Francesca Ronco

Iron chelation therapy associated with improvement of hematopoiesis in transfusion-dependent patients.

BACKGROUND: It is well known that iron overload may cause multiple organ failure. In chronically transfused patients, optimal iron chelation therapy is associated with reduced morbidity and mortality. Furthermore, chelation therapy has been associated with erythroid responses.

Quality of life in elderly patients with acute myeloid leukemia: patients may be more accurate than physicians

Background The aim of this study was to evaluate changes in quality of life scores and their association with therapy and survival in unselected elderly patients with acute myeloid leukemia. Design and Methods From February 2003 to February 2007, 113 patients aged more than 60 years with de novo acute myeloid leukemia were enrolled in a prospective observational study. Two different quality of life instruments were employed: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – C30 (EORTC QLQ-C30) and a health-related quality of life questionnaire for patients with hematologic diseases (QOL-E). Results Forty-eight patients (42.4%) received intensive chemotherapy and 65 (57.6%) were given palliative treatments. Age greater than 70 years (P=0.007) and concomitant diseases (P=0.019) had a significant impact on treatment allocation. At diagnosis, general quality of life was affected [median QOL-E standardized score 54, interquartile range 46–70; median EORTC global score 50, interquartile range 41–66]. Most patients were given a good ECOG Performance Status (< 2), which did not correlate with the patients’ perception of quality of life. At multivariate analysis, palliative approaches (P=0.016), age more than 70 years (P=0.013) and concomitant diseases (P=0.035) each had an independent negative impact on survival. In a multivariate model corrected for age, concomitant diseases and treatment option, survival was independently predicted by QOL-E functional (P=0.002) and EORTC QLQ-C30 physical function (P=0.030) scores. Conclusions Quality of life could have an important role in elderly acute myeloid leukemia patients at diagnosis as a prognostic factor for survival and a potential factor for treatment decisions.

Darbepoetin alfa for the treatment of anemia associated with myelodysplastic syndromes: efficacy and quality of life.

To evaluate efficacy, safety, changes in biological features, and quality of life (QoL) in low-risk anemic patients with MDS treated with darbepoetin alfa (DPO), 41 patients received DPO 150 μg weekly for 24 weeks. The dose was increased to 300 μg weekly in non-responsive patients. During treatment, 10/17 (59%) transfusion-dependent (TD) and 13/23 (56%) transfusion-free (TF) patients responded. In TF patients, Hb increased from 9.2 ± 0.9 g/dL to 10.3 ± 1.4 g/dL by 24 weeks (p = 0.004). The mean response duration was 22 weeks (95% CI: 19.7–24.0) in TF patients compared with 15.1 weeks (95% CI: 13.3–17.5) in TD patients. Response to treatment was associated with increases in QoL. Decreases in the percentage of apoptotic progenitor cells (p = 0.007) and CD34+ cells (p = 0.005) were observed. These results confirm previous studies demonstrating the safety and efficacy of DPO in anemic patients with MDS. Biological changes and improvement in QoL were associated with response. Adequate dosing is to be determined.

Changes in RPS14 expression levels during lenalidomide treatment in Low- and Intermediate-1-risk myelodysplastic syndromes with chromosome 5q deletion.

Background:  Haploinsufficiency of the ribosomal protein S14 RPS14 gene, located in the common deleted region of chromosome 5q, is a potential causal factor of 5q− syndrome. Lenalidomide elicits high response rates and morphological improvements in myelodysplastic syndrome (MDS) patients with chromosome 5q deletion [del(5q)].

CRLF2 overexpression identifies an unfavourable subgroup of adult B-cell precursor acute lymphoblastic leukemia lacking recurrent genetic abnormalities

BACKGROUND A deregulated CRLF2 (d-CRLF2) expression was described in B-cell acute lymphoblastic leukemia without recurrent fusion genes (B-NEG ALL). While the role of d-CRLF2 in children has been extensively described, little is known about its role and impact in adult ALL. METHODS Expression levels of CRLF2 were evaluated by quantitative real-time PCR in 102 newly-diagnosed adult B-NEG ALL and correlated with the clinico-biological characteristics and outcome. Incidence and clinical impact of the P2RY8/CRLF2 transcript was also assessed. RESULTS High CRLF2 levels, as continuous variable, were significantly associated with hyperleucocytosis (p=0.0002) and thrombocytopenia (p=0.005); when a cut-point at ΔCt≤8 was applied, 35 cases (34.3%), mostly males (80%), proved positive for CRLF2 expression. High CRLF2 levels, as continuous or categorical variable, were associated with a worse disease-free (p=0.003 and p=0.015) and overall survival (p=0.017 and 0.0038). Furthermore, when CRLF2 was analyzed as a categorical variable, a high statistical association was found with IKZF1 deletion and mutations in the JAK/STAT pathway (p=0.001 and p<0.0001, respectively). Finally, the P2RY8/CRLF2 transcript, identified in 8/102 patients (7.8%), was associated with a poor outcome. CONCLUSIONS In adult B-NEG ALL, high CRLF2 expression is associated with distinct clinico-biological features and an unfavourable prognosis in both univariate and multivariate analysis; similarly, P2RY8/CRLF2 positivity correlates with a poor outcome. The quantification of CRLF2 is an important prognostic marker in adult B-lineage ALL without known genetic lesions.

