Laura Cannella

Comorbidities and FLT3‐ITD abnormalities as independent prognostic indicators of survival in Elderly acute myeloid leukaemia patients

Elderly acute myeloid leukaemia (AML) patients have a dismal prognosis due to biological features of disease in itself and to presence of comorbidities. Aim of this study was to evaluate the prognostic impact of comorbidity prognostic score systems applied in our population of patients. as well as other clinical‐biological features. We retrospectively considered the outcome of 120 patients aged >65 years diagnosed as having AML between January 2001 and December 2005. Comorbidities were evaluated by using Charlson comorbidity index (CCI), Hematopoietic cell transplantation comorbidity index (HCTCI) and a score proposed by Dombret et al. in 2007. Median patient age was 67 years. Forty‐six patients were treated with intensive chemotherapy and 23 reached a complete remission. Seventy‐four patients received only supportive therapies or low‐dose chemotherapy. Multivariate analysis showed the effects of leukocytosis (p = 0.0013), antecedent Myelodysplastic syndrome (MDS) (p = 0.011), FLT3 abnormalities (p = 0.032), CCI (p = 0.0037) and Dombret et al. score (p = 0.045) as independent prognostic parameters for survival. Based on these variables we were able to stratify patients in low and high risk, with different median overall survival: patients were considered as low risk if they had none or only one of the above mentioned adverse factors for survival, with a median overall survival of 447 days. Patients with two or more adverse factors were categorized as high risk: this subgroup had a median overall survival of 227 days (p = 0.001). Comorbidities are independent factors that influence survival. Application of CCI and Dombret score may help to better identify patients at diagnosis who can benefit from intensive chemotherapy. Copyright

Early hemorrhagic death before starting therapy in acute promyelocytic leukemia: association with high WBC count, late diagnosis and delayed treatment initiation

Early death is one of the major causes of failure in acute promyelocytic leukemia (APL), it occurs in approximately 5–10% of newly diagnosed cases and is most frequently due to severe intracranial or pulmonary bleeding. In the present single center study, we reviewed the clinical and biological

Evaluation of comorbidities at diagnosis predicts outcome in myelodysplastic syndrome patients

Recent data suggest that proper assessment of comorbidities is useful to predict the outcome of MDS patients receiving allogeneic stem cell transplantation. However, the results obtained in this highly selected subset of patients cannot be applied to the whole MDS population. We evaluated the impact of comorbidities in 418 consecutive MDS patients diagnosed at our institute from 1992 to 2005. All patients were classified according to WHO criteria and all received only conservative and supportive treatment. One or more comorbidities were detected in 390 patients (93%) at the time of diagnosis, with a higher incidence in older patients. Cardiac diseases were the most frequent comorbidities (30%) while diabetes and correlated adverse events were the second cause of comorbidity (20%). We applied 3 comorbidity prognostic scores (CCI, HCT-CI and a MDS-CI score proposed by Della Porta et al.). According to CCI score, 253 patients had a score 0, 111 patients had a score 1 and 54 patients had a score >2. According to HCT-CI, 209 patients had a score 0, 105 patients had a score 1 and 106 patients had a score >2. With MDS-CI score, 288 patients had a score 0 and 129 patients had a score >1. We found a significant correlation between survival and stratification according to CCI and MDS-CI scores (p=0.01 and 0.02, respectively), but not according to HCT-CI score. The number of comorbidities as evaluated according to CCI was directly correlated to the development of RBC transfusion-dependency and was associated to a significantly higher risk of death not related to leukemic evolution (HR = 2.12, p ≤ 0.001). Conversely, higher risk of non-leukemic death did not correlate with higher transfusional requirement according to HCT-CI and MDS-CI scores (p = 0.3 and 0.43, respectively). As suggested by Della Porta et al., also in our experience the presence of cardiac, liver, renal, pulmonary diseases and solid tumours was found to independently affect the risk of death in a multivariable Cox regression analysis (p values from <0.01 to 0.004). In conclusion, assessment of comorbidities at diagnosis in MDS patients may improve the ability of therapeutic decisions.

