Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intravenous busulfan (i.v. BU) has demonstrated safety when administered at 0.8 mg/kg per dose i.v. every 6 hours x 16 doses. We evaluated the safety and pharmacokinetics (PK) of giving the same total daily i.v. BU dose (3.2 mg/kg) either divided as a twice-daily infusion or as a single infusion to patients undergoing hematopoietic stem cell transplantation (HSCT). Twelve patients with hematologic malignant disease were treated; 7 patients had non-Hodgkin's lymphoma, 4 patients had acute myeloid leukemia, and 1 patient had chronic myelogenous leukemia. The first cohort (group A) received, on the basis of actual body weight, i.v. BU at 1.6 mg/kg per dose over 4 hours every 12 hours for 4 days (day -7 to day -4). The second cohort (group B) received 3.2 mg/kg per dose of i.v. BU (same total dose as group A) as a single infusion over 4 hours daily for 4 days. In both groups the i.v. BU was followed by cyclophosphamide 60 mg/kg daily for 2 days (day -3 and day -2). Blood specimens were collected on the first, fifth, and seventh doses for group A and on the first and fourth doses for group B to determine the disposition of i.v. BU. Peripheral blood stem cells (autologous in 7 cases and HLA-matched allogeneic in 5 cases) were given 2 days after completion of cyclophosphamide administration (day 0), and granulocyte colony-stimulating factor 5 microg/kg was started on the same day. GVHD prophylaxis consisted of tacrolimus plus methotrexate for recipients of allogeneic stem cells. One patient developed presumed fungal pneumonia and died of multisystem organ dysfunction on day +21 before hematologic reconstitution could be evaluated. Another was reported to have sudden death of undetermined cause at home on day 40. The remaining patients had engraftment (absolute neutrophil count >500/microL) at a median of 11 days and sustained platelet counts >20,000/microL at a median of 14 days. Significant regimen-related toxicity (grade III-IV) was limited to hepatic toxicity (2 cases) catheter infection (2 cases), epistaxis (3 cases), diarrhea (1 case), anorexia (1 case), mucositis (1 case), hyperglycemia (1 case), pneumonia (1 case), and sepsis (1). In group B there was 1 case of mild venoocclusive disease, which resolved without sequelae. No central nervous system or pulmonary toxicity was noted. Pharmacokinetic parameters, including clearance, half-life, maximum concentration, and area under the curve, demonstrated that the first dose profile was highly predictive of later dose PK profiles. No accumulation of the drug was noted. The change in dosing schedule did not increase toxicity or end-organ damage despite higher plasma concentration-times. Although further study for long-term efficacy is warranted, i.v. BU can be given safely with reproducible results on a twice-daily divided or single-daily dosing schedule to patients undergoing HSCT.
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PMID:Evaluation of safety and pharmacokinetics of administering intravenous busulfan in a twice-daily or daily schedule to patients with advanced hematologic malignant disease undergoing stem cell transplantation. 1237 50

