Elena Crisà

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.

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.

Telomere loss in Philadelphia-negative hematopoiesis after successful treatment of chronic myeloid leukemia: Evidence for premature aging of the myeloid compartment

Telomere shortening, a well-known marker of aging and cellular stress, occurs under several conditions in the hematopoietic compartment, including aplastic anemia and following iatrogenic noxae. We decided to verify whether pathological telomere erosion also arises in restored Philadelphia-negative (Ph-negative) hematopoiesis following successful treatment of chronic myeloid leukemia (CML). Eighty-one CML patients in complete cytogenetic remission were compared to 76 age-matched healthy subjects. Myeloid cells of CML patients had shorter telomeres than controls (6521 bp vs 7233 bp, p<0.001). This difference was specific for the myeloid compartment, since it was not observed in lymphoid cells (6774 bp vs 6909 bp, p=0.620). Acquired Ph-negative cytogenetic abnormalities (p=0.010), lack of complete molecular remission (p=0.016) and age (p=0.013) were independent predictors of telomere shortening. Telomere dynamics were assessed over a median follow-up period of 22 months. We documented accelerated non-physiological ongoing telomere shortening in 17/59 CML patients (28%). Patients experiencing grade 2-4 hematological toxicity, during CML remission possessed significantly shorter telomeres compared to those lacking toxicity (p=0.005 for any toxicity, p=0.007 for anemia). CML patients suffer from significant and often ongoing telomere stress resulting in premature and selective aging of the myeloid compartment which might have long-term consequences on function and integrity of Ph-negative hematopoiesis.

Excellent therapeutic results achieved in chronic myeloid leukemia patients with front-line imatinib and early treatment modifications in suboptimal responders: a retrospective study on 91 unselected patients.

Second generation tyrosine kinase‐inhibitors (TKI) have been claimed to represent now the first‐choice therapy for chronic myeloid leukemia (CML). Indeed, they generally induce faster and deeper molecular responses compared to imatinib that, however, is equally effective in at least 50% of patients. Moreover, some recent reports have questioned the long term safety of dasatinib and nilotinib. Therefore, upfront imatinib with early shift to second generation TKI for patients with slow/incomplete response might be as effective as front‐line second generation TKI, with a possibly better safety profile. We retrospectively evaluated 91 chronic phase CML patients (median follow‐up 57 months, median age 61 years), treated front‐line with standard‐dose imatinib and early therapy modifications (at 3–12 months) in case of unsatisfactory response or intolerance. Thirty‐three patients (24 with unsatisfactory response, 9 intolerant) changed therapy, either by increasing imatinib dose (11/91) or by switching to second generation TKI (22 directly, 4 after high‐dose imatinib). Globally, our strategy led to complete cytogenetic response (CCyR) in 98% of the patients, major molecular response (MMR) in 88% and molecular response 4 logs (MR4.0) in 62%. Three patients in CCyR (3%), 2 of them in MMR too, suddenly progressed to blastic phase. At the last follow‐up nine patients had died, seven of CML‐unrelated causes and two only of CML progression. These results suggest that our strategy could be as effective as front line second generation TKI, with most of patients still receiving imatinib, a drug of better known long‐term side effects and lower cost. Am. J. Hematol. 88:838–842, 2013.

Long-term follow-up of myelodysplastic syndrome patients with moderate/severe anaemia receiving human recombinant erythropoietin + 13-cis-retinoic acid and dihydroxylated vitamin D3: independent positive impact of erythroid response on survival.

We previously reported a 60% erythroid response rate with recombinant erythropoietin + 13‐cis retinoic acid + dihydroxylated vitamin D3 in 63 elderly myelodysplastic patients (median age 75 years) with unfavourable features for response to erythropoietin alone [70% transfusion‐dependent, 35% refractory anaemia with ring sideroblasts/refractory anaemia with excess of blasts type 1 (RAEB1), 70% with International Prognostic Scoring System (IPSS) Intermediate‐1 or ‐2]. This report updates that case study at a 7‐year follow‐up, and compared the impact on overall survival of erythroid response to known prognostic factors. The erythroid response duration (median 17 months; 22 in non‐RAEB patients, with 20% patients in response after 6 years of therapy) was longer than in most studies with erythropoietin alone. Overall survival (median 55 months in non‐RAEB, 15 in RAEB1 patients) was negatively affected by RAEB1 diagnosis, IPSS and WPSS intermediate scores and transfusion‐dependence. In the multivariate analysis, erythroid response maintained an independent positive impact on survival, particularly in non‐RAEB patients in the first 3 years from diagnosis (90% survival compared to 50% of non‐responders). In conclusion, the long‐term follow‐up confirmed the achievement, by our combined treatment, of fairly long‐lasting erythroid response in the majority of MDS patients with unfavourable prognostic features for response to erythropoietin: this translated in a survival benefit that was independent from other prognostic features.

