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      Survival in adult acute lymphoblastic leukaemia (ALL): A report from the Swedish ALL Registry

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          Abstract

          Objectives

          As new, effective therapies emerge for acute lymphoblastic leukaemia (ALL), the results of clinical trials need to relate to standard of care.

          Methods

          We used the population‐based Swedish ALL Registry to evaluate characteristics, treatment and long‐term outcome in 933 patients with diagnosis between 1997 and 2015.

          Results

          The median age was 53 years. The frequency of Philadelphia (Ph)‐positive leukaemia was 34% of examined B‐ALL with a peak incidence at 50‐59 years. Five‐year overall survival (OS) improved between 1997‐2006 and 2007‐2015; in patients 18‐45 years from 50% (95% CI 43‐57) to 65% (95% CI 58‐72), 46‐65 years from 25% (95% CI 18‐32) to 46% (95% CI 37‐55) and >65 years from 7% (95% CI 2.6‐11) to 11% (95% CI 5.9‐16) ( P < 0.05). Men with Ph‐neg B‐ALL 46‐65 years had inferior OS compared with women ( P < 0.01). Standardised mortality ratio was 5.7 (95% CI 5.0‐6.3) for patients who survived 5 years from diagnosis. In multivariable analysis, Ph‐positive disease was not associated with impaired prognosis but with lower risk of death in 2007‐2015.

          Conclusions

          In a population‐based cohort, OS has improved in adult ALL, especially for Ph‐positive disease but for middle‐aged men with Ph‐negative B‐ALL outcome was poor. Cure without late toxicity or relapse is still desired.

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          Most cited references36

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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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            Results of NOPHO ALL2008 treatment for patients aged 1–45 years with acute lymphoblastic leukemia

            Adults with acute lymphoblastic leukemia (ALL) do worse than children. From 7/2008 to 12/2014, Nordic and Baltic centers treated 1509 consecutive patients aged 1-45 years with Philadelphia chromosome-negative ALL according to the NOPHO ALL2008 without cranial irradiation. Overall, 1022 patients were of age 1-9 years (A), 266 were 10-17 years (B) and 221 were 18-45 years (C). Sixteen patients (three adults) died during induction. All others achieved remission after induction or 1-3 intensive blocks. Subsequently, 45 patients (12 adults) died, 122 patients relapsed (32 adults) with a median time to relapse of 1.6 years and 13 (no adult) developed a second malignancy. Median follow-up time was 4.6 years. Among the three age groups, older patients more often had higher risk ALL due to T-ALL (32%/25%/9%, P<0.001), KMT2A rearrangements (6%/5%/3%, P<0.001) and higher day 29 residual leukemia for B-lineage (P<0.001), but not T-ALL (P=0.53). Event-free survival rates (pEFS5y) were 89±1% (A), 80±3% (B) and 74±4% (C) with significant differences only for non-high risk groups. Except for thrombosis, pancreatitis and osteonecrosis, the risk of 19 specified toxicities was not enhanced by age above 10 years. In conclusion, a pediatric-based protocol is tolerable and effective for young adults, despite their increased frequency of higher risk features.
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              Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome–positive ALL

              Prognosis of Philadelphia-positive (Ph(+)) acute lymphoblastic leukemia (ALL) in the elderly has improved during the imatinib era. We investigated dasatinib, another potent tyrosine kinase inhibitor, in combination with low-intensity chemotherapy. Patients older than age 55 years were included in the European Working Group on Adult ALL (EWALL) study number 01 for Ph(+) ALL (EWALL-PH-01 international study) and were treated with dasatinib 140 mg/day (100 mg/day over 70 years) with intrathecal chemotherapy, vincristine, and dexamethasone during induction. Patients in complete remission continued consolidation with dasatinib, sequentially with cytarabine, asparaginase, and methotrexate for 6 months. Maintenance therapy was dasatinib and vincristine/dexamethasone reinductions for 18 months followed by dasatinib until relapse or death. Seventy-one patients with a median age of 69 years were enrolled; 77% had a high comorbidity score. Complete remission rate was 96% and 65% of patients achieved a 3-log reduction in BCR-ABL1 transcript levels during consolidation. Only 7 patients underwent allogeneic hematopoietic stem cell transplantation. At 5 years, overall survival was 36% and up to 45% taking into account deaths unrelated to disease or treatment as competitors. Thirty-six patients relapsed, 24 were tested for mutation by Sanger sequencing, and 75% were T315I-positive. BCR-ABL1(T315I) was tested by allele-specific oligonucleotide reverse transcription-quantitative polymerase chain reaction in 43 patients and detection was associated with short-term relapses. Ten patients (23%) were positive before any therapy and 8 relapsed, all with this mutation. In conclusion, dasatinib combined with low-intensity chemotherapy was well-tolerated and gave long-term survival in 36% of elderly patients with Ph(+) ALL. Monitoring of BCR-ABL1(T315I) from diagnosis identified patients with at high risk of early relapse and may help to personalize therapy.
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                Author and article information

                Contributors
                emma.lennmyr@medsci.uu.se
                Journal
                Eur J Haematol
                Eur. J. Haematol
                10.1111/(ISSN)1600-0609
                EJH
                European Journal of Haematology
                John Wiley and Sons Inc. (Hoboken )
                0902-4441
                1600-0609
                06 June 2019
                August 2019
                : 103
                : 2 ( doiID: 10.1111/ejh.2019.103.issue-2 )
                : 88-98
                Affiliations
                [ 1 ] Department of Medical Sciences Uppsala University Uppsala Sweden
                [ 2 ] Department of Haematology, Oncology and Radiophysics Skåne University Hospital Lund Sweden
                [ 3 ] Department of Haematology University Hospital of Linköping Linköping Sweden
                [ 4 ] Department of Medicine, Section of Haematology and Coagulation Sahlgrenska University Hospital Göteborg Sweden
                [ 5 ] Department of Haematology, Cancer Centre University Hospital of Umeå Umeå Sweden
                [ 6 ] Division of Haematology, Department of Medicine Karolinska Institute, Karolinska University Hospital Stockholm Sweden
                [ 7 ] Department of Medicine, School of Medical Sciences Örebro University Örebro Sweden
                [ 8 ] Department of Medicine Central Hospital Skövde Skövde Sweden
                Author notes
                [*] [* ] Correspondence

                Emma Lennmyr, Uppsala University Hospital, Akademiska Sjukhuset, Blod och Tumörsjukdomar, Sektionen för Hematologi, Avd 50C, Ing 50, 5 trappor, S‐751 85 Uppsala, Sweden.

                Email: emma.lennmyr@ 123456medsci.uu.se

                Author information
                https://orcid.org/0000-0002-1737-5568
                https://orcid.org/0000-0002-0283-4418
                Article
                EJH13247
                10.1111/ejh.13247
                6851994
                31074910
                0eefa58f-a806-4151-8324-13199d70ea54
                © 2019 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 21 March 2019
                : 01 May 2019
                : 03 May 2019
                Page count
                Figures: 4, Tables: 2, Pages: 11, Words: 7516
                Funding
                Funded by: Uppsala University and Uppsala County Council/Region agreement on medical training and clinical research (ALF)
                Funded by: Lions Cancer Foundation Uppsala
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                August 2019
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.1 mode:remove_FC converted:13.11.2019

                Hematology
                acute lymphoblastic leukaemia,adult,philadelphia‐positive
                Hematology
                acute lymphoblastic leukaemia, adult, philadelphia‐positive

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