Federico Vozella

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.

Proteasome inhibitors for the treatment of multiple myeloma

ABSTRACT Introduction: Multiple Myeloma (MM) management is rapidly evolving, with a spectrum of novel treatments that have changed our approach to the therapy. Proteasome inhibitors (PIs) have revolutionized the scenario of both relapsed/refractory and newly diagnosed patients. The efficacy of bortezomib, the first PI approved, followed by carfilzomib and, the oral ixazomib, have been tested in several trials as single agents or in combination. Areas covered: In this review, the authors summarize mechanism of action, efficacy and safety of proteasome inhibitors in MM and focus on data derived from clinical trials, analyzing adverse events and their relative management. Expert opinion: The authors believe that, currently, the best course of action in the treatment of MM is to use PIs in combination with immunomodulatory drugs (IMiDs) and/or with monoclonal antibodies for all patients. However, based on the patient-specific characteristics, it is important to avoid inappropriate discontinuation by knowing the single side effects of every agent in order to balance their efficacy and safety.

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

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.

Biventricular assessment of light-chain amyloidosis using 3D speckle tracking echocardiography: Differentiation from other forms of myocardial hypertrophy

BACKGROUND Given that in patients with cardiac amyloidosis (CA), deposition of amyloid protein is not restricted to the left ventricular (LV) myocardium, it can be hypothesized that the diagnostic value of deformation mechanics would be enhanced by considering right ventricular (RV) strain measures. The aim of the present study was to examine the potential utility of left ventricular (LV) and right ventricular (RV) deformation and rotational parameters derived from three-dimensional speckle-tracking echocardiograph (3DSTE) to diagnose cardiac amyloidosis and differentiate this disease from other forms of myocardial hypertrophy. METHODS Twenty-three patients with biopsy-proven light-chain (AL) amyloidosis, 23 patients with systemic arterial hypertension (HTN), 23 patients with hypertrophic cardiomyopathy (HCM), 23 athletes and 23 normal controls were prospectively studied by conventional echocardiography and 3DSTE. LV longitudinal strain (LV LS), LV circumferential strain (LV CS), RV global longitudinal strain and RV free-wall longitudinal strain (RV FW LS) were obtained by 3DSTE, as well as LV rotation and rotational velocities. RESULTS LV and RV longitudinal strains were reduced in cardiac amyloidosis (CA) patients compared to controls. By multivariate analysis, LV basal LS (p = 0.002), LV peak basal rotation (p = 0.003), and RV basal FW LS (p = 0.014) were independently associated with CA in the overall population. A significant improvement in global χ2 value was noted with RV 3D-strain parameters over only LV-3DSTE + conventional indices for detection of CA (p < 0.001). Comparison of ROC curves showed that the AUC using combined LV basal LS, LV basal rotation and RV basal FW LS had a higher discriminative value than the other echocardiographic parameters used for detecting CA (AUC 0.93, 95%CI 0.81-0.97). CONCLUSIONS Three-dimensional speckle tracking echocardiography reveals regional and global biventricular dysfunction in CA. Assessment of RV ventricular dysfunction has an additive value in differentiating CA from other causes of myocardial wall thickening.

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.

Dataset on the use of 3D speckle tracking echocardiography in light-chain amyloidosis

The dataset presented in this article is related to the research article entitled “Biventricular assessment of light-chain amyloidosis using 3D speckle tracking echocardiography: Differentiation from other forms of myocardial hypertrophy” (Vitarelli et al., 2018) [1], which examined the potential utility of left ventricular (LV) and right ventricular (RV) deformation and rotational parameters derived from three-dimensional speckle-tracking echocardiography (3DSTE) to diagnose cardiac amyloidosis(CA) and differentiate this disease from other forms of myocardial hypertrophy. The combined assessment of LV basal longitudinal strain, LV basal rotation and RV basal longitudinal strain had a high discriminative power for detecting CA. The data of this study provides more understanding on the value of LV 3DSTE deformation parameters as well as RV parameters in this particular cardiomyopathy.

Independent prognostic impact of CD15 on complete remission achievement in patients with acute myeloid leukemia.

The prognostic role of CD15 in acute myeloid leukemia (AML) has been tested in different studies with conflicting results. To address this issue, we retrospectively evaluated a cohort of 460 AML patients of all ages with the exclusion of acute promyelocytic leukemia (M/F 243/217, median age 50.6 years [range 0.9‐81.2]) intensively treated at our institute between January 1999 and December 2010. CD15 positivity was found in 171 of 406 evaluable patients (42.1%). Complete remission (CR) was achieved by 334 patients (72.6%), while 82 (17.8%) were resistant and 44 (9.6%) died during induction: the median CR duration was 15.5 months (range 0.6‐176.0), with 2‐year disease‐free survival rate of 45.1% (95% confidence interval 39.6‐50.6). The median overall survival was 14.4 months (range 0.3‐177.0), with 2‐year overall survival rate of 42.2% (95% confidence interval 37.5‐46.9). At univariate analysis for CR achievement, age < 60 years (P < .001), World Health Organization classification (P = .045), low‐risk karyotype (P < .001), no high‐risk karyotype (P = .006), positivity for AML‐ETO (P = .004)/CBFβ‐MYH11 (P = .003)/CD15 (P = .006)/CD11b (P = .013), negativity for FLT3‐ITD (P = .001), Hb > 8 g/dL (P = .020), and white blood cell < 50 × 109/L (P = .034) had a favorable impact. At a multivariate logistic regression model, CD15 positivity (P = .002), age < 60 years (P = .008), white blood cell < 50 × 109/L (P = .017), and low‐risk/no high‐risk karyotype (P = .026/P = .025) retained an independent prognostic role on CR achievement. The baseline assessment of CD15 positivity appears to have a role in the risk evaluation for CR achievement in AML patients undergoing intensive chemotherapy and should be assessed in prospective studies together with other clinical and biologic features already reported.

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