Scholarly article on topic 'Haploidentical T-cell replete transplantation with post-transplant cyclophosphamide for patients in or above the 6th decade of age compared with allogeneic hematopoietic stem cell transplantation from an HLA-matched related or unrelated donor'

Haploidentical T-cell replete transplantation with post-transplant cyclophosphamide for patients in or above the 6th decade of age compared with allogeneic hematopoietic stem cell transplantation from an HLA-matched related or unrelated donor Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — Didier Blaise, Sabine Fürst, Roberto Crocchiolo, Jean El-Cheikh, Angela Granata, et al.

Abstract It has recently been shown that a T cell–replete allogeneic (allo) hematopoietic stem cell transplantation (HSCT) from a haploidentical donor (haplo-ID) could be a valid treatment for hematological malignancies. However, little data exist concerning older populations. We provided transplantation to 31 patients over the age of 55 years from a haplo-ID and compared their outcomes with patients of the same ages who underwent transplantation from a matched related (MRD) or an unrelated donor (UD). All 3 groups were comparable, except for their conditioning. Patients in haplo-ID group received 2 days of post-transplantation high-dose cyclophosphamide followed by cyclosporine A and mycophenolate mofetil, whereas patients in other groups received pretransplantation antithymocyte globulin, cyclosporine A, and additional mycophenolate mofetil in case of 1-antigen mismatch. All patients but 1 in the haplo-ID group engrafted. The incidence of grades 2 to 4 acute graft-versus-host disease (GVHD) was not statistically different between recipients from haplo-ID (cumulative incidence, 23%) and MRD (cumulative incidence, 21%) transplantations but it was lower than after UD HSCT (cumulative incidence, 44%). No patient in the haplo-ID group developed severe chronic GVHD, compared with cumulative incidences of 16% and 14% after MRD (P = .02) and UD (P = .03) grafts, respectively. The cumulative incidences of relapse were similar in the 3 groups, whereas nonrelapse mortality after UD HSCT was 3-fold higher than after haplo-ID or MRD HSCT. Overall, 2-year overall survival (70%), progression-free survival (67%), and progression and severe chronic GVHD–free survival (67%) probabilities after haplo-ID did not statistically differ from MRD transplantation (78%, 64%, and 51%, respectively), although they were higher than after UD transplantation (51% [P = .08], 38% [P = .02], and 31% [P = .007]). We conclude that T cell–replete haplo-ID HSCT followed by post-transplantation high-dose- cyclophosphamide in patients over 55 years is associated with promising results, similar to MRD HSCT, and is deserving prospective evaluation.

Similar topics of scientific paper in Clinical medicine , author of scholarly article — Didier Blaise, Sabine Fürst, Roberto Crocchiolo, Jean El-Cheikh, Angela Granata, et al.

Academic research paper on topic "Haploidentical T-cell replete transplantation with post-transplant cyclophosphamide for patients in or above the 6th decade of age compared with allogeneic hematopoietic stem cell transplantation from an HLA-matched related or unrelated donor"

Accepted Manuscript

Haploidentical T-cell replete transplantation with post-transplant cyclophosphamide

for patients in or above the 6 decade of age compared with allogeneic hematopoietic stem cell transplantation from an HLA-matched related or unrelated donor

Didier Blaise, Sabine Fürst, Roberto Crocchiolo, Jean El-Cheikh, Angela Granata, Samia Harbi, Reda Bouabdallah, Raynier Devillier, Stephania Bramanti, Claude Lemarie, Christophe Picard, Christian Chabannon, Pierre-Jean Weiller, Catherine Faucher, Bilal Mohty, Norbert Vey, Luca Castagna

PII: S1083-8791(15)00577-7

DOI: 10.1016/j.bbmt.2015.08.029

Reference: YBBMT 53966

To appear in: Biology of Blood and Marrow Transplantation

Received Date: 29 April 2015 Accepted Date: 20 August 2015

Please cite this article as: Blaise D, Fürst S, Crocchiolo R, El-Cheikh J, Granata A, Harbi S, Bouabdallah R, Devillier R, Bramanti S, Lemarie C, Picard C, Chabannon C, Weiller PJ, Faucher C, Mohty B, Vey N, Castagna L, Haploidentical T-cell replete transplantation with post-transplant cyclophosphamide

for patients in or above the 6 decade of age compared with allogeneic hematopoietic stem cell transplantation from an HLA-matched related or unrelated donor, Biology of Blood and Marrow Transplantation (2015), doi: 10.1016/j.bbmt.2015.08.029.

