Accepted Article
ARTICLE TYPE: ORIGINAL ARTICLE ACCEPTED DATE: 24- FEB- 2014
ORIGINAL ARTICLE ACCEPTED DATE: 24TH FEBRUARY 2014
EXPERTS
CONSIDERATIONS
ON
HLA-HAPLOIDENTICAL
STEM
CELL
TRANSPLANTATION F Patriarca (1), L Luznik (2), M Medeot (1), M Zecca (3), A Bacigalupo (4), P Di Bartolomeo (5), W Arcese (6), P Corradini (7), F Ciceri (8), L Vago (8), CG Kanakry (2), K Fleischhauer (8), M Martelli (9), A Bosi (10), A Rambaldi (11), S Cesaro (12), D Russo (13) and R Fanin (1). (1) Department of Hematology, Stem Cell Transplant Unit, DISM, University Hospital, Udine, Italy; (2) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, USA; (3) Pediatric Hematology / Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; (4) Division of Hematology and Bone Marrow Transplantation, IRCSS San Martino, Genova, Italy; (5) Department of Hematology, Bone Marrow Transplant Center, Santo Spirito Hospital, Pescara, Italy; (6) Department of Hematology, Stem Cell Transplant Unit, Tor Vergata University, Roma, Italy; (7) Division of Hematology and Bone Marrow Transplantation, Fondazione IRCCS Istituto Nazionale dei Tumori e Università di Milano, Milano, Italy; (8) Hematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milano, Italy; (9) Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy; (10) Department of Hematology, University of Firenze, Firenze, Italy; (11) Department of Hematology, Ospedale Papa Giovanni XXIII, Bergamo, Italy; (12) Pediatric Hematology Oncology, Policlinico G. B. Rossi, Verona, Italy; (13) Unit of Blood Diseases and Stem Cell Transplantation, University of Brescia, Brescia, Italy. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/ejh.12322 This article is protected by copyright. All rights reserved.
Accepted Article
Running title: stem cell transplantation from HLA-haploidentical donor.
Correspondence to: Francesca Patriarca, MD Division of Hematology and Cellular Therapies Unit ‘Carlo Melzi’ Azienda Ospedaliera-Universitaria piazzale S. Maria della Misericordia 1 33100 Udine tel +39 0432 559662 fax +39 0432 559661 e-mail: [email protected]
ABSTRACT
Recently, novel strategies to control graft-versus-host disease and facilitate engraftment
have allowed an increasing number of human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplantation (haploHSCT) to be performed. A meeting was convened to review the biological rationale and the clinical results of various T-cell-depleted (TCD) and T-cellreplete (TCR) HLA-haploidentical “transplant platforms”. The objective of the meeting was to promote discussion and consent among leading researchers in the field on 3 main crucial issues for haploHSCT: 1) eligibility criteria, 2) choice of the most suitable donor, and 3) choice of the most appropriate transplant platform. The experts in attendance agreed that a patient who is eligible for an allogeneic transplant and lacks an HLA-identical sibling or an HLA-matched-unrelated donor should be considered for an alternative donor transplant. Together with the experience of the individual center, the most important decision criteria in choosing an alternative donor source should be the rapidity of transplantation so as to avoid disease relapse/progression. The choice of This article is protected by copyright. All rights reserved.
Accepted Article
the mismatched donor should be driven by younger age, ABO compatibility, and CMV status. If a TCD transplant is planned, NK-alloreactive donors and/or the mother should be preferred. Prospective comparative studies are needed to establish the relative efficacy of different transplant platforms. However, expertise in stem cell manipulation and in adoptive immunotherapy is essential if a TCD transplant platform is chosen.
KEY WORDS: allogeneic stem cell transplantation, HLA-haploidentical donors, T-cell depletion, post-transplantation cyclophosphamide.
