Thalidomide versus dexamethasone for the treatment of relapsed and/or refractory multiple myeloma: results from OPTIMUM, a randomized trial

Background

Thalidomide has potent antimyeloma activity, but no prospective, randomized controlled trial has evaluated thalidomide monotherapy in patients with relapsed/refractory multiple myeloma.

Design and Methods

We conducted an international, randomized, open-label, four-arm, phase III trial to compare three different doses of thalidomide (100, 200, or 400 mg/day) with standard dexamethasone in patients who had received one to three prior therapies. The primary end-point was time to progression.

Results

In the intent-to-treat population (N=499), the median time to progression was 6.1, 7.0, 7.6, and 9.1 months in patients treated with dexamethasone, and thalidomide 100, 200, and 400 mg/day, respectively; the difference between treatment groups was not statistically significant. In the per-protocol population (n=465), the median time to progression was 6.0, 7.0, 8.0, and 9.1 months, respectively. In patients who had received two or three prior therapies, thalidomide significantly prolonged the time to progression at all dose levels compared to the result achieved with dexamethasone. Response rates and median survival were similar in all treatment groups, but the median duration of response was significantly longer in all thalidomide groups than in the dexamethasone group. Adverse events reported in the thalidomide groups, such as fatigue, constipation and neuropathy, confirmed the known safety profile of thalidomide.

Conclusions

Although thalidomide was not superior to dexamethasone in this randomized trial, thalidomide monotherapy may be considered an effective salvage therapy option for patients with relapsed/refractory multiple myeloma, particularly those with a good prognosis and those who have received two or three prior therapies. The recommended starting dose of thalidomide monotherapy is 400 mg/day, which can be rapidly reduced for patients who do not tolerate this treatment. (Clinical trial registration number: {"type":"clinical-trial","attrs":{"text":"NCT00452569","term_id":"NCT00452569"}}NCT00452569)     

Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma

In multiple myeloma (MM), the addition of thalidomide or bortezomib to the standard oral melphalan/prednisone combination significantly increased response rate and event-free survival. In this multicenter phase 1/2 trial, dosing, safety, and efficacy of the 4-drug combination, bortezomib, melphalan, prednisone, and thalidomide (VMPT) was determined. Bortezomib was administered at 3 dose levels (1.0 mg/m2, 1.3 mg/m2, or 1.6 mg/m2) on days 1, 4, 15, and 22; melphalan was given at a dose of 6 mg/m2 on days 1 through 5 and prednisone at 60 mg/m2 on days 1 through 5. Thalidomide was delivered at 50 mg on days 1 through 35. Each course was repeated every 35 days. The maximum tolerated dose of bortezomib was 1.3 mg/m2. Thirty patients with relapsed or refractory MM were enrolled; 20 patients (67%) achieved a partial response (PR) including 13 patients (43%) who achieved at least a very good PR. Among 14 patients who received VMPT as second-line treatment, the PR rate was 79% and the immunofixation-negative complete response rate 36%. The 1-year progression-free survival was 61%, and the 1-year survival from study entry was 84%. Grade 3 nonhematologic adverse events included infections (5 patients), fatigue (1), vasculitis (1), and peripheral neuropathy (2); no grade 4 toxicities were recorded. Initial results showed that VMPT is an effective salvage therapy with a very high proportion of responses. The incidence of neurotoxicities was unexpectedly low.     

Use of Continuous Glucose Monitoring to Estimate Insulin Requirements in Patients with Type 1 Diabetes Mellitus During a Short Course of Prednisone

Background

Insulin requirements to maintain normoglycemia during glucocorticoid therapy and stress are often difficult to estimate. To simulate insulin resistance during stress, adults with type 1 diabetes mellitus (T1DM) were given a three-day course of prednisone.

