Impact of reduction of therapy on infectious complications in childhood acute lymphoblastic leukemia.

BACKGROUND: Infections are a major cause of morbidity and mortality in childhood acute lymphoblastic leukemia (ALL) and only limited information is available on infectious complications. PATIENTS AND METHODS: We investigated infectious complications in 293 children during different treatment phases of the multicenter protocol COALL-06-97. We also evaluated whether therapy reduction in prognostically good risk patients receiving either the low risk or high risk treatment arm would lead to fewer infectious complications. RESULTS: Thirty of 293 patients had no infections; 263 patients had 682 infectious complications (median 2, range 1-9), five of them lethal. Two thirds of the infections occurred during periods of neutropenia. The most frequent infectious episodes were fever of unknown origin (FUO): 483/682 (70.8%), microbiologically documented infections (MDI): 100/682 (14.6%), (61 gram-positive, 36 gram-negative, 3 fungal isolates), and clinically documented infections (CDI): 99/682 (14.5%). With standard reinduction, 44% low risk and 57% high risk patients had infections versus 26% low risk and 38% high risk patients with reduced reinduction therapy (P < 0.01). CONCLUSIONS: Most patients treated with intensive combination therapy for ALL experience one to several serious infections during treatment. The wide range in number of infectious episodes and the lack of infections in a small subset of patients in spite of uniform treatment suggest genetic as well as possibly environmental factors to have a role. Moderate reduction of chemotherapy may significantly reduce the rate of infectious episodes.

Expression of the outcome predictor in acute leukemia 1 (OPAL1) gene is not an independent prognostic factor in patients treated according to COALL or St Jude protocols.

New prognostic factors may result in better risk classification and improved treatment of children with acute lymphoblastic leukemia (ALL). Recently, high expression of a gene named OPAL1 (outcome predictor in acute leukemia) was reported to be associated with favorable prognosis in ALL. Therefore, we investigated whether OPAL1 expression was of prognostic importance in 2 independent cohorts of children with ALL treated on Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL)-92/97 (n = 180) and St Jude Total 13 protocols (n = 257). We observed a consistently higher (2.8-fold) expression of OPAL1 in TEL-AML1-positive ALL compared with TEL-AML1-negative ALL in both cohorts, but higher OPAL1 expression was not consistently associated with other favorable prognostic indicators such as age and white blood cell count, or ALL genetic subtype. Lower OPAL1 expression was also not associated with increased in vitro drug resistance. Multivariate analyses including known risk factors showed that OPAL1 expression was not independently related to prognosis in either the COALL or St Jude cohorts. In conclusion, OPAL1 expression may not be an independent prognostic feature in childhood ALL, and its previously reported prognostic impact appears to be treatment dependent.

The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia.

Childhood acute lymphoblastic leukemia (ALL) consists of various subtypes that respond differently to cytotoxic drugs and therefore have a markedly different clinical outcome. We used microarrays to investigate, in 190 children with ALL at initial diagnosis, whether 70 key apoptosis genes were differentially expressed between leukemic subgroups defined by lineage, genetic subtype, in vitro drug resistance, and clinical outcome. The expression of 44 of 70 genes was significantly different in T-versus B-lineage ALL, 22 genes differed in hyperdiploid versus nonhyperdiploid, 16 in TEL-AML1-positive versus-negative, and 13 in E2A-rearranged versus germ-line B-lineage ALL. Expression of MCL1 and DAPK1 was significantly associated with prednisolone sensitivity, whereas BCL2L13, HRK, and TNF were related to L-asparaginase resistance. BCL2L13 overexpression was also associated with unfavorable clinical outcome (P < .001). Multivariate analysis including known risk factors revealed that BCL2L13 expression was an independent prognostic factor (P = .011). The same trend was observed in a validation group of 92 children with ALL treated on a different protocol at St Jude (P = .051). In conclusion, ALL subtypes have a unique expression pattern of apoptosis genes and our data suggest that selective genes are linked to cellular drug resistance and prognosis in childhood B-lineage ALL.

