A Randomized, Double Blind, Placebo-Controlled, Phase 1 Safety, and Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 Seronegative Adults (MTN-026).

Dapivirine (DPV), formulated as vaginal ring, demonstrated HIV risk reduction. MTN-026 explored DPV, formulated as rectal gel, for safety, pharmacokinetics (PK), and acceptability. HIV-uninfected men and women aged 18-45 years were enrolled at United States and Thailand sites and randomized 2:1 to receive DPV 0.05% or placebo gel via rectal applicator. A single-dose phase was followed by seven observed daily doses. Plasma and fluid and tissue from both rectum and cervix were collected at baseline and after the final dose over 72 h for PK, ex-vivo HIV-1 biopsy challenge, histology, and flow cytometry. Twenty-eight participants were randomized; 2 terminated early; 9 were female and 19 male; 12 were white, 11 Asian, 4 black, and 1 other race/ethnicity. Mean age was 28.5 and 34.2 years in the DPV and placebo arms, respectively. Thirty adverse events occurred (all Grade 1 or 2, except one unrelated Grade 3) without study arm differences. DPV rectal tissue concentrations [median (interquartile range)] 0.5-1 and 2 h after a single dose were 256 ng/g [below the lower limit of quantification (BLQ)-666] and BLQ (BLQ-600), respectively, then BLQ (BLQ-BLQ) from 24 to 72 h; concentrations following multiple doses were similar. The largest median DPV plasma concentrations were 0.33 ng/mL (0.15-0.48) after one dose and 0.40 (0.33-0.49) after seven doses. The DPV rectal gel was acceptable and without safety concerns. While DPV plasma concentrations were similar to the vaginal ring, rectal tissue concentrations were well below vaginal ring tissue concentrations, suggesting need for reformulation. Clinical trial number: NCT03239483.

Prevalence and determinants of anal human papillomavirus infection in men who have sex with men and transgender women.

Human papillomavirus (HPV) prevalence varies by population. This study investigated anal HPV type detection risk by country in a population of men who have sex with men (MSM) and transgender women (TW) at risk of HIV. Sexually active HIV-1-uninfected MSM and TW were enrolled at eight sites: four in the United States (US), two in Thailand, one in Peru, and one in South Africa. Baseline anal HPV swabs were collected, and DNA typing was performed. One hundred and ninety-five participants, 76 (42%) from the US, had a mean age of 30.9 years (range 18-64). In 182 participants with results available, anal HPV infection was common with 169 (93%) with ≥1 type, 132 (73%) with ≥1 nine-valent vaccine types, and 66 (36%) with HPV 16. Participants in the US had a higher prevalence of HPV 16 (56%, p = 0.004) and HPV 6 (69%, p < 0.001) compared to the other regions. Stimulant drug use was significantly associated with HPV 6 detection. Anal HPV is highly prevalent in this population of MSM and TW sampled from four countries, with HPV 16 the most commonly detected type. The nine-valent HPV vaccine has the potential to provide significant protection if given prior to exposure.

Risk Factors for Incidence of Sexually Transmitted Infections Among Women in a Human Immunodeficiency Virus Chemoprevention Trial: VOICE (MTN-003).

BACKGROUND: In sub-Saharan Africa, there are limited data on the incidence of sexually transmitted infections (STIs) among women, largely because routine screening for asymptomatic infection is not performed. We conducted a secondary analysis to measure STI incidence rates and determine risk factors for new STI acquisition among women enrolled in the VOICE trial. METHODS: We analyzed data from 4843 women screened for chlamydia, gonorrhoea, syphilis, and trichomonas infection at baseline, annually, at interim visits when clinically indicated and at their study termination visit. Risk reduction counseling and condoms were provided throughout the trial. RESULTS: Twenty percent of evaluable participants had one or more curable STIs at baseline. Over 5660 person-years at risk (PYAR) of observation, incidence rates were 13.8% (95% confidence interval [CI], 12.7-14.8) PYAR for chlamydia, 3.5% (95% CI, 3.0-4.1) PYAR gonorrhea, 0.1% (95% CI, 0.6-1.1) PYAR syphilis, and 6.6% (95% CI, 5.8-7.2) PYAR trichomoniasis. South African sites had the highest incidence of chlamydia. The Uganda site had the highest incidence of gonorrhoea and syphilis, and Zimbabwe the lowest incidence overall. The majority of these cases were diagnosed at a routine scheduled testing visit. In multivariate analysis, positive baseline STI, younger than 25 years, being unmarried, and some alcohol consumption were associated with acquiring a new STI. CONCLUSIONS: We observed high rates of STIs during follow up among women in the VOICE study. Women living in human immunodeficiency virus endemic countries should be screened for common STIs.

