Mario Annunziata

Rituximab for warm‐type idiopathic autoimmune hemolytic anemia: a retrospective study of 11 adult patients

Warm‐type idiopathic autoimmune hemolytic anemia (AIHA) is a relatively common hematologic disorder resulting from autoantibody production against red blood cells. Steroids represent the first‐line therapeutic option, and immunosuppressive agents as well as splenectomy are used for refractory cases. Recently, the anti‐CD20 monoclonal antibody rituximab has been shown to control autoimmune hemolysis in patients with refractory chronic disease. We report results from a retrospective analysis of 11 adult patients receiving rituximab for steroid‐refractory AIHA of the warm type at a mean age of 55 yr (range 23–81 yr). All patients were given methyl‐prednisolone as first‐line treatment and some of them also received azathioprine and intravenous high‐dose immunoglobulins. One patient underwent splenectomy. All patients were considered refractory to steroids and/or immunosuppressive drugs and all were then given weekly rituximab (375 mg/m2) for four consecutive weeks. An increase in hemoglobin (Hgb) levels in response to rituximab, with a mean increment of 3.3 g/dL (95% CI 2.1–4.4), was observed in all cases. Four patients required packed red cell transfusions before starting rituximab and all became transfusion‐free. At a mean follow‐up of 604 d (range 30–2884 d) since the treatment of AIHA with rituximab, all patients are alive, eight (73%) of them in complete remission (CR) and three (27%) in partial remission (PR). A moderate hemolysis still persisted in six (54%) patients. In conclusion, our experience clearly demonstrates that anti‐CD20 monoclonal antibody rituximab is an effective and safe alternative treatment option for idiopathic AIHA, in particular, for steroid‐refractory disease.

Charlson comorbidity index and adult comorbidity evaluation-27 scores might predict treatment compliance and development of pleural effusions in elderly patients with chronic myeloid leukemia treated with second-line dasatinib

Background Comorbidities may affect survival and choice of treatment among cancer patients. In fact, comorbidities have been identified as significant determinants of response to therapy in older patients with acute myeloid leukemia, breast cancer, head and neck cancer, and lung cancer. The Charlson comorbidity index and adult comorbidity evaluation-27 are lists of comorbidities with a weight assigned from 1 to 6 for the former and from 0 to 3 for the latter score, derived from relative risk estimates of a proportional hazard regression model using clinical data. Design and Methods We retrospectively evaluated the Charlson index and adult comorbidity evaluation-27 score in a cohort of 125 elderly (> 60 years) patients with chronic phase chronic myeloid leukemia who received dasatinib after showing resistance or intolerance to imatinib with the aim of establishing associations between comorbidities and the development of pleural effusions or compliance with the drug treatment. Results We found a significant association between the Charlson index as well as the adult comorbidity evaluation-27 score and the rate of drug reduction or suspension: with regards to the Charlson index, 49% of score 0 patients had a dose reduction compared to 63% of patients with score 1, 74% of those with score 2 and 100% of patients with score 3–5 (P=0.03); with regards to the adult comorbidity evaluation-27 score, 45% of patients had score 0–1 and 69% of patients with score 2–3 had a dose reduction. Of the 65 patients with Charlson score 0, 29% had at least one suspension of treatment (79% for hematologic and 21% for non-hematologic toxicity), compared to 46% of patients with score 1 (37% for hematologic and 69% for non-hematologic toxicity), 58% of patients with score 2 (36% for hematologic and 64% for non-hematologic toxicity) and 100% of patients with score 3 or 4 (all patients for both types of toxicity). High adult comorbidity index-27 scores identified patients at high risk of grade 3/4 hematologic toxicity. Forty-one patients (32.8%) experienced pleural effusion during treatment: the highest scores for both indices were associated with an increased risk of pleural effusions. Conclusions In elderly patients with chronic myeloid leukemia treated with dasatinib, the rate of drug reduction or suspension and the incidence of pleural effusions seem to be associated with the presence of comorbidities: stratification according to the Charlson index and adult comorbidity evaluation-27 score before dasatinib therapy may enable the identification of patients at risk of major toxicities.

