Luigi Petrucci

5-Azacitidine efficacy and safety in patients aged >65 years with myelodysplastic syndromes outside clinical trials

Abstract The efficacy and safety of azacitidine in elderly patients (aged >65 years) with myelodysplastic syndromes (MDS) treated outside clinical trials are reported. Thirty-eight patients with MDS received azacitidine (75 mg/m2, schedule 5+2 +2): seven patients were classified as having refractory cytopenia with multilineage dysplasia (RCMD), nine patients with refractory anemia with excess of blasts (RAEB) type 1, 18 patients with RAEB type 2 and four patients with chronic myelomonocytic leukemia type 2 (CMML-2). According to International Working Group (IWG) 2006 criteria, after the first four cycles we detected complete remission in seven patients (CR, 18%), improvement of bone marrow dysplasia and reduction of blast percentage in seven patients (partial response, 18%), stable disease in 20 patients (53%) and progression to acute leukemia in four patients (10%). Median overall survival for all patients treated was 16.4 months. Only mild non-hematologic toxicity was detected (grade 1–2 nausea and pruritus), whereas 55% of patients experienced hematologic side effects (25% grade 3–4 thrombocytopenia and 30% grade 3–4 neutropenia). Our results suggest that advanced age should not preclude effective treatment with azacitidine in non-selected elderly patients wih MDS.

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.

Isolated central nervous system relapse after nine years of complete molecular remission in a lymphoid blast crisis of chronic myeloid leukemia treated with imatinib

Extramedullary blast crisis (BC) of chronic myeloid leukemia CML) has been observed in 7–10% of patients, with or withut other manifestation of disease progression [1]. Cerebrospinal nvolvement as a site of extramedullary BC is rare, but since the dvent of imatinib as first-line treatment for CML, there have een several reports describing patients with isolated central nerous system (CNS) involvement [1–5], because the drug poorly enetrates the blood-brain barrier. Here we report a case of a ymphoid BC, developed under IFN therapy, which reached comlete molecular remission with imatinib and presented an isolated elapse of the same disease in CNS after nine years of imatinib herapy. A 71-year-old female was diagnosed with Philadelphia+ CML in anuary 2001 and was initially treated with interferon (IFN ) at he maximum tolerated dose of 5 MU/day. After 6 months of treatent, she developed a sudden leucocytosis (WBC 52 × 109 /l). At hat time bone marrow examination showed a total infiltration by 0% blast cells: immunophenotypic analysis revealed a blastic poplation, which was positive for the following superficial antigens: D34, CD79-a, CD19 and CD38, CD13, CD33, CD66-C, TdT+, and egative for CD10, CD20, leading to a diagnosis of lymphoid BC. ytogenetic analysis at the time of acute transformation showed uplication of Ph+ chromosome in 20 analysed metaphases. Cererospinal fluid (CSF) analysis at that time did not reveal evidence of isease. The patient was started on imatinib at the dose of 600 mg aily and achieved a complete haematological response after 1onth and a complete cytogenetic response (CCR) after 3 months. complete molecular response (CMR) was reached after 3 years f treatment (ratio BCR-ABL1/ABL1 < 0.001IS), with imatinib being ontinued at 400 mg/day for the following nine years, without any ign of toxicity. In September 2010, the patient suddenly develped left hypoacusia, left lower limb weakness and right visual loss. MRI showed a solid tissue around the left facial nerve. Optical xamination revealed bilateral papilloedema. Bone marrow examnation confirmed CCR and RQ-PCR showed a residual disease with BCR-ABL1/ABL1 ratio of 0.2%IS. CSF analysis demonstrated high cell ount (1,300 cells/mm3): cytological examination revealed lymhoblast infiltration. Immunophenotypic analysis performed on SF showed the same phenotype detected at diagnosis (positivty for CD34, CD79-a, CD19 and CD38, CD13, CD33, CD66-C, TdT, egativity for CD10, CD20) and FISH analysis detected duplicaion of Ph+ chromosome. RQ-PCR performed on CSF showed a CR-ABL1/ABL1 ratio of 120% IS. A diagnosis of extramedullary BC

