To assess the correlations between clinical and biological stages of HIV infection and HIV isolation, peripheral blood mononuclear cells from 389 HIV-infected patients were studied by 30-day cocultures with normal lymphocytes. HIV isolation was successful in 279/389 patients (71.7%). Positive isolation was more frequent in CDC IV cases (82%) than in CDC II and III cases (63.6% and 78.4% respectively). There was a close correlation between culture positivity and serum beta 2-microglobulin, CD4+ cell counts and serum p24 antigen. The day of peak detection of reverse transcriptase activity or peak p24 antigen in coculture supernatants was selected as a coculture kinetic parameter. The day of peak detection of HIV in culture occurred earlier in CDC IV cases than in CDC II and III cases, and was a prognostic factor in AIDS progression at 2 years. These data suggest that in vitro parameters related to both viral burden and replicative capacity of HIV isolates are relevant indicators of disease progression.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

Toxicity and effectiveness of high-dose idarubicin during AML induction therapy: results of a pilot study in children.

BACKGROUND: Idarubicin (IDR) is one of the most effective, but also toxic drugs in the treatment of AML. The standard dose used in children and adults is 8-12 mg/m2 during induction. PATIENTS AND METHODS: To improve outcome, we increased the IDR dose from 12 mg/m2 (standard dose in study AML-BFM 93), applied over three days during induction therapy (AIE = Ara-C, Idarubicin, Etoposide) to 14 mg/m2 in a pilot study including 17 patients (16 with de novo AML, one with secondary AML). Outcome and toxicities were compared with the other patients of study AML-BFM 93, treated with 3 x 12 mg/m2 IDR or 6 x 30 mg/m2 daunorubicin (DNR). RESULTS: Patients of the pilot study achieved a good blast cell reduction in the bone marrow on day 15, a high CR rate of 94% and a low relapse rate (3/17 pts.), however, not significantly different to the IDR (12 mg/m2) group. Hematological toxicity was high, median duration until neutrophil recovery > 500/microliter was 25.0 (12-66) days, and similar to the IDR (12 mg/m2) and DNR groups. Duration of thrombocytopenia (time to > 20,000/microliter) was 21 (10-66) days in the pilot study compared to 19 (7-26) days in DNR patients (p = 0.08). Four of 17 pilot patients presented with severe WHO grades 3/4 of mucositis during induction. One patient died in long-lasting aplasia after the 3rd treatment block. CONCLUSION: Results of this pilot study show that the IDR 14 mg/m2 regimen was effective but also toxic. According to our results which, however, are based on small patient numbers, an improved outcome compared to the IDR 12 mg/m2 regimen seems to be unlikely, therefore the possibly increased toxicity might not be acceptable.

Acute Disease↗

PubMedDate not supplied

A heterozygous frameshift mutation in the Fanconi anemia C gene in familial T-ALL and secondary malignancy.

BACKGROUND: Patients with Fanconi Anemia (FANC) have a well documented increased risk to develop malignancies, especially Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). The risk for heterozygous individuals is not clear, epidemiological data are inconsistent. If the risk for heterozygous individuals to develop malignancies was increased, they should be found in groups of patients with AML or MDS at higher proportion than in the normal population. We are currently screening a pediatric population with hematologic malignancies for mutations in the FANCA, FANCC and FANCG gene, and report here on siblings carrying a heterozygous frameshift mutation in the FANCC Gene. PATIENTS AND METHODS: Using PCR based single strand conformational analysis we screened the DNA from pediatric patients suffering from 1 degree or 2 degrees MDS, CMML/JMML or AML for mutations in the FANCA (43 exons), FANCC (14 exons) and FANCG (14 exons) gene, and included one patient with refractory T-ALL, being the brother of a patient with T-ALL and MDS transforming into AML. Aberrant PCR products were directly sequenced. Flowcytometric measurement of mitogen-sensitivity and G2-phase arrest is used to evaluate cultured stimulated lymphocytes from individuals carrying FANC-mutations. RESULTS: A novel heterozygous frame-shift mutation, 377-378delGA in the FANCC gene was found in 2 siblings, both suffering from T-ALL with subsequent MDS transforming to AML in one of them. No other mutation was found by direct sequencing of the complete FANCC gene. Both patients died under therapy. The parents (first degree cousins) and one healthy brother are also carriers. Their lymphocytes show a higher mutagen sensitivity than normal, but do not get blocked in G2 phase as being typical for Fanconi Anemia. CONCLUSION: As the mutation causes a premature Stopcodon within exon 4 of the FANCC gene it has to be regarded as a causal FANCC gene defect. The findings within this family support the hypothesis of an increased risk to develop malignancies in heterozygous carriers of FANC-mutations. A systematic screening of further patients is needed, and we are currently examining a larger cohort to get a better estimate of the true risk of heterozygosity.

DNA Mutational Analysis↗

PubMedDate not supplied

[Improved treatment results in children with AML: Results of study AML-BFM 93].

