The KAART Trial: a randomized controlled trial of HAART compared to the combination of HAART and \chemotherapy in treatment-naive patients with HIV-associated Kaposi sarcoma (HIV-KS) in KwaZulu-Natal (KZN), South Africa A Mosam, F Shaik, TS Uldrick, GH Friedland, DT Scadden, J Aboobaker, HM Coovadia From 12 International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI) Bethesda, MD, USA. 26-27 April, 2010
907 Background: The combination of anthracyclines and taxanes are effective in the treatment of metastatic breast cancer. Liposomal doxorubicin has been shown to be as effective as doxorubicin with less toxicity, however its efficacy in combination with docetaxel has yet to be determined. Methods: Monthly liposomal doxorubicin (Doxil 30 mg/m2) in combination with weekly docetaxel (30 mg/m2) was evaluated in women with metastatic breast cancer. Cycles were continued until disease progression or unacceptable toxicity. Radiologic assessment was performed every 2 months. The primary outcome was time to progression. Secondary endpoints included overall response rate, median survival and toxicity. Results: Between 12/2002 and 6/2004, 8 women were enrolled. Seven were available for evaluation, 4 with recurrent disease and 3 with a new diagnosis. The mean age was 48 (33–60) years. Three (43%) tumors were ER/PR negative, and 5 (71%) over-expressed her-2/neu. ECOG performance status 0:1:2 was 1:5:1. The median number of cycles was 4 (2–10). Four women stopped due to intolerable toxicity and 3 due to progressive disease. After 2 cycles, 5 (71%) had a partial response, and 2 (29%) had stable disease. The median time to progression was 12 (4.5- 19) months. Once off-study, all women received additional therapy. With a median 14.5 (4–23) month follow-up, there have been no deaths. All patients had Grade 3/4 toxicities, including: stomatitis 4 (57%), neutropenia 3 (43%), infections 3 (43%), and nausea/vomiting 3 (43%). Conclusions: Monthly liposomal doxorubicin plus weekly docetaxel in woman with metastatic breast cancer resulted in an encouraging response, but was poorly tolerated. Further evaluation of this combination with improved supportive care may be warranted. No significant financial relationships to disclose.
Address: 1Mailman School of Public Health, Columbia University, New York. New York, USA, 2Columbia University – South Africa Fogarty AIDS International Training and Research Program, New York, New York, USA, 3PI NCT00380770, 4Department of Dermatology, Doris Duke Medical Research Institute; Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, South Africa, 5Department of Oncology, Doris Duke Medical Research Institute; Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, South Africa, 6Victor Daitz Chair of HIV Research, Doris Duke Medical Research Institute; Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, South Africa, 7Yale University, New Have, Connecticut, USA and 8Harvard Medical School, Boston, Massachusetts, USA * Corresponding author
Background Quality of Life (QOL) assessment is important in oncology studies. Effect of therapy on QOL is important in HIV-KS, as decreasing morbidity is a goal of therapy. This is the first prospective study to evaluate the effect of HAART, +/- chemotherapy, on QOL in African patients with HIV-KS. Within the KAART study, we assessed the impact of HAART over 12 months in all patients, differences in QOL between arms, as well as associations between QOL and several clinical parameters. Methods KAART is a randomized, controlled, open label trial of HAART vs. HAART plus chemotherapy (CXT) in treatment-naive South African patients with HIV-KS. QOL outcomes were assessed prospectively in English or isiZulu using EORTC-QOL30. We evaluated intra-group changes between baseline and month 12 QOL scores (Wilcoxon rank sign test), changes between baseline and month 12 QOL scores between the two groups (Mann-Whitney test), and the relationship between clinical responses and global QOL (Kruskal-Wallis test). Given multiple comparisons, p-values <0.01 are considered statistically significant; 0.01< p <0.05 represent important