Patient-reported outcomes for the myelodysplastic syndromes: a new MDS-specific measure of quality of life

To the editor: In their recommendations for diagnosis and treatment of the myelodysplastic syndromes (MDS),[1][1] the European Leukemia Net point out the crucial role of quality of life (QoL) assessment, as affected patients are most often elderly and have a largely incurable disease. We agree that

Differences in hematological and non-hematological toxicity during treatment with imatinib in patients with early and late chronic phase chronic myeloid leukemia

Imatinib is a relatively specific inhibitor of the BCR/ABL tyrosine kinase, effective in chronic myeloid leukemia (CML). The aim of our study was to analyse the frequency and type of hematological and non-hematological adverse events in our series of late and early chronic phase patients with CML treated with imatinib and correlate the grade of hematological toxicity with the response obtained. Hematological events were seen in 59 out of 150 (39%) late chronic phase (CP) patients: of these, 24% experienced toxicity Grade 3–4. Of the 100 early CP patients, 26 (26%) had hematological adverse event: 7% experienced toxicity Grade 3–4 (p = 0.0001). We found that only in early CP patients, the occurrence of hematological side effects of any grade within 6 months of therapy had a negative influence on cytogenetic response. We compared the incidence of non-hematological adverse events occurring in late and in early CP patients and found that in these latter, some side effects were more frequent, such as weight gain, periorbital edema, muscle cramps, skin rashes, diarrhea, weeping. On the contrary, we found that bone pain and hemorrhagic events were more common in late CP patients. Grade 3–4 adverse events were recorded at rates below 4% and decreased over time: in late CP patients hemorrhages and muscle cramps were the most common side effects of Grade 3–4, whereas in early CP patients, the most frequent events were nausea, weight gain and cutaneous rash. We have observed that hematological and non-hematological side effects during imatinib therapy are different among late and early CP patients and that severe hematological toxicity may influence cytogenetic response only in early CP patients.

Refractory cytopenia with unilineage dysplasia: analysis of prognostic factors and survival in 126 patients

According to the revised WHO classification of 2008, dysplasia in ≥10% of one bone marrow lineage and one cytopenia constitutes the low-risk category of unilineage cytopenia and unilineage dysplasia (UCUD). We retrospectively reclassified, according to WHO, low-risk MDS from our database and found 126 subjects with these features at diagnosis: 79 patients were categorized as refractory anemia (RA), 23 patients as refractory neutropenia (RN), and 24 as refractory thrombocytopenia (RT). We did not find differences between the three subgroups as regards sex, median age, and cytogenetic aberrations. Lower PMN count (0.8 × 109/L) was observed in the RN category, as well as lower platelet count in the RT category (51 × 109/L). Moreover, we found a lower rate of patients requiring RBC transfusions, during the disease course, in the RT category (45.8%) as compared to RA (62%) and RN (69%) groups (p = 0.05); a lower incidence of infections at diagnosis in the RT category (20.8%) compared to RA (32%) and RN (43%) categories (p = 0.03); and a higher incidence of hemorrhagic symptoms at diagnosis in the RT category (41.6%) and RN category (26%) as compared to the RA group (5%) (p = 0.001). Application of different scoring systems (Bournemouth and Spanish scores, WPSS) revealed a low OS in high-risk patients within the RT category, compared to RA and RN categories, although unlikely to reflect the consequences of low OS found in the former category. Statistically significant differences were also evidenced in the incidence of acute myeloid leukemia (AML) evolution and overall survival: 7/79 (8%) patients with the RA category evolved to AML in a median time of 89 months, whereas 4/23 (17%) of the RN category and 1/24 (4%) of the RT category experienced disease progression, in a median time of 33.8 and 12.8 months, respectively (p = 0.03). The RT category had a lower overall survival (15.9 months) as compared to RA (48.2 months) and RN (35.9 months) categories (p < 0.001). In conclusion, in our study, application of the revised 2008 WHO classification confirmed the importance of separating patients with unilineage dysplasia for prognostic disease assessment; from our results it seems that the RT category has a worse outcome.