Long-Term Results in Multiple Myeloma After High-Dose Melphalan and Autologous Transplantation According to Response Categories in the Era of Old Drugs

BACKGROUND The aim of this study was to investigate the correlation between the long-term prognosis of multiple myeloma (MM) and the quality of response to therapy in a cohort of 173 patients treated with high-dose melphalan (HDM) and autologous transplantation in the era of old drugs. PATIENTS AND METHODS A total of 173 patients with de novo MM who received a transplant between 1994 and 2010 were analyzed. VAD (vincristine, doxorubicin [Adriamycin], dexamethasone) was used as front-line regimen before auto-HPCT. The conditioning was HDM 200 mg/m(2). Patients were evaluated for clinical response using the criteria from the European Group for Blood and Marrow Transplantation, modified to include near complete remission (nCR) and very good partial remission (VGPR). RESULTS The response distribution after transplantation in our series was complete remission (CR) in 33 cases (19%), nearly complete remission (nCR) in 38 cases (22%), VGPR in 30 cases (17%), partial remission (PR) in 65 cases (38%), and stable disease (SD) in 7 cases (4%). Patients were followed for 48 ± 36 months. Median overall survival (OS) was not reached for the CR group. Progression-free survival (PFS) was 122 months for CR, 55 months for nCR, 56 months for VGPR, 32 months for PR, and 22 months for SD. Significant differences in PFS and OS were found between the CR and nCR groups (P = .003 and P = .001, respectively), between the CR and VGPR groups (P = .002 and P = .001, respectively), and between the CR and PR groups (P = .000 and P = .001, respectively). Responses were clustered in 3 main categories, ie, CR, nCR + VGPR + PR, and SD. The respective 10-year PFS and OS values were 58% and 70% for CR, 15% and 18% for nCR + VGPR + PR, and 0% and 0% for SD. CONCLUSION The achievement of depth and prolonged response represents the most important prognostic factor. The relapse rate is low for patients in CR after 10 years of follow-up, possibly signifying a cure.

A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study

In the GIMEMA LAL 0904 protocol, adult Philadelphia positive acute lymphoblastic leukemia patients were treated with chemotherapy for induction and consolidation, followed by maintenance with imatinib. The protocol was subsequently amended and imatinib was incorporated in the induction and post-remission phase together with chemotherapy. Due to the toxicity of this combined approach, the protocol was further amended to a sequential scheme based on imatinib plus steroids as induction, followed by consolidation with chemotherapy plus imatinib and, when applicable, by a hematopoietic stem cell transplant. Fifty-one patients (median age 45.9 years) were enrolled in the final sequential protocol. At the end of induction (day +50), 96% of evaluable patients (n=49) achieved a complete hematologic remission; after consolidation, all were in complete hematologic remission. No deaths in induction were recorded. Overall survival and disease-free survival at 60 months are 48.8% and 45.8%, respectively. At day +50 (end of imatinib induction), a more than 1.3 log-reduction of BCR-ABL1 levels was associated with a significantly longer disease-free survival (55.6%, 95%CI: 39.0–79.3 vs. 20%, 95%CI: 5.8–69.1; P=0.03), overall survival (59.1%, 95%CI: 42.3–82.6 vs. 20%, 95%CI: 5.8–69.1; P=0.02) and lower incidence of relapse (20.5%, 95%CI: 7.2–38.6 vs. 60.0%, 95%CI: 21.6–84.3; P=0.01). Mean BCR-ABL1 levels remained significantly higher in patients who subsequently relapsed. Finally, BCR-ABL1p190 patients showed a significantly faster molecular response than BCR-ABL1p210 patients (P=0.023). Though the study was not powered to evaluate the role of allogeneic stem cell transplant, allografting positively impacted on both overall and disease-free survival. In conclusion, a sequential approach with imatinib alone in induction, consolidated by chemotherapy plus imatinib followed by a stem cell transplant is a feasible, well-tolerated and effective strategy for adult Philadelphia positive acute lymphoblastic leukemia, leading to the best long-term survival rates so far reported. (clinicaltrials.gov identifier: 00458848).