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Haploidentical T-cell replete transplantation with post-transplant cyclophosphamide for patients in or above the 6th decade of age compared with allogeneic hematopoietic stem cell transplantation from an HLA-matched related or unrelated donor.

Running Title: Haplo HSCT in older patients

Didier Blaise 1'2,3,4, Sabine Fürst 1i2, Roberto Crocchiolo 5, Jean El-Cheikh 1i2, Angela Granata 1'2, Samia Harbi 1'2, Reda Bouabdallah 2, Raynier Devillier 1'2, Stephania Bramanti 5, Claude Lemarie 6, Christophe Picard 7, Christian Chabannon 3'4'6'8, PierreJean Weiller 1'2'4' Catherine Faucher 1'2' Bilal Mohty 1'2' Norbert Vey 2'3'4 and Luca Castagna 1'2'5.

1: Transplant and cellular therapy Unit' Institut Paoli Calmettes' Marseille' France

2: Hematology department' Institut Paoli Calmettes' Marseille' France

3: Centre de Recherche en Cancérologie de Marseille (CRCM)' Marseille' France

4: Aix-Marseille University (AMU)' Marseille' France

5: Humanitas Cancer Center' Milano' Italy

6: Cell therapy facility' Institut Paoli Calmettes' Marseille' France

7: HLA immunogenetic Laboratory' Blood Bank' Marseille

8: Inserm CBT-510' Clinical investigation center in biotherapy' Institut Paoli Calmettes' Marseille' France

Corresponding Author: Didier Blaise' MD' Transplant and cellular therapy unit' Institut Paoli Calmettes' Marseille' France

Email: blaised@ipc.unicancer.fr Phone number: +33 4 91 22 37 54 Fax number: + 33 4 91 22 34 43 Short Title: Haplo for elderly Counts:

• Abstract words: 250

• Text words: 2466

• Figure: 1

• Table: 2

• References: 33

Financial Disclosure statement: None

Abstract

It has recently been shown that a T-replete allogeneic-hematopoietic stem-cell transplantation (allo-HSCT) from a haploidentical donor (haplo-ID) could be a valid treatment for hematological malignancies. However little data exist concerning older population. We transplanted 31 patients over the age of 55 years from a Haplo-ID and compared their outcome with same-age patients transplanted from a matched-related (MRD) or an unrelated donor (UD). All 3 groups were comparable except for conditioning. Patients in haplo-ID group received two days of post-transplant highdose cyclophosphamide (PT-HDCy) followed with cyclosporine A (CSA) and mycophenolate-mofetil (MMF) while patients in other groups received pre-transplant antithymocyte-globulins, CSA and additional MMF in case of one antigen mismatched. All patients engrafted, but one in haplo-ID group. Grade 2-4 acute graft-versus-host disease (aGVHD) was not statistically different between Haplo-ID (cumulative incidence (CI):23%) and MRD (CI:21%) transplants but lower than after UD-HSCT (CI:44%). No patient in the Haplo-ID group developed any severe cGVHD as compared to a CI of 16% and 14% after MRD (p=0.02) and UD (p=0.03) grafts. The CIs of relapse were similar in the 3 groups while non-relapse mortality after UD-HSCT was 3-fold higher than after Haplo-ID or MRD HSCT. Overall, 2-year overall survival (70%), progression-free survival (67%) and progression-and-severe cGVHD-free survival (67%) probabilities after haplo-ID did not statistically differ from MRD transplant (78%, 64% and 51% respectively) while they were higher than after UD transplant (51% (p=0.08), 38%(p=0.02) and 31%; P=0,007)). We conclude that T-replete Haplo-ID HSCT followed by PT-HDCy in patients over 55 years is associated

with promising results similar to MRD HSCT deserving prospective evaluation.

