Anil Tulpule

Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity.

BACKGROUND Proteins of the BCL-2 family regulate clonal selection and survival of lymphocytes, and are frequently overexpressed in lymphomas. Navitoclax is a targeted high-affinity small molecule that inhibits the anti-apoptotic activity of BCL-2 and BCL-XL. We aimed to assess the safety and antitumour activity of navitoclax in patients with lymphoid tumours, and establish the drugs pharmacokinetic and pharmacodynamic profiles. METHODS In this phase 1 dose-escalation study, patients (aged ≥18 years) with relapsed or refractory lymphoid malignancies were enrolled and treated at seven sites in the USA between November, 2006, and November, 2009. A modified Fibonacci 3+3 design was used to assign patients to receive oral navitoclax once daily by one of two dosing schedules: intermittently for the first 14 days of a 21-day cycle (14/21) at doses of 10, 20, 40, 80, 110, 160, 225, 315, or 440 mg/day; or continuously for 21 days of a 21-day cycle (21/21) at doses of 200, 275, 325, or 425 mg/day. Study endpoints were safety, maximum tolerated dose, pharmacokinetic profile, pharmacodynamic effects on platelets and T cells, and antitumour activity. This trial is registered with ClinicalTrials.gov, number NCT00406809. FINDINGS 55 patients were enrolled (median age 59 years, IQR 51-67), 38 to receive the 14/21 dosing schedule, and 17 to receive the 21/21 dosing schedule. Common toxic effects included grade 1 or 2 anaemia (41 patients), infection (39), diarrhoea (31), nausea (29), and fatigue (21); and grade 3 or 4 thrombocytopenia (29), lymphocytopenia (18), and neutropenia (18). On the intermittent 14/21 schedule, dose-limiting toxic effects were hospital admissions for bronchitis (one) and pleural effusion (one), grade 3 increase in aminotransferases (one), grade 4 thrombocytopenia (one), and grade 3 cardiac arrhythmia (one). To reduce platelet nadir associated with intermittent 14/21 dosing, we assessed a 150 mg/day lead-in dose followed by a continuous 21/21 dosing schedule. On the 21/21 dosing schedule, two patients did not complete the first cycle and were excluded from assessment of dose-limiting toxic effects; dose-limiting toxic effects were grade 4 thrombocytopenia (one), grade 3 increase in aminotransferases (one), and grade 3 gastrointestinal bleeding (one). Navitoclax showed a pharmacodynamic effect on circulating platelets and T cells. Clinical responses occurred across the range of doses and in several tumour types. Ten of 46 patients with assessable disease had a partial response, and these responders had median progression-free survival of 455 days (IQR 40-218). INTERPRETATION Navitoclax has a novel mechanism of peripheral thrombocytopenia and T-cell lymphopenia, attributable to high-affinity inhibition of BCL-XL and BCL-2, respectively. On the basis of these findings, a 150 mg 7-day lead-in dose followed by a 325 mg dose administered on a continuous 21/21 dosing schedule was selected for phase 2 study. FUNDING Abbott Laboratories, Genentech, and National Cancer Institute, National Institutes of Health.

Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin's lymphoma associated with human immunodeficiency virus infection

BACKGROUND Reduced doses of cytotoxic chemotherapy or standard-dose therapy plus a myeloid colony-stimulating factor decreases hematologic toxicity and its complications in patients with non-Hodgkins lymphoma associated with infection with the human immunodeficiency virus (HIV). However, the effect of reducing the doses of cytotoxic chemotherapeutic agents on clinical outcome is not known. METHODS We randomly assigned 198 HIV-seropositive patients with previously untreated, aggressive non-Hodgkins lymphoma to receive standard-dose therapy with methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) along with granulocyte-macrophage colony-stimulating factor (GM-CSF; n=94) or reduced-dose m-BACOD with GM-CSF administered only as indicated (n=98). RESULTS A complete response was achieved in 39 of the 94 assessable patients assigned to low-dose therapy (41 percent) and in 42 of the 81 assessable patients assigned to standard-dose therapy (52 percent, P= 0.56). There were no significant differences in overall or disease-free survival; median survival times were 35 weeks for patients receiving low-dose therapy and 31 weeks for those receiving standard-dose therapy (risk ratio for death in the standard-dose group=1.17; 95 percent confidence interval, 0.84 to 1.63; P=0.25). Toxic effects of chemotherapy rated grade 3 or higher occurred in 66 of 94 patients assigned to standard-dose therapy (70 percent) and 50 of 98 patients assigned to low-dose treatment (51 percent, P=0.008). Hematologic toxicity accounted for the difference. CONCLUSIONS As compared with treatment with standard doses of cytotoxic chemotherapy (m-BACOD), reduced doses caused significantly fewer hematologic toxic effects yet had similar efficacy in patients with HIV-related lymphoma. Dose-modified chemotherapy should be considered for most HIV-infected patients with lymphoma.

