Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma.

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.).

A Pilot Study of Lenalidomide Maintenance Therapy after Autologous Transplantation in Relapsed or Refractory Classical Hodgkin Lymphoma.

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.

Lenalidomide after stem-cell transplantation for multiple myeloma.

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.).

A phase 2 multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma.

Relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) remains a clinical challenge, with limited effective treatment options available after stem cell transplantation. In a multicenter phase 2 study, the efficacy of lenalidomide in rel/ref cHL patients was evaluated at a dose of 25 mg/d on days 1-21 of a 28-day cycle. Patients remained on lenalidomide until disease progression or an unacceptable adverse event (AE) occurred. Thirty-eight cHL patients were enrolled with a median of 4 (range, 2-9) prior therapies; 87% had undergone prior stem cell transplantation and 55% of patients did not respond to their last prior therapy. Of 36 evaluable patients, responses were 1 complete remission (CR), 6 partial remissions (PRs), and 5 patients with stable disease (SD) for ≥ 6 months resulting in an International Working Committee (IWC) objective overall response rate (ORR) of 19% and a cytostatic ORR of 33%. Decreased chemokine (CCL17 and CCL22) plasma levels at 2 weeks were associated with a subsequent response. The treatment was well tolerated, and the most common grade 3/4 AEs were neutropenia (47%), anemia (29%), and thrombocytopenia (18%). Four patients discontinued lenalidomide because of rash, elevated transaminases/bilirubin, and cytopenias. We provide preliminary evidence of lenalidomide's activity in patients with rel/ref cHL, and therefore exploration of lenalidomide in combination with other active agents is warranted. This trial is registered at www.ClinicalTrials.gov as NCT00540007.

A phase II study of the oral VEGF receptor tyrosine kinase inhibitor vatalanib (PTK787/ZK222584) in myelodysplastic syndrome: Cancer and Leukemia Group B study 10105 (Alliance).

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.

A validation study of new cryopreservation bags for implementation in a blood and marrow transplant laboratory.

BACKGROUND: A new cryopreservation bag for hematopoietic cell transplantation requires validation as a safe alternative to the bag currently being used in the laboratory. STUDY DESIGN AND METHODS: The new bag was validated using both laboratory and clinical criteria. Laboratory validation proceeded using paired samples of mononuclear cells processed using standard procedures. Cells cryopreserved in the new and old bags were compared for viability, cell counts, CD34 enumeration, colony-forming unit assays, and bag integrity. After completion of laboratory investigations, engraftment with the new bags was followed and compared to historical engraftment using the old bags. RESULTS: There were no significant differences between the old and new bags detected using laboratory studies. Bag integrity was equivalent. The validation data suggested impaired cell function after cryopreservation in the new bags, but there were no significant differences in engraftment potential using either material. Days to engraftment was longer using the new bags, but statistical analysis revealed an association with CD34 dose and not with cryopreservation bag type. CONCLUSION: The new bags were noninferior to the old bags. A change in cryopreservation bag type may appear to affect cell function and potentially affect engraftment. Multiple analyses may be needed to understand the effect of cell processing changes.

A prospective, randomized, double-blind controlled trial of acetaminophen and diphenhydramine pretransfusion medication versus placebo for the prevention of transfusion reactions.

BACKGROUND: Acetaminophen and diphenhydramine are commonly used as pretransfusion medications to prevent transfusion reactions. The purpose of this study was to prospectively compare the risk of transfusion reactions in hematology/oncology patients who receive acetaminophen with diphenhydramine or placebo before transfusion. STUDY DESIGN AND METHODS: A randomized, double-blind, placebo-controlled transfusion reaction study of 315 eligible patients was performed. Inclusion criteria were patients aged 18 to 65 years admitted to the leukemia or bone marrow transplant (BMT) services. Patients were excluded if they had a known allergy to either acetaminophen or diphenhydramine or had a documented history of a febrile or allergic transfusion reaction. All blood products were administered using a leukofilter. Study medications were given 30 minutes before transfusions and no other acetaminophen or diphenhydramine was given within 4 hours of administration of the study medications. Patients were monitored for the development of reaction symptoms within 4 hours after the transfusion. RESULTS: A total of 154 active drug patients were compared to 161 placebo patients. There was no significant difference in the overall risk of transfusion reactions between the two groups. However, analysis of specific reaction types revealed a significant decrease in the risk of febrile reactions when pretransfusion medication is used in addition to bedside leukoreduction. CONCLUSIONS: Pretransfusion medication of leukemia or BMT patients without a history of transfusion reaction does not decrease the overall risk of transfusion reactions. However, pretransfusion medication may decrease the risk of febrile nonhemolytic transfusion reactions to leukoreduced blood products.