Introduction

Patients presenting with hematological malignancies have a median age of 66 years (1). Over the last decade, reduced-intensity (RIC) or low-toxicity (LTC) conditionings have been associated with reduced regimen related mortality allowing for HLA-Identical (HLA-ID) allo-HSCT (2) in previously unfit or older patients (3). However most transplant eligible patients lack a suitable matched related (MRD) donor (4). In addition MRD to elderly patients are elderly themselves with frequent conditions contraindicating donation. Matched (MUD) or 1-antigen mismatched (1-Ag MM) (MMUD) unrelated donors are frequently used when a suitable MRD is lacking, with publications reporting similar results. However these publications have mainly described younger patients receiving myeloablative-conditioning with data from older population being lacking (5, 6). In addition even a MMUD is not always found (4). Presently, other alternative graft sources such as unrelated cord blood or one-haplotype matched related donor (haplo-ID) are seldom used in older patients, because these being perceived as too toxic. Overall this translates to a low rate of allo-HSCT performed in a population with the highest incidence of hematologic malignancies that usually present with the poorest prognosis unless allo-HSCT. Thus, in order to meet this unmet-medical need it is critical developing innovative efficient therapeutic strategies .

Recently, several teams successfully introduced T-replete Haplo-ID transplant combining RIC or ablative conditioning and new schemes for GvHD prophylaxis, reducing transplant toxicities and in turn increasing the number of patients that can benefit from an allo-HSCT. Because of

decreased toxicity documented with this transplant technology when compared to previous haplo-ID transplant attempts, this possibility may represent a real breakthrough in allowing for an expanded number of patients needing an allo-HSCT that can be offered an allo-HSCT. However, the suitability of haplo-ID HSCT in the patients over age of 55 and who usually present with more comorbidities remains unknown.

In this perspective, we report here a series of 31 patients aged of 55 years or beyond with high-risk hematological malignancies treated with an allo-HSCT from a related haplo-ID using high-dose post-transplant cyclophosphamide (HD-PTCy) as previously described by the Johns Hopkins group (7). This cohort is compared to 2 series of patients with the same characteristics transplanted from a MRD or a UD.

Patients and Methods

From January 2011 until November 2013, 31 consecutive patients older than 55 years underwent T-cell replete haplo-ID allo-HSCT for a hematological malignancy in institut Paoli Calmettes, Marseille and were included in this analysis. During the same period and in the same institution, 110 patients older than 55 years received allo-HSCT from a MRD (n= 47) or UD (n= 63 of whom 13 presented with one antigen mismatched) with all patients receiving a similar RIC regimen (3, 8). Informed consent was obtained from all patients included in this study approved by our institutional review board.

Inclusion criteria. For patients with an allo-HSCT indication, our strategy according to French standards was to first try to identify a HLA identical or 1-AG-MM related or unrelated donor. In the case such a donor was not identified, patients were eligible for a Haplo-ID allo-HSCT. Previous autologous and allo HSCT was not considered contra-indications. In the case of previous allo-HSCT, the initial donor was considered as ineligible for a second donation.

Overall patients were ineligible for allo-HSCT if they had uncontrolled infections, active CNS disease, a Karnofsky performance status <60%, or severe organ dysfunction as previously reported (3, 9).

The comorbidity index of each patient was calculated using the hematopoietic cell transplantation comorbidity index (HCT-CI) (10). Disease risk index was retrospectively assessed according to Armand et al. (11)

Conditioning regimen and GVHD prophylaxis. For Haplo-ID HSCT, the intensity of the conditioning regimen was progressively increased over time when experience with haplo-HSCT associated with the original non-myeloablative conditioning (NMAC) regimen was felt to be insufficient in regards to tumor control in high-risk patients

notably for patients with myeloid malignancies. Thus the initial NMAC consisted of Cyclophosphamide (Cy) (14.5 mg/kg/day on D-6 and D-5), fludarabine (30 mg/m2/day from D-6 to D-2) and 2 Gy Total Body Irradiation (TBI) (day-1) (12).

