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STEM CELL TRANSPLANTATION IN PYRUVATE KINASE DEFICIENCY
Author(s):
Stephanie Van Straaten
,
Stephanie Van Straaten
Affiliations:
Laboratory of Clinical Chemistry and Hematology,UMC Utrecht,Utrecht,Netherlands;Van Creveldkliniek,UMC Utrecht,Utrecht,Netherlands
Marc Bierings
,
Marc Bierings
Affiliations:
Pediatric blood and marrow transplant program,Wilhelmina Pediatric Hospital,Utrecht,Netherlands
Paola Bianchi
,
Paola Bianchi
Affiliations:
Oncohematology Unit,Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano,Milan,Italy;Pathophysiology of anemia Unit,Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano,Milan,Italy
Kensuke Akiyoshi
,
Kensuke Akiyoshi
Affiliations:
Department of Pediatrics and Child Neurology,Oita University Faculty of Medicine, Hasama, Yufu,Oita,Japan
Hitoshi Kanno
,
Hitoshi Kanno
Affiliations:
Department of Transfusion Medicine and Cell Processing, Faculty of Medicine,Tokyo Women's Medical University,Tokyo,Japan
Isabel Badell Serra
,
Isabel Badell Serra
Affiliations:
Directora Unidad Pediátrica de Trasplante Hematopoyético,Hospital Santa Creu i Sant Pau,Barcelona,Spain
Jing Chen
,
Jing Chen
Affiliations:
Department of hematology oncology,Shanghai Children's Medical Center. Shanghai Jiao Tong University School of Medicine,Shanghai,China
Xiaohang Huang
,
Xiaohang Huang
Affiliations:
Department of hematology oncology,Shanghai Children's Medical Center. Shanghai Jiao Tong University School of Medicine,Shanghai,China
Eduard van Beers
,
Eduard van Beers
Affiliations:
Department of Internal Medicine,UMC Utrecht,Utrecht,Netherlands
Supachai Ekwattanakit
,
Supachai Ekwattanakit
Affiliations:
Department of Medicine,Faculty of Medicine Siriraj Hospital, Mahidol University,Bangkok,Thailand
Tayfun Gungor
,
Tayfun Gungor
Affiliations:
Division of Stem Cell Transplantation,University Children`s Hospital,Zurich,Switzerland
Wijnanda Adriana Kors
,
Wijnanda Adriana Kors
Affiliations:
department of pediatric oncology,VU university medical center,Amsterdam,Netherlands
Frans Smiers
,
Frans Smiers
Affiliations:
Department of pediatric haematology,Leiden University Hospital,Leiden,Netherlands
Reinier Raymakers
,
Reinier Raymakers
Affiliations:
Department of internal medicine,University Medical Center Utrecht,Utrecht,Netherlands
Lucrecia Yanez
,
Lucrecia Yanez
Affiliations:
Servicio de Hematología,Hospital Universitario Marqués de Valdecilla,Santander,Spain
Julian Sevilla
,
Julian Sevilla
Affiliations:
Servicio Hemato-Oncología Pediatrica,Hospital Infantil Universitario Niño Jesús.,Madrid,Spain
Wouter van Solinge
,
Wouter van Solinge
Affiliations:
Laboratory of Clinical Chemistry and Hematology,UMC Utrecht,Utrecht,Netherlands
José Carlos Segovia
,
José Carlos Segovia
Affiliations:
Differentiation and Cytometry Unit. Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT),Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER),Madrid,Spain
Richard van Wijk
Richard van Wijk
Affiliations:
Laboratory of Clinical Chemistry and Hematology,UMC Utrecht,Utrecht,Netherlands
(Abstract release date: 05/18/17) EHA Library. van Straaten S. 06/24/17; 181739; S452
Ms. Stephanie van Straaten
Ms. Stephanie van Straaten
Contributions
PDF Abstract
Abstract

Abstract: S452

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 11:45 - 12:00

Location: Room N109

Background

Pyruvate kinase deficiency (PKD) is the most common glycolytic enzyme defect causing hereditary non-spherocytic hemolytic anemia. PKD does not have a specific curative treatment. Therefo­­re treatment is mainly supportive, consisting of regular red blood cell transfusions, splenectomy and chelation therapy for iron overload. This does impact life expectancy and quality of life for affected patients. Hematopoietic allogeneic stem cell transplantation (HSCT) has the potential to cure the disease. However, there is little experience in applying HSCT in PKD and guidelines are not available. To date, only four cases of HSCT have been published. Thus, additional data are required to help the establishment of HSCT guidelines and support future strategies, such as gene therapy.

Aims
The aim of this study was to make a worldwide inventory of all cases of PKD that have been treated by HSCT, and to evaluate indication, procedures employed, and outcome.