Methods

Ten patients (7 women, 3 men) using continuous subcutaneous insulin infusion pumps wore the Medtronic Minimed CGMS^® (Northridge, CA) device. Mean (standard deviation) age was 43.1 (14.9) years, body mass index 23.9 (4.7) kg/m², hemoglobin A1c 6.8% (1.2%), and duration of diabetes 18.7 (10.8) years. Each patient wore the CGMS for one baseline day (day 1), followed by three days of self-administered prednisone (60 mg/dl; days 2–4), and one post-prednisone day (day 5).

Results

Analysis using Wilcoxon signed rank test (values are median [25th percentile, 75th percentile]) indicated a significant difference between day 1 and the mean of days on prednisone (days 2–4) for average glucose level (110.0 [81.0, 158.0] mg/dl vs 149.2 [137.7, 168.0] mg/dl; p = .022), area under the glucose curve and above the upper limit of 180 mg/dl per day (0.5 [0, 8.0] mg/dl·d vs 14.0 [7.7, 24.7] mg/dl·d; p = .002), and total daily insulin dose (TDI) , (0.5 [0.4, 0.6] U/kg·d vs 0.9 [0.8, 1.0] U/kg·d; p = .002). In addition, the TDI was significantly different for day 1 vs day 5 (0.5 [0.4, 0.6] U/kg·d vs 0.6 [0.5, 0.8] U/kg·d; p = .002). Basal rates and insulin boluses were increased by an average of 69% (range: 30–100%) six hours after the first prednisone dose and returned to baseline amounts on the evening of day 4.

Conclusions

For adults with T1DM, insulin requirements during prednisone induced insulin resistance may need to be increased by 70% or more to normalize blood glucose levels.     

Salvage treatment with lenalidomide and dexamethasone in relapsed/refractory mantle cell lymphoma: clinical results and effects on microenvironment and neo-angiogenic biomarkers

Background

Preclinical studies have highlighted the activity of lenalidomide in mantle cell lymphoma and its anti-proliferative synergy with dexamethasone.

Design and Methods

In this prospective, multicenter, phase II study, patients with relapsed/refractory mantle cell lymphoma who were not eligible for, or had relapsed after, intensive treatments received lenalidomide 25 mg/day (days 1–21 of each 28-day cycle) and dexamethasone (40 mg/day on days 1, 8, 15, and 22) for up to 12 months.

Results

The primary end-points, overall and complete response rates, were achieved by 17 of 33 (52%; 95% confidence interval [CI], 35–68%) and 8 of 33 patients (24%; 95% CI, 13–41%), respectively, by the end of treatment. Fifteen patients (45%) discontinued treatment prematurely, 13 due to lack of response. The median progression-free and overall survival were 12 months (95% CI, 5–19 months) and 20 months (95% CI, 12 months to not estimable), respectively. Treatment resulted in a significant increase in microvessel density (P=0.033) and non-significant increases in macrophage and natural killer cell counts, while serum levels of neoangiogenic factors did not change significantly. Grade 3/4 adverse events were neutropenia (53%), leukopenia (25%), thrombocytopenia (22%), infections (12%), and febrile neutropenia (12%).

Conclusions

These results confirm a favorable safety and activity profile of lenalidomide in relapsed/refractory mantle cell lymphoma. The contribution of dexamethasone in achieving these results is unclear because of its possible detrimental effect on the immune activation generated by lenalidomide and a higher risk of developing infectious complications. (clinicaltrials.gov identifier: NCT00786851).     

The human immunodeficiency virus-1 protease inhibitor nelfinavir impairs proteasome activity and inhibits the proliferation of multiple myeloma cells in vitro and in vivo

Background

Multiple myeloma is characterized by the accumulation of tumor plasma cells in the bone marrow. Despite therapeutic improvements brought by proteasome inhibitors such as bortezomib, myeloma remains an incurable disease. In a variety of human cancers, human immunodeficiency virus protease inhibitors (e.g. nelfinavir) effectively inhibit tumor progression, but their impact on myeloma is unknown. We assessed the in vitro and in vivo effects of nelfinavir on multiple myeloma.