Following this, RIC included Cy (14.5 mg/kg/day on D-7 and D-6), fludarabine (30

22 mg/m2/day from D-6 toD-2) and Intravenous (IV) Busulfan (Bu) (130 mg/m2/day on D-

3 and D-2). Following this, Thiothepa (5mg/kg on D-6) was introduced instead of pre-

transplant Cy. In all cases Cy (50 mg/kg/day) was administered on days +3 and +4.

Further GVHD prophylaxis consisted of cyclosporine A (CsA) and mycophenolate

mofetil (MMF) initiated on day+5 as initially reported (9, 12 ).

RIC for MRD or UD based allo-HSCT was identical for all patients as previously reported (3, 8): Fludarabine (30 mg/m2/day from D-6 to D-2), Iv Bu (130 mg/m2/day on D-4 and D-3) and antithymocyte globulins (ATG) (2.5 mg/kg on D-3 and D-2) (Thymoglobulin; Genzyme, St. Germain-en-Laye, France). GVHD prophylaxis consisted of CsA starting on D-1 and MMF was added in case of 1-AG-MM transplant.

Stem cell sources and donors. For haplo-ID HSCT, potential family members were typed at the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 loci at a highresolution level. All the donor/recipient pairs exhibited a median of 4 mismatches (range 2-5) on the unshared haplotype. HLA Antibody screening was performed in the patient as previously reported (9) to help determining donor choice. 0-1 Ag MM donors shared 6 or 5 over 6 antigens with the patient (high resolution molecular typing of HLA-A, -B,-DRB1) when related or 10 or 9 over 10 antigens (high resolution molecular typing of HLA-A, -B, -Cw, -DRB1, and -DQ) when unrelated. For the few donors who underwent bone marrow harvest under general anesthesia, the target dose was 4x108 nuclear cells/kg of recipient weight. Otherwise most

donors were mobilized with G-CSF (Granocyte; Chugai; France) with a CD34+ cells target of 4x106/kg. Both harvest modalities have been previously detailed (9). Grafts were infused unmanipulated on day 0 except in case of ABO incompatibility. Supportive care has been previously reported (3, 9)

Engraftment and GVHD evaluation. Neutrophil and Platelet engraftment were defined as previously reported (9). Acute and chronic GVHD were graded as previously reported (9) according to international criteria (13, 14). Statistical methods.

We analyzed the cumulative incidences of acute GVHD (aGVHD) and cGVHD, non-relapse mortality (NRM) and relapse or progression using competing risk analysis and Gray test for comparison among groups (15). Death without evidence of relapse was considered as a competing event for the incidence of relapse. Similarly, the occurrence of relapse was considered as a competing event for the incidence of NRM while relapse, progression, and deaths were treated as competing risks when analyzing the incidence of GVHD. PFS and OS were calculated using the Kaplan-Meier method, and results were compared using the log- rank test (16). A p-value < 0.05 was considered as significant. We also compared the three groups of patient using a composite endpoint integrating the probability of survival without progression or development of extensive cGVHD (cGF-PFS) as previously described (17). All survival analyses were computed on the R 3.1.0 statistical software (http://www.R-project.org). Data from haplo HSCT group were compared with MRD and with UD HSCT groups.

Results.

Patient and transplant characteristics are reported in Table 1. UD were more often CMV negative. PBSC were more often collected from MRD than from Haplo-ID (p=0.02) and NMAC was more often used in Haplo-ID HSCT recipients (p<0.0001, see table 1 for further details).

All, but one patient, engrafted with a longer time to reconstitute platelets counts after Haplo-ID HSCT (table 2).

