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Contents lists available atScienceDirect

Transplant Immunology

journal homepage:www.elsevier.com/locate/trim

Letter to the Editor

T-cell depletion eﬀects of low-dose antithymocyte globulin for GVHD

prophylaxis in HLA-matched allogeneic peripheral blood stem cell

transplantation

Souichi Shiratori⁎,1_{, Mizuha Kosugi-Kanaya}1_{, Eiko Hayase, Kohei Okada, Hideki Goto,}

Junichi Sugita, Masahiro Onozawa, Masao Nakagawa, Kaoru Kahata, Daigo Hashimoto, Tomoyuki Endo, Takeshi Kondo, Takanori Teshima

Department of Hematology, Hokkaido University, Faculty of Medicine, Sapporo, Japan

Dear Editor,

Allogeneic hematopoietic stem cell transplantation (HSCT) is po-tentially curative treatment for patients with hematological malig-nancies, but graft-versus-host disease (GVHD) remains a major problem after HSCT. Compared to bone marrow transplantation (BMT), per-ipheral blood stem cell transplantation (PBSCT) is a risk for severe

acute and chronic GVHD[1]. Recent large scale randomized controlled

trials indicate that antithymocyte globulin (ATG) reduces severe acute

GVHD and chronic GVHD after PBSCT [2,3]. However, doses of ATG

diﬀer between studies and optimal dose of ATG needs to be determined. Lower dose of ATG was suggested to have a survival beneﬁt compared

to higher dose of ATG[4]. In this study, we evaluated eﬀects of

low-dose rabbit ATG (Thymoglobulin; ATG-T) on T-cell depletion in the context of GVHD prophylaxis after PBSCT.

A total of 12 patients with a median age of 53, including 5 patients who underwent HLA-matched PBSCT with 2 mg/kg of ATG-T (1 mg/kg on days -2 and -1 before transplantation) and 7 patients who underwent HLA-matched PBSCT without ATG-T were examined in this study. Diagnosis included myelodysplastic syndrome in 6 patients, acute myeloid leukemia in 5 patients, and acute lymphoblastic leukemia in 1 patient. We analyzed peripheral blood T-cell subsets on day 28 after PBSCT in these patients by flow cytometry. The following monoclonal antibodies were purchased from BD Biosciences (Franklin Lakes, USA), BioLegend (San Diego, USA) or e-Bioscience (San Diego, USA); anti-CD45RA-FITC, anti-CD27-PE, anti-CD4-PerCP/Cy5.5, anti- Foxp3-APC, anti-CD3-Pacific Blue, and anti-CD8-BV510. Intracellular Foxp3 was stained using a Cytofix/Cytoperm kit (e-Bioscience). CD4 gated cells were separated into four populations, including naïve T cells defined as

CD45RA+_Foxp3−_{cells, memory/eﬀector T cells deﬁned as CD45RA}−

Foxp3−_{cells, regulatory T cells deﬁned as Foxp3}+_{cells, and}

cytokine-secreting T cells deﬁned as CD45RA−_Foxp3dim_cells_[5,6]_{. CD8 gated}

cells were separated into three functionally diﬀerent populations,

including naïve T cells deﬁned as CD45RA+_CD27+_{cells, memory T}

cells defined as CD45RA−_CD27+_{cells, and effector T cells defined as}

CD27−_cells_[7,8]_{. Statistical analysis of were carried out using}

Mann-Whitney U test. All P-values were two-sided and a P-value under 0.05 was used as the cut-oﬀ for statistical signiﬁcance. All written data are shown as mean value ± SD.

All patients received myeloablative conditioning regimen and achieved neutrophil engraftment. Grade II to IV acute GVHD developed in none of 5 patients with ATG-T, but in 3 of 7 patients without ATG-T. Chronic GVHD developed in 1 of 5 patients with ATG-T and in 4 of 7 patients without ATG-T. Flow cytometric analysis of T-cell subsets in the peripheral blood on day 28 after PBSCT showed that frequencies of

naïve CD4+_{and CD8}+_{T-cell fractions were distinctively less in ATG-T}

treated patients than controls (Naïve CD4+_{T cells: 8.9% ± 3.7% vs}

29.5% ± 13.7%; P = 0.005, Naïve CD8+_{T cells: 12.2% ± 4.7% vs}

28.6% ± 17.1%; P = 0.048) (Fig. 1). Concordantly, absolute numbers

of both naïve CD4+_{and CD8}+_{T-cells were signiﬁcantly decreased in}

patients with ATG-T, and ATG-T also signiﬁcantly decreased in absolute

numbers of all T-cell subsets evaluated (Table 1).

Although the dose of ATG-T used in this study seems to be minimal ever reported, a total 2 mg/kg of ATG-T given on day -2 and -1 was suﬃcient to decrease T cells in vivo. Donor T cells that promote GVHD

reside mainly within the naïve T-cell fraction[9]. ATG-T preferentially

depletes naïve T-cell fraction due to its high aﬃnity against naïve T

cells[10]. We showed the signiﬁcant depletion of naïve T cell fractions

with 2 mg/kg of ATG-T. Now we are conducting a prospective, multi-center, phase II study to evaluate the eﬃcacy of 2 mg/kg of ATG-T containing GVHD prophylaxis for HLA-matched PBSCT after myeloa-blative conditioning (UMIN-CTR UMIN000018645).

Ethical approval

This study was approved by the institutional review board of

https://doi.org/10.1016/j.trim.2017.11.001

Received 15 August 2017; Received in revised form 5 November 2017; Accepted 7 November 2017

⁎_{Corresponding author at: Department of Hematology, Hokkaido University, Faculty of Medicine, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan.}

1E-mail address:_{These authors contributed equally to this work.}[email protected](S. Shiratori).

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Hokkaido University.

Funding disclosure and conﬂict of interest

All authors received no ﬁnancial support, and have no conﬂicts of interest.

Authors' contribution

S. Shiratori interpreted data, preparation of the article, ﬁgure and tables. M. K-K. performed recruitment and treatment of patients, and ﬂow cytometric analysis of T-cell subsets. E. H., K. O., H. G., J. S., M. O., M. N., K. K., D. H., T. E., and T. K. performed recruitment and treatment

of patients. T.T. designed the study, reviewed and edited the article. References

[1] U. Holtick, M. Albrecht, J.M. Chemnitz, et al., Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malig-nancies in adults, Cochrane Database Syst. Rev. 20 (2014) CD010189. [2] J. Finke, W.A. Bethge, C. Schmoor, et al., Standard graft-versus-host disease

pro-phylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial, Lancet Oncol. 10 (2009) 855–864.

[3] N. Kröger, C. Solano, C. Wolschke, et al., Antilymphocyte globulin for prevention of chronic graft-versus-host disease, N. Engl. J. Med. 374 (2016) 43–53.

[4] L. Binkert, M. Medinger, J.P. Halter, et al., Lower dose anti-thymocyte globulin for GvHD prophylaxis results in improved survival after allogeneic stem cell trans-plantation, Bone Marrow Transplant. 50 (2015) 1331–1336.

[5] M. Miyara, Y. Yoshioka, A. Kitoh, et al., Functional delineation and diﬀerentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor, Immunity 30 (2009) 899–911.

[6] C.G. Kanakry, S. Ganguly, M. Zahurak, et al., Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide, Sci. Transl. Med. 5 (2013) 211ra157.

[7] D. Hamann, P.A. Baars, M.H. Rep, et al., Phenotypic and functional separation of memory and eﬀector human CD8+ T cells, J. Exp. Med. 186 (1997) 1407–1418. [8] P. Romero, A. Zippelius, I. Kurth, et al., Four functionally distinct populations of

human eﬀector-memory CD8+ T lymphocytes, J. Immunol. 178 (2007) 4112–4119.

[9] M. Bleakley, S. Heimfeld, K.R. Loeb, et al., Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts, J. Clin. Invest. 125 (2015) 2677–2689.

[10] M.C. Ruzek, K.S. Neﬀ, M. Luong, et al., In vivo characterization of rabbit anti-mouse thymocyte globulin: a surrogate for rabbit anti-human thymocyte globulin, Transplantation 88 (2009) 170–179.

Fig. 1. Flow cytometric analysis of T-cell subsets after PBSCT.

Flow cytometric analysis of CD4+_{and CD8}+_{T-cell subsets}

in peripheral blood on day 28 after PBSCT in patients with low-dose ATG-T (n = 5) and without low-dose ATG-T (n = 7). *p < 0.05; **p < 0.01.

Table 1

Absolute numbers of T cell subsets in peripheral blood on day 28 after PBSCT.

