PREMIUM: A French prospective multicenter observational study of factors impacting on efficacy and compliance to cetuximab treatment in first-line KRAS wild-type metastatic colorectal cancer.

BACKGROUND: Cetuximab improves progression-free survival (PFS) and overall survival (OS) in patients with KRAS wild type (wt) metastatic colorectal cancer (mCRC). Few data are available on factors impacting both efficacy and compliance to cetuximab treatment, which is, in combination with chemotherapy, a standard-of-care first-line treatment regimen for patients with KRAS wt mCRC. PATIENTS AND METHODS: PREMIUM is a prospective, French multicenter, observational study that recruited patients with KRAS wt mCRC scheduled to receive cetuximab, with or without first-line chemotherapy, as part of routine clinical practice, between October 28, 2009 and April 5, 2012 (ClinicalTrials.gov Identifier: NCT01756625). The main endpoints were the factors impacting on efficacy and compliance to cetuximab treatment. Predefined efficacy endpoints were PFS and safety. RESULTS: A total of 493 patients were recruited by 94 physicians. Median follow-up was 12.9 months. Median progression-free survival was 11 months [9.6-12]. In univariate analyses, ECOG performance status (PS), smoking status, primary tumor location, number of metastatic organs, metastasis resectability, surgery, folliculitis, xerosis and paronychia maximum grade, and acne preventive treatment were statistically significant. In multivariate analysis (Hazard Ratios of multivariate stepwise Cox models), ECOG PS, surgery, xerosis and folliculitis were positive prognostics factors for longer PFS. Among all patients, 69 (14%) were non-compliant. In multivariate analysis, no variables were statistically significant. The safety profile of cetuximab was consistent with previous studies. CONCLUSIONS: ECOG PS <2, surgical treatment performed, and maximum grade xerosis or folliculitis developed were predictive factors of cetuximab efficacy on KRAS wt mCRC patients. Unfortunately, we failed in identifying predictive factors for compliance in these patients.

Granulocyte colony-stimulating factor-mobilized peripheral blood CD34+ cells from children contain the same levels of long-term culture-initiating cells producing the same numbers of colony-forming cells as those from adults, but display greater in vitro monocyte/macrophage potential.

Autologous peripheral blood progenitor cell (PBPC) transplantation is now commonly used in children. The ontogenic differences in haematopoiesis published in recent years suggest differences in the categories of mobilized PBPCs between children and adults. We investigated the frequency and distribution of mature progenitor cells (colony-forming cells, CFCs) and primitive progenitor cells [CD34+ CD38- and CD34+ Thy-1+ cells, long-term culture-initiating cells (LTC-ICs)] in children and adults mobilized using granulocyte colony-stimulating factor alone. We found similar proportions of granulocyte colony-forming units (CFU-G) and/or macrophage CFUs (CFU-M), mixed lineage CFUs (CFU-Mix) and megakarocyte CFUs (CFU-Mk), CD34+ CD38- and CD34+ Thy-1+ cells, and LTC-ICs (16.5 +/- 3.5 vs. 10.65 +/- 5 per 104 CD34+ cells), which produced the same number of CFCs (5 +/- 1 vs. 6 +/- 1 CFCs/LTC-ICs) in PB CD34+ cells from children and adults. However, we noted a higher proportion of erythroid blast-forming units (BFU-E) in PB CD34+ cells from adults (x 1.5, P = 0.003). Using cord blood as a third ageing point, we observed an inverse age-related propensity for commitment to the monocyte/macrophage lineage that was still found after normalizing the data per body weight and processed blood mass. This ontogeny-related programming was detected from the LTC-IC level, which produced 1.7 times more CFU-M in children than in adults (P = 0.048). These subtle differences in commitment between children and adults, shown here for the first time, are of interest for the in vitro manipulation of PBPCs and, in particular, for application in adoptive immunotherapy in children.

CFU-Mk content of immunoselected CD34+ peripheral blood progenitor cells, evaluated with an adapted serum-free methylcellulose assay, is predictive of platelet lineage reconstitution in children with solid tumors.

