Paola Volpicelli

Discontinuation of alpha-interferon treatment in patients with chronic myeloid leukemia in long-lasting complete molecular response

To evaluate follow-up after α-interferon (IFN) discontinuation, 23 patients with chronic myeloid leukemia (CML) in stable complete molecular response (CMolR) with IFN were revisited. After a median IFN treatment of 105.8 months (IR 56.1 – 127.3), all patients discontinued IFN for prolonged CMolR (12), intolerance (8) or planned ABMT (3). After 12.5 months, one patient developed an extramedullar blast crisis. Four patients needed to start imatinib, all achieving again molecular response. Eighteen patients are still off-therapy (median time from IFN discontinuation 125.5 months, IR 86.9–205.3); among these, five are BCR-ABL negative, six present with a sporadic positivity (BCR-ABL ratio < 0.1) and seven show a stable and long-lasting mild positivity (BCR-ABL ratio < 0.5). Patients in prolonged CMolR with IFN have low risk of recurrence after discontinuation; the reappearance of a BCR-ABL positivity < 0.5 did not always precede a relapse, suggesting mechanisms of immunological control induced by IFN.

Prognostic features of patients with myelodysplastic syndromes aged < 50 years: update of a single-institution experience

Abstract Fewer than 10% of patients with myelodysplastic syndromes (MDS) are younger than 50 years. A series of 91 younger patients (median age 44 years with female prevalence) are reported and compared with elderly patients. Frequent karyotypic changes were trisomy 8 (9.8%) and monosomy 7 (5%). Twenty-three patients had occupational exposure to potential mutagens (benzene and solvents), with a male predominance, higher frequency of refractory cytopenia with multilineage dysplasia (RCMD) (52%) and higher frequency of monosomy 7 (21.7%). At a median follow-up of 72 months, 22 patients (24%) evolved to acute leukemia, with higher frequency being observed among the exposed cohort (39% vs. 19% non-exposed). Unfavorable factors for overall survival were: age > 40 years, > 5% of blasts, trilinear bone marrow involvement and intermediate–high World Health Organization Prognostic Scoring System (WPSS) risk. The present results suggest that younger MDS could be identified as a distinct subset. For patients belonging to the low/intermediate-I risk group, due to a low transformation rate, aggressive approaches should rarely be recommended.

Impact of exclusion criteria for the DASISION and ENESTnd trials in the front-line treatment of a 'real-life' patient population with chronic myeloid leukaemia.

Both Dasision and ENESTnd trials had many exclusion criteria, with a possible selection bias compared with the real‐life. To address the impact of this bias on the first‐line treatment in the current clinical practice, we revised 207 unselected newly diagnosed chronic phase chronic myeloid leukaemia (CML) patients [M/F 108/99, median age 58.8 years, interquartile range 42.3–70.2] treated with front‐line imatinib from June 2002 to June 2013 at our Institution, and evaluated how many of them would have been excluded from enrolment in the two trials. Twenty‐eight patients (13.5%) should have been excluded by both trials because of polycomorbidities (12), severe cardiomyopathy (five), age > 80 with frailty (three), drug abuse (two) or other severe concomitant diseases (six). In addition, eight patients should have been excluded by Dasision due to isolated chronic obstructive broncopulmonar disease, and 19 patients should have been excluded by ENESTnd due to isolated diabetes (10), arrhythmia (four), acute myocardial infarction > 6 months before CML diagnosis (two), chronic pancreatic disease (two) and peripheral arterial obstructive disease (one). On the whole, 36 patients (17.4%) would have been excluded by Dasision trial and 47 (22.7%) by ENESTnd trial. The patients potentially not eligible for both trials were significantly older and with imatinib had a worse outcome compared with patients potentially eligible. Our data highlight that an automatic transposition of results available in clinical controlled trials into the frontline real‐life management of CML patients should be regarded with caution. Copyright

Very short-term lenalidomide treatment associated with durable resolution of anemia in a patient with myelodysplastic syndrome with chromosome 5q deletion.