Four different regimens of farnesyltransferase inhibitor tipifarnib in older, untreated acute myeloid leukemia patients: North American Intergroup Phase II study SWOG S0432.

We report on 348 patients ≥ 70 years (median age 78 years) with acute myeloid leukemia (>50% with secondary AML) randomized to receive either 600 mg or 300 mg of tipifarnib orally twice daily on days 1-21 or days 1-7 and 15-21, repeated every 28 days (4 treatment regimens). Responses were seen in all regimens, with overall response rate (CR + CRi + PR) highest (20%) among patients receiving tipifarnib 300 mg twice daily on days 1-21. Toxicities were acceptable. Unless predictors of response to tipifarnib are identified, further study as a single agent in this population is unwarranted.

Prognostic implications of additional chromosome abnormalities among patients with de novo acute promyelocytic leukemia with t(15;17).

This retrospective study performed by the Eastern Cooperative Oncology Group and the Southwest Oncology Group enrolled 140 acute promyelocytic leukemia (APL) patients with t(15;17) to determine the influence of additional karyotypic abnormalities on treatment outcome. Karyotypes were centrally reviewed by both study groups. The complete response rate after induction for patients with t(15;17) treated with chemotherapy, or all-trans retinoic acid (ATRA) as induction therapy was not affected by additional cytogenetic aberrations. Disease-free (DFS) and overall survival (OS) were unaffected by additional cytogenetic abnormalities if treatment was chemotherapy without ATRA. Patients with t(15;17) only, treated with ATRA with or without chemotherapy, had an improved DFS (P = 0.06) and a better OS (P = 0.01) compared with ATRA-treated patients with additional cytogenetic abnormalities. Patients with APL and t(15;17) alone are significantly more sensitive to treatment with ATRA than are patients with t(15;17) and additional cytogenetic abnormalities.

A phase 2 study of lenalidomide monotherapy in patients with deletion 5q acute myeloid leukemia: Southwest Oncology Group Study S0605.

Older acute myeloid leukemia (AML) patients with a chromosome 5q deletion have poor outcomes with conventional chemotherapy. This phase 2 study explored the safety and efficacy of single-agent lenalidomide in previously untreated older AML patients with del(5q) who declined standard chemotherapy. Patients were treated with lenalidomide 50 mg daily for 28 days as induction therapy and 10 mg daily for 21 days of a 28-day cycle as maintenance until disease progression or unacceptable toxicity. Among 37 evaluable patients, the median age was 74 years (range, 60-94), 21 (57%) were female, 19 (51%) had prior myelodysplastic syndrome, and 30 (81%) had pretreatment cytogenetic studies evaluated centrally. Six had isolated del(5q), 1 had del(5q) and +8, 23 had complex cytogenetics, and 7 others had del(5q) identified locally. Fourteen patients (38%) completed induction therapy: 7 patients died during induction therapy, 8 had disease progression, 7 had nonfatal adverse events, and 1 entered hospice. Eight patients started maintenance therapy. Five patients (14%) achieved a partial or complete response, 2 with isolated del(5q) and 3 with complex cytogenetics. Relapse-free survival was 5 months (range, 0-19). Median overall survival was 2 months for the entire population. In conclusion, lenalidomide as a single agent has modest activity in older del(5q) AML patients. Southwest Oncology Group Study S0605 is registered at www.clinicaltrials.gov as NCT00352365.

Southwest Oncology Group Study S0530: a phase 2 trial of clofarabine and cytarabine for relapsed or refractory acute lymphocytic leukaemia.

Clofarabine and cytarabine target different steps in DNA synthesis and replication, are synergistic in vivo, and have non-overlapping toxicities, making this combination a potentially promising treatment for acute lymphocytic leukaemia. Thirty-seven patients were treated. The median age was 41 years, 44% of patients were either in ≥2nd relapse or had refractory disease and 59% of patients had poor risk cytogenetics. Six out of 36 patients (17%) achieved a complete remission with or without complete count recovery; median overall survival was 3 months. Nucleoside transporter expression did not predict outcome. This regimen lacked sufficient activity to warrant further testing.

Effect of complete remission and responses less than complete remission on survival in acute myeloid leukemia: a combined Eastern Cooperative Oncology Group, Southwest Oncology Group, and M. D. Anderson Cancer Center Study.