INTRODUCTION
Interest in allogeneic hematopoietic stem cell transplantation (HSCT) from alternative
donors arises from the need to ensure a rapid identification of a source of stem cells for all patients with high-risk hematologic malignancies. Alternative donor sources include partially HLAmismatched-unrelated donors (MMUD), umbilical cord blood (UCB) units, and human leukocyte antigen (HLA)-haploidentical-related donors. Early attempts at HLA-haploidentical HSCT (haploHSCT) were met with negative results due to high rates of severe graft-versus-host disease (GVHD), graft rejection, and overwhelming infections (1-5). The promise of haploHSCT is the availability of a donor for nearly all patients that require allogeneic HSCT and the possibility to use that donor for subsequent adoptive immunotherapy. Over the past two decades, haploHSCT has been made markedly safer through the development of various
“transplant
platforms,”
which
combine
different
conditioning
regimens,
immunomodulation, and stem cell sources. The aim of this paper is to present the biological rationale and the clinical results of different strategies of haploidentical transplant, as well as to report discussion and consensus among experts on indications and choice among different donors and transplantation strategies and on the management of post-transplant complications. This article is protected by copyright. All rights reserved.
Accepted Article
METHODS
A scientific conference entitled ‘Biological rationale and clinical experiences in
haploidentical stem cell transplantation’ was held in Udine, Italy, on October 4-5, 2012. The attendees were primarily Italian except for one participant from the United States. The meeting was composed of two sections: T-cell-depleted (TCD) haploHSCT (three speakers) and T-cell-replete (TCR) haploHSCT (four speakers). The format of each presentation included a brief introduction about the current state of knowledge in the topic area, presentation of original biological and clinical experience, and discussion among all participants, during which 3 crucial issues for haploHSCT were discussed: 1) eligibility criteria, 2) choice of the most suitable donor, and 3) choice of the most appropriate transplantation platform. This manuscript reviews the 7 speakers’ presentations and summarizes relevant considerations on the 3 identified issues as emerged from experts’ discussion and revision of the literature. References are provided for published data, while the reliability of personal, unpublished experiences is guaranteed by each speaker.
Since the main clinical data that are available in the field of
haploHSCT come from prospective non-randomized studies and retrospective comparisons due to lack of prospective, randomized trials, considerations of the experts should not be regarded as evidence-based recommendations. However, the statements of the experts indicate how scientific results are perceived by medical practitioners and how they are applied in daily clinical practice, clearly indicating the need for further studies in this field.
This article is protected by copyright. All rights reserved.
Accepted Article
RESULTS
T-CELL-DEPLETED TRANSPLANTS CD34+ positively selected haploidentical transplants and NK alloreactivity (Massimo Martelli) Martelli summarized the experience of the group in Perugia starting from their pioneering
study dating back to the beginning of the 1990s. At that time, the few existing experiences with TCD haplotransplants in leukemic patients were largely unsuccessful mainly because of high rates of graft failure (6-9), which was thought to be the result of both the immunologic rejection mediated by the host residual immune system and the competition between donor and residual host stem cells for limited available niches in the BM stroma. Aversa and colleagues designed an enhanced myeloablative and immunosuppressive conditioning by adding thiotepa and rabbit anti-thymocyte globulin (ATG) to total body irradiation (TBI) and cyclophosphamide (Cy), followed by the infusion of “megadoses” (CD34+ > 10 x 106/kg body weight) of ex-vivo T-cell depleted donor stem cells harvested from both bone marrow and G-CSF primed peripheral blood (PB) (10). This transplant platform ensured for the first time a high rate of engraftment (>90%) in adult leukemic patients, with 18% incidence of acute GVHD, despite no post-grafting immunosuppression. Modifications of this platform were made over subsequent years, including replacement of Cy with fludarabine in the conditioning regimen and further reduction of the graft T-cell content by positive CD34+ cells immunoselection by magnetic beads (Table 1). High rates of engraftment with low rates of acute and chronic GVHD (1000 in SPI assay are excluded; however, DSA titer is not unanimously considered as a mandatory test for the choice of the donor. Possible strategies for DSAs reduction in allosensitized recipients before This article is protected by copyright. All rights reserved.
Accepted Article
transplantation are plasma exchange, rituximab, and intravenous gamma globulin, and such strategies have been effective in facilitating engraftment after haploHSCT with PTCy (76).
