Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies in pediatric patients with acute myelogenous leukemia (AML) have suggested that 2-chlorodeoxyadenosine (2CdA) is an effective therapeutic agent. Santana et al (J Clin Oncol 1992; 10: 364-370) reported a CR rate of 8/17 (95% Cl 23-72%) in children with relapsed AML and a median first CR of 21 months. The activity of 2CdA in adults with relapsed or refractory leukemia was therefore investigated in a phase I study. In the phase II study, based on biochemical modulation rationale, 2CdA was combined with Ara-C for adults with relapsed AML to test the effectiveness of this combination therapy. In the phase I study 27 patients (25 AML and two MDS) with a median first CR duration of 21 weeks, received 2CdA at doses ranging from 5 to 13 mg/m2/day by continuous infusion (CI) for 7 days. In vitro and ex vivo pharmacologic studies performed to determine the effect of pretreatment with 2CdA on Ara-CTP accumulation in leukemic blasts demonstrated a 50-65% increase in the rate of Ara-CTP accumulation. Based on this biochemical modulation, 2CdA (12 mg/m2/day x 5 days by CI) was combined with Ara-C (1 g/m2/day over 2 h) in a phase II study. Seventeen patients (15 AML, two MDS) with relapsed AML (median 1st CR of 19 weeks) were treated. In the phase I study two patients died before the day 14 marrow (ED). Marrow hypoplasia developed in 16 of the remaining 25. Leukemic regrowth occurred in nine after a median hypoplastic period of 2 weeks (range 1-3 weeks). The other seven patients died with aplastic marrows, median duration of hypoplasia was 2 weeks, range 1-4 weeks. None achieved CR and the median survival was 10.5 weeks. Toxicity generally was mild except for three late occurring cases of grade III or IV renal dysfunction and two cases of tumor lysis syndrome. The MTD was 10.8 mg/m2/day x 7 days. In the phase II study two patients, both with AML, achieved CR (95% CI 1-33%). In both cases leukemia relapsed after 10 weeks and 17 weeks. There was one ED. Most (11/16) cleared their marrow although leukemic infiltrate regrew in six cases. Toxicity was generally mild, with two episodes of grade 2 GI bleeding, one episode of severe renal dysfunction and one case of grade 2 CNS toxicity. We conclude that as a single agent 2CdA at the MTD is a cytoreductive agent but is not sufficient to achieve CR in adults with relapsed AML. While combination of Ara-C with 2CdA increases the Ara-CTP uptake in these heavily treated patients this regimen does not appear to be an improvement over existing modalities.
 ...
PMID:Clinical and laboratory studies of 2-chlorodeoxyadenosine +/- cytosine arabinoside for relapsed or refractory acute myelogenous leukemia in adults. 884 90

Tumor lysis syndrome (TLS) is a well recognized complication of chemotherapy and radiotherapy for leukemia, lymphoma as well as rapidly growing malignancies. Less described is the occurrence of TLS following steroid therapy alone. Herein, we report on a 32-year-old male with myelodysplastic syndrome, characterized by refractory anemia with excess blasts in transformation, who developed acute oliguric renal failure 12 hours after methylprednisolone 1.0 g for presumed autoimmune thrombocytopenia. Laboratory investigations revealed typical findings of TLS, including hyperkalemia, marked hyperuricemia, hyperphosphotemia, hypocalcemia and urine uric acid to creatinine ratio 1.8 (> 1.0). Long hemodialysis (8 hours) was initiated for 3 consecutive sessions. Renal function recovered 1 week later. This case high-lights that single-dose steroid administration in a patient with hematological malignancy may cause the potential life-threatening complications of TLS. Prophylactic management prior to the use of steroid therapy for a variety of purposes is absolutely required in high-risk patients.
 ...
PMID:Steroid-induced tumor lysis syndrome in a patient with preleukemia. 1265 64

Myelodysplastic syndrome (MDS) often transforms into acute leukemia, usually of a myeloid phenotype. However, the transformation of MDS into acute lymphoblastic leukemia (ALL) is extremely rare. We present a case of refractory anemia with excess of blasts (RAEB) that transformed into ALL. MDS (RAEB) was diagnosed in a 68-year-old Japanese woman in August 2001. Two months later, MDS progressed to erythroleukemia (French-American-British [FAB]classification, acute myeloid leukemia [AML]-M6), and in December, 2001, she was treated with combined chemotherapy containing aclarubicin, cytarabine, and granulocyte colony-stimulating factor, which improved her clinical symptoms. However, 1 month after the chemotherapy, she developed ALL. The blasts at that time had a markedly basophilic cytoplasm with multiple cytoplasmic vacuoles, and their morphology mimicked that of ALL-L3. The blasts also expressed CD13, a myeloid marker, in addition to lymphoid markers. Southern-blot analysis revealed rearrangement of the immunoglobulin heavy chain, but no additional chromosomal abnormality characteristic of ALL-L3 was detected. The patient was treated with chemotherapy, but she developed tumor lysis syndrome and died of multiple organ failure. Although the precise mechanism of lymphoid transformation is not yet fully understood, this case clinically supports the nature of MDS as a pluripotent hematopoietic stem cell disorder.
 ...
PMID:Transformation of myelodysplastic syndrome to acute lymphoblastic leukemia: a case report and review of the literature. 1500 42

