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Oral use of the selective FLT3 kinase inhibitor gilteritinib in patients who had relapsed or refractory acute myeloid leukemia with FLT3 mutations led to a median overall survival of 9.3 months (vs. 5.6 months with standard chemotherapy) and complete remission with full or partial hematologic recovery in 34.0% of patients (vs. 15.3%).

Background The phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial of ponatinib showed robust long-term benefit in relapsed Philadelphia chromosome-positive (Ph+) leukemia; arterial occlusive events (AOEs) occurred in ≥ 25% of patients based on investigator reporting. However, AOE rates vary depending on the definitions and reporting approach used. Methods To better understand clinically relevant AOEs with ponatinib, an independent cardiovascular adjudication committee reviewed 5-year AOE data from the PACE trial according to a charter-defined process and standardized event definitions. Results A total of 449 patients with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) received ponatinib (median age 59 y; 47% female; 93% ≥ 2 prior tyrosine kinase inhibitors (TKIs); median follow-up, 37.3 months). The adjudicated AOE rate (17%) was lower than the non-adjudicated rate (i.e., rate before adjudication; 25%). The only adjudicated AOE in > 2% of patients was peripheral arterial occlusive disease (4%). Exposure-adjusted incidence of newly occurring adjudicated AOEs decreased over time. Patients with multiple baseline cardiovascular risk factors had higher adjudicated AOE rates than those without risk factors. Conclusions This independent adjudication study identified lower AOE rates than previously reported, suggesting earlier overestimation that may inaccurately reflect AOE risk with ponatinib. This trial was registered under ClinicalTrials.gov identifier NCT01207440 on September 23, 2010 ( https://clinicaltrials.gov/ct2/show/NCT01207440 ).

Purpose of Review The goal of this review is to summarize what is known about pregnancy in women with chronic myeloid leukemia (CML): there are very few guidelines regarding how to treat women who are pregnant at the time of CML diagnosis, and similarly, few guidelines regarding family planning for women already on tyrosine kinase inhibitor therapy who might want to start family planning. Recent Findings Most patients with CML achieve excellent control with first line tyrosine kinase inhibitor therapy that includes either imatinib, dasatinib, nilotinib, or bosutinib. For men, tyrosine kinase inhibitor (TKI) therapy does not affect sperm number or function, and female partners of men on therapy who become pregnant do not have an increased risk of miscarriage or babies with fetal malformation. However, for women, all TKIs are teratogenic and should be avoided at least in the first trimester of pregnancy. However, a small study suggests that women who have achieved a stable deep response therapy can safely stop therapy prior to a planned pregnancy and may not need any intervention during the pregnancy. Another small study suggests that nilotinib and imatinib have the lowest rate of transfer across the placenta. Summary Providing well-documented guidelines for women with CML is challenging as TKI therapy is teratogenic. However, valuable information can be gained from small series of patients as summarized here.

Hypophosphatemia, with associated changes in bone and mineral metabolism, developed in some patients with chronic myelogenous leukemia or gastrointestinal stromal tumors who were receiving imatinib, which inhibits several tyrosine kinases associated with these two diseases. The drug may thus inhibit bone remodeling in some patients. Hypophosphatemia developed in some patients with chronic myelogenous leukemia or gastrointestinal stromal tumors who were receiving imatinib. The drug may inhibit bone remodeling in some patients. Imatinib mesylate (Gleevec, Novartis) inhibits several tyrosine kinases associated with disease. These enzymes include BCR-ABL in patients with chronic myelogenous leukemia (CML), C-KIT in patients with gastrointestinal stromal tumors, and platelet-derived growth factor (PDGF) receptors α and β in patients with certain myeloproliferative disorders and dermatofibrosarcoma protuberans, respectively. 1 Most patients appear to tolerate imatinib well, and no consistent metabolic abnormalities during routine electrolyte screening have been reported. 2 However, we noted that hypophosphatemia (a serum phosphate level of less than 2.5 mg per deciliter [0.8 mmol per liter]) developed in some patients with newly diagnosed CML who began imatinib therapy as . . .

A mouse model shows that osteoblast activating β-catenin mutations alone are sufficient to initiate the development of acute myeloid leukaemia acting through increased Notch signalling. Notch involvement in leukaemia The tumour microenvironment has profound influences on tumorigenesis, and genetic alterations in stromal cells can contribute to the development of cancer. Stavroula Kousteni and colleagues show in a mouse model that activating mutations in β-catenin in osteoblasts are sufficient to initiate the development of acute myeloid leukaemia (AML). These mutations trigger the release of ligands from osteoblasts that activate the Notch signalling pathway in haematopoietic cells; inhibition of the Notch pathway ameliorates the disease. The observation of increased β-catenin signalling in osteoblasts in patients with myeloproliferative disease and AML suggests that a similar mechanism may contribute to leukaemia in humans. Cells of the osteoblast lineage affect the homing 1 , 2 and the number of long-term repopulating haematopoietic stem cells 3 , 4 , haematopoietic stem cell mobilization and lineage determination and B cell lymphopoiesis 5 , 6 , 7 . Osteoblasts were recently implicated in pre-leukaemic conditions in mice 8 , 9 . However, a single genetic change in osteoblasts that can induce leukaemogenesis has not been shown. Here we show that an activating mutation of β-catenin in mouse osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukaemia with common chromosomal aberrations and cell autonomous progression. Activated β-catenin stimulates expression of the Notch ligand jagged 1 in osteoblasts. Subsequent activation of Notch signalling in haematopoietic stem cell progenitors induces the malignant changes. Genetic or pharmacological inhibition of Notch signalling ameliorates acute myeloid leukaemia and demonstrates the pathogenic role of the Notch pathway. In 38% of patients with myelodysplastic syndromes or acute myeloid leukaemia, increased β-catenin signalling and nuclear accumulation was identified in osteoblasts and these patients showed increased Notch signalling in haematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce acute myeloid leukaemia, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to acute myeloid leukaemia.

