011, a total of 333 patients were enrolled (157 in cohort 1 and 176 in cohort 2). In cohort 1, 63 (56%) of 112 FLT3-ITD-positive patients and 16 (36%) of 44 FLT3-ITD-negative patients achieved composite complete remission, with three (3%) FLT3-ITD-positive patients and two (5%) FLT3-ITD-negative patients achieving complete remission. In cohort 2, 62 (46%) of 136 FLT3-ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 12 (30%) of 40 FLT3-ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. Across both cohorts (ie, the intention-to-treat population of 333 patients), grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients were febrile neutropenia (76 23% of 333), anaemia (75 23%), thrombocytopenia (39 12%), QT interval corrected using Fridericia's formula (QTcF) prolongation (33 10%), neutropenia (31 9%), leucopenia (22 7%), decreased platelet count (20 6%), and pneumonia (17 5%). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (126 38% of 333; 76 treatment related), acute myeloid leukaemia progression (73 22%), pneumonia (40 12%; 14 treatment related), QTcF prolongation (33 10%; 32 treatment related), sepsis (25 8%; eight treatment related), and pyrexia (18 5%; nine treatment related). Notable serious adverse events occurring in less than 5% of patients were torsades de pointes (one <1%) and hepatic failure (two 1%). In total, 125 (38%) of 333 patients died within the study treatment period, including the 30-day follow-up. 18 (5%) patients died because of an adverse event considered by the investigator to be treatment related (ten 6% of 157 patients in cohort 1 and eight 5% of 176 in cohort 2.
Single-agent quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3-ITD mutations. These findings confirm that targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor is a promising clinical strategy to help improve clinical outcomes in patients with very few options. Phase 3 studies (NCT02039726; NCT02668653) will examine quizartinib at lower starting doses.
Ambit Biosciences/Daiichi Sankyo.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
PDF
