Maintenance Therapy for B-Chronic Lymphocytic Leukemia

Although modern treatment options for B-chronic lymphocytic leukemia (CLL) produce high response rates, virtually all patients relapse, presumably due to the persistence of minimal residual disease (MRD). Novel approaches that maintain response and therefore delay growth of MRD may ultimately improve survival outcomes. In CLL, any type of continued therapy must be not only well tolerated but also convenient to ensure compliance. There has been some exploration of rituximab as maintenance therapy in CLL; however, given its limited clinical activity as a single agent, other options need to be studied. One such agent is the immunomodulatory drug lenalidomide, which has demonstrated clinical activity both in patients with relapsed or refractory CLL and in the frontline setting. Other attractive agents being explored in the maintenance setting include epigallocatechin gallate, curcumin, and the citrus pectin-derived galectin-3 inhibitor GCS-100. These naturally occurring compounds are well tolerated, and they inhibit survival signals in the microenvironment necessary for tumor development, making them well suited for evaluation as maintenance therapy for CLL.

Novel Agents for the Treatment of Chronic Lymphocytic Leukemia

Abstract: Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Currently, the most effective treatment for CLL consists of a combination of fludarabine, cyclophosphamide, and rituximab. Although this approach has encouraging results, patients with CLL eventually relapse and require additional therapies. Many of the current therapeutic regimens for CLL are myelotoxic, immunosuppressive, and associated with infectious complications. Targeted therapies can often minimize these complications. The US Food and Drug Administration has recently approved 2 agents, bendamustine and ofatumumab, for the treatment of CLL. Emerging therapies ranging from new monoclonal antibodies to small molecules that interfere with vital pathways in signal transduction and cell cycle regulation are currently being developed. This article will focus on novel agents in earlier development phases for CLL, including the immunomodulator lenalidomide; monoclonal antibodies, such as lumiliximab, GA-101, and small molecule immunopharmaceuticals; BCL-2 inhibitors, such as oblimersen, obatoclax, and ABT-263; and protein kinase inhibitors, such as flavopiridol, spleen tyrosine kinase inhibitors, and phosphatidylinositol 3-kinase inhibitors.

Umbilical Cord Blood Transplantation

Abstract: mbilical cord blood transplantation (CBT) has been widely used as an alternative source of hematopoietic cell support for stem cell transplant patients. CBT offers several advantages over traditional stem cell sources, such as immediate availability, absence of risk for donors, lower risk of acute graft-versus-host disease, and a less stringent requirement for human leukocyte antigen matching. Recent studies suggest that CBT is a safe and effective strategy for adult patients lacking a suitable related or unrelated donor. However, delayed engraftment and delayed immune reconstitution are significant clinical problems. Novel strategies, such as the use of multiple donors, cotransplantation with accessory cells, ex vivo expansion of cord blood hematopoietic progenitor cells, graft manipulation to improve T-cell recovery, and pharmacologic interventions to restore early thymopoiesis, hold promise to enhance engraftment and immune reconstitution after CBT. These approaches may significantly increase the quality and availability of cord blood for transplantation.

Osteosarcoma: A Review of Diagnosis, Management, and Treatment Strategies

Abstract: Despite significant advancements in the diagnosis and treatment of osteosarcoma to date, overall survival has remained relatively constant for over 2 decades. The challenge in osteosarcoma stems from the extreme variability from one tumor to the next, making it unlikely that a single target approach would be able to address all or even a majority of patients. Awareness, education, and proper referral patterns serve to minimize avoidable errors in diagnosis and treatment. However, it is unlikely that these efforts alone will significantly improve survival outcomes. Modern multi-agent chemotherapy has resulted in the greatest improvement in overall survival to date, and it is very likely that future improvements in survival will arise from combination-targeted chemotherapy in addition to conventional treatment.

A New Anticoagulant for a New Era: Review of Recent Data on Dabigatran Etexilate

Abstract: Dabigatran etexilate is an oral direct thrombin inhibitor that could be administered in fixed doses and does not require laboratory monitoring. It is currently being evaluated through the RE-VOLUTION clinical trials program, which will involve more than 38,000 patients by the time it is completed. These clinical trials will evaluate the efficacy and safety of dabigatran etexilate for several indications. This article will review the clinical development of dabigatran, the published trial data, and the potential indications for this promising oral anticoagulant.

PARP Inhibitors in Breast Cancer

Abstract: The therapeutic implications of DNA damage in cancer therapy have long been appreciated and form the basis of many successful cytotoxic chemotherapy and radiotherapy treatment strategies. A novel class of DNA repair defect targeted therapeutics that inhibit poly (ADP-Ribose) polymerase (PARP) are being rapidly developed in breast cancer based on exciting preliminary clinical activity as single agents in BRCA mutation–associated breast cancer and in combination with chemotherapy in triple-negative breast cancer. Though there is widespread enthusiasm to move these drugs forward quickly, much remains to be understood about the optimal use of the novel agents. Here we review the clinical development of PARP inhibitors in breast cancer and highlight clinical trials in progress. We also provide commentary on a series of outstanding questions in the field, the answers to which will be critical for the successful development of PARP inhibitor–based strategies in early- and late-stage breast cancer.

