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2.
N Engl J Med ; 387(2): 132-147, 2022 07 14.
Article in English | MEDLINE | ID: mdl-35660812

ABSTRACT

BACKGROUND: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown. METHODS: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival. RESULTS: Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P<0.001); median progression-free survival was 46.2 months and 67.5 months. The percentage of patients with a partial response or better was 95.0% in the RVD-alone group and 97.5% in the transplantation group (P = 0.55); 42.0% and 46.8%, respectively, had a complete response or better (P = 0.99). Treatment-related adverse events of grade 3 or higher occurred in 78.2% and 94.2%, respectively; 5-year survival was 79.2% and 80.7% (hazard ratio for death, 1.10; 95% CI, 0.73 to 1.65). CONCLUSIONS: Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone. No overall survival benefit was observed. (Funded by the National Heart, Lung, and Blood Institute and others; DETERMINATION ClinicalTrials.gov number, NCT01208662.).


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Maintenance Chemotherapy , Multiple Myeloma , Stem Cell Transplantation , Adult , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bortezomib/administration & dosage , Bortezomib/adverse effects , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Disease Progression , Disease-Free Survival , Humans , Lenalidomide/administration & dosage , Lenalidomide/adverse effects , Maintenance Chemotherapy/methods , Melphalan/administration & dosage , Multiple Myeloma/diagnosis , Multiple Myeloma/drug therapy , Multiple Myeloma/surgery , Transplantation, Autologous
3.
Biol Blood Marrow Transplant ; 26(12): 2223-2228, 2020 12.
Article in English | MEDLINE | ID: mdl-32829079

ABSTRACT

For patients with relapsed or refractory classical Hodgkin lymphoma (cHL), salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) remains the standard of care. Even with this aggressive treatment strategy, 5-year progression-free survival is ≤50%, and there remains interest in maintenance strategies to improve long-term disease-free survival. Lenalidomide is an immunomodulatory agent with demonstrated activity in multiple subtypes of lymphoma including cHL, and has also been shown to improve both progression-free and overall survival as maintenance therapy after ASCT in multiple myeloma. This multicenter study evaluated maintenance lenalidomide after ASCT for patients with cHL. Patients were enrolled 60 to 90 days post-transplant and received oral lenalidomide on days 1 to 28 of 28-day cycles for a maximum of 18 cycles. Lenalidomide was started at 15 mg daily and increased to maximum of 25 mg daily if tolerated. The primary objective of this study was to assess the feasibility of this regimen, with a goal <30% rate of discontinuation at or before cycle 12 for drug-related reasons. Twenty-seven patients were enrolled and 26 received at least 1 dose of lenalidomide. With a median follow-up of 51.3 months (range, 12.2 to 76.2 months), 23 of 26 patients were alive. Median event-free survival was 9.4 months and median progression-free survival had not been reached, with 17 of 26 patients (65.4%) remaining in remission at last follow-up. Excluding 4 patients who discontinued therapy for progression and 2 who discontinued due to noncompliance, the discontinuation rate at or before cycle 12 was 52%. Treatment was complicated by a high frequency of hematologic adverse events, with 15 patients (58%) experiencing grade 3 to 4 hematologic toxicity and 5 (19%) experiencing grade 4 hematologic toxicity. We conclude that the regimen of maintenance lenalidomide explored in this study is not feasible for patients with cHL immediately following ASCT. An alternative lenalidomide dose or schedule may be better tolerated following ASCT for patients with relapsed or refractory cHL.


Subject(s)
Hodgkin Disease , Multiple Myeloma , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Disease-Free Survival , Hodgkin Disease/drug therapy , Humans , Lenalidomide/therapeutic use , Multiple Myeloma/drug therapy , Pilot Projects , Transplantation, Autologous , Treatment Outcome
4.
Am J Hematol ; 95(6): 583-593, 2020 06.
Article in English | MEDLINE | ID: mdl-32170769

