Clinical results according to age in patients with chronic myeloid leukemia receiving imatinib frontline: The younger, the later, the worse?

OBJECTIVES: To evaluate differences in clinical results according to age among patients with chronic myeloid leukemia (CML). METHODS: 207 consecutive CML patients treated with imatinib frontline were revised, dividing them in young adults (>20 < 45 years) (YA), middle-aged adults (≥45 < 65 years) (MA) and elderly (≥65 years) (EL). RESULTS: Cumulative incidence of complete cytogenetic response (CCyR) and major molecular response (MMolR) were significantly higher in MA compared with YA and EL (P < .001 for CCyR and P = .001 for MMolR). Number of total events was lower in MA (8 [11.1%] vs 21 [34.4%] in YA and 28 [37.8%] in EL, P = .001): no difference was observed for blastic evolution (P = .478). Number of deaths was higher in the EL (12 [16.2%] vs 2 [3.2%] in YA and 0 in MA, P < .001): however, 11/12 deaths in EL were not related to CML. The PFS curve in MA was significantly longer than in YA and in EL (P = .02). The OS curve in EL was significantly shorter than in YA and in MA (P < .001). CONCLUSIONS: Age at diagnosis influences significantly the course of CML patients treated with imatinib: a possible explanation of the counterintuitive worse course in YA is the delayed diagnosis compared to elderly.

Factors predicting survival in chronic lymphocytic leukemia patients developing Richter syndrome transformation into Hodgkin lymphoma.

We hereby report the clinical and biologic features of 33 of 4680 (0.7%) patients with chronic lymphocytic leukemia (CLL), managed at 10 Italian centers, who developed Hodgkin lymphoma (HL), a rare variant of Richter syndrome. The median age at CLL and at HL diagnosis were 61 years (range 41-80) and 70 years (range 46-82), respectively, with a median interval from CLL to the diagnosis of HL of 90 months (range 0-258). In 3 cases, CLL and HL were diagnosed simultaneously. Hl was characterized by advanced stage in 79% of cases, International Prognostic Score (IPS) ≥4 in 50%, extranodal involvement in 39%, B symptoms in 70%. Prior treatment for CLL had been received by 82% of patients and included fludarabine in 67%. Coexistence of CLL and HL was detected in the same bioptic tissue in 87% of cases. The most common administered treatment was the ABVD regimen given to 22 patients (66.6%). The complete response (CR) rate after ABVD was 68%, and was influenced by the IPS (P = .03) and interval from the last CLL treatment (P = .057). Survival from HL was also influenced by the IPS (P = .006) and time from the last CLL treatment (P = .047). The achievement of CR with ABVD was the only significant and independent factor predicting survival (P = .037). Taken together, our results show that the IPS and the interval from the prior CLL treatment influence the likelihood of achieving CR after ABVD, which is the most important factor predicting survival of patients with CLL developing HL.

Italian external and multicentric validation of the MD Anderson Cancer Center nomogram and prognostic index for chronic lymphocytic leukaemia patients: analysis of 1502 cases.

We performed an external and multicentric validation of the nomogram and prognostic index (PI) proposed by the MD Anderson Cancer Center to prognostically stratify chronic lymphocytic leukaemia (CLL) patients in 1502 CLL cases. All six parameters involved in the nomogram and PI (age, sex, absolute lymphocyte count, number of lymph node groups, Rai stage and ß2-microglobulin) were independently associated with survival. The nomogram was accurate in predicting survival (c-index = 0·82). According to the PI, 38·7% of patients were at low-risk, 58·3% at intermediate-risk and 3% at high-risk. The estimated median survival times were: not reached for low-risk, 13·4 years for intermediate-risk and 3·4 years for high-risk. The estimated median and 5-year survival by PI were similar to those originally reported. The PI remained a predictor of survival when analysis was limited to 847 Rai stage 0 (P < 0·0001) and 151 clinical monoclonal B-cell lymphocytosis (cMBL) cases (P = 0·033). Finally, the PI allowed prediction of time to therapy in all patients (P < 0·0001), in Rai 0 (P < 0·0001) and in cMBL cases (P = 0·044). Our results confirm the ability of the PI to predict prognosis, even in early stage disease cases. The study also extended the utility of the PI to cMBL cases.

Oral anticoagulant therapy in Italian patients 80 yr of age or older with atrial fibrillation: a pilot study of low vs. standard PT/INR targets.