Preclinical and Clinical Activity of ATP Mimetic JAK2 Inhibitors

Abstract: The discovery of a common Janus kinase 2 (JAK2) point mutation, JAK2V617F, in myeloproliferative neoplasms has generated enormous interest in the development and therapeutic use of small molecule JAK2 inhibitor–targeted therapy in these diseases. A handful of compounds are currently in clinical development in primary myelofibrosis or post-polycythemia vera (PV)/essential thrombocythemia (ET) myelofibrosis. To date, clinical benefit has been demonstrated in terms of reduction of splenomegaly, improvement in constitutional symptoms, and control of leukocytosis. Some of the drugs have also been evaluated in PV and ET, with demonstrated activity against erythrocytosis, thrombocytosis, pruritus, and splenomegaly. However, drug effect on bone marrow fibrosis or JAK2 allele burden has been modest so far. Regardless, it is important to keep in mind that current anti-JAK2 treatment trials constitute only the beginning of many upcoming similar clinical trials, and that it is premature to make generalizations or any form of comparative conclusions regarding drug activity or toxicity.

Early Cervical Neoplasia: Advances in Screening and Treatment Modalities

Abstract: Cervical cancer is one of the most common causes of cancer in women worldwide. However, improvements in screening programs and treatment modalities have significantly reduced the morbidity and mortality of this disease. The discovery that infection with the human papillomavirus is a crucial part of the causative pathway in cervical cancer pathogenesis has revolutionized screening and prompted investigations into alternatives to traditional cytologic evaluation, which may be useful in low-resource settings. Concomitant with improved screening has been a shift towards greater detection of both preinvasive and early-stage neoplastic disease. Earlier detection not only allows for surgical management of disease, with the avoidance of chemotherapy and radiation, but also the possibility of fertility preservation. As surgical technologies advance to encompass minimally-invasive procedures, interventions for early-stage cervical cancer are becoming increasingly effective in disease eradication while permitting patients to maintain their quality of life.

Castleman Disease in the 21st Century: An Update on Diagnosis, Assessment, and Therapy

Abstract: Castleman disease (CD) is a nonclonal lymphoproliferative disorder that can affect single lymph node stations or, alternatively, can be generalized. Interleukin 6 (IL6) plays a pivotal role in the pathophysiology of CD. Human herpesvirus 8 (HHV8), which encodes a viral homolog of IL6, is the driving force in HIV-positive patients. The role of HHV8 in HIV-negative CD is controversial. Historically, the prognosis of patients with generalized or multicentric CD has been thought to be poor. However, CD responds extremely well to monoclonal antibodies directed at the IL6 receptor or IL6 itself, and in general, the long-term outcome of HIV-negative CD is excellent. Important strides forward have also been made in the management of HIV-positive CD.

Phase II Trial of FOLFOX6, Bevacizumab, and Cetuximab in the First-line Treatment of Metastatic Colorectal Cancer

Abstract: Purpose: To examine FOLFOX/bevacizumab/cetuximab in the first-line treatment of metastatic colorectal cancer (mCRC). Methods: Design: Randomized phase II trial aimed at achieving a 60% objective response rate (ORR). Due to frequent cetuximab-related hypersensitivity reactions the trial was amended to a single-arm design. Eligibility: Previously untreated mCRC, measurable disease, Eastern Cooperative Oncology Group performance status (ECOG-PS) 0–1. Treatment: Modified FOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 350 mg, and 5-fluorouracil 400 mg/m2 bolus; 2.4 g/m2 infusion, 46 h) day 1; bevacizumab 5 mg/kg on day 1; cetuximab 400 mg/m2 on day 1, then 250 mg/m2 on days 1 and 8, every 14 days (1 cycle) until progressive disease (PD); restaging occurred every 4 cycles. Results: With emerging negative progression-free survival (PFS) data from a similarly designed trial, this trial closed early. Enrollment (N=31) was from August 2005–June 2008. Patient characteristics: Median age was 55 years (29–78); 58% were male; 71% were ECOG-PS 0. Ten cycles (median) were completed (range 2–62). The ORR was 55% (95% confidence interval [CI], 36–73%); 11 patients (35%) had stable disease; 1 patient (3%) had PD; 2 patients (6%) were unevaluable. Median PFS was 9 months (95% CI, 8.3–15.2 months); median overall survival was 25.7 months (95% CI, 15.4–27.6 months). Grade 3/4 toxicities (>1 patient) included neutropenia (25%), rash (23%; grade 2 events, 45%), diarrhea (19%), fatigue (16%), pain (16%), anemia (13%), sensory neuropathy (13%), deep-vein thrombosis (10%), nausea (10%), pulmonary embolism (7%), anorexia (6%), and vomiting (6%). Conclusion: In this limited trial, it is unclear whether cetuximab contributed to FOLFOX/bevacizumab efficacy, although the response rate, PFS, and overall survival were high. The regimen was generally well-tolerated, with expected skin effects; thromboembolic rates should be assessed in larger analyses. Cetuximab’s role in first-line mCRC treatment is likely best guided by K-RAS testing in future clinical trials.