Phase II Multicenter Study of Bendamustine Plus Rituximab in Patients With Relapsed Indolent B-Cell and Mantle Cell Non-Hodgkin's Lymphoma

PURPOSE Bendamustine HCl is a bifunctional mechlorethamine derivative with clinical activity in the treatment of non-Hodgkins lymphoma. This study evaluated bendamustine plus rituximab in 67 adults with relapsed, indolent B-cell or mantle cell lymphoma without documented resistance to prior rituximab. PATIENTS AND METHODS Patients received rituximab 375 mg/m(2) intravenously on day 1 and bendamustine 90 mg/m(2) intravenously on days 2 and 3 of each 28-day cycle for four to six cycles. An additional dose of rituximab was administered 1 week before the first cycle and 4 weeks after the last cycle. Sixty-six patients (median age, 60 years) received at least one dose of both drugs. RESULTS Overall response rate was 92% (41% complete response, 14% unconfirmed complete response, and 38% partial response). Median duration of response was 21 months (95% CI, 18 to 24 months). Median progression-free survival time was 23 months (95% CI, 20 to 26 months). Outcomes were similar for patients with indolent or mantle cell histologies. The combination was generally well tolerated; the primary toxicity was myelosuppression (grade 3 or 4 neutropenia, 36%; grade 3 or 4 thrombocytopenia, 9%). CONCLUSION Bendamustine plus rituximab is an active combination in patients with relapsed indolent and mantle cell lymphoma.

Phase I/II Clinical and Pharmacokinetic Evaluation of Liposomal Daunorubicin

PURPOSE Since liposomal encapsulation of anticancer drugs may enhance antitumor activity while reducing toxicity in vitro, we evaluated liposomally encapsulated daunorubucin (DaunoXome; Vestar, Inc, San Dimas, CA) for safety, pharmacokinetics, and potential efficacy in patients with AIDS-related Kaposis sarcoma (AIDS-KS). PATIENTS AND METHODS Forty patients with advanced AIDS-KS were accrued. Successive cohorts received DaunoXome at doses of 10, 20, 30, and 40 mg/m2 given once every 3 weeks, and 40, 50, and 60 mg/m2 given once every 2 weeks. Selected KS and solid-tumor patients underwent pharmacokinetic evaluation. RESULTS The area under the plasma concentration curve (AUC) ranged from 16.9 micrograms.h/mL to 375.3 micrograms./mL and the alpha half-life ranged from 7.8 to 8.3 hours at 10 mg/m2 to 60 mg/m2, respectively. Both pharmacokinetic profiles were significantly better compared with free daunorubicin. DaunoXome was well tolerated with no significant alopecia, mucositis, or vomiting. Neutropenia (< 1,000/microL occurred in 17% of cycles and was severe (< 500/microL) in only 2%. Anemia and thrombocytopenia were uncommon. Other adverse events included mild to moderate fatigue, nausea, and diarrhea. Even after cumulative doses greater than 1,000 mg/m2, no significant declines in cardiac function were observed. Twenty-two patients who received 50 and 60 mg/m2 were assessable for tumor response; 12 (55%) had a partial response (PR) or clinical complete response (CR). The median survival duration in all patients was 9 months. Prognostic factors for short survival were low CD4 lymphocyte counts (P = .004) and prior anthracycline therapy (P = .02). CONCLUSION DaunoXome has an improved pharmacokinetic profile compared with free daunorubicin, and is well tolerated. DaunoXome can be given safely at doses up to 60 mg/m2 every 2 weeks and has significant antitumor activity in patients with AIDS-KS.

AIDS-Related Burkitt's Lymphoma Versus Diffuse Large-Cell Lymphoma in the Pre–Highly Active Antiretroviral Therapy (HAART) and HAART Eras: Significant Differences in Survival With Standard Chemotherapy

PURPOSE To compare outcomes of patients with HIV-Burkitts lymphoma (HIV-BL) and HIV-diffuse large-cell lymphoma (HIV-DLCL) after treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or M-BACOD (methotrexate, bleomycin, cyclophosphamide, etoposide) in pre-highly active antiretroviral therapy (HAART) versus HAART eras. PATIENTS AND METHODS Three hundred sixty-three patients with AIDS-related lymphoma diagnosed from 1982 to 2003 were reviewed retrospectively, including 262 in the pre-HAART (HIV-BL, 117; HIV-DLCL, 145) and 101 in the HAART era (HIV-BL, 18; HIV-DLCL, 83). Pre-HAART included those who did not receive HAART, and HAART era included those diagnosed after January 1997 who received HAART. RESULTS There were no significant differences between groups in terms of age, sex, history of injection drug use, prior AIDS, lactate dehydrogenase level, and disease stage at diagnosis. Compared with HIV-BL, HIV-DLCL was associated with significantly lower CD4 counts in the pre-HAART but not the HAART era. Although the overall median survival was similar for both groups in the pre-HAART era (HIV-BL, 6.4 months v HIV-DLCL, 8.3 months; P = .43), survival was significantly worse in patients with HIV-BL in the HAART era (HIV-BL, 5.7 months v HIV-DLCL, 43.2 months; P = .0003). Failure to attain complete remission and CD4 count less than 100 cells/mm(3) independently predicted for poor survival in the pre-HAART era. In comparison, histology of HIV-BL and no attainment of complete remission were independent poor prognostic factors in the HAART era. CONCLUSION Survival of patients with HIV-DLCL has improved in the HAART era, along with CD4 count, whereas survival of similarly treated patients with HIV-BL remained poor. The current practice of using the same regimen for both groups of patients should be re-evaluated.

