Ruxolitinib Adherence in Myelofibrosis and Polycythemia Vera: the "RAMP" Italian multicenter prospective study.

Ruxolitinib is beneficial in patients with myelofibrosis (MF) and polycythemia vera (PV). Information on ruxolitinib adherence is scant. The Ruxolitinib Adherence in Myelofibrosis and Polycythemia Vera (RAMP) prospective multicenter study (NCT06078319) included 189 ruxolitinib-treated patients. Patients completed the Adherence to Refills and Medications Scale (ARMS) and Distress Thermometer and Problem List (DTPL) at the earliest convenience, after registration in the study, and at later timepoints. At week-0, low adherence (ARMS > 14) and high distress (DT ≥ 4) were declared by 49.7% and 40.2% of patients, respectively. The main reason for low adherence was difficult ruxolitinib supply (49%), intentional (4.3%) and unintentional (46.7%) non-take. In multivariable regression analysis, low adherence was associated to male sex (p = 0.001), high distress (p < 0.001), and treatment duration ≥ 1 year (p = 0.03). Over time, rates of low adherence and high distress remained stable, but unintentional non-take decreased from 47.9% to 26.0% at week-48. MF patients with stable high adherence/low distress were more likely to obtain/maintain the spleen response at week-24. Low adherence to ruxolitinib represents an unmet clinical need that require a multifaceted approach, based on reason behind it (patients characteristics and treatment duration). Its recognition may help distinguishing patients who are truly refractory and those in need of therapy optimization.

Beta-1-integrin expression in adult acute lymphoblastic leukemia: possible relationship with the stem cell antigen CD34.

In the hemopoietic system, interactions between stem cells and components of the bone marrow microenvironment play a pivotal role in blood cell proliferation and differentiation. Among the adhesion molecules, the integrins of the beta 1-subfamily are known to direct cell-cell and cell-matrix interactions and evidence has been provided that CD34-positive stem cells bind either to the bone marrow stroma or to the extracellular matrix proteins through the beta 1-integrins. It seems that changes in their expression pattern or signalling function are likely to reflect disturbances at the hemopoietic bone marrow microenvironmental level. Any alteration of their biological functions makes them attractive candidates for playing decisive roles in the leukemic processes. In this view, beta 1-integrins have been recognized to mediate those cellular interactions and migrations that are important in the biology of leukemia. In this paper we review some aspects of the role played by beta 1-integrins, especially VLA-4 and VLA-5, in adult acute lymphoblastic leukemia in relation with the expression rate of the stem cell antigen CD34.

In vitro sensitivity of B-CLL cells to fludarabine and interferons.

In this study we evaluated the cytotoxicity of Fludarabine (FAMP) both alone and in combination with alpha and beta interferon (IFN) against B-cells from patients affected by chronic lymphocytic leukemia (CLL). We used an in vitro colorimetric assay based on the bioreduction of the tetrazolium salt XTT by viable cells. Fludarabine concentrations ranging from 0.03 to 30 microM were tested on cells collected from 22 B-CLL patients. For each fludarabine concentration, 800 I.U. of either alpha or beta IFN were added. Interferon alone did not exert any cytotoxic effect, while Fludarabine showed a strong cytotoxicity against B-CLL cells. The concentration of Fludarabine required to induce a 50% cytotoxicity (IC50) was below 3 microM (the achievable serum level after standard dose in vivo administration) for 19 out of 22 patients. After IFNs supplementation to Fludarabine, it was possible to identify three groups of samples. The first in which IFNs addition did not produce almost any significant change in Fludarabine cytotoxicity (13/22), the second in which there was an improvement in FAMP IC50 (6/22), and finally the third group in which IFNs worsened it (3/22). Stage of disease was the only identified factor accounting for these different results. The second group included samples from 5 patients at stage A and one at stage B, while in the third group all three samples were from patients at stage C. Interferon-alpha and -beta induced the same degree of FAMP IC50 variation.(ABSTRACT TRUNCATED AT 250 WORDS)

Vitro drug-induced apoptosis in freshly isolated leukemic cells: a flow cytometric analysis.

Fludarabine is considered a useful drug in the management of B-CLL resistant to conventional chemotherapy as it is able to trigger apoptosis in neoplastic B cells. In order to analyze this aspect, we tested by means of a simple and rapid flow cytometric method the in vitro apoptotic response of CD5+ B-CLL lymphocytes to FAMP, in comparison with other cytoreductive agents such as Interferons. Our findings showed that apoptosis occurred significantly in lymphocytes cultured with FAMP, but not with IFNs. In conclusion, flow cytometry allows an easy and rapid detection of in vitro drug-induced apoptosis, possibly representing also a reliable assay for testing tumor cell sensitivity or resistance.

CD34 expression in adult acute lymphoblastic leukemia.

The expression of the pluripotent stem cell antigen CD34 was evaluated at diagnosis in forty-five adult patients with de novo ALL. Comparison of clinical and hematological features between CD34 positive (24/45) and CD34 negative (21/45) patients showed that the former were of older age, had more pronounced lymphoid organ involvement and higher serum LDH levels. Immunophenotypic analysis of marrow blast cells revealed a significant predominance of the 'null' phenotype in the CD34 positive group, together with a strong expression of the VLA-4 and VLA-5 integrins (fibronectin receptors). CD34 positive ALL were also more frequently associated with either aberrant myeloid-related antigens (CD13, CD33) or the P-gp/MDR-1 phenotype. Only 11 out of 24 (45%) CD34 positive patients achieved complete remission after induction chemotherapy, compared to 20/21 (95%) CD34 negative cases. Furthermore, survival was significantly shorter in the CD34 positive group (6.6 mo. vs 13.5 mo.). These results suggest that in ALL, as in AML, CD34 positivity may predict a poor prognosis.