Evolving role of ribonucleoside reductase inhibitors in hematologic malignancies

Ribonucleotide reductases catalyze the de novo biosynthesis of deoxyribonucleosides for DNA synthesis. Increased ribonucleotide reductases activity has been associated with malignant transformation and tumor cell growth. The ribonucleotide reductases inhibitors may bind with the R1 subunit of the enzyme (Class 1) or the nonheme iron (Class 2). This review focuses on the therapeutic use of ribonucleotide reductases inhibitors in hematologic malignancies. Hydroxyurea, fludarabine and cladribine have established roles in the management of hematologic malignancies, while other ribonucleotide reductases inhibitors, such as gemcitabine, tezacitabine and heterocyclic carboxaldehyde thiosemicarbazones (e.g., triapine) are being evaluated in clinical trials.     

TNF-alpha targeted therapeutic approaches in patients with hematologic malignancies

Tumor necrosis factor (TNF)-alpha is a major effector and regulatory cytokine with a pleiotropic role in the pathogenesis of several immune-regulated diseases, including graft versus host disease (GVHD) and hematologic malignancies, such as multiple myeloma (MM), myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Curative treatment for the above diseases are not currently available for most patients. Therapeutic approaches inactivating or blocking TNF-alpha are being evaluated in clinical trials. This review describes the development of the soluble TNF-alpha receptor (p75 TNF-R: Fc; etanercept) and other agents inactivating or blocking TNF-alpha in the management of patients with hematologic malignancies. The satisfactory safety profile of etanercept--as demonstrated in patients with autoimmune diseases--has been confirmed in patients with hematologic malignancies and GVHD. Studies to assess whether etanercept, either as a single agent or in combination with cytotoxic and/or immune therapy, may increase response rates and/or survival in patients with MM, MDS, AML and other hematologic malignancies are now warranted.     

Richter syndrome: biology, incidence, and therapeutic strategies

Richter's transformation denotes the development of high-grade non-Hodgkin lymphoma, prolymphocytic leukemia, Hodgkin disease, or acute leukemia in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma. A search of published articles in Medline (PubMed) and abstracts from professional meetings was performed. An electronic database search of patients with CLL at The University of Texas M. D. Anderson Cancer Center (Houston, TX) determined the incidence of Richter syndrome (RS) in patients with CLL between 1992 and 2002. RS occurs in approximately 5% of patients with CLL. The large cells of RS may arise through transformation of the original CLL clone or represent a new neoplasm. RS may be triggered by viral infections, such as Epstein-Barr virus. Trisomy 12 and chromosome 11 abnormalities are more frequent in patients with RS than in the overall population of patients with CLL. Multiple genetic defects, such as mutations of the p53 tumor suppressor gene, p16INK4A, and p21, loss of p27 expression, deletion of retinoblastoma, increased copy number of C-MYC, and decreased expression of the A-MYB gene, have been described. These abnormalities may cause CLL cells to proliferate and-by facilitating the acquisition of new genetic abnormalities-to transform into RS cells. Therapeutic strategies include intensive chemotherapy, monoclonal antibodies, and stem cell transplantation. The response rates range from 5% to 43% (complete response, 5-38%), and the median survival duration ranges from 5 months to 8 months. In conclusion, RS may be triggered by viral infections or by genetic defects. Current treatments are aggressive, but prognosis is poor. Novel curative treatment strategies are needed.     

Activity of interferon-alpha and isotretinoin in patients with advanced, refractory lymphoid malignancies

BACKGROUND: Interferon-alpha (IFN-alpha) and retinoids have shown nonoverlapping toxicity and each has shown antitumor activity in patients with lymphoma. The aim of the current study was to assess the toxicity, safety, and efficacy of IFN-alpha combined with isotretinoin in patients with advanced, refractory lymphoid malignancies. METHODS: Adults with biopsy-proven advanced lymphoid malignancy were treated. Patients with compromised bone marrow function (platelet counts as low as 30 x 10(9)/L) were eligible. Treatment was comprised of IFN-alpha at a starting daily dose of 3 mega units subcutaneously and isotretinoin orally starting at a dose of 1 mg/kg daily in 2 divided doses. RESULTS: Forty-four patients were evaluable. Their median age was 57 years (range, 18-82 years). Eighteen patients had advanced cutaneous T-cell lymphoma, 6 patients had peripheral T-cell lymphoma, 14 patients had Hodgkin disease, and 6 patients had a variety of other lymphoid malignancies. Patients with Hodgkin disease had received a median of 6 previous therapies (range, 3-12 therapies) and patients with other lymphoid malignancies had received a median of 4 previous therapies (range, 1-9 therapies). The median duration of treatment was 4 months (range, 0.25-38 months). The overall response rate was 38.6% (complete response in 5 patients [11.3%] and partial response in 12 patients [27.3%]). The median response duration was 3 months (range, 1-95+ months). The most common toxicities were low-grade fever, flu-like symptoms, and fatigue (IFN-alpha effects); dry mouth and skin and hypertriglyceridemia (cis-retinoic acid effects); and thrombocytopenia (which generally occurred in patients with low baseline platelet counts). CONCLUSIONS: IFN-alpha and isotretinoin combination therapy had antitumor activity and was well tolerated in heavily pretreated patients with lymphoid malignancies.     

