Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease.

BACKGROUND: The up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease. METHODS: In this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient-reported outcomes were also assessed. RESULTS: A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active-treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain. CONCLUSIONS: In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN ClinicalTrials.gov number, NCT01895361 .).

Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial.

BACKGROUND: Chronic immune thrombocytopenic purpura (ITP) is characterised by accelerated platelet destruction and decreased platelet production. Short-term administration of the thrombopoiesis-stimulating protein, romiplostim, has been shown to increase platelet counts in most patients with chronic ITP. We assessed the long-term administration of romiplostim in splenectomised and non-splenectomised patients with ITP. METHODS: In two parallel trials, 63 splenectomised and 62 non-splenectomised patients with ITP and a mean of three platelet counts 30x10(9)/L or less were randomly assigned 2:1 to subcutaneous injections of romiplostim (n=42 in splenectomised study and n=41 in non-splenectomised study) or placebo (n=21 in both studies) every week for 24 weeks. Doses of study drug were adjusted to maintain platelet counts of 50x10(9)/L to 200x10(9)/L. The primary objectives were to assess the efficacy of romiplostim as measured by a durable platelet response (platelet count > or =50x10(9)/L during 6 or more of the last 8 weeks of treatment) and treatment safety. Analysis was per protocol. These studies are registered with ClinicalTrials.gov, numbers NCT00102323 and NCT00102336. FINDINGS: A durable platelet response was achieved by 16 of 42 splenectomised patients given romplostim versus none of 21 given placebo (difference in proportion of patients responding 38% [95% CI 23.4-52.8], p=0.0013), and by 25 of 41 non-splenectomised patients given romplostim versus one of 21 given placebo (56% [38.7-73.7], p<0.0001). The overall platelet response rate (either durable or transient platelet response) was noted in 88% (36/41) of non-splenectomised and 79% (33/42) of splenectomised patients given romiplostim compared with 14% (three of 21) of non-splenectomised and no splenectomised patients given placebo (p<0.0001). Patients given romiplostim achieved platelet counts of 50x10(9)/L or more on a mean of 13.8 (SE 0.9) weeks (mean 12.3 [1.2] weeks in splenectomised group vs 15.2 [1.2] weeks in non-splenectomised group) compared with 0.8 (0.4) weeks for those given placebo (0.2 [0.1] weeks vs 1.3 [0.8] weeks). 87% (20/23) of patients given romiplostim (12/12 splenectomised and eight of 11 non-splenectomised patients) reduced or discontinued concurrent therapy compared with 38% (six of 16) of those given placebo (one of six splenectomised and five of ten non-splenectomised patients). Adverse events were much the same in patients given romiplostim and placebo. No antibodies against romiplostim or thrombopoietin were detected. INTERPRETATION: Romiplostim was well tolerated, and increased and maintained platelet counts in splenectomised and non-splenectomised patients with ITP. Many patients were able to reduce or discontinue other ITP medications. Stimulation of platelet production by romiplostim may provide a new therapeutic option for patients with ITP.

Predictors of toxicity and toxicity profile of adjuvant chemotherapy in elderly breast cancer patients.

Women older than 70 years have been underrepresented in breast cancer adjuvant chemotherapy trials due to concerns about toxicity, safety and tolerance of chemotherapy. The aim of our study was to assess the tolerance of chemotherapy in older women with breast cancer and determine patterns of toxicity including the impact of age, chemotherapy regimen, functional status and comorbid conditions on this toxicity. We retrospectively reviewed the charts of early stage (stages 1 and 2) breast cancer patients older than 70 years from 1998 to 2004. A total of 62 patients, with mean age of 74.3 years, were identified. Chemotherapy was completed in 89% patients. Overall 79% completed chemotherapy without any significant side-effects, dose reductions, or breaks during chemotherapy. Using logistic regression model increasing age was not associated with early termination of chemotherapy (p = 0.19, OR: 0.868, 95% CI: 0.7-1.076). However, increasing age, lower functional status, and higher comorbidity index scores were associated with reduction in dose and breaks in chemotherapy. None of the patients who received pegfilgrastim prophylactically developed high-grade neutropenia. Our study suggests that adjuvant chemotherapy is safe in elderly patients. Older patients with good functional status and low comorbidity index scores tolerate chemotherapy as well as the younger patients. Prophylactic use of pegfilgrastim may reduce occurrence of severe neutropenia and related toxicity such as febrile neutropenia in the elderly patient.

Breast Cancer Litigation: An Update with Practice Guidelines.

Cases involving breast cancer are the second most common cause of malpractice litigation. The leading allegation is failure to diagnose, followed by improper treatment. The most common physicians involved are those giving direct care to women: obstetricians/gynecologists, family medicine physicians, and internists. This review addresses frequent areas of litigation, offering practice guidelines for avoidance of malpractice claims. In addition, two new areas of breast cancer management will be reviewed-breast cancer prevention and breast cancer genetic testing-as potential new areas of malpractice litigation.

Phase II trial of idiotype vaccination in previously treated patients with indolent non-Hodgkin's lymphoma resulting in durable clinical responses.