ABSTRACT

Immunochemotherapy followed by autologous transplant (ASCT) in CALGB/Alliance 59909 achieved a median progression-free survival (PFS) in mantle cell lymphoma (MCL) of 5 years, but late recurrences occurred. We evaluated tolerability and efficacy of adding post-transplant bortezomib consolidation (BC) or maintenance (BM) to this regimen in CALGB/Alliance 50403, a randomized phase II trial. Following augmented-dose R-CHOP/ methotrexate, high-dose cytarabine-based stem cell mobilization, cyclophosphamide/carmustine/etoposide (CBV) autotransplant, and rituximab, patients were randomized to BC (1.3 mg/m2 IV days 1, 4, 8, 11 of a 3-week cycle for four cycles) or BM (1.6 mg/m2 IV once weekly × 4 every 8 weeks for 18 months) beginning day 90. The primary endpoint was PFS, measured from randomization for each arm. Proliferation signature, Ki67, and postinduction minimal residual disease (MRD) in bone marrow were assessed. Of 151 patients enrolled; 118 (80%) underwent ASCT, and 102 (68%) were randomized. Both arms met the primary endpoint, with median PFS significantly greater than 4 years (P < .001). The 8-year PFS estimates in the BC and BM arms were 54.1% (95% CI 40.9%-71.5%) and 64.4% (95% 51.8%-79.0%), respectively. Progression-free survival was significantly longer for transplanted patients on 50403 compared with those on 59909. Both the PFS and OS were significantly better for those who were MRD-negative post-induction. The high risk proliferation signature was associated with adverse outcome. Both BM and BC were efficacious and tolerable, although toxicity was significant. The comparison between studies 50403 and 59909 with long-term follow up suggests a PFS benefit from the addition of BC or BM post- transplant.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bortezomib/administration & dosage , Consolidation Chemotherapy , Lymphoma, Mantle-Cell/therapy , Maintenance Chemotherapy , Rituximab/administration & dosage , Adolescent , Adult , Aged , Autografts , Bortezomib/adverse effects , Carmustine/administration & dosage , Cyclophosphamide/administration & dosage , Etoposide/administration & dosage , Female , Humans , Male , Middle Aged
5.
Biol Blood Marrow Transplant ; 25(10): 1984-1992, 2019 10.
Article in English | MEDLINE | ID: mdl-31212080

ABSTRACT

Relapse remains the major cause of death in older patients transplanted for acute myeloid leukemia (AML) in first complete remission or for patients with advanced myelodysplastic syndrome (MDS) at any age. Conventional myeloablative conditioning followed by allogeneic blood or marrow transplantation is associated with significantly less relapse compared with reduced-intensity conditioning when performed in younger patients with AML or MDS, but the toxicity of this approach in older patients is prohibitive. We hypothesized that pharmacokinetic targeting to optimize busulfan (BU) exposure, combined with the administration of azacitidine (AZA) post-transplant would mitigate the risk of relapse while reducing nonrelapse mortality and ultimately improve progression-free survival (PFS). On this phase II multicenter study, 63 patients (40 unrelated donors and 23 matched related donors) received a uniform conditioning regimen consisting of fludarabine i.v. (days -7 to -3), BU targeted to a daily area under the curve (AUC) of 4000 µM/min (days -6 to -3) after the administration of a 25-mg/m2 i.v. test dose on 1 day between days -14 to -9, and antithymocyte globulin (days -6, -5, and -4 (2 doses for matched related donors and 3 for matched unrelated donors only). Beginning on days +42 to +90, all patients were planned to receive up to 6 monthly cycles of AZA at 32 mg/m2 subcutaneously for 5 days. The median age was 62 years (range, 44 to 74); 13 had AML and 50 had MDS; 87% of patients were within 20% of the target AUC based on a validation sample. Forty-one patients (65%) started AZA at a median of 61 days (range, 43 to 91) post-transplant, and 17 patients (41%) completed all 6 cycles of AZA. The cumulative incidence of nonrelapse mortality at 2 years was 33.4% (95% confidence interval [CI], 22%-45%). The cumulative incidence of relapse was 25% (95% CI, 15%-37%) at 2 years. With a median follow-up of 58.9 months, the estimated PFS probability at 2 years and 5 years after transplantation was 41.2% (80% CI, 33.9%-49.9%) and 26.9% (80% CI, 20.4%-35.5%), respectively, for the entire group with a median PFS of 15.8 months (95% CI, 6.7 to 28.3). The probability of overall survival at 2 and 5 years was 45.7% (95% CI, 34.9%-59.9%) and 31.2% (95% CI, 21.3% to 45.8%), respectively, for the entire group with a median overall survival of 19.2 months (95% CI, 8.7 to 37.5). In summary, we demonstrated the feasibility of a novel reduced-intensity conditioning regimen with test dose BU targeted to an AUC of 4000 µM/min. The feasibility of AZA in this setting appears to be limited if applied to an unselected population of older hematopoietic stem cell transplantation recipients. (ClinicalTrials.gov Identifier: NCT01168219.).


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Azacitidine/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/therapy , Transplantation Conditioning/methods , Transplantation, Homologous/methods , Adult , Aged , Antimetabolites, Antineoplastic/pharmacology , Azacitidine/pharmacology , Female , Humans , Male , Middle Aged
6.
Clin Cancer Res ; 24(9): 2060-2073, 2018 05 01.
Article in English | MEDLINE | ID: mdl-29437791