A Phase I Study of CPI-613 in Combination with High-Dose Cytarabine and Mitoxantrone for Relapsed or Refractory Acute Myeloid Leukemia.

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.

Pharmacokinetics of palifermin administered as the standard dose and as a collapsed dose in patients with hematologic malignancies.

STUDY OBJECTIVE: To assess the pharmacokinetic profile of palifermin after intravenous dosing with either a collapsed dose of 180 microg/kg/day for 1 day or a standard dose of 60 microg/kg/day for 3 days, before and after myeloablative chemoradiotherapy and peripheral blood progenitor cell (PBPC) transplantation. DESIGN: Prospective, open-label pharmacokinetic study. SETTING: University-affiliated hematology and oncology center. PATIENTS: Twenty-five adult patients with hematologic malignancies receiving myeloablative therapy; 13 were in the standard-dose group, and 12 were in the collapsed-dose group. INTERVENTION: Patients received total-body irradiation (study days -8 to -5), etoposide (day -4), cyclophosphamide (day -2), and PBPC transplantation (day 0). Standard-dose palifermin was administered on days -11, -10, -9, 0, 1, and 2; collapsed-dose palifermin was administered on days -11 and 0. MEASUREMENTS AND MAIN RESULTS: Baseline demographic and clinical characteristics were recorded. Blood samples were obtained for pharmacokinetic assessment, presence of palifermin antibodies, and routine chemistry and hematology panels. Adverse events were documented daily. For both dosing groups, palifermin concentrations declined rapidly (>or= 98%) in the first 30 minutes and increased slightly between 1 and 4 hours after dosing, with a terminal decay phase. For standard-dose palifermin, mean values for area under the serum concentration-time curve (AUC) were within 15% between doses 1 and 3 and within 1% between doses 1 and 4. For collapsed-dose palifermin, mean AUC values and other pharmacokinetic parameters were within 2% between doses 1 and 2. Mean AUC on days -11 and 0 were approximately 4-fold higher for collapseddose palifermin than for standard-dose palifermin. Both dosing regimens were well tolerated. CONCLUSIONS: Our results were consistent with approximately dose-linear pharmacokinetics for the two dosing regimens, with no observed accumulation. A randomized, controlled study is warranted to assess the safety and efficacy of collapsed-dose palifermin, which may provide a more convenient administration schedule.

Final Results of a Phase 1 Study of Vorinostat, Pegylated Liposomal Doxorubicin, and Bortezomib in Relapsed or Refractory Multiple Myeloma.

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.

Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial.

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.

Prospective, randomized comparison of high-dose chemotherapy with stem-cell support versus intermediate-dose chemotherapy after surgery and adjuvant chemotherapy in women with high-risk primary breast cancer: a report of CALGB 9082, SWOG 9114, and NCIC MA-13.