Yttrium-90 ibritumomab tiuxetan radioimmunotherapy in Richter syndrome

BACKGROUND: (90)Y ibritumomab tiuxetan is a radioimmunotherapeutic construct that is reported to be an effective treatment for patients with lymphoma. The aim of the current analysis was to evaluate retrospectively the efficacy and safety of (90)Y ibritumomab tiuxetan in patients with Richter syndrome (RS). METHODS: Patients with histologically proven CD20-positive RS and < 25% lymphoma and/or chronic lymphocytic leukemia in the bone marrow were treated. Patients received an imaging dose of (111)In-labeled ibritumomab tiuxetan of 1.6 mg (5.0 mCi of (111)In) intravenously. One week later, they received 0.3 or 0.4 mCi/kg of (90)Y ibritumomab tiuxetan. Rituximab, at a dose of 250 mg/m(2) intravenously, was given immediately before ibritumomab tiuxetan on Days 1 and 8. RESULTS: Seven patients were treated. Their median age was 56 years (range, 44-70 years). The median time to transformation was 7.9 years (range, 0.7-28.4 years). The median number of previous therapies received was five (range, one to seven previous therapies). The median number of previous therapies received for RS was one (range, none to three previous therapies). Six patients were treated previously with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytosine arabinoside. No patient responded to (90)Y ibritumomab tiuxetan therapy. All patients developed disease progression. The median time to disease progression was 41 days (range, 39-89 days). Side effects included hematologic toxicity. Grade 3-4 (according to the second version of the National Cancer Institute Common Toxicity Criteria) thrombocytopenia and neutropenia occurred in 5 patients (71%) and 2 patients (29%), respectively. There was one episode of septic shock in a patient with Grade 4 neutropenia. CONCLUSIONS: (90)Y ibritumomab tiuxetan had no significant antitumor activity and hematologic toxicity was severe in these heavily pretreated patients with RS.     

Gemtuzumab ozogamicin,fludarabine, cytarabine and cyclosporine combination regimen in patients with CD33+ primary resistant or relapsed acute myeloid leukemia

Clinical resistance to gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia (AML) is associated with blast multidrug resistance (MDR) phenotype. A Phase II study of Mylotarg, fludarabine, ara-C and the MDR-modifier, cyclosporine (CSA) (MFAC) was conducted in 32 patients with primary resistant (11, 34%) or relapsed (21, 66%) AML. Nine (28%) patients obtained complete remission (CR), two (6%) CR with incomplete platelet recovery. Overall median survival was 5.3 months, 12-month survival rate 19%. Fourteen patients (44%) developed grade 3/4 hyperbilirubinemia; six (18%) grade 3/4 hepatic transaminitis; three (9%) hepatic veno-occlusive disease (VOD). CSA inclusion in gemtuzumab ozogamicin-based regimens is feasible. MFAC is an effective regimen for refractory AML.     

Comparison of allogeneic stem cell transplantation,high-dose cytarabine,and autologous peripheral stem cell transplantation as postremission treatment in patients with de novo acute myelogenous leukemia

BACKGROUND: Postremission therapy is critical in maintaining complete remission (CR) in patients with de novo acute myelogenous leukemia (AML). The aim of this trial was to compare allogeneic stem cell transplantation (SCT), high-dose cytarabine (ara-C; HiDAC), and autologous SCT as postremission therapy in patients with de novo AML. METHODS: One hundred twenty patients age 相似文献   

Clinical Outcomes of Patients With Breast Cancer in a Phase I Clinic: The M. D. Anderson Cancer Center Experience

PurposePatients with metastatic breast cancer (MBC) refractory to standard therapy have a poor prognosis. We assessed prognostic factors and clinical outcomes for patients with MBC referred to a phase I clinic focused primarily on targeted agents.Patients and MethodsWe reviewed the medical records of sequential patients with MBC who presented to our phase I clinic between September 2004 and May 2008 to assess baseline patient characteristics, overall survival (OS), and clinical benefit.ResultsA total of 92 patients were identified, with a median age of 53 years (range, 28–83 years). The median number of previous therapies was 5 (range, 1–16 therapies). Of 92 patients, 78 were eligible for and offered ≥ 1 phase I clinical trial. With a median follow-up of 7.4 months, the median OS was 6.7 months (95% CI, 5.2–9.7). In multivariate analysis, independent factors predicting shorter survival were ≥ 10 previous treatments (vs. < 10 previous treatments; hazard ratio [HR], 3.27; 95% CI, 1.37–7.81; P = .008), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2/3 (vs. 0/1; HR, 2.92; 95% CI, 1.28–6.66; P = .01), and albumin level < 3.5 g/dL (vs. > 3.5 g/dL; HR, 2.88; 95% CI, 1.41–5.89; P = .004).ConclusionPatients with locally advanced or metastatic breast cancer referred for our phase I studies had a median survival of 6.7 months. Heavily pretreated disease, poor ECOG PS, and/or low albumin levels were associated with significantly shorter survival in a multivariate analysis.