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Registry-Based Studies in Adult Acute Lymphoblastic Leukemia in Sweden: Survival and Quality of Life
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.ORCID iD: 0000-0002-1737-5568
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
Abstract [en]

Acute lymphoblastic leukemia (ALL), a common child malignancy, also constitutes a minor fraction of adult cancer with approximately 50 new cases per year in Sweden. While the five-year overall survival (OS) in pediatric ALL is more than 90%, the prognosis in adults is dismal. Using the Swedish ALL quality registry, this thesis investigates treatment and outcome of adult ALL according to national guidelines. In addition, the introduction of patient-reported outcome in the ALL and Acute Myeloid Leukemia registries is evaluated. 

In Paper I, measurement of minimal residual disease by flow cytometry was found to be feasible but not consistently applied in the 35 patients with Philadelphia (Ph)-negative B-ALL investigated. In Paper II, treatment, toxicity and outcome of 155 patients, 55-85 years (y) with ALL diagnosis between 2005 and 2012 were studied in detail by patient charts review. An age-adopted protocol recommended from 2009 did not result in better outcome. In Paper III, disease recurrence in the same cohort as Paper II was studied. The median overall survival (OS) after ALL relapse was 3.6 months. In Paper IV, the whole ALL registry was studied and OS was estimated in 930 adult patients diagnosed in the periods 1997-2006 and 2007-2015. Five year OS improved in patients 18-45y from 50% to 65%, in patients 46-65y from 25% to 46%, and in patients >65y from 7% to 11%. This demonstrates that young patients have the best prognosis, in part due to the introduction of a dose-intense “pediatric-like” chemotherapy protocol. Compared to women, middle-aged men were found to have a worse outcome.

Historically, Philadelphia-positive (Ph-pos) ALL has a poor prognosis compared to Ph-negative ALL. In this material, the frequency of Ph-pos ALL was 34% of examined B-ALL. Analysis of the whole registry revealed that in 2007-2015, i.e. after the introduction of the tyrosine kinase inhibitor imatinib, Ph-pos ALL was no longer associated with inferior OS. In Paper V, ALL and Acute Myeloid Leukemia patients, six months after diagnosis, completed a web or paper questionnaire regarding quality of life, symptoms and experience with care. The response rate was 64%. Depression symptoms were frequent (18%), especially in young women who reported worrying about fertility.

In summary, although OS in adult ALL has improved, more effective and less toxic therapies in upfront treatment are highly warranted. Collection of patient-reported outcome in a national quality registry is feasible and can add important aspects of cancer care that are not usually addressed.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. , p. 69
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1630
Keywords [en]
Acute Lymphoblastic Leukemia, Philadelphia Chromosome, Overall Survival, Population-based, Quality Registry, Relapse, Patient-Reported Outcome, Health-Related Quality of Life, Depression
National Category
Hematology
Identifiers
URN: urn:nbn:se:uu:diva-401431ISBN: 978-91-513-0853-1 (print)OAI: oai:DiVA.org:uu-401431DiVA, id: diva2:1385886
Public defence
2020-03-06, H:son-Holmdahlsalen, Akademiska sjukhuset, ing 100, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2020-02-13 Created: 2020-01-15 Last updated: 2020-02-13
List of papers
1. Satisfactory outcome after intensive chemotherapy with pragmatic use of minimal residual disease (MRD) monitoring in older patients with Philadelphia-negative B cell precursor acute lymphoblastic leukaemia: a Swedish registry-based study
Open this publication in new window or tab >>Satisfactory outcome after intensive chemotherapy with pragmatic use of minimal residual disease (MRD) monitoring in older patients with Philadelphia-negative B cell precursor acute lymphoblastic leukaemia: a Swedish registry-based study
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2015 (English)In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 32, no 4, article id 135Article in journal (Refereed) Published
Abstract [en]

The introduction of minimal residual disease (MRD) monitoring, in the Swedish national guidelines for acute lymphoblastic leukaemia, was evaluated in 35 patients aged 46-79 years (median 61), who were diagnosed from 2007 to 2011 and treated with high-intensity, block-based chemotherapy (ABCDV/VABA induction). Both a high complete remission rate (91 %) and acceptable overall survival (OS) rate (47 %) at 5 years were achieved. MRD by flow cytometry was measured in 73 % of the patients reaching complete remission after the first course, but was omitted by the clinicians for eight patients who were either over 70 years of age or already met conventional high-risk criteria. Factors negatively influencing OS were age over 65 years and WHO status >= 2. MRD < 0.1 % after induction had positive impact on continuous complete remission but not on OS. Only five patients were allocated to allogeneic haematopoietic stem cell transplantation in first remission, mainly due to conventional high risk factors. Thus, use of intensive remission induction therapy is effective in a selection of older patients. In a population for whom the possibilities of treatment escalation are limited, the optimal role of MRD monitoring remains to be determined.

