Sorafenib and omacetaxine mepesuccinate as a safe and effective treatment for acute myeloid leukemia carrying internal tandem duplication of Fms-like tyrosine kinase 3.

BACKGROUND: Omacetaxine mepesuccinate (OME) has antileukemic effects against acute myeloid leukemia (AML) carrying an internal tandem duplication of Fms-like tyrosine kinase 3 (FLT3-ITD). A phase 2 clinical trial was conducted to evaluate a combination treatment of sorafenib and omacetaxine mepesuccinate (SOME). METHODS: Relapsed or refractory (R/R) or newly diagnosed patients were treated with sorafenib (200-400 mg twice daily) and OME (2 mg daily) for 7 (first course) or 5 days (second course onward) every 21 days until disease progression or allogeneic hematopoietic stem cell transplantation (HSCT). The primary endpoint was composite complete remission, which was defined as complete remission (CR) plus complete remission with incomplete hematologic recovery (CRi). Secondary endpoints were leukemia-free survival (LFS) and overall survival (OS). RESULTS: Thirty-nine R/R patients and 5 newly diagnosed patients were recruited. Among the R/R patients, 28 achieved CR or CRi. Two patients showed partial remission, and 9 patients did not respond. Among the 5 newly diagnosed patients, 4 achieved CR, and 1 achieved CRi. The median LFS and OS were 5.6 and 10.9 months, respectively. Prior Fms-like tyrosine kinase 3 (FLT3) inhibitor exposure (P = .007), 2 or more inductions (P = .001), and coexisting IDH2 (P = .008) and RUNX1 mutations (P = .003) were associated with lower CR/CRi rates. HSCT consolidation and deep molecular responses (defined as an FLT3-ITD variant allelic frequency [VAF] ≤ 0.1% or a nucleophosmin 1 [NPM1] mutant VAF ≤ 0.01%) were associated with better OS and LFS. Prior FLT3 inhibitor exposure and 2 or more inductions were associated with inferior LFS. CONCLUSIONS: SOME was safe and effective for R/R and newly diagnosed FLT3-ITD AML.

Homoharringtonine (omacetaxine mepesuccinate) as an adjunct for FLT3-ITD acute myeloid leukemia.

An in vitro drug-screening platform on patient samples was developed and validated to design personalized treatment for relapsed/refractory acute myeloid leukemia (AML). Unbiased clustering and correlation showed that homoharringtonine (HHT), also known as omacetaxine mepesuccinate, exhibited preferential antileukemia effect against AML carrying internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD). It worked synergistically with FLT3 inhibitors to suppress leukemia growth in vitro and in xenograft mouse models. Mechanistically, the effect was mediated by protein synthesis inhibition and reduction of short-lived proteins, including total and phosphorylated forms of FLT3 and its downstream signaling proteins. A phase 2 clinical trial of sorafenib and HHT combination treatment in FLT3-ITD AML patients resulted in complete remission (true or with insufficient hematological recovery) in 20 of 24 patients (83.3%), reduction of ITD allelic burden, and median leukemia-free and overall survivals of 12 and 33 weeks. The regimen has successfully bridged five patients to allogeneic hematopoietic stem cell transplantation and was well tolerated in patients unfit for conventional chemotherapy, including elderly and heavily pretreated patients. This study validated the principle and clinical relevance of in vitro drug testing and identified an improved treatment for FLT3-ITD AML. The results provided the foundation for phase 2/3 clinical trials to ascertain the clinical efficacy of FLT3 inhibitors and HHT in combination.

Hematological Practice in Hong Kong and China.

Thalassemias and hemophilias are the most important inherited hematological diseases in Hong Kong and China. Prenatal diagnosis has significantly decreased the burden of these diseases. For thalassemia major, adequate transfusion and iron chelation therapy have dramatically improved patient outlook. Hematopoietic stem cell transplantation is curative for thalassemia major and is increasingly adopted. The efficacy of arsenic trioxide in acute promyelocytic leukemia (APL) was discovered in China. An oral formulation of arsenic trioxide was developed in Hong Kong for newly diagnosed and relapsed APL patients. With combination chemotherapy containing non-P-glycoprotein-dependent drugs and L-asparaginase, durable remission can be achieved in the most patients.

Midtreatment ¹8F-FDG PET/CT Scan for Early Response Assessment of SMILE Therapy in Natural Killer/T-Cell Lymphoma: A Prospective Study from a Single Center.