GVHD. As reported in Table 2, the cumulative incidences of grade 2-4 or 3-4 aGVHD were not statistically different between Haplo-ID and MRD transplants but there was a trend for a lower incidence after haplo-ID than after any UD HSCT. No Haplo-ID patient developed severe cGVHD as compared to a cumulative incidence of 16% and 14% after MRD (p=0.02) and UD (p=0.03) grafts respectively. Non relapse mortality (NRM), relapse rate, and survival. The median (range) follow-up of surviving patients was 23 (6-43) months, respectively 22, 24 and 24 months in the 3 groups. The cumulative incidences of NRM were similar after Haplo-ID and MRD transplants but 3-fold higher after UD HSCT (table 2). Of note, no patients died from GVHD after Haplo-ID HSCT as compared to 4 and 17 after MRD (p=0.09) and UD (p=0.001) respectively. The cumulative incidences of relapse were similar in the 3 groups occurring at a median of 7 months (5-24) after HSCT. Overall, 17 patients died from disease progression without any difference between the three groups (19%, 11% and 10% after Haplo-ID, MRD and UD grafts respectively). The 2-year OS and PFS probabilities were not different between Haplo-ID and MRD transplants but were higher in Haplo-ID recipients compared to the UD group (Table 2 and figure 1). Eventually patients in the Haplo-ID group presented with 2-year

cGF-PFS probability of 67% vs. 51 and 31% in the MRD (p=NS) and UD (p=0.007) groups respectively (table 2 and figure 2).

Discussion

Haplo-HSCT using T-cell replete graft is presently being developed worldwide with increasing reports of alleviation of the initial concerns about engraftment failures and GVHD. Indeed, Haplo-HSCT has the potential advantage of permitting a rapid donor identification for virtually every single patient: this allows for a timely transplant limiting the risk of relapse prior to transplant in contrast to the time needed to identify and qualifying an UD. Additionally this avoids the costs associated to the unrelated donor search and graft procurement. The use of a T-replete graft has also the benefit of avoiding sophisticated and expensive cell processing, making this method affordable to most transplant centers. Although several other platforms using T-cell replete graft have been developed (18, 19, 20 , 21) the scheme pioneered by the Johns Hopkins University group is characterized by its relative simplicity, low incidences of cGVHD and of post-transplant NRM and an easy reproducibility (12 , 2224).

In this report, all patients were older than 55 years with a median age of 62 years. The age of this cohort is definitively higher than the median age in previous reports of Haplo-ID HSCT that ranged from 25 to 48 years (12, 18, 20, 21, 25, 26). The Johns Hopkins group reported in a conference in 2013 the outcome of a large series of 273 patients with a median age of 61 (50-75) years with promising results (27). The 31 Haplo-ID recipients we reported here achieved a 2-year 70% and 67% OS and PFS. When taking into account that the median age was 62 years, that 58% of the patients had a HCT-CI of 3 or more and that 35% of the patients had a high or very-high DRI these results can, at the minimum, be considered encouraging and promising. Results are similar to the ones achieved after HLA-ID sibling HSCT in

older patient, illustrating also the real progresses achieved in allogeneic HSCT in this population, in major part due to the introduction of NMAC and RIC. However the lower cGVHD occurrence and severity after Haplo-ID HSCT set the stage for a better quality of life even if prospective comparison remains to be performed. The 2-year PFS in the Haplo-ID cohort was 67% statistically higher than that observed in the UD group (38%) (p=0.02). The outcome we report in our UD cohort are similar those recently reported in the literature for this range of age (28, 29 , 30) although focusing on AML and cannot be attributed to the use of an intermediate dose of ATG. First in a recent large analysis from the CIBMTR focusing on the use of RIC for AML patients, McClune et al reported a 2-year DFS of 31% and 34% for patients aged of 60-64 and > 65 respectively, with half of the patients receiving a HSCT from a MRD (28). Our results about UD HSCT are even similar to reported younger population in the US and Europe: Saber et al reported for the CIBMTR a 3-year OS and LFS of 37% and 34% after HSCT from 8/8 UD in 1193 patients with AML with a median age of 51 years (29). A recent Italian prospective evaluation of MUD using RIC and exvivo T cell depletion reported a 5-year OS and PFS of 39 and 29% in a population with a median age of 41 years (30). Finally, the role of alternative donors in older patients has been recently evaluated, by a retrospective study from CIBMTR (31) which included 740 AML patients older than 50 years (median age: 58 years), results after MUD (8/8) HSCT were compared with the ones achieved after HSCT from 7/8 UD or cord blood. As mentioned by the authors, only 29 Haplo-ID HSCT done for AML in patients aged more than 55 years were reported to CIBMTR in the same period precluding any comparison. Overall the 3-year PFS was not different between MUD (39%) and MMUD (34%) HSCT but was higher than after CBT (29%). The

similarity of results between MMUD and MUD will need further confirmation. Age was a determinant factor of outcome with a significant excess of death in the patients aged over 60 years.