Design and Methods

The effects of nelfinavir (1–10 μM) on proteasome activity, proliferation and viability of myeloma cell lines and plasma cells from patients were assessed by measuring PERK, AKT, STAT3 and ERK1/2 phosphorylation and CHOP expression with immunoblotting or flow cytometry. The in vivo effect was assessed in NOD/SCID mice injected with luciferase expressing human myeloma cell lines and treated with nelfinavir at a dose of 75 mg/kg/day. Tumor progression was evaluated using a bioluminescent system.

Results

Nelfinavir inhibited 26S chymotrypsin-like proteasome activity, impaired proliferation and triggered apoptosis of the myeloma cell lines and fresh plasma cells. It activated the pro-apoptotic unfolded protein response pathway by inducing PERK phosphorylation and CHOP expression. Cell death triggered by nelfinavir treatment correlated with decreased phosphorylation of AKT, STAT3 and ERK1/2. Nelfinavir enhanced the anti-proliferative activity of bortezomib, dexamethasone and histone deacetylase inhibitors and delayed tumor growth in a myeloma mouse model.

Conclusions

These results suggest that nelfinavir, used at a pharmacological dosage, alone or in combination, may be useful in the treatment of myeloma. Our data provide a preclinical basis for clinical trials using nelfinavir in patients with myeloma.     

Phase I clinical and pharmacokinetic study of a novel schedule of flavopiridol in relapsed or refractory acute leukemias

Background

A pharmacokinetically derived schedule of flavopiridol administered as a 30 min intravenous bolus followed by 4-hour continuous intravenous infusion (IVB/CIVI) is active in fludarabine-refractory chronic lymphocytic leukemia, but no studies examining the feasibility and maximum tolerated dose of this schedule have been reported in acute leukemia.

Design and Methods

We conducted a phase I dose escalation trial of single-agent flavopiridol in adults with relapsed/refractory acute leukemias, utilizing a modification of the intravenous bolus/continuous intravenous infusion approach, intensifying treatment for administration on days 1, 2, and 3 of 21-day cycles.

Results

Twenty-four adults with relapsed/refractory acute myeloid leukemia (n=19) or acute lymphoblastic leukemia (n=5) were enrolled. The median age was 62 years (range, 23–78). The maximum tolerated dose of flavopiridol was 40mg/m² intravenous bolus plus 60mg/m² continuous intravenous infusion (40/60). The dose limiting toxicity was secretory diarrhea. Life-threatening hyperacute tumor lysis syndrome requiring hemodialysis on day 1 was observed in one patient. Pharmacokinetics were dose-dependent with increased clearance observed at the two highest dose levels. Diarrhea occurrence and severity significantly correlated with flavopiridol concentrations at the end of the 4-hour infusion, volume of distribution, and elimination half-life. Modest anti-leukemic activity was observed, with most patients experiencing dramatic but transient reduction/clearance of circulating blasts lasting for 10–14 days. One refractory acute myeloid leukemia patient had short-lived complete remission with incomplete count recovery.

Conclusions

Flavopiridol as a single agent given by intravenous bolus/continuous intravenous infusion causes marked, immediate cytoreduction in relapsed/refractory acute leukemias, but objective clinical responses were uncommon. With this schedule, the dose is limited by secretory diarrhea (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00101231","term_id":"NCT00101231"}}NCT00101231).     

Meta-analysis of one- vs. two-stage laparoscopic/endoscopic management of common bile duct stones

Background

The present study is a meta-analysis of English articles comparing one-stage [laparoscopic common bile duct exploration or intra-operative endoscopic retrograde cholangiopancreatography (ERCP)] vs. two-stage (laparoscopic cholecystectomy preceded or followed by ERCP) management of common bile duct stones.

Methods

MEDLINE/PubMed and Science Citation Index databases (1990–2011) were searched for randomized, controlled trials that met the inclusion criteria for data extraction. Outcomes were calculated as odds ratios (ORs) with 95% confidence intervals (CIs) using RevMan 5.1.

