Background— Peripheral blood CD34 ⁺ cells and circulating endothelial progenitor cells (EPCs) increase in myocardial infarction and vascular injuries as a reflection of endothelial damage. Despite the occurrence of endothelial dysfunction in heart failure (HF), no data are available on EPC mobilization in this setting. We investigated the pattern of CD34 ⁺ cells and EPC mobilization during HF and their correlation with the severity and origin of the disease. Methods and Results— Peripheral blood CD34 ⁺ cells (n=91) and EPCs (n=41), assessed both as CD34 ⁺ cells coexpressing AC133 and vascular endothelial growth factor (VEGF) receptor-2 and as endothelial colony-forming units, were studied in HF patients (mean age 67±11 years) and 45 gender- and age-matched controls. Tumor necrosis factor-α (TNF-α) and its receptors (sTNFR-1 and sTNFR-2), VEGF, stromal derived factor-1 (SDF-1), granulocyte-colony stimulating factor (G-CSF), and B-type natriuretic peptide were also measured. CD34 ⁺ cells, EPCs, TNF-α and receptors, VEGF, SDF-1, and B-type natriuretic peptide were increased in HF. CD34 ⁺ cells and EPCs were inversely related to functional class and to TNF-α, being decreased in New York Heart Association class IV compared with class I and II and controls. No role was found for the origin of the disease. Conclusions— CD34 ⁺ cells and EPC mobilization occurs in HF and shows a biphasic response, with elevation and depression in the early and advanced phases, respectively. This could be related to the myelosuppressive role of TNF-α.

Key Points: CLL patients harboring mutated IGHV genes but neither 11q or 17p deletion experience durable remission after frontline FCR.

Aims There is increasing evidence that stem cell (SC) mobilization to the heart and their differentiation into cardiac cells is a naturally occurring process. We sought to assess the safety and feasibility of granulocyte-colony stimulating factor (G-CSF) administration in humans to enhance SC mobilization and left ventricle (LV) injury repair during myocardial infarction (MI). Methods and results Twenty patients with STEMI (mean age, 61±10 years), of whom 14 were submitted to primary percutaneous coronary intervention, were randomized to G-CSF (5 µg/kg/day s.c. for 4 consecutive days) or placebo. At entry and then at months 3 and 6, ^99mTc-sestamibi gated-SPECT was performed to estimate extension of perfusion defect (PD) and LV function. The study drug was well tolerated and induced a significant increase of white blood count, CD34⁺ cells, and CD34⁺ cells coexpressing AC133 and VEGFR-2. At follow-up, treated and placebo groups did not differ for the angiographic coronary late loss and showed a similar pattern of PD recovery, whereas in the former at 6 months LVEF and especially LVEDV tended to be relatively higher (P=0.068) and lower (P=0.054), respectively. Conclusion G-CSF administration in acute MI patients was feasible and did not lead to any clinical or angiographic adverse events and resulted in CD34⁺ and CD34⁺AC133⁺VEGFR2⁺ cell mobilization.

BACKGROUND: Patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) frequently relapse on imatinib with acquisition of BCR‐ABL kinase domain (KD) mutations. To analyze the changes that second‐generation tyrosine kinase inhibitors (TKIs) have brought in mutation frequency and type, a database review was undertaken of the results of all the BCR‐ABL KD mutation analyses performed in the authors' laboratory from January 2004 to January 2013.METHODS: Interrogation of the database retrieved 450 mutation analyses in 272 patients with Ph+ ALL. Prescreening of samples was performed with denaturing high‐performance liquid chromatography (D‐HPLC), followed by direct sequencing of D‐HPLC–positive cases.RESULTS: BCR‐ABL KD mutations were detected in 70% of imatinib‐resistant patients, with T315I, E255K, and Y253H mutations accounting for 75% of cases. Seventy‐eight percent of the patients reported to be resistant to second‐generation TKIs after imatinib failure were positive for mutations, and 58% of them had multiple mutations. Analysis of patients relapsing on dasatinib revealed a newly acquired T315I mutation in almost two‐thirds of the cases. Direct sequencing detected no mutations at diagnosis, even in patients who relapsed after a few months.CONCLUSIONS: Second‐generation TKIs ensure a more rapid debulking of the leukemic clone and have much fewer insensitive mutations, but long‐term disease control remains a problem, and the T315I mutation is revealed to be an even more frequent enemy. BCR‐ABL KD mutation screening of patients with Ph+ ALL who are receiving imatinib or second‐generation TKIs would be a precious ally for timely treatment optimization. In contrast, the clinical usefulness of conventional direct sequencing at diagnosis seems to be very low. Cancer 2014;120:1002–1009. © 2013 American Cancer Society.

In a phase II trial, we evaluated chlorambucil and rituximab (CLB‐R) as first‐line induction treatment with or without R as maintenance for elderly chronic lymphocytic leukemia (CLL) patients. Treatment consisted of eight 28‐day cycles of CLB (8 mg/m²/day, days 1–7) and R (day 1 of cycle 3, 375 mg/m²; cycles 4–8, 500 mg/m²). Responders were randomized to 12 8‐week doses of R (375 mg/m²) or observation. As per intention‐to‐treat analysis, 82.4% (95% CI, 74.25–90.46%) of 85 patients achieved an overall response (OR), 16.5% a complete response (CR), 2.4% a CR with incomplete bone marrow recovery. The OR was similar across Binet stages (A 86.4%, B 81.6%, and C 78.6%) and age categories (60–64 years, 92.3%; 65–69, 85.2%; 70–74, 75.0%; ≥75, 81.0%). CLB‐R was well tolerated. After a median follow‐up of 34.2 months, the median progression‐free survival (PFS) was 34.7 months (95% CI, 33.1–39.5). TP53 abnormalities, complex karyotype, and low CD20 gene expression predicted lack of response; SF3B1 mutation and BIRC3 disruption low CR rates. IGHV mutations significantly predicted PFS. R maintenance tended towards a better PFS than observation and was safe and most beneficial for patients in partial response and for unmutated IGHV cases. CLB‐R represents a promising option for elderly CLL patients. Am. J. Hematol. 89:480–486, 2014.