[Show abstract][Hide abstract] ABSTRACT: The introduction of newer cytotoxic monoclonal antibodies and chimeric antigen receptor modified T cells is opening a new age in the management of B-lineage adult acute lymphoblastic leukemia. This therapeutic change must be very positively acknowledged because of the limits of intensive chemotherapy programs and allogeneic stem cell transplantation. In fact, with these traditional therapeutic tools the cure can be achieved in only 40-50% of the patients. The failure rates are particularly high in the elderly, in patients with post-induction persistence of minimal residual disease and especially in refractory/relapsed disease. The place of the novel immunotherapeutics in improving the outcome of adult patients with B-lineage acute lymphoblastic leukemia is reviewed.
Mediterranean Journal of Hematology and Infectious Diseases 12/2015; 7(1):e2015001. DOI:10.4084/MJHID.2015.001
[Show abstract][Hide abstract] ABSTRACT: Almost 90 % of children and 50 % of adults with acute lymphoblastic leukemia (ALL) are cured by modern treatment regimens, with significant variations due to several disease- and host-related characteristics. The attainment of an early remission and the avoidance of relapse and treatment-related mortality are the fundamental therapeutic steps. In remission patients, the assessment of the disease response to early intensive therapy through the detection and monitoring of minimal residual disease (MRD) can accurately refine the individual prognosis and is increasingly used to support a risk-oriented treatment strategy. In this way, only the patients with an unfavorable MRD response are preferably selected for allogeneic stem cell transplantation, irrespective of their clinical risk class. This choice spares transplant-related toxicities to MRD responsive cases. Further advancement is expected by integrating the MRD analysis with improved pediatric-type regimens and novel targeting agents for ALL subsets at higher risk of relapse.
[Show abstract][Hide abstract] ABSTRACT: Patients with essential thrombocythemia (ET) aged less than 60 years, who have not suffered a previous vascular event (low-risk patients), may develop thrombotic or hemorrhagic events. So far, it has not been possible to identify useful markers capable of predicting which of these patients are more likely to develop an event and therefore who needs to be treated. In the present study, we analysed the relationship between vascular complications and longitudinal blood counts of 136 low-risk ET patients taken over a sustained period of time (blood cells dynamism). After a median follow-up of 60 months, 45 out of 136 patients (33 %) suffered 40 major thrombotic and 5 severe hemorrhagic complications. A total number of 5,781 blood counts were collected longitudinally. Thrombotic and hemorrhagic events were studied together (primary endpoint) but also separately (thrombotic alone = secondary endpoint; hemorrhagic alone = tertiary endpoint). The primary endpoint showed no significant association between platelet and WBC count at diagnosis and risk of any event (platelet, p = 0.797; WBC, p = 0.178), while Hb at baseline did show an association (p = 0.024). In the dynamic analysis with Cox regression model, where the blood count values were studied by time of follow-up, we observed that the risk for Hb was 1.49 (95 % CI 1.13-1.97) for every increase of 1 g/dL, and that this risk then marginally decreased during follow-up. WBC was associated with an increased risk at baseline for every increase of 1 × 10(9)/L (hazard ratio (HR) 1.07, 95 % CI 1.01-1.13, p = 0.034), the risk was stable during follow-up (HR 0.95, p = 0.187 at 60 months). Also, for each increment at baseline of 100 × 10(9) platelets/L, HR was increased by 1.08 (95 % CI 0.97-1.22, p = 0.159) and decreases during follow-up. In conclusion, this study is the first to evaluate in ET low-risk patients, the risk of developing a thrombotic/hemorrhagic event considering blood counts over time. Overall our study shows that the risk changes over time. For example, the risk associated with WCC is not linear as previously reported. An interesting new finding is that PLT and even Hb contribute to the risk of developing vascular events. Future treatments should take into consideration these findings and aim to control all parameters over time. We believe this early study may help develop a dynamic analysis model to predict thrombosis in the single patient. Further studies are now warranted to further validate our findings.
Internal and Emergency Medicine 01/2015; 10(4). DOI:10.1007/s11739-015-1186-8 · 2.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Following the introduction of targeted therapy with tyrosine kinase inhibitors (TKI) at the beginning of the past decade, the outcome of patients with Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) has dramatically improved. Presently, the use of refined programs with first/second generation TKI's and chemotherapy together with allogeneic stem cell transplantation allow up to 50% of all patients to be cured. Further progress is expected with the new TKI ponatinib, overcoming resistance caused by T315I point mutation, other targeted therapies, autologous transplantation in molecularly negative patients, therapeutic monoclonal antibodies like inotuzumab ozogamicin and blinatumomab, and chimeric antigen receptor-modified T cells. Ph+ ALL could become curable in the near future even without allogeneic stem cell transplantation, minimizing the risk of therapy-related death and improving greatly the quality of patients' life.
[Show abstract][Hide abstract] ABSTRACT: In this issue of Blood, Fielding et al demonstrate a significant enhancement of long-term outcomes for a large series of adult patients with Philadelphia-positive acute lymphoblastic leukemia (Ph1 ALL), who were prospectively treated in 2 sequential cohorts with an imatinib-containing protocol.
[Show abstract][Hide abstract] ABSTRACT: Acute lymphoblastic leukemia (ALL) is curable in about 40-50% of adult patients, however this is subject to ample variations owing to several host- and disease-related prognostic characteristics. Currently, the study of minimal residual disease (MRD) following induction and early consolidation therapy stands out as the most sensitive individual prognostic marker to define the risk of relapse following the achievement of remission, and ultimately that of treatment failure or success. Because substantial therapeutic advancement is now being achieved using intensified pediatric-type regimens, MRD analysis is especially useful to orientate stem cell transplantation choices. These strategic innovations are progressively leading to greater than 50% cure rates.