Results

Nine trials with 933 patients were studied. No significant differences was observed between the two groups with regard to bile duct clearance (OR, 0.89; 95% CI, 0.65–1.21), mortality (OR, 1.2; 95% CI, 0.32–4.52), total morbidity (OR, 0.75; 95% CI, 0.53–1.06), major morbidity (OR, 0.95; 95% CI, 0.60–1.52) and the need for additional procedures (OR, 1.58; 95% CI, 0.76–3.30).

Conclusions

Outcomes after one-stage laparoscopic/endoscopic management of bile duct stones are no different to the outcomes after two-stage management.     

Estimates of mortality attributable to influenza and RSV in the United States during 1997–2009 by influenza type or subtype,age, cause of death,and risk status

Background

Influenza and respiratory syncytial virus (RSV) cause substantial mortality from respiratory and other causes in the USA, especially among people aged 65 and older.

Objectives

We estimated the influenza-attributable mortality and RSV-attributable mortality in the USA, stratified by age and risk status, using outcome definitions with different sensitivity and specificity.

Methods

Influenza- and RSV-associated mortality was assessed from October 1997–March 2009 using multiple linear regression modeling on data obtained from designated government repositories.

Results

The main outcomes and measures included mortality outcome definitions—pneumonia and influenza, respiratory broad, and cardiorespiratory disease. A seasonal average of 10 682 (2287–16 363), 19 100 (4862–29 245), and 28 169 (6797–42 316) deaths was attributed to influenza for pneumonia and influenza, respiratory broad, and cardiorespiratory outcome definitions, respectively. Corresponding values for RSV were 6211 (4584–8169), 11 300 (8546–14 244), and 17 199 (13 384–21 891), respectively. A/H3N2 accounted for seasonal average of 71% influenza-attributable deaths; influenza B accounted for most (51–95%) deaths during four seasons. Approximately 70% influenza-attributable deaths occurred in individuals ≥75 years, with increasing mortality for influenza A/H3N2 and B, but not A/H1N1. In children aged 0–4 years, an average of 97 deaths was attributed to influenza (A/H3N2 = 49, B = 33, A/H1N1 = 15) and 165 to respiratory broad outcome definition (RSV). Influenza-attributable mortality was 2·94-fold higher in high-risk individuals.

Conclusions

Influenza-attributable mortality was highest in older and high-risk individuals and mortality in children was higher than reported in passive Centers for Disease Control and Prevention surveillance. Influenza B-attributable mortality was higher than A in four of 12 seasons. Our estimates represent an updated assessment of influenza-attributable mortality in the USA.     

Laparoscopic three-port distal pancreatectomy

Aims

Laparoscopic distal pancreatectomy is becoming a more commonly used procedure, which may involve the use of four to seven ports, depending on the technique. Initial data on feasibility, safety and outcome with the three-port laparoscopic distal pancreatectomy are presented.

Methods

The patient is placed in a partial thoracoabdominal position exposing the left flank in a reverse Trendelenberg position. A 10-mm Hassan trocar is inserted through a subcostal anterior axillary incision. A 5-mm midclavicular and 10-mm posterior axillary line trocar are placed. The specimen is retrieved from the anterior axillary line port.

Results

Ten women and seven men, aged 26–88 years (mean 61 years), were evaluated. Their body mass indexes ranged from 18–37 (mean 27). Pancreatic lesion size ranged from 1.0–5.5 cm (mean 3.0 cm). Operative time was 116–296 min (mean 170 min). Blood loss was 10–300 ml (mean 142 ml). No operation required conversion or additional trocar placement. Post-operative stay was 2–7 days (mean 4 days). No patient developed a pancreatic fistula.

Conclusion

Operative time, blood loss and post-operative stay of this three-port technique compare favourably with published data.     

Coagulation factors V, VIII, and X, prothrombin time and activated partial thromboplastin time test results in thawed plasma stored at 1�C6 oC for 5 days

Background

The aim of this study was to evaluate whether thawed plasma stored for 5 days at 1–6 ºC is appropriate for use.

