Effects of signal transduction inhibitor 571 in acute myelogenous leukemia cells.

STI571 is a 2-phenylalaminopyrimidine derivative that inhibits c-abl, Bcr-Abl, and platelet-derived growth factor receptor tyrosine kinases. Recently, inhibition of stem cell factor (SCF)-induced c-kit phosphorylation and cell proliferation by STI571 was reported in the human myeloid cell line MO7e. Because approximately 70% of acute myelogenous leukemia (AML) cases are c-kit positive, we evaluated in vitro effects of STI571 on c-kit-positive cell lines and primary AML blast cells. At concentrations >5 microM, the drug marginally inhibited SCF-independent proliferation of cell lines and most of AML blasts. Treatment of AML cells with cytarabine and STI571 showed synergistic effect at low concentrations. Western blotting analysis documented a distinct band of M(r) 145,000 specific for c-kit in cell lines and in AML samples. There was no correlation between the level of the c-kit expression evaluated by Western blotting and percentage of c-kit-positive blasts as measured by flow cytometry. Neither in cell lines nor in primary AML cells, c-kit autophosphorylation was detectable under standard growth conditions. SCF-induced phosphorylation of c-kit in MO7e cells was inhibited by STI571. In a c-kit-positive AML-4 cell line, as well as in AML samples, c-kit phosphorylation was not induced by SCF exposure, suggesting that in these cases, the receptor could not be functionally activated. In conclusion, with the exception of MO7e, SCF did not induce phosphorylation of c-kit, and cell proliferation was not modulated in the presence of STI571. We did not detect any SCF-independent c-kit phosphorylation in our experimental systems. Consequently, STI571 exerted only a limited inhibitory effect on the cell growth.     

Management of Myelofibrosis-Related Cytopenias

Purpose of Review

Cytopenias, particularly anemia, are frequently encountered in patients with myelofibrosis. Management of cytopenias in myelofibrosis can be very challenging because current therapeutic interventions are only of modest efficacy and ruxolitinib, the only approved drug for myelofibrosis, is myelosuppressive. Yet, dose optimization of ruxolitinib is important for its survival benefit in patients with advanced disease. We sought to summarize the data on treatments for cytopenias available at present and review promising agents in development and emerging strategies.

Recent Findings

The activin receptor ligand traps hold considerable promise for the treatment of anemia and could represent an attractive combination strategy with ruxolitinib. Low-dose thalidomide, which could offset both anemia and thrombocytopenia caused by ruxolitinib, represents another potential partner for ruxolitinib. The anti-fibrotic agent PRM-151 produced sustained improvements in cytopenias in some patients, and further data on this drug are eagerly awaited. Finally, several preclinical leads with translational potential are worthy of clinical investigation as strategies to halt/reverse bone marrow fibrosis and thereby improve cytopenias.

Summary

Cytopenias remain a significant hurdle in myelofibrosis management, but several novel investigational agents hold considerable promise for the future.

     

Significance of thrombocytopenia in patients with primary and postessential thrombocythemia/polycythemia vera myelofibrosis

Severe thrombocytopenia (platelets <50 × 10⁹/L) is associated with very poor outcome of patients with myelofibrosis (MF). As patients with primary myelofibrosis (PMF) differ from patients with postessential thrombocythemia (PET‐MF) and postpolycythemia vera myelofibrosis (PPV‐MF), we aimed to evaluate the significance of low platelets among these patients. We present clinical characteristics and outcome of patients with either PMF, PPV‐MF, or PET‐MF, and thrombocytopenia who presented to our institution between 1984 and 2015. Of 1269 patients (877 PMF, 212 PPV‐MF, 180 PET‐MF), 11% and 14% had platelets either <50 × 10⁹/L or between 50‐100 × 10⁹/L, respectively. Patients with platelets <50 × 10⁹/L were most anemic and transfusion dependent, had highest blast count and unfavorable karyotype. In general, their overall and leukemia‐free survival was the shortest with median time of 15 and 13 months, respectively; with incidence of acute leukemia almost twice as high as in the remaining patients (6.9 vs 3.6 cases per 100 person‐years). Nevertheless, this observation remains mostly significant for patients with PMF, as those with PEV/PVT‐MF have already significantly inferior prognosis with platelets <100 × 10⁹/L.     