UNLABELLED: In a prospective study of newly diagnosed or relapsed histologically proven extranodal natural killer/T-cell lymphoma (ENKTL) patients, we aimed to determine the accuracy of midtreatment (18)F-FDG PET for response assessment using both visual and quantitative analyses. METHODS: Twenty-four patients (12 men, 12 women; median age, 50 y; age range, 16-83 y) were referred for pre-, mid- (after 2-3 cycles of SMILE [prednisolone, methotrexate, ifosfamide, L-asparaginase, etoposide] chemotherapy), and end-treatment PET/CT scans (n = 24, 24, and 17, respectively) using a standardized protocol. Sixty-five PET/CT scans were analyzed visually using the Deauville 5-point score (DS), and the lesion with the highest maximum standardized uptake value (SUV(max)) was recorded. Survival curves were obtained using Kaplan-Meier analysis and compared using the log rank test, followed by multivariate analysis using the Cox proportional hazards model to assess the independent effects of International Prognostic Index (IPI) score (0-1 vs. 2-5), stage (stage I/II vs. stage III/IV), sex, DS (1-3 vs. 4-5), SUV(max), and change in SUV(max) on overall survival (OS) and progression-free survival (PFS). The mean (±SD) follow-up period was 32 mo (±21 mo). RESULTS: For 2-y OS, the following parameters were predictive: IPI score (P = 0.047), DS at mid- and end-treatment (P < 0.001), and SUV(max) at mid- and end-treatment (P < 0.001 and 0.045, respectively). For 2-y PFS, the following parameters were predictive: sex (P = 0.006), stage (P = 0.034), IPI score (P = 0.038), DS at mid- and end-treatment (P < 0.001 and 0.001, respectively), and SUV(max) at midtreatment (P = 0.001). Multivariate analysis showed DS on mid- and end-treatment scans to be the only significant independent predictor of both OS (P = 0.004 and 0.018, respectively) and PFS (P = 0.004 and 0.014, respectively). The 2-y estimate for OS and PFS was 81% and 62%, respectively, in patients with a DS of 1-3, compared with 17% in patients with a DS of 4-5 (P < 0.001 and 0.001, respectively). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the midtreatment DS for prediction of OS and PFS were 63%, 94%, 83%, 83%, and 83%, respectively. CONCLUSION: Midtreatment PET/CT is a valuable tool for early treatment response assessment in extranodal natural killer/T-cell lymphoma patients.

A novel tescalcin-sodium/hydrogen exchange axis underlying sorafenib resistance in FLT3-ITD+ AML.

Internal tandem duplication (ITD) of fms-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia (AML) is associated with inferior clinical prognosis. Sorafenib is effective in clearing leukemic blasts in chemorefractory FLT3-ITD(+) AML, but leukemia progression invariably occurs. Mechanisms of drug resistance are not completely understood. We hypothesized that a gene encoding tescalcin (TESC), known to be upregulated at leukemia progression during continuous sorafenib treatment and activate an Na(+)/H(+) exchanger type-1 (NHE1), may underlie tyrosine kinase inhibitor resistance. TESC was highly expressed in FLT3-ITD(+) AML lines MOLM-13 and MV4-11, and its knockdown by small-interfering RNA lowered intracellular pH (pHi) and induced apoptosis. The results were recapitulated by treatment with an NHE1 inhibitor, 5-(N,N-hexamethylene) amiloride (HMA). Induction of sorafenib resistance in the MOLM-13 cell line (M13-RE) significantly increased its sensitivity to HMA. The later also enhanced suppression of FLT3 signaling by sorafenib in otherwise resistant cell lines. HMA treatment of MOLM-13 and MV4-11 as well as primary FLT3-ITD(+) AML cells significantly reduced leukemia initiation in anti-CD122-primed NOD/SCID mouse xenotransplantation. These observations provided novel information about the pathogenetic role of a TESC-NHE1-pHi axis in mediating sorafenib resistance in AML.

Sorafenib treatment of FLT3-ITD(+) acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation.

Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 (FLT3) gene occurs in 30% of acute myeloid leukemias (AMLs) and confers a poor prognosis. Thirteen relapsed or chemo-refractory FLT3-ITD(+) AML patients were treated with sorafenib (200-400 mg twice daily). Twelve patients showed clearance or near clearance of bone marrow myeloblasts after 27 (range 21-84) days with evidence of differentiation of leukemia cells. The sorafenib response was lost in most patients after 72 (range 54-287) days but the FLT3 and downstream effectors remained suppressed. Gene expression profiling showed that leukemia cells that have become sorafenib resistant expressed several genes including ALDH1A1, JAK3, and MMP15, whose functions were unknown in AML. Nonobese diabetic/severe combined immunodeficiency mice transplanted with leukemia cells from patients before and during sorafenib resistance recapitulated the clinical results. Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations, and might provide important leads to further improvement of treatment outcome with FLT3 inhibitors.

Non-gastric marginal zone B cell lymphoma: clinicopathologic features and treatment results.