Materials and methods

Samples taken from thawed plasma units stored for 5 days at 1–6 ºC were prepared for assays of the levels of factor V, factor VIII, and factor X, and for measurements of the activated partial thromboplastin time (aPTT) and prothrombin time (PT). The results obtained were then compared with those from other similar studies.

Results

The average decreases in percentages of coagulation factors from day 1 to day 5 were 20% for factor V, 11% for factor X, and 25% for total factor VIII. The changes in the range of coagulation factors over the 5-day storage period were statistically significant, but the values remained within the haemostatic range. The average increases in the levels of PT and aPTT from day 1 to day 5 were also not clinically pathological.

Conclusions

Thawed fresh-frozen plasma stored for 5 days at 1–6 °C can be used in different cases of coagulopathy and can be used as an alternative to plasma frozen within 24 hours of phlebotomy.     

Display of Glucose Distributions by Date, Time of Day, and Day of Week: New and Improved Methods

Objective

There is a need for improved methods for display of glucose distributions to facilitate comparisons by date, time of day, day of the week, and other variables for data obtained using self-monitoring of blood glucose (SMBG) and continuous glucose monitoring (CGM).

Method

Stacked bar charts are utilized for multiple ranges of glucose values, e.g., very low, low, borderline low, target range, borderline high, high, and very high. Glucose ranges for these categories can be defined by the user, e.g., <40, 40–70, 71–80, 81–140, 141–180, 181–250, and 251–400 mg/dl. Glucose distributions can be displayed by time of day, in relation to meals, by date, or by day of week. The graphic display can be generated using general purpose spreadsheet software such as Microsoft Excel or with special purpose software.

Result

Stacked bar charts are extremely compact and effective. They facilitate comparison of multiple days, multiple time segments within a day, preprandial and postprandial glucose levels, days of the week, treatment periods, patients, and groups of patients. They are superior to use of pie charts in terms of compactness and in their ability to facilitate comparisons using multiple criteria and multiple subsets of the data. One can identify episodes of hypoglycemia and hyperglycemia and can display standard errors of estimates of percentages. Interpretation of these graphs is readily learned and requires minimal training.

Conclusion

Use of stacked bar charts is generally superior to use of pie charts for display of glucose distributions and can potentially facilitate the analysis and interpretation of SMBG and CGM data.     

Importance of blood glucose meter and carbohydrate estimation accuracy

Background

The clinical significance of blood glucose meter (BGM) error in the presence of increasing carbohydrate errors in diabetes patients who use both the BGM result and the carbohydrate estimation to dose insulin is unknown.

Methods

This Monte Carlo simulation modeled diabetes patients who calculate insulin dosages based on BGM results and carbohydrate estimations. It evaluated the likelihood of on-target insulin dosing and clinically significant insulin dose errors based on data from five BGMs with different levels of performance (expressed as bias and imprecision [coefficient of variation (%CV)]) and increasing levels of carbohydrate estimation errors. The study was performed across three separate preprandial glucose (PPG) ranges (90–150, 150–270, and 270–450 mg/dl).

Results

When carbohydrate estimation is accurate (%CV = 0%), the likelihood for on-target insulin doses ranged 50.1–98.5%. The likelihood depended on BGM performance and PPG range. In the presence of carbohydrate estimation errors (%CV = 5–20%), the likelihood of on-target insulin dosages markedly decreased (range, 27.2–80.1%) for all BGMs, the likelihood of insulin underdosing (range, 0–12.8%) and overdosing (range, 0–32.3%) increased, and the influence of BGM error on insulin dosing accuracy was blunted. Even in the presence of carbohydrate error, the BGM with the best performance (bias 1.35% and %CV = 4.84) had the highest probability for on-target insulin dosages.

Conclusions

Both BGM and carbohydrate estimation error contribute to insulin dosing inaccuracies. The BGM with the best performance was associated with the most on-target insulin dosages.     