Keywords
Acute lymphoblastic leukaemia, Adults, Minimal residual disease, Flow cytometry
National Category
Cancer and Oncology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-258836 (URN)10.1007/s12032-015-0582-2 (DOI)000351474100049 ()25796502 (PubMedID)
Available from: 2015-07-23 Created: 2015-07-20 Last updated: 2020-01-15Bibliographically approved
2. Age but not Philadelphia positivity impairs outcome in older/elderly patients with acute lymphoblastic leukemia in Sweden
Open this publication in new window or tab >>Age but not Philadelphia positivity impairs outcome in older/elderly patients with acute lymphoblastic leukemia in Sweden
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2017 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 99, no 2, p. 141-149Article in journal (Refereed) Published
Abstract [en]

ObjectivesOlder/elderly patients with acute lymphoblastic leukemia (ALL) are poorly represented in clinical trials. MethodsUsing Swedish national leukemia registries, we investigated disease/patient characteristics, treatment choices, outcome, and the impact of an age-adapted protocol (introduced in 2009) in this population-based study of patients aged 55-85years, diagnosed with ALL 2005-2012. ResultsOf 174 patients, 82% had B-phenotype, 11% Burkitt leukemia (excluded), and 7% T-phenotype. Philadelphia chromosome positivity (Ph+) occurred in 35%. Of the 155 B- and T-ALL patients, 80% were treated with intensive protocols, and 20% with a palliative approach. Higher age and WHO performance status 2 influenced the choice of palliation. Intensive, palliative, and both approaches resulted in complete remission rate 83/16/70% and 3-year overall survival (OS) 32/3/26%. The age-adapted protocol did not improve outcome. With intensive treatment, platelet count 35x10(9)/L and age 75years were adverse prognostic factors for OS, Ph+ was not. Male sex was an adverse prognostic factor in the 55-64 year age-group. ConclusionsWe report a high frequency of Ph+ in older/elderly patients, with no evidence of poorer outcome compared to Ph-negative disease. Overall prognosis for elderly patients with ALL remains dismal, despite the use of age-adapted treatment.

Place, publisher, year, edition, pages
WILEY, 2017
Keywords
acute lymphoblastic leukemia, chemotherapy, elderly, epidemiology
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-329913 (URN)10.1111/ejh.12896 (DOI)000404936400005 ()
Available from: 2017-10-20 Created: 2017-10-20 Last updated: 2020-01-15Bibliographically approved
3. Real-world data on first relapse of acute lymphoblastic leukemia in patients > 55 years
Open this publication in new window or tab >>Real-world data on first relapse of acute lymphoblastic leukemia in patients > 55 years
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2018 (English)In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 59, no 10, p. 2470-2473Article in journal, Letter (Other academic) Published
Place, publisher, year, edition, pages
Taylor & Francis Group, 2018
National Category
Cancer and Oncology Hematology
Identifiers
urn:nbn:se:uu:diva-374878 (URN)10.1080/10428194.2017.1416369 (DOI)000455166400026 ()29345172 (PubMedID)
Funder
Thuréus stiftelse för främjande av geriatrisk forskningErik, Karin och Gösta Selanders Foundation
Available from: 2019-01-24 Created: 2019-01-24 Last updated: 2020-01-15Bibliographically approved
4. Survival in adult acute lymphoblastic leukaemia (ALL): A report from the Swedish ALL Registry
Open this publication in new window or tab >>Survival in adult acute lymphoblastic leukaemia (ALL): A report from the Swedish ALL Registry
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2019 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 103, no 2, p. 88-98Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
acute lymphoblastic leukaemia, adult, Philadelphia-positive
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-390495 (URN)10.1111/ejh.13247 (DOI)000475475200003 ()31074910 (PubMedID)
Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2020-01-15Bibliographically approved
5. Introducing Patient Reported Outcome in the Acute Leukemia Quality Registries in Sweden
Open this publication in new window or tab >>Introducing Patient Reported Outcome in the Acute Leukemia Quality Registries in Sweden
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(English)Manuscript (preprint) (Other academic)
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-402409 (URN)
Available from: 2020-01-14 Created: 2020-01-14 Last updated: 2020-01-15

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