An interesting finding of the present study may be that despite a lower cGVHD in the Haplo-ID cohort, disease control is at least as effective as after MRD or UD transplant. Indeed, incidence of relapse or progression was 23% after Haplo-HSCT vs. 25% and 31% after MRD and UD respectively (p=NS). This is even achieved when patients receiving HSCT from Haplo-ID grafts were prepared with a lower intensity conditioning which has been shown to impact disease control in other studies (32). This observation is important as it suggests good antitumor effect after this procedure, which in other reports remains controversial.

To better appreciate the post-transplant impact of HSCT according to donor, we used a composite endpoint combining death, disease progression and severe cGVHD incidence (17). This composite end-point represent an effort assessing the quality of life (QOL) of patients surviving without disease taking severe cGVHD as a surrogate marker of this QOL as severe cGVHD remains the most important event impacting QOL after transplant (33). This composite endpoint was more often reached after Haplo HSCT than after transplant from any other donor source.

Obviously this analysis is hampered by the usual limitations related to its retrospective nature: possible patient selection biases, not sufficient control population, and heterogeneity in diagnosis and conditioning regimens. However this is an analysis from a single institution reporting a relatively large number of older patients treated over a short and recent period of time allowing for some homogeneity.

Altogether, these results including the ones reported here invite to investigate the place of Haplo-ID as compared with the use of allo-HSCT from an UD for older patients with suitable a haplo-ID.

For these reasons the French NCI (Institut National du Cancer: INCa) has recently granted funding for a prospective national study investigating the relative role of haplo-ID vs. UD HSCT when MRD does not exist in patients older than 55 years of age.

Acknowledg ments

Authors would like to express their gratitude to Finn Bo Petersen, Intermountain Healthcare hospital, Salt Lake City, Utah, USA for his fruitful suggestions and discussion.

Authors are appreciative of the work performed by the transplant Unit nursing staff in Institut Paoli Calmettes under the supervision of Laurence Caymaris, Head nurse. They are also thankful to the patients and their family. Authorship Contribution:

DB and LC contributed to patient care, designed the study, collected and analyzed data and wrote the manuscript

RC contributed to patient care, performed statistical analysis and approved manuscript

AG, RD and SH contributed to patient care, data collection and verification and approved manuscript

SF, JEL, RB, DB, CL, CC, CF, BM and NV contributed to patient care and data collection, read and approved manuscript Conflict of interest

Authors do not declare any conflict of interest

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Table 1 : Patient and transplant characteristics.

Haplo N=31 MRD N=47 UD N=63 Haplo Vs. MRD Haplo Vs. UD

Year of transplant 2013 (2011-2013) 2012 (2011-2014) 2012 (2011-2013) NS NS

Median Age 62 (56-73) 62 (55-71) 64 (57-71) NS NS

Gender

Male Female to Male 17 (55%) 19% 28 (61%) 31% 30 (48%) 13% NS NS

CMV NS 0.01

+ Donor / - recipient 15% 10% 48%

+ Donor / + recipient 54% 64% 24%

- Donor / - recipient 24% 16% 24%

- Donor / + recipient 7% 10% 4%

Diagnosis NS NS

AML ALL MSD MPD HL NHL CLL MM CML 10 (32%) 1 (3%) 5 (16%) / 2 (6%) 7 (22%) 3 (10%) 3 (10%) / 14 (30%) 4 (8%) 5 (10%) 2 (4%) / 10 (21%) 4 (8%) 7 (32%) 1 (2%) 18 (29%) 5 (8%) 12 (19%) 2 (3%) 1 (1%) 13 (21%) 3 (5%) ^ 7 (11%) 2 (3%)

