Role of autologous and allogeneic stem cell transplantation in myeloma.

The treatment of multiple myeloma (MM), a largely incurable B-cell hematologic malignancy, is changing dramatically. Autologous stem cell transplantation (SCT) and the approval of two new classes of drugs, immunomodulators and proteosome inhibitors, have resulted in improved response rates and increased overall survivals. Thalidomide, bortezomib and lenalidomide have been combined with corticosteroids, alkylators and anthracyclines in front-line MM treatment. Phase 2 and preliminary phase 3 studies have reported very high response rates and complete response rates formerly seen only with SCT. When patients with MM who have received these new drugs then proceed to transplant, major response rates are further increased. Owing to limited follow-up, it is unclear whether these higher response rates translate into increased survival. Despite these improvements, the disease remains incurable for all but a small fraction of patients. Allogeneic SCT is potentially curative, due in part to a graft-versus-myeloma effect but is limited by mortality. Mortality can be reduced through the use of lower intensity conditioning regimens but this comes at a cost of higher rates of disease progression and relapse. Strategies to improve outcomes of allogeneic transplants include more intensive, yet non-myeloablative conditioning regimens, tandem transplants, peripheral blood cells, graft engineering, post-transplant maintenance and targeted conditioning therapies

Effect of remission status and induction chemotherapy regimen on outcome of autologous stem cell transplantation for mantle cell lymphoma.

We analysed the outcomes of autologous stem cell transplantation (ASCT) following high-dose therapy with respect to remission status at the time of transplantation and induction regimen used in 56 consecutive patients with mantle cell lymphoma (MCL). Twenty-one patients received induction chemotherapy with HyperCVAD with or without rituximab (+/-R) followed by ASCT in first complete or partial remission (CR1/PR1), 15 received CHOP (+/-R) followed by ASCT in CR1/PR1 and 20 received ASCT following disease progression. Estimates of overall and progression-free survival (PFS) at 3 years among patients transplanted in CR1/PR1 were 93% and 63% compared with 46% and 36% for patients transplanted with relapsed/refractory disease, respectively. The hazard of mortality among patients transplanted with relapsed/refractory disease was 6.09 times that of patients transplanted in CR1/PR1 (P = 0.006). Patients in the CHOP (+/-R) group had a higher risk of failure for PFS compared with patients in the HyperCVAD (+/-R) group, though the difference did not reach statistical significance (hazard ratio 3.67, P = 0.11). These results suggest that ASCT in CR1/PR1 leads to improved survival outcomes for patients with MCL compared to ASCT with relapsed/refractory disease, and a HyperCVAD (+/-R) induction regimen may be associated with an improved PFS among patients transplanted in CR1/PR1

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies

170: Long-Term Outcome of Nonmyeloalative Allografting from HLA-Identical Sibling for Multiple Myeloma (MM)

n/

Hyperon weak radiative decays in chiral perturbation theory

We investigate the leading-order amplitudes for weak radiative decays of hyperons in chiral perturbation theory. We consistently include contributions from the next-to-leading order weak-interaction Lagrangian. It is shown that due to these terms Hara's theorem is violated. The data for the decays of charged hyperons can be easily accounted for. However, at this order in the chiral expansion, the four amplitudes for the decays of neutral hyperons satisfy relations which are in disagreement with the data. The asymmetry parameters for all the decays can not be accounted for without higher-order terms. We shortly comment on the effect of the 27-plet part of the weak interaction.Comment: 8 pages of REVTeX and using macro-package "feynman.tex" (available at http://xxx.lanl.gov/ftp/hep-ph/papers/macros) for the 2 figure