Imatinib dose escalation in 74 failure or suboptimal response chronic myeloid leukaemia patients at 3‐year follow‐up

We report here on the long-term efficacy of imatinib dose escalation in 74 patients after failure to imatinib conventional dose (13 with hematologic failure and 57 patients with cytogenetic resistance) or suboptimal response (four patients for cytogenetic or molecular). Fifty-four patients received imatinib dose escalation from 400 to 600 mg and 20 patients to 800 mg. A major cytogenetic response was achieved in 41 patients (72%) who escalated imatinib dose for cytogenetic failure and in six patients (46%) with hematologic failure (P = 0.002). Complete cytogenetic response (CCyR) was achieved in 27 (37%) patients: 38% of the hematological failure patients and 42% of the cytogenetic resistant patients (P = 0.345). Cytogenetic suboptimal response patients obtained complete molecular response, whereas the patient, who escalated the dose for molecular suboptimal response at 18 months, did not obtain improvement. After 3 years of follow-up all responding patients are in sustained CCyR. The estimated 2-year PFS and OS is 87% and 85%, respectively. In conclusion, imatinib dose escalation appears to induce sustained responses in CML patients with cytogenetic resistance, in particular in those with acquired resistance. In hematological failure patients, a rapid switch to second generation TKI is instead recommended.

Health-related quality of life and symptom assessment in randomized controlled trials of patients with leukemia and myelodysplastic syndromes: What have we learned?

Health-related quality of life (HRQOL) and other patient-reported outcomes (PROs) are crucial for a comprehensive evaluation of treatment effectiveness. A systematic review of randomized controlled trials (RCTs) with a PRO endpoint conducted in patients with leukemia and myelodysplastic syndromes (MDS) was performed. Eligible studies were evaluated independently, according to a pre-defined coding scheme, by two reviewers. Thirteen RCTs, enrolling overall 3380 patients were identified. There were four RCTs involving acute myeloid leukemia patients (AML), one with acute lymphoid leukemia (ALL), five with chronic lymphocytic leukemia (CLL) and three with MDS. Six RCTs accurately documented PRO methodology assessment and were thus considered likely to robustly inform clinical decision-making. Of these, three RCTs dealt with AML, two with CLL, one with MDS. A growing number of RCTs in leukemia and MDS have included a PRO component in recent years. Inclusion of PROs in RCTs is feasible and can provide unique information to facilitate clinical decision-making.

Clinical and biological features of acute promyelocytic leukemia patients developing retinoic acid syndrome during induction treatment with all-trans retinoic acid and idarubicin

Although all-trans retinoic acid (ATRA) is generally well tolerated, some patients develop a potentially severe and life-threatening complication referred to as retinoic acid syndrome (RAS). We analyzed here the biological and clinical characteristics of 110 consecutive patients with genetically

Cytogenetic and molecular responses in chronic phase chronic myeloid leukaemia patients receiving low dose of imatinib for intolerance to standard dose.

Imatinib mesylate is the gold standard treatment of chronic myeloid leukaemia (CML) and 400 mg/day is considered the standard dose. Although it is generally well tolerated, some patients require temporary drug discontinuation and permanent dose reduction because of haematological or non‐haematological toxicities. Whether or not reduced doses are effective as the standard dose in inducing and/or maintaining complete cytogenetic and molecular response is not clear. We report the outcome of 45 CML patients in early (17) and late (28) chronic phase (CP) in whom, within a series of 250 patients treated with imatinib, reduced the dose of the drug after experiencing adverse events. Median time interval between the start of therapy and dose reduction was 58 days, whereas median administered dose was 300 mg/day. At 6 months from reduction, major cytogenetic responses (MCRs) were observed in 67% of patients, with 58% being complete cytogenetic remission (CCR), and complete molecular response (CMR) were obtained in 18% of patients. At 12 months, all patients who had obtained MCR reached CCR: this was significantly higher in low risk patients (87%) versus non‐low risk patients (66 and 46%), and in early phase (82%) versus late phase (53.5%). CMR and major molecular response (MMR) were detected in 20 and 22% of patients, respectively. Low dose imatinib appears effective in patients with intolerance to standard dose, even though long‐term effects remain to be established. Copyright