PURPOSE: It is known that complete remission (CR) prolongs survival in acute myeloid leukemia (AML). In 2003, less stringent response categories were introduced, most notably CR with incomplete platelet recovery (CRp). Although the significance of CRp for survival remains unclear, reports of AML trials frequently combine CR with CRp rather than considering CR as a separate entity. PATIENTS AND METHODS: This practice led us to retrospectively examine the effect of CR on outcome in newly diagnosed AML, by using data from 6,283 patients treated on Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group (SWOG) protocols or at M. D. Anderson Cancer Center. This effect was then contrasted with the effect of CRp in the M. D. Anderson Cancer Center cohort. RESULTS: At least 94% of patients receiving cytarabine-based therapy and surviving for more than 3 or 5 years achieved a CR with either initial or salvage therapy; limited data suggest the same for patients receiving initial therapies that did not contain cytarabine. Patients with CR were more likely to live beyond 3 or 5 years than patients with CRp. The likelihood of achieving a CR rather than CRp was greater for patients with AML who had better prognosis. After adjustment for covariates, the relapse-free survival of patients achieving CR was longer than that of patients achieving CRp, whereas patients with CRp survived longer than those with resistant disease. CONCLUSION: Our data indicate that CR is of unique clinical significance and should be reported as separate response in trials of newly diagnosed AML. Nonetheless, our findings validate CRp as a clinically meaningful response.

Sequential phase II Southwest Oncology Group studies (S0112 and S0301) of daunorubicin and cytarabine by continuous infusion, without and with ciclosporin, in older patients with previously untreated acute myeloid leukaemia.

Attempts to overcome multi-drug resistance in acute myeloid leukaemia (AML) have been limited by toxicities. To investigate the effect of reducing peak drug levels, we performed sequential phase II studies using continuous infusion daunorubicin and cytarabine without (AD) and then with ciclosporin (ADC) in older patients with AML. Untreated patients (age 56+ years) received daunorubicin (45 mg/m2 per day for 3 d) and cytarabine (200 mg/m2 per day for 7 d), both by continuous infusion, without (S0112, 60 patients) and then with (S0301, 50 patients) the addition of ciclosporin. Complete response (CR) rates were 38% on S0112 and 44% on S0301. Fatal induction toxicities occurred in 17% and 12% respectively, arising primarily from infection and haemorrhage. Median overall and relapse-free survival was 7 and 8 months for AD respectively, and 6 and 14 months for ADC. Patients with phenotypic or functional P-glycoprotein had somewhat higher CR rates with ADC than AD, although confidence intervals overlapped. In these sequential trials, continuous infusion AD produced CR rates comparable to those with bolus daunorubicin. The addition of ciclosporin did not cause undue toxicities, produced a similar CR rate, and possibly improved relapse-free survival. Further correlate analyses did not identify a subpopulation specifically benefitting from the addition of ciclosporin.

Connective tissue growth factor (CTGF) expression and outcome in adult patients with acute lymphoblastic leukemia.

We compared the gene expression profile of adult acute lymphoblastic leukemia (ALL) to normal hematopoietic and non-ALL samples using oligonucleotide arrays. Connective tissue growth factor (CTGF) was the highest overexpressed gene in B-cell ALL compared with the other groups, and displayed heterogeneous expression, suggesting it might have prognostic relevance. CTGF expression was examined by quantitative reverse transcriptase-polymerase chain reaction (ORT-PCR) on 79 adult ALL specimens. CTGF expression levels were significantly increased in ALL cases with B-lineage (P < .001), unfavorable cytogenetics (P < .001), and blasts expressing CD34 (P < .001). In a multivariate proportional hazards model, higher CTGF expression levels corresponded to worsening of overall survival (OS; hazard ratio 1.36, for each 10-fold increase in expression; P = .019). Further studies are ongoing to confirm the prognostic value of CTGF expression in ALL and to investigate its role in normal and abnormal lymphocyte biology.

The clinical spectrum of adult acute myeloid leukaemia associated with core binding factor translocations.

To better understand the spectrum of adult acute myeloid leukaemia (AML) associated with core binding factor (CBF) translocations, 370 patients with newly diagnosed CBF-associated AML were analysed. Patients' age ranged from 16-83 years (median 39 years) with a slight male predominance (55%); 53% had inv(16); 47% had t(8;21). Patients with t(8;21) tended to be younger (P = 0.056), have lower peripheral blood white cell counts (P < 0.0001) and were more likely to have additional cytogenetic abnormalities (P < 0.0001). Loss of sex chromosome, del(9q) and complex abnormalities were more common among patients with t(8;21), while +22 and +21 were more common with inv(16). Overall, 87% [95% confidence interval (CI) 83-90%] of patients achieved complete response (CR) with no difference between t(8;21) and inv(16); however, the CR rate was lower in older patients due to increased resistant disease and early deaths. Ten-year overall survival (OS) was 44% (95% CI 39-50%) and, in multivariate analysis, was shorter with increasing age (P < 0.0001), increased peripheral blast percentage (P = 0.0006), in patients with complex cytogenetic abnormalities in addition to the CBF translocation (P = 0.021), and in patients with t(8;21) (P = 0.025). OS was superior in patients who received regimens with high-dose cytarabine, a combination of fludarabine and intermediate-dose cytarabine, or haematopoietic cell transplantation.