PURPOSE: The prognosis for women with primary breast cancer involving multiple axillary nodes remains poor. High-dose chemotherapy with stem-cell support produced promising results in initial clinical trials conducted at single institutions. PATIENTS AND METHODS: Seven hundred eighty-five women aged 22 to 66 years with stage IIA, IIB, or IIIA breast cancer involving 10 or more axillary lymph nodes were randomized after surgery and standard adjuvant chemotherapy to either high-dose cyclophosphamide, cisplatin, and carmustine (HD-CPB) with stem-cell support or intermediate-dose cyclophosphamide, cisplatin, and carmustine (ID-CPB) with G-CSF support but without stem cells. Planned treatment for all patients included locoregional radiation therapy. Hormone-receptor-positive patients were to receive 5 years of tamoxifen. Event-free survival (EFS) was the primary end point. RESULTS: Median follow-up was 7.3 years. Event-free survival was not significantly different between the two treatment groups (P = .24). The probability of being free of an event at 5 years with HD-CPB was 61% (95% CI, 56% to 65%), and was 58% (95% CI, 53% to 63%) for ID-CPB. Thirty-three patients died of causes attributed to HD-CPB, compared with no therapy-related deaths among women treated with ID-CPB. Overall survival for the two arms was identical at 71% at 5 years (P = .75). CONCLUSION: HD-CPB with stem-cell support was not superior to ID-CPB for event-free or overall survival among all randomized women with high-risk primary breast cancer.

Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B.

PURPOSE: The array of options for the initial management of follicular small cleaved lymphoma (FSCL) and follicular mixed lymphoma (FML) ranges from little or no therapy to the use of intensive combinations of drugs. The Cancer and Leukemia Group B (CALGB) compared two contrasting approaches: a single agent, and combination chemotherapy capable of curing diffuse aggressive lymphomas. PATIENTS AND METHODS: A total of 228 patients with stage III or IV FSCL or FML were randomized to cyclophosphamide or the combination of cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-B). Treatment was continued in responders for 2 years beyond maximal response. The primary end point was survival in the most common subtype, FSCL. RESULTS: Ninety-one percent of all patients responded; complete responses were seen in 66% of those treated with cyclophosphamide and in 60% treated with CHOP-B (P =.36). At 10 years with either cyclophosphamide or CHOP-B, respectively, overall time to failure (25% failure free v 33%; P =.107) and survival (44% alive v 46%; P =.79) were similar by treatment. Outcomes in FSCL also were similar. In 46 patients with FML, at 10 years the combination was associated with better failure-free (9% v 48%; P =.005) and overall (25% v 61%; P =.024) survival. Acute toxic effects were more common with combination chemotherapy. Second malignancies, which might be attributed to treatment, were seen with both approaches. CONCLUSION: There is no advantage to the initial use of the relatively intensive combination, CHOP-B, for patients with FSCL compared with the less toxic single agent, cyclophosphamide. However, in an unplanned subgroup analysis, patients with FML who received the combination experienced improved disease control and survival.

Dose escalation studies of cytarabine, daunorubicin, and etoposide with and without multidrug resistance modulation with PSC-833 in untreated adults with acute myeloid leukemia younger than 60 years: final induction results of Cancer and Leukemia Group B Study 9621.

PURPOSE: P-glycoprotein (Pgp) is strongly inhibited by PSC-833. A chemotherapy dose-escalation study was performed with PSC-833 in patients younger than 60 years with untreated acute myeloid leukemia. Clinical rather than pharmacokinetic end points were used to develop two induction therapies containing drugs susceptible to Pgp-mediated efflux and associated with comparable toxicities at the maximum-tolerated doses. PATIENTS AND METHODS: A total of 410 patients were enrolled. Fifteen induction regimens containing variable doses of daunorubicin (DNR) and etoposide (ETOP) and fixed doses of cytarabine were evaluated with (ADEP) or without (ADE) a fixed dose of PSC-833. RESULTS: Doses selected for phase III testing were DNR 90 mg/m(2) and ETOP 100 mg/m(2) in ADE, and DNR and ETOP each 40 mg/m(2) in ADEP. Intolerable mucosal toxicity occurred at higher doses of ADEP. Although the design of this study precludes direct comparisons, there was an apparent advantage for receiving ADEP with respect to disease-free and overall survival in patients < or = 45 years old, despite the significantly lower doses of DNR and ETOP given in ADEP compared with ADE. CONCLUSION: A large clinical data set was used to develop induction regimens containing two drugs susceptible to Pgp-mediated efflux, with and without an inhibitor of Pgp function. The chosen doses have comparable antileukemia activity and toxicity, making them suitable for use in a phase III comparative study of induction chemotherapy for patients with acute myeloid leukemia younger than 60 years. That trial will also clarify whether patients < or = 45 years old are especially likely to benefit from Pgp inhibition during induction therapy.