Disability and Decline in Physical Function Associated with Hospital Use at End of Life

Background

Hospital use near the end of life is often undesirable to patients, represents considerable Medicare cost, and varies widely across regions.

Objective

To concurrently examine regional and patient factors, including disability and functional decline, associated with end-of-life hospital use.

Design/Participants

We sampled decedents aged 65 and older (n = 2,493) from the Health and Retirement Study (2000–2006), and linked data from individual Medicare claims and the Dartmouth Atlas of Health Care. Two-part regression models estimated the relationship between total hospital days in the last 6 months and patient characteristics including physical function, while adjusting for regional resources and hospital care intensity (HCI).

Key Results

Median hospital days was 7 (range = 0–183). 53% of respondents had functional decline. Compared with decedents without functional decline, those with severe disability or decline had more regression-adjusted hospital days (range 3.47–9.05, depending on category). Dementia was associated with fewer days (−3.02); while chronic kidney disease (2.37), diabetes (2.40), stroke or transient ischemic attack (2.11), and congestive heart failure (1.74) were associated with more days. African Americans and Hispanics had more days (5.91 and 4.61, respectively). Those with family nearby had 1.62 fewer days and hospice enrollees had 1.88 fewer days. Additional hospital days were associated with urban residence (1.74) and residence in a region with more specialists (1.97) and higher HCI (2.27).

Conclusions

Functional decline is significantly associated with end-of-life hospital use among older adults. To improve care and reduce costs, health care programs and policies should address specific needs of patients with functional decline and disability.

Electronic supplementary material

The online version of this article (doi:10.1007/s11606-012-2013-9) contains supplementary material, which is available to authorized users.KEY WORDS: disability, end-of-life decisions, functional decline, Medicare, Medigap     

Low,fixed dose defibrotide in management of hepatic veno-occlusive disease post stem cell transplantation

Objective/background

Hepatic veno-occlusive disease (VOD) is well recognized potentially serious regimen-related toxicity seen after stem cell transplantation. Severe VOD is associated with poor long-term outcomes with very high mortality. Besides supportive care, only defibrotide has been found to be effective in the management of VOD. The recommended dose of defibrotide is 25 mg/kg/d but there has been no classical dose finding study done for this drug. A higher dose of defibrotide is associated with increased risk of bleeding and this drug is prohibitively expensive. We report our experience of using fixed low dose of defibrotide in patients with VOD.

Association Between Race, Depression, and Antiretroviral Therapy Adherence in a Low-Income Population with HIV Infection

Background

Racial disparities exist in many aspects of HIV/AIDS. Comorbid depression adds to the complexity of disease management. However, prior research does not clearly show an association between race and antiretroviral therapy (ART) adherence, or depression and adherence. It is also not known whether the co-existence of depression modifies any racial differences that may exist.

Objective

To examine racial differences in ART adherence and whether the presence of comorbid depression moderates these differences among Medicaid-enrolled HIV-infected patients.

Design

Retrospective cohort study.

Setting

Multi-state Medicaid database (Thomson Reuters MarketScan®).

Participants

Data for 7,034 HIV-infected patients with at least two months of antiretroviral drug claims between 2003 and 2007 were assessed.

Main Measures

Antiretroviral therapy adherence (90 % days covered) were measured for a 12-month period. The main independent variables of interest were race and depression. Other covariates included patient variables, clinical variables (comorbidity and disease severity), and therapy-related variables.

Key Results

In this study sample, over 66 % of patients were of black race, and almost 50 % experienced depression during the study period. A significantly higher portion of non-black patients were able to achieve optimal adherence (≥90 %) compared to black patients (38.6 % vs. 28.7 %, p < 0.001). In fact, black patients had nearly 30 % decreased odds of being optimally adherent to antiretroviral drugs compared to non-black patients (OR = 0.70, 95 % CI: 0.63–0.78), and was unchanged regard less of whether the patient had depression. Antidepressant treatment nearly doubled the odds of optimal ART adherence among patients with depression (OR = 1.92, 95 % CI: 1.12–3.29).