Choice of a transplantation platform “Mega-doses” of TCD haploHSCT have successfully reduced the incidences of graft failure
and GVHD, but are associated with high rates of NRM secondary to slow immune reconstitution and infectious complications. In contrast, TCR haploHSCT may be associated with higher rates of GVHD, but NRM may be lower, particularly when using PTCy. Although RIC haploHSCT approaches may be associated with higher rates of relapse, the PTCy approach has been extended safely to the myeloablative conditioning setting (44-46, 48, 77, 78) and to the use of PBSCs as the donor graft source (46, 79). Not unexpectedly, all haploHSCT studies showed significantly worse outcomes for patients transplanted in relapse compared with in remission (48, 58, 68), including PFS rates of ≤14% for TCD approaches (80, 81). The significant heterogeneity in study design and
patients treated complicates any comparisons between various haploHSCT approaches. A retrospective comparison of 65 adult patients with advanced hematologic malignancies uniformly conditioned with melphalan, fludarabine, and thiotepa showed a lower NRM (16% versus 42%) and prolonged PFS (50% versus 21%) for PTCy compared with TCD haploHSCT (45). However, these data should be cautiously interpreted, and a definitive answer of relative efficacy requires prospective randomized comparisons. A particular benefit for advanced HL patients undergoing haplotransplant with PT/Cy has been reported by several groups (60, 82). Again, prospective comparative studies are needed to corroborate these observations. A “center effect,” with better RFS after TCD haplotransplants emerged from an EBMT study (68). This effect is likely based on more experience providing better patient selection, timing of transplantation, and management of post-transplant complications as well as the infrastructure for
This article is protected by copyright. All rights reserved.
Accepted Article
complex strategies of post-transplant adoptive immunotherapy to reduce the risk of life-threatening infections and relapse (18, 83). Due to the lack of prospective comparative studies useful to recommend a specific transplantation platform, this decision should currently be based on the expertise of a particular center. In choosing a TCD platform, the center has to have expertise in the manipulation of stem cells and other cellular products and have in-place a strategy for adoptive immunotherapy to accelerate immune reconstitution and reduce the risk of infections. Unmanipulated platforms are attractive because the treatment is relatively inexpensive and requires no expertise in graft manipulation. Among the TCR platforms, RIC followed by PTCy and MAC followed by G-CSF-primed marrow combined with an intensive in vivo GVHD prophylaxis are the most consolidated strategies, currently adopted for several hundred patients each.
Future Considerations: The experts agree that the most compelling needs in future clinical research are the following: -
Prospective comparisons between alternative donor sources: MMUD, UCB, and haploidentical donor sources. The BMT CTN randomized RIC phase 3 study comparing HLA-haploidentical versus UCB HSCT will answer important questions regarding the risk and benefits of these two donor sources. Comparative studies in the setting of myeloablative conditioning are needed.
-
Prospective comparison between HLA-haploHSCT and HLA-matched-related and unrelated HSCT.
-
Addressing the question of whether particular donor sources are more effective for specific diseases, such as Hodgkin lymphoma.
-
Determination of the utility of HLA-haploidentical transplantation for patients with active, aggressive diseases. The GITMO group is attempting to answer this question through testing
This article is protected by copyright. All rights reserved.
Accepted Article
the relative efficacy of various alternative donor transplants for patients with active AML without an HLA-sibling donor in a phase II prospective multicenter trial (GANDALF-01).
CONFLICT OF INTEREST: The authors declare no conflict of interest.
AKNOWLEDGEMENTS: The organizers and the authors of the conference proceedings would like to extend their
gratitude to all participants for sharing their ideas, slide presentation, and manuscripts and for making this event possible.
Table 1. Author
T-depleted Martelli transplants
Reference Conditioning regimen 10 TBI 8 Gy+ thiotepa10 mg/kg + fludarabine 200 mg/mq
Zecca
original data presented at the meeting
Corradini
23
T-replete Luznik transplants
40
TBI + thiotepa + fludarabine or melphalan or cyclophosphamide; busulfan + melphalan + cyclophosphamide; other cyclophosphamide 60 mg/kg + fludarabine 120 mg/mq + thiotepa 10 mg/kg + TBI 2 Gy cyclophosphamide29 mg/kg + fludarabine 150 mg/mq +
This article is protected by copyright. All rights reserved.