BACKGROUND: In the multicenter trial AML-BFM 93 daunorubicin or idarubicin was randomly applied in all patients during induction in combination with cytarabine and etoposide. After induction all patients were stratified to the standard or high risk group. To improve outcome in high risk patients high dose cytarabine and mitoxantrone (HAM) was introduced. The placing of HAM as either the 2nd or 3rd therapy block was randomized to evaluate the efficacy and toxicity accordingly. PATIENTS AND METHODS: 471 children with de novo AML entered the trial AML-BFM 93 (161 standard risk, 310 high risk). RESULTS: Overall, 387 of 471 (82 %) patients achieved remission, 5-year survival, event free survival (EFS), and disease free survival were 60 % SE 3 %, 51 % SE 2 % and 62 % SE 3 %, respectively. Idarubicin-based induction resulted in a significantly better blast cell reduction in the bone marrow on day 15 (25 of 144=17 % patients with > 5 % blasts compared to 46 of 149=31 % patients after daunorubicin, pchi(2)=0.01). This was, however, mainly seen in high risk patients treated with idarubicin (19 % vs. 38 %, pchi(2)=0.007). Cardiotoxicity, WHO grade 1 - 3 shortening fraction reduction after induction occurred in 6 % patients in both arms. In the total group of patients probabilities of five years event-free survival and disease-free survival were similar for patients treated with daunorubicin or idarubicin. However, in patients presenting with more than 5 % blasts on day 15 there was a trend for a better outcome after treatment with idarubicin (p logrank 0.06). Outcome in high risk patients was superior in study 93 compared to study 87 (remission rate and 5-year pEFS in study AML-BFM 93 vs. study 87: 78 % vs. 68 %, p=0.007, and 44 % vs. 31 %, p logrank=0.01). The placing of HAM as the 2nd or 3rd therapy block was of minor importance. However, patients who received the daunorubicin treatment during induction benefited from early HAM. CONCLUSION: Compared to study AML-BFM 87 treatment results in study AML 93 improved significantly in high risk patients. This can partly be contributed to the better response on day 15 after idarubicin induction but is mainly due to the introduction of HAM.

Acute Disease↗

PubMedDate not supplied

[Classification of AML by morphologic, immunologic and cytogenetic criteria. Review with reference to subtypes in the AML-BFM-87 study].

The current FAB classification of acute myelogenous leukemia (AML) by morphologic, immunologic and cytogenetic features is described and the incidence of subtypes and variant forms of AML in study AML-BFM-87 is given. In general, lymphoblastic or myeloid blast populations can be identified by morphologic, cytochemical and immunologic parameters, while immunophenotyping facilitates diagnosis in biphenotypic leukemia. Furthermore, the AML subtypes M0 and M7 (defined in 1985 and 1991) can only be ascertained by the presence of lineage-associated markers. Whereas chromosome aberrations provide an insight into the neoplastic process and assure diagnosis. Thus, next to morphologic findings, immunologic and cytogenetic studies are essential for a definite diagnosis of AML.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

[Prognostic significance of eosinophilia in children with acute myeloid leukemia in the studies AML-BFM-78 and -83].

Initial eosinophilia (greater than or equal to 3%) in the bone marrow was found in 73 out of 269 (27%) patients studied in AML studies BFM-78 and -83. It was predominantly seen in children with FAB types M2 (44%) and M4 (41%). Atypical eosinophils were mostly found in FAB type M4 (20/28 = 71%). Cytogenetic studies in eight children with FAB M4 and eosinophilia showed normal karyotypes in four patients, inversion 16 in one and other aberrations in three children. Study AML-BFM-78 did not demonstrate any differences in prognosis between patients with and without eosinophilia (event-free survival = EFS after 5 years 37%, SD 8%, vs. 38%, SD 6%). In study AML-BFM-83, however, a clear increase in EFS was seen in children with eosinophilia (EFS 72%, SD 8%, vs. 43%, SD 5%, p = 0.001). This improvement of prognosis mainly concerns patients with FAB M4 and eosinophilia (EFS 81%, SD 10%, vs. 23%, SD 11%, p = 0.006). None of the 12 children in study AML-BFM-83 with FAB M4 and atypical eosinophils has suffered a relapse, two patients belong to the early death group. Multivariate analysis shows only eosinophilia as a favorable prognostic factor in FAB type M4. According to these results FAB type M 4 with eosinophilia is a favorable prognostic parameter in children treated according to the therapy protocol of study AML-BFM-83.

Adolescent↗

PubMedDate not supplied

[Incidence and prognostic significance of Auer rods in children with acute myeloid leukemia in the studies AML-BFM-78 and -83].

The prognostic significance of Auer rods in children with AML was investigated in 129 patients of the study AML-BFM-78 and 154 patients of the study AML-BFM-83. Auer rods were found in 68 patients (53%) in the study AML-BFM-78 and 69 patients (45%) in the study AML-BFM-83. The incidence was higher in the subtypes FAB M1 (61%) and M2 (75%) compared to the subtypes FAB M4 (44%) and M5 (5%). In both studies the remission rate was higher in Auer rod-positive patients. Moreover, in the study AML-BFM-83 patients with Auer rods had a significant longer remission duration: the probability of an event-free interval (EFI) of 5 years was 77% (SD 6%) in Auer rod-positive patients compared with 44% (SD 7%) in Auer rod-negative patients (p less than 0.01). In the study AML-BFM-78 no differences regarding remission duration between both groups were detected. Analysis of the individual FAB subtypes revealed a significant higher event-free survival rate (EFS) after 5 years in Auer rod-positive compared with 18% (SD 12%) in Auer rod-negative patients (p less than 0.0001). No prognostic significance of Auer rods in other subtypes could be detected. In the overall group of all patients absence of Auer rods was associated with the unfavourable parameters hyperleucocytosis (greater than or equal to 100 x 10(3)/microliters) and acute monocytic leukemia (FAB M5) (p less than 0.01, p less than 0.001, respectively). The multivariate analysis in the study AML-BFM-83 showed that Auer rods were of prognostic significance independent from the initial leukocyte count and the FAB type M5.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