Q12 Hours Research Articles

Infectious Morbidity and Hospitalization Requirements of Patients with Acute Myeloid Leukemia Receiving Intensive Outpatient Consolidation.

Limited inpatient resources have focused interest upon the outpatient administration of intensive post-remission consolidation of acute myeloid leukemia (AML). Experience is limited in this regard (Blood 2002, 100:766a). In August 2001 a program of post-remission outpatient consolidation was instituted in our centre. A total of 68 cycles were administered to 35 patients with AML over 36 months. Standard prophylaxis included ciprofloxacillin and acyclovir. Our study was designed to look at infectious complications and requirement for hospitalization. Median age of patients was 54.5 years (range 20–77). Chemotherapy consisted of either high-dose cytarabine (1.5gm/m2 q12 hours x 12 doses in patients < 60 yrs) in 39 cycles, or intermediate-dose cytarabine (0.5gm/m2 q12 hours x 12 doses in patients >60 yrs) in 29. Upon completion of chemotherapy, patients continued to be evaluated daily on an ambulatory basis. Granulocyte colony stimulating factor was initiated on day eight of each cycle, along with blood product support. Median time to an absolute neutrophil count of ≥0.5 x 109/L, was 19.8 days (15–35). Only 26/68 (38%) required admission, with a median hospital stay of 19.7 days (5–96). A febrile neutropenic event (FNE) occurred in 46/68 (68%) cycles of outpatient consolidation, with blood cultures revealing a causative microorganism in 27/46 (59%). Viridans group Streptococci were the most common pathogen isolated, accounting for 12 cases, while Gram negative organisms were found in 5 patients. 15/46 (33%) patients were admitted to hospital at the onset of their FNE with 3 requiring inotropic support and endotracheal intubation. All three had septic shock and acute respiratory distress syndrome with documented Streptococcus mitis bacteremia; one of these patients died while the other two recovered fully. 31/46 (67%) cases of FNE were treated initially with outpatient antimicrobial therapy. The most commonly used empiric antibiotic regimen was vancomycin and ceftriaxone. 23/46 (50%) episodes of FNE were treated entirely on an outpatient basis; 8/46 (17%) failed outpatient antibiotics and required some inpatient care. Three patients were admitted for reasons other than FNE (psychosocial support, 1; relapse of AML, 1; central venous catheter infection, 1). Overall mean duration of hospitalization for each cycle of consolidation given was 7.5 days. The mortality of 2.9% seen in our group compares favorably with other published data (NEJM , 1994; 331:896). In conclusion intensive outpatient consolidation for AML is feasible, as it is associated with acceptable infectious morbidity, with the majority of cases (62% of cycles) being managed entirely on an ambulatory basis. The short mean duration of hospitalization of only 7.5 days per cycle, compares favorably with published data (NEJM 1995 332:217) and is likely economically advantageous. A comprehensive cost-analysis of outpatient versus inpatient costs for AML consolidation is under evaluation at our institution.

Decitabine-Induced Differentiation Syndrome in a Patient with Acute Myeloid Leukemia: A Case Report.

