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Prognostic factors, treatment and outcome in adult acute lymphoblastic leukemia: Population-based studies in Sweden
Örebro University, School of Health Sciences.ORCID iD: 0000-0002-0283-4418
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Acute lymphoblastic leukemia (ALL) has poor prognosis in older/elderly adults and in high-risk/relapsed disease. Recommended treatment of ALL was evaluated (study I-IV). Data was obtained from the Swedish Acute Leukemia registries and from patient records.

I. We assessed ALL relapse treatment and outcome in 76 patients aged 15-65 years (y). Complete remission (CR) was achieved in 50/71 patients (70%). Of them, 29 underwent allogeneic hematopoietic stem cell transplantation (hSCT). Five year overall survival (OS) was 15%, but close to 50% in 19 patients <35y after hSCT.

II. We studied outcome of treatment with the Hyper-CVAD protocol in 19 of 24 patients with T-ALL aged 18-72y. CR was reached in 89%, but 5y leukemia-free survival was only 29%, and 20% in 15 patients not transplanted in CR1. Six patients received hSCT in CR2. Finally, 5y OS in all 19 patients was 47%. The only negative prognostic factor found was age ≥35y.

III. We evaluated minimal residual disease (MRD) monitoring in 35 patients with Philadelphia (Ph) negative B-ALL aged 46-79y and treated with the ABCDV protocol. The CR rate was 91%. MRD was measured by flow cytometry in 73% in CR1 (MRD1) and omitted in those >70y or with high-risk ALL. Five patients received hSCT (only one due to MRD). Five year OS in the whole cohort was 47%. Continuous CR but not OS was improved in patients with MRD1 <0.1 %.

IV. We studied 155 patients with ALL (Ph+ in 35%) aged 55-85y and treated with remission induction/palliation (124/31). Both, intensive, and palliative treatment resulted in the CR rates of 70/83/16% and 3y OS of 26/32/3%. OS was negatively influenced by age and platelet count ≤35×109/L (but not Ph+). OS was not enhanced by introduction of an age-adapted protocol.

We concluded that intensive treatment with subsequent allogeneic hSCT is the most reasonable option in younger patients with ALL recurrence (I). Hyper-CVAD has low relapse-preventing efficacy (II). MRD guided intensification is probably feasible in only a minority of older patients (III). Prognosis in elderly ALL is poor, but no longer impaired by Ph+ (IV).

Place, publisher, year, edition, pages
Örebro: Örebro university , 2016. , 56 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 134
Keyword [en]
Acute Lymphoblastic Leukemia, adult, chemotherapy, prognosis, population-based
National Category
Cancer and Oncology Hematology Family Medicine
Research subject
Oncology
Identifiers
URN: urn:nbn:se:oru:diva-47424ISBN: 978-91-7529-121-5 (print)OAI: oai:DiVA.org:oru-47424DiVA: diva2:894482
Public defence
2016-03-18, Universitetssjukhuset, hörsal C2, Södra Grev Rosengatan, Örebro, 13:00 (English)
Opponent
Supervisors
Available from: 2016-01-15 Created: 2016-01-15 Last updated: 2017-10-17Bibliographically approved
List of papers
1. High curability via intensive reinduction chemotherapy and stem cell transplantation in young adults with relapsed acute lymphoblastic leukemia in Sweden 2003-2007
Open this publication in new window or tab >>High curability via intensive reinduction chemotherapy and stem cell transplantation in young adults with relapsed acute lymphoblastic leukemia in Sweden 2003-2007
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2012 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 97, no 9, 1414-1421 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: A minority of patients with adult acute lymphoblastic leukemia who relapse are rescued. The aim of this population-based study was to assess the results of reinduction treatment and allogeneic stem cell transplantation in patients in second complete remission.

DESIGN AND METHODS: Between 2003-2007, 76 adults (<66 years) with relapsed acute lymphoblastic leukemia (Burkitt's leukemia excluded) were prospectively reported to The Swedish Adult Acute Leukemia Registry and later evaluated.

RESULTS: Reinduction with: (i) mitoxantrone, etoposide, and cytarabine (MEA); (ii) fludarabine, cytarabine, pegylated-asparaginase plus granulocyte colony-stimulating factor (FLAG-Asp); and (iii) cytarabine, betamethasone, cyclophosphamide, daunorubicin, and vincristine (ABCDV) resulted in complete remission in 6/9 (67%), 10/16 (63%) and 9/21 (43%) of the patients, respectively. Allogeneic stem cell transplantation was performed during second complete remission in 29 patients. Multivariate analysis regarding overall survival after relapse revealed that age over 35 years at diagnosis and relapse within 18 months were negative prognostic factors. Overall survival rates at 3 and 5 years were 22% (95% CI: 13-32) and 15% (95% CI: 7-24). Of 19 patients less than 35 years at diagnosis who underwent allogeneic stem cell transplantation in second remission, ten (53%) are still alive at a median of 5.5 years (range, 4.2-8.3) after relapse, whereas all patients over 35 years old at diagnosis have died.