ATG-T (n = 5) No ATG-T (n = 7) P Total CD3+_{T cells} _{74.8 ± 53.4/μl} _{424.7 ± 192.6/μl} _0.003 Total CD4+ T cells 37.6 ± 28.4/μl 193.7 ± 99.7/μl 0.003 Naive CD4+ T cells 3.5 ± 2.8/μl 55.8 ± 34.0/μl 0.003 Memory/eﬀector CD4+ T cells 29.0 ± 19.0/μl 120.3 ± 71.7/μl 0.018 Regulatory T-cells 3.8 ± 6.6/μl 13.3 ± 4.7/μl 0.048 Cytokine-secreting CD4+ T-cells 1.3 ± 1.4/μl 4.3 ± 2.1/μl 0.018 Total CD8+ T cells 30.8 ± 20.2/μl 209.8 ± 141.1/μl 0.003 Naive CD8+ T cells 3.2 ± 2.0/μl 67.8 ± 67.5/μl 0.004 Memory CD8+ T cells 17.4 ± 10.0/μl 77.2 ± 47.7/μl 0.005 Eﬀector CD8+ T cells 10.1 ± 10.3/μl 64.8 ± 63.0/μl 0.010

S. Shiratori et al. 7UDQVSODQW,PPXQRORJ\²

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2017 8

The International Congress of BMT 2017 (Seoul)

HLA-haploidentical Peripheral Blood Stem Cell Transplantaiton

Using Post-Transplant Cyclophosphamide - a single institute

analysis -

Junichi Sugita, Takanori Teshima

Department of Hematology, Faculty of Medicine, Hokkaido University, Sapporo, Japan

Background: HLA-haploidentical stem cell transplantation using post-transplant

cyclophosphamide (PTCy) is increasingly performed. We previously conducted a prospective multicenter phase II study (Haplo13) of PTCy-based HLA-haploidentical peripheral blood stem cell transplantation (PTCy-haploPBSCT) after reduced-intensity conditioning and reported the safety and efficacy of PTCy-haploPBSCT in Japanese patients.

Methods: We conducted a retrospective analysis of PTCy-based HLA-haploidentical

peripheral blood stem cell transplantation (PTCy-haploPBSCT) in our institute. Busulfan (BU) based myeloablative conditioning (MAC) regimen consisted of Fludarabine (Flu, 150mg/m2), BU (12.8 mg/kg), and TBI (4 Gy). Total body irradiation (TBI) based MAC regimen consisted of Flu (90 mg/m2), and TBI (12 Gy). Reduced intensity conditioning regimen consisted of Flu (150 mg/m2), BU (6.4 mg/kg), and TBI (4 Gy). GVHD prophylaxis consisted of Cy (40-50 mg/kg/day on days 3 and 4), tacrolimus, and mycophenolate mofetil.

Results: Forty-seven patients received PTCy-haploPBSCT between 2014 and 2017.

Median age was 43 (range 18-70) with 31 male and 16 female. Diagnosis of the patients included AML (n=21), ALL (n=11), MDS (n=6), lymphoma (n=5), and other (n=4).Ten patients had a history of prior allogeneic stem cell transplantation.Eighteen patients received MAC regimen and 29 patients received RIC regimen. Neutrophil engraftment was achieved in all patients with a median of 14 days (range, 12-25). The cumulative incidence of grades II to IV and III to IV acute graft-versus-host disease (GVHD) were 19% and 2%. The cumulative incidence of chronic GVHD was 27% at 2 year. Overall survival, disease free survival, relapse rate, and NRM were 78%, 56%, 39%, and 5%, respectively, at 2 year.

Conclusions: Our results suggest that PTCy-haploPBSCT achieved low incidences

of GVHD and NRM and stable donor engraftment. We are now conducting prospective multicenter phase II studies (Haplo14, Haplo16, Haplo17) by Japan Study Group for Cell Therapy and Transplantation (JSCT).

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HLA-haploidentical Peripheral Blood Stem Cell Transplantation Using Post-Transplant

Cyclophosphamide a single institute analysis

-Junichi Sugita, Takanori Teshima

The International Congress of BMT 2017

In conjunction with 22nd_{Annual Congress of KSBMT}

Department of Hematology, Faculty of Medicine, Hokkaido University, Sapporo, Japan

COI disclosure

Junichi Sugita

I have no personal or financial interests to declare: I have no financial support from an industry source at the current presentation.

Allogeneic hematopoietic stem cell transplantation in Japan (1992 - 2015) 0 500 1000 1500 2000 2500 3000 3500 4000 199219931994199519961997199819992000200120022003200420052006200720082009201020112012201320142015 Allo-CBT UR-BMT Rel-PBSCT Rel-BMT 0 100 200 300 400 500 600 700 800 '00 '01 '02 '03 '04 '05 '06 '07 '08 '09 '10 '11 '12 '13 '14 Num be r of T ra ns pl ant s Year The Japanese Data Center for Hematopoietic Cell Transplantation

HLA 1 antigen mismatch

HLA-haploidentical HLA-haploidentical SCT is increasing in Japan

T-cell deplete: TCD (ex vivo T-cell depletion)

T-cell replete: TCR (in vivo T-cell depletion)

CD34 positive selection (Aversa, Italy)

CD3/CD19 depletion (Handgretinger, Germany) TCRαβ/CD19 depletion (Handgretinger, Germany)

CsA+MTX+MMF+ATG, G-CSF primed BM+PB (China)

CsA+MTX+ATG(Korea)

Tac+mPSL+ATG(Ikegame, Japan)

CsA+MMF+Alemtuzumab(Canada)

CsA+MTX+Alemtuzumab(Kanda, Japan)

Several strategies to overcome HLA barriers in HLA-haploidentical SCT

Posttransplant cyclophosphamide

(Post CY)

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JOHNS HOPKINS, Baltimore

Patients, donors, and graft characteristics

Patients with hematological malignancies were enrolled in three similar clinical trials of non-myeloablative conditioning and transplantation of partially HLA-mismatched bone marrow at Johns Hopkins, Fred Hutchinson Cancer Research Center, or BMT Group of Georgia and Hahnemann University Hospital. Donors were first-degree relatives who were identical at one HLA-haplotype and mismatched at one or more loci of an unshared haplotype. Of the 210 patients, 149 were male. The median age of the patients at transplantation was 52 (range, 1-73). Eligible diagnoses included acute leukemia in 2nd or subsequent remission or in first complete remission with poor risk features; Hodgkin lymphoma (HL); Non-Hodgkin Lymphoma (NHL); chronic lymphocytic leukemia (CLL) with duration of remission < 6 months after chemotherapy or high risk features; multiple myeloma (MM) in resistant relapse or in relapse after autologous transplant; myelodysplastic syndrome (MDS); parox-ysmal nocturnal hemoglobinuria (PNH); chronic myeloid leukemia (CML) beyond first chronic phase (CP1), or interferon- or imatinib resistant CML in CP1; and chronic myeloproliferative disorders other than CML. The two leading indications for transplantation were non-Hodgkin lymphoma (n ¼ 66) and acute myeloid leukemia (n ¼ 43).

Patients and their donors were heavily mismatched on the unshared HLA locus, with a median mismatch of four out of ﬁve of the HLA antigens that were typed.

The donor graft contained a median of 3.7 " 108_{mononuclear cells, of which 10% were T cells and 1%}

expressed the CD34 antigen. Transplantation procedure

All patients were intended to be treated as outpatients. Conditioning for transplantation (Fig. 1)

consisted of cyclophosphamide 14.5 mg/kg/day on days #6 and #5, ﬂudarabine 30 mg/m2_{/day for ﬁve}

consecutive days starting on day #6, and 2 Gy total body irradiation given in a single fraction on day #1. Bone marrow was harvested from donors and infused into recipients on day 0. The graft was depleted of red-blood cells and plasma but there was no manipulation to deplete graft T-cells. GVHD prophylaxis consisted of cyclophosphamide 50 mg/kg IV, together with Mesna, each on days 3 and 4, mycophe-nolate mofetil 15 mg/kg po tid (maximum 3 g/day) from day 5–35, and tacrolimus from day 5–180. Tacrolimus levels were monitored at least weekly with a desired concentration from 5 to 15 ng/ml. Prophylactic antimicrobial therapy was started on day #6 and included norﬂoxacin, ﬂuconazole, val-cyclovir, and appropriate prophylaxis of Pneumocystis carinii pneumonia.

Engraftment and donor chimerism

Of the 210 patients transplanted, 204 were evaluable for donor cell engraftment. Twenty-seven patients (13%) failed to engraft. Nearly all patients with primary or secondary graft failure experi-enced recovery of autologous hematopoiesis. As reported previously, the median time to a neutrophil

count of $500/ml was 15 days, and the median time to an unsupported platelet count of $20,000/ml was

24 days.

