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      Clinical significance of occult central nervous system disease in adult acute lymphoblastic leukemia: a multicenter report from the Campus ALL Network


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          In acute lymphoblastic leukemia (ALL), flow cytometry (FCM) detects leukemic cells in patients’ cerebrospinal fluid (CSF) more accurately than conventional cytology (CC). However, the clinical significance of FCM positivity with a negative cytology (i.e., occult central nervous system [CNS] disease) is not clear. In the framework of the national Campus ALL program, we retrospectively evaluated the incidence of occult CNS disease and its impact on outcome in 240 adult patients with newly diagnosed ALL. All CSF samples were investigated by CC and FCM. The presence of ≥10 phenotypically abnormal events, forming a cluster, was considered to be FCM positivity. No CNS involvement was documented in 179 patients, while 18 were positive by modified conventional morphology with CC and 43 were occult CNS disease positive. The relapse rate was significantly lower in CNS disease negative patients and the disease-free and overall survival (OS) were significantly longer in CNS disease negative patients than in those with manifest or occult CNS disease positivity. In multivariate analysis, the status of manifest and occult CNS disease positivity was independently associated with a worse OS. In conclusion, we demonstrate that in adult ALL patients at diagnosis FCM can detect occult CNS disease at high sensitivity and that the status of occult CNS disease positivity is associated with an adverse outcome. (Registered at clinicaltrials.gov identifier: NCT03803670).

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          Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia.

          To evaluate the efficacy and toxicity of Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), a dose-intensive regimen, in adult acute lymphocytic leukemia (ALL). Adults with newly diagnosed ALL referred since 1992 were entered onto the study; treatment was initiated in 204 patients between 1992 and January 1998. No exclusions were made because of older age, poor performance status, organ dysfunction, or active infection. Median age was 39.5 years; 37% were at least 50 years old. Mature B-cell disease (Burkitt type) was present in 9%, T-cell disease in 17%. Leukocytosis of more than 30 x 10(9)/L was found in 26%, Philadelphia chromosome-positive disease in 16% (20% of patients with assessable metaphases), CNS leukemia at the time of diagnosis in 7%, and a mediastinal mass in 7%. Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal CNS prophylaxis and supportive care with antibiotic prophylaxis and granulocyte colony-stimulating factor therapy. Maintenance in patients with nonmature B-cell ALL included 2 years of treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP). Overall, 185 patients (91%) achieved complete remission (CR) and 12 (6%) died during induction therapy. Estimated 5-year survival and 5-year CR rates were 39% and 38%, respectively. The incidence of CNS relapse was low (4%). Compared with 222 patients treated with vincristine, doxorubicin, and dexamethasone (VAD) regimens, our patients had a better CR rate (91% v 75%, P <.01) and CR rate after one course (74% v 55%, P <.01) and better survival (P <.01), and a smaller percentage had more than 5% day 14 blasts (34% v 48%, P =.01). Previous prognostic models remained predictive for outcome with Hyper-CVAD therapy. Hyper-CVAD therapy is superior to our previous regimens and should be compared with established regimens in adult ALL.
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            Flow cytometric immunophenotyping for hematologic neoplasms.

            Flow cytometric immunophenotyping remains an indispensable tool for the diagnosis, classification, staging, and monitoring of hematologic neoplasms. The last 10 years have seen advances in flow cytometry instrumentation and availability of an expanded range of antibodies and fluorochromes that have improved our ability to identify different normal cell populations and recognize phenotypic aberrancies, even when present in a small proportion of the cells analyzed. Phenotypically abnormal populations have been documented in many hematologic neoplasms, including lymphoma, chronic lymphoid leukemias, plasma cell neoplasms, acute leukemia, paroxysmal nocturnal hemoglobinuria, mast cell disease, myelodysplastic syndromes, and myeloproliferative disorders. The past decade has also seen refinement of the criteria used to identify distinct disease entities with widespread adoption of the 2001 World Health Organization (WHO) classification. This classification endorses a multiparametric approach to diagnosis and outlines the morphologic, immunophenotypic, and genotypic features characteristic of each disease entity. When should flow cytometric immunophenotyping be applied? The recent Bethesda International Consensus Conference on flow cytometric immunophenotypic analysis of hematolymphoid neoplasms made recommendations on the medical indications for flow cytometric testing. This review discusses how flow cytometric testing is currently applied in these clinical situations and how the information obtained can be used to direct other testing.
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              Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial.

