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In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.

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Chemotherapeutic agents without cross-resistance to prior therapies may enhance PBSC collection and improve patient outcomes by exacting a more potent direct antitumor effect before autologous stem cell transplant. Bendamustine has broad clinical activity in transplantable lymphoid malignancies, but concern remains over the potential adverse impact of this combined alkylator-nucleoside analog on stem cell mobilization. We performed a prospective, nonrandomized phase II study including 34 patients with multiple myeloma (MM) (n=34; International Staging System (ISS) stages I (35%), II (29%) and III (24%); not scored (13%)) to evaluate bendamustine's efficacy and safety as a stem cell mobilizing agent. Patients received bendamustine (120 mg/m2 IV days 1, 2), etoposide (200 mg/m2 IV days 1-3) and dexamethasone (40 mg PO days 1- 4) (bendamustine, etoposide and dexamethasone (BED)) followed by filgrastim (10 µg/kg/day SC; through collection). All patients (100%) successfully yielded stem cells (median of 21.60 × 106/kg of body weight; range 9.24-55.5 × 106/kg), and 88% required a single apheresis. Six nonhematologic serious adverse events were observed in 6 patients including: neutropenic fever (1, grade 3), bone pain (1, grade 3) and renal insufficiency (1, grade 1). In conclusion, BED safely and effectively mobilizes hematopoietic stem cells.

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BACKGROUND: High-dose therapy and autologous stem cell transplantation (ASCT) improves outcomes for patients with mantle cell lymphoma (MCL), but relapse ultimately occurs in most patients. Recently presented interim results from a phase III prospective trial suggest maintenance rituximab (MR) after ASCT for MCL improves progression-free survival (PFS). The maturation of these data and any benefit of MR on overall survival (OS) remain to be defined. PATIENTS AND METHODS: In this retrospective study, we examined a cohort of consecutive patients with MCL that underwent ASCT for MCL at our center and evaluated their outcomes according to whether they received MR after ASCT (n = 50) or did not (n = 107). MR was treated as a time-dependent covariate to account for variation in timing of its initiation. RESULTS: MR was associated with an improved PFS [hazard ratio (HR) 0.44; confidence interval (CI) (0.24-0.80), P = 0.007] and overall survival (OS; HR 0.46; CI 0.23-0.93, P = 0.03) following a multivariate adjustment for confounding factors with a median follow-up of ∼5 years. Grade 4 neutropenia was increased (34% versus 18%, P = 0.04) in the MR group, but no effect on the rate of mortality unrelated to relapse was observed. CONCLUSIONS: These data support that MR after ASCT for MCL confers a benefit in PFS and additionally suggest it may improve OS. General application of this strategy will require confirmation of benefit in prospective randomized trials.

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Minimal residual disease (MRD) is associated with adverse outcome in acute myeloid leukemia (AML) after myeloablative (MA) hematopoietic cell transplantation (HCT). We compared this association with that seen after nonmyeloablative (NMA) conditioning in 241 adults receiving NMA (n=86) or MA (n=155) HCT for AML in first remission with pre-HCT bone marrow aspirates assessed by flow cytometry. NMA patients were older and had more comorbidities and secondary leukemias. Three-year relapse estimates were 28% and 57% for MRD(neg) and MRD(pos) NMA patients, and 22% and 63% for MA patients. Three-year overall survival (OS) estimates were 48% and 41% for MRD(neg) and MRD(pos) NMA patients and 76% and 25% for MA patients. This similar OS after NMA conditioning was largely accounted for by higher non-relapse mortality (NRM) in MRD(neg) (30%) compared with MRD(pos) (10%) patients, whereas the reverse was found for MRD(neg) (7%) and MRD(pos) (23%) MA patients. A statistically significant difference between MA and NMA patients in the association of MRD with OS (P<0.001) and NRM (P=0.002) but not relapse (P=0.17) was confirmed. After adjustment, the risk of relapse was 4.51 times (P<0.001) higher for MRD(pos) patients. These data indicate that the negative impact of MRD on relapse risk is similar after NMA and MA conditioning.

