Phase 2 study of epigenetic priming with decitabine followed by cytarabine for acute myeloid leukemia in older patients.

Acute myeloid leukemia (AML) in older patients has a poor prognosis, low complete remission (CR) rates, and poor overall survival (OS). Preclinical studies have shown synergistic effects of epigenetic priming with hypomethylating agents followed by cytarabine. Based on these data, we hypothesized that an induction regimen using epigenetic priming with decitabine, followed by cytarabine would be effective and safe in older patients with previously untreated AML. Here, we conducted a phase 2 trial in which older patients with previously untreated AML received an induction regimen consisting of 1 or 2 courses of decitabine 20 mg/m2 intravenously (IV) for 5 days followed by cytarabine 100 mg/m2 continuous IV infusion for 5 days. Forty-four patients (median age 76 years) were enrolled, and CR/CRi was achieved by 26 patients (59% of all patients, 66.7% of evaluable patients). Fourteen of 21 (66.7%) patients with adverse cytogenetics achieved CR including six out of seven evaluable patients with TP53 mutations. The 4- and 8-week mortality rates were 2.3% and 9.1%, respectively, with median OS of 10.7 months. These results suggest epigenetic priming with decitabine followed by cytarabine should be considered as an option for first-line therapy in older patients with AML. This trial was registered at www.clinicaltrials.gov as # NCT01829503.

Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial.

BACKGROUND: Patients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population. METHODS: This was a multicenter, open-label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two-stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1-10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1-5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy. RESULTS: The composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%-26.8%) and 30.8% (95% confidence interval, 9.1%-61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts. CONCLUSIONS: The combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need.

A prospective study of the use of central venous catheters in patients newly diagnosed with acute myeloid leukemia treated with induction chemotherapy.

PURPOSE: Central venous catheters (CVCs) are widely used in acute myeloid leukemia (AML) patients. Complications associated with CVCs are frequently encountered and contribute to morbidity and mortality. Prospective studies investigating and comparing complications of different types of CVCs in AML patients and their effects on the quality of life are limited. METHODS: We conducted a prospective observational study and evaluated the complications associated with the use of CVCs in adult AML patients during induction chemotherapy and evaluated quality of life outcomes as reported by the patients during and after their hospitalization. RESULTS: Fifty newly diagnosed patients with AML (median age, 59 years) who received intensive induction chemotherapy were enrolled in the study. Twenty-nine patients (58%) had a peripherally inserted central catheters (PICCs) placed and 21 (42%) patients received a Hickmann tunneled central catheter (TCC). Three percent of cases developed catheter-related thrombosis in PICCs and no thrombosis in TCCs. Catheter-related bloodstream infection was diagnosed in 8% of patients. CVC occlusion occurred in 44 patients (88%). The total number of occlusion events was 128; 97% of patients with PICCs and 76% of patients with TCCs (p = 0.003). All patients reported that the use of CVC simplified their course of treatment. Most patients reported similar restrictions in activity associated with TCCs and PICCs. CONCLUSION: The present study demonstrates that thrombosis and catheter-related bloodstream infections remain important complications of CVCs in AML patients. Occlusion rates were higher with the use of PICCs and the use of CVCs impacted the quality of life.

Phase 1 clinical trial of adoptive immunotherapy using "off-the-shelf" activated natural killer cells in patients with refractory and relapsed acute myeloid leukemia.

BACKGROUND AIMS: Activated NK cells (aNK) generated by expansion of a human interleukin-2-dependent NK cell line (NK-92) were shown to mediate strong anti-leukemia activity. This phase 1 study evaluated feasibility, safety, and activity of aNK cells adoptively transferred to patients with refractory/relapsed acute myeloid leukemia (AML). In addition, effects of these aNK cells on the patient's immune system were evaluated. METHODS: Two cell-dose levels (1 × 109 cells/m2 and 3 × 109 cells/m2) were used. One treatment course consisted of two infusions of the same cell dose, each cell infusion delivered 24 h apart. The aNK cells were administered in the outpatient setting. RESULTS: Seven patients with refractory/relapsed AML were treated with a total of 20 aNK cell infusions. None of the 7 patients experienced dose-limiting toxicities during the aNK cell administration or during 21 days of the post-infusion observation period. No grade 3-4 toxicities (probable or definite) related to aNK cell infusions occurred. Activity was transient in 3 of 7 patients. No significant changes in the patient's lymphocyte counts, subsets frequency, phenotype or activity were observed post-infusion. Cell dose-dependent effects in the plasma levels of several cytokines were observed. DISCUSSION: The trial demonstrated the safety and feasibility of adoptive cell therapy with "off-the-shelf" aNK cells in patients with refractory/relapsed AML. These data provide the foundation for future combination immunotherapy trials and for the optimization of aNK cell based therapies in patients with AML.