Despite nine studies reporting the results achieved when treating patients with chronic myeloid leukemia (CML) with interferon (rIFNalpha) and cytarabine (araC), the optimal doses and schedule for this combination remain to be determined. Results of imatinib mesylate (STI-571) in chronic phase CML are preliminary, thus, trials of rIFNalpha-2b/araC in CML are of continued interest. We report the results of CALGB study 9013, providing a 10-year follow-up on 88 evaluable previously untreated patients. Cycles of therapy with rIFNalpha-2b and araC sufficient to cause a decline in either the white blood cell (WBC) count to < 2000/microl or platelets to < 50,000/microl were given. The starting dose of rIFNalpha-2b was 5 million units (mu)/m2/day subcutaneously (s.c.) and of araC 10 mg/m2 twice daily s.c. Treatment was discontinued when cytopenia occurred and was restarted when both the WBC and platelet counts had recovered. Bone marrow was obtained regularly for morphologic, cytogenetic and molecular studies. Medians at entry included age 48 years, WBC = 89,900/microl and platelets = 345,000/microl. The performance status was 0 or 1 in 88%; splenomegaly was present in 46%. Fifty five (63%) patients had a complete hematologic response and 10 (11%) had a partial hematologic response for an overall response rate of 74%. Median time to best response was 5.3 months. Median survival for all patients from study entry was 81 months, the 5-year survival probability was 65%. When 28 patients were censored at the time of bone marrow transplantation the median survival was 82 months. Grade 3 anorexia, nausea, vomiting and diarrhea developed in 15, 27, 13 and 7%, respectively. Mild to moderate elevations of transaminases occurred in 42%, and were severe in 5%. Sixty-three patients had adequate follow-up cytogenetic studies: 10 had a complete cytogenetic response (CCyR), 23 partial (PCyR, 50-99% normal cells), 20 minor and 10 no response (CALGB criteria). Thus, the CCyR plus PCyR rate among these 63 patients was 52%. Assuming the 25 patients with no cytogenetic follow-up as non-responders, 38% of the 88 patients had at least a PCyR. The median time to CCyR or PCyR was 5.6 months. The median time to best response in these 33 patients was 10.0 months, and median duration of cytogenetic response was 28 months. Cytogenetic responders had significantly longer survival than non-responders (p = 0.01) using a landmark analysis at 18 months. This intermittent schedule of rIFNalpha-2b/ara-C has a high response rate in patients with CML with acceptable toxicity.
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PMID:Treatment of the chronic phase of chronic myeloid leukemia with an intermittent schedule of recombinant interferon alfa-2b and cytarabine: results from CALGB study 9013. 1269 Nov 41

Non-Hodgkin's lymphoma (NHL) occurring as a synchronous malignancy with chronic myelogenous leukemia (CML) is rare. To our knowledge, this is the first case reported of a patient who developed mantle cell lymphoma (MCL) after therapy with imatinib mesylate for CML. After a 3-year history of CML, the patient developed a lymphocytosis associated with diarrhea, anorexia, and weight loss. Imaging studies revealed abdominal adenopathy and extensive lymphomatous infiltration of the liver, stomach, pancreas, and kidneys. Flow cytometric and cytogenetic studies were consistent with MCL. Fluorescence in situ hybridization (FISH) of the bone marrow revealed a genetically distinct lymphoid neoplasm rather than an extramedullary blast crisis of CML. The development of lung cancer, prostate cancer, CML and MCL in this patient suggests a genetic predisposition, although other factors, including environmental exposures and therapy with imatinib mesylate could have had a contributory or synergistic role in the development of MCL.
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PMID:Blastic mantle cell lymphoma developing concurrently in a patient with chronic myelogenous leukemia and a review of the literature. 1505 16

Imatinib mesylate (Gleevec), Glivec, formerly STI571; Novartis Pharma AG; Basel, Switzerland) is a rationally-designed, molecularly-specific oral anticancer agent that selectively inhibits several protein tyrosine kinases central to the pathogenesis of human cancer. It has demonstrated remarkable clinical efficacy in patients with chronic myeloid leukemia and malignant gastrointestinal stromal tumors. Treatment with imatinib is generally well tolerated, and the risk for severe adverse effects is low. Adverse effects most commonly include mild-to-moderate edema, nausea and vomiting, diarrhea, muscle cramps, and cutaneous reactions. Hepatic transaminase level elevations and myelosuppression occur less frequently and resolve with interruption of imatinib therapy. In general, the incidence and severity of adverse effects tend to correlate with imatinib dose and, in chronic myeloid leukemia patients, the phase of disease; but, patient age and other factors are also associated with some types of reactions. With prompt and appropriate intervention, adverse effects in imatinib-treated patients have proven to be manageable across the spectrum of severity, and they seldom require permanent cessation of therapy. Dose reduction is not usually necessary, and reduction to subtherapeutic levels is not recommended.
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PMID:Indications for imatinib mesylate therapy and clinical management. 1516 82