Fig. 1. Treatment schema for nonmyeloablative conditioning regimen in HLA-haploidentical transplantation with post-transplantation cyclophosphamide. MMF ¼ mycophenolate mofetil; TBI ¼ total body irradiation; Cy ¼ cyclophosphamide; G-CSF ¼ granulocyte colony stimulating factor.

Ashley T. Munchel et al. / Best Practice & Research Clinical Haematology 24 (2011) 359–368 363

GVHD

Fig. 2shows the cumulative incidence of grade 2–4 aGVHD was 27%, grade 3–4 aGVHD was 5% and chronic GVHD was 13%. This coincides with the data previously reported in the 67 patients, which had shown a cumulative incidence of grade 2–4 aGVHD of 34%, grade 3–4 aGVHD of 6%[45].

Relapse and non-relapse mortality

The cumulative incidences of relapse and non-relapse mortality were 55% and 18%, respectively (Fig. 3). One hundred thirteen patients have died. The causes of death are relapse (n ¼ 79), infection (n ¼ 15), pulmonary complications (n ¼ 7), GVHD (n ¼ 5), other (n ¼ 4), or unknown (n ¼ 3). Fig. 2. Cumulative incidence of acute (A) and chronic (B) GVHD after nonmyeloablative haploidentical stem cell transplantation with post-transplantation cyclophosphamide.

Fig. 3. Cumulative incidence of relapse and non-relapse mortality after nonmyeloablative haploidentical stem cell transplantation with post-transplantation cyclophosphamide.

GVHD

Fig. 2shows the cumulative incidence of grade 2–4 aGVHD was 27%, grade 3–4 aGVHD was 5% and chronic GVHD was 13%. This coincides with the data previously reported in the 67 patients, which had shown a cumulative incidence of grade 2–4 aGVHD of 34%, grade 3–4 aGVHD of 6%[45]. Relapse and non-relapse mortality

The cumulative incidences of relapse and non-relapse mortality were 55% and 18%, respectively (Fig. 3). One hundred thirteen patients have died. The causes of death are relapse (n ¼ 79), infection (n ¼ 15), pulmonary complications (n ¼ 7), GVHD (n ¼ 5), other (n ¼ 4), or unknown (n ¼ 3). Fig. 2. Cumulative incidence of acute (A) and chronic (B) GVHD after nonmyeloablative haploidentical stem cell transplantation with post-transplantation cyclophosphamide.

Fig. 3. Cumulative incidence of relapse and non-relapse mortality after nonmyeloablative haploidentical stem cell transplantation with post-transplantation cyclophosphamide.

Ashley T. Munchel et al. / Best Practice & Research Clinical Haematology 24 (2011) 359–368 364 aGVHD cGVHD II-IV: 27% III-IV: 5% 13% relapse / NRM relapse: 55% NRM: 18%

Luznik L, et al. Biol. Blood Marrow Transplant. 2008. Kasamon YL, Biol. Blood Marrow Transplant. 2010.

- 2 0255 5 4 5 0 05 3₎ 3 412

(55 2 0 4 2 0255

55 2 0 4 2 0255

Rationale of posttransplant cyclophosphamide

Selective depletion of alloreactive T-cells

JSCT Haplo13 Study

This prospective multicenter phase II study (UMIN000010316) was conducted by the Japan Study Group for Cell Therapy and Transplantation (JSCT).

Patients, donors, and graft characteristics

Patients with hematological malignancies were enrolled in three similar clinical trials of non-myeloablative conditioning and transplantation of partially HLA-mismatched bone marrow at Johns Hopkins, Fred Hutchinson Cancer Research Center, or BMT Group of Georgia and Hahnemann University Hospital. Donors were first-degree relatives who were identical at one HLA-haplotype and mismatched at one or more loci of an unshared haplotype. Of the 210 patients, 149 were male. The median age of the patients at transplantation was 52 (range, 1-73). Eligible diagnoses included acute leukemia in 2nd or subsequent remission or in first complete remission with poor risk features; Hodgkin lymphoma (HL); Non-Hodgkin Lymphoma (NHL); chronic lymphocytic leukemia (CLL) with duration of remission < 6 months after chemotherapy or high risk features; multiple myeloma (MM) in resistant relapse or in relapse after autologous transplant; myelodysplastic syndrome (MDS); parox-ysmal nocturnal hemoglobinuria (PNH); chronic myeloid leukemia (CML) beyond first chronic phase (CP1), or interferon- or imatinib resistant CML in CP1; and chronic myeloproliferative disorders other than CML. The two leading indications for transplantation were non-Hodgkin lymphoma (n ¼ 66) and acute myeloid leukemia (n ¼ 43).

Patients and their donors were heavily mismatched on the unshared HLA locus, with a median mismatch of four out of ﬁve of the HLA antigens that were typed.

The donor graft contained a median of 3.7 " 108_{mononuclear cells, of which 10% were T cells and 1%}

expressed the CD34 antigen. Transplantation procedure

All patients were intended to be treated as outpatients. Conditioning for transplantation (Fig. 1)

consisted of cyclophosphamide 14.5 mg/kg/day on days #6 and #5, ﬂudarabine 30 mg/m2_{/day for ﬁve}

consecutive days starting on day #6, and 2 Gy total body irradiation given in a single fraction on day #1. Bone marrow was harvested from donors and infused into recipients on day 0. The graft was depleted of red-blood cells and plasma but there was no manipulation to deplete graft T-cells. GVHD prophylaxis consisted of cyclophosphamide 50 mg/kg IV, together with Mesna, each on days 3 and 4, mycophe-nolate mofetil 15 mg/kg po tid (maximum 3 g/day) from day 5–35, and tacrolimus from day 5–180. Tacrolimus levels were monitored at least weekly with a desired concentration from 5 to 15 ng/ml. Prophylactic antimicrobial therapy was started on day #6 and included norﬂoxacin, ﬂuconazole, val-cyclovir, and appropriate prophylaxis of Pneumocystis carinii pneumonia.

Engraftment and donor chimerism

Of the 210 patients transplanted, 204 were evaluable for donor cell engraftment. Twenty-seven patients (13%) failed to engraft. Nearly all patients with primary or secondary graft failure experi-enced recovery of autologous hematopoiesis. As reported previously, the median time to a neutrophil

count of $500/ml was 15 days, and the median time to an unsupported platelet count of $20,000/ml was

24 days.

Fig. 1. Treatment schema for nonmyeloablative conditioning regimen in HLA-haploidentical transplantation with post-transplantation cyclophosphamide. MMF ¼ mycophenolate mofetil; TBI ¼ total body irradiation; Cy ¼ cyclophosphamide; G-CSF ¼ granulocyte colony stimulating factor.

PBSCT iv BU 3.2 mg/kg/day

Patients aged from 15 to 65 with hematological malignancies who has no HLA-matched related or unrelated available donor were enrolled.

Sugita J, Biol. Blood Marrow Transplant. 2015.

Johns Hopkins1 BM (n=210) US/UK/AU2 PBSC (n=53) Haplo133 PBSC (n=31) Conditioning

regimen Flu/CY/TBI Flu/CY/TBI _{+BU(6.4mg/kg)}Flu/CY/TBI

GVHD

prophylaxis PTCy+Tac+MMF PTCy+Tac+MMF PTCy+Tac+MMF

Engraftment 87% day15 (11-42) 96% day17 (12-29) 87% day19 (15-27) acute GVHD II-IV III-IV 28%_4% 53%_8% 23%_3% Chronic GVHD 13% 16% 15% NRM _18% _17% _23% Relapse 55% 28% 45%

1) Munchel AT, Best Pract Res Clin Haematol. 2011. 2) Raj K, Biology of Blood and Marrow Transplantation. 2014. 3) Sugita J, Biol. Blood Marrow Transplant. 2015.

Flu (150mg/m2_{) + ivBU (12.8mg/kg) + TBI (4Gy)}

BU based regimen TBI based regimen

Flu (90mg/m2_{) + TBI (12Gy)}

Myeloablative conditioning (MAC)

BU based regimen

Reduced-intensity conditioning (RIC)

single institute analysis

-We conducted a retrospective analysis of 47 patients who received PTCy-based HLA-haploidentical peripheral blood stem cell transplantation in Hokkaido university between March 2014 and April 2017.