BACKGROUND: Oral anticoagulation therapy (OAT), which aims to prevent thromboembolism in patients with atrial fibrillation (AF), is underused in subjects who are over the age of 80 yr because of the associated bleeding risk. The aim of this study was to evaluate the efficacy and safety of OAT with low (2.0) vs. standard (2.5) PT/international normalised ratio (INR) targets in patients over the age of 80. MATERIALS AND METHODS: Of 233 patients aged 80 yr or older with AF on OAT, 58 had unstable PT/INR values and achieved reduced targets. These patients were enrolled as a group (A) in a case-control study and were treated with a low (2.0) PT/INR target. They were compared with a second group (B) of 58 additional patients who were matched for age and CHADS scores and treated with a standard (2.5) PT/INR target. Group A OAT parameters were also compared before and after the PT/INR reduction. The time in the therapeutic range (TTR%), PT/INR values >5, haemorrhages and strokes were prospectively evaluated in the two groups after 2 yr of follow-up. RESULTS: Of the 116 enrolled patients, 55 group A and 57 group B patients were evaluated. The TTR was 72.59% in group A and 64.43% in group B (P < 0.01). The percent of PT/INR values >5 was 0.68% for group A and 1.42% for group B (P < 0.05). Haemorrhages and thromboses occurred only in group B patients. The before and after analysis in group A showed that a low INR target produced an increase in the TTR (53.05% vs. 72.59%; P < 0.0001) and a reduction in the PT/INR values > 5 (1.72% vs. 0.68%; P < 0.001). CONCLUSIONS: A low PT/INR target seems effective and safe in Italian patients with AF over the age of 80. Further trials are needed to confirm the hypothesis generated by this study.

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.

Management of elderly and unfit patients with chronic lymphocytic leukemia.

INTRODUCTION: About 75% of patients with chronic lymphocytic leukemia (CLL) are more than 65 years at the time of diagnosis. Treatment of the elderly remains complicated due to multiple factors, such as comorbidities, decline in functional reserve and fitness. Since chronological age by itself cannot properly predict life expectancy and treatment tolerance, an accurate assessment of the fitness status is of crucial importance for an optimal treatment choice. Areas covered: This review will discuss the most relevant aspects concerning the issues experienced in the management of elderly/unfit patients with CLL. The most frequently observed age-related toxicities, fitness assessments, supportive care measures and treatment options for elderly patients and for patients who are deemed unfit will be discussed. Literature search methodology included examination of PubMed index. Expert commentary: During the last decade, different trials focusing on elderly/unfit patients have investigated more tolerable chemoimmunotherapy schedules and, more recently, the activity and safety of chemo-free regimens. Chlorambucil combined with an anti-CD20 monoclonal antibody has shown clinical activity with a relatively good profile of toxicity. The recent introduction of the B-cell receptor antagonists, ibrutinib and idelalisib, and other targeted drugs in development (e.g. venetoclax), is broadening the therapeutic armamentarium of elderly CLL patients.

Effectiveness and safety of therapy with vitamin K antagonists in Italian patients aged 80 years or older: a multicentre retrospective study comparing the Zeus algorithm with the PARMA algorithm or manual therapy.

BACKGROUND: The use of oral anticoagulant therapy (OAT) has constantly increased in the prevention of thromboembolism, particularly in patients 80 years of age or older. OBJECTIVE: The aim of this multicentre study was to evaluate the efficacy and safety of vitamin K antagonists (VKAs) in elderly patients managed with a computer dosing algorithm compared with a dosage decided by expert physicians. MATERIALS AND METHODS: Nine Italian thrombosis centres utilising the Zeus dosing algorithm were involved. The before-after study enrolled patients managed firstly by medical staff (manual system) or with the PARMA algorithm for 12 months from July 2008 to June 2009 and then with the Zeus algorithm during the analogous period from 2010 to 2011. Of 7605 patients in the OAT maintenance phase, 2281 were older than 80 years (mean age 84.2 years). Data for these 2281 patients managed with both modalities were analysed. RESULTS: Of the 2281 patients 80 years of age or older, 1776 underwent OAT for atrial fibrillation (AF). Use of a dosing algorithm increased the OAT quality: time in therapeutic range (TTR) was significantly (p < 0.001) higher during the Zeus period than during the manual period (71.6 vs. 68.8 %). The TTR achieved with Zeus was similar to that obtained with the PARMA algorithm. In addition, patients managed with Zeus took a weekly drug dosage significantly (p < 0.01) lower than that both suggested by PARMA and prescribed by expert physicians, with a reduced number of adverse events. CONCLUSIONS: This study confirms that the effectiveness and safety of VKA therapy in patients 80 years of age or older increases with computer dosing algorithms.