trends. Results 111 participants had QOL information. Median global health score (perfect score = 100) was 50 at baseline, improving to 67 at month 12 (p<0.001). Significant improvements in median scores from baseline to month 12 were seen in emotional, cognitive, and social scales, but not physical function and role function. Most symptom scales (fatigue, pain, dyspnea, insomnia, appetite, diarrhea, and constipation) showed significant improvement over time. Improvement in nausea was borderline (p=0.03). There were no statistically significant changes over time between arms; however role function (p=0.011) trended toward greater improvement in the CXT arm. Complete or partial response was associated with increased global health scores (p<0.001), while number or severity of adverse events, adherence, HIV viral load, or CD4 count were not. Conclusion African HIV-KS patients benefit significantly in their overall global health status, functioning and symptoms from HAART. Partial and complete responses to therapy are significant predictors of global health, and the role of early chemotherapy in advanced HIV-KS merits further investigation. Improving QOL is an important goal in the treatment of advanced KS in resource-limited settings. QOL results from this study inform treatment paradigms for management of African patients with HIV-KS.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a multisystemic autosomal recessive disease due to primary thymidine phosphorylase (TP) deficiency. To restore TP activity, we performed reduced intensity allogeneic stem cell transplantations (alloSCTs) in two patients. In the first, alloSCT failed to engraft, but the second achieved mixed donor chimerism, which partially restored buffy coat TP activity and lowered plasma nucleosides. Thus, alloSCT can correct biochemical abnormalities in the blood of patients with MNGIE, but clinical efficacy remains unproven.
10073 Background: The response rate in patients with soft tissue sarcomas (STS) treated with the DNA-alkylator temozolomide (TZ) is 15%. DNA methylation dependent silencing of mismatch repair proteins may contribute to TZ resistance by eliminating the tumor cell’s ability to link the recognition of DNA damage caused by alkylating agents with an apoptotic response. Preclinical studies have shown that gene silencing may be reversed with a DNA methyl transferase inhibitor (e.g, azacitidine (AZ)). We hypothesized that sequential AZ treatment followed by TZ would reverse the silencing of mismatch repair proteins in tumors cell, thereby increasing the apoptotic effect of TZ. Methods: Patients with unresectable or metastatic STS, life expectancy >3 months, KPS ≥ 60%, and sufficient hematologic, hepatic, and renal function were enrolled. A standard 3+3 design was used to determine the MTD with levels 1-3 dosed with AZ (SQ days 1-5) 25 mg/m2, 50 mg/m2, and 75 mg/m2 respectively, and TZ (PO days 8-12) constant at 200 mg/m2. Results: Twelve patients (9 male 3 female) were enrolled: 3 in cohort 1, 3 in cohort 2, and 6 in cohort 3. Ages ranged from 41-81, with a median of 57. Diagnoses included: liposarcoma (5), synovial cell sarcoma (1), granular cell tumor (1), desmoplastic round cell tumor (1), pleomorphic sarcoma (1), endometrial stromal sarcoma (1), and leiomyosarcoma (2). The most common toxicities were nausea, thrombocytopenia, hypoalbuminemia, hyperglycemia, and elevated alkaline phosphatase. One DLT (grade 4 neutropenia) was observed at dose level 3. The recommended Phase II dose was determined to be AZ 75 mg/m2 and TZ200 mg/m2. All 6 patients treated on the lower dose levels showed progressive disease after 2 cycles. Of those treated at the highest dose, 2 patients demonstrated progressive disease, 2 demonstrated stable disease and 1 demonstrated a partial response. Conclusions: The combination of TZ plus AZ was well tolerated, and the recommended Phase II dose for the combination is consistent with the conventional single agent doses. An expansion study is being implemented to allow for further analysis of the safety and efficacy of this combination of drugs in patients with STS.