Outcomes of patients diagnosed with acute myeloid leukemia after solid organ transplantation.

Organ transplant recipients are at an increased risk for subsequent cancer including acute myeloid leukemia (AML). Treatment of AML following solid transplantation represents a clinical challenge as most patients have significant comorbidities at the time of AML diagnosis. In this study, we evaluated the treatment and outcomes of patients who developed AML following solid organ transplantation at our institution and reviewed the literature on outcomes for these patients. The study cohort consisted of 14 patients (median age 66 years, range 52-77 years) with newly diagnosed AML following solid organ transplantation. The median interval time between solid organ transplantation and AML diagnosis was 72 months (range 15-368 months). Seven patients received standard induction chemotherapy, four patients received intermediate type therapy, and the remaining three patients were deemed not fit for therapy and received palliative and supportive care. Six of the 11 treated patients (55%) achieved complete remission (CR). The median overall survival (OS) for all patients was 6 months. The median OS for the patients who achieved complete remission after therapy was 17 months and 2 months for the remaining patients. Despite initial CR, relapse rates are still high, suggesting that alternative strategies for post-remission therapies are warranted.

Leukapheresis in patients newly diagnosed with acute myeloid leukemia.

Hyperleukocytosis is present in 5 to 20 percent of patients with newly diagnosed acute myeloid leukemia (AML). The management of hyperleukocytosis, when symptoms of leukostasis occur, includes intensive supportive care and interventions for rapid cytoreduction. Leukapheresis is a rapid and effective means of cytoreduction and has been used in AML patients. In the current study, we evaluated the outcomes of 68 newly diagnosed AML patients that underwent leukapheresis and the effects of leukapheresis on various laboratory parameters. A total of 127 leukapheresis cycles were performed. The median number of leukapheresis cycles was 2 (range, 1-8). The overall survival for all patients was 4.2 months (95% CI 1.2-9.7 months). The median overall survival for patients who achieved complete remission after induction chemotherapy was significantly higher (19.1 months [95% CI 12.1-41.8 months]) than patients that did not achieve complete remission (0.46 months [95% CI 0.33-0.99 months]). Stepwise logistic regression demonstrated that elevated number of peripheral blasts, low platelet count and elevated bilirubin at AML diagnosis were predictive of death within a week. Leukapheresis was effective in reducing the peripheral blood leukocytes and leukemia blasts and was a safe procedure with regard to organ function, coagulation parameters, red blood cells and platelet count. The high initial response rates in newly diagnosed AML patients fit to receive intensive chemotherapy suggest that leukapheresis could be beneficial in reducing the complications associated with hyperleukocytosis until systemic intensive chemotherapy commences.

Plateletpheresis for postsplenectomy rebound thrombocytosis in a patient with chronic immune thrombocytopenic purpura on romiplostim.

Immune thrombocytopenic purpura (ITP) is an autoimmune disease in which IgG-coated platelets are removed from circulation by the spleen, and platelet production is impaired due to increased thrombopoietin (TPO) clearance. Romiplostim, a novel TPO-mimetic agent, is approved for patients with ITP that are unresponsive to traditional treatments. However, there is little experience when using this drug before splenectomy. We describe herein the case of a young female with chronic ITP who was treated with romiplostim, underwent splenectomy shortly thereafter, and required plateletpheresis for postoperative rebound thrombocytosis with concomitant neurologic symptoms.

Outcomes of Patients With Acute Myeloid Leukemia Who Relapse After 5 Years of Complete Remission.

Leukemia relapse 5 years after achieving first complete remission (CR1) is uncommon in patients with acute myeloid leukemia (AML). In this study, we evaluated the outcomes of AML patients with late relapse at our institution and reviewed the literature for these patients. The study cohort consisted of nine AML patients with late relapse. The median interval between CR1 and AML relapse was 6.1 years (range: 5.116.2 years). At relapse, the karyotype was different from the initial AML diagnosis in 50% of patients. At the time of AML relapse, seven patients received induction chemotherapy and two patients received hypomethylating agents with an overall CR rate of 66%. The median time to relapse after achieving second CR (CR2) was 16.5 months [95% confidence interval (CI): 9.4, NA]. The median overall survival after first relapse was 28.6 months (95% CI: 7.3, 3.466.5 months). Despite initial CR after reinduction therapy, relapse rates are still high, suggesting that alternative strategies for postremission therapies are warranted in CR2. These approaches include the use of allogeneic hematogenic cell transplantation and the use of newly approved AML agents as maintenance therapy in nontransplant eligible patients.

Why doesn't imatinib cure chronic myeloid leukemia?