Clinical relevance of hypogammaglobulinemia, clinical and biologic variables on the infection risk and outcome of patients with stage A chronic lymphocytic leukemia

The prognostic effect of hypogammaglobulinemia (HGG), clinical and biologic characteristics on the infection risk and outcome has been retrospectively analyzed in 899 patients with stage A chronic lymphocytic leukemia (CLL). Low levels of IgG were recorded in 19.9% of patients at presentation, low levels of IgM and/or IgA in 10.4% and an additional 20% of patients developed HGG during the course of the disease. Before the start of any treatment, 160 (12.9%) patients experienced at least one grade ≥3 infection requiring a systemic anti-infective treatment and/or hospitalization. While IgG levels at diagnosis were not associated with an increased risk of grade ≥3 infection or with an adverse outcome, a significantly increased rate of grade ≥3 infections was recorded in patients with unmutated IGHV (p=0.011) and unfavorable FISH aberrations (p=0.009). Late onset HGG, more frequently recorded in patients with Rai stage I-II (p=0.001) and unmutated IGHV (p=0.001), was also associated with a higher rate of severe infections (p=0.002). These data indicate that, stage A patients with clinical and biologic characteristics of a more aggressive disease develop more frequently late onset HGG, grade ≥3 infections and require a closer clinical monitoring.

Tolerability and efficacy of busulfan and fludarabine as allogeneic pretransplant conditioning therapy in acute myeloid leukemia: comparison with busulfan and cyclophosphamide regimen.

BACKGROUND The aim of this study was to compare safety and efficacy of the association of busulfan with cyclophosphamide (BuCy2) versus busulfan and fludarabine (BuFlu) as a conditioning regimen in allogeneic hematopoietic progenitor cell transplantation (allo-HPCT) in patients with acute myeloid leukemia (AML). PATIENTS AND METHODS A total of 65 consecutive patients who received an allo-HPCT from Human Leucocyte Antigen-matched sibling donors were analyzed. The conditioning was BuCy2 in 48 patients and BuFlu in 17 patients. RESULTS There were no significant differences between the 2 cohorts in hematological engraftment, incidence of extrahematological toxicities, and acute graft versus host disease (GVHD). The incidence of chronic GVHD was 34% in the BuCy2 group versus 57% in the BuFlu group (P = .03). Transplant-related mortality was 17% (8 patients) in the BuCy2 group versus 0 in the BuFlu arm. Disease-related mortality was similar in the whole study population; in high-risk AML patients it was 11% in the BuCy2 group and 19% in the BuFlu group (P = .015). The probability of disease-free and event-free survival at 2 years was, respectively, 70% and 60% in the BuCy2 group and 59% and 58% in the BuFlu group (P = .06 and P = not significant [ns]). The probability of overall survival at 2 years was 71% in the BuCy2 group and 63% in the BuFlu group (P = ns), and in the high-risk group it was 83% and 67% in the BuCy2 and BuFlu group, respectively (P = ns). CONCLUSION BuFlu is well tolerated and is less toxic than BuCy2 and our results did not suggest that in high-risk AML, BuCy2 should be the favorite regimen in terms of efficacy.

Genetic risk of prediabetes and diabetes development in chronic myeloid leukemia patients treated with nilotinib

Impaired fasting glucose and type 2 diabetes represent adverse events in patients with chronic myeloid leukemia (CML) treated with the second generation tyrosine kinase inhibitor nilotinib. An unweighted genetic risk score (uGRS) for the prediction of insulin resistance, consisting of 10 multiple single-nucleotide polymorphisms, has been proposed. We evaluated uGRS predictivity in 61 CML patients treated with nilotinib. Patients were genotyped for IRS1, GRB14, ARL15, PPARG, PEPD, ANKRD55/MAP3K1, PDGFC, LYPLAL1, RSPO3, and FAM13A1 genes. The uGRS was based on the sum of the risk alleles within the set of selected single-nucleotide polymorphisms. Molecular response (MR)3.0 and MR4.0 were achieved in 90% and 79% of patients, respectively. Before treatment, none of the patients had abnormal blood glucose. During treatment and subsequent follow-up at 80.2 months (range: 1-298), seven patients (11.5%) had developed diabetes that required oral treatment, a median of 14 months (range: 3-98) after starting nilotinib treatment. Twelve patients (19.7%) had developed prediabetes. Prediabetes/diabetes-free survival was significantly higher in patients with a uGRS <10 than in those with higher scores (100% vs. 22.8 ± 12.4%, p <0.001). Each increment of one unit in the uGRS caused a 42% increase in the prediabetes/diabetes risk (hazard ratio = 1.42, confidence interval: 1.04-1.94, p = 0.026). The presence of more than 10 allelic variants associated with insulin secretion, processing, sensitivity, and clearance is predictive of prediabetes/diabetes development in CML patients treated with nilotinib. In clinical practice, uGRS could help tailor the best tyrosine kinase inhibitor therapy.