Dear Editor, Dose–response relationship and the precise mechanism of action of lenalidomide in myelodysplastic syndromes (MDS) are still unclear, despite the remarkable response rates in patients with chromosome 5q deletion (del 5q) [1, 2]. A selective effect of lenalidomide on the hematopoietic del5q clone has been described, with inhibition of proteins critical for cell survival or stimulation of tumor suppressor genes on that region [3]. In this context, a critical role of the ribosomal protein RPS14, located in the common deleted region of del5q, has been recently reported [4]. During lenalidomide treatment, most patients usually require transient dose interruption followed by dose reduction due to early adverse events (mainly neutropenia and/or thrombocytopenia) [2]. Few case reports have shown sustained long-term RBC-transfusion independency even after short-term treatment [5–7]. Here, we report a durable response achieved in a patient with del5q MDS after only 17 days of lenalidomide treatment. A 77-year-old female was referred to our hospital in September 2006 because of progressive anemia. Our laboratory tests revealed severe macrocytic anemia (hemoglobin, Hb, 7.0 g/dL; MCV, 122 fl), moderate neutropenia (WBC, 2.42×10 L; absolute neutrophil count, ANC, 1.0× 10 L) and mild thrombocytosis (platelet count, PLT, 475×10 L). A BM examination showed trilinear severe dysplasia, 12% blasts, and del5q in all analyzed metaphases [46, XX, del(5) (q13q31)] [5, 8]. The patient was thus diagnosed with RAEB-2, intermediate-2 International Prognostic Scoring System (IPSS). Treatment with recombinant human erythropoietin (EPO-α, 80.000 IU weekly) was started in October 2006. Erythroid response was achieved in January 2007, lasting until December 2007, when a relapse of anemia with transfusional requirement occurred. In October 2008, lenalidomide 10 mg daily was started. Baseline peripheral blood evaluation revealed Hb, 9.1 g/dL; ANC, 1.5×10 L; and PLT, 658×10 L. BM smear showed persistent trilineage dysplasia, 8% blasts, and isolated del5q (RAEB-1 with intermediate-1 IPSS). After 17 days of treatment, lenalidomide was halted due to severe neutropenia (ANC, 0.39×10 L) with increased transfusion requirement, severe asthenia, nausea, gastrointestinal pain, and a skin infection requiring oral antibiotics. After 2 weeks of lenalidomide deferral, neutrophil count rapidly recovered, but the patient was hospitalized because of paroxysmal atrial fibrillation and thyrotoxic crisis. In November 2008, the patient achieved a complete hematological response (Hb, 12.3 g/dL; WBC, 4.19×10 L; ANC, 2.0×10 L; PLT, 353×10 L) without therapy, and lenalidomide was definitely discontinued at the patients request. At 3 and 6 months after lenalidomide treatment, BM examination showed persistence of moderate trilinear dysplasia without blasts. Partial cytogenetic response was documented in May 2009 (46, XX, del(5) (q13q31) [7]/ 46,XX [13]) and L. Cannella : R. Latagliata (*) :M. Breccia : I. Carmosino : G. Loglisci : P. Volpicelli :A. Ferretti :M. Santopietro : F. Vozella :C. Girmenia :G. Alimena Department of Cellular Biotechnology and Hematology, Sapienza University of Rome, Via Benevento, 6, 00161 Roma, Italy e-mail: rob.lati@libero.it

TPO-RAs in pITP: description of a case series and analysis of predictive factors for response

To report our experience concerning sustained response (SR) after TPO‐RA discontinuation in adult pITP patients and to identify possible predictive factors for outcome.

Pregnancy in patients with myelodysplastic syndromes (MDS)

We report 6 pregnancies in 5 females with low-risk myelodysplastic syndromes (MDS) (median age at diagnosis 28 years, range 26-29) observed in the last 15 years. In 2 cases pregnancy was concomitant to the diagnosis of MDS, in the remaining 4 cases the intervals from diagnosis were 2, 3, 4 and 9 years, respectively. One patient had a foetal growth retardation corrected with steroid treatment while the remaining 5 pregnancies were uneventful. After a median time from delivery of 104 months (range 18-187) none of the patients developed acute myeloid leukemia (AML) and all are alive in stable disease. In conclusion, selected females with low-risk MDS could not be discouraged to have full term pregnancies.

Complete Clearance of Ph+ Metaphases after 3 Months Is a Very Early Indicator of Good Response to Imatinib as Front-Line Treatment in Chronic Myelogenous Leukemia

Aim: To address the incidence and the prognostic role of a very early standard complete cytogenetic response (CCyR) or all Ph– metaphases (MET–, when <20 cells were evaluable). Methods: We revised 182 chronic phase chronic myelogenous leukemia patients treated with frontline imatinib (IM) at two institutions from June 2002 to June 2011. Results: After 3 months of treatment, 138 patients (75.8%) achieved CCyR/MET– while 44 patients (24.2%) still presented Ph+ metaphases (MET+) (<33%, 24 patients; ≥33%, 20 patients). On univariate analysis, palpable spleen enlargement (p < 0.001), WBC count >100.0 × 109/l at onset (p < 0.001), and male gender (p = 0.019) had a negative impact on achievement of CCyR/MET– at 3 months. Among patients with CCyR/MET– after 3 months, there were 15 failures (10.8%) compared to 21 (47.7%) among patients with MET+ (p < 0.001). The 5-year overall survival was 97.0% in patients CCyR/MET– at 3 months and 91.8% in patients MET+ at 3 months (p = 0.277); the 5-year progression-free survival was 88.2% in patients CCyR/MET– at 3 months and 48.4% in patients MET+ at 3 months (p < 0.001). Conclusions: The achievement of CCyR/MET– at 3 months seems to have prognostic relevance and could be a very early and useful indicator of an excellent response to IM beyond European LeukemiaNet guidelines.