ABSTRACT

Purpose: CPI-613, a lipoate analogue that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase (KGDH), has activity in patients with myeloid malignancies. This study explored the role of mitochondrial metabolism in chemotherapy response and determined the MTD, efficacy, and safety of CPI-613 combined with high-dose cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia.Experimental Design: The role of mitochondrial response to chemotherapy was assessed in cell lines and animal models. A phase I study of CPI-613 plus cytarabine and mitoxantrone was conducted in patients with relapsed or refractory AML.Results: Exposure to chemotherapy induced mitochondrial oxygen consumption that depended on PDH. CPI-613 sensitized AML cells to chemotherapy indicating that mitochondrial metabolism is a source of resistance. Loss of p53 did not alter response to CPI-613. The phase I study enrolled 67 patients and 62 were evaluable for response. The overall response rate was 50% (26CR+5CRi/62). Median survival was 6.7 months. In patients over 60 years old, the CR/CRi rate was 47% (15/32) with a median survival of 6.9 months. The response rate for patients with poor-risk cytogenetics also was encouraging with 46% (11/24 patients) achieving a CR or CRi. RNA sequencing analysis of a subset of baseline bone marrow samples revealed a gene expression signature consistent with the presence of B cells in the pretreatment marrow of responders.Conclusions: The addition of CPI-613 to chemotherapy is a promising approach in older patients and those with poor-risk cytogenetics. Clin Cancer Res; 24(9); 2060-73. ©2018 AACR.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Adult , Aged , Animals , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers , Biopsy , Bone Marrow/pathology , Caprylates/administration & dosage , Cell Line , Cell Respiration/drug effects , Cytarabine/administration & dosage , Drug Resistance, Neoplasm , Female , Humans , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/mortality , Male , Mice , Middle Aged , Mitochondria/drug effects , Mitochondria/genetics , Mitochondria/metabolism , Mitoxantrone/administration & dosage , Neoplasm Grading , Neoplasm Staging , Oxygen Consumption/drug effects , Recurrence , Retreatment , Sulfides/administration & dosage , Treatment Outcome , Young Adult
7.
Leuk Lymphoma ; 59(8): 1871-1877, 2018 08.
Article in English | MEDLINE | ID: mdl-29252084

ABSTRACT

High-dose glucocorticoids such as prednisone are combined with cytotoxic chemotherapy in the R-CHOP or dose adjusted R-EPOCH regimens used for non-Hodgkin lymphoma (NHL). In this retrospective study, our primary objective was to evaluate the incidence of hyperglycemia during first-line R-CHOP or DA-EPOCH-R. The secondary objectives were to evaluate the incidence of chemotherapy alteration and overall survival in those with and without hyperglycemia. One hundred and sixty patients were eligible. We found that 47% of all patients had at least one hyperglycemic episode and hyperglycemia was associated with chemotherapy alteration (p = .028). Multivariate analysis revealed international prognostic index (IPI) ≥ 3 (p = .045) and chemotherapy alteration (p = .001) were associated with decreased overall survival. We conclude that hyperglycemia is common during first-line NHL treatment with R-CHOP or DA-EPOCH-R, even in the absence of known diabetes and is associated with alterations of chemotherapy. Baseline pre-PET scan fasting blood glucose of 100 mg/dL or higher may predict hyperglycemia during therapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hyperglycemia/diagnosis , Lymphoma, Non-Hodgkin/drug therapy , Aged , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antibodies, Monoclonal, Murine-Derived/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Blood Glucose/analysis , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Etoposide/administration & dosage , Etoposide/adverse effects , Female , Humans , Hyperglycemia/blood , Hyperglycemia/chemically induced , Kaplan-Meier Estimate , Lymphoma, Non-Hodgkin/blood , Male , Middle Aged , Prednisone/administration & dosage , Prednisone/adverse effects , Retrospective Studies , Rituximab/administration & dosage , Rituximab/adverse effects , Vincristine/administration & dosage , Vincristine/adverse effects
8.
Lancet Haematol ; 4(9): e431-e442, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28826616

ABSTRACT

BACKGROUND: In the CALGB (Alliance) 100104 study, lenalidomide versus placebo after autologous stem-cell transplantation (ASCT) was investigated for patients with newly diagnosed myeloma. That study showed improved time to progression and overall survival and an increase in second primary malignancies for lenalidomide at a median follow-up of 34 months. Here we report an updated intention-to-treat analysis of CALGB (Alliance) 100104 at a median follow-up of 91 months. METHODS: Patients were eligible for this randomised, double-blind, placebo-controlled, phase 3 trial if they had symptomatic disease requiring treatment; had received, at most, two induction regimens; and had achieved stable disease or better in the first 100 days after ASCT. We randomly assigned patients to either lenalidomide or placebo groups using permuted block randomisation, with a fixed block size of six. Randomisation was stratified by three factors: normal or elevated ß2 microglobulin concentration at registration (≤2·5 mg/L vs >2·5 mg/L), previous use or non-use of thalidomide during induction therapy, and previous use or non-use of lenalidomide during induction therapy. The starting dose was two capsules (10 mg) per day, escalated to three capsules (15 mg) per day after 3 months. The primary endpoint was time to progression (time of progressive disease or death from any cause), with intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00114101. New patients are no longer being recruited, but some patients remain on treatment and in follow-up. FINDINGS: Between April 14, 2005, and July 2, 2009, 460 patients were randomly assigned to receive either lenalidomide (n=231) or placebo (n=229). After three interim analyses, the study was unblinded at a median follow-up of 18 months, at which point 86 (67%) of 128 patients without progressive disease in the placebo group chose to cross over to the lenalidomide group. The median follow-up for the updated survival analysis, as of Oct 19, 2016, was 91 months (IQR 83·6-103·1). The median time to progression was 57·3 months (95% CI 44·2-73·3) for the lenalidomide group and 28·9 months (23·0-36·3) for the placebo group (hazard ratio 0·57, 95% CI 0·46-0·71; p<0·0001). The most common grade 3-4 adverse events were neutropenia (116 [50%] patients in the lenalidomide group and 41 [18%] patients in the placebo group) and thrombocytopenia (34 [15%] patients in the lenalidomide group and 12 [5%] patients in the placebo group). 18 (8%) haematological and 14 (6%) solid tumour second primary malignancies were diagnosed after randomisation and before disease progression in the lenalidomide group, compared with three (1%) haematological and nine (4%) solid tumour second primary malignancies in the placebo group. Three haematological and five solid tumour second primary malignancies in the placebo group were in the crossover subgroup. INTERPRETATION: Despite an increase in haematological adverse events and second primary malignancies, lenalidomide maintenance therapy after ASCT significantly improved time to progression and could be considered a standard of care. FUNDING: The National Cancer Institute.