              We analyzed the benefits of a risk-adapted postremission strategy in adult lymphoblastic leukemia (ALL), and re-evaluated stem-cell transplantation (SCT) for high-risk ALL. A total of 922 adult patients entered onto the trial according to risk groups: standard-risk ALL (group 1), high-risk ALL (group 2), Philadelphia chromosome-positive ALL (group 3), and CNS-positive ALL (group 4). All received a standard four-drug/4-week induction course. Patients from group 1 who achieved a complete remission (CR) after one course of induction therapy were randomly assigned between intensive and less intensive postremission chemotherapy, whereas those who achieved CR after salvage therapy were then included in group 2. Patients in groups 2, 3, and 4 with an HLA-identical sibling were assigned to allogeneic SCT. In groups 3 and 4, autologous SCT was offered to all other patients, whereas in group 2 they were randomly assigned between chemotherapy and autologous SCT. Overall, 771 patients achieved CR (84%). Median disease-free survival (DFS) was 17.5 months, with 3-year DFS at 37%. In group 1, the 3-year DFS rate was 41%, with no difference between arms of postremission randomization. In groups 2 and 4, the 3-year DFS rates were 38% and 44%, respectively. In group 2, autologous SCT and chemotherapy resulted in comparable median DFS. Patients with an HLA-matched sibling (groups 2 and 4) had improved DFS. Three-year DFS was 24% in group 3. Allogeneic SCT improved DFS in high-risk ALL in the first CR. Autologous SCT did not confer a significant benefit over chemotherapy for high-risk ALL.

                Author and article information

                Fondazione Ferrata Storti
                01 January 2021
                01 January 2021
                : 106
                : 1
                [1 ]Ematologia Dipartimento di Biomedicina e Prevenzione, Università degli Studi di Roma “Tor Vergata” , Roma
                [2 ]GIMEMA Data Center , Roma
                [3 ]Ematologia Dipartimento di Scienze Mediche e Chirurgiche, Università degli Studi di Modena e Reggio Emilia , Azienda Ospedaliera di Modena, Modena
                [4 ]Dipartimento di Medicina, Sezione di Ematologia, Università@ di Verona , Verona
                [5 ]Ematologia ed Immunologia Clinica , Azienda Ospedaliera di Padova, Padova
                [6 ]UO Ematologia, Azienda Ospedaliero-Universitaria Pisana , Pisa
                [7 ]U.O. di Ematologia e Trapianto di Cellule Staminali, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo , Foggia
                [8 ]UOC di Ematologia, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico , Milano
                [9 ]Clinica di Ematologia, AOU Ospedali Riuniti di Ancona, Ancona
                [10 ]Ematologia, Ospedale Sant’Eugenio, Dipartimento di Biomedicina e Prevenzione, Università degli Studi di Roma “Tor Vergata” , Roma
                [11 ]Ematologia, Policlinico Universitario-Campus Biomedico , Roma
                [12 ]Divisione di Ematologica, Fondazione IRCCS Policlinico San Matteo, Università di Pavia , Pavia
                [13 ]Ematologia e Trapianto di Cellule Staminali, Ospedale Vito Fazzi , Lecce
                [14 ]Ematologia, Dipartimento di Onco-Ematologia, Fondazione Policlinico Tor Vergata , Roma
                [15 ]Ematologia, Dipartimento di Medicina Traslazionale e di Precisione, Università “Sapienza” , Roma
                [16 ]Dipartimento di Medicina Molecolare, Università “Sapienza” , Roma, Italy
                Author notes
                MARIA ILARIA DEL PRINCIPE del.principe@ 123456med.uniroma2.it


                This study was carried out as part of the routine clinical workup of patients. The authors declare no competing financial interests.


                MIDP, AV and AG designed the study, interpreted data, wrote the manuscript; AP analyzed data and performed statistical analysis; EB, FF, MB, FL, SI, EO, GR, NF, ST, BN, CS, PZ, MD, MC, GD, MS, GP provided patients information, collected clinical data and contributed to data analysis; MAC and CC obtained flow cytometry data; IDS interpreted data and contributed to data analysis; RF wrote and revised the manuscript. All authors approved the manuscript.

                Copyright© 2021 Ferrata Storti Foundation

                This article is distributed under the terms of the Creative Commons Attribution Noncommercial License ( by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

                Page count
                Figures: 3, Tables: 3, Equations: 0, References: 38, Pages: 7


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