Immunosuppressive therapy ATG Fresenius 20 mg/kg or ATG Thymoglobulin 610 mg/kg ATG
Source of stem cells CD34+ selected PBSC CD3+ ≤ 1 x 104/kg
alemtuzumab 15 mg
CD34+ selectedPBSC CD3+ ≤ 1 x 104/kg
tacrolimus since day 5 MMF since day 5 cyclophosphamide
unmanipulated BM
CD34+ selected PBSC CD3+ ≤ 1 x 104/kg
Accepted Article
Bacigalupo
48
Ciceri
51
Di 58 Bartolomeo
TBI 2 Gy
50 mg/kg day +3, +4
TBI 9.9 Gy + fludarabine 150 mg/mq in pts< 56 years; thiotepa 10 mg/kg + busulfan 9.6 mg/kg + fludarabine 150 mg/mqin pts> 56 years treosulfan 42 g/mq + fludarabine150 mg/mq
unmanipulated cyclosporine 2mg/kg since day 0 BM MMF since day +1 cyclophosphamide 50 mg/kg day + 3, +5
thiotepa 10 mg/kg + busulfan 9.6 mg/kg + fludarabine 150 mg/mq; thiotepa 5 mg/kg + busulfan 6.4 mg/kg + fludarabine150 mg/mq
G-CSF primed BM
ATG Fresenius 30 mg/kg rituximab 500 mg rapamycin since day -6 MMF since day +1 ATG Fresenius 20 mg/kg basiliximab 20 mg day 0, +4 methotrexate day+1, +3, +6,+11 cyclosporine since day -7 MMF since day +7
unmanipulated PBSC
Table 2. T-depletedtransplants
T-repletetransplants
Martelli
Zecca
Corradini
Luznik
Bacigalupo
Ciceri
Di Bartolomeo
10
original data presented at the meeting
23
40
48
51
58
104
83
28
68
50
59
80
33 (969)
7.6 (0.224)
38 (15-65)
46 (1-71)
42 (18-66)
50 (14-69)
37 (5-71)
Disease
AL 104 (100%)
AL 73(88%) MDS 10 (12%)
AL 4 (14%) Lymphoma 22 (79%) MM 2 (7%)
AL 31 (46%) Lymphoma26 (38%) Other11 (16%)
AL 37 (74%) MPN 8 (16%) Lymphoma 5 (10%)
AL 63 (79%) Lymphoma 7 (9%) Other10 (12%)
AL 63 (79%) Lymphoma 7 (9%) Other10 (12%)
High riskat HSCT
49 (47%) All MAC
25/73 AL (34%)
15 (53%)
19/63 (23%)
27 (54%)
52 (88%)
35 (44%)
All MAC
All RIC
All RIC
All MAC
MAC
64/16
Reference
N° of patients Medianage (range)
MAC/RIC
This article is protected by copyright. All rights reserved.
Accepted Article
Median CD34+ cells infused (range) Primary engraftment Median days to > 0.5 x109/L neutrophil (range) Median days to > 20 x 109/L platelet (range) II-IV acute GVHD III-IV acute GVHD Chronic GVHD Extensive chronic GVHD NRM (CI) Relapse (CI)
EFS
OS
13.8 (5.129.7)
22 (8-41)
10.5 (1.515)
4.8
4.0 (0.110)
NA
2 (0.7-11)
94/101 (91%)
77/83 (93%)
28/28 (100%)
57/66 (87%)
45/47 (96%)
59/59 (100%)
73/80 (91%)
11 (930)
13 (8-27)
14 (8-18)
15
18 ( 13-30)
NA
21 (12-38)
15 (1145)
13 (7-93)
11 (8-17)
24
23 (14-58)
NA
28 (14185)
8%
20%
26% .