Incidence, risk factors and management of pleural effusions during dasatinib treatment in unselected elderly patients with chronic myelogenous leukaemia

To assess the most important features and clinical impact of pleural effusions, which are a common toxicity during dasatinib treatment and often impair its high efficacy, 172 unselected consecutive patients with chronic myelogenous leukaemia in chronic phase treated in 27 Italian centres, with dasatinib when aged >60 years for resistance/intolerance to imatinib, were examined. During treatment, 52/172 patients (30.2%) presented pleural effusion, which was grades 1–2 in 38 patients and grades 3–4 in 14 patients (8.1% of the entire cohort of patients), according to the WHO scale; in 14/52 patients (26.9%), there was a concomitant pericardial effusion. Pleural effusion was recurrent in 25/52 patients (48.0%). Median time from dasatinib to first pleural effusion was 11.0 months (interquartile range 3.6–18.6). Eleven patients (6.4%) required permanent dasatinib discontinuation. Only presence of concomitant pulmonary disease ( p = 0.035) and initial daily dose of dasatinib (140 mg vs 100 mg, p = 0.014) were significantly associated with pleural effusions. There were no differences among patients with or without pleural effusions as concerns response rates and overall survival. Pleural effusions were common in our unselected ‘real‐life’ population of elderly patients but were clinically manageable and did not seem to affect treatment results. Copyright

Vincristine as salvage treatment for refractory thrombotic thrombocytopenic purpura.

Abstract Vincristine (1.4 mg/m2 on day 1, followed by 1 mg on days 4 and 7) was given to eight patients with thrombotic thrombocytopenic purpura (TTP) who were refractory to plasma exchange (n=4) or plasma infusion (n=4). Seven of eight patients (87%) achieved a complete response; one was refractory to treatment and died within a few weeks. After a median follow-up of 50 months, all responding patients are alive and well. Two patients relapsed and were successfully retreated with vincristine. Toxicity was mild, consisting of two episodes of leukopenia and one of autonomic neuropathy leading to paralytic ileus in a patient aged 70 years. We conclude that vincristine is highly effective in the treatment of patients suffering from refractory TTP, with negligible toxicity.

Dasatinib is safe and effective in unselected chronic myeloid leukaemia elderly patients resistant/intolerant to imatinib

To highlight dasatinib role in the elderly, 125 unselected patients with CP-CML aged >60 years resistant/intolerant to imatinib were retrospectively evaluated. Grade 3-4 haematological and extra-haematological toxicities were reported in 39 (31.2%) and 34 (27.2%) patients; grade 3-4 haematological toxicity was higher in patients with 140 mg starting dose (50.0% vs 19.6%, p=0.001). Grade 3-4 pleuro-pericardial effusions occurred in 10 patients (8.0%). Dose reductions were more common in patients with 140 mg (88.4% vs 26.7%, p<0.001). Of 122 evaluable patients, 72 (59.1%) had cytogenetic response [12 (9.8%) partial, 60 (49.3%) complete]. Overall, 38/60 patients in complete CyR also achieved a molecular response. Cumulative OS at 24 and 48 months were 93.1% (95% CI 88.4-97.8) and 84.2% (95% CI 74.6-93.7). Dasatinib, at the recommended dose of 100mg/day, is effective and safe also in unselected elderly subjects.

Fludarabine plus cyclophosphamide for the treatment of advanced chronic lymphocytic leukemia

Abstract: Objectives: Therapeutic results in advanced chronic lymphocytic leukemia (CLL) are still unsatisfactory in terms of complete remission achievement and duration, in spite of the extensive use of purine analogs. The objective of this study was to describe the clinical characteristics and treatment results from a series of 32 patients managed with a therapeutic program based on the combination of fludarabine and cyclophosphamide (CTX).

Immunophenotypic analysis enables the correct prediction of t(8;21) in acute myeloid leukaemia.

Immunophenotypic findings from 14 patients affected by acute myeloid leukaemia (AML) with t(8;21) were compared to those obtained from 79 AML patients with normal or other aberrant karyotypes. Classic lineage markers, adhesion molecules, surface enzymes, stem‐cell‐ related antigens and HLA‐DR were investigated. Following evaluation by the Mann‐Whitney test, we found that t(8;21) AMLs showed a significantly higher expression of CD19, CD34, CD56, CD45RA and CD54. Conversely, blasts from patients in the control group significantly expressed higher levels of CD45R0, CD33, CD36, CD11b and CD14. In order to split the data at the best cut‐off point to achieve the most homogenous subset with regard to cytogenetic pattern, i.e. t(8;21) or not, the CART (Classification and Regression Trees) method was applied. In the univariate analysis by CART, statistically significant differences were found when CD19 was dichotomized at 10%, CD34 at 37%, CD45RA at 84%, CD54 at 21%, CD56 at 12% , CD36 at 14%, CD45R0 at 25%, CD11b at 18% and CD14 at 12%. Once cut‐off points were established by CART, we applied the logistic regression model to establish which combination of two or more antigens was most predictive for t(8;21). The combination CD19‐CD34 at the cut‐off points indicated above correctly classified 92/93 cases (98.9%). The addition of any other antigen combination to the CD19/CD34 model failed to improve the level of prediction. We conclude that AML with t(8;21) displays an exclusive immunophenotype that is highly predictive of the cytogenetic pattern.