Tumor lysis syndrome (TLS) is defined by metabolic derangements occurring in the setting of rapid tumor destruction. In acute myelogenous leukemia (AML), TLS frequency, risk stratification, monitoring, and management strategies are based largely on case series and data from other malignancies. A single-center, retrospective cohort study was conducted to estimate TLS incidence and identify TLS predictive factors in a patient population undergoing myeloid leukemia induction chemotherapy. This study included 194 patients, aged 18-86 years, with AML or advanced myelodysplastic syndrome undergoing primary myeloid leukemia induction chemotherapy. Nineteen patients (9.8%) developed TLS. In univariate analysis, elevated pre-chemotherapy values for uric acid (P < 0.0001), creatinine (P = 0.0025), lactate dehydrogenase (LDH) (P = 0.0001), white blood cell (P = 0.0058), gender (P = 0.0064) and chronic myelomonocytic leukemia history (P = 0.0292) were significant predictors. In multivariate analysis, LDH (P = 0.0042), uric acid (P < 0.0001) and gender (P = 0.0073) remained significant TLS predictors. A predictive model was then designed using a scoring system based on these factors. This analysis may lay the groundwork for the development of the first evidence-based guidelines for TLS monitoring and management in this patient population.
 ...
PMID:A predictive model for the detection of tumor lysis syndrome during AML induction therapy. 1675 59

The use of nucleoside analog-based chemo-immunotherapeutic regimens over the last decade has significantly improved outcomes in patients with chronic lymphocytic leukemia (CLL). Nonetheless, virtually all patients with CLL relapse from chemoimmmunotherapy and current available therapies are not curative. Identifying therapies that effectively eliminate CLL cells and lack immunesuppression represent an exciting new therapeutic approach. IMiDs are a class of immunomodulating drugs that increase T-cell and NK-cell directed killing of tumor cells. The first generation molecule is thalidomide followed by a second generation molecule lenalidomide that lacks neurotoxicity and is being explored more extensively in clinical trials. Lenalidomide has been shown to benefit patients with multiple myeloma, myelodysplastic syndromes, and lymphoma. Initial reports in patients with relapsed and refractory CLL have shown promising responses. In a subset of patients with CLL complete responses have been noted. Subsequent studies, however, have suggested that this class of drug can also have serious and potentially life-threatening side effects including myelosuppression, tumor flare reaction and in a small subset of patients tumor lysis syndrome. Tumor flare with both thalidomide and lenalidomide appear to be disease specific to CLL and may reflect clinical manifestation of CLL tumor cell activation. As a consequence of these disease specific effects, the optimal safe dose of lenalidomide in CLL remains to be determined but appears to be lower than that tolerated in other B-cell malignancies. To date, biomarkers for response remain poorly defined and the relationship of clinical benefit to tumor flare is uncertain. This review examines the existing literature on the use of IMiDs in patients with CLL and provides suggestions for future research in this area.
 ...
PMID:Thalidomide and lenalidomide as new therapeutics for the treatment of chronic lymphocytic leukemia. 2005 57

Lenalidomide is an immunomodulatory drug that has shown preliminary activity in the treatment of chronic lymphocytic leukemia (CLL). Much is known about the safety profile of lenalidomide from experience in other hematologic malignancies, such as myelodysplastic syndromes and multiple myeloma. In addition to the known adverse effects associated with lenalidomide (e.g., myelosuppression, rash, fatigue), some unique effects (e.g., tumor flare reactions, tumor lysis syndrome) have arisen during clinical studies of CLL. Typical signs of tumor flare reactions include early onset of painful enlargement of the lymph nodes or spleen, with or without low-grade fever, rash, and bone pain. Management may require nonsteroidal anti-inflammatory drugs or a short course of corticosteroids. Dose delays or reductions usually are not required for tumor flare reactions. Signs of tumor lysis syndrome may include shortness of breath, peripheral edema, generalized weakness, sweating, fever, and tachycardia. Untreated tumor lysis syndrome can result in renal impairment and congestive heart failure. Careful monitoring and appropriate management of treatment-related side effects can help ensure that patients with CLL achieve maximum therapeutic benefit from lenalidomide therapy.
 ...
PMID:Management of patients with chronic lymphocytic leukemia treated with lenalidomide. 2068 5

Lenalidomide is an oral immunomodulatory drug used in multiple myeloma and myelodysplastic syndrome and most recently it has shown to be effective in the treatment of various lymphoproliferative disorders such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma. The mechanism of action of lenalidomide varies depending on the pathology, and in the case of CLL, it appears to primarily act by restoring the damaged mechanisms of tumour immunosurveillance. This review discusses the potential mechanism of action and efficacy of lenalidomide, alone or in combination, in treatment of CLL and its toxic effects such as tumor lysis syndrome (TLS) and tumor flare reaction (TFR), that make its management different from other hematologic malignancies.
...
PMID:Lenalidomide and chronic lymphocytic leukemia. 2416 24

Lenalidomide is an oral immunomodulatory agent approved in relapsed multiple myeloma with dexamethasone, for transfusion-dependent anemia in myelodysplastic syndrome associated with deletion 5q, and in relapsed/progressive mantle cell lymphoma following bortezomib. In recent clinical trials, lenalidomide has shown promising activity in hematologic malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Starting doses and dosing schedules vary by malignancy, with lenalidomide started at a lower dose for CLL than for NHL or multiple myeloma. Certain adverse events (AEs) are common across tumor types (e.g., neutropenia, thrombocytopenia, fatigue), whereas others are more often associated with CLL patients (e.g., tumor lysis syndrome and tumor flare reaction). Effective management requires awareness of these differences as well as appropriate prophylaxis, monitoring, and treatment of AEs. This article reviews the efficacy and safety of lenalidomide in CLL and NHL, focusing on approaches for the advanced practitioner to improve patient quality of life through optimal management of side effects. With these steps, lenalidomide can be administered safely, at the best starting doses and with minimal dose interruptions or reductions across hematologic malignancies.
...
PMID:Approaches to Managing Safety With Lenalidomide in Hematologic Malignancies. 2611 71