34%
12%
29%
24%
2%
4%
9%
6%
6%
13%
5%
7%
11%
17%
NA
26%
20%
17%
ARTICLE TYPE: ORIGINAL ARTICLE ACCEPTED DATE: 24- FEB- 2014
ORIGINAL ARTICLE ACCEPTED DATE: 24TH FEBRUARY 2014
EXPERTS
CONSIDERATIONS
ON
HLA-HAPLOIDENTICAL
STEM
CELL
TRANSPLANTATION F Patriarca (1), L Luznik (2), M Medeot (1), M Zecca (3), A Bacigalupo (4), P Di Bartolomeo (5), W Arcese (6), P Corradini (7), F Ciceri (8), L Vago (8), CG Kanakry (2), K Fleischhauer (8), M Martelli (9), A Bosi (10), A Rambaldi (11), S Cesaro (12), D Russo (13) and R Fanin (1). (1) Department of Hematology, Stem Cell Transplant Unit, DISM, University Hospital, Udine, Italy; (2) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, USA; (3) Pediatric Hematology / Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; (4) Division of Hematology and Bone Marrow Transplantation, IRCSS San Martino, Genova, Italy; (5) Department of Hematology, Bone Marrow Transplant Center, Santo Spirito Hospital, Pescara, Italy; (6) Department of Hematology, Stem Cell Transplant Unit, Tor Vergata University, Roma, Italy; (7) Division of Hematology and Bone Marrow Transplantation, Fondazione IRCCS Istituto Nazionale dei Tumori e Università di Milano, Milano, Italy; (8) Hematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milano, Italy; (9) Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy; (10) Department of Hematology, University of Firenze, Firenze, Italy; (11) Department of Hematology, Ospedale Papa Giovanni XXIII, Bergamo, Italy; (12) Pediatric Hematology Oncology, Policlinico G. B. Rossi, Verona, Italy; (13) Unit of Blood Diseases and Stem Cell Transplantation, University of Brescia, Brescia, Italy. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/ejh.12322 This article is protected by copyright. All rights reserved.
Accepted Article
Running title: stem cell transplantation from HLA-haploidentical donor.
Correspondence to: Francesca Patriarca, MD Division of Hematology and Cellular Therapies Unit ‘Carlo Melzi’ Azienda Ospedaliera-Universitaria piazzale S. Maria della Misericordia 1 33100 Udine tel +39 0432 559662 fax +39 0432 559661 e-mail: [email protected]
ABSTRACT
Recently, novel strategies to control graft-versus-host disease and facilitate engraftment
have allowed an increasing number of human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplantation (haploHSCT) to be performed. A meeting was convened to review the biological rationale and the clinical results of various T-cell-depleted (TCD) and T-cellreplete (TCR) HLA-haploidentical “transplant platforms”. The objective of the meeting was to promote discussion and consent among leading researchers in the field on 3 main crucial issues for haploHSCT: 1) eligibility criteria, 2) choice of the most suitable donor, and 3) choice of the most appropriate transplant platform. The experts in attendance agreed that a patient who is eligible for an allogeneic transplant and lacks an HLA-identical sibling or an HLA-matched-unrelated donor should be considered for an alternative donor transplant. Together with the experience of the individual center, the most important decision criteria in choosing an alternative donor source should be the rapidity of transplantation so as to avoid disease relapse/progression. The choice of This article is protected by copyright. All rights reserved.
Accepted Article
the mismatched donor should be driven by younger age, ABO compatibility, and CMV status. If a TCD transplant is planned, NK-alloreactive donors and/or the mother should be preferred. Prospective comparative studies are needed to establish the relative efficacy of different transplant platforms. However, expertise in stem cell manipulation and in adoptive immunotherapy is essential if a TCD transplant platform is chosen.
KEY WORDS: allogeneic stem cell transplantation, HLA-haploidentical donors, T-cell depletion, post-transplantation cyclophosphamide.