We describe a patient with chronic myelogenous leukemia who developing severe intestinal bleeding after allogeneic peripheral blood stem cells transplantation (allo-PBSCT). PBSC were obtained from an HLA one-locus mismatch sibling donor. On day 26 after PBSCT, although there was no sign of graft-versus-host disease (GVHD) in either the skin or the liver, diarrhea and severe intestinal bleeding occurred. The histopathological examination of the colon revealed complete denudation of the epithelial cells of the mucosa and no obvious apoptosis. Neither red cell fragments nor hemorrhagic diathesis was seen during this episode and the patient was diagnosed as having GVHD. Methylpredonisolone followed by FK506 may be effective in controlling intestinal bleeding and was used in our patient. Acute GVHD involving only the intestine has rarely been described but when using HLA-mismatched PBSCs, acute GVHD may occur severely and atypically.
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PMID:Graft-versus-host disease confined solely to intestine after allogeneic peripheral blood stem cells transplantation in a patient with chronic myelogenous leukemia. 1520 68

The purpose of this study was to determine dose-limiting toxicities and pharmacokinetics of imatinib in children with refractory or recurrent Philadelphia chromosome-positive (Ph(+)) leukemias. Oral imatinib was administered daily at dose levels ranging from 260 to 570 mg/m(2). Plasma pharmacokinetic studies were performed on days 1 and 8 of course 1. There were 31 children who received 479 courses of imatinib. The most common toxicities encountered, which occurred in less than 5% of courses, were grade 1 or 2 nausea, vomiting, fatigue, diarrhea, and reversible increases in serum transaminases. One patient at the 440-mg/m(2) dose level had dose-limiting weight gain. There were no other first-course dose-limiting toxicities. A maximum tolerated dosage was not defined. Among 12 chronic myeloid leukemia (CML) patients evaluable for cytogenetic response, 10 had a complete response and 1 had a partial response. Among 10 acute lymphoblastic leukemia (ALL) patients evaluable for morphologic response, 7 achieved an M1 and 1 achieved an M2 bone marrow. We observed marked interpatient variability in the pharmacokinetic parameters. In conclusion, we found that daily oral imatinib is well tolerated in children at doses ranging from 260 to 570 mg/m(2). Doses of 260 and 340 mg/m(2) provide systemic exposures similar to those of adults who are treated with daily doses of 400 and 600 mg, respectively.
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PMID:Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: results from a Children's Oncology Group phase 1 study. 1523 74

Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor of the human gastrointestinal tract, is thought to originate from the interstitial cells of Cajal. The mutation of c-kit, cording KIT, is essential in the development of GIST. Imatinib mesylate (IM), an agent for chronic myeloid leukemia, was reported to inhibit tyrosine kinase activity of KIT and to be highly effective for GIST. We report, here, a case of huge gastric GIST who underwent neoadjuvant therapy followed by surgical resection. The patient was a 62-year-old man with GIST in cardia (KIT+, CD34+, mitotic rate 5/50 HPF), whose chief complaint was general fatigue. Because the huge tumor, 7.5 cm in size, directly invaded the pancreas, total gastrectomy with distal pancreatosplenectomy was necessary for curative resection. IM was administered (400 mg/body/day) as a neoadjuvant treatment for down-staging of the tumor. Leucopenia (grade 2) and diarrhea (grade 1) were observed as the adverse effects of IM. Partial response was obtained. He underwent proximal gastrectomy without pancreatosplenectomy since CT no longer showed direct invasion to the pancreas. Histological examination of the resected specimen revealed the extensive degeneration of the tumor, in which tumor cells containing condensed nuclei had decreased remarkably. Interestingly, mitotic rate decreased to 0/50 HPF in the effective area of the resected specimen, indicating that recurrent risk might be decreased. A part of the viable tumor cells, however, had the same feature to that in the biopsied specimen before treatment. The results suggest that the heterogeneity of GIST induces different sensitivity to IM. The postoperative course was uneventful and no sign of recurrence was observed 3 months after surgery. Neoadjuvant therapy with IM may become a useful strategy for GIST, as it reduces the tumor size and decreases the recurrence rate.
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PMID:[A case of gastric GIST treated preoperatively by imatinib mesylate]. 1533 47