Gene expression profiling of adult acute myeloid leukemia identifies novel biologic clusters for risk classification and outcome prediction.

To determine whether gene expression profiling could improve risk classification and outcome prediction in older acute myeloid leukemia (AML) patients, expression profiles were obtained in pretreatment leukemic samples from 170 patients whose median age was 65 years. Unsupervised clustering methods were used to classify patients into 6 cluster groups (designated A to F) that varied significantly in rates of resistant disease (RD; P < .001), complete response (CR; P = .023), and disease-free survival (DFS; P = .023). Cluster A (n = 24), dominated by NPM1 mutations (78%), normal karyotypes (75%), and genes associated with signaling and apoptosis, had the best DFS (27%) and overall survival (OS; 25% at 5 years). Patients in clusters B (n = 22) and C (n = 31) had the worst OS (5% and 6%, respectively); cluster B was distinguished by the highest rate of RD (77%) and multidrug resistant gene expression (ABCG2, MDR1). Cluster D was characterized by a "proliferative" gene signature with the highest proportion of detectable cytogenetic abnormalities (76%; including 83% of all favorable and 34% of unfavorable karyotypes). Cluster F (n = 33) was dominated by monocytic leukemias (97% of cases), also showing increased NPM1 mutations (61%). These gene expression signatures provide insights into novel groups of AML not predicted by traditional studies that impact prognosis and potential therapy.

Age and acute myeloid leukemia.

We conducted a retrospective analysis of 968 adults with acute myeloid leukemia (AML) on 5 recent Southwest Oncology Group trials to understand how the nature of AML changes with age. Older study patients with AML presented with poorer performance status, lower white blood cell counts, and a lower percentage of marrow blasts. Multidrug resistance was found in 33% of AMLs in patients younger than age 56 compared with 57% in patients older than 75. The percentage of patients with favorable cytogenetics dropped from 17% in those younger than age 56 to 4% in those older than 75. In contrast, the proportion of patients with unfavorable cytogenetics increased from 35% in those younger than age 56 to 51% in patients older than 75. Particularly striking were the increases in abnormalities of chromosomes 5, 7, and 17 among the elderly. The increased incidence of unfavorable cytogenetics contributed to their poorer outcome, and, within each cytogenetic risk group, treatment outcome deteriorated markedly with age. Finally, the combination of a poor performance status and advanced age identified a group of patients with a very high likelihood of dying within 30 days of initiating induction therapy. The distinct biology and clinical responses seen argue for age-specific assessments when evaluating therapies for AML.

Impact of trisomy 8 (+8) on clinical presentation, treatment response, and survival in acute myeloid leukemia: a Southwest Oncology Group study.

The prognostic impact of trisomy 8, alone or with other clonal aberrations, was evaluated in 849 patients with previously untreated acute myeloid leukemia (AML) who were registered to 5 Southwest Oncology Group trials. At presentation, 108 (12.7%) patients had +8 in their karyotypes, including 43 (5.1%) patients with +8 as the sole aberration; 307 (36.2%) were normal, and 434 (51.1%) had other cytogenetic abnormalities. Patients with +8 were slightly older (P =.033), had lower WBC (P =.011), and had lower percentages of peripheral blasts (P =.0004) than the patients without +8. Median survival time for all patients with +8 was 9.9 months (95% CI, 6.5-12.5), similar to that of "unfavorable" cytogenetics risk groups (8.3 months; 95% CI, 6.8-9.5.) Patients with +8 had significantly lower peripheral blasts (P =.0002), WBC (P <.0001) counts, and decreased overall survival (OS) than patients with normal cytogenetics (9.9 months vs 15.4 months; P =.006). However, survival of patients with +8 as the sole aberration did not differ significantly from those with normal cytogenetics (P =.36). Thus, the trisomy 8 group as a whole had poor survival, which was largely attributable to worsened outcomes among patients whose trisomy 8 was associated with other unfavorable cytogenetic abnormalities.