Osteoblasts, the bone forming cells, affect self-renewal and expansion of hematopoietic stem cells (HSCs), as well as homing of healthy hematopoietic cells and tumor cells into the bone marrow. Constitutive activation of β-catenin in osteoblasts is sufficient to alter the differentiation potential of myeloid and lymphoid progenitors and to initiate the development of acute myeloid leukemia (AML) in mice. We show here that Notch1 is the receptor mediating the leukemogenic properties of osteoblast-activated β-catenin in HSCs. Moreover, using cell-specific gene inactivation mouse models, we show that FoxO1 expression in osteoblasts is required for and mediates the leukemogenic properties of β-catenin. At the molecular level, FoxO1 interacts with β-catenin in osteoblasts to induce expression of the Notch ligand, Jagged-1. Subsequent activation of Notch signaling in long-term repopulating HSC progenitors induces the leukemogenic transformation of HSCs and ultimately leads to the development of AML. These findings identify FoxO1 expressed in osteoblasts as a factor affecting hematopoiesis and provide a molecular mechanism whereby the FoxO1/activated β-catenin interaction results in AML. These observations support the notion that the bone marrow niche is an instigator of leukemia and raise the prospect that FoxO1 oncogenic properties may occur in other tissues.

Cells of the osteoblast lineage affect homing, 1, 2 number of long term repopulating hematopoietic stem cells (HSCs) 3, 4, HSC mobilization and lineage determination and B lymphopoiesis 5-8. More recently osteoblasts were implicated in pre-leukemic conditions in mice 9, 10. Yet, it has not been shown that a single genetic event taking place in osteoblasts can induce leukemogenesis. We show here that in mice, an activating mutation of β-catenin in osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukemia (AML) with common chromosomal aberrations and cell autonomous progression. Activated β-catenin stimulates expression of the Notch ligand Jagged-1 in osteoblasts. Subsequent activation of Notch signaling in HSC progenitors induces the malignant changes. Demonstrating the pathogenetic role of the Notch pathway, genetic or pharmacological inhibition of Notch signaling ameliorates AML. Nuclear accumulation and increased β-catenin signaling in osteoblasts was also identified in 38% of patients with MDS/AML. These patients showed increased Notch signaling in hematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce AML, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to AML.

A mouse model shows that osteoblast activating [beta]-catenin mutations alone are sufficient to initiate the development of acute myeloid leukaemia acting through increased Notch signalling. Notch involvement in leukaemia The tumour microenvironment has profound influences on tumorigenesis, and genetic alterations in stromal cells can contribute to the development of cancer. Stavroula Kousteni and colleagues show in a mouse model that activating mutations in [beta]-catenin in osteoblasts are sufficient to initiate the development of acute myeloid leukaemia (AML). These mutations trigger the release of ligands from osteoblasts that activate the Notch signalling pathway in haematopoietic cells; inhibition of the Notch pathway ameliorates the disease. The observation of increased [beta]-catenin signalling in osteoblasts in patients with myeloproliferative disease and AML suggests that a similar mechanism may contribute to leukaemia in humans. Cells of the osteoblast lineage affect the homing.sup.1,2 and the number of long-term repopulating haematopoietic stem cells.sup.3,4, haematopoietic stem cell mobilization and lineage determination and B cell lymphopoiesis.sup.5,6,7. Osteoblasts were recently implicated in pre-leukaemic conditions in mice.sup.8,9. However, a single genetic change in osteoblasts that can induce leukaemogenesis has not been shown. Here we show that an activating mutation of [beta]-catenin in mouse osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukaemia with common chromosomal aberrations and cell autonomous progression. Activated [beta]-catenin stimulates expression of the Notch ligand jagged 1 in osteoblasts. Subsequent activation of Notch signalling in haematopoietic stem cell progenitors induces the malignant changes. Genetic or pharmacological inhibition of Notch signalling ameliorates acute myeloid leukaemia and demonstrates the pathogenic role of the Notch pathway. In 38% of patients with myelodysplastic syndromes or acute myeloid leukaemia, increased [beta]-catenin signalling and nuclear accumulation was identified in osteoblasts and these patients showed increased Notch signalling in haematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce acute myeloid leukaemia, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to acute myeloid leukaemia.

To the Editor: Berman and colleagues (May 11 issue) 1 report their findings regarding the development of hypophosphatemia and associated changes in bone and mineral metabolism in patients with either chronic myelogenous leukemia or gastrointestinal stromal tumors who are taking imatinib. We have reviewed the global database of clinical trials sponsored by Novartis, as well as spontaneous post-marketing reports that cover approximately 200,000 patient-years of treatment with imatinib (unpublished data). There was a low incidence of reported hypophosphatemia or potential related events, although we recognize that the observations may be underreported. Serum phosphate levels were routinely measured in two clinical trials . . .