Laparoscopic adrenal surgery for recurrent tumours in patients with hereditary phaeochromocytoma.

OBJECTIVE: To report our experience with Laparoscopic Partial Adrenalectomy (LPA) for recurrent tumours in patients with hereditary phaeochromocytoma. PATIENTS AND METHODS: Five patients with hereditary phaeochromocytoma (4 with von Hippel-Lindau disease and 1 with Multiple Endocrine Neoplasia 2B), who had undergone adrenal surgery previously, presented with recurrent adrenal tumours. One patient was pregnant at 20 weeks of gestation. All patients underwent hormonal evaluation, genetic screening and imaging with CT or MRI, metaiodobenzylguanidine (MIBG) scintigraphy. RESULTS: Of the 7 attempted LPA in five patients, five procedures (71%) were successfully completed and total adrenalectomy was needed on two occasions. The adrenal vein could be spared in all patients except one. There were no intra-operative complications. The adrenal function was adequate in all patients without need for steroid supplementation except one patient who lost both adrenals eventually. There was no correlation between the preservation of adrenal vein and adrenocortical function. CONCLUSION: Laparoscopic partial adrenalectomy is feasible, safe and effective in recurrent phaeochromocytoma, despite previous adrenal surgery and is technically easier if the previous approach had been laparoscopic as well. Patients with hereditary phaeochromocytoma are prone for recurrent tumours and may need repeated surgical procedures. Hence, minimally invasive approach is ideal for these patients.

Successful antifungal combination therapy with voriconazole and caspofungin.

A 12-year-old boy in third remission of an acute lymphoblastic leukaemia developed infection of lung and paranasal sinuses with Aspergillus flavus in neutropenia. Because of the high risk of leukaemia-relapse bone marrow transplantation (BMT) from a matched unrelated donor was carried out despite invasive pulmonary aspergillosis (IPA). It is the first reported patient with IPA, who was successfully treated by the antifungal combination therapy with voriconazole and caspofungin therapy during myeloablative BMT. Despite 6 weeks of aplasia, a dramatic decrease of lesions highly suggestive of aspergillosis was observed after BMT. Since discharge-oral voriconazole monotherapy has been continued.

Laparoscopic partial adrenalectomy for recurrent pheochromocytoma in a boy with Von Hippel-Lindau disease.

We describe a case of a boy with Von Hippel-Lindau disease who presented with recurrent right adrenal pheochromocytoma 4.5 years after laparoscopic bilateral partial adrenalectomy. The boy had a second laparoscopic adrenal-sparing removal of the tumor. By this technique, not only the recurrent tumor was successfully removed but also the unaffected adrenal cortex could be preserved for the second time. To our knowledge, this is the first published case of its type.

Thioguanine offers no advantage over mercaptopurine in maintenance treatment of childhood ALL: results of the randomized trial COALL-92.

The German cooperative study group for childhood acute lymphoblastic leukemia (COALL-92) was designed to examine the clinical effectiveness of thioguanine (TG) versus mercaptopurine (MP) in maintenance treatment of childhood acute lymphoblastic leukemia (ALL) in a randomized multicenter trial. TG and MP are prodrugs and have to be converted intracellularly to 6-thioguanine nucleotides (TGNs) for cytostatic activity. TG is converted into TGN in fewer steps and has been shown to be more cytotoxic in equimolar doses in vitro compared with 6-MP. Therefore, a higher effectiveness of TG in maintenance treatment was postulated. Of 521 patients enrolled into the protocol, 474 were randomized to receive either MP or TG during maintenance therapy in a daily oral dose. After a median observation time of 6.6 years, the probability of event-free survival was 79% +/- 3% for the MP group (238 children) and 78% +/- 3% in the TG group (236 patients). In spite of TGN levels, exceeding those of the MP group 7 times, treatment with TG did not improve the outcome but was more complicated to handle due to a specific toxicity profile of prolonged myelosuppression with marked thrombocytopenia. Therefore, MP should remain the preferred drug for maintenance treatment of ALL, unless other studies demonstrate superiority of TG in larger trials or selected patient groups.