INTRODUCTION
Interest in allogeneic hematopoietic stem cell transplantation (HSCT) from alternative
donors arises from the need to ensure a rapid identification of a source of stem cells for all patients with high-risk hematologic malignancies. Alternative donor sources include partially HLAmismatched-unrelated donors (MMUD), umbilical cord blood (UCB) units, and human leukocyte antigen (HLA)-haploidentical-related donors. Early attempts at HLA-haploidentical HSCT (haploHSCT) were met with negative results due to high rates of severe graft-versus-host disease (GVHD), graft rejection, and overwhelming infections (1-5). The promise of haploHSCT is the availability of a donor for nearly all patients that require allogeneic HSCT and the possibility to use that donor for subsequent adoptive immunotherapy. Over the past two decades, haploHSCT has been made markedly safer through the development of various
“transplant
platforms,”
which
combine
different
conditioning
regimens,
immunomodulation, and stem cell sources. The aim of this paper is to present the biological rationale and the clinical results of different strategies of haploidentical transplant, as well as to report discussion and consensus among experts on indications and choice among different donors and transplantation strategies and on the management of post-transplant complications. This article is protected by copyright. All rights reserved.
Accepted Article
METHODS
A scientific conference entitled ‘Biological rationale and clinical experiences in
haploidentical stem cell transplantation’ was held in Udine, Italy, on October 4-5, 2012. The attendees were primarily Italian except for one participant from the United States. The meeting was composed of two sections: T-cell-depleted (TCD) haploHSCT (three speakers) and T-cell-replete (TCR) haploHSCT (four speakers). The format of each presentation included a brief introduction about the current state of knowledge in the topic area, presentation of original biological and clinical experience, and discussion among all participants, during which 3 crucial issues for haploHSCT were discussed: 1) eligibility criteria, 2) choice of the most suitable donor, and 3) choice of the most appropriate transplantation platform. This manuscript reviews the 7 speakers’ presentations and summarizes relevant considerations on the 3 identified issues as emerged from experts’ discussion and revision of the literature. References are provided for published data, while the reliability of personal, unpublished experiences is guaranteed by each speaker.
Since the main clinical data that are available in the field of
haploHSCT come from prospective non-randomized studies and retrospective comparisons due to lack of prospective, randomized trials, considerations of the experts should not be regarded as evidence-based recommendations. However, the statements of the experts indicate how scientific results are perceived by medical practitioners and how they are applied in daily clinical practice, clearly indicating the need for further studies in this field.
This article is protected by copyright. All rights reserved.
Accepted Article
RESULTS
T-CELL-DEPLETED TRANSPLANTS CD34+ positively selected haploidentical transplants and NK alloreactivity (Massimo Martelli) Martelli summarized the experience of the group in Perugia starting from their pioneering
study dating back to the beginning of the 1990s. At that time, the few existing experiences with TCD haplotransplants in leukemic patients were largely unsuccessful mainly because of high rates of graft failure (6-9), which was thought to be the result of both the immunologic rejection mediated by the host residual immune system and the competition between donor and residual host stem cells for limited available niches in the BM stroma. Aversa and colleagues designed an enhanced myeloablative and immunosuppressive conditioning by adding thiotepa and rabbit anti-thymocyte globulin (ATG) to total body irradiation (TBI) and cyclophosphamide (Cy), followed by the infusion of “megadoses” (CD34+ > 10 x 106/kg body weight) of ex-vivo T-cell depleted donor stem cells harvested from both bone marrow and G-CSF primed peripheral blood (PB) (10). This transplant platform ensured for the first time a high rate of engraftment (>90%) in adult leukemic patients, with 18% incidence of acute GVHD, despite no post-grafting immunosuppression. Modifications of this platform were made over subsequent years, including replacement of Cy with fludarabine in the conditioning regimen and further reduction of the graft T-cell content by positive CD34+ cells immunoselection by magnetic beads (Table 1). High rates of engraftment with low rates of acute and chronic GVHD (1000 in SPI assay are excluded; however, DSA titer is not unanimously considered as a mandatory test for the choice of the donor. Possible strategies for DSAs reduction in allosensitized recipients before This article is protected by copyright. All rights reserved.
Accepted Article
transplantation are plasma exchange, rituximab, and intravenous gamma globulin, and such strategies have been effective in facilitating engraftment after haploHSCT with PTCy (76).