The optimal treatment strategy and outcome of non-gastric marginal zone lymphoma (MZL) remains undefined. The role of rituximab and fludarabine in MZL has not been critically appraised and compared with conventional chemotherapy. We retrospectively analyzed 81 consecutive patients with non-gastric MZL (mucosa-associated lymphoid tissue lymphoma, n=66; splenic MZL, n=11; nodal MZL, n=4). As a group, the treatment results were favorable, with an overall response rate of 87% and a complete response (CR) rate of 73%. The CR rate was similar for conventional chemotherapy, and rituximab- and fludarabine-containing regimens. However, the relapse rate was significantly decreased in rituximab- and fludarabine-containing regimens. The use of rituximab and fludarabine was associated with acceptable side effects. For splenic MZL, splenectomy was significantly associated with a superior CR rate. Early stage, good performance status, and low international prognostic index risk scores significantly impacted on CR rate and survivals. Rituximab and fludarabine were safe for non-gastric MZL and resulted in more durable remissions.

Paracrine effects of direct intramyocardial implantation of bone marrow derived cells to enhance neovascularization in chronic ischaemic myocardium.

OBJECTIVE: To determine the optimal bone marrow (BM) cell types, and their potential mechanisms of action for neovascularization in chronic ischaemic myocardium. METHODS AND RESULTS: The functional effects, angiogenic potential and cytokine expression of direct intramyocardial implantation of autologous BM CD31-positive endothelial progenitor cells (EPC, n=9), BM mononuclear cells (MNCs, n=9), and saline (n=9) were compared in a swine model of chronic ischaemic myocardium. Autologous BM cells were harvested and catheter-based electromechanical mapping-guided direct intramyocardial injection was performed to target ischaemic myocardium. After 12 weeks, injection of BM-MNC resulted in significant improvements in left ventricular dP/dt (+21+/-8%, P=0.032), left ventricular pressure (+17+/-4%, P=0.048) and regional microsphere myocardial perfusion over ischaemic endocardium (+74+/-28%, P<0.05) and epicardium (+73+/-29%, P<0.05). No significant effects were observed following injection of BM-EPC or saline. Capillary density (1132+/-69 versus 903+/-44 per mm(2), P=0.047) and expression of mRNA of vascular endothelial growth factor (VEGF, 32.3+/-5.6 versus 13.1+/-3.7, P<0.05,) and angiopoietin-2 (23.9+/-3.6 versus 13.7+/-3.1, P<0.05) in ischaemic myocardium was significantly greater in the BM-MNC group than the saline group. The capillary density in ischaemic myocardium demonstrated a significant positive correlation with VEGF expression (r=0.61, P<0.001). CONCLUSION: Catheter-based direct intramyocardial injection of BM-MNC enhanced angiogenesis more effectively than BM-EPC or saline, possibly via a paracrine effect, with increased expression of VEGF that subsequently improved cardiac performance of ischaemic myocardium.

Transvenous cryoablation reduces platelet activation during pulmonary vein ablation compared with radiofrequency energy in patients with atrial fibrillation.

BACKGROUND: Radiofrequency (RF) ablation procedures for atrial fibrillation (AF) are associated with potential risks of thromboembolism, which may be minimized by the use of cryoablation that preserves the integrity of endocardium. The objective of this study was to compare the thrombogenic potential of transvenous cryoablation versus RF ablation during pulmonary vein (PV) isolation. METHODS AND RESULTS: Thirty consecutive patients with paroxysmal AF were randomized to undergo segmental PV isolation procedure using 4-mm tip RF ablation (n = 15) or cryoablation (CryoCor, San Diego, CA, USA) (n = 15). Blood samples were drawn after sheath insertion (baseline), after transseptal puncture, before ablation (after heparin administration), and after isolation of a superior PV. Activation of coagulation was measured with plasma levels of prothrombin fragment 1 + 2 (F1 + 2) and thrombin-antithrombin III complex (TAT), and platelets by plasma level of beta-thromboglobulin (beta-TG) and flow cytometric enumerating of P-selectin (CD62)-positive platelets. In both groups, the plasma level of beta-TG, F1 + 2, and TAT were elevated after sheath insertion. The percentage changes in plasma level of beta-TG, F1 + 2, and TAT and CD41/62-positive platelets from baseline after transseptal puncture and before ablation were similar (P > 0.05). However, the percentage changes in CD62-positive platelets from baseline were significantly higher in patients treated with RF ablation (82 +/- 20%) than with cryoablation (22 +/- 14%, P = 0.02), although their plasma levels of beta-TG, F1 + 2, and TAT were not different (P > 0.05). CONCLUSIONS: Significant platelet and coagulation activations were observed during PV ablation procedures, and heparin administration only prevented activation of coagulation but not platelets. Persistent platelets activation was observed during RF energy application, but not during cryoablation.