Imatinib mesylate has transformed the treatment for chronic myeloid leukemia (CML). The vast majority of patients obtain hematologic remission, with a low probability of progression of disease. Yet imatinib rarely cures CML, and current recommendations dictate lifelong treatment with imatinib. In this review we analyze the biology behind the failure of imatinib to fully eradicate CML. We review evidence that indicates that the leukemic stem cell for CML is inherently resistant to imatinib, and that imatinib treatment itself may enhance this resistance.

Improved quality of life for romiplostim-treated patients with chronic immune thrombocytopenic purpura: results from two randomized, placebo-controlled trials.

Health-related quality of life (HRQoL) is a major concern for adults with chronic immune thrombocytopenic purpura (ITP) due to the symptoms associated with the disease and its treatment. This study utilized the ITP-patient assessment questionnaire (ITP-PAQ), a specialized HRQoL questionnaire for ITP, to investigate the humanistic burden of ITP and the impact of romiplostim therapy on HRQoL in two, placebo-controlled, phase 3 clinical trials of splenectomized and non-splenectomized patients. ITP-PAQ was self-administered to ITP patients at baseline, and weeks 4, 12 and 24 of treatment. Splenectomized patients had lower baseline HRQoL scores than non-splenectomized patients in seven of 10 scales (P < 0.05). After 24 weeks of romiplostim therapy, splenectomized patients showed significant improvements over placebo in four of 10 ITP-PAQ Scales (Symptoms, P = 0.0337; Bother, P = 0.0126; Social Activity, P = 0.0145; and Women's Reproductive Health, P = 0.0184). Non-splenectomized patients demonstrated significant improvement over placebo in the Activity Scale (P = 0.0458). Data pooled from the two trials, adjusted for splenectomy status, showed significant improvement for romiplostim-treated patients in six scales; Symptoms, Bother, Activity, Fear, Social Activity and Women's Reproductive Health. These results suggest that adult patients with chronic ITP have improved HRQoL following romiplostim therapy.

Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial.

BACKGROUND: Chronic immune thrombocytopenic purpura (ITP) is characterised by accelerated platelet destruction and decreased platelet production. Short-term administration of the thrombopoiesis-stimulating protein, romiplostim, has been shown to increase platelet counts in most patients with chronic ITP. We assessed the long-term administration of romiplostim in splenectomised and non-splenectomised patients with ITP. METHODS: In two parallel trials, 63 splenectomised and 62 non-splenectomised patients with ITP and a mean of three platelet counts 30x10(9)/L or less were randomly assigned 2:1 to subcutaneous injections of romiplostim (n=42 in splenectomised study and n=41 in non-splenectomised study) or placebo (n=21 in both studies) every week for 24 weeks. Doses of study drug were adjusted to maintain platelet counts of 50x10(9)/L to 200x10(9)/L. The primary objectives were to assess the efficacy of romiplostim as measured by a durable platelet response (platelet count > or =50x10(9)/L during 6 or more of the last 8 weeks of treatment) and treatment safety. Analysis was per protocol. These studies are registered with ClinicalTrials.gov, numbers NCT00102323 and NCT00102336. FINDINGS: A durable platelet response was achieved by 16 of 42 splenectomised patients given romplostim versus none of 21 given placebo (difference in proportion of patients responding 38% [95% CI 23.4-52.8], p=0.0013), and by 25 of 41 non-splenectomised patients given romplostim versus one of 21 given placebo (56% [38.7-73.7], p<0.0001). The overall platelet response rate (either durable or transient platelet response) was noted in 88% (36/41) of non-splenectomised and 79% (33/42) of splenectomised patients given romiplostim compared with 14% (three of 21) of non-splenectomised and no splenectomised patients given placebo (p<0.0001). Patients given romiplostim achieved platelet counts of 50x10(9)/L or more on a mean of 13.8 (SE 0.9) weeks (mean 12.3 [1.2] weeks in splenectomised group vs 15.2 [1.2] weeks in non-splenectomised group) compared with 0.8 (0.4) weeks for those given placebo (0.2 [0.1] weeks vs 1.3 [0.8] weeks). 87% (20/23) of patients given romiplostim (12/12 splenectomised and eight of 11 non-splenectomised patients) reduced or discontinued concurrent therapy compared with 38% (six of 16) of those given placebo (one of six splenectomised and five of ten non-splenectomised patients). Adverse events were much the same in patients given romiplostim and placebo. No antibodies against romiplostim or thrombopoietin were detected. INTERPRETATION: Romiplostim was well tolerated, and increased and maintained platelet counts in splenectomised and non-splenectomised patients with ITP. Many patients were able to reduce or discontinue other ITP medications. Stimulation of platelet production by romiplostim may provide a new therapeutic option for patients with ITP.

Effect of a proton pump inhibitor on the pharmacokinetics of imatinib.