Choice of a transplantation platform “Mega-doses” of TCD haploHSCT have successfully reduced the incidences of graft failure
and GVHD, but are associated with high rates of NRM secondary to slow immune reconstitution and infectious complications. In contrast, TCR haploHSCT may be associated with higher rates of GVHD, but NRM may be lower, particularly when using PTCy. Although RIC haploHSCT approaches may be associated with higher rates of relapse, the PTCy approach has been extended safely to the myeloablative conditioning setting (44-46, 48, 77, 78) and to the use of PBSCs as the donor graft source (46, 79). Not unexpectedly, all haploHSCT studies showed significantly worse outcomes for patients transplanted in relapse compared with in remission (48, 58, 68), including PFS rates of ≤14% for TCD approaches (80, 81). The significant heterogeneity in study design and
patients treated complicates any comparisons between various haploHSCT approaches. A retrospective comparison of 65 adult patients with advanced hematologic malignancies uniformly conditioned with melphalan, fludarabine, and thiotepa showed a lower NRM (16% versus 42%) and prolonged PFS (50% versus 21%) for PTCy compared with TCD haploHSCT (45). However, these data should be cautiously interpreted, and a definitive answer of relative efficacy requires prospective randomized comparisons. A particular benefit for advanced HL patients undergoing haplotransplant with PT/Cy has been reported by several groups (60, 82). Again, prospective comparative studies are needed to corroborate these observations. A “center effect,” with better RFS after TCD haplotransplants emerged from an EBMT study (68). This effect is likely based on more experience providing better patient selection, timing of transplantation, and management of post-transplant complications as well as the infrastructure for
This article is protected by copyright. All rights reserved.
Accepted Article
complex strategies of post-transplant adoptive immunotherapy to reduce the risk of life-threatening infections and relapse (18, 83). Due to the lack of prospective comparative studies useful to recommend a specific transplantation platform, this decision should currently be based on the expertise of a particular center. In choosing a TCD platform, the center has to have expertise in the manipulation of stem cells and other cellular products and have in-place a strategy for adoptive immunotherapy to accelerate immune reconstitution and reduce the risk of infections. Unmanipulated platforms are attractive because the treatment is relatively inexpensive and requires no expertise in graft manipulation. Among the TCR platforms, RIC followed by PTCy and MAC followed by G-CSF-primed marrow combined with an intensive in vivo GVHD prophylaxis are the most consolidated strategies, currently adopted for several hundred patients each.
Future Considerations: The experts agree that the most compelling needs in future clinical research are the following: -
Prospective comparisons between alternative donor sources: MMUD, UCB, and haploidentical donor sources. The BMT CTN randomized RIC phase 3 study comparing HLA-haploidentical versus UCB HSCT will answer important questions regarding the risk and benefits of these two donor sources. Comparative studies in the setting of myeloablative conditioning are needed.
-
Prospective comparison between HLA-haploHSCT and HLA-matched-related and unrelated HSCT.
-
Addressing the question of whether particular donor sources are more effective for specific diseases, such as Hodgkin lymphoma.
-
Determination of the utility of HLA-haploidentical transplantation for patients with active, aggressive diseases. The GITMO group is attempting to answer this question through testing
This article is protected by copyright. All rights reserved.
Accepted Article
the relative efficacy of various alternative donor transplants for patients with active AML without an HLA-sibling donor in a phase II prospective multicenter trial (GANDALF-01).
CONFLICT OF INTEREST: The authors declare no conflict of interest.
AKNOWLEDGEMENTS: The organizers and the authors of the conference proceedings would like to extend their
gratitude to all participants for sharing their ideas, slide presentation, and manuscripts and for making this event possible.
Table 1. Author
T-depleted Martelli transplants
Reference Conditioning regimen 10 TBI 8 Gy+ thiotepa10 mg/kg + fludarabine 200 mg/mq
Zecca
original data presented at the meeting
Corradini
23
T-replete Luznik transplants
40
TBI + thiotepa + fludarabine or melphalan or cyclophosphamide; busulfan + melphalan + cyclophosphamide; other cyclophosphamide 60 mg/kg + fludarabine 120 mg/mq + thiotepa 10 mg/kg + TBI 2 Gy cyclophosphamide29 mg/kg + fludarabine 150 mg/mq +
This article is protected by copyright. All rights reserved.