Age influences initial dose and compliance to imatinib in chronic myeloid leukemia elderly patients but concomitant comorbidities appear to influence overall and event-free survival

We applied Charlson comorbidity index (CCI) stratification on a large cohort of chronic myeloid leukemia (CML) very elderly patients (>75 years) treated with imatinib, in order to observe the impact of concomitant diseases on both compliance and outcome. One hundred and eighty-one patients were recruited by 21 Italian centers. There were 95 males and 86 females, median age 78.6 years (range 75-93.6). According to Sokal score, 106 patients were classified as intermediate risk and 55 as high risk (not available in 20 patients). According to CCI stratification, 71 patients had score 0 and 110 a score ≥ 1. Imatinib standard dose was reduced at start of therapy (200-300 mg/day) in 68 patients independently from the evaluation of baseline comorbidities, but based only on physician judgement: 43.6% of these patients had score 0 compared to 34% of patients who had score ≥ 1. Significant differences were found in terms of subsequent dose reduction (39% of patients with score 0 compared to 53% of patients with score ≥ 1) and in terms of drug discontinuation due to toxicity (35% of patients with score 0 vs 65% of patients with score ≥ 1). We did not find significant differences as regards occurrence of hematologic side effects, probably as a consequence of the initial dose reduction: 39% of patients with score 0 experienced grade 3/4 hematologic toxicity (most commonly anemia) compared to 42% of patients with score ≥ 1. Independently from the initial dose, comorbidities again did not have an impact on development of grade 3/4 non-hematologic side effects (most commonly skin rash, muscle cramps and fluid retention): 62% of patients with score 0 compared to 52.5% of patients with score ≥ 1. Notwithstanding the reduced dose and the weight of comorbidities we did not find significant differences but only a trend in terms of efficacy: 66% of patients with score 0 achieved a CCyR compared to 54% of patients with score ≥ 1. Comorbidities appeared to have an impact on median OS (40.8 months for patients with score 0 vs 20.16 months for patients with score ≥ 1) on EFS and on non-CML death rate. Our results suggest that treatment of very elderly CML patients might be influenced by personal physician perception: evaluation at baseline of comorbidities according to CCI should improve initial decision-making in this subset of patients.

Ifosfamide, Epirubicin and Etoposide (IEV) Regimen as Salvage and Mobilization Therapy for Refractory or Early Relapsing Patients with Aggressive Non-Hodgkin's Lymphoma

The prognosis of early relapsing or refractory aggressive non-Hodgkins lymphoma (NHL) is still poor. Effective salvage therapy should be able to induce high response rate as well as to mobilize hematopoietic precursors. A combination of ifosfamide, epirubicin and etoposide (IEV) was given to 28 patients with refractory or relapsing high grade NHL (4 lymphoblastic lymphoma and 24 large cell lymphoma). All patients were evaluated for response. After 2 courses of IEV, the overall and complete response rate were 64% and 39%, respectively. All patients were controlled for mobilization of peripheral blood stem cells, which was successful in 26 out of 28 (93%). Overall, 25 out of 26 patients proceeded to autologous stem cell transplantation (ASCT). Toxicity was mild, with no occurrence of severe persisting extra-hematologic side-effects. Following the entire therapeutic program, including IEV and ASCT, median progression free survival has not yet been reached and 21 patients are alive (18 in continuous complete remission) after a median follow-up of 18 months. Our results demonstrate that treatment with IEV regimen is effective in refractory or relapsing aggressive NHL, resulting in a high percentage of successful stem cell mobilization and feasibility of ASCT.

High-dose cytarabine as consolidation treatment for patients with acute myeloid leukemia with t(8;21).

Seventeen patients affected by acute myeloid leukemia (AML) with t(8;21) were prospectively programmed to receive three courses of high-dose cytarabine (HDARA-C) as post-remission therapy. The median age was 39 years and in all cases t(8;21) was the only karyotypic abnormality. Complete remission (CR) was achieved in 14 out of 17 cases (82%) and, after first consolidation with NOVIA regimen (intermediate dose ARA-C plus mitoxantrone), all patients received the three planned courses of HDARA-C (3g/m(2) q12h on days 1, 3, 5). There were two documented infections, while all patients experienced fever of unknown origin (FUO). Nonhematological toxicity was mild. Thirteen out of 14 patients are in continuous CR after a median follow-up of 44 months. One patient relapsed at 16 months and, following CR2 achievement, underwent allogeneic transplantation; he died 3 months later while in CR from acute graft versus host disease (GVHD). Survival at 5 years is projected at 79%. Our data confirm the efficacy of repeated courses of HDARAC for patients with t(8;21) AML.