Subject(s)
Multiple Myeloma/therapy , Thalidomide/analogs & derivatives , Adult , Double-Blind Method , Female , Follow-Up Studies , Hematopoietic Stem Cell Transplantation , Humans , Lenalidomide , Male , Middle Aged , Multiple Myeloma/drug therapy , Multiple Myeloma/surgery , Placebos , Survival Analysis , Thalidomide/therapeutic use , Transplantation, Autologous , Young Adult
9.
Clin Lymphoma Myeloma Leuk ; 17(7): 424-432, 2017 07.
Article in English | MEDLINE | ID: mdl-28655599

ABSTRACT

INTRODUCTION/BACKGROUND: Deacetylase inhibitors have synergistic activity in combination with proteasome inhibitors and anthracyclines in preclinical models of multiple myeloma (MM). We therefore evaluated the safety and efficacy of the deacetylase inhibitor vorinostat in combination with pegylated liposomal doxorubicin (PLD) and bortezomib in relapsed/refractory MM. PATIENTS AND METHODS: Thirty-two patients were treated with PLD and bortezomib in combination with escalating doses of vorinostat on days 4 to 11 or 1 to 14. RESULTS: The maximum tolerated dose of vorinostat was 400 mg on days 4 to 11. Neutropenia and thrombocytopenia attributable to protocol therapy were seen in 59% and 94% of patients, of which 37% and 47% were of grade 3 or higher severity, respectively. Constitutional and gastrointestinal adverse events of all grades were common, the majority of which were less than grade 3 in severity. The overall response rate (partial response rate or better) was 65% and the clinical benefit rate (minimal response rate or better) 74%. The overall response rate was 83%, 71%, and 45% for patients with bortezomib-naive, -sensitive, and -refractory MM, respectively. The median progression-free survival was 13.9 months and the 3-year overall survival 77%. Whole blood proteasome activity assays demonstrated a potential impact of vorinostat on the chymotryptic-like activity of the proteasome. CONCLUSION: Further evaluation of PLD, bortezomib, and deacetylase inhibitor combinations is warranted, with special attention directed toward strategies to improve tolerability.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bortezomib/therapeutic use , Doxorubicin/analogs & derivatives , Hydroxamic Acids/therapeutic use , Proteasome Inhibitors/therapeutic use , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Bortezomib/administration & dosage , Bortezomib/pharmacology , Doxorubicin/administration & dosage , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Drug Resistance, Neoplasm , Female , Humans , Hydroxamic Acids/administration & dosage , Hydroxamic Acids/pharmacology , Male , Middle Aged , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Neoplasm Recurrence, Local , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/pharmacology , Polyethylene Glycols/therapeutic use , Proteasome Inhibitors/administration & dosage , Proteasome Inhibitors/pharmacology , Vorinostat
10.
Clin Lymphoma Myeloma Leuk ; 16(2): 76-81, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26725264