PURPOSE: To evaluate idiotype (Id) vaccination as a single agent in previously treated patients with indolent non-Hodgkin's lymphoma. PATIENTS AND METHODS: Patients underwent biopsy for determination of their lymphoma-specific Id sequence. Recombinant Id protein was manufactured and covalently linked with keyhole limpet hemocyanin (KLH) to generate Id/KLH. Patients received Id/KLH 1 mg on day 1 subcutaneously, with granulocyte-macrophage colony-stimulating factor 250 mug on days 1 to 4, monthly for 6 months. Booster injections were administered until progression. Both clinical and immune responses were evaluated. RESULTS: Thirty-two previously treated patients received at least one injection of Id/KLH, and 31 were assessed for efficacy. Responses were observed in four patients (one complete response and three partial responses). Median time to onset of response was 5.9 months (range, 2.3 to 14.1 months). Median duration of response has not been reached but should be at least 19.4 months (range, 10.4 to 27.2+ months). Median time to progression is 13.5 months. The most common adverse events were mild to moderate injection site reactions. Six (67%) of nine patients tested demonstrated a cellular immune response, and four (20%) of 20 patients demonstrated an antibody response against their Id. CONCLUSION: This trial demonstrates that Id/KLH alone can induce tumor regression and durable objective responses. Further study of Id/KLH is recommended in other settings where efficacy may be further enhanced as in first-line therapy or after cytoreductive therapy.

Intramedullary spinal cord metastasis in breast cancer: clinical features, diagnosis, and therapeutic consideration.

Intramedullary spinal cord metastases (ISCMs) are very rare, but can cause devastating complications from underlying breast cancer. We report the case of a woman with known metastatic breast cancer and progressive neurologic deterioration caused by an ISCM. The epidemiology, pathogenesis, clinical presentation, diagnostic considerations, and therapeutic options are discussed.

HIV-associated primary cervical non-Hodgkin's lymphoma and two other cases of primary pelvic non-Hodgkin's lymphoma.

BACKGROUND: Although there have been few case series of primary pelvic non-Hodgkin's lymphoma (NHL) reported over the past two decades, no patient with acquired immunodeficiency syndrome (AIDS)-related primary pelvic NHL has been reported. CASE: We report a human immunodeficiency virus (HIV)-infected patient with primary cervical NHL. After surgical biopsy, she received standard NHL combination chemotherapy plus standard HIV highly active antiretroviral therapy (HAART), and remains disease free 38 months since therapy. We also report two other cases of primary pelvic NHL. CONCLUSIONS: Primary pelvic NHL is rare, with clinical presentation similar to other common gynecologic malignancies. It is treated with combination chemotherapy and pelvic radiotherapy, and generally has good prognosis. Adding HAART to other standard therapies for patients with AIDS-related pelvic lymphoma may improve the prognosis of this category of patients.

Pharmacokinetics of doxorubicin administered i.v. as Myocet (TLC D-99; liposome-encapsulated doxorubicin citrate) compared with conventional doxorubicin when given in combination with cyclophosphamide in patients with metastatic breast cancer.

Myocet (TLC D-99) is a liposomal formulation of the anti-neoplastic drug doxorubicin with an improved therapeutic index compared with conventional doxorubicin. The objective of this study was to assess the plasma disposition of doxorubicin when administered i.v. as TLC D-99 and to compare this to conventional drug. Metabolite (doxorubicinol) plasma levels were also quantitated in both treatment groups. Plasma was collected during the first course of treatment from 10 patients receiving TLC D-99 60 mg/m and 10 receiving conventional doxorubicin 60 mg/m2, each with cyclophosphamide 600 mg/m2. Samples were assayed for total doxorubicin (all doxorubicin regardless of whether it is encapsulated or not), encapsulated doxorubicin (TLC D-99 group only) and doxorubicinol using high-performance liquid chromatography. Plasma concentrations of total doxorubicin were higher in patients receiving TLC D-99 than in patients receiving conventional doxorubicin. The clearance of total doxorubicin after administration of TLC D-99 was lower (approximately 9-fold) and the volume of distribution at steady state was less (25-fold) than that of doxorubicin after conventional drug. Doxorubicinol was detected in the plasma of all patients in both treatment groups. The mean AUC(0-infinity) of doxorubicinol for patients receiving TLC D-99 (1.5+/-0.4 M x h) was not statistically different than that in patients receiving conventional doxorubicin (1.8+/-0.4 M x h), although the appearance of the peak doxorubicinol concentration occurred later and was lower in patients receiving TLC D-99. There was a correlation between the plasma AUC(0-infinity) of total doxorubicin and the degree of myelosuppression in patients receiving conventional doxorubicin, but this correlation was not found in patients receiving TLC D-99.

Initial management of immune thrombocytopenic purpura in adults: a randomized controlled trial comparing intermittent anti-D with routine care.

We conducted a randomized clinical trial in adults with a new diagnosis of ITP and a platelet count <30000/muL to test the hypothesis that initial intermittent treatment with anti-D may avoid or defer the need for splenectomy when compared to current routine care (glucocorticoid treatment, followed by splenectomy). Splenectomy was to be performed in the anti-D group if patients failed to respond to three consecutive anti-D treatments given within 10 days. The incidences of splenectomy were 14 of 37 (38%) in the routine care group and 14 of 33 (42%) in the anti-D group (absolute risk reduction = 4.6% in favor of the routine care group, 95% CI, -18.4 to 27.6%). However, splenectomy was performed prematurely, not according to the protocol, in 11 of 14 patients in the anti-D group. The median time to splenectomy was 36 days (range, 9-78) in the routine care group and 112 days (range, 19-558) in the anti-D group (P = 0.045 at 100 days after randomization, P = 0.840 at 1 year after randomization, using log-rank analysis). Patients in the anti-D group were treated with prednisone for fewer days (70 days) compared to the routine care group (112 days, P = 0.01). No major bleeding events occurred. In this study, initial treatment of patients with intermittent anti-D initially deferred splenectomy. Whether our aggressive regimen of anti-D could have prevented splenectomy if it had been adhered to in all patients remains uncertain. However, compliance with this anti-D regimen was not feasible for many patients and/or their physicians.