Lenalidomide for myelodysplastic syndromes with del(5q): how long should it last?

Lenalidomide induces in patients with myelodysplastic syndrome (MDS) and del(5q) erythroid and cytogenetic response rates as high as 75% and 50%, respectively. It is still unclear, however, how long lenalidomide treatment should be continued and whether or not the drug could be interrupted. To assess the feasibility of lenalidomide discontinuation, we revised a cohort of 16 low‐risk MDS patients with del(5q) treated at our institute in a phase II multicentric Italian study. Among the 12 responding patients, four discontinued lenalidomide while in complete response. All four patients needed during treatment a permanent lenalidomide reduction from 10 to 5 mg/day because of haematological toxicity (three patients) or grade 3 muscular and bone pain (one patient). At lenalidomide discontinuation after 16, 20, 27 and 20 months from the start, respectively, all four patients were in complete hematologic response and three forth in complete cytogenetic response. Three patients are still in response after 36, 30 and 20 months from lenalidomide discontinuation, respectively: The remaining patient relapsed after 20 months, and she is now receiving a new course of lenalidomide. In conclusion, long‐lasting remissions are achievable in MDS patients with del(5q) in complete response after lenalidomide discontinuation. Copyright

Incidence of persistent/late chronic anemia in newly diagnosed patients with chronic myeloid leukemia responsive to imatinib

In patients with chronic myeloid leukemia (CML) responsive to imatinib, it is still unknown whether the long‐lasting treatment could induce the appearance of a persistent/late chronic anemia. To highlight this issue, we revised 128 patients with CML (M/F 64/64, median age at diagnosis 56.9 years, interquartile range 43.0–69.3) treated at our Institution with 1st line imatinib for at least 36 months and in stable complete cytogenetic response. At the 36th month of imatinib, a chronic anemia (Hb < 12 g/dl for > 6 months) was present in 38/128 patients (29.6%): the anemia was moderate (Hb > 8 ≤ 10 g/dl) in 12 patients (9.3%) and mild (Hb > 10 < 12 g/dl) in 26 patients (20.3%). All patients with persistent/late chronic anemia had a low reticulocyte count and 8/38 a condition of iron deficiency without clinical and instrumental signs of chronic blood loss. Four out of 38 patients (10.5%) needed red cell transfusions during the follow‐up. At a landmark analysis from the 36th month of imatinib treatment, cumulative 4‐year overall survival (OS) for patients with chronic anemia was 94.4% (CI 95% 83.8–100) compared to 93.5% (CI 95% 87.2–99.8) for patients without chronic anemia (P = 0.617). In conclusion, the occurrence of a late chronic anemia during long‐lasting treatment with imatinib has been observed in about 30% of our responsive patients: its occurrence does not seem to affect OS, but its real impact should be evaluated on a larger cohort of patients. Am. J. Hematol. 90:105–108, 2015.

Decisional flow with a scoring system to start platelet-lowering treatment in patients with essential thrombocythemia: long-term results

We prospectively tested, at diagnosis in essential thrombocythemia (ET) patients with no clear indication to platelet (PLT)-lowering treatment, a scoring system based on age, PLT level, cardiovascular diseases, previous thrombotic events, smoking and dysmetabolic diseases. From 04/92 to 03/98, 168 consecutive patients were enrolled. Hydroxyurea (HU) was started at diagnosis in 32 “symptomatic” patients and in 33 patients aged >70 years. The remaining 103 patients (“asymptomatic” and aged <70 years) were classified according to our scoring system. Thirty-two patients with score ≥4 started HU early after diagnosis. The remaining 71 patients with score <4 at diagnosis received anti-aggregating agents only; of them, 24 (33.8%) started HU during follow-up after a median time from diagnosis of 28 months, while 47 (66.2%) did not start any PLT-lowering treatment. Thrombotic complications occurred in 9/103 patients (8.7%); in particular, they occurred in 4/32 patients (12.5%) with score ≥4 receiving HU since diagnosis and in 5/71 (7%) with score <4 under anti-aggregating agents only. This scoring system appears effective to discriminate a different risk of thrombotic events, and could be useful to decide when a PLT-lowering therapy needs to be started.