ABSTRACT

INTRODUCTION: Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) was developed in an effort to overcome inadequate drug concentrations and compensate for increased drug clearance. The goal of the present study was to examine the risk factors and outcomes of patients with aggressive non-Hodgkin lymphoma (aNHL) treated with DA-EPOCH. PATIENTS AND METHODS: We report the data from 136 patients with previously untreated aNHL who received infusional DA-EPOCH chemotherapy with or without rituximab from 2005 to 2013. Overall survival was estimated using Kaplan-Meier methods. Univariate and multivariate logistic regression was used to determine the factors associated with death, progression, or relapse at 2 years. RESULTS: The overall response rate was 82%. The relapse-free survival rate at 1, 3, and 5 years was 68%, 63%, and 52% with 95% confidence intervals (CIs) of 0.59% to 0.85%, 0.54% to 0.70%, and 0.31% to 0.70%, respectively. Patients with T-cell aNHL had an increased risk of death, progression, or relapse (Odds Ratio, 3.5; 95% CI, 1.4-8.8) compared with those with B-cell aNHL. In multivariate analysis, current smoking, disease in the bone marrow, and the number of cycles completed were independent predictors of death and relapse. CONCLUSION: Our data suggest that EPOCH with or without rituximab is active in both B- and T-cell aNHL. Toxicity did not significantly affect timing of treatment delivery or treatment outcomes. Dose adjustment by hematopoietic nadir similarly had no effect. The effect of smoking during chemotherapy should be evaluated further.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Lymphoma, Non-Hodgkin/drug therapy , Rituximab/administration & dosage , B-Lymphocytes/drug effects , Cyclophosphamide/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Etoposide/administration & dosage , Humans , Neoplasm Recurrence, Local/drug therapy , Prednisone/administration & dosage , Prognosis , Survival Rate , T-Lymphocytes/drug effects , Treatment Outcome , Vincristine/administration & dosage
11.
Clin Case Rep ; 3(7): 615-7, 2015 Jul.
Article in English | MEDLINE | ID: mdl-26273453

ABSTRACT

We report a 53-year-old man diagnosed with Richter syndrome. He was heavily pretreated and was refractory to prior therapy. He received rituximab and ibrutinib, and achieved a significant response after 1 month of therapy. Our case illustrates the importance of investigation of rituximab and ibrutinib in Richter's syndrome.

12.
J Community Support Oncol ; 13(3): 87-94, 2015 Mar.
Article in English | MEDLINE | ID: mdl-26287032

ABSTRACT

BACKGROUND: Problems with sexual functioning are common following therapy for breast and gynecologic cancers, although there are few effective treatments. OBJECTIVE: To assess the impact of ArginMax, a nutritional supplement comprised of extracts of L-arginine, ginseng, gingko, and damiana, as well as multivitamins and minerals, on sexual functioning and quality of life in female cancer survivors. METHODS: This was a 12-week, randomized, placebo-controlled trial of eligible patients who were 6 months or more from active treatment and reporting problems with sexual interest, satisfaction, and functioning after therapy. The participants took 3 capsules of Arginmax or placebo twice daily. Outcome measures were the Female Sexual Function Inventory (FSFI) and the Functional Assessment of Cancer Therapy - General (FACT-G). Assessments were done at baseline, 4, 8, and 12 weeks. RESULTS: 186 patients with a median age of 50 years were accrued between May 10, 2007 and March 24, 2010. 76% of the patients were non-Hispanic white. Most had breast or a gynecologic cancer (78% and 12%, respectively). At 12 weeks, there were no differences between the ArginMax group (n = 96) and placebo (n = 92) group in sexual desire, arousal, lubrication, orgasm,satisfaction or pain. However, FACT-G total scores were significantly better for participants who took ArginMax compared with those who took placebo (least squares [LS] means, 87.5 vs 82.9, respectively; P = .009). The Fact-G subscales that were most affected were Physical (25.37 vs. 23.51, P = .001) and Functional Well-Being (22.46 vs. 20.72, P = .007). Toxicities were similar for both groups. LIMITATIONS: Study results are limited by a lack of data on the participants' psychological and physical symptoms and sexual partner variables. CONCLUSIONS: ArginMax had no significant impact on sexual functioning, but patient quality of life was significantly better at 12 weeks in participants who received ArginMax.

13.
Clin Cancer Res ; 20(20): 5255-64, 2014 Oct 15.
Article in English | MEDLINE | ID: mdl-25165100

ABSTRACT

PURPOSE: The lipoate derivative CPI-613 is a first-in-class agent that targets mitochondrial metabolism. This study determined the effects of CPI-613 on mitochondrial function and defined the MTD, pharmacokinetics, and safety in patients with relapsed or refractory hematologic malignancies. EXPERIMENTAL DESIGN: Human leukemia cell lines were exposed to CPI-613 and mitochondrial function was assayed. A phase I trial was conducted in which CPI-613 was given as a 2-hour infusion on days 1 and 4 for 3 weeks every 28 days. RESULTS: CPI-613 inhibited mitochondrial respiration of human leukemia cells consistent with the proposed mechanism of action. In the phase I trial, 26 patients were enrolled. CPI-613 was well tolerated with no marrow suppression observed. When the infusion time was shortened to 1 hour, renal failure occurred in 2 patients. At 3,780 mg/m(2), there were two dose-limiting toxicities (DLT). At a dose of 2,940 mg/m(2) over 2 hours, no DLTs were observed, establishing this as the MTD. Renal failure occurred in a total of 4 patients and resolved in all but 1, who chose hospice care. CPI-613 has a triphasic elimination with an alpha half-life of approximately 1.34 hours. Of the 21 evaluable, heavily pretreated patients, 4 achieved an objective response and 2 achieved prolonged stabilization of disease for a clinical benefit rate of 29%. Following drug exposure, gene expression profiles of peripheral blood mononuclear cells from responders demonstrated immune activation. CONCLUSION: CPI-613 inhibits mitochondrial function and demonstrates activity in a heavily pretreated cohort of patients.


