Tees M.T.,Colorado Blood Cancer Institute |
Flinn I.W.,Tennesee Oncology
Current Treatment Options in Oncology | Year: 2017
The overall benefit of maintenance therapy for patients with an indolent lymphoma continues to go unanswered. A myriad of variables contribute to the lack of clear clinical guidance. First, the disease course is slow and treatment may not be required for years, requiring a long follow-up to prospectively study. Second, due to the long lag time from study initiation to conclusion, many of the induction therapies used at the onset of the study may not be favored at present, providing a conclusion that cannot be reconciled with current clinical practice. For example, bendamustine and rituximab are typically the favored initial treatment agents in follicular lymphoma, which was not true when many maintenance trials were initiated. Third, several studies’ inclusion criteria allow for patient enrollment at both initial diagnosis as well as at disease recurrence. In some studies, patients who are asymptomatic are started on therapy, counter to the accepted watch and wait approach. This contributes to the difficulty of generalizing results. The question of the benefit of maintenance therapy has been studied enough, and there may not be a smoking gun in the foreseeable future. However, what does hold promise is focusing on the patients with minimum residual disease after conclusion of chemotherapy. This may be a population that could receive benefit from a prolonged treatment approach. In the meantime, maintenance therapy should not be used in all patients, and the rationale for use should be data-driven, as well as an assessment of a patient’s potential intolerability of cytotoxic chemotherapy. © 2017, Springer Science+Business Media New York.
Tees M.T.,Colorado Blood Cancer Institute |
Flinn I.W.,Tennesee Oncology
Expert Review of Hematology | Year: 2017
Introduction: Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are considered indolent lymphocytic malignancies, more often requiring active surveillance rather than intervention. Despite the indolent nature of CLL/SLL, treatment is likely indicated in a patients’ lifetime. Recent changes in the therapeutic landscape have created more options to the clinician. Areas covered: The authors provide a broad assessment of the current state of disease, including the work-up, prognostic features, and mutational aspects of the disease that should be acknowledged when developing a rational treatment plan. Key studies, guideline recommendations, and expert analysis are used to create this update on CLL/SLL. Expert commentary: The recent pace of treatment additions in CLL/SLL is a welcome addition. Moving forward, it is anticipated that treatment modalities will continue to evolve, leading to additional management options that truly would define CLL/SLL as a chronic disease. © 2016 Informa UK Limited, trading as Taylor & Francis Group.
Casulo C.,University of Rochester |
Vose J.M.,University of Nebraska Medical Center |
Ho W.Y.,Genentech |
Ho W.Y.,Ingenica Inc |
And 6 more authors.
Clinical Immunology | Year: 2014
PRO131921 is a third-generation, humanized anti-CD20 monoclonal antibody with increased antibody-dependent cytotoxicity and complement-dependent cytotoxicity compared to rituximab. In this phase I study, PRO131921 was administered as a single agent to patients with CD20+, relapsed or refractory, indolent non-Hodgkin lymphoma (NHL) who had been treated with a prior rituximab-containing regimen. The primary aim of this study was safety and tolerability of PRO131921. The secondary aim of the study, and focus of this report, was to determine the pharmacokinetics (PK) profile of PRO131921 and establish a correlation between drug exposure and clinical efficacy. Patients were treated with PRO131921 by intravenous infusion weekly for 4weeks and the dose was escalated based on safety in a 3+3 design. Twenty-four patients were treated with PRO131921 at doses from 25mg/m2 to 800mg/m2. Analysis of PK data demonstrated a correlation between higher normalized drug exposure (normalized AUC) and tumor shrinkage (p=0035). Also, normalized AUC levels were higher among responders and subjects displaying tumor shrinkage versus subjects progressing or showing no regression (p=0.030). In conclusion, PRO131921 demonstrated clinical activity in rituximab-relapsed and refractory indolent NHL patients. The observation that higher normalized AUC may be associated with improved clinical responses has potential implications in future trials of monoclonal antibody-based therapies, and emphasizes the importance of early PK studies to optimize antibody efficacy. © 2014 Elsevier Inc.
Bartlett N.L.,University of Washington |
Chen R.,City of Hope |
Fanale M.A.,University of Houston |
Brice P.,Hospital Saint Louis |
And 10 more authors.