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Patient characteristics (n=47)

Median Age (range) 43 (18-70)

Gender Male Female 31 (66%)16 (34%) Diagnosis AML ALL MDS Lymphoma Others 21 (45%) 11 (23%) 6 (13%) 5 (11%) 4 ( 9%) Disease status 1st_CR 2nd CR-non CR 19 (40%) 7 (15%) 21 (45%) Allogeneic Transplantation 1st_{Transplantation} 2nd_{or 3}rd_{Transplantation} 38 (79%)_{10 (}_21%)

BU based regimen(n=7) TBI based regimen(n=12)

Flu (90mg/m2_{) + TBI (12Gy)}

Myeloablative conditioning (MAC)

BU based regimen(n=28)

Reduced-intensity conditioning (RIC)

Peripheral blood stem cell (PBSC)

CD34: 5.4 x 10

6

_{/kg (2.4-9.9)}

CD3 : 1.5 x 10

8

_{/kg (0.5-3.8)}

Donor relationship

Parent

Sibling

Child

Other

13 (28%)

16 (34%)

2 ( 4%)

CY (50 mg/kg, day3, 4), n=31

CY (40 mg/kg, day3, 4), n=9

OR + Tacrolimus (day5-) + MMF (15 mg/kg x 3, day5-) 0 5 10 15 20 25 30 0.0 0.2 0.4 0.6 0.8 1.0

Days after transplantation

Cu m ul at iv e in ci de nc e Neutrophil engraftment 100% median day14 (12-25)

Engraftment

0 20 40 60 80 100 0.0 0.2 0.4 0.6 0.8 1.0 Cu m ul at iv e in ci de nc e

acute GVHD

II-IV: 19% III-IV: 2%

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0 200 400 600 0.0 0.2 0.4 0.6 0.8 1.0

chronic GVHD

Cu m ul at iv e in ci de nc e all grade: 27% mod-sev: 20% 0 100 200 300 400 500 600 700 0.0 0.2 0.4 0.6 0.8 1.0 Pr oba bi lit y

OS 78% DFS 56%

OS DFS NRM

NRM 5% 0 200 400 600 0.0 0.2 0.4 0.6 0.8 1.0

Cu m ul at iv e in ci de nc e

Relapse

39% 0 100 200 300 400 500 600 700 0.0 0.2 0.4 0.6 0.8 1.0 Pr oba bi lit y

OS (disease risk index)

90% 71% 54% high intermediate very high P=0.05 0 200 400 600 0.0 0.2 0.4 0.6 0.8 1.0 1yr 66% 2yr 86%

Rates of off-immunosuppressant

Summary

Engraftment _{(median day14)}100%

acute GVHD II-IV 19% III-IV 2% chronic GVHD all : 27% mod-sev : 20% NRM at 2yr 5% Relapse at 2 yr 39% DFS at 2yr 56% OS at 2yr 78%

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Haplo14 RIC Haplo13 Haplo16 RIC Haplo17 RIC Haplo14 MAC Haplo16 MAC Haplo17 MAC n=283 2013 2014 2016 2017

Prospective Multicenter Phase II studies in Japan

n=31

n=81 n=53

n=59 n=59

August 25 (Fri), 2017 [EN] Scientific Session III GVHD “PTCY-Haplo transplant” Takanori Teshima

Conclusions

n Our results suggest that PTCy-haploPBSCT achieved low incidences of GVHD and NRM with an acceptable relapse rate. n We are now conducting prospective

phase II studies of PTCy-haploPBSCT using myeloablative conditioning and reduced intensity conditioning.

Acknowledgement

North Japan Hematology Study Group (NJHSG)

Japan Study Group for Cell Therapy and Transplantation (JSCT) Department of Hematology, Faculty of Medicine, Hokkaido University

Takanori Teshima Daigo Hashimoto Masahiro Onozawa Souichi Shiratori Eiko Hayase Tomoyuki Endo Kaoru Kahata Masao Nakagawa Hideki Goto Kohei Okada

(16)

2017 8

The International Congress of BMT 2017 (Seoul)

T-cell depletion effects of minimal low-dose antithymocyte globulin

for GVHD prophylaxis in HLA-matched allogeneic peripheral blood

stem cell transplantation

Souichi Shiratori, Mizuha Kosugi-Kanaya, Takanori Teshima

Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan

Background

Incidence of graft-versus-host disease (GVHD) is higher in patients receiving allogeneic peripheral blood stem cell transplantation (PBSCT) than bone marrow transplantation. Antithymocyte globulin (ATG) has been shown to reduce GVHD after PBSCT, but its optimal dose remains to be determined. We conducted NJHSG-ATG, a pilot study to evaluate a minimal low-dose rabbit ATG (Thymoglobulin; ATG-T) for GVHD prophylaxis at a dose of 2 mg/kg of ATG-T (1 mg/kg on days -2 and -1) before HLA-matched PBSCT.

Methods

To evaluate the T-cell depletion effects of low-dose ATG-T in NJHSG-ATG study, we analyzed peripheral blood T-cell subsets by flow cytometry in patients who underwent PBSCT with or without low-dose ATG-T.

Results

We analyzed peripheral blood on day 28 after PBSCT in total 11 patients, including 3 patients who were enrolled in NJHSG-ATG study, 2 patients who underwent

HLA-matched PBSCT with the same dose of ATG-T as NJHSG-ATG study but could not be enrolled for the organ dysfunction, and 6 patients who underwent

HLA-matched PBSCT without ATG-T at the period of NJHSG-ATG study in our institution. Flow cytometric analysis showed that the numbers of total CD3+, CD4+, and CD8+ T cells were significantly decreased in patients with low-dose ATG-T compared to those without low-dose ATG-T. In particular, naïve T cell fractions were significantly depleted by low-dose ATG-T compared to memory/effector fractions in both CD4+ and CD8+ T cells.

Conclusion

This study suggested that low-dose ATG-T in NJHSG-ATG study has a potential to reduce GVHD. Now we are conducting a prospective, multicenter, phase II study to evaluate the efficacy of this GVHD prophylaxis for HLA-matched PBSCT.

(17)

24/Aug/2017 ICBMT

T-cell depletion effects of minimal low-dose antithymocyte globulin for GVHD prophylaxis in HLA-matched allogeneic

peripheral blood stem cell transplantation Souichi Shiratori, Mizuha Kosugi-Kanaya,

Takanori Teshima

Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan

24/Aug/2017 ICBMT

International congress of BMT 2017

Disclosure of COI

Name of first author Souichi Shiratori I have no COI

with regard to our presentation.

24/Aug/2017 ICBMT

Introduction

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curable treatment for patients with hematological malignancies, but graft-versus-host disease (GVHD) remains a major problem after HSCT.

Compared to bone marrow transplantation (BMT), peripheral blood stem cell transplantation (PBSCT) is a risk for severe acute GVHD and chronic GVHD

Recent randomized controlled trials indicate that antithymocyte globulin (ATG) reduces severe acute GVHD and chronic GVHD after PBSCT, however, doses of ATG differ between studies and optimal dose of ATG need to be determined.

24/Aug/2017 ICBMT

Introduction

24/Aug/2017 ICBMT

Introduction

Extensive chronic GVHD Grade III-IV acute GVHD

PBSCT

PBSCT BMT

BMT

(Nagafuji K, Int J Hematol, 2010) 24/Aug/2017 ICBMT

Introduction

Non-relapse mortality Overall survival

PBSCT BMT

(18)

24/Aug/2017 ICBMT

Introduction

HLA-matched BMT

Standard risk High risk

HLA-matched PBSCT HLA matched BMT HLA-matched PBSCT (Inamonoto Y, Haematologica, 2016) GRFS 24/Aug/2017 ICBMT Introduction

24/Aug/2017 ICBMT

IntroductionT h e ne w e ngl a nd jou r na l o f m e dicine

n engl j med 374;1 nejm.org January 7, 2016 43 The authors’ affiliations are listed in the Appendix. Address reprint requests to Dr. Kröger at the Department of Stem Cell Transplantation, University Medical Cen-ter Hamburg-Eppendorf, Martinistra♯e 52, 20246 Hamburg, Germany, or at nkroeger@ uke . de.

Drs. Kröger and Solano contributed equal-ly to this article.

This article was updated on January 7, 2016, at NEJM.org.

N Engl J Med 2016;374:43-53. DOI: 10.1056/NEJMoa1506002

BACKGROUND

Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclu-sion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling.

METHODS

We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease.

RESULTS

After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P = 0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P = 0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD–free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P = 0.005).

CONCLUSIONS

The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after alloge-neic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD–free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Soci-ety for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275.)

ABS TR ACT

Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease

Nicolaus Kröger, M.D., Carlos Solano, M.D., Christine Wolschke, M.D., Giuseppe Bandini, M.D., Francesca Patriarca, M.D., Massimo Pini, M.D., Arnon Nagler, M.D., Carmine Selleri, M.D., Antonio Risitano, M.D., Ph.D., Giuseppe Messina, M.D., Wolfgang Bethge, M.D., Jaime Pérez de Oteiza, M.D., Rafael Duarte, M.D., Angelo Michele Carella, M.D., Michele Cimminiello, M.D.,

Stefano Guidi, M.D., Jürgen Finke, M.D., Nicola Mordini, M.D., Christelle Ferra, M.D., Jorge Sierra, M.D., Ph.D., Domenico Russo, M.D.,

Mario Petrini, M.D., Giuseppe Milone, M.D., Fabio Benedetti, M.D., Marion Heinzelmann, Domenico Pastore, M.D., Manuel Jurado, M.D.,

Elisabetta Terruzzi, M.D., Franco Narni, M.D., Andreas Völp, Ph.D., Francis Ayuk, M.D., Tapani Ruutu, M.D., and Francesca Bonifazi, M.D.