Conclusions

Black race was significantly associated with worse ART adherence, which was not modified by the presence of depression. Under-diagnosis and under-treatment of depression may hinder ART adherence among HIV-infected patients of all races.KEY WORDS: HIV, adherence, depression, race, Medicaid     

Intravenous melphalan, thalidomide and prednisone in refractory and relapsed multiple myeloma

OBJECTIVES: Thalidomide combined with conventional chemotherapies including oral melphalan shows significant anti-myeloma activity. To address this issue, feasibility and efficacy of a three drug combination consisting of intravenous (i.v.) melphalan, thalidomide and prednisone [M(i.v.)PT] was evaluated in advanced myeloma patients. PATIENTS AND METHODS: Twenty-four advanced myeloma patients were treated with multiple cycles of a regimen consisting of low dose i.v. melphalan (20 mg/m2) at d 1, thalidomide at the dose of 50-100 mg/d given continuously and oral prednisone at the planned dose of 50 mg/d every other day. Intravenous melphalan was administered every fourth month. Median time from diagnosis was 40 months (range: 8-144 months). Fifteen patients (66%) had previously been treated with a combination of thalidomide and dexamethasone or with thalidomide alone. RESULTS: Overall, on an intent-to treat basis, 14 patients responded: three achieved near complete remission (nCR), seven achieved partial response (PR), four minimal response (MR). Six patients showed stable disease (SD) and four-disease progression. Interestingly, of five patients who had previously progressed while on thalidomide and prednisone, one reached nCR, two PR and one MR. After a median follow up of 14 months, median progression free survival was 9 months. Response duration was longer than that induced by the previous line of treatment in eight patients (33%). Thalidomide-associated toxicity mainly consisted of constipation, tingling and sedation. CONCLUSIONS: M(i.v.)PT is an effective regimen, which can overcome resistance to thalidomide plus prednisone in advanced myeloma with acceptable toxicity.     

Phase I trial of a novel human monoclonal antibody mAb216 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia

Background

This phase I trial was conducted to determine the safety and pharmacokinetics of monoclonal antibody 216, a human monoclonal Immunoglobulin M antibody targeting a linear B-cell lactosamine antigen, administered alone and in combination with vincristine in patients with relapsed or refractory B-cell acute lymphoblastic leukemia, and to preliminarily assess tumor targeting and efficacy.

Design and Methods

Three cohorts of patients received escalating doses of monoclonal antibody 216 administered as an intravenous infusion. In the case of poor response to the first dose of monoclonal antibody 216 alone, defined as less than 75% reduction in peripheral blood blast count, a second dose of the antibody with vincristine was given between days 4 and 7. Responses were assessed weekly until day 35. Serum concentration of monoclonal antibody 216 was measured before and after infusion. Monoclonal antibody 216 targeting was determined with an anti-idiotypic antibody to monoclonal antibody 216 and preliminary efficacy was analyzed by changes in peripheral blood blasts.

Results

Thirteen patients were enrolled. One episode of grade 3 epistaxis was the only dose-limiting toxicity observed. All patients showed a poor response to the first monoclonal antibody 216 infusion with a decrease in peripheral blasts from 6–65% in 9 patients. In 8 patients, addition of vincristine to monoclonal antibody 216 resulted in an average reduction of the peripheral blasts of 81%. One patient without peripheral blasts achieved a hypoplastic marrow without evidence of leukemia after one infusion of monoclonal antibody 216 and monoclonal antibody 216/vincristine each. Monoclonal antibody 216 was detected on peripheral blasts in all patients.

Conclusions

Treatment with monoclonal antibody 216 in combination with vincristine is feasible and well tolerated in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. Binding of monoclonal antibody 216 to leukemic blasts was efficient, and favorable early responses were observed.     