Journal of Hematology and Oncology | Year: 2014
Background: Brentuximab vedotin is a CD30-directed antibody-drug conjugate. Retreatment with brentuximab vedotin monotherapy was investigated in patients with CD30-positive Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (ALCL) who relapsed after achieving complete or partial remission (CR or PR) with initial brentuximab vedotin therapy in a previous study (ClinicalTrials.gov NCT00947856). Methods. Twenty-one patients with HL and 8 patients with systemic ALCL were retreated; 3 patients with systemic ALCL were retreated twice. Patients generally received brentuximab vedotin 1.8 mg/kg intravenously approximately every 3 weeks over 30 minutes as an outpatient infusion. The primary objectives of this study were to assess safety and to estimate antitumor activity of brentuximab vedotin retreatment. Results: The objective response rate was 60% (30% CR) in HL patients and 88% (63% CR) in systemic ALCL patients. The estimated median duration of response for patients with an objective response was 9.5 months (range, 0.0+ to 28.0+ months) at the time of study closure. Of the 19 patients with objective response, 7 patients had not had an event of disease progression or death at the time of study closure; duration of response for these patients ranged from 3.5 to 28 months. Of the 11 patients with CR, 45% had response durations of over 1 year. Adverse events (AEs) occurring in ≥25% of patients during the retreatment period were generally similar in type and frequency to those observed in the pivotal trials of brentuximab vedotin monotherapy, with the exception of peripheral neuropathy, which is known to have a cumulative effect. Grade 3 or higher events were observed in 48% of patients; these were generally transient and managed by dose modifications or delays. Deaths due to AEs occurred in 3 HL patients; none were considered to be related to brentuximab vedotin retreatment. Discussion. With the exception of a higher rate of peripheral motor neuropathy, retreatment with brentuximab vedotin was associated with similar side effects seen in the pivotal trials. Conclusions: Retreatment with brentuximab vedotin monotherapy is associated with response rates in 68% (39% CR) of patients with relapsed HL and systemic ALCL. Trial registration. United States registry and results database ClinicalTrials.gov NCT00947856. © 2014 Bartlett et al.; licensee BioMed Central Ltd.
Gopal A.K.,University of Washington |
Ramchandren R.,Barbara Ann Karmanos Cancer Institute |
O'Connor O.A.,Columbia University |
Berryman R.B.,Baylor University |
And 8 more authors.
Blood | Year: 2012
Hodgkin lymphoma (HL) relapsing after allogeneic stem cell transplantation (alloSCT) presents a major clinical challenge. In the present investigation, we evaluated brentuximab vedotin, a CD30- directed Ab-drug conjugate, in 25 HL patients (median age, 32 years; range, 20- 56) with recurrent disease after alloSCT (11 unrelated donors). Patients were > 100 days after alloSCT, had no active GVHD, and received a median of 9 (range, 5-19) prior regimens. Nineteen (76%) had refractory disease immediately before enrollment. Patients received 1.2 or 1.8 mg/kg of brentuximab vedotin IV every 3 weeks (median, 8 cycles; range, 1-16). Overall and complete response rates were 50% and 38%, respectively, among 24 evaluable patients. Median time to response was 8.1 weeks, median progression-free survival was 7.8 months, and the median overall survival was not reached. Cough, fatigue, and pyrexia (52% each), nausea and peripheral sensory neuropathy (48% each), and dyspnea (40%) were the most frequent adverse events. The most common adverse events ≥ grade 3 were neutropenia (24%), anemia (20%), thrombocytopenia (16%), and hyperglycemia (12%). Cytomegalovirus was detected in 5 patients (potentially clinically significant in 1). These results support the potential utility of brentuximab vedotin for selected patients with HL relapsing after alloSCT. These trials are registered with www.clinicaltrials.gov as NCT01026233, NCT01026415, and NCT00947856. © 2012 by The American Society of Hematology.
Swords R.T.,Sylvester Comprehensive Cancer Center |
Erba H.P.,University of Michigan |
Deangelo D.J.,Dana-Farber Cancer Institute |
Bixby D.L.,University of Michigan |
And 9 more authors.
British Journal of Haematology | Year: 2015
This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m2, respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed. © 2015 John Wiley & Sons Ltd.
Vij R.,University of Washington |
Wang M.,University of Texas M. D. Anderson Cancer Center |
Kaufman J.L.,Emory University |
Lonial S.,Emory University |
And 21 more authors.
Blood | Year: 2012
Carfilzomib is a selective proteasome inhibitor that binds irreversibly to its target. In phase 1 studies, carfilzomib elicited promising responses and an acceptable toxicity profile in patients with relapsed and/or refractory multiple myeloma (R/R MM). In the present phase 2, multicenter, open-label study, 129 bortezomibnaive patients with R/R MM (median of 2 prior therapies) were separated into Cohort 1, scheduled to receive intravenous carfilzomib 20 mg/m2 for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m2 for cycle 1 and then 27 mg/m2 for all subsequent cycles. The primary end point was an overall response rate (≥ partial response) of 42.4% in Cohort 1 and 52.2% in Cohort 2. The clinical benefit response (overall response rate + minimal response) was 59.3% and 64.2% in Cohorts 1 and 2, respectively. Median duration of response was 13.1 months and not reached, and median time to progression was 8.3 months and not reached, respectively. The most common treatment-emergent adverse events were fatigue (62.0%) and nausea (48.8%). Single-agent carfilzomib elicited a low incidence of peripheral neuropathy - 17.1% overall (1 grade 3; no grade 4) - in these pretreated bortezomib-naive patients. The results of the present study support the use of carfilzomib in R/R MM patients. This trial is registered at www.clinicaltrials.gov as NCT00530816. © 2012 by The American Society of Hematology.