Immunosuppressive therapy ATG Fresenius 20 mg/kg or ATG Thymoglobulin 610 mg/kg ATG
Source of stem cells CD34+ selected PBSC CD3+ ≤ 1 x 104/kg
alemtuzumab 15 mg
CD34+ selectedPBSC CD3+ ≤ 1 x 104/kg
tacrolimus since day 5 MMF since day 5 cyclophosphamide
unmanipulated BM
CD34+ selected PBSC CD3+ ≤ 1 x 104/kg
Accepted Article
Bacigalupo
48
Ciceri
51
Di 58 Bartolomeo
TBI 2 Gy
50 mg/kg day +3, +4
TBI 9.9 Gy + fludarabine 150 mg/mq in pts< 56 years; thiotepa 10 mg/kg + busulfan 9.6 mg/kg + fludarabine 150 mg/mqin pts> 56 years treosulfan 42 g/mq + fludarabine150 mg/mq
unmanipulated cyclosporine 2mg/kg since day 0 BM MMF since day +1 cyclophosphamide 50 mg/kg day + 3, +5
thiotepa 10 mg/kg + busulfan 9.6 mg/kg + fludarabine 150 mg/mq; thiotepa 5 mg/kg + busulfan 6.4 mg/kg + fludarabine150 mg/mq
G-CSF primed BM
ATG Fresenius 30 mg/kg rituximab 500 mg rapamycin since day -6 MMF since day +1 ATG Fresenius 20 mg/kg basiliximab 20 mg day 0, +4 methotrexate day+1, +3, +6,+11 cyclosporine since day -7 MMF since day +7
unmanipulated PBSC
Table 2. T-depletedtransplants
T-repletetransplants
Martelli
Zecca
Corradini
Luznik
Bacigalupo
Ciceri
Di Bartolomeo
10
original data presented at the meeting
23
40
48
51
58
104
83
28
68
50
59
80
33 (969)
7.6 (0.224)
38 (15-65)
46 (1-71)
42 (18-66)
50 (14-69)
37 (5-71)
Disease
AL 104 (100%)
AL 73(88%) MDS 10 (12%)
AL 4 (14%) Lymphoma 22 (79%) MM 2 (7%)
AL 31 (46%) Lymphoma26 (38%) Other11 (16%)
AL 37 (74%) MPN 8 (16%) Lymphoma 5 (10%)
AL 63 (79%) Lymphoma 7 (9%) Other10 (12%)
AL 63 (79%) Lymphoma 7 (9%) Other10 (12%)
High riskat HSCT
49 (47%) All MAC
25/73 AL (34%)
15 (53%)
19/63 (23%)
27 (54%)
52 (88%)
35 (44%)
All MAC
All RIC
All RIC
All MAC
MAC
64/16
Reference
N° of patients Medianage (range)
MAC/RIC
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Accepted Article
Median CD34+ cells infused (range) Primary engraftment Median days to > 0.5 x109/L neutrophil (range) Median days to > 20 x 109/L platelet (range) II-IV acute GVHD III-IV acute GVHD Chronic GVHD Extensive chronic GVHD NRM (CI) Relapse (CI)
EFS
OS
13.8 (5.129.7)
22 (8-41)
10.5 (1.515)
4.8
4.0 (0.110)
NA
2 (0.7-11)
94/101 (91%)
77/83 (93%)
28/28 (100%)
57/66 (87%)
45/47 (96%)
59/59 (100%)
73/80 (91%)
11 (930)
13 (8-27)
14 (8-18)
15
18 ( 13-30)
NA
21 (12-38)
15 (1145)
13 (7-93)
11 (8-17)
24
23 (14-58)
NA
28 (14185)
8%
20%
26% .
34%
12%
29%
24%
2%
4%
9%
6%
6%
13%
5%
7%
11%
17%
NA
26%
20%
17%