We report here for the first time a case of “decitabine-induced differentiation syndrome” in a patient (pt) with acute myeloid leukemia (AML). The cytosine analog decitabine, after incorporating into DNA, irreversibly binds DNA methyltransferase (DNMT) enzymes where cytosine residues are targeted for methylation. This allows replication of unmethylated DNA with subsequent re-expression of genes previously silenced by promoter methylation. It has been suggested that decitabine at low doses may have differentiating effects, as compared to cytotoxic effects at higher doses. A previous phase I trial demonstrated clinical activity of low dose decitabine in patients with myeloid malignancies (Issa, et al., Blood 2004). Given the close relationship of DNA methylation and histone deacetylation in modulating gene expression, we are currently conducting a phase I trial (OSU 0336) of low dose decitabine (15mg/m2 IV over 1 hour on days 1–10) alone (step 1) or in combination with escalating doses of the histone deacetylase inhibitor valproic acid (step 2) in AML. An 82 year old male pt with untreated, secondary AML (65% bone marrow blasts, 95% marrow cellularity) was enrolled on step 1 of the study and given 15mg/m2/day of decitabine for 10 consecutive days. At the time of initiation of therapy, the pt had a white blood cell (WBC) count of 8,700/uL with absolute neutrophil count (ANC) of 1,500/uL and absolute blast count (ABC) of 3,200/uL. At day 11, the pt had WBC 1,000/uL with ANC of 450/uL and ABC of 150/uL and was clinically well. However, at day 17, he presented with cough and shortness of breath, without fever. WBC had risen to 18,700/uL with ANC of 11,000/uL and ABC of 750/uL. The patient developed worsening hypoxia and required mechanical ventilation. Chest radiograph demonstrated diffuse interstitial infiltrates, but bronchoscopy and lavage (on day 18 and repeated on day 24) did not identify an infectious etiology. Due to clinical concern for a differentiation syndrome similar to the “retinoic acid syndrome” occurring in acute promyelocytic leukemia patients treated with all-trans-retinoic-acid (ATRA), the pt was started on dexamethasone 10mg IV q12 hours beginning on day 18, in addition to broad spectrum antimicrobial coverage. Peripheral blood smears during the following week showed evidence of myeloid differentiation, and by day 25 no circulating blasts were found (WBC 4,300/uL, ANC 3,000/uL) while the overall clinical condition improved. The pt was finally extubated on day 38 but within 24 hours required emergent re-intubation due to nasogastric feeding aspiration and died at day 53. In summary, these preliminary data support the biological activity of low dose decitabine in AML and suggest that clinical precautions similar to those implemented for the “retinoic acid syndrome” in ATRA-treated APL should be considered in decitabine-treated AML when myeloid differentiation and rising neutrophil counts are observed.

Dose Dense, High Intensity Induction Therapy Followed by Early High Dose Chemotherapy (HDT) and Autologous Hematopoietic Stem Cell Transplantation(AHSCT) for Mantle Cell Lymphoma (MCL).

Introduction: Though response may occur with standard therapy, early relapse is common with advanced stage MCL, suggesting the importance of drug resistance in this disease process.It appears that repeated cycles of aggressive chemotherapy to a point of maximum response, followed by HDT and AHSCT, provides improved disease free intervals, though the impact on overall survival (OS) remains uncertain. A concern with this approach is that the eventual high relapse rate seen in most trials may be due to the emergence of drug resistance prior to HDT. In an attempt to circumvent the problem of drug resistance due to multiple cycles of chemotherapy, we designed a dose dense approach using only one cycle of an aggressive induction regimen. Patients demonstrating at least PR and a BM uninvolved by morphology and flow cytometry studies proceeded with chemotherapy-primed PBPC collection, before receiving HDT and AHSCT.Patients and Methods: HIDAC 3 gm/m2 over 1 hour q12 hours for 12 doses in combination with mitoxantrone 12mg/m2 daily for 3 days were given as induction therapy. Responders were mobilised with either VP-16 2 gm/m2 or cyclophosphamide 4 gm/m2 followed by G-CSF 10 mcg/kg daily until stem cell collection. The preparative regimen consisted of BCNU 15mg/kg over 2 hours D-6, VP-16 60mg/kg over 4 hours D-4 and cyclophosphasmide 100mg/kg over 2 hours D-2.Results: Twenty one stage IV patients and 2 stage III patients were enrolled, including 7 with relapsed/refratory disease. Median age was 56 yo(40–74). Nine (39%) patients achieved CR and 11 (48%) patients achieved PR with all showing >80% reduction in tumor size. Three patients died after induction: 1 from sepsis; 2 from disease progression. Seventeen (74%) of the 20 patients with CR or > 50% PR proceeded to PBPC mobilisation whereas 3 were deemed too ill to undergo HDT (2 of these were in CR from induction). A total of 14 (10 previously untreated and 4 had failed prior therapy) eventually had adequate stem cell collected and underwent planned HDT and were fully evaluable for outcome. There was no TRM to HDT and while only 6 patients entered HDT in CR, all 14 patients attained a CR at recovery from transplant. With a median follow-up from study entry for these 14 autotransplant patients of 36 months (17–68), 8 patients are still alive and in CR. The estimated 4 year OS and event free survival (EFS) for these 14 patients were both 64% and the median survival was 57 months.(see figure)Conclusions: The study shows that a dose dense, high intensity approach for advanced MCL provides a very high CR and PR rate. Those who were able to complete this protocol have a high chance of achieving favorable disease free survival. [Display omitted]