AIMS: Imatinib mesylate (Gleevec/Glivec), which has revolutionized the treatment of chronic myeloid leukemias (CML) and gastrointestinal stromal tumours (GIST), has been reported to cause gastric upset. Consequently, proton pump inhibitors (PPI) are frequently co-administered with imatinib. Because PPI can elevate gastric pH and delay gastric emptying or antagonize ATP-binding-cassette transporters, they could influence imatinib absorption and pharmacokinetics. We aimed to evaluate whether use of omeprazole has a significant effect on imatinib pharmacokinetics. METHODS: Twelve healthy subjects were enrolled in a two-period, open-label, single-institution, randomized cross-over, fixed-schedule study. In one period, each subject received 400 mg imatinib orally. In the other period, 40 mg omeprazole (Prilosec) was administered orally for 5 days, and on day 5 it was administered 15 min before 400 mg imatinib. Plasma concentrations of imatinib and its active N-desmethyl metabolite CGP74588 were assayed by LC-MS, and data were analyzed non-compartmentally. RESULTS: PPI administration did not significantly affect the imatinib area under the plasma concentration vs time curve (AUC) (34.1 microg ml(-1) h alone vs 33.1 microg ml(-1) h with omeprazole, P= 0.64; 80% power), maximum plasma concentration (C(max)) (2.04 microg ml(-1) alone vs 2.02 microg ml(-1) with omeprazole, P= 0.97), or half-life (13.4 h alone vs 14.1 h with omeprazole, P= 0.13). CONCLUSIONS: Our results indicate that the use of omeprazole does not significantly affect the pharmacokinetics of imatinib, as opposed to, for example, dasatinib where PPI decreased AUC and C(max) two-fold.

Inhibition of Src family kinases enhances retinoic acid induced gene expression and myeloid differentiation.

Treatment of acute promyelocytic leukemia with retinoic acid (RA) results in differentiation of the leukemic cells and clinical remission. However, the cellular factors that regulate RA-induced myeloid differentiation are largely unknown, and other forms of acute myelogenous leukemia (AML) do not respond to this differentiation therapy. A greater understanding of the molecules that positively or negatively regulate RA-induced differentiation should facilitate the development of more effective differentiation therapies. In this study, we investigated the potential role of Src family kinases (SFK) in the regulation of RA-induced gene expression and myeloid differentiation. We report that inhibition of SFKs markedly enhanced RA-induced differentiation in myeloid cell lines and primary AML cells, as assessed by flow-cytometric analysis of cell surface markers, morphologic analysis, and nitroblue tetrazolium reduction. In addition, inhibition of SFKs enhanced expression from retinoic acid receptor (RAR) target genes encoding CCAAT/enhancer binding protein epsilon (C/EBPepsilon), PU.1, intercellular adhesion molecule-1 (ICAM-1), and cathepsin D. Moreover, a constitutively active Src inhibited RAR-dependent transcription, whereas a kinase-dead Src exerted little effect. These studies provide the first demonstration that SFKs act to negatively regulate RA-induced gene expression and myeloid differentiation and suggest that the combination of SFK inhibition and RA treatment may be therapeutically beneficial in AML.

A phase-1 study of dasatinib plus all-trans retinoic acid in acute myeloid leukemia.

Src family kinases (SFKs) are hyperactivated in acute myeloid leukemia (AML). SFKs impede the retinoic acid receptor, and SFK inhibitors enhance all-trans retinoic acid (ATRA)-mediated cellular differentiation in AML cell lines and primary blasts. To translate these findings into the clinic, we undertook a phase-I dose-escalation study of the combination of the SFK inhibitor dasatinib and ATRA in patients with high-risk myeloid neoplasms. Nine subjects were enrolled: six received 70 mg dasatinib plus 45 mg/m2 ATRA daily, and three received 100 mg dasatinib plus 45 mg/m2 ATRA daily for 28 days. Headache and QTc prolongations were the only two grade 3 adverse events observed. No significant clinical responses were observed. We conclude that the combination of 70 mg dasatinib and 45 mg/m2 ATRA daily is safe with acceptable toxicity. Our results provide the safety profile for further investigations into the clinical efficacy of this combination therapy in myeloid malignancies.

The NPM-RAR fusion protein associated with the t(5;17) variant of APL does not interact with PML.

The PML protein localizes to regions of the nucleus known as nuclear bodies or PODs. However, in t(15;17) Acute Promyelocytic Leukemia (APL) blasts, PML is found in a micro-punctate pattern. In order to test the hypothesis that delocalization of PML from PODs is necessary for APL, we investigated the interaction of the t(5;17) APL fusion protein NPM-RAR with PML. NPM-RAR localizes diffusely throughout the nucleoplasm. NPM-RAR does not alter the localization of PML in transfected HeLa cells, and does not associate with PML in vitro. These studies suggest that NPM-RAR does not interact with PML.