Subject(s)
Antineoplastic Agents/therapeutic use , Caprylates/therapeutic use , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/pathology , Sulfides/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/pharmacology , Caprylates/pharmacology , Cell Line, Tumor , Drug Administration Schedule , Female , Hematologic Neoplasms/diagnosis , Hematologic Neoplasms/metabolism , Hematologic Neoplasms/mortality , Humans , Leukemia/drug therapy , Leukemia/metabolism , Leukemia/pathology , Male , Middle Aged , Mitochondria/drug effects , Mitochondria/metabolism , Neoplasm Staging , Positron-Emission Tomography , Sulfides/pharmacology , Tomography, X-Ray Computed , Treatment Outcome , Young Adult
14.
Br J Clin Pharmacol ; 78(5): 1005-13, 2014 Nov.
Article in English | MEDLINE | ID: mdl-24838014

ABSTRACT

AIMS: Vatalanib is an oral anti-angiogenesis agent that inhibits vascular endothelial growth factor receptor tyrosine kinases, which in patients showed auto induction of metabolism and variability in pharmacokinetic (PK) disposition. The objective was to characterize the population PK and time-dependent change in vatalanib clearance and assess exposure-toxicity relationship in patients with myelodysplastic syndrome (MDS). METHODS: This was an open-label phase II study of vatalanib in MDS patients receiving 750-1250 mg once daily in 28-day cycles. Serial blood samples were obtained and plasma vatalanib concentrations measured by HPLC. Population PK analysis was performed using nonmem 7.2 with FO estimation since FOCE failed. The final model was evaluated using goodness-of-fit plots, bootstrap analysis, and visual predictive check. RESULTS: Pharmacokinetic data were complete for 137 patients (86 M, 51 F), of median age 70 years (range 20-91). A one-compartment model with lagged first-order absorption and time-dependent change in oral clearance was fitted to the vatalanib plasma concentration versus time data. The population means for pre-induction and post-induction oral clearance were 24.1 l h(-1) (range: 9.6-45.5) and 54.9 l h(-1) (range: 39.8-75.6), respectively. The apparent oral clearance increased 2.3-fold, (range: 1.7-4.1-fold) from first dose to steady state. Our data did not identify a significant relationship of the predefined covariates with vatalanib pharmacokinetics, although power to detect such a relationship was limited. CONCLUSIONS: Vatalanib pharmacokinetics were highly variable and the extent of auto induction was not determined to correlate with any of the pre-defined covariates.


Subject(s)
Angiogenesis Inhibitors/pharmacokinetics , Myelodysplastic Syndromes/drug therapy , Phthalazines/pharmacokinetics , Pyridines/pharmacokinetics , Adult , Aged , Aged, 80 and over , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/adverse effects , Angiogenesis Inhibitors/therapeutic use , Area Under Curve , Computer Simulation , Data Interpretation, Statistical , Female , Humans , Male , Metabolic Clearance Rate , Middle Aged , Models, Biological , Myelodysplastic Syndromes/metabolism , Phthalazines/administration & dosage , Phthalazines/adverse effects , Phthalazines/therapeutic use , Prospective Studies , Pyridines/administration & dosage , Pyridines/adverse effects , Pyridines/therapeutic use , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Time Factors , Young Adult
15.
Am J Hosp Palliat Care ; 31(7): 710-6, 2014 Nov.
Article in English | MEDLINE | ID: mdl-23946253

ABSTRACT

The purpose of this study was to examine the relationship between hematopoietic cell transplant candidate and proxy advance care planning (ACP) behavior and attitudes. A total of 49 candidates and 44 proxies completed the Advance Directive Attitudes Survey, Multidimensional Health Locus of Control Scale, Family Decision Making Self-Efficacy Scale, and the State-Trait Anxiety Inventory. In all, 45% of candidates reported completing an advance directive (AD), while only 26% had ADs on file; 80% of candidates discussed ACP wishes with their loved ones and 15% discussed ACP wishes with their medical team. The AD completers were significantly (1) older, (2) more positive about ADs, and (3) were less likely to believe that health events happen by chance. Discrepancies between reported ACP behavior and communication with health care practitioners have implications for end-of-life care.