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Hematopoietic cell transplantation (HCT) from a matched related donor (MRD) benefits many adults with acute myeloid leukemia (AML) in first complete remission (CR1). The majority of patients does not have such a donor and will require an alternative donor if HCT is to be undertaken. We retrospectively analyzed 226 adult AML CR1 patients undergoing myeloablative unrelated donor (URD) (10/10 match, n=62; 9/10, n=29) or MRD (n=135) HCT from 1996 to 2007. The 5-year estimates of overall survival, relapse and nonrelapse mortality (NRM) were 57.9, 29.7 and 16.0%, respectively. Failure for each of these outcomes was slightly higher for 10/10 URD than MRD HCT, although statistical significance was not reached for any end point. The adjusted hazard ratios (HRs) were 1.43 (0.89-2.30, P=0.14) for overall mortality, 1.17 (0.66-2.08, P=0.60) for relapse and 1.79 (0.86-3.74, P=0.12) for NRM, respectively, and the adjusted odds ratio for grades 2-4 acute graft-versus-host disease was 1.50 (0.70-3.24, P=0.30). Overall mortality among 9/10 and 10/10 URD recipients was similar (adjusted HR 1.16 (0.52-2.61), P=0.71). These data indicate that URD HCT can provide long-term survival for CR1 AML; outcomes for 10/10 URD HCT, and possibly 9/10 URD HCT, suggest that this modality should be considered in the absence of a suitable MRD.

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For more than a decade, Ab conjugated to a radionuclide emitting particulate radiation has been used in the management of leukemia in an effort to deliver targeted doses of radiation to BM, spleen and other sites of disease, while sparing normal organs. This radioimmunotherapy (RIT) approach has been employed to achieve significant remissions in patients with AML, particularly when used at high doses of radioactivity in conjunction with myeloablation. This report focuses on the therapeutic aspects of radiolabeled Ab for leukemia. Clinical results from recent leukemia RIT studies are reviewed, with emphasis on approaches being evaluated to improve rates of response and survival. Discussion of pre-clinical studies are limited to those that offer insights into future directions for clinical RIT studies of leukemia.

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The impact of the follicular lymphoma (FL) histologic grade on outcomes after high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) is unknown. We evaluated 219 consecutive patients with grades 1-3 FL who underwent HDT and ASCT at our center. Overall survival (OS), progression-free survival (PFS), relapse and non-relapse mortality (NRM) was estimated for each grade after controlling for other predictive factors. The number of patients with grades 1, 2 and 3 FL was 106 (48%), 75 (34%) and 38 (17%), respectively. Five-year outcome estimates for the entire cohort included 60% OS, 39% PFS and 46% relapse (median follow-up=7.8 years). PFS and relapse were nearly identical among patients with grade 3 FL versus grades 1-2 FL after adjusting for other contributing factors (hazard ratio (HR)=0.90, P=0.68; HR=1.07, P=0.80, respectively). The hazard for mortality (HR=0.70, P=0.23) and NRM (HR=0.33, P=0.07) was non-significantly lower among patients with grade 3 FL compared to patients with grades 1-2 disease. Factors associated with inferior PFS included elevated lactate dehydrogenase (HR=1.52, P=0.03), chemoresistance (HR=1.82, P=0.02), > or =2 prior therapies (HR=1.8, P=0.03) and prior radiation (HR=1.99, P=0.003). These data suggest that the histologic grade of FL does not impact PFS or relapse following HDT and ASCT.

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Radiolabeled monoclonal antibodies have been used with encouraging results in conjunction with stem cell transplantation for patients with hematologic malignancies targeting a variety of surface antigens including CD33, CD45 and CD66 for leukemias, CD20 and CD22 for non-Hodgkin's lymphomas, and ferritin for Hodgkin's disease. The results obtained targeting epithelial antigens on solid tumors, however, have generally been less encouraging, primarily due to the relative insensitivity of these malignancies to ionizing radiation. In this report we review clinical studies that have incorporated myeloablative doses of targeted radiation using radiolabeled antibodies in conjunction with stem cell transplant regimens.

