- Predictive value of the new renal response criteria in AL amyloidosis treated with high dose melphalan and stem cell transplantation. [Letter]
- AJAm J Hematol 2018 Feb 12
- Incidence of leukopenia and thrombocytopenia with cisplatin plus mitomycin-c versus melphalan in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). [Journal Article]
- CCCancer Chemother Pharmacol 2018 Feb 10
- CONCLUSIONS: Melphalan and CIS + MMC regimens were associated with comparable incidences of leukopenia and thrombocytopenia. Severe leukopenia and severe thrombocytopenia were rare following CRS/HIPEC using both chemotherapy regimens.
- Combination of a hypomethylating agent and inhibitors of PARP and HDAC traps PARP1 and DNMT1 to chromatin, acetylates DNA repair proteins, down-regulates NuRD and induces apoptosis in human leukemia and lymphoma cells. [Journal Article]
- OOncotarget 2018 Jan 09; 9(3):3908-3921
- Combination of drugs that target different aspects of aberrant cellular processes is an efficacious treatment for hematological malignancies. Hypomethylating agents (HMAs) and inhibitors of poly(ADP-...
Combination of drugs that target different aspects of aberrant cellular processes is an efficacious treatment for hematological malignancies. Hypomethylating agents (HMAs) and inhibitors of poly(ADP-ribose) polymerases (PARPis) and histone deacetylases (HDACis) are clinically active anti-tumor drugs. We hypothesized that their combination would be synergistically cytotoxic to leukemia and lymphoma cells. Exposure of AML and lymphoma cell lines to the combination of the PARPi niraparib (Npb), the HMA decitabine (DAC) and the HDACi romidepsin (Rom) or panobinostat (Pano) synergistically inhibited cell proliferation by up to 70% via activation of the ATM pathway, increased production of reactive oxygen species, decreased mitochondrial membrane potential, and activated apoptosis. Addition of the DNA alkylating agents busulfan (Bu) and/or melphalan enhanced the anti-proliferative/cytotoxic effects of the triple-drug combination. [Npb+DAC+Rom] significantly increased the level of chromatin-bound PARP1 and DNMT1 and caused acetylation of DNA repair proteins, including Ku70, Ku80, PARP1, DDB1, ERCC1 and XPF/ERCC4. This three-drug combination down-regulated the components of the nucleosome-remodeling deacetylase (NuRD) complex, which is involved in DNA-damage repair. Addition of Bu to this combination further enhanced these effects on NuRD. The trapping of PARP1 and DNMT1 to chromatin, acetylation of DNA repair proteins, and down-regulation of NuRD may all have increased double-strand DNA break (DSB) formation as suggested by activation of the DNA-damage response, concomitantly resulting in tumor cell death. Similar synergistic cytotoxicity was observed in blood mononuclear cells isolated from patients with AML and lymphoma. Our results provide a rationale for the development of [Npb+DAC+Rom/Pano] combination therapies for leukemia and lymphoma patients.
- Phase 1/2 Trial of Carfilzomib Plus High Dose Melphalan Preparative Regimen for Salvage AHCT Followed by Maintenance Carfilzomib in Patients with Relapsed/Refractory Multiple Myeloma. [Journal Article]
- BBBiol Blood Marrow Transplant 2018 Feb 01
- We performed a phase 1/2 trial to investigate the safety and activity of the second generation proteasome inhibitor Carfilzomib (K) on days -3/-2 in combination with melphalan 200 mg/m2(MEL200) on da...
We performed a phase 1/2 trial to investigate the safety and activity of the second generation proteasome inhibitor Carfilzomib (K) on days -3/-2 in combination with melphalan 200 mg/m2(MEL200) on day -2 (K-MEL) in patients with relapsed multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (phases 1 and 2). Patients without progression received 12 cycles of K maintenance at 36 mg/m2days 1,8,15 (schedule A) or days 1,2,15,16 (schedule B), with patients being treated for 2 cycles in each schedule and on the patient-preferred schedule for the remaining cycles (phase 2). Patients had received a median of 3 prior lines of therapy, 56% had prior AHCT and 51% prior K. During phase 1 (N=15), the maximum tolerated dose of K in combination with MEL200 was not reached so the maximum tested dose of 27mg/m2/(day-3) and56 mg/m2(day-2) was utilized in phase 2. Rate of ≥ VGPR after K-MEL (N=44) was 59.2% (vs. 13.7% prior to K-MEL). Among patients starting maintenance (N=27) 12 month progression-free and overall-survival were 66.7% and 88.1% respectively. There was no strong patient preference for either schedule. Two patients discontinued maintenance due to toxicity. K-MEL followed by K maintenance is safe and active salvage therapy in MM.