Original Article

The New England Journal of Medicine

n engl j med 374;1 nejm.org January 7, 2016

50 T h e ne w e ngl a nd jou r na l o f m e dicine A B Patients (%) 100 80 60 40 20 0 0 3 6 9 12 15 24 Months since SCT P=0.17 No. at Risk ATG Non-ATG 83 72 78 67 61 61 58 60 55 58 52 56 18 49 54 21 47 54 33 35 ATG Non-ATG C Patients (%) 100 80 60 40 20 0 0 3 6 9 12 15 24 Months since SCT P=0.21 No. at Risk ATG Non-ATG 8372 7667 6161 5860 5558 5256 18 49 54 21 47 54 3335 ATG Non-ATG D Patients (%) 100 80 60 40 20 0 0 3 6 9 12 15 24 Months since SCT P=0.46 No. at Risk ATG Non-ATG 8372 7868 7064 6363 6261 5860 18 54 59 21 53 56 3635 ATG Non-ATG E F Patients (%) 100 80 60 40 20 0 0 3 6 9 12 15 24 Months since SCT P=0.005 No. at Risk ATG Non-ATG 83 72 76 67 47 32 42 21 37 19 35 17 18 34 16 21 34 15 22 8 ATG Non-ATG Patients (%) 100 80 60 40 20 0 0 3 6 9 12 15 24 Months since SCT P=0.60 No. at Risk ATG Non-ATG 83 72 78 68 70 64 63 63 62 61 58 60 18 54 59 21 53 56 36 36 ATG Non-ATG Patients (%) 100 80 60 40 20 0 0 3 6 9 12 15 24 Months since SCT P<0.001 No. at Risk ATG Non-ATG 63 47 58 43 49 23 43 18 41 18 39 18 18 37 17 21 37 16 24 9 ATG Non-ATG

Incidence of Clinical Extensive Chronic GVHD Relapse

Relapse-free Survival Overall Survival

Nonrelapse-Related Death Chronic GVHD–free+Relapse-free Survival

ATG non ATG Extensive cGVHD

n engl j med 374;1 nejm.org January 7, 2016

50

T h e ne w engl a nd jou r na l o f m edicine

A B Patients (%) 100 80 60 40 20 0 0 3 6 9 12 15 24 Months since SCT P=0.17 No. at Risk ATG Non-ATG 8372 7867 6161 5860 5558 5256 18 49 54 21 47 54 3335 ATG Non-ATG C Patients (%) 100 80 60 40 20 0 0 3 6 9 12 15 24 Months since SCT P=0.21 No. at Risk ATG Non-ATG 8372 7667 6161 5860 5558 5256 18 49 54 21 47 54 3335 ATG Non-ATG D Patients (%) 100 80 60 40 20 0 0 3 6 9 12 15 24 Months since SCT P=0.46 No. at Risk ATG Non-ATG 8372 7868 7064 6363 6261 5860 18 54 59 21 53 56 3635 ATG Non-ATG E F Patients (%) 100 80 60 40 20 0 0 3 6 9 12 15 24 Months since SCT P=0.005 No. at Risk ATG Non-ATG 8372 7667 4732 4221 3719 3517 18 34 16 21 34 15 228 ATG Non-ATG Patients (%) 100 80 60 40 20 0 0 3 6 9 12 15 24 Months since SCT P=0.60 No. at Risk ATG Non-ATG 8372 7868 7064 6363 6261 5860 18 54 59 21 53 56 3636 ATG Non-ATG Patients (%) 100 80 60 40 20 0 0 3 6 9 12 15 24 Months since SCT P<0.001 No. at Risk ATG Non-ATG 6347 5843 4923 4318 4118 3918 18 37 17 21 37 16 249 ATG Non-ATG

Incidence of Clinical Extensive Chronic GVHD Relapse

Relapse-free Survival Overall Survival

Nonrelapse-Related Death Chronic GVHD–free+Relapse-free Survival

cGVHD free relapse free survival T h e ne w e ngl a nd jou r na l o f m e dicine

n engl j med 374;1 nejm.org January 7, 2016 43

The authors’ affiliations are listed in the Appendix. Address reprint requests to Dr. Kröger at the Department of Stem Cell Transplantation, University Medical Cen-ter Hamburg-Eppendorf, Martinistra♯e 52, 20246 Hamburg, Germany, or at nkroeger@ uke . de.

Drs. Kröger and Solano contributed equal-ly to this article.

This article was updated on January 7, 2016, at NEJM.org.

N Engl J Med 2016;374:43-53. DOI: 10.1056/NEJMoa1506002

BACKGROUND

Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclu-sion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling.

METHODS

We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease.

RESULTS

After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P = 0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P = 0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD–free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P = 0.005).

CONCLUSIONS

The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after alloge-neic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD–free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Soci-ety for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275.)

ABS TR ACT

Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease

Nicolaus Kröger, M.D., Carlos Solano, M.D., Christine Wolschke, M.D., Giuseppe Bandini, M.D., Francesca Patriarca, M.D., Massimo Pini, M.D., Arnon Nagler, M.D., Carmine Selleri, M.D., Antonio Risitano, M.D., Ph.D., Giuseppe Messina, M.D., Wolfgang Bethge, M.D., Jaime Pérez de Oteiza, M.D., Rafael Duarte, M.D., Angelo Michele Carella, M.D., Michele Cimminiello, M.D.,

Stefano Guidi, M.D., Jürgen Finke, M.D., Nicola Mordini, M.D., Christelle Ferra, M.D., Jorge Sierra, M.D., Ph.D., Domenico Russo, M.D.,

Mario Petrini, M.D., Giuseppe Milone, M.D., Fabio Benedetti, M.D., Marion Heinzelmann, Domenico Pastore, M.D., Manuel Jurado, M.D.,

Elisabetta Terruzzi, M.D., Franco Narni, M.D., Andreas Völp, Ph.D., Francis Ayuk, M.D., Tapani Ruutu, M.D., and Francesca Bonifazi, M.D.

Original Article

ATG non ATG

(Kröger N, N Engl J Med, 2016) 24/Aug/2017 ICBMT

Introduction

-4 -3 -2 -1 0 1 2 3 4 5

Rabbit ATG (Thymoglobulin; ATG-T)

1mg/kg/day PBSCT

CSA/TAC+sMTX

Conditioning

NJHSG (North Japan Hematology Study Group) -ATG study

Six patients were enrolled in this study. No patient developed grade II to IV acute GVHD.

Chronic GVHD developed in 3 patients, however, 2 patients achieved CR and 1 patient achieved PR only by an increase in dose of calcineurin inhibitors.

24/Aug/2017 ICBMT

Study aim

To evaluate effects of 2 mg/kg of ATG-T on T-cell depletion in the context of GVHD

prophylaxis after PBSCT.

24/Aug/2017 ICBMT

Methods

A total of 12 patients who underwent HLA-matched PBSCT were enrolled. T-cell subsets of PB on day 28 after PBSCT were analyzed by flow cytometry. CD4 gated cells were separated into four populations.

Naïve T cells: CD45RA+_Foxp3-_cells

Memory/effector T cells: CD45RA-_Foxp3-_cells

Cytokine-secreting T cells: CD45RA-_Foxp3dim_cells.

Regulatory T cells: Foxp3+_cells

CD8 gated cells were separated into three populations.

Naive T cells: CD45RA+_CD27+_cellsM

Memory T cells: CD45RA-_CD27+_cells

Effector T cells: CD27-_cells.

