Reinduction therapy in 297 children with acute lymphoblastic leukemia in first bone marrow relapse: a Pediatric Oncology Group Study

Many children with acute lymphoblastic leukemia (ALL) develop a marrow relapse during or shortly following initial continuation chemotherapy. Achievement of a second complete remission is the initial step in a successful retreatment effort. Reinduction results using two or three drugs have been unsatisfactory, and previous reports of four-drug reinduction programs have included relatively small numbers of patients. Pediatric Oncology Group protocol 8303 was designed for patients with ALL in first marrow relapse during or within 6 months after cessation of chemotherapy. The results of reinduction therapy in 297 study patients are described here. Four-drug reinduction therapy consisted of daily oral prednisone, weekly vincristine and daunorubicin, and asparaginase three times weekly for 4 weeks (PVDA). CNS retreatment consisted of two doses of triple intrathecal chemotherapy. Of the 297 patients receiving reinduction, 245, or 82%, entered second complete remission, six died of infection or progressive disease, and 46 others still had M2 or M3 bone marrow status. Forty of these latter patients received four doses (during a 2-week period) of teniposide and cytarabine, after which 13 (32%) achieved complete remission status. Thus, the overall second complete remission rate with PVDA with or without teniposide/cytarabine was 258 of 297, or 87%. The treatment program was generally well tolerated. Among the numerous factors analyzed by using logistic regression, only female sex (P = .035), the presence of blasts on the blood smear at the time of relapse (P = .0002), and a length of initial complete remission less than 12 months (P = .021) were independent predictors of failure to enter second remission. We conclude that the intensive reinduction program described here is a highly effective first step in the delivery of salvage therapy to patients with ALL in first marrow relapse. The current challenge is to develop improved continuation treatment for these children.     

Chloramphenicol-induced bone marrow injury: possible role of bacterial metabolites of chloramphenicol

To explore the potential role of some bacterial metabolites of chloramphenicol (CAP) in CAP-induced hematotoxicity, we examined their cytotoxic effects on bone marrow cells in vitro using a number of cytotoxicity parameters. Among the metabolites tested, dehydro-CAP (DHCAP) and p-nitrophenyl-2-amino-3 hydroxypropanone-HCI (NPAP) were more toxic than CAP. DHCAP was at least as toxic as nitroso-CAP. At concentrations of less than or equal to 10(-4) mol/L, DHCAP caused total irreversible inhibition of myeloid colony (CFU-GM) growth and 80% inhibition of DNA synthesis in human bone marrow. Incubation of human bone marrow cells with 10(-4) mol/L nitroso-CAP or DHCAP for 24 hours resulted in 75% and 65% cell death respectively. Although DHCAP was 10- to 20-fold more cytotoxic than CAP, it was only one third as effective in inhibiting mitochondrial protein synthesis, indicating that DHCAP exerts its toxic effect by alternate mechanisms. The cytotoxicity of DHCAP and its relative stability, compared to the unstable nitroso CAP, suggest that this bacterial metabolite of CAP, and possibly others, may play a significant role in CAP-induced hematotoxicity.     

Effectiveness of intensified rotational combination chemotherapy for late hematologic relapse of childhood acute lymphoblastic leukemia

Relapsed acute lymphoblastic leukemia (ALL) usually carries a dire prognosis. We evaluated the effectiveness and long-term complications of intensive rotational combination chemotherapy for late hematologic relapse (median, 16 months after elective cessation of therapy) among 34 children and young adults (ages 4 to 23 years). Concurrent central nervous system (CNS) relapse was present in 3 cases and testicular relapse in 4. Secondary therapy comprised an intensive five-drug reinduction (6 weeks) followed by continuation treatment with four drug pairs, rotated weekly in 4-week cycles over 120 weeks. Intrathecal chemotherapy (methotrexate, hydrocortisone, cytarabine) was given three times during reinduction and every 8 weeks during continuation. Treatment was electively discontinued at week 120 in the absence of detectable disease. Thirty-three patients (97%) attained a second complete remission. At a median follow-up of 9.3 years (range, 4.5 to 11.4), estimates of 5-year second event-free and overall survival (+/- SE) are 65% +/- 8% and 79% +/- 7%, respectively. Eleven patients had a second relapse (9 marrow, 2 testicular) and one developed secondary myeloid leukemia. There have been no CNS relapses or deaths in remission. Treatment was well-tolerated and was given largely on an outpatient basis. Late effects are primarily endocrinologic; one child had a second malignant solid tumor (presumed related to initial radiation therapy) that was treated successfully. Intensive treatment with alternating non-cross-resistant drug pairs for late hematologic relapses of ALL is effective and well-tolerated, and produces results similar to those achieved in patients with newly diagnosed ALL. Event- free survival compares favorably with reports of other relapse regimens, including those incorporating bone marrow transplantation.     