Preclinical and clinical experience with dasatinib in philadelphia chromosome-negative leukemias and myeloid disorders

Recent advances in the molecular characterization of Philadelphia chromosome-negative (Ph?) leukemias and related myeloid disorders have provided a clear rationale for investigating novel targeted therapies. Dasatinib is a tyrosine kinase inhibitor with activity against BCR-ABL, platelet-derived growth factor receptors (PDGFRs), c- KIT, fibroblast growth factor receptors (FGFRs), SRC family kinases (SFKs), and EPHA receptors, all of which have been implicated in the pathogenesis of Ph? leukemias and myeloid disorders. This review presents emerging data on the preclinical and clinical activity of dasatinib in these diseases, which suggest that larger clinical studies are warranted.     

Simultaneous endoscopic and video-assisted retroperitoneal debridement in walled-off pancreatic necrosis using a laparoscopic access platform:Two case reports

BACKGROUND Infected walled-off necrosis is a potentially life-threatening complication of necrotizing pancreatitis.While some patients can be treated by drainage alone,many patients also need evacuation of the infected debris.Central necroses in relation to the pancreatic bed are easily reached via an endoscopic transluminal approach,whereas necroses that involve the paracolic gutters and the pelvis are most efficiently treated via a percutaneous approach.Large and complex necroses may need a combination of the two methods.CASE SUMMARY Transluminal and percutaneous drainage followed by simultaneous endoscopic and modified video-assisted retroperitoneal debridement was carried out in two patients with very large(32-38 cm),infected walled-off necroses using a laparoscopic access platform.After 34 d and 86 d and a total of 9 and 14 procedures,respectively,complete regression of the walled-off necroses was achieved.The laparoscopic access platform improved both access to the cavities as well as the overview.Simultaneous transluminal and percutaneous necrosectomy are feasible with the laparoscopic access platform serving as a useful adjunctive.CONCLUSION This approach may be necessary to control infection and achieve regression in some patients with complex collections.     

A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome

We previously reported the feasibility of clofarabine and cytarabine combinations in AML. Questions remain as to (1) the therapeutic advantage of this combination and (2) the role of lower doses of clofarabine and cytarabine in older patients. We have conducted an adaptively randomized study of lower-dose clofarabine with or without low-dose cytarabine in previously untreated patients with AML aged 60 years and older. Patients received 30 mg/m(2) clofarabine intravenously daily for 5 days with or without 20 mg/m(2) cytarabine subcutaneously daily for 14 days as induction. Consolidation consisted of 3 days of clofarabine with or without 7 days of cytarabine. Seventy patients were enrolled. The median age was 71 years (range, 60-83 years). Sixteen patients received clofarabine and 54 the combination. Overall, 56% achieved complete remission (CR). CR rate was significantly higher with the combination (63% vs 31%; P = .025). Induction mortality was 19% with the combination versus 31% with clofarabine alone (P = .276). The combination showed better event-free survival (7.1 months vs 1.7 months; P = .04), but not overall survival (11.4 months vs 5.8 months; P = .1). Clofarabine plus low-dose cytarabine has a higher response rate than clofarabine alone with comparable toxicity. This trial is registered at www.clinicaltrials.gov as no. NCT00088218.     

Results of imatinib mesylate therapy in chronic myelogenous leukaemia with variant Philadelphia chromosome

Five to 10 per cent of patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukaemia (CML) have variant translocations involving chromosomes other than 9 and 22. We investigated the characteristics and outcome of patients with variant translocations treated with imatinib. Among 721 patients, 44 (6%) had variant translocations, involving one (n = 39) or two (n = 4) additional chromosomes. Nineteen patients (44%) were in chronic (12 previously untreated), 24 (55%) in accelerated and one (2%) in blastic phase. A major cytogenetic response was achieved in 14 (74%) patients treated in chronic phase and in 14 (58%) treated in accelerated phase. Six of 13 (46%) evaluable patients had deletion of derivative chromosome 9, and there was a trend for a lower response rate in these patients. We compared the 43 patients in chronic or accelerated phase to 678 patients with classic Ph treated with imatinib. The only significant difference in clinical characteristics was a higher frequency of accelerated phase among those with variant translocations (56%) compared with those with classic translocations (38%). No differences in outcome were evident. In a multivariate analysis, variant Ph translocations had no impact in response rate, overall survival or duration of response. We conclude that patients with variant Ph translocations have a similar prognosis to those with classic Ph translocations when treated with imatinib.