Months from Diagnosis to HSCT 14 (3-215) 8 (2-179) 23 (5-279) NS NS

Status at transplant CR Active disease 19 (61%) 12 (39%) 28 (60%) 19 (40%) 44 (70%) 19 (30%) NS NS

Disease Risk Index NS NS

Low Intermediate High-Very high 3 (10%) 17 (55%) 11 (35%) 5 (11%) 30 (64%) 12 (25%) 6 (10%) 40 (63%) 17(27%)

Previous transplant Autologous Allogeneic 5 (16%) 2 (6%) 11 (23%) 0 12 (19%) 0 NS NS

Donor origin Sibling Offspring Unrelated 14 (45%) y 17 (55%) 47 (100%) / / / 63 (100%) NA NA

HCT-CI NS NS

T 00 O M Al 9 (29%) 4 (13%) 18 (58%) 14 (31%)* 9 (20%) 24 (55%) 16 (28%)§ 15 (26%) 26 (49%)

Stem cell source 0.02 NS

PBSC BM 27 (87%) 4 (13%) 47 (100%) 60 (95%) 3 (5%)

Conditioning regimen NMAC RIC 21 (68%) 10 (32%) / 47 (100%) / / 63 (100%) / <0.0001 <0.0001

Abbreviations:

HCT-CI (Hematopoietic Cell Transplantation-Specific Comorbidity Index) was available for *44 patients and §58 patients

AML: acute myeloid leukemia; ALL: acute lymphoid leukemia; MSD: Myelodysplastic syndrome; MF: myelofibrosis; HL: Hodgkin lymphoma; NHL: non-Hodgkin lymphoma CLL : chronic lymphocytic leukemia; MM : multiple myeloma; CML : chronic myeloid leukemia; PBSC: peripheral blood stem cells; BM: bone marrow; NMAC: nonmyeloablative conditioning regimen; RIC: reduced intensity conditioning regimen; LTC: reduced toxicity conditioning regimen. NS: Nor significant; NA: not appropriate

Table 2. Clinical results.

Haplo N=31 Q S H UD N=63 Haplo Vs. MRD Haplo Vs. UD

Engraftment ANC > 500 PLT > 20 000 a? ^ CO CO ■ i m o o a> CM CM 18 (14-25) 11 (9-20) 17 (13-35) 11 (5-84) NS <0.00 01 NS <0.00 01

aGVHD Grade 2-4 Grade 3-4 23%(8-38) 10% (0-20) 21% (9-33) 13% (3-22) 44% (32-57) 25% (15-36) NS NS 0.05 0.07

2 year cGVHD Overall Severe 13% (1-25) 0% 35% (21-50) 16% (5-26) 24% (13-35) 14% (6-23) 0.03 0.02 0.22 0.03

2 year NRM 10% (0-20) 11% (2-20) 34% (22-45) NS 0.01

2 year Relapse/progression 23% (8-39) 25% (11-40) 31% (18-43) NS NS

2 year OS 70% (54-86) 78% (66-90) 51% (38-64) NS 0.08

2 year PFS 67% (50-84) 64% (49-79) 38% (23-49) NS 0.02

2 year PFS without severe cGVHD 67% (50-84) 51% (35-67) 31% (16-40) NS 0.007

Causes of non-disease related death GVHD Infection Organ Toxicity Secondary cancer Accident 1 (33%) 1 (33%) 1 (33%) 4 (80%) (20%) 17 (68%) 3 (12%) 4 (16%) 1 (4%)

Abbreviations:

ANC: absolute neutrophil count PLT: platelet

aGVHD: acute graft-vs.-host disease cGVHD: chronic graft-vs.-host disease NRM: Non-relapse mortality OS: overall survival PFS: progression-free survival

Figure legend: Comparison of progression-free survival and severe chronic GVHD-free and progression-free survival

Fig 1: Progression-free Survival (Haplo vs. MRD: p=NS; Haplo vs. UD: p=0.02)

Fig 2: Severe cGVHD-free and progression-free survival (Haplo vs. MRD: p=NS; Haplo vs. UD: p=0.007)

Plain line: Haplo HSCT; dashed line: MRD HSCT; dotted line: UD line; X axis: months post transplant

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