Richardson P.G.,Dana-Farber Cancer Institute |
Siegel D.S.,John Theurer Cancer Center |
Vij R.,University of Washington |
Hofmeister C.C.,Ohio State University |
And 20 more authors.
Blood | Year: 2014
This multicenter, open-label, randomized phase 2 study assessed the efficacy and safety of pomalidomide (POM) with/without low-dose dexamethasone (LoDEX) in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received ≥2 prior therapies (including lenalidomide [LEN] and bortezomib [BORT]) and had progressed within 60 days of their last therapy were randomized to POM (4 mg/day on days 1-21 of each 28-day cycle) with/without LoDEX (40 mg/week). The primary end point was progression-free survival (PFS). In total, 221 patients (median 5 priortherapies, range1-13) received POM+LoDEX (n = 113) or POM (n = 108). With a median follow-up of 14.2 months, median PFS was 4.2 and 2.7 months (hazard ratio = 0.68, P = .003), overall response rates (ORRs) were 33% and 18% (P = .013), median response duration was 8.3 and 10.7 months, and median overall survival (OS) was 16.5 and 13.6 months, respectively. Refractoriness to LEN, or resistance to both LEN and BORT, did not affect outcomes with POM+LoDEX (median PFS 3.8 months for both; ORRs 30% and 31%; and median OS 16 and 13.4 months). Grade 3-4 neutropenia occurred in 41% (POM+LoDEX) and 48% (POM); no grade 3-4 peripheral neuropathy was reported. POM+LoDEX was effective and generally well tolerated and provides an important new treatment option for RRMM patients who have received multiple prior therapies. This trial was registered at www.clinicaltrials.gov as #NCT00833833. © 2014 by The American Society of Hematology.
Simoneau T.L.,Rush University Medical Center |
Mikulich-Gilbertson S.K.,University of Colorado at Denver |
Natvig C.,University of Colorado at Denver |
Kilbourn K.,University of Colorado at Denver |
And 5 more authors.
Psycho-Oncology | Year: 2013
Purpose A full-time 24/7 caregiver is required for 100 days or longer following an allogeneic blood or marrow transplant during which time caregivers have multiple demands. Although distress in caregivers is documented, generalization is limited by small sample sizes, restricted range of assessments, and lack of information as to which caregivers may be more vulnerable to distress. The purpose of this study was to describe the peri-transplant psychological status of a sample of caregivers of allogeneic transplant patients. Methods We assessed caregiver mood, stress, burden, and sleep using valid self-report measures in 109 caregivers of allogeneic transplant patients prior to stem cell transplantation. Caregivers' scores were compared with norms or established cutoff scores for behavioral measures. Additionally, demographic characteristics such as age and sex were tested as predictors of distress. Results Caregivers showed significant levels of anxiety, stress, intrusion and avoidance behaviors, and poor sleep at the start of transplant compared with established norms. Younger caregivers were more distressed than older caregivers. There were no differences in levels of distress between male and female caregivers. Conclusion The peri-transplant period is a time of heightened anxiety and distress for caregivers of allogeneic transplant patients. This study indicates that caregivers would benefit from support programs in the peri-transplant period. Recommendations for types of support that may be helpful to caregivers are provided, but additional research is needed to validate that these programs would help caregivers providing care to patients receiving an allogeneic transplant in the peri-transplant period. Copyright © 2013 John Wiley & Sons, Ltd. Copyright © 2013 John Wiley & Sons, Ltd.
PubMed | University of Alberta, University of Washington, Fred Hutchinson Cancer Research Center, Swedish Neuroscience Institute and Colorado Blood Cancer Institute
Type: | Journal: Journal of the neurological sciences | Year: 2017
Aggressive immunosuppression followed by autologous hematopoietic stem cell transplantation (aHSCT) can be an effective treatment for severe multiple sclerosis (MS), but not all stages of disease may benefit equally. The case of a 49-year-old woman with advanced secondary-progressive MS whose clinical course was not improved by aHSCT and who seven years after transplantation succumbed to complications of severe MS disease-related disability is presented. Autopsy findings of ongoing neurodegeneration despite only rare infiltrating T-lymphocytes illustrate that late MS disease may not represent a suitable disease stage for aHSCT.