Ciprofloxacin plus piperacillin compared with tobramycin plus piperacillin as empirical therapy in febrile neutropenic patients. A randomized, double-blind trial.

BACKGROUND: Therapy with an aminoglycoside and a beta-lactam remains common empirical therapy for febrile neutropenic patients. Concerns of aminoglycoside-induced ototoxicity and nephrotoxicity have led to studies of alternate regimens. OBJECTIVE: To determine whether ciprofloxacin-piperacillin is equivalent to tobramycin-piperacillin as empirical therapy for neutropenic fever. DESIGN: Randomized, double-blind multicenter trial. SETTING: Seven U.S. university-affiliated hospitals and one private research center. PATIENTS: Febrile (temperature >/= 38 degrees C), neutropenic (neutrophil level < 1 x 10(9) cells/L) hospitalized patients who had leukemia, lymphoma, or solid tumors, or were undergoing bone marrow transplantation. INTERVENTIONS: Patients received piperacillin, 50 mg/kg of body weight intravenously every 4 hours, and ciprofloxacin, 400 mg intravenously every 8 hours, or tobramycin, 2 mg/kg intravenously every 8 hours. MEASUREMENTS: Success was defined as resolution of infection and previously positive cultures without the need to give additional antimicrobial agents. RESULTS: 543 febrile episodes were evaluated, of which 471 were clinically evaluable (234 in the ciprofloxacin-piperacillin group and 237 in the tobramycin-piperacillin group). Success rates in the ciprofloxacin-piperacillin group (63 of 234 febrile episodes) and tobramycin-piperacillin group (52 of 237 episodes) were similar (27% vs. 22%, respectively; difference, 5.0 percentage points [95% CI, -2.3 to 12.8 percentage points]), as was survival (96.2% of patients receiving ciprofloxacin-piperacillin versus 94.1% of patients receiving tobramycin-piperacillin; difference, 2.1 percentage points [CI, -2.2 to 6.4 percentage points]). Additions to the initial antimicrobial regimen were the most common reason for treatment failure in both groups (accounting for 67% of failures in the ciprofloxacin-piperacillin group and 72% in the tobramycin-piperacillin group; difference, 5.0 percentage points [CI, -13.8 to 3.7 percentage points]). Fevers resolved faster in patients receiving ciprofloxacin-piperacillin than in patients receiving tobramycin-piperacillin (mean, 5 vs. 6 days) (P = 0.005). No significant differences in adverse events or toxicity were noted (P = 0.083). CONCLUSION: Ciprofloxacin-piperacillin is as safe and effective as tobramycin-piperacillin for empirical therapy of neutropenic fever.

Effect of ArginMax on sexual functioning and quality of life among female cancer survivors: results of the WFU CCOP Research Base Protocol 97106.

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.

Low plasma concentrations of retinol and alpha-tocopherol in hematopoietic stem cell transplant recipients: the effect of mucositis and the risk of infection.