Paclitaxel Is Safe and Effective in the Treatment of Advanced AIDS-Related Kaposi's Sarcoma

PURPOSE Liposomal anthracyclines are the present standard treatment for advanced AIDS-related Kaposis sarcoma (KS). No effective therapies have been defined for use after treatment failure of these agents. A phase II trial was thus conducted with paclitaxel in patients with advanced KS to assess safety and antitumor activity. MATERIALS AND METHODS A regimen of paclitaxel at a dose of 100 mg/m(2) was given every 2 weeks to patients with advanced AIDS-related KS. Patients were treated until complete remission, disease progression, or unacceptable toxicity occurred. RESULTS Fifty-six patients with advanced AIDS-related KS were accrued. Tumor-associated edema was present in 70% of patients and visceral involvement in 45%. Forty patients (71%) had received prior systemic therapy; 31 of these were resistant to an anthracycline. The median entry CD4(+) lymphocyte count was 20 cells/mm(3) (range, 0 to 358). A median of 10 cycles (range, 1 to 54+) of paclitaxel was administered. Fifty-nine percent of patients showed complete (n = 1) or partial response (n = 32) to paclitaxel. The median duration of response was 10.4 months (range, 2.8 to 26.7+ months) and the median survival was 15.4 months. The main side effects of therapy were grade 3 or 4 neutropenia in 61% of patients and mild-to-moderate alopecia in 87%. CONCLUSION Paclitaxel at 100 mg/m(2) given every 2 weeks is active and well tolerated in the treatment of advanced and previously treated AIDS-related KS. The median duration of response is among the longest observed for any regimen or single agent reported for AIDS-related KS. Paclitaxel at this dosage and schedule is a treatment option for patients with advanced AIDS-related KS, including those who have experienced treatment failure of prior systemic therapy.

The effects of preparations of human chorionic gonadotropin on AIDS- related Kaposi's sarcoma

BACKGROUND Kaposis sarcoma is the most common cancer in patients with the acquired immunodeficiency syndrome (AIDS). Recently, certain preparations of human chorionic gonadotropin (hCG) have been shown to inhibit the growth of Kaposis sarcoma cell lines in vitro and in immunodeficient mice. METHODS After in vitro evaluation of four commercially available hCG preparations, the most active product was evaluated in 36 patients with AIDS-related Kaposis sarcoma. In a phase 1-2 trial, 24 patients received intralesional injections of hCG three times a week for two weeks at doses of 250, 500, 1000, or 2000 IU (6 patients each). In each patient three nodular lesions were injected, two with the drug and one with diluent alone. In a double-blind trial, 12 additional patients were randomly assigned to receive intralesional injections of 2000 IU of hCG or diluent alone (6 patients each; two lesions per patient). At the conclusion of therapy, the lesions were measured, their gross appearance assessed, and biopsy specimens evaluated. RESULTS A.P.L. (Wyeth-Ayerst), which had the most in vitro activity against Kaposis sarcoma cell lines, was selected for the clinical investigation. Treatment with A.P.L. was well tolerated at all doses. In the cohorts given 250, 500, 1000, and 2000 IU, 1, 5, 5, and 10 of the 12 injected lesions responded, respectively (P=0.03 for trend). Complete tumor regression was observed in one lesion each at the 250-IU and 500-IU doses, in two lesions given the 1000-IU dose, and in five lesions given the 2000-IU dose. In the double-blind study, none of the 12 lesions in the six patients injected with diluent had responses, as compared with 10 of the 12 lesions in the six patients injected with hCG (P=0.015). Microscopical evidence of apoptosis was observed only in hCG-treated lesions. The percentage of cells that died increased in a dose-dependent manner (P<0.001). Serum levels of follicle-stimulating hormone (P=0.002) and luteinizing hormone (P=0.001) declined after the last injection of hCG, but there was no effect on these hormones in the diluent-treated patients. CONCLUSIONS The intralesional injection of hCG induces the regression of AIDS-related Kaposis sarcoma lesions in a dose-dependent manner. The response of these tumors appears to be mediated by the induction of apoptosis.