Fatal fulminant varicella hepatitis presenting as acute abdominal pain

Purpose: We report the case of a 38-year-old male, on prednisone for an asthma exacerbation, admitted for severe abdominal pain and fever of 38.6C. His abdomen was soft, with normal abdominal sounds, non-tender to palpation but with voluntary guarding; the liver span was 18cm. He had a diffuse eruption of vesicles, pustules and hemorrhagic bullae over the trunk, neck, face and scalp. The CBC, chemistries, amylase, lipase, bilirubin and alkaline phosphatase were normal. AST and ALT were 59 IU/L and 125 IU/L respectively. The ultrasound and CTScan of the abdomen, small bowel follow-through, upper GI series and EGD were essentially normal. Within 24hours of his admission, the patient developed severe encephalopathy, oliguric renal failure, respiratory failure, distributive shock and disseminated intravascular coagulopathy. At this time, his laboratory values were as follow: AST 14,600 IU/L, ALT 6,540 IU/L, INR 10, creatinine 5, platelets count 44, PTT 62. The patient was started on acyclovir 10mg/kg q8 hours for varicella hepatitis. A biopsy of the skin lesions revealed severe acantholysis, bullous formation in the epidermis and multinucleated giant cells. Direct immunofluorescence and viral culture of the skin tissue were positive for VZV. The patient expired 13 days after his presentation despite aggressive resuscitation.

Comparative cost analysis of prostaglandin analogues dinoprostone and misoprostol as labor preinduction agents

Objective: To compare the relative cost efficacy of three commercially available prostaglandin analogues, misoprostol (Cytotec®, PGE 1), dinoprostone gel (Prepidil®, PGE 2), and dinoprostone pessary (Cervidil®, PGE 2), as labor preinduction agents. Methods: The investigation was conducted as a prospective randomized, blinded phase III clinical trial. One hundred twelve gravid females undergoing induction of labor with an unfavorable cervix (Bishop score ≤5) were enrolled and randomized to receive either Cytotec® 50 μg q6 hours × 2 doses, Prepidil® 0.5 mg q6 hours × 2 doses, or Cervidil® 10 mg × 1 intravaginally. Twelve hours after initial treatment, cervical Bishop score was reassigned by the same blinded initial examiner and oxytocin induction initiated per standardized protocol. Therapeutic efficacy and cost of the labor preinduction/induction with the study treatments were compared. Statistical comparisons between groups were made using ANOVA with Bonferroni post test, Wilcoxon rank sum test, and χ 2 test. Results: The three study groups did not differ significantly with respect to parity, gestational age, indication for induction, or initial cervical Bishop score. A significantly greater proportion of patients had a favorable cervix (Bishop score ≥6) after the initial preinduction interval in the Cytotec® (79.0%) and Cervidil® groups (60.5%) as compared to Prepidil® (40.0%) ( P < .05). The average relative cost per patient for prostaglandin preinduction was significantly less with Cytotec® ($0.42) as compared to both Cervidil® ($168.00) and Prepidil® ($184.17) ( P < .0001). A greater percentage of patients treated with Cytotec® (42.1%) achieved active labor and delivered without the use of oxytocin when compared to Cervidil® (15.8%) or Prepidil® treatment groups (2.9%) ( P < .05). Additionally, time to delivery (±SD) was significantly shorter in the Cytotec® group (24.0 ± 10.8 h) as compared to the Cervidil® (32.2 ± 14.7 h) or Prepidil® groups (33.9 ± 16.2 h) ( P < .05). This reduction in time resulted in a significantly lower overall mean cost per patient incurred by labor induction in the Cytotec® group ($723.66) as compared to the Cervidil® ($1058.90) or Prepidil® treatment ($1124.84) ( P < .01). No significant differences were noted with respect to rate of cesarean delivery. Conclusion: Misoprostol is more cost-effective than the comparable commercial dinoprostone prostaglandin preparations as an adjuvant to labor induction in patients with an unfavorable cervix.