BACKGROUND: Although vitamin deficiencies are rare in the United States, acute reductions in concentrations of plasma retinol (vitamin A) or alpha-tocopherol (vitamin E) have been associated with impaired immune responses in some clinical settings. OBJECTIVE: The objectives were to determine the plasma concentrations of retinol and alpha-tocopherol in patients undergoing dose-intensive therapy and hematopoietic stem cell transplant and to examine the association of plasma concentrations with clinical outcomes reflecting immunity. DESIGN: This was an observational trial of 120 consecutive recipients of hematopoietic stem cell transplant and a multivariate analysis of plasma vitamin concentrations, mucositis, infections in the first 30 d, and herpes zoster infections in the first year after hematopoietic stem cell transplant. RESULTS: Plasma retinol and alpha-tocopherol concentrations declined from baseline to day 7, typically recovering without specific replacement toward baseline by day 14. The severity of mucositis was a strong predictor of low plasma retinol on day 7 (P = 0.001). Eighty-two patients (68%) had at least one plasma retinol concentration < or = 1.05 micro mol/L, a concentration previously determined to be of immunologic significance, during the peritransplant period (day -8 to day 14). Men more frequently acquired herpes zoster than women, and men who developed hyporetinolemia (< or = 1.05 micro mol/L) had a significantly higher risk of herpes zoster (OR: 6.6; 95% CI: 1.5, 29.6). Plasma alpha-tocopherol was not associated with any clinical event measured in this study. CONCLUSION: Hyporetinolemia is common, particularly in subjects with severe mucositis, and is associated with an increased risk of herpes zoster infection in recipients of hematopoietic stem cell transplant. Additional investigations are required to determine whether these findings indicate a causal relation.

A phase III, randomized, double-blind, placebo-controlled, study of iseganan for the reduction of stomatitis in patients receiving stomatotoxic chemotherapy.

The invasion and colonization of oral cavity mucosal tissues by microflora may contribute to the pathophysiology of ulcerative oral mucositis (UOM). Iseganan is an analog of protegrin-1, a naturally occurring peptide with broad-spectrum microbicidal activity. A randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of iseganan in preventing UOM after stomatotoxic therapy. Patients received an oral rinse, consisting of iseganan 9mg or placebo, to be swished/swallowed six times daily, starting with stomatotoxic therapy and continuing up to 21 days. Patients were assessed for stomatitis and UOM, and administered a questionnaire evaluating mouth pain and difficulty swallowing thrice weekly. The primary study efficacy endpoint was the proportion of patients who did not have peak stomatitis NCI-CTC grade >or=2. Between November 2001 and June 2002, 502 patients were randomized to receive iseganan (251) or placebo (251). Equivalent numbers of patients in both cohorts received bone marrow or peripheral blood allogeneic or autologous stem cell transplantation (SCT). Forty-three percent and 37% of iseganan and placebo patients, respectively, did not have peak stomatitis grade =2 (P = 0.182). There was no significant difference between the cohorts in stomatitis severity, incidence of UOM, peak mouth pain, peak difficulty swallowing, amount of opiate analgesics used, or adverse event type or incidence. A major impact of Iseganan on reducing stomatitis, UOM, or its clinical sequelae in patients receiving stomatotoxic therapy was not detected on this study.

A phase III, randomized, double-blind, placebo-controlled, multinational trial of iseganan for the prevention of oral mucositis in patients receiving stomatotoxic chemotherapy (PROMPT-CT trial).

Microfloral invasion and colonization of oral cavity mucosal tissues contribute to the pathophysiology of ulcerative oral mucositis (UOM). Iseganan is an analog of Protegrin-1, a naturally occurring peptide with broad-spectrum microbicidal activity. A randomized, double-blind, placebo-controlled study was conducted to evaluate iseganan in preventing UOM after stomatotoxic therapy. Patients received an oral rinse of iseganan 9 mg or placebo, swished/swallowed 6 times daily, starting with stomatotoxic therapy and continuing for 21-28 days. One hundred sixty three and 160 patients, respectively, were randomized to receive iseganan or placebo. One hundred and two patients (32%) were affected by a drug dispensing error, caused by a flawed computerized allocation system. Among all 323 patients, analyzed according to randomization assignment, 43% and 33% of iseganan and placebo patients, respectively, did not develop UOM (P = 0.067). On an 11-point scale, iseganan patients experienced less mouth pain (3.0 and 3.8 (P = 0.041), throat pain (3.8 and 4.6 (P = 0.048)), and difficulty swallowing (3.9 and 4.7 (P = 0.074)), compared to placebo patients. On the 5-point NCI CTC scale, iseganan patients experienced lower stomatitis scores (1.6 and 2.0 (P = 0.0131). Iseganan was well tolerated; no systemic absorption was detected. Iseganan is safe and may be effective in reducing UOM and its clinical sequelae.