Positron emission tomography response at the time of autologous stem cell transplantation predicts outcome of patients with relapsed and/or refractory Hodgkin's lymphoma responding to prior salvage therapy

Background

High-dose chemotherapy followed by autologous stem cell transplantation is the standard treatment for relapsed and/or refractory Hodgkin’s lymphoma although half of patients relapse after transplantation. Predictive factors, such as relapse within 12 months, Ann-Arbor stage at relapse, and relapse in previously irradiated fields are classically used to identify patients with poor outcome. Recently, 18-fluorodeoxyglucose positron emission tomography has emerged as a new method for providing information to predict outcome. The aim of this study was to confirm the predictive value of positron emission tomography status after salvage therapy and to compare single versus tandem autologous stem cell transplantation in patients with relapsed and/or refractory Hodgkin’s lymphoma.

Design and Methods

We report a series of 111 consecutive patients with treatment-sensitive relapsed and/or treatment-refractory Hodgkin’s lymphoma who achieved complete (positron emission tomography-negative group) or partial remission (positron emission tomography-positive group) at positron emission tomography evaluation after salvage chemotherapy and who underwent single or tandem autologous stem cell transplantation.

Results

Five-year overall and progression-free survival rates were 81% and 64%, respectively. There were significant differences in 5-year progression-free survival (79% versus 23%; P<0.001) and 5-year overall survival (90% versus 55%, P=0.001) between the positron emission tomography-negative and -positive groups, respectively. A complete response, as determined by positron emission tomography evaluation, after salvage therapy predicted significantly better 5-year overall survival rates in both intermediate (91% versus 50%; P=0.029) and unfavorable (89% versus 58%; P=0.026) risk subgroup analyses. In the positron emission tomography-positive subgroup, tandem transplantation improved 5-year progression-free survival from 0% (in the single transplantation group) to 43% (P=0.034). Multivariate analysis showed that positron emission tomography status (hazard ratio: 5.26 [2.57–10.73]) and tandem transplantation (hazard ratio: 0.39 [0.19–0.78]) but not risk factors at relapse (hazard ratio: 1.77 [0.80–3.92]) significantly influenced progression-free survival, while only tomography status significantly influenced overall survival (hazard ratio: 4.03 [1.38–11.75]).

Conclusions

In patients with relapsed/refractory Hodgkin’s lymphoma responding to prior salvage therapy, positron emission tomography response at time of autologous stem cell transplantation favorably influences outcome and enables identification of patients requiring single or tandem transplantation.     

Effects of chromium malate on glycometabolism,glycometabolism‐related enzyme levels and lipid metabolism in type 2 diabetic rats: A dose–response and curative effects study

Aims/Introduction

The present study was designed to evaluate the effect of chromium malate on glycometabolism, glycometabolism-related enzyme levels and lipid metabolism in type 2 diabetic rats, and dose–response and curative effects.

Materials and Methods

The model of type 2 diabetes rats was developed, and daily treatment with chromium malate was given for 4 weeks. A rat enzyme-linked immunosorbent assay kit was used to assay glycometabolism, glycometabolism-related enzyme levels and lipid metabolism changes.

Results

The results showed that the antihyperglycemic activity increased with administration of chromium malate in a dose–dependent manner. The serum insulin level, insulin resistance index and C-peptide level of the chromium malate groups at a dose of 17.5, 20.0 and 20.8 μg chromium/kg bodyweight were significantly lower than that of the model, chromium trichloride and chromium picolinate groups. The hepatic glycogen, glucose-6-phosphate dehydrogenase and glucokinase levels of the chromium malate groups at a dose of 17.5, 20.0 and 20.8 μg chromium/kg bodyweight were significantly higher than that of the model, chromium trichloride and chromium picolinate groups. Chromium malate at a dose of 20.0 and 20.8 μg chromium/kg bodyweight significantly changed the total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides levels compared with the chromium trichloride and chromium picolinate groups.

Conclusions

The results showed that chromium malate exhibits greater benefits in treating type 2 diabetes, and the curative effect of chromium malate is superior to chromium trichloride and chromium picolinate.