- The Efficacy and Long-Term Outcomes of Autologous Stem Cell Transplantation in POEMS Syndrome: a Nation-Wide Survey in Japan. [Journal Article]
- BBBiol Blood Marrow Transplant 2018 Jan 31
- POEMS syndrome is a rare plasma cell dyscrasia presenting with polyneuropathy, λ-type M protein, VEGF elevation, and systemic manifestations. The standard treatment has not been established, but auto...
POEMS syndrome is a rare plasma cell dyscrasia presenting with polyneuropathy, λ-type M protein, VEGF elevation, and systemic manifestations. The standard treatment has not been established, but autologous stem cell transplantation (ASCT) has exhibited effectiveness in this syndrome. However, the efficacy and long-term outcomes of ASCT have not been systematically studied. To clarify the efficacy and long-term outcomes of ASCT-treated patients in Japan, we performed a multicenter retrospective study assessing the clinical course of patients registered to the Japan Society for Hematopoietic Cell Transplantation TRUMP database. Between January 2000 and December 2011, 95 patients (58 males) were registered to the TRUMP database with a median age of 53 years (range, 28-72). The conditioning regimen was melphalan in 93/94 patients (99%), and 69 patients (74.2%) received a melphalan dose ≥200 mg/m2. The median CD34 cell dose was 2.47 × 106/kg (0.31-20 × 106/kg). After ASCT, patients' performance status was dramatically improved (ECOG PS 0-1: 20.0% vs. 71.6%, p < 0.0001). Over a median follow-up of 46.6 months, 10 patients died, and 5-year overall survival was 88.8% (N = 95). Progression-free survival at 3 years was 78.3% (N = 70, median follow-up, 54.4 months). These data support the promising role of ASCT in patients with POEMS syndrome for both prolonging survival and improving QoL. However, disease recurrence remains a major issue for long survivors.
- Evaluation of thrombosis-related biomarkers before and after therapy in patients with multiple myeloma. [Journal Article]
- JBJ Blood Med 2018; 9:1-7
- CONCLUSIONS: These results suggest that both MM and therapies for MM can induce a hypercoagulable state. The elevated risk of thrombosis conferred by hypercoagulability increases patient morbidity and mortality. Attention should be paid to therapy-related thrombosis when new therapeutic regimens are selected for MM patients.
- Pegylated Filgrastim Versus Filgrastim for Stem Cell Mobilization in Multiple Myeloma After Novel Agent Induction. [Journal Article]
- CLClin Lymphoma Myeloma Leuk 2018 Jan 05
- CONCLUSIONS: The present study has demonstrated that a single dose of pegfilgrastim is comparable to filgrastim in terms of the timing and efficacy of PBSC harvest and could potentially spare the patient 6 days of filgrastim injections. In addition, ours is the first study to compare these growth factors using vinorelbine/cyclophosphamide as mobilization chemotherapy.
- Healthcare resource utilization and costs in amyloid light-chain amyloidosis: a real-world study using US claims data. [Journal Article]
- JCJ Comp Eff Res 2018 Feb 02
- CONCLUSIONS: AL chemotherapy-based prescribing practices changed. Total annual healthcare costs increased over time among AL amyloidosis patients.
- Efficacy and safety of autologous peripheral blood stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia: A study protocol for a multicenter exploratory prospective study (Auto-Ph17 study). [Journal Article]
- MMedicine (Baltimore) 2017; 96(52):e9568
- The prognosis of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL) has been dramatically improved since the introduction of tyrosine kinase inhibitors (TKIs). Although allogene...
The prognosis of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL) has been dramatically improved since the introduction of tyrosine kinase inhibitors (TKIs). Although allogeneic hematopoietic cell transplantation (allo-HCT) is a major treatment option, the role of autologous peripheral blood stem cell transplantation (auto-PBSCT) has been reconsidered, especially in patients who achieved early molecular remission.
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- Pharmacokinetics, Tissue Localization, Toxicity, and Treatment Efficacy in the First Small Animal (Rabbit) Model of Intra-Arterial Chemotherapy for Retinoblastoma. [Journal Article]
- IOInvest Ophthalmol Vis Sci 2018 Jan 01; 59(1):446-454
- CONCLUSIONS: This first small-animal model of IAC has excellent vitreous and retinal tissue drug penetration, achieving levels sufficient to kill human retinoblastoma cells, facilitating future IAC drug discovery.