Subject(s)
Advance Care Planning/organization & administration , Advance Directives/psychology , Hematopoietic Stem Cell Transplantation/psychology , Proxy/psychology , Terminal Care/psychology , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Decision Making , Female , Humans , Male , Middle Aged , North Carolina , Sex Factors , Socioeconomic Factors , Surveys and Questionnaires , Young Adult
16.
Am J Hosp Palliat Care ; 31(8): 853-6, 2014 Dec.
Article in English | MEDLINE | ID: mdl-24142596

ABSTRACT

Hematopoietic stem cell transplantation (HCT) is associated with a high risk of morbidity, making advance care planning (ACP) essential. The purpose of this study was to assess and compare proxy and HCT candidate distress levels (Distress Thermometer) before (T1) and after (T2) ACP question completion. 79 participants (40 HCT candidates, 39 proxies) rated their distress. The T1, T2 mean distress scores (SD) for HCT candidates were 3.13(2.27), 2.96(2.10); 43% and 38% endorsed clinically significant distress (≥4). Proxies reported 4.21(2.48), 4.33 (2.46); 62% endorsed significant distress at T1, T2. The majority of proxies endorsed distress levels that were clinically significant and comparatively higher (T1 (p = 0.047) and T2 (p = 0.009)) than their paired HCT recipients. Responding to questions about ACP did not increase overall distress ratings.


Subject(s)
Hematopoietic Stem Cell Transplantation/psychology , Proxy/psychology , Stress, Psychological/epidemiology , Adult , Advance Care Planning , Female , Humans , Male , Stress, Psychological/etiology
17.
Invest New Drugs ; 31(5): 1311-20, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23700288

ABSTRACT

BACKGROUND: Angiogenesis is implicated in the pathophysiology and progression of myelodysplastic syndromes (MDS). Vatalanib (PTK787/ZK222584; Novartis and Schering AG) inhibits receptor tyrosine kinases of vascular endothelial growth factor, platelet derived growth factor and c-Kit. We examined whether vatalanib induces hematological responses in MDS and/or delays progression to acute myeloid leukemia (AML) or death. METHODS: Two cohorts were studied. Vatalanib 1250 mg orally was given once daily (cohort 1) or 750-1250 mg once daily in an intra-patient dose escalating schedule (cohort 2) in 28-day cycles to 155 patients with MDS; 142 patients were evaluable for response and 153 for toxicity. RESULTS: The median age was 70.5 years; 51 % had low risk (International Prognostic Scoring System {IPSS} Low/Intermediate-1) and 32 % had high risk (IPSS Intermediate-2/High) MDS. Hematological improvement was achieved in 7/142 (5 %) patients; all 7 were among the 47 patients able to remain on vatalanib for at least 3 months (hematological improvement achieved in 15 % of these 47 patients). For patients with low risk and high risk MDS, respectively, median progression-free survivals were 15 and 6 months, median times to transformation to AML were 28 and 6 months, and median overall survivals were 36 and 10 months. The most frequent non-hematological adverse events grade ≥ 2 were fatigue, nausea or vomiting, dizziness, anorexia, ataxia, diarrhea, and pain. Two deaths (one intra-cerebral hemorrhage and one sudden death) were possibly related to vatalanib. CONCLUSIONS: Vatalanib induces improvement in blood counts in a small proportion of MDS patients. Clinical applicability is limited by side effects.


Subject(s)
Antineoplastic Agents/therapeutic use , Myelodysplastic Syndromes/drug therapy , Phthalazines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyridines/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Disease-Free Survival , Female , Humans , Leukemia/drug therapy , Male , Middle Aged , Phthalazines/adverse effects , Protein Kinase Inhibitors/adverse effects , Pyridines/adverse effects , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Treatment Outcome
18.
N Engl J Med ; 366(19): 1770-81, 2012 May 10.
Article in English | MEDLINE | ID: mdl-22571201

ABSTRACT

BACKGROUND: Data are lacking on whether lenalidomide maintenance therapy prolongs the time to disease progression after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma. METHODS: Between April 2005 and July 2009, we randomly assigned 460 patients who were younger than 71 years of age and had stable disease or a marginal, partial, or complete response 100 days after undergoing stem-cell transplantation to lenalidomide or placebo, which was administered until disease progression. The starting dose of lenalidomide was 10 mg per day (range, 5 to 15). RESULTS: The study-drug assignments were unblinded in 2009, when a planned interim analysis showed a significantly longer time to disease progression in the lenalidomide group. At unblinding, 20% of patients who received lenalidomide and 44% of patients who received placebo had progressive disease or had died (P<0.001); of the remaining 128 patients who received placebo and who did not have progressive disease, 86 crossed over to lenalidomide. At a median follow-up of 34 months, 86 of 231 patients who received lenalidomide (37%) and 132 of 229 patients who received placebo (58%) had disease progression or had died. The median time to progression was 46 months in the lenalidomide group and 27 months in the placebo group (P<0.001). A total of 35 patients who received lenalidomide (15%) and 53 patients who received placebo (23%) died (P=0.03). More grade 3 or 4 hematologic adverse events and grade 3 nonhematologic adverse events occurred in patients who received lenalidomide (P<0.001 for both comparisons). Second primary cancers occurred in 18 patients who received lenalidomide (8%) and 6 patients who received placebo (3%). CONCLUSIONS: Lenalidomide maintenance therapy, initiated at day 100 after hematopoietic stem-cell transplantation, was associated with more toxicity and second cancers but a significantly longer time to disease progression and significantly improved overall survival among patients with myeloma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00114101.).