Statistical analysis was carried out using Mann–Whitney U-test. Statistical

analyses were performed with EZR. (Kanda Y, Bone Marrow Transplant, 2013)

(Miyara M, Immunity, 2009) (Kanakry CG, Sci Transl Med, 2013)

(Hamann D, J Exp Med, 1997) (Romero P, J Immunol, 2007)

(19)

24/Aug/2017 ICBMT Results Pt No. 1 2 3 4 5 6 7 8 9 10 11 12 Age/Sex 52/M 61/M 31/M 53/M 59/M 18/M 48/F 61/M 31/M 53/F 58/M 55/M Disease MDS MDS AML MDS AML ALL AML MDS MDS MDS AML AML Donor type R R UR R R R R R R R R R Conditioning Bu based Bu based TBI based Bu based Bu based TBI based TBI based Bu based TBI based TBI based Bu based Bu based Disease Status CR untreated CR non CR CR non CR CR non CR non CR untreated non CR non CR GVHD prophylaxis CsA+sMTX CsA+sMTX CsA+sMTX Tac+sMTX Tac+sMTX Tac+sMTX Tac+sMTX Tac+sMTX Tac+sMTX Tac+sMTX Tac+sMTX Tac+sMTX Low-dose ATG Yes Yes Yes Yes Yes No No No No No No No 24/Aug/2017 ICBMT Results Pt No. 1 2 3 4 5 6 7 8 9 10 11 12 Age/Sex 52/M 61/M 31/M 53/M 59/M 18/M 48/F 61/M 31/M 53/F 58/M 55/M Disease MDS MDS AML MDS AML ALL AML MDS MDS MDS AML AML Donor type R R UR R R R R R R R R R Conditioning Bu based Bu based TBI based Bu based Bu based TBI based TBI based Bu based TBI based TBI based Bu based Bu based Disease Status CR untreated CR non CR CR non CR CR non CR non CR untreated non CR non CR Low-dose ATG Yes Yes Yes Yes Yes No No No No No No No GVHD prophylaxis CsA+sMTX CsA+sMTX CsA+sMTX Tac+sMTX Tac+sMTX Tac+sMTX Tac+sMTX Tac+sMTX Tac+sMTX Tac+sMTX Tac+sMTX Tac+sMTX 24/Aug/2017 ICBMT Results Pt No. 1 2 3 4 5 6 7 8 9 10 11 12 aGVHD No No No No No Grade III Grade II No No No Grade II No Neutrophil engraftment day 15 day 12 day 14 day 15 day 15 day 11 day 13 day 13 day 12 day 12 day 12 day 14 Outcome Alive in CR Alive in CR after 2nd_HSCT Alive in CR Died of TRM after 2nd_HSCT Died of TRM after 2nd_HSCT Alive in CR Alive with disease relapse

Alive in CR Alive in CR Alive in CR Died of disease progression Died of disease progression

cGVHD Moderate No No No No Severe Moderate Severe No Mild No No Relapse No day 228 No day 154 day 127 No day 1333 No No No day 120 day 111 24/Aug/2017 ICBMT Results Pt No. 1 2 3 4 5 6 7 8 9 10 11 12 aGVHD No No No No No Grade III Grade II No No No Grade II No Neutrophil engraftment day 15 day 12 day 14 day 15 day 15 day 11 day 13 day 13 day 12 day 12 day 12 day 14 Outcome Alive in CR Alive in CR after 2nd_HSCT Alive in CR Died of TRM after 2nd_HSCT Died of TRM after 2nd_HSCT Alive in CR Alive with disease relapse

Alive in CR Alive in CR Alive in CR Died of disease progression Died of disease progression

cGVHD Moderate No No No No Severe Moderate Severe No Mild No No Relapse No day 228 No day 154 day 127 No day 1333 No No No day 120 day 111 24/Aug/2017 ICBMT Results

Flow cytometric analysis of T-cell subsets on day 28 after PBSCT

24/Aug/2017 ICBMT Results 0% 20% 40% 60% 80% 100% 120% ATG no ATG 0% 20% 40% 60% 80% 100% 120% 140% ATG no ATG CD4+_{T cell fractions} Naive CD4+_{T cells} Memory/effector CD4+_{T cells} Cytokine-secreting CD4+_T-cells Regulatory T-cells Naive CD8+_{T cells} Memory CD8+_{T cells} Effector CD8+_{T cells} ** * *p < 0.05; **p < 0.01 CD8+_{T cell fractions}

(20)

24/Aug/2017 ICBMT Results 0 100 200 300 0 100 200 300 400 500 (/µl) (/µl) Total CD4+_{T cells} Total CD3+_{T cells} 0 100 200 300 400 (/µl) Total CD8+_{T cells} ATG no ATG

ATG no ATG ATG no ATG

** _** ** *p < 0.05; **p < 0.01 24/Aug/2017 ICBMT Results 0 20 40 60 (/µl) Naive T cells ATG no ATG 0 50 100 150 200 250 (/µl)Memory/effector T cells ATG no ATG 2 4 6 ATG no ATG 0 5 10 15 ATG no ATG

(/µl) Regulatory T-cells (/µl)Cytokine-secreting T-cells

CD4+_{T cell} populations ** * * * *p < 0.05; **p < 0.01 24/Aug/2017 ICBMT Results 0 50 100 150 200 0 20 40 60 80 (/µl) Naive T cells ATG no ATG (/µl) Memory T cells ATG no ATG 0 40 80 120 (/µl) Effector T cells ATG no ATG ** ** * *p < 0.05; **p < 0.01 CD8+_{T cell populations} 24/Aug/2017 ICBMT Summery

Flow cytometric analysis of T-cells in PB on day 28 after PBSCT

showed that frequencies of naïve CD4+_{and CD8}+_{T-cell fractions were}

distinctively less in patients with low-dose ATG-T than those without it.

Absolute numbers of total CD3+_{, CD4}+_{, and CD8}+ _{T cells were}

significantly less in patients with low-dose ATG-T than those without it. ATG-T also decreased in absolute numbers of all T-cell subsets

evaluated in this study, and in particular, naïve CD4+_{and CD8}+_T-cells

were shown the most significant decrease in patients with low-dose ATG-T.

Clinical course of the patients enrolled in this study also indicated the inhibitory effect on both acute and chronic GVHD by low-dose ATG-T.

24/Aug/2017 ICBMT

Discussion

(Ruzek MC, Transplantation, 2009) 24/Aug/2017 ICBMT

Discussion

(Ruzek MC, Transplantation, 2009)

Naive CD8+_{T cells}

(21)

24/Aug/2017 ICBMT

Discussion

ATG-T: 4.5 mg/kg

(Bosch M, Cytotherapy, 2012) 24/Aug/2017 ICBMT

Conclusion

Our preliminary data suggested that 2 mg/kg of ATG-T may result in reduction of acute and chronic GVHD.

Now we are conducting a prospective, multicenter, phase II study to evaluate the efficacy of 2 mg/kg of ATG-T containing GVHD prophylaxis for HLA-matched PBSCT (UMIN-CTR UMIN000018645).

24/Aug/2017 ICBMT

Acknowledgement

Department of Hematology

Hokkaido University Faculty of Medicine

Eiko Hayase Kohei Okada Hideki Goto Junichi Sugita Masahiro Onozawa Masao Nakagawa Kaoru Kahata Daigo Hashimoto Tomoyuki Endo Takeshi Kondo

North Japan Hematology Study Group (NJHSG)

Japan Study Group for Cell Therapy and Transplantation (JSCT)

(22)

2017 12 59

th

_{ASH Annual Meeting & Exposition (Atlanta)}

Feasibility and kinetics of CD34+ hematopoietic cells mobilization

by low-dose pegfilgrastim in lymphoma patients

Hideki Goto1, Daisuke Hidaka1, Satoshi Yamamoto2, Koji Hayasaka3, Rie Michimata3, Ikuko Kagawa3, Kana Sunagoya3, Hiroaki Iijima4, Eiko Hayase1, Souichi Shiratori1, Kohei Okada1, Junichi Sugita1, Masahiro Onozawa1, Daigo Hashimoto1, Kaoru Kahata1, Katsuya Fujimoto1, Tomoyuki Endo1, Chikara Shimizu3, Takanori Teshima1. 1: Hokkaido University Faculty of Medicine, Graduate School of Medicine,

Department of Hematology, Sapporo, Japan

2: Sapporo City General Hospital, Department of Hematology, Sapporo, Japan 3: Hokkaido University Hospital, Division of Laboratory and Transfusion Medicine 4: Hokkaido University Hospital, Clinical Research and Medical Innovation Center, Department of Biostatistics, Sapporo, Japan

Introduction

Hematopoietic stem cell rescue with autologous peripheral blood stem cells (PBSC) following high-dose chemotherapy has been used for the treatment of lymphoma and myeloma. Granulocyte colony-stimulating factor (G-CSF) is used for PBSC

mobilization but data on PBSC mobilization by pegfilgrastim is limited. Recent studies showed successful PBSC harvest by single dose of pegfilgrastim given at 6mg or 12mg within 4 days after chemotherapy in patients with malignant lymphoma.

However, administration of pegfilgrastim early after chemotherapy treatment induces overshoot of neutrophils, which may result in rapid plasma clearance of G-CSF due to internalization of the G-CSF/G-CSF receptor complexes via endocytosis in

neutrophils. Previous studies demonstrated that day 7 injection of pegfilgrastim in the course of chemotherapy mitigated the neutrophil overshoot compared to day 4

injection of pegfilgrastim. We hypothesized that day 7 administration of lower dose 3.6mg pegfilgrastim could avoid neutrophil overshoot and efficiently mobilize PBSCs. Here we show the kinetics of CD34+ PBSC mobilization after 3.6mg pegfilgrastim given on day 7 in the course of chemotherapy.