CONCLUSIONS: Allogeneic stem cell transplantation remains the treatment of choice for young adults with relapsed acute lymphoblastic leukemia. Both (i) mitoxantrone, etoposide, and cytarabine and (ii) fludarabine, cytarabine, pegylated-asparaginase plus granulocyte colony-stimulating factor seem effective as reinduction treatments and should be further evaluated. New salvage strategies are needed, especially for patients over 35 years old at diagnosis.

Place, publisher, year, edition, pages
Ferrata Storti Foundation, 2012
Keyword
Acute lymphoblastic leukaemia, Adults, Minimal residual disease, Flow cytometry
National Category
Hematology Family Medicine
Identifiers
urn:nbn:se:oru:diva-48485 (URN)10.3324/haematol.2011.057851 (DOI)000308908300022 ()22511497 (PubMedID)2-s2.0-84865851061 (Scopus ID)
Available from: 2016-02-23 Created: 2016-02-23 Last updated: 2017-11-30Bibliographically approved
2. High relapse rate of T cell acute lymphoblastic leukemia in adults treated with Hyper-CVAD chemotherapy in Sweden
Open this publication in new window or tab >>High relapse rate of T cell acute lymphoblastic leukemia in adults treated with Hyper-CVAD chemotherapy in Sweden
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2014 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 92, no 5, 377-381 p.Article in journal (Refereed) Published
Abstract [en]

Background: Hyper-CVAD is widely used to treat acute lymphoblastic leukemia (ALL) and aggressive lymphomas. This multicenter, population-based study assessed the efficacy of Hyper-CVAD as first-line therapy in patients with T-cell ALL (T-ALL).

Patients and methods: Between October 2002 and September 2006, 24 patients were diagnosed with T-ALL in Sweden; 19 were eligible for treatment with the protocol.

Results: The median age was 32 yr (range 18-72 yr). Complete remission (CR) was obtained in 17 of 19 (89%) patients, and the treatment was relatively well tolerated. Allogeneic stem cell transplantation (SCT) was recommended in high-risk disease and was performed in four patients upfront. Two- and 5-yr leukemia-free survivals (LFS) in 17 patients with CR achievement were identical, at 29% (95% confidence interval [CI]: 8-51). Two- and 5-yr overall survival (OS) in whole cohort was 63% (95% CI: 42-85) and 47% (95% CI: 26-69), respectively. The 5-yr LFS for 15 patients who did not receive allogeneic SCT upfront were 20% (95% CI: 0-40), although 14 of 15 completed the protocol (eight cycles). Relapse occurred in 2 of 4 upfront-transplanted patients and in 12 of 15 patients treated with chemotherapy alone, six of whom received allogeneic SCT in CR2. Age ≥35 yr influenced OS negatively in univariate analysis (HR 5.1, 95% CI: 1.55-16.7).

Conclusions: Hyper-CVAD treatment resulted in a high CR rate and appeared safe, but it showed poor efficacy at preventing relapse. Therefore, this treatment is no longer recommended for adults with T-ALL in Sweden.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2014
Keyword
antineoplastic combined chemotherapy protocols; treatment outcome; precursor T-cell lymphoblastic leukemia-lymphoma; stem cell transplantation
National Category
Hematology Family Medicine
Identifiers
urn:nbn:se:oru:diva-48486 (URN)10.1111/ejh.12269 (DOI)000334267500002 ()24443846 (PubMedID)2-s2.0-84898801134 (Scopus ID)
Available from: 2016-02-23 Created: 2016-02-23 Last updated: 2017-11-30Bibliographically approved
3. 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, 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.

Keyword
Acute lymphoblastic leukaemia, Adults, Minimal residual disease, Flow cytometry
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:oru:diva-44342 (URN)10.1007/s12032-015-0582-2 (DOI)000351474100049 ()25796502 (PubMedID)
Note

Funding Agency:

Lions Cancer Research Foundation, Uppsala

Available from: 2015-04-20 Created: 2015-04-20 Last updated: 2017-12-04Bibliographically approved
4. Age but not Philadelphia positivity impairs outcome in older/elderly patients with Acute Lymphoblastic Leukemia in the Swedish population
Open this publication in new window or tab >>Age but not Philadelphia positivity impairs outcome in older/elderly patients with Acute Lymphoblastic Leukemia in the Swedish population
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(English)Manuscript (preprint) (Other academic)
National Category
Family Medicine
Identifiers
urn:nbn:se:oru:diva-48533 (URN)
Available from: 2016-02-23 Created: 2016-02-23 Last updated: 2017-10-17Bibliographically approved

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