Improving the therapeutic index of anthracycline chemotherapy: focus on liposomal doxorubicin (Myocet).

Anthracyclines are valuable cytotoxic agents in cancer treatment. However, their usefulness is limited by cumulative dose-dependent cardiotoxicity that may manifest as life-threatening congestive heart failure. To avoid cardiotoxicity, the use of doxorubicin is typically capped at a safe cumulative dose. Liposomal formulations may reduce cardiac risks whilst maintaining anti-cancer efficacy. Efficacy and safety studies of non-pegylated liposomal doxorubicin (NPLD) in metastatic breast cancer (MBC) are reviewed, along with studies that examine efficacy and cardiac tolerability in combination with newer agents such as paclitaxel and trastuzumab. These show that cardiac safety of liposomal doxorubicin is similar to that of epirubicin in cumulative dose, but that the formulation, unlike epirubicin, has similar anti-cancer efficacy to doxorubicin at equimolar doses. Liposomal doxorubicin may have a better therapeutic index than non-liposomal anthracyclines. This justifies further studies in patients where cumulative cardiotoxicity is a concern, as does study of its use with other potentially cardiotoxic agents.

Prognostic factors in HIV-related diffuse large-cell lymphoma: before versus after highly active antiretroviral therapy.

PURPOSE To compare the prognostic factors for survival and the validity of the International Prognostic Index (IPI) in patients with HIV-related diffuse large-cell lymphoma (HIV-DLCL) treated with curative intent in the pre-highly active antiretroviral therapy (HAART) era versus the HAART era. PATIENTS AND METHODS We retrospectively reviewed 192 patients with HIV-DLCL diagnosed from 1982 to 2003. Pre-HAART era included 120 patients who did not receive HAART, whereas the HAART era included 72 patients diagnosed after January 1997 who received HAART. RESULTS There were no statistically significant differences in terms of either lymphoma or HIV-related characteristics in the two time periods. The complete response rate improved from 32% in the pre-HAART to 57% in the HAART era (P = .0006), and median survival time improved from 8.3 to 43.2 months (P = .0005). In groups with low-, low-intermediate-, and high-intermediate-risk IPI disease, 3-year overall survival rates were 20%, 22%, and 5% in the pre-HAART era and 64%, 64%, and 50% in the HAART era, respectively. On multivariate analysis, factors independently associated with decreased survival in both periods were increasing IPI scores and failure to attain complete remission, whereas CD4 less than 100 cells/microL predicted shorter survival in only the pre-HAART era. CONCLUSION Prognostic factors and overall survival of patients with HIV-DLCC have changed. Clinical outcomes in patients with HIV-DLCL are now approaching the outcomes of patients with de novo lymphoma.

Liposome-Encapsulated Doxorubicin in Combination With Standard Agents (cyclophosphamide, vincristine, prednisone) in Patients With Newly Diagnosed AIDS-Related Non-Hodgkin's Lymphoma: Results of Therapy and Correlates of Response

PURPOSE To evaluate the safety and efficacy of liposomal doxorubicin (Myocet; Medeus Pharma Ltd, Herts,UK) when substituted for doxorubicin in the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) in patients with newly diagnosed AIDS-related non-Hodgkins lymphoma (AIDS-NHL). Secondary objectives were to assess the impact of HIV viral control on response and survival, and to correlate MDR-1 expression with outcome. PATIENTS AND METHODS Liposomal doxorubicin at doses of 40, 50, 60, and 80 mg/m(2) was given with fixed doses of cyclophosphamide, vincristine, and prednisone every 21 days. All patients received concurrent highly active antiretroviral therapy. NHL tissues were evaluated for multidrug resistance (MDR-1) expression. RESULTS Twenty-four patients were accrued. 67% had high or high-intermediate International Prognostic Index scores; the median CD4 lymphocyte count was 112/mm(3) (range, 19/mm(3) to 791/mm(3)). No dose-limiting toxicities were observed at any level, with myelosuppression being the most frequent toxicity. Overall response rate was 88%, with 75% complete responses (CRs), and 13% partial responses. The median duration of CR was 15.6+ months (range, 1.7 to 43.5+ months). Effective HIV viral control during chemotherapy was associated with significantly improved survival (P =.027), but CRs were attained independent of HIV viral control. MDR-1 expression did not correlate with response, suggesting that the liposomal doxorubicin may evade this resistance mechanism. CONCLUSION Liposomal doxorubicin in combination with cyclophosphamide, vincristine, and prednisone is active in AIDS-NHL, with complete remissions achieved in 75% independent of HIV viral control or tissue MDR-1 expression. HIV viral control is associated with a significant improvement in survival. Additional studies are warranted.