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It is becoming increasingly clear that the intrinsic and protein-induced topological properties of the DNA helix influence transcriptional efficiency. In this report we describe the properties of two upstream activating regions that influence transcription from the non-overlapping tandem promoters of the ilvGMEDA operon of Escherichia coli. One 20 base-pair region between the promoter sites contains an intrinsic DNA bend that activates transcription from the downstream promoter. The other region contains an integration host factor (IHF) binding site that overlaps the upstream promoter site. IHF binding at this site represses transcription from the upstream promoter and enhances transcription from the downstream promoter. IHF also induces a severe bend in the DNA at its target binding site in the upstream promoter region. The activating property of the 20 base-pair DNA sequence located between the promoters is dependent upon the helical phasing of the sequence-directed DNA bend that it encodes. However, the IHF-mediated activation of transcription is not dependent upon the helical phasing (spatial orientation) of the upstream IHF and downstream promoter sites. The IHF-mediated activation of transcription is also uninfluenced by the presence or absence of the intrinsic DNA bend between its binding site and the downstream promoter site. These results suggest the interesting possibility that IHF activates transcription from the nearby downstream promoter simply by bending the DNA helix in the absence of specific IHF-RNA polymerase or upstream DNA-RNA polymerase interactions.

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The structural genes of the ilvGMEDA operon of Escherichia coli are preceded by two promoters, ilvPG1 and ilvPG2, and a leader-attenuator region. Alkylation protection and hydroxyl radical footprinting techniques have been used to demonstrate that integration host factor (IHF) interacts with the nucleotides in a consensus-like DNA sequence located immediately downstream of the RNA polymerase transcriptional pause site in the leader-attenuator region. In the presence of purified IHF protein, in vitro transcriptional pausing of RNA polymerase at the leader-attenuator pause site is increased 2-fold and, concomitantly, a 2-fold increase in transcriptional termination at the attenuator is observed. Strains containing chromosomal transcriptional fusions of various segments of the ilvGMEDA promoter-attenuator region to the galK gene were used to show that IHF also decreases the in vivo basal level of transcriptional readthrough at the attenuator 2-fold. The binding of IHF to another target site in the ilvPG1 promoter region represses transcription from this promoter and causes a 4-fold stimulation of transcription initiation from the downstream ilvPG2 promoter 4-fold. This IHF-mediated control of transcription initiation from the upstream promoter region is independent of the regulation of transcription termination effected by IHF interaction at the attenuator site. Thus, IHF is capable of regulating the expression of the ilvGMEDA operon in opposing manners; it can activate transcription initiation of this operon from the ilvPG2 promoter 4-fold and increase the termination of this transcription at the downstream attenuator 2-fold.

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We evaluated the ability of low doses of botulinum A toxin, an inhibitor of acetylcholine release at the neuromuscular junction, to denervate and relax the spastic rhabdosphincter in 11 men with spinal cord injury and detrusor-sphincter dyssynergia. Toxin concentration, injection volume, percutaneous versus cystoscopic injection of the sphincter and number of injections were evaluated in 3 treatment protocols. All 10 patients evaluated by electromyography after injection showed signs of sphincter denervation. Bulbosphincteric reflexes in the 10 patients evaluated after injection were more difficult to obtain, and they showed a decreased amplitude and normal latency. The urethral pressure profile in the 7 patients in whom it was measured before and after treatment decreased an average of 27 cm. water after toxin injections. Post-void residual urine volume decreased by an average of 146 cc after the toxin injections in 8 patients. In the 8 patients for whom it could be determined toxin effects lasted an average of 50 days. The toxin also decreased autonomic dysreflexia in 5 patients.

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