Methods

This is an international case series. Queries were send to national and international databanks and to physicians involved in HSCT on PKD patients. The latter were asked to complete a questionnaire on disease characteristics, pre-transplant condition, transplant regimen and post-transplant outcome. Two additional cases were included from a recently published report (Kim. 2016. Bone Marrow Transplantation)

Results

From 1996 to 2016 a total of 16 PKD-patients were reported to have been treated by stem cell transplantation. Eight patients were treated in the EU and eight in Asian centres, respectively. No patient resulted to be transplanted in the US. Median age at transplantation was 6,5 years. (10 patients (62,5%) were <10 years; 6 (37,5%) >10 years), seven patients (43,8%) were splenectomized at the time of HSCT.
Fifteen patients (94%) reached engraftment. The sixteenth patient showed mixed chimerism followed by spontaneous transition to full donor chimerism after splenectomy six months post transplantation. Two patients suffered from secondary graft loss. One of these had recovery to 91% donor chimerism after donor lymphocyte infusion. Outcome in the other patient is unknown. GvHD grade 4 was reported in 6/16 cases (38%). There was no obvious relation between GvHD prophylaxis or any other clinical factors and the occurrence of GvHD grade 2-4 in our patients. Two-year cumulative survival was 74%. Two patients did not reach the two-year milestone yet. All five patients who did not survive died of transplant-related causes. Patients who did not survive were significantly older (p=0.036) and were all treated in a European center (p=0.026) (see Table). Also, they had suffered more often from GvHD grade 2-4 (p=0.031). Nine out of ten patients (90%) younger than ten years old survived transplantation, whereas two out of six (33.3%) patients older than ten survived.  Patients younger than ten years old were less often splenectomized (p=0.001). All Asian patients (8/8) survived transplantation, whereas three out of eight European patients survived. Patients treated in Asian hospitals differed from European patients in that they were younger (p=0.001), less often splenectomized (p=0.041) and had a lower ferritin level prior to transplantation (p=0.048). They were more often transplanted with peripheral blood stem cells (p=0.014) and more often conditioned on a cyclophosphamide (p=0.007) regimen.

Conclusion
This is the first study on outcome of HSCT in PKD patients. Due to the still relatively small number of cases  no definite conclusions on the safety of HSCT in PKD can be drawn. However, we  observed a better survival for patients transplanted before the age of ten. This difference could also explain difference in survival between patients transplanted in Europe versus Asia. The high rate of severe GvHD in this cohort is a reason for concern. The strong decline in survival of patients older than ten years of age indicates the need for very careful selection of HSCT-candidates.

Session topic: 27. Enzymopathies, membranopathies and other anemias

Keyword(s): Stem cell transplant, Hemolytic anemia, Treatment

Abstract: S452

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 11:45 - 12:00

Location: Room N109

Background

Pyruvate kinase deficiency (PKD) is the most common glycolytic enzyme defect causing hereditary non-spherocytic hemolytic anemia. PKD does not have a specific curative treatment. Therefo­­re treatment is mainly supportive, consisting of regular red blood cell transfusions, splenectomy and chelation therapy for iron overload. This does impact life expectancy and quality of life for affected patients. Hematopoietic allogeneic stem cell transplantation (HSCT) has the potential to cure the disease. However, there is little experience in applying HSCT in PKD and guidelines are not available. To date, only four cases of HSCT have been published. Thus, additional data are required to help the establishment of HSCT guidelines and support future strategies, such as gene therapy.

Aims
The aim of this study was to make a worldwide inventory of all cases of PKD that have been treated by HSCT, and to evaluate indication, procedures employed, and outcome.

Methods

This is an international case series. Queries were send to national and international databanks and to physicians involved in HSCT on PKD patients. The latter were asked to complete a questionnaire on disease characteristics, pre-transplant condition, transplant regimen and post-transplant outcome. Two additional cases were included from a recently published report (Kim. 2016. Bone Marrow Transplantation)

Results

From 1996 to 2016 a total of 16 PKD-patients were reported to have been treated by stem cell transplantation. Eight patients were treated in the EU and eight in Asian centres, respectively. No patient resulted to be transplanted in the US. Median age at transplantation was 6,5 years. (10 patients (62,5%) were <10 years; 6 (37,5%) >10 years), seven patients (43,8%) were splenectomized at the time of HSCT.
Fifteen patients (94%) reached engraftment. The sixteenth patient showed mixed chimerism followed by spontaneous transition to full donor chimerism after splenectomy six months post transplantation. Two patients suffered from secondary graft loss. One of these had recovery to 91% donor chimerism after donor lymphocyte infusion. Outcome in the other patient is unknown. GvHD grade 4 was reported in 6/16 cases (38%). There was no obvious relation between GvHD prophylaxis or any other clinical factors and the occurrence of GvHD grade 2-4 in our patients. Two-year cumulative survival was 74%. Two patients did not reach the two-year milestone yet. All five patients who did not survive died of transplant-related causes. Patients who did not survive were significantly older (p=0.036) and were all treated in a European center (p=0.026) (see Table). Also, they had suffered more often from GvHD grade 2-4 (p=0.031). Nine out of ten patients (90%) younger than ten years old survived transplantation, whereas two out of six (33.3%) patients older than ten survived.  Patients younger than ten years old were less often splenectomized (p=0.001). All Asian patients (8/8) survived transplantation, whereas three out of eight European patients survived. Patients treated in Asian hospitals differed from European patients in that they were younger (p=0.001), less often splenectomized (p=0.041) and had a lower ferritin level prior to transplantation (p=0.048). They were more often transplanted with peripheral blood stem cells (p=0.014) and more often conditioned on a cyclophosphamide (p=0.007) regimen.

Conclusion
This is the first study on outcome of HSCT in PKD patients. Due to the still relatively small number of cases  no definite conclusions on the safety of HSCT in PKD can be drawn. However, we  observed a better survival for patients transplanted before the age of ten. This difference could also explain difference in survival between patients transplanted in Europe versus Asia. The high rate of severe GvHD in this cohort is a reason for concern. The strong decline in survival of patients older than ten years of age indicates the need for very careful selection of HSCT-candidates.

Session topic: 27. Enzymopathies, membranopathies and other anemias

Keyword(s): Stem cell transplant, Hemolytic anemia, Treatment

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