Subject(s)
Antineoplastic Agents/therapeutic use , Multiple Myeloma/drug therapy , Stem Cell Transplantation , Thalidomide/analogs & derivatives , Adult , Aged , Antineoplastic Agents/adverse effects , Disease-Free Survival , Double-Blind Method , Female , Follow-Up Studies , Humans , Lenalidomide , Maintenance Chemotherapy , Male , Middle Aged , Multiple Myeloma/mortality , Multiple Myeloma/therapy , Neoplasms, Second Primary/epidemiology , Thalidomide/adverse effects , Thalidomide/therapeutic use
19.
J Support Oncol ; 10(5): 195-201, 2012.
Article in English | MEDLINE | ID: mdl-22266154

ABSTRACT

BACKGROUND: Chronic lymphocytic leukemia (CLL) patients are at high risk for acute respiratory illness (ARI). OBJECTIVE: We evaluated the safety and efficacy of a proprietary extract of Panax quinquefolius, CVT-E002, in reducing ARI. METHODS: This was a double-blind, placebo-controlled, randomized trial of 293 subjects with early-stage, untreated CLL conducted January-March 2009. RESULTS: ARI was common, occurring on about 10% of days during the study period. There were no significant differences of the 2 a priori primary end points: ARI days (8.5 ± 17.2 for CVT-E002 vs 6.8 ± 13.3 for placebo) and severe ARI days (2.9 ± 9.5 for CVT-E002 vs 2.6 ± 9.8 for placebo). However, 51% of CVT-E002 vs 56% of placebo recipients experienced at least 1 ARI (difference, -5%; 95% confidence interval [CI], -16% to 7%); more intense ARI occurred in 32% of CVT-E002 vs 39% of placebo recipients (difference, -7%; 95% CI, -18% to 4%), and symptom-specific evaluation showed reduced moderate to severe sore throat (P = .004) and a lower rate of grade ≥3 toxicities (P = .02) in CVT-E002 recipients. Greater seroconversion (4-fold increases in antibody titer) vs 9 common viral pathogens was documented in CVT-E002 recipients (16% vs 7%, P = .04). LIMITATIONS: Serologic evaluation of antibody titers was not tied to a specific illness, but covered the entire study period. CONCLUSION: CVT-E002 was well tolerated. It did not reduce the number of ARI days or antibiotic use; however, there was a trend toward reduced rates of moderate to severe ARI and significantly less sore throat, suggesting that the increased rate of seroconversion most likely reflects CVT-E002-enhanced antibody responses.


Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/complications , Panax , Plant Extracts/therapeutic use , Respiratory Tract Infections/prevention & control , Acute Disease , Adult , Aged , Anti-Bacterial Agents/therapeutic use , Double-Blind Method , Female , Humans , Incidence , Male , Middle Aged , Plant Extracts/adverse effects , Respiratory Tract Infections/epidemiology
20.
Haematologica ; 97(5): 758-65, 2012 May.
Article in English | MEDLINE | ID: mdl-22133772

ABSTRACT

BACKGROUND: A phase II trial of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) from the National Cancer Institute showed promising activity in untreated diffuse large B-cell lymphoma. The Cancer and Leukemia Group B conducted a study to determine if these results could be reproduced in a multi-institutional setting. DESIGN AND METHODS: The study included 69 patients with untreated diffuse large B-cell lymphoma at least 18 years of age and at least stage II. Radiaton therapy was not permitted on study. Median age was 58 years (range 23-83) and 40% had high-intermediate or high International Prognostic Index risk. Immunohistochemical biomarkers for cell of origin and proliferation were performed. RESULTS: With a median follow up of 62 months, time to progression and overall survival were 81% and 84%, respectively, and time to progression was 87%, 92% and 54% for low/low-intermediate, high-intermediate and high International Prognostic Index risk groups, respectively, at 5-years and beyond. The time to progression and event-free survival of germinal center B-cell lymphoma were 100% and 94%, respectively, and non-germinal center B-cell GCB diffuse large B-cell lymphoma were 67% and 58%, respectively, at 62 months (germinal center vs. non-germinal center B cell P=0.008). DA-EPOCH-R was tolerated without significant grade 4 non-hematologic toxicities. CONCLUSIONS: These results provide the first confirmation by a multi-institutional group that DA-EPOCH-R provides high durable remissions in diffuse large B-cell lymphoma and is effective in both germinal center and non-germinal center B-cell subtypes. The trial was registered at ClinicalTrials.Gov (NCT00032019).


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/pathology , Mediastinal Neoplasms/drug therapy , Mediastinal Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Biomarkers, Tumor/metabolism , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Etoposide/administration & dosage , Female , Follow-Up Studies , Humans , Immunoenzyme Techniques , Lymphoma, Large B-Cell, Diffuse/mortality , Male , Mediastinal Neoplasms/mortality , Middle Aged , Neoplasm Staging , Prednisone/administration & dosage , Prognosis , Remission Induction , Rituximab , Survival Rate , Vincristine/administration & dosage , Young Adult
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