Paradoxical central nervous system immune reconstitution syndrome in acquired immunodeficiency syndrome-related primary central nervous system lymphomaAcquired immunodeficiency syndrome (AIDS)-related primary central nervous system lymphoma (AR-PCNSL) is an Epstein-Barr (EBV)-associated malignancy that occurs in severely immunocompromised human immunodeficiency virus (HIV)-infected patients.Lack of EBV-specific CD4 + T cells contributes to its pathogenesis. 1Although AR-PCNSL incidence in the United States (US) decreased with availability of combination antiretroviral therapy (cART), 26 PCNSL cases per 100,000 person-years continue to occur in persons with AIDS, making up over 10% of US HIV-associated lymphoma cases.Prognosis remains poor, with greater than 75% 2-year mortality. 2Neurological co-morbidities, difficulties distinguishing AR-PCNSL from other CNS pathology, undertreatment of AR-PCNSL and health care disparities may contribute to mortality. 3Central nervous system immune reconstitution inflammatory syndrome (CNS-IRIS) is characterized by neurological deterioration despite immune recovery from an immunodeficient state.In AIDS patients with CNS opportunistic infections (OIs) such as Cryptococcus, John Cunningham (JC) virus or cytomegalovirus (CMV), 4 CNS-IRIS can complicate cART.CNS-IRIS is described as paradoxical when neurological deterioration occurs despite cART and treatment of a known underlying CNS infection.Risk factors include low CD4 + nadir at time of cART initiation and rate of peripheral HIV viral load (VL) decay.Diagnosis is supported by neuroradiological findings and in some cases, evidence of T-cell infiltration in pathological specimens. 5CNS-IRIS is associated with high morbidity and mortality, largely attributed to exacerbated neuroinflammation associated with antigen specific T cells. 6hanges in antigen-presenting cells, exaggerated innate immune responses, and dynamics of CSF HIV viremia may also contribute to CNS-IRIS pathogenesis. 6,7To our knowledge, paradoxical CNS-IRIS has not been previously described in the treatment of AR-PCNSL.We describe the case of a 54-year old man with HIV, not on cART, who presented with several months functional decline and more than two weeks progressively worsening altered mental status.Brain magnetic resonance imaging (MRI) showed a ring-enhancing left basal ganglia lesion with edema and mass effect.CSF examination was remarkable for 98 white blood cells (WBC)/mL and elevated protein.Microbiology studies were negative (Table 1). 8,9Peripheral CD4 + lymphocyte count was 2 cells/uL and HIV VL was 569,422 copies/mL.The patient started cART and was administered two weeks of empiric toxoplasmosis therapy.Despite antibiotics and decreasing HIV VL, he had no neurological improvement.Stereotactic needle brain biopsy was performed.Pathology revealed CD20 + , EBV + malignant lymphoid cells diagnostic of AR-PCNSL.He was referred to the National Cancer Institute (NCI) for treatment.At the NCI, his Eastern Cooperative Oncology Group (ECOG) performance status was 3 due to neurological compromise.Neurological exam demonstrated mixed aphasia, with limited speech production (anomia) and reception (difficulty with complex commands), but relatively preserved repetition.Right arm strength was decreased (4/5 deltoids, biceps and triceps, 2/5 finger extensors).CD4 + count was 52 cells/uL (CD4 + /CD8 + ratio 0.02) and HIV VL 397 copies/mL.Anti-toxoplasmosis antibodies
Roll-out of combination antiretroviral therapy (cART) in South Africa should impact on AIDS-associated Kaposi's sarcoma (KS). Government provision began in 2003, with 23% coverage for World Health Organization (WHO) stage IV AIDS in 2006. To assess the effect of cART availability on KS management, we evaluated records from 701 KS patients seen at a tertiary oncology centre in KwaZulu-Natal, South Africa, from 1995 to 2006. Associations between cART use and measures of KS care were evaluated. cART availability was 0% prior to 2001, 9.6% (2001-2003) and 44% (2004-2006). Documentation of HIV status increased incrementally from 65% to 92%. cART was associated with chemotherapy administration: 56% on cART versus 17% not on cART (P < 0.001); and less loss to follow-up, 13% on cART versus 38% not on cART (P < 0.001). cART availability improves the care of AIDS-associated KS. Further increases in cART availability for this population are needed in South Africa.
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