How many patients can proceed from chronic myeloid leukaemia diagnosis to deep molecular response and long-lasting imatinib discontinuation? A real life experience.

Keywords: imatinib discontinuation; chronic myeloid leukaemia; tyrosine kinase inhibitor; treatment cessation

Long‐term therapy‐free remission in a patient with platelet‐derived growth factor receptor beta‐rearranged myeloproliferative neoplasm

To the Editor: Myeloid neoplasms harboring a translocation involving platelet-derived growth factor receptor beta (PDGFRB) are rare hematologic malignancies which present with leukocytosis, often with monocytosis and eosinophilia, usually accompanied by anemia and thrombocytopenia. More than 20 PDGFRB fusion partners have been identified, the most frequent being ETV6, and the natural history of this neoplasm has been radically changed by the introduction of imatinib, which can lead to complete remission in the vast majority of patients [1]. Here we present the case of a 59-year-old man diagnosed with PDGFRB-ETV6 myeloproliferative neoplasm who achieved a long-term therapy-free remission after obtaining complete response with imatinib. In June 2002 he was referred to our clinic because of an incidental finding of neutrophilic leukocytosis (leukocytes 29,900/mL, neutrophils 54%) and mild thrombocytopenia (platelets 106,000/mL). Peripheral blood smear showed the presence of immature precursors (mielocytes 1.6% and metamyelocytes 14.5%), with a 3.3% of eosinophils and a 1.4% of monocytes. Physical examination revealed mild splenomegaly. Morphological examination demonstrated a hypercellular bone marrow with mild myeloid hyperplasia, mild megacaryocyte dysplasia, and no excess of blasts. BCRABL1 transcript was absent. Cytogenetic evaluation showed a t(5;12)(q33;p13) and the Real Time-Polymerase Chain Reaction (RT-PCR) confirmed the presence of PDGFRBETV6 fusion transcript. The patient was started on imatinib 400 mg/die in December 2002 and achieved hematologic remission in one month. Complete cytogenetic response was obtained in July 2003 and molecular remission was demonstrated by both RTand nested-PCR in October 2004. In January 2011, in consideration of the confirmed long lasting cytogenetic and molecular remission, imatinib dosage was reduced to 100 mg/die and in April 2012 it was definitely stopped due to strong patient’s desire. After discontinuing imatinib, the patient was closely monitored and the PDGFRB-ETV6 fusion transcript remained negative. In April 2016, 4 years after stopping his treatment, our patient is doing well, in complete hematologic, cytogenetic, and molecular remission. Recently, two studies tried to identify genetic variants that might contribute to disease pathogenesis, phenotype, and clinical outcome in PDGFR-rearranged neoplasms, using next generation sequencing. Genetic variants in myeloid disease-relevant genes could be found only in 2 out of 10 patients with FIP1L1-PDGFRA and in none of the 3 ones with PDGFRB translocations [2,3], confirming that PDGFR translocations are the driver mutations in these neoplasms. This finding could explain the excellent therapeutic results with imatinib and supports the feasibility of treatment discontinuation for patients in persistent molecular remission. Nowadays therapy discontinuation has become a topic of increasing interest in chronic hematologic malignancies, since very effective treatments are available and the goal of cure might be achievable in some patients. In chronic myeloid leukemia, imatinib discontinuation for patients in persistent molecular remission has been proven to be safe and it is entering in routine clinical practice [4]. In PDGFRA-rearranged neoplasms, a few studies regarding imatinib cessation are available. While in a first report by Klion et al. all the 4 patients who stopped imatinib relapsed [5], another experience demonstrated that some patients can remain off therapy without losing their response [6]. Indeed, two recent studies reported that around 50% of the patients with PDGFRA translocation who achieved complete molecular remission with imatinib maintained it after stopping treatment [7,8]. Importantly, all the patients who relapsed regained a complete response after restarting imatinib [5,7,8]. For PDGFRB-related diseases data are lacking. In a recent report by Cheah et al. [9], 3 among 26 patients with PDGFRB-rearranged neoplasms discontinued imatinib: two of them were non-responders or intolerant and the other one received allogeneic stem cell transplantation. Excluding the aforementioned post-transplant case, to our knowledge this is the first report describing a patient with PDGFRB-rearranged neoplasm experiencing a long-term remission after imatinib discontinuation. Therefore, our experience suggests that imatinib cessation is feasible also in PDGFRBrearranged neoplasms, even though more data are necessary in order to advise it in routine clinical practice.