Mediterranean Journal of Hematology and Infectious Diseases 01/2014; 6(1):e2014062. DOI:10.4084/MJHID.2014.062
[Show abstract][Hide abstract] ABSTRACT: Acute lymphoblastic leukemia (ALL) is a disseminated malignancy of B- or T-lymphoblasts which imposes a rapid and accurate diagnostic process to support an optimal risk-oriented therapy and thus increase the curability rate. The need for a precise diagnostic algorithm is underlined by the awareness that both ALL therapy and related success rates may vary greatly between ALL subsets, from standard chemotherapy in patients with standard-risk ALL, to allotransplantation (SCT) and targeted therapy in high-risk patients and cases expressing suitable biological targets, respectively. This review summarizes how best to identify ALL and the most relevant ALL subsets.
Mediterranean Journal of Hematology and Infectious Diseases 01/2014; 6(1):e2014073. DOI:10.4084/MJHID.2014.073
[Show abstract][Hide abstract] ABSTRACT: We evaluate the long-term results of a prospective clinical study enrolling more than 100 adult patients with Burkitt lymphoma/leukemia. Depending on extent of disease, treatment consisted of six-eight rituximab infusions and four-six intensive chemotherapy courses (attenuated in patients aged >55 years) with high-dose methotrexate, fractionated ifosfamide/cyclophosphamide, other drugs in rotation, and intrathecal chemoprophylaxis. One-hundred five patients were treated (median age 47 years, range 17-78 years); 48% had Burkitt leukemia, 25% were older than 60 years, 37% exhibited an Eastern Cooperative Oncology Group performance score >1, and 14% were HIV-positive. Complete response rate and 3-year overall and disease-free survival were 79%, 67% and 75%, respectively, ranging from 100% to 45% for survival (P=0.000) and from 100% to 60% for disease-free survival (P=0.01) in patients with low, intermediate and high adapted international prognostic index. In multivariate analysis, only age (< vs >60 years) and performance status (0-1 vs >1) retained prognostic significance, identifying three risk groups with overall and disease-free survival probabilities of 88% and 87.5%, 57% (P=0.0000) and 70.5%, 20% and 28.5% (P=0.0001), respectively. Relapse rate was only 7% in patients treated with an intercycle interval <25 days. This regimen achieved 100% curability in patients with low adapted international prognostic index (21% of total), and very close to 90% in patients aged ≤60 years with performance score 0-1 (48% of total). Rapid Burkitt lymphoma/leukemia diagnosis with prompt patient referral to prevent clinical deterioration, and careful supervision of treatment without chemotherapy delay can achieve outstanding therapeutic results. ClinicalTrial.gov ID, NCT01290120.
[Show abstract][Hide abstract] ABSTRACT: The study by Topp et al in this issue of Blood confirms that blinatumomab can significantly reduce the relapse risk and improve survival in patients with minimal residual disease (MRD)+ B-precursor acute lymphoblastic leukemia (ALL).
[Show abstract][Hide abstract] ABSTRACT: Acute lymphoblastic leukemia (ALL) in adults is currently associated with an overall survival rate of around 40% at 5 years. This is an unsatisfactory result that makes it imperative to dissect further the biology of the disease in order to identify highly specific therapeutic targets to implement selectively the cure rate. The recognition of discrete ALL subsets followed by the application of risk-oriented therapies has been a major achievement over the past 30 years.
[Show abstract][Hide abstract] ABSTRACT: Among acute myeloid leukemia (AML) patients with a normal karyotype (CN-AML), NPM1 and CEBPA mutations define World Health Organization 2008 provisional entities accounting for approximately 60% of patients, but the remaining 40% are molecularly poorly characterized. Using whole-exome sequencing of one CN-AML patient lacking mutations in NPM1, CEBPA, FLT3-ITD, IDH1, and MLL-PTD, we newly identified a clonal somatic mutation in BCOR (BCL6 corepressor), a gene located on chromosome Xp11.4. Further analyses of 553 AML patients showed that BCOR mutations occurred in 3.8% of unselected CN-AML patients and represented a substantial fraction (17.1%) of CN-AML patients showing the same genotype as the AML index patient subjected to whole-exome sequencing. BCOR somatic mutations were: (1) disruptive events similar to the germline BCOR mutations causing the oculo-facio-cardio-dental genetic syndrome; (2) associated with decreased BCOR mRNA levels, absence of full-length BCOR, and absent or low expression of a truncated BCOR protein; (3) virtually mutually exclusive with NPM1 mutations; and (4) frequently associated with DNMT3A mutations, suggesting cooperativity among these genetic alterations. Finally, BCOR mutations tended to be associated with an inferior outcome in a cohort of 422 CN-AML patients (25.6% vs 56.7% overall survival at 2 years; P = .032). Our results for the first time implicate BCOR in CN-AML pathogenesis.
[Show abstract][Hide abstract] ABSTRACT: The prognostic significance of CD20 expression in acute lymphoblastic leukemia has been investigated in children and adults but is still a subject of debate. The aim of our study was to correlate CD20 expression with clinical-biological characteristics and outcome in 172 Philadelphia chromosome negative patients prospectively treated in a multicenter trial introducing the molecular evaluation of minimal residual disease for therapeutic purposes. We considered 20% as the threshold for CD20 positivity. Complete remission rate, minimal residual disease negativity rate at weeks 10, 16 and 22, and disease-free and overall survival were similar among CD20-positive and -negative patients, even considering minimal residual disease results and related therapeutic choices. Our study failed to demonstrate any prognostic significance for CD20 expression in Philadelphia chromosome negative acute lymphoblastic leukemia. This conclusion is supported for the first time by a comparable minimal residual disease response rate among CD20-positive and -negative and positive patients.