Clofarabine (2-chloro-2'-fluoro-deoxy-9-beta-D-arabinofuranosyladenine) is a second-generation nucleoside analog with activity in acute leukemias. As clofarabine is a potent inhibitor of ribonucleotide reductase (RnR), we hypothesized that clofarabine will modulate ara-c triphosphate accumulation and increase the antileukemic activity of cytarabine (ara-C). We conducted a phase 1-2 study of clofarabine plus ara-C in 32 patients with relapsed acute leukemia (25 acute myeloid leukemia [AML], 2 acute lymphoblastic leukemia [ALL]), 4 high-risk myelodysplastic syndrome (MDS), and 1 blast-phase chronic myeloid leukemia (CML).(1) Clofarabine was given as a 1-hour intravenous infusion for 5 days (days 2 through 6) followed 4 hours later by ara-C at 1 g/m(2) per day as a 2-hour intravenous infusion for 5 days (days 1 through 5). The phase 2 dose of clofarabine was 40 mg/m(2) per day for 5 days. Among all patients, 7 (22%) achieved complete remission (CR), and 5 (16%) achieved CR with incomplete platelet recovery (CRp), for an overall response rate of 38%. No responses occurred in 3 patients with ALL and CML. One patient (3%) died during induction. Adverse events were mainly less than or equal to grade 2, including transient liver test abnormalities, nausea/vomiting, diarrhea, skin rashes, mucositis, and palmoplantar erythrodysesthesias. Plasma clofarabine levels generated clofarabine triphosphate accumulation, which resulted in an increase in ara-CTP in the leukemic blasts. The combination of clofarabine with ara-C is safe and active. Cellular pharmacology data support the biochemical modulation strategy.
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PMID:Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. 1548 72

We encountered 2 children with intractable diarrhea after allogeneic hematopoietic stem cell transplantation (SCT). In both cases, salazosulfapyridine (SASP) was administered to treat the diarrhea. One patient was a 14-year-old male with acute myelogenous leukemia who received SCT from a related HLA-identical donor. The leukemia recurred early, and a second SCT from the same donor was performed approximately half a year later. Because intestinal graft-versus-host disease (GVHD) was observed, steroids and octreotide were administered, but the symptoms were not improved. Thereafter, SASP was administered, and the symptoms remitted 9 days later. The other patient was a 12-year-old male with chronic myelogenous leukemia who received SCT from an unrelated HLA-identical donor. Diarrhea and abdominal pain developed early after engraftment and did not respond to either steroids or tacrolimus. Oral administration of SASP was initiated on day 236, and the diarrhea remitted 4 days later without recurrence thereafter. SASP may be effective in children for the digestive system symptoms of chronic GVHD.
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PMID:Experience with the use of salazosulfapyridine for intractable diarrhea after hematopoietic stem cell transplantation. 1564 61

Graft-versus-host disease and disease relapse are the 2 major causes of failure of allogeneic hematopoietic stem cell transplantation (SCT). Ideally, patients who undergo transplantation for malignancies would receive the minimum effective acute graft-versus-host disease (GVHD) prophylaxis to maximize the graft-versus-tumor potential of the allogeneic SCT. Tailoring acute GVHD prophylaxis to the risk for each patient has long been a goal for SCT, but no practical way to adjust acute GVHD prophylaxis has been developed. In murine models of acute GVHD, gut damage from the preparative regimen resulting in the release of many mediators is crucial for initiation of acute GVHD. Using diarrhea as a marker of gut damage, we performed a retrospective study of patients at the Johns Hopkins Hospital given matched sibling transplants for chronic myelogenous leukemia to determine whether gut damage during the preparative regimen is predictive of the development of acute GVHD in humans. Logistic regression models were used to perform the retrospective analysis of the relation of diarrhea during the preparative regimen to a significant acute GVHD grade. This work demonstrated a significant positive correlation between the sum of diarrhea on days 4 to 7 after SCT and acute GVHD and showed a borderline significant positive correlation between the sum of diarrhea on days 1 to 3 and acute GVHD. This is the first correlation demonstrated between gut damage during the preparative regimen and acute GVHD severity in humans. This suggests that damage from the preparative regimen could be used as a marker for the risk of acute GVHD. Prospective trials would have to test whether acute GVHD prophylaxis could be adjusted according to this risk. This may result in a greater graft-versus-tumor effect for patients with less risk of acute GVHD.
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PMID:Gastrointestinal toxicity from the preparative regimen is associated with an increased risk of graft-versus-host disease. 1568 70


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