Etoposide, intermediate-dose cytarabine and carboplatin (VAC): A combination therapy for the blastic phase of chronic myelogenous leukemia

Carboplatin is a second-generation platinum compound that in combination with etoposide and intermediate doses of cytarabine, in early clinical trials has demonstrated high efficacy in refractory acute myelogenous leukemia and the blastic phase of CML. Starting in April 1992, 17 consecutive patients with the blastic phase (BP) of chronic myelogenous leukemia (CML) and a median age of 33 years (range 10 to 45) received a new treatment regimen consisting of etoposide (100 mg/m2/d i.v. over one hour), intermediate-dose cytarabine (500 mg/m2/d i.v. over one hour, q12 hours) and carboplatin (150 mg/m2/d continuous infusion) on days 1 3 and 8 10 (VAC regimen). The BP phenotype was myeloid in 16 patients and hybrid in one. At the time of their BP diagnoses, two patients showed extramedullary involvement, in eight patients the BP was preceded by an accelerated phase. Overall, 11 of 17 patients (65%) achieved complete remission and 7 of 11 responding patients (64%) manifested a cytogenetic conversion ranging from 38% to 100% Ph-negative metaphases: one patient died in CR of hemothorax, three died of sepsis during induction therapy and three patients (17.5%) had resistant disease. As of April 1996, four patients are alive, three of them in first remission at +7, +10, +16 months after CR, and one in BP at +38 months after the start of VAC therapy. Profound myelosuppression was observed in all patients; extrahematologic toxicity, especially involved the gastro-intestinal tract, with grade > 2 mucositis in five patients (29.5%) and liver dysfunction in five (29.5%). No renal toxicity or ototoxicity was observed. Despite the brief relapse-free duration, the high remission rate and tolerable toxicity indicate that the VAC combination chemotherapy has a high antileukemic efficacy, and warrants further evaluation for the treatment of CML in acute phase, provided a post-remission BMT strategy is feasible.

Oral Idarubicin and Low Dose Cytarabine as the Initial Treatment of Acute Myeloid Leukemia in Elderly Patients

Idarubicin (IDR) is an anthracycline that can be administered orally. Low dose cytarabine (LDARAC) has been commonly used in the treatment of acute myeloid leukemia (AML) in elderly patients. A comination of oral IDR (20 mg/m(2) for 3 days) and LDARAC (10 mg/m(2) q12 hours for 10 days) was given in 32 patients aged 65 to 82 years (median 76) with de novo AML. Eight patients whose marrow remained blastic by day 20 received a second course (IDR for 2 days and LDARAC for 5 days). Complete remission (CR) was achieved in 13 cases (40.5%), (one course 12, two courses 1). There was 1 early death, 3 deaths in aplasia, 2 partial remissions and 13 failures. All but 5 patients were entirely managed in hospital. The median duration of neutropenia was 18 days and only 1 patient obtained CR without therapeutic aplasia. The extrahematologic toxicity was mild with 3 reversible cardiac events. These results are comparable to those obtained with conventional chemotherapy and this regimen could be proposed as induction treatment of AML in elderly patients.

Cross over double blind efficacy assessment of Morphin Sulfate Contin (MSC) Given q12 vs q8 hours: Preliminary few

Cross over double blind efficacy assessment of Morphin Sulfate Contin (MSC) Given q12 vs q8 hours: Preliminary few

Treatment of acute nonlymphocytic leukemia in the elderly with intermediate high-dose cytosine arabinoside.

Effective treatment of the elderly patients (greater than or equal to 65 years) with acute nonlymphocytic leukemia (ANLL) remains elusive and controversial. In the present study, single-agent Cytosine Arabinoside (ARA-C) was administered at an intermediate dose level (500 mg/m2 intravenously [I.V.] 1-hour infusion q12 hours for 12 doses) to 30 newly diagnosed and previously untreated patients. Complete remission was achieved in seven patients after the initial cycle of treatment, in two patients after retreatment, and in one patient after delayed recovery of his peripheral count over a 6-month period. The toxicity of this schedule was primarily hematologic, and the response rate was in keeping with that reported by other groups using aggressive multiagent regimens.