FLT3 Inhibitors for the Treatment of Acute Myeloid Leukemia

Abstract: The fms-like receptor tyrosine kinase-3 (FLT3), which is important for the normal development of hematopoietic stem cells and cells of the immune system, is frequently mutated in patients with acute myeloid leukemia (AML). FLT3 is, therefore, a potential therapeutic target in AML. Recently, FLT3 inhibitors have shown therapeutic activity in AML patients with FLT3 mutations. Sorafenib and sunitinib were the first FLT3 inhibitors to be studied in the clinic and have the most clinically relevant data. Limited data are available for midostaurin (PKC412), lestaurtinib (CEP-701), tandutinib (MLN518), AC220, and KW-2449. It is likely that optimal application of these agents will involve combinations of inhibitors and combinations of inhibitors and chemotherapy, potentially with a mammalian target of rapamycin inhibitor such as everolimus or temsirolimus. This review discusses the theoretical rationale for the use of these agents and summarizes the relevant clinical data.

BRAF Testing in Advanced Colorectal Cancer: Is It Ready for Prime Time?

Abstract: iven that KRAS mutant colorectal tumors do not respond to anti-EGFR monoclonal antibodies such as cetuximab or panitumumab, it is now standard that all patients with metastatic colorectal cancer who are candidates for these therapies undergo KRAS testing. BRAF encodes a protein kinase, which is involved in intracellular signaling and cell growth and is a principal downstream effector of KRAS. BRAF is now increasingly being investigated in metastatic colorectal carcinoma. BRAF mutations occur in less than 10–15% of tumors and appear to be poor prognostic markers. However the predictive nature of this biomarker is yet undefined. This article will review the evidence behind both KRAS and BRAF testing in metastatic colorectal cancer.

Multimodality Therapy: Bone-targeted Radioisotope Therapy of Prostate Cancer

Abstract: Accumulating data suggest that bone-seeking radiopharmaceuticals can be used to treat prostate cancer bone metastasis and improve the clinical outcome of patients with advanced prostate cancer. It remains to be elucidated whether radiopharmaceuticals enhance the disruption of the onco-niche or the eradication of micrometastatic cells in the bone marrow. The purpose of this review is to investigate the role of bone-targeted radioisotope therapy in the setting of multimodality therapy for advanced prostate cancer. We examine available data and evaluate whether dose escalation, newer generations, or repeated dosing of radiopharmaceuticals enhance their antitumor effects and whether their combination with hormone ablative therapy, chemotherapy, or novel targeted therapy can improve clinical efficacy.

Daptomycin Use in Patients With Cancer and Neutropenia: Data From a Retrospective Registry

Clinical data for daptomycin in the treatment of neutropenic cancer patients with documented gram-positive infections are
limited. For this study, neutropenic patients were identified from an ongoing retrospective registry (Cubicin Outcome Registry and Experience [CORE]; 2006 program year). Clinical outcomes included cure, improved, failed, and nonevaluable response, and were assessed at the end of daptomycin therapy. Patients who had a nonevaluable clinical response were only included in the safety analysis. Eighty-four patients were identified, of which 72 (86%) were clinically evaluable. Thirty-four (47%) evaluable patients had severe neutropenia (<100 cells/mm3). Hematologic malignancies were most common (82%). Bacteremia was the most common infection (76%), and vancomycin-resistant enterococci (50%), coagulase-negative staphylococci (24%), and Staphylococcus aureus (11%) were the most common pathogens isolated. Sixty-three patients (88%) received prior antibiotics, including vancomycin (83%), cefepime (17%), and linezolid (16%). The overall success rate (cure + improved) was 90%. Success rates stratified by degree of neutropenia were 85% for patients with less than 100 cells/mm3, 93% for those with 100–499 cells/mm3, and 100% for those with 500–1,000 cells/mm3. The median final daptomycin dose was 6 mg/kg (range, 3–8) and the median duration of therapy was 13 days (range, 1–86). Of the 84 patients analyzed for safety, 24 (29%) developed 44 adverse events; only 5 (6%) patients had adverse events possibly related to daptomycin. The results suggest that daptomycin may be useful for specific cases involving neutropenic patients, and comparative clinical trials are feasible.