Management of elderly and unfit patients with chronic lymphocytic leukemia

ABSTRACT Introduction: About 75% of patients with chronic lymphocytic leukemia (CLL) are more than 65 years at the time of diagnosis. Treatment of the elderly remains complicated due to multiple factors, such as comorbidities, decline in functional reserve and fitness. Since chronological age by itself cannot properly predict life expectancy and treatment tolerance, an accurate assessment of the fitness status is of crucial importance for an optimal treatment choice. Areas covered: This review will discuss the most relevant aspects concerning the issues experienced in the management of elderly/unfit patients with CLL. The most frequently observed age-related toxicities, fitness assessments, supportive care measures and treatment options for elderly patients and for patients who are deemed unfit will be discussed. Literature search methodology included examination of PubMed index. Expert commentary: During the last decade, different trials focusing on elderly/unfit patients have investigated more tolerable chemoimmunotherapy schedules and, more recently, the activity and safety of chemo-free regimens. Chlorambucil combined with an anti-CD20 monoclonal antibody has shown clinical activity with a relatively good profile of toxicity. The recent introduction of the B-cell receptor antagonists, ibrutinib and idelalisib, and other targeted drugs in development (e.g. venetoclax), is broadening the therapeutic armamentarium of elderly CLL patients.

Combination of azacitidine and ESA in myelodysplastic patients: the need for prospective studies.

We read with great interest the paper by Itzkynson et al. [1] hat reported the results of the combination of erythropoietin and zacitidine in myelodysplastic syndrome (MDS) patients. Overall, 2 out of 282 patients were treated concomitantly with azacitiine and erythropoietic stimulating agents (ESA) for a relatively hort period of time (median duration 5.8 months). The authors eported an overall response rate of 53% in patients treated with the ombination compared to 43% in patients treated with azacitidine lone, without statistically significant difference. No differences ere reported in terms of complete response (CR) and marrow esponse (mCR) between the two groups of subjects, whereas the ate of hematologic improvement-erythroid (HI-E) was superior in he combination group (44%) compared to azacitidine alone group 27%), with an increased rate of patients becoming transfusion ndependent in the former group. Again no difference in terms of rogression rate was observed, whereas ESA-treated patients had longer survival (OS), with a median of 19.6 months compared to 1.9 months for patients who did not receive ESA. With the aim to valuate the possible effect of the above described combination, 60 DS patients treated with azacitidine in our institute, 8 of whom eceived the drug in association with ESA, were retrospectively anaysed. There were 44 males and 16 females, median age 69 years range 44–83). According to WHO criteria [2], 35 patients were

Clinical relevance of hypogammaglobulinemia, clinical and biologic variables on the infection risk and outcome of patients with stage A chronic lymphocytic leukemia

The prognostic effect of hypogammaglobulinemia (HGG), clinical and biologic characteristics on the infection risk and outcome has been retrospectively analyzed in 899 patients with stage A chronic lymphocytic leukemia (CLL). Low levels of IgG were recorded in 19.9% of patients at presentation, low levels of IgM and/or IgA in 10.4% and an additional 20% of patients developed HGG during the course of the disease. Before the start of any treatment, 160 (12.9%) patients experienced at least one grade ≥3 infection requiring a systemic anti-infective treatment and/or hospitalization. While IgG levels at diagnosis were not associated with an increased risk of grade ≥3 infection or with an adverse outcome, a significantly increased rate of grade ≥3 infections was recorded in patients with unmutated IGHV (p=0.011) and unfavorable FISH aberrations (p=0.009). Late onset HGG, more frequently recorded in patients with Rai stage I-II (p=0.001) and unmutated IGHV (p=0.001), was also associated with a higher rate of severe infections (p=0.002). These data indicate that, stage A patients with clinical and biologic characteristics of a more aggressive disease develop more frequently late onset HGG, grade ≥3 infections and require a closer clinical monitoring.