Patients and Methods

Between February 2016 and May 2017, twenty patients with malignant lymphoma enrolled in this study (14 DLBCL, 2 AITL, 2 ALCL, 1 ATLL, 1 FL). Median age was 54 (range 30-65). Eight patients had clinical stage - . Median number of prior

chemotherapy was 0 (range 0-2). All patients received cytotoxic chemotherapy (13 CHOP, 2 DeVIC, 2 ESHAP, 1 DHAP, 1 EPOCH, 1 HD-AraC) on day 1 and 3.6mg of pegfilgrastim was administered subcutaneously on day 7. Peripheral blood CD34+ cell counts were analyzed from day 11 to 14 after chemotherapy by flowcytometric

(23)

analysis using single platform method based on ISHAGE guideline. The primary objective is to clarify the kinetics of peripheral blood CD34+ cells without harvesting intervention. CD34+ values on each time point is statistically tested using one-sample t-test. To visualize the primary result, bar graph with mean and its confidence interval on each day is represented with the reference line (figure). The secondary objectives are to find peak point of CD34+ cell counts after each chemotherapy regimen and the feasibility of pegfilgrastim administration on day 7. Successful mobilization was

defined as to achieve more than 10×106/L peripheral blood CD34+ cells on any time points between day 11 and 14. All patients were assessed for toxicity according to the National Cancer Institute Common Toxicity Criteria, version 4.0. This study was approved by the institutional review board and conducted in accordance with the Declaration of Helsinki.

Results

Successful mobilization was achieved in 19 of the 20 patients (95%). Mean number (SD) of WBC (×109/L) on each day between day 11 and day 14 was 5.4 (3.7), 11.4 (9.1), 14.2 (9.1) and 13.9 (7.4), respectively. Mean number (SD) of CD34+ cells (×106/L) on each day between day 11 and day 14 was 20.3 (22.5), 38.0 (35.7), 40.3 (39.8), and 40.1 (53.5), respectively. The 98.75% confidence interval [CI] of CD34+ cells (×106/L) on each day between day 11 and day 14 was [6.39-34.22],

[16.16-60.25], [15.77-64.97] and [7.09-73.16], respectively (Figure). The number of CD34+ cells on day 12 or 13 showed significantly higher than 10×106/L CD34+ cell (P = 0.0022 and 0.0030, respectively) (Figure). We then compared the peak of CD34+ cells in a peripheral blood in each chemotherapy regimens. The peak day of CD34+ cell in patients who received CHOP regimen was day 13 (mean 54.3 ×106/L, range 15.8–151.0×106/L) . However, in 4 of 5 patients who received platinum containing regimen, CD34+ cells failed to reach the peak before day 14 because of prolonged myelosuppression. The number of prior

chemotherapy regimen (0 vs 1-2) was not associated with the kinetics of CD34+ cells (p = 0.35). No infectious events including febrile neutropenia were observed. Back pain and LDH elevation (Grade 1-2) were the main adverse events related to pegfilgrastim administration. We had not detected any severe adverse events.

Conclusion

Our data indicated that 3.6mg pegfilgrastim on day 7 can mobilize CD34+ cells to

peripheral blood without any severe adverse events.

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Ta bl e1 : Pa tie nt s ch ara st eri st ics N = 20 Ag e me di an (ra ng e) 54 (3 0-6 5) Ma le : F ema le 9:1 1 Bo dy su rf ace a re a (BSA) me di an (ra ng e) 1.66 (1 .4 1-2 .0 8) D ise ase (N ) D LBC L 14 FL 1 AI T L 2 AL C L 2 AT LL 1 C lin ica l st ag e (N ) 4 6 3 7 In te rn at io na l Pro gn ost ic In de x (I PI ) (N ) Low 6 Lo w -in te rme di at e 8 H ig h-i nt erme di at e 4 High 1 U nkn ow n 1 C he mo th era py re gi me n (N ) CHOP 13 D eVI C 2 ESH AP 2 D H AP 1 EPO C H 1 H D -Ara C 1