Chemotherapy Resistance Abrogation in Metastatic Melanoma

Melanoma is rapidly increasing in incidence throughout the world. Based on American Cancer Society estimates, there will have been approximately 68,720 new cases of invasive melanoma diagnosed in 2009 in the United States. The increase in melanoma incidence has not been paralleled by the development of new therapeutic agents with a significant impact on survival. The promise of targeted therapy has not yet been brought to bear, making chemotherapy with alkylating agents the mainstay of therapy of metastatic melanoma despite the dismally low response rates. The resistance of tumors to these agents is in part due to DNA repair mechanisms that allow cells to survive alkylation damage. Several novel agents targeting the abrogation of DNA repair pathways alone and in combination with cytotoxic agents have been developed with varying measures of success. This review summarizes the current knowledge of the dysregulation of DNA repair pathways as mechanisms of resistance to chemotherapy in melanoma and their potential as targets for novel developmental therapeutics.

Renal Cell Carcinoma Therapy in 2010: Many Options With Little Comparative Data

As a component of the American Recovery and Reinvestment Act of 2009, comparative effectiveness (CE) studies have been established as a priority in medical research. In the setting of metastatic renal cell carcinoma (mRCC), the theme of CE research is particularly applicable, given the recent approvals of several targeted agents with somewhat overlapping indications. Herein, ongoing comparative clinical trials are discussed that may resolve clinical equipoise in using these agents. Furthermore, ongoing biomarker analyses are reviewed that may ultimately identify subpopulations with unique benefit from specific targeted therapies. Finally, available cost-effectiveness data for targeted therapies in mRCC are presented. The amalgam of these studies may offer the oncologist greater clarity in clinical decision-making.

The Rationale for the Use of Non-platinum Chemotherapy Doublets for Metastatic and Recurrent Cervical Carcinoma

Ongoing drug discovery and synergy in cytotoxic combinations have served as the dominant theme for clinical research in women with metastatic and recurrent cervical cancer. The results of the most recent phase III randomized clinical trials conducted by the Gynecologic Oncology Group in this population evaluated the tolerability and efficacy of cisplatin-based chemotherapy doublets. Possibly as a consequence of the increasing use of radiosensitizing cisplatin with concurrent pelvic radiotherapy for treatment of locally advanced disease prior to recurrence, the response rates obtained with platinum-based regimens have decreased with each successive trial. There is clearly a need for a re-appraisal of therapeutic options for women with recurrent and metastatic cervical cancer, many of whom may harbor platinum-resistant clones. In this article we will provide a rationale for the use of non-platinum–based chemotherapy doublets for this patient population.

First-line Use of EGFR Tyrosine Kinase Inhibitors in Patients With NSCLC Containing EGFR Mutations

While the small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib have modest clinical benefit in unselected patients with non–small cell lung cancer after platinum-based chemotherapy, an emerging and potentially more elegant strategy is to move these agents to the frontline setting for select patients. Those with somatic mutations in EGFR respond dramatically to EGFR inhibitors, and mounting evidence from recent clinical trials, particularly the Iressa Pan-Asia Study (IPASS) trial, confirms superior response rates, progression-free survival, and tolerability with this targeted therapy compared with conventional chemotherapy. Here, we review the studies supporting the use of EGFR tyrosine kinase inhibitors in the frontline setting in
patients with EGFR mutations.

Hypomethylating Agent Induction Therapy Followed By Hematopoietic Cell Transplantation Is Feasible in Patients With Myelodysplastic Syndromes

Disease remission in patients with myelodysplastic syndromes can be achieved with azanucleosides, which act as pyrimidine analogs and hypomethylating agents. However, despite treatment with azanucleoside induction, patients with myelodysplastic syndromes nearly always relapse. Allogeneic hematopoietic cell transplantation (HCT) can be curative, but it is risky. Given that azanucleosides affect human leukocyte antigen expression and lymphocyte reactivity, we conducted a retrospective study to define the impact of pre-HCT azanucleoside therapy on post-HCT donor chimerism. Patients receiving azanucleoside induction therapy achieved rapid and high levels of donor chimerism post-transplant. Lineage analysis also found rapid donor chimerism of lymphocyte and granulocyte subsets. These data indicate the feasibility of pretransplant azanucleoside therapy in patients who subsequently receive an HCT.

Highlights from the 32nd Annual San Antonio Breast Cancer Symposium December 9–13, 2009 San Antonio, Texas

Highlights from the 32nd Annual San Antonio Breast Cancer Symposium December 9–13, 2009 San Antonio, Texas Breast Cancer In Focus A Comparison of Denosumab Versus Zoledronic Acid for the Prevention […]