Persistence of circulating blasts after 1 week of multiagent chemotherapy confers a poor prognosis in childhood acute lymphoblastic leukemia

Early response to therapy, typically assessed by bone marrow status, is predictive of outcome in childhood acute lymphoblastic leukemia (ALL). Less is known about the significance of early clearance of blast cells in peripheral blood. We reviewed medical records of all patients with ALL enrolled on St Jude Total Therapy Study XI (February 1984 to September 1988) to determine the presence of blast cells in peripheral blood at diagnosis and after 1 week of intensive induction therapy. Of the 358 patients, 59 lacked evidence of circulating blast cells at diagnosis, and data were unavailable for 2 patients. The prognostic significance of persistent circulating blast cells in the remaining 297 patients was assessed in a multivariate analysis that included known adverse prognostic factors. Persistent circulating leukemic blasts were present at day 8 in 41 patients (14%). Compared with the "blast- negative" group, these patients had a significantly higher frequency of several adverse clinical features (leukocyte count > 50 x 10(9)/L, mediastinal mass, central nervous system leukemia, T-cell phenotype, lack of CD10 expression, and L2 morphology) and a significantly poorer 5-year event-free survival (34% +/- 8% [SE] v 77% +/- 3%, P < .01). By multivariate analysis, blast cell persistence at week 1 was the most significant adverse feature in the overall cohort (relative risk, 2.9; 95% confidence interval, 1.8 to 4.8) and in an analysis limited to B- lineage cases (relative risk, 3.6; 95% confidence interval, 1.9 to 7.1). Patients identified by this simple, noninvasive measure may benefit from early modification of therapy.     

Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug development

Following reports of death from cardiac arrhythmias with drugs like terfenadine and cisapride, the International Conference for Harmonization formulated a guidance (E14) document. This specifies that all new drugs must undergo a ‘thorough QT/QTc’ (TQT) study to detect drug-induced QT prolongation, a surrogate marker of ventricular tachycardia, especially torsades de pointes (TdPs). With better understanding of data from several completed TQT studies, regulatory requirements have undergone some changes since the E14 guidance was implemented in October 2005. This article reviews the implications of the E14 guidance and the changes in its interpretation including choice of baseline QT, demonstration of assay sensitivity, statistical analysis of the effect of new drug and positive control, and PK-PD modelling. Some issues like use of automated QT measurements remain unresolved. Pharmaceutical companies too are modifying Phase 1 studies to detect QTc liability early in order to save time and resources. After the E14 guidance, development of several drugs that prolong QTc by >5 ms is being abandoned by sponsors. However, all drugs that prolong the QT interval do not increase risk of TdP. Researchers in regulatory agencies, academia and industry are working to find better biomarkers of drug-induced TdP which could prevent many useful drugs from being prematurely abandoned. Drug-induced TdP is a rare occurrence. With fewer drugs that prolong QT interval reaching the licensing stage, knowing which of these drugs are torsadogenic is proving to be elusive. Thus, paradoxically, the effectiveness of the E14 guidance itself has made prospective validation of new biomarkers difficult.This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010     

Left bundle-branch block with right axis deviation—a unique aberrancy during supraventricular tachycardia

A tachycardia with left bundle-branch block morphology and right axis deviation points to the diagnosis of ventricular tachycardia. Conversely, any supraventricular tachycardia with left bundle-branch block is typically associated with a normal or leftward QRS axis. We present the case of a 34-year-old man showing atrioventricular nodal reentrant tachycardia with left bundle-branch block/right axis deviation as an exception to this rule.     

Suburothelial Myofibroblasts in the Human Overactive Bladder and the Effect of Botulinum Neurotoxin Type A Treatment

Background

An increasing body of evidence suggests a possible role of suburothelial myofibroblasts (MFs) in bladder mechanosensation and in the pathophysiology of detrusor overactivity (DO).

Objective

To determine whether markers of MFs, including gap junction protein connexin43 (Cx43) and c-kit have altered immunohistochemical expression in the suburothelium of patients with neurogenic DO (NDO) or idiopathic DO (IDO) and whether this is affected by successful treatment of DO with botulinum neurotoxin type A (BoNTA).

Design, setting, and participants

Patients with NDO (n = 10) or IDO (n = 11) were treated in a single-centre, open-label study of intradetrusor BoNTA injections. Control tissue was obtained from 10 patients undergoing pelvic-floor repair procedures who had no overactive bladder (OAB) symptoms. This study is registered with ClinicalTrials.gov, number NCT00662064.

Interventions

Bladder biopsies performed with flexible cystoscopes were obtained from control subjects and from NDO and IDO patients before BoNTA treatment and at 4 wk and 16 wk after treatment. They were studied with quantitative immunofluorescence using antibodies to connexin 43 (Cx43), vimentin, and c-kit.

Measurements

Differences in Cx43, vimentin, and c-kit immunoreactivity between control subjects and NDO or IDO patients (primary outcomes). Changes in NDO or IDO, Cx43 immunoreactivity, and c-kit immunoreactivity after BoNTA treatment (secondary outcomes).

Results and limitations

Cx43 immunoreactivity was increased in both IDO and NDO patients compared to controls, but remained unchanged after BoNTA treatment. C-kit immunoreactivity was similar in NDO/IDO patients and controls and remained unchanged after BoNTA treatment.

Conclusions

Increased gap junction formation in the suburothelium has been demonstrated in biopsies from humans with DO. It is hypothesised that this change could have a significant role in the pathogenesis of the detrusor abnormality. Successful treatment of NDO or IDO does not appear to be associated with changes in the expression of Cx43 or c-kit on suburothelial MFs.     

Dysmyelinating neuropathy in benign form of megalencephalic leukoencephalopathy with subcortical cysts: a novel observation from south India

A 37-year-old gentleman presented with macrocephaly since early childhood and progressive impairment of motor and cognitive functions. Magnetic resonance imaging revealed extensive white matter involvement and frontotemporal subcortical cysts. Absent ankle jerk and abnormal nerve conduction study raised a possibility of associated peripheral neuropathy. Sural nerve biopsy was suggestive of dysmyelinating neuropathy. This report serves to expand the clinical spectrum of this rare leukodystrophy.