Immunoselected CD34+ peripheral blood progenitor cell (PBPC) transplantation is now frequently used to support autologous hematopoiesis after myeloablative therapy, its feasability having been proved by several groups. However, we and others observed delayed platelet recovery. We hypothesized that immunoselection processing might induce selective loss of megakaryocyte progenitors, or a decrease in their proliferation. We used a colony-forming units megakaryocyte (CFU-Mk) assay to evaluate these consequences and predict platelet recovery in patients. In CD34+ PBPCs from 10 children with solid tumors, we observed no selective loss in CFU-Mk numbers during immunoselection processing and no impairment of clonogenicity. The CFU-Mk yield (59.2 +/- 11.3%) was at least similar to the CD34+ yield (44.2 +/- 3.8%). We assessed the predictive value of CFU-Mk numbers infused for recovery of platelet lineage. We found an inverse correlation between the time taken to reach a platelet count greater than 50 x 10(9)/L and only the CFU-Mk dose (r = -0.71; p = 0.022) among the different type of progenitors, including colony-forming units granulocyte-macrophage (CFU-GM), burst-forming units erythrocyte (BFU-E) and colony-forming units-mixed (CFU-Mix). These findings suggest that CFU-Mk number could be used as sole predictive functional parameter for platelet reconstitution in children after immunoselection of CD34+ cells, in particular for low CD34+ cell dose, and thus as an indicator for initial quality of hematopoietic cells before in vitro expansion.

Molecular detection of a late-appearing BCR-ABL gene in a child with T-cell acute lymphoblastic leukemia.

Approximately 2-5% of children with newly diagnosed acute lymphoblastic leukemia (ALL) have a Philadelphia (Ph) chromosome detectable on cytogenetic analysis, which is associated with a poor prognosis. In rare ALL cases the Ph chromosome may appear in leukemic cells during the course of the disease. We report here the case of a 5.5-year-old male patient with T-ALL who was found to have the b2a2 BCR-ABL mRNA transcript by reverse transcriptase-polymerase chain reaction (RT-PCR) at first marrow relapse. At the time of initial diagnosis, no BCR-ABL transcripts had been detected by PCR in the patient's blood and marrow samples. Further studies were performed using a competitive PCR titration assay and the fluorescence in situ hybridization (FISH) method to monitor the leukemic clone. Progression of the disease was associated with a higher BCR-ABL transcript level and an increasing proportion of BCR-ABL-positive cells. Metaphase FISH analysis identified the presence of the BCR-ABL fusion gene on a normal chromosome 22. This study shows that a late-appearing Ph translocation in ALL may be cytogenetically invisible. Quantitative RT-PCR and FISH techniques are appropriate and efficient methods for detecting these rare ALL variants expressing the BCR-ABL fusion gene and for estimating the level of residual disease following treatment.

rhGM-CSF vs placebo following rhGM-CSF-mobilized PBPC transplantation: a phase III double-blind randomized trial.

In this placebo-controlled randomized trial we evaluated the hematological and clinical effects of r-Hu GM-CSF after high-dose chemotherapy (HDC) followed by GM-CSF-mobilized PBPC transplantation. Fifty patients with poor prognosis malignancies were randomized in a double-blind study to receive either GM-CSF or placebo after HDC followed by PBPC rescue. For all patients, PBPCs were recruited using a combination of VP-16 (300 mg/m2 on days 1 and 2), cytoxan (3 g/m2 on days 3 and 4) and GM-CSF (5 micrograms/kg from day 5). No differences were demonstrated between the two groups in median time to neutrophil or platelet recoveries. There was no significant difference between the GM-CSF group and the placebo group in the median duration of post-transplant hospitalization, in the number of days of antibiotic treatment, in the number of infections and in red blood cell or platelet transfusion requirements. There was a significant difference with an advantage for the placebo group in the mean duration of febrile days (P = 0.01). We conclude that the administration of GM-CSF in patients transplanted with GM-CSF-mobilized PBPC is not associated with a clinical benefit in term of tempo of engraftment, numbers of documented infections, transfusion requirements and mucositis grading.