Role of Chemotherapy and Allografting in the Treatment of Acute Lymphoblastic Leukemia

We report the clinical outcomes of 83 patients with acute lymphoblastic leukemia (median age, 46 years; range, 18-75 years) treated at our institution between 1999 and 2011. Treatment refers to clinical trials open for accrual at the time of diagnosis or to institutional guidelines. Upfront allografting was considered for younger high-risk patients. Seventy-eight of 83 (94%) patients achieved complete remission after induction, although 53% of them eventually relapsed. Forty of 70 patients younger than 61 years underwent allografting. The median follow-up was 7.4 years (range, 0.2-15.0 years). Overall, the 5-year overall survival (OS) and event-free survival (EFS) were 40% and 39%, respectively. In patients undergoing transplantation, OS and EFS at 5 years were both 53%, whereas in a nontransplantation setting, both OS and EFS were 35% at 5 years (P = .044 for both OS and EFS). By multivariate analysis, the independent predictors of OS and EFS were age and leukocytosis in the overall population and allografting in young patients.

The use of erythropoiesis-stimulating agents is safe and effective in the management of anaemia in myelofibrosis patients treated with ruxolitinib

Erythropoiesis‐stimulating agents (ESAs) were combined with ruxolitinib in 59 anaemic myelofibrosis patients (93% with Dynamic International Prognostic Scoring System [DIPSS] intermediate‐2/high risk; 52·5% transfusion‐dependent). Anaemia response (AR) rate was 54% and 76% of patients responded at 5 years. A further 15% displayed minor improvement in anaemia and 78% of patients reduced spleen size. Endogenous erythropoietin levels <125 u/l correlated with a higher AR rate (63% vs. 20%, P = 0·008). No thrombotic events or other toxicities occurred. Overall survival was 62% at 4 years, influenced by DIPSS and transfusion dependency. ESAs seem effective in improving anaemia in ruxruxolitinib‐treated myelofibrosis patients.

O-020 Erythropoietin alpha therapy in 1110 lower-risk MDS patients: A real life survey from the network of regional Italian MDS Registries

Background: Erythroid stimulating agents (ESAs) are a common treatment for lower risk anaemic MDS patients (pts). The response rate varies from 20 to 60% according to the different published studies and ESAs are recommended in International Guidelines. Many clinical and biological parameters have been proposed as predictors of response. Little is known about ESAs therapy in real life. Purpose:We performed an analysis based on the network of regional Italian MDS Registries in order to assess which group of patients could benefit more of ESAs treatment. Materials and Methods: From 2487 pts enrolled in the Registry from 1999 to November 2012, we selected a group of 1411 low or intermediate-1 cases with follow-up data available. No differences in leukemic evolution rate have been observed by ESAs treatment (p=0,279). Subsequently, in order to study the effect of ESAs on survival, we excluded the 92 pts who experienced a leukemic evolution and the cases whose evolution was influenced by lenalidomide and/or azacytidine treatments. Cases treated with ESAs other than erythropoietin alpha (EPOa) were excluded because of the low number of observations and/or incomplete information and/or inhomogeneous dosages. Finally, we obtained a data base of 1110 pts treated by EPOa or observation only. We evaluated Overall Survival (OS) according to EPOa treatment considering the degree of anaemia at baseline. Results: The 1110 pts were subdivided according to Hb level as follows: 123 (11%) with Hb 10 g/dL. Three hundred and fifty six pts were treated by EPOa. The difference in OS by EPOa treatment in the whole cohort was not statistically significant. However, when considering patients not yet transfusion dependent with Hb levels ranging from 8 g/dL to 10 g/dL, there was a clear statistically significant difference in OS: median time 216 months in EPOa treated group vs 99 months in non treated pts (p=0,002). The influence of EPOa on OS in pts with Hb 10 g/dL did not reached a significant level. Additionally, no statistically significant difference was observed in deaths for thrombotic events. Conclusions: Our real life experience confirms that EPOa treatment is safe inMDS patients and it is particularly useful in prolonging OS of the selected group of lower risk pts with mild anaemia not yet transfusion dependent.