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Ad m in is tr a. on o f 3. 6m g pe gfi lg ra s. m o n da y 7 in the c our se of c he m othe rapy can m obiliz e CD 34 + ce lls t o pe rip he ra l bl oo d w ith ou t an y se ve re adve rse e ve nts. H id eki G ot o 1, D ai su ke Hi dak a 1, S ato sh i Y am am oto 2, K oj i Hay as ak a 3, Ri e Mi ch im ata 3, Ik uk o Kag aw a 3, K an a Su nag oy a 3, Hi ro ak i Ii jim a 4, E ik o Hay as e 1, S ou ic hi S hi rato ri 1, K oh ei O kad a 1, J un ic hi S ug ita 1, Mas ah iro O no zaw a 1, D ai go Has hi m oto 1, K ao ru K ah ata 1, K ats uy a Fu jim oto 1, T omo yu ki E nd o 1, C hi kar a Sh im izu 3, T ak an or i T es hi m a 1 Conclusion 1)   Ho kk ai do U ni ve rs ity Ho sp ital , D ep ar tm en t o f He m ato lo gy , S ap po ro , J ap an 2) S ap po ro C ity G en er al Ho sp ital , D ep ar tm en t o f He m ato lo gy , S ap po ro , J ap an 3) Ho kk ai do U ni ve rs ity Ho sp ital , D iv is io n of L ab or ato ry an d Tr an sf us io n Me di ci ne , S ap po ro , J ap an 4 ) Ho kk ai do U ni ve rs ity Ho sp ital , C lin ic al Re se ar ch an d Me di cal In no vaQ on C en te r, D ep ar tm en t o f B io staQ sQ cs , S ap po ro , J ap an R es u lts Fi gu re 2 . A) K in eQ cs o f pe rip he ral b lo od CD 34 + ce ll. B ) Sp ag he V pl ots o f CD 34 + cel l. 0 20 40 60 80 100 120 140 160 _Day 11 12 13 14 CD 34+ cel ls ×1 0 6/L 233 ×1 0 6/L o n day 1 4 0 5 10 15 20 25 _Day 1 4 7 14 11~ 21 WBC ×1 0 9/L Fi gu re 1 . Ki ne Qc s of p er ip he ral b lo od w hi te blood c ell (W BC). Su cc es sf ul m ob ili zaQ on w as ac hi ev ed in 19 o f th e 20 p aQ en ts ( 95 % ). Me an n um be r (SD) of W BC ( 10 9/L ) o n eac h day b etw ee n day 1 1 an d day 1 4 w as 5 .4 ( 3. 7) , 1 1. 4 (9 .1 ), 14 .2 (9 .1 ) an d 13 .9 (7 .4 ), re sp ec Qv el y (F ig ur e 1) . Me an n um be r ( SD ) o f C D 34 + ce lls ( 10 6/ L) o n eac h day b etw ee n day 1 1 an d day 1 4 w as 2 0. 3 (2 2. 5) , 3 8. 0 (3 5. 7) , 4 0. 3 (3 9. 8) , an d 40. 1 (53. 5), resp ecQvel y. Th e 98. 75% co nfi den ce in terval [CI] of CD34+ cel ls ( 10 6/L ) on e ac h day b etw ee n day 1 1 an d day 14 w as [6 .3 9-3 4.2 2] , [1 6.1 6-6 0.2 5] , [1 5. 77 -6 4. 97 ] an d [7 .0 9-73 .1 6] , re sp ec Qv el y (F ig ur e 2) . T he n um be r o f C D 34 + ce lls o n day 12 o r 13 s ho w ed s ig ni fic an tly h ig he r th an 10 10 6/L C D 34 + ce ll (O ne -s am pl e t-te st: P = 0. 00 22 an d 0. 00 30 , r es pe cQ ve ly : ) He m ato po ie Qc s te m c el l re sc ue w ith au to lo go us p er ip he ral b lo od s te m c el ls ( PB SC ) fo llo w in g hi gh -d os e ch em oth er ap y has b ee n us ed f or th e tr eatm en t of l ym ph om a an d m ye lo m a. G ran ul oc yte c ol on y-sQ m ul aQ ng f ac to r (G -C SF ) is u se d fo r PB SC m ob ili zaQ on b ut data on P BS C m ob ili zaQ on b y pe gfi lg ras Qm is li m ite d. Re ce nt stu di es s ho w ed s uc ce ss fu l P BS C har ve st by si ng le do se of pe gfi lg ras Qm gi ve n at 6m g or 12 m g w ith in 6 day s aj er ch emo th erap y in paQen ts wi th mal ign an t lymp ho ma 1). H ow ev er , ad m in is tr aQ on of pe gfi lg ras Qm e ar ly aj er c he m oth er ap y tr eatm en t in du ce s ov er sh oo t of n eu tr op hi ls , w hi ch m ay r es ul t in r ap id p las m a cl ear an ce o f G -C SF d ue to i nte rn al izaQ on o f th e G -C SF /G -C SF re ce pto r c om pl ex es v ia en do cy to si s in n eu tr op hi ls . P re vi ou s stu di es d em on str ate d th at day 7 in je cQ on o f p eg fil gr as Qm in th e co ur se o f c he m oth er ap y m iQ gate d th e ne utr op hi l o ve rs ho ot co m par ed to d ay 4 in je cQ on o f p eg fil gr as Qm . W e hy po th es ize d th at day 7 ad m in is tr aQ on o f lo w er d os e 3. 6m g pe gfi lg ras Qm c ou ld av oi d ne utr op hi l ov er sh oo t an d effi ci en tly m ob ili ze PB SC s. He re w e sh ow th e ki ne Qc s of C D 34 + PB SC m ob ili zaQ on aj er 3 .6 m g pe gfi lg ras Qm g iv en on d ay 7 in th e co ur se o f c he m oth er ap y. 1) MG K im e t al B on e Mar ro w T ran sp lan taQ on 2 01 5; 5 0: 5 23 -5 30 Me th o d s Stu d y d es ig n Background Da y 1 7 11 12 13 14 Star t ch emo th era py Pegfil gra s.m 3.6m g s.c . CD3 4 co un t ① ② ③ ④ Enr ollm ent CD 34 + ce ll co un ts (Peri ph era l b lo od ) Ne xt co urs e of c he m othe rapy Fo llo w -u p pe rio d 21 B etw ee n Fe br uar y 20 16 an d May 2 01 7, tw en ty p aQ en ts w ith m al ig nan t ly m ph om a en ro lle d in th is s tu dy . A ll paQ en ts r ec ei ve d cy to to xi c ch em oth er ap y on d ay 1 an d 3. 6m g of p eg fil gr as Qm w as ad m in is te re d su bc utan eo us ly o n day 7 . Pe rip he ral b lo od C D 34 + ce ll co un ts w er e an al yze d fr om d ay 1 1 to 1 4 aj er c he m oth er ap y by fl ow cy to m etr ic an al ys is u si ng s in gl e pl ao or m m eth od b as ed o n IS HA G E gu id el in e. S uc ce ss fu l m ob ili zaQ on w as d efi ne d as to ac hi ev e m or e th an 1 0 10 6 / L pe rip he ral b lo od C D 34 + ce lls o n an y Qm e po in ts b etw ee n day 1 1 an d 14 . T he p rim ar y ob je cQ ve is to c lar ify th e ki ne Qc s of p er ip he ral b lo od C D 34 + ce lls w ith ou t har ve sQ ng in te rv en Qo n. T he m ai n se co nd ar y ob je cQ ve s ar e to fi nd p eak p oi nt of C D 34 + ce ll co un ts aj er e ac h ch em oth er ap y re gi m en an d th e fe as ib ili ty o f pe gfi lg ras Qm ad m in is tr aQ on on d ay 7 . C D 34 + val ue s on e ac h Qm e po in t i s staQ sQ cal ly te ste d us in g on e-sam pl e t-te st. T o vi su - al ize th e pr im ar y re su lt, b ar g rap h w ith m ean an d its c on fid en ce i nte rv al o n eac h day i s re pr es en te d w ith th e re fe re nc e lin e. A ll paQ en ts w er e as se ss ed fo r to xi ci ty ac co rd in g to th e N aQ on al C an ce r In sQ tu te C om m on T ox ic ity C rite ria, v er si on 4 .0 . T hi s stu dy w as ap pr ov ed b y th e in sQ tu Qo nal re vi ew b oar d an d co nd uc te d in ac co rd an ce w ith th e D ec lar aQ on o f He ls in ki . Co nfl ic t o f In te re st: Re se ar ch fu nd in g w as p ro vi de d by K yo w a Hak ko K iri n. Th e PaQ en ts w ho r ec ei ve d pl aQ nu m co ntai ni ng r eg im en , C D 34 + ce lls f ai le d to re ac h th e pe ak b ef or e day 14 b ec au se o f pr olong ed m ye losuppr ession (Fig ur e 3). The num be r of pr ior che m othe rapy re gi m en ( 0 vs 1 -2 ) w as n ot as so ci ate d w ith th e ki ne Qc s of C D 34 + ce lls (p = 0. 35 ) (Data not shown). The re was no rel aQ o n sh ip b etween C D 34+ cel l m ob ili zaQ on an d BS A (F ig ur e 4) . B ac k pai n an d LD H el ev aQ on ( G rad e 1-2) w er e th e mai n ad verse even ts rel ated to pe gfi lg ras Qm ad m in is tr aQ on . W e had n ot de te ct ed any se ve re adv er se ev ent s (T ab le 2 ). Pri or ch emo th era py re gi me n nu mb er (N ) 0 13 1 or 2 7 Pri or au to lo go us st em ce ll tra nsp la nt at io n (N ) Y es 0 No 20 0 10 20 10 5 0 Day 11 12 13 14 CD 34+ cel ls ×1 0 6/L ×1 0 9/L D HA P ES HA P WBC 0 10 20 10 5 0 Day 11 12 13 14 Fi gu re 3 . Ki ne Qc s of p er ip he ral b lo od C D 34 + ce ll (A , B ) an d W BC (C , D ) i n a tr eatm en t w ith pl aQ nu m c on tai ni ng re gi m en . Table2: Ad ve rse Eve nt s 0 10 20 30 40 50 60 70 80 ×1 0 6/L D ay 11 12 13 14 N =2 0, Me an , 98 .7 5% C I CD 34+ cel ls R es u lts Me an , SD Fi gu re 4. Pe ar so n co rr el aQ on co effici en t (r) an d p-val ue (p ) be tw ee n CD 34 + ce ll m ob ili zaQ on an d BS A. Max C D34 + ce ll Bo dy s ur fac e ar ea ×1 0 6/L r = -0 .0 07 3 p = 0. 97 6

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2018 2 BMT Tandem Meetings (Salt Lake City)

Myeloablative Versus Reduced Intensity Conditioning in

HLAHaploidentical Peripheral Blood Stem Cell Transplantation

Using Posttransplant Cyclophosphamide

Junichi Sugita1, Toshihiro Miyamoto2, Yasuhiko Shibasaki3, Koji Nagafuji4, Shuichi Ota5, Tatsuo Furukawa6, Miho Nara7, Yusuke Kagaya8, Keitaro Matsuo9, Koichi Akashi2, Shuichi Taniguchi10, Mine Harada11, Takanori Teshima1

1_{Hokkaido University} 2_{Kyushu University} 3_{Niigata University} 4_{Kurume University}

5_{Sapporo Hokuyu Hospital} 6_{Nagaoka Red Cross Hospital} 7_{Akita University}

8_{Japanese Red Cross Nagoya First Hospital} 9_{Aichi Cancer Center Research Institution} 10_{Toranomon Hospital}

11_{Karatsu Higashimatsuura Medical Association}

HLAhaploidentical stem cell transplantation using posttransplant cyclophosphamide (PTCyhaploSCT) Is increasingly performed worldwide. Since relapse remains a major problem, myeloablative conditioned (MAC) peripheral blood stem cell transplantation (PBSCT) approach using PTCy (PTCyhaploPBSCT) has been developed. However, it remains to be investigated whether this approach could increase risks of GVHD and nonrelapse mortality (NRM) compared to reducedintensity conditioned (RIC)

PTCyhaploPBSCT or not.

We conducted a prospective, multicenter, phase II study to evaluate the safety and efficacy of PTCyhaploPBSCT following MAC and RIC regimen (JSCT Haplo14). MAC regimen was fludarabine (Flu, 90 mg/m2) plus total body irradiation (TBI, 12 Gy), or Flu (150 mg/m2), busulfan (BU, 12.8 mg/kg), and TBI (4Gy). RIC regimen was Flu (150 mg/m2), BU (6.4 mg/kg), and TBI (4Gy). GVHD prophylaxis consisted of cyclophosphamide (50 mg/kg/day on days 3 and 4) and tacrolimus plus mycophenolate mofetil.

Fifty patients with a median age of 36 (range, 17 to 60) and 77 patients with a median age of 58 (range, 22 to 65) were enrolled in the MAC protocol and the RIC protocol, respectively, between 2014 and 2016. Diagnoses included AML/MDS (MAC; n=27, RIC; n=46), ALL (MAC; n=11, RIC; n=14), lymphoma (MAC; n=6, RIC; n=14), and