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Contents lists available at ScienceDirect

Transplant Immunology

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

Letter to the Editor

T-cell depletion effects of low-dose antithymocyte globulin for GVHDprophylaxis in HLA-matched allogeneic peripheral blood stem celltransplantation

Souichi Shiratori⁎,1, Mizuha Kosugi-Kanaya1, Eiko Hayase, Kohei Okada, Hideki Goto,Junichi Sugita, Masahiro Onozawa, Masao Nakagawa, Kaoru Kahata, Daigo Hashimoto,Tomoyuki Endo, Takeshi Kondo, Takanori TeshimaDepartment 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 problemafter HSCT. Compared to bone marrow transplantation (BMT), per-ipheral blood stem cell transplantation (PBSCT) is a risk for severeacute and chronic GVHD [1]. Recent large scale randomized controlledtrials indicate that antithymocyte globulin (ATG) reduces severe acuteGVHD and chronic GVHD after PBSCT [2,3]. However, doses of ATGdiffer between studies and optimal dose of ATG needs to be determined.Lower dose of ATG was suggested to have a survival benefit comparedto higher dose of ATG [4]. In this study, we evaluated effects of low-dose rabbit ATG (Thymoglobulin; ATG-T) on T-cell depletion in thecontext of GVHD prophylaxis after PBSCT.

A total of 12 patients with a median age of 53, including 5 patientswho underwent HLA-matched PBSCT with 2 mg/kg of ATG-T (1 mg/kgon days -2 and -1 before transplantation) and 7 patients who underwentHLA-matched PBSCT without ATG-T were examined in this study.Diagnosis included myelodysplastic syndrome in 6 patients, acutemyeloid leukemia in 5 patients, and acute lymphoblastic leukemia in 1patient. We analyzed peripheral blood T-cell subsets on day 28 afterPBSCT in these patients by flow cytometry. The following monoclonalantibodies 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 wasstained using a Cytofix/Cytoperm kit (e-Bioscience). CD4 gated cellswere separated into four populations, including naïve T cells defined asCD45RA+ 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 gatedcells were separated into three functionally different populations,

including naïve T cells defined as CD45RA+ CD27+ cells, memory Tcells defined as CD45RA− CD27+ cells, and effector T cells defined asCD27− 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 0.05was used as the cut-off for statistical significance. All written data areshown as mean value ± SD.

All patients received myeloablative conditioning regimen andachieved neutrophil engraftment. Grade II to IV acute GVHD developedin 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 7patients without ATG-T. Flow cytometric analysis of T-cell subsets inthe peripheral blood on day 28 after PBSCT showed that frequencies ofnaïve CD4+ and CD8+ T-cell fractions were distinctively less in ATG-Ttreated patients than controls (Naïve CD4+ T cells: 8.9% ± 3.7% vs29.5% ± 13.7%; P= 0.005, Naïve CD8+ T cells: 12.2% ± 4.7% vs28.6% ± 17.1%; P = 0.048) (Fig. 1). Concordantly, absolute numbersof both naïve CD4+ and CD8+ T-cells were significantly decreased inpatients with ATG-T, and ATG-T also significantly decreased in absolutenumbers of all T-cell subsets evaluated (Table 1).

Although the dose of ATG-T used in this study seems to be minimalever reported, a total 2 mg/kg of ATG-T given on day -2 and -1 wassufficient to decrease T cells in vivo. Donor T cells that promote GVHDreside mainly within the naïve T-cell fraction [9]. ATG-T preferentiallydepletes naïve T-cell fraction due to its high affinity against naïve Tcells [10]. We showed the significant depletion of naïve T cell fractionswith 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-Tcontaining 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.2017.11.001Received 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.

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

http://www.sciencedirect.com/science/journal/09663274

2. 研究成果論文

8

https://www.elsevier.com/locate/trim

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


mailto:[email protected]


http://crossmark.crossref.org/dialog/?doi=10.1016/j.trim.2017.11.001&domain=pdf

Hokkaido University.

Funding disclosure and conflict of interest

All authors received no financial support, and have no conflicts ofinterest.

Authors' contribution

S. Shiratori interpreted data, preparation of the article, figure andtables. M. K-K. performed recruitment and treatment of patients, andflow 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 bloodallogeneic 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 transplantationfrom matched unrelated donors: a randomised, open-label, multicentre phase 3trial, Lancet Oncol. 10 (2009) 855–864.

[3] N. Kröger, C. Solano, C. Wolschke, et al., Antilymphocyte globulin for prevention ofchronic 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 forGvHD 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 differentiationdynamics 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 expressiondrives 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 ofmemory 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 ofhuman 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 patientstransplanted 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-mousethymocyte globulin: a surrogate for rabbit anti-human thymocyte globulin,Transplantation 88 (2009) 170–179.

Fig. 1. Flow cytometric analysis of T-cell subsets afterPBSCT.Flow cytometric analysis of CD4+ and CD8+ T-cell subsetsin peripheral blood on day 28 after PBSCT in patients withlow-dose ATG-T (n = 5) and without low-dose ATG-T(n = 7). *p < 0.05; **p < 0.01.

Table 1Absolute 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 0.003Total CD4+ T cells 37.6 ± 28.4/μl 193.7 ± 99.7/μl 0.003Naive CD4+ T cells 3.5 ± 2.8/μl 55.8 ± 34.0/μl 0.003Memory/effector CD4+ T cells 29.0 ± 19.0/μl 120.3 ± 71.7/μl 0.018Regulatory T-cells 3.8 ± 6.6/μl 13.3 ± 4.7/μl 0.048Cytokine-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 0.003Naive CD8+ T cells 3.2 ± 2.0/μl 67.8 ± 67.5/μl 0.004Memory CD8+ T cells 17.4 ± 10.0/μl 77.2 ± 47.7/μl 0.005Effector CD8+ T cells 10.1 ± 10.3/μl 64.8 ± 63.0/μl 0.010

S. Shiratori et al.

http://refhub.elsevier.com/S0966-3274(17)30111-9/rf0005

9





























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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).

10

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

Cyclophosphamide- a single institute analysis -

Junichi Sugita, Takanori Teshima

The International Congress of BMT 2017In conjunction with 22nd Annual Congress of KSBMT

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

COI disclosureJunichi Sugita

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

Allogeneic hematopoietic stem cell transplantation in Japan(1992 - 2015)

0

500

1000

1500

2000

2500

3000

3500

4000

199219931994199519961997199819992000200120022003200420052006200720082009201020112012201320142015

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UR-BMT

Rel-PBSCT

Rel-BMT

0

100

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400

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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 barriersin HLA-haploidentical SCT

Posttransplant cyclophosphamide (Post CY)

11

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 JohnsHopkins, Fred Hutchinson Cancer Research Center, or BMT Group of Georgia and HahnemannUniversity Hospital. Donors were first-degree relatives who were identical at one HLA-haplotype andmismatched at one or more loci of an unshared haplotype. Of the 210 patients, 149 were male. Themedian age of the patients at transplantation was 52 (range, 1-73). Eligible diagnoses included acuteleukemia 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) withduration of remission< 6months after chemotherapy or high risk features; multiple myeloma (MM) inresistant 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 otherthan CML. The two leading indications for transplantation were non-Hodgkin lymphoma (n ¼ 66) andacute myeloid leukemia (n ¼ 43).

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

The donor graft contained amedian of 3.7" 108mononuclear cells, of which 10%were Tcells 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 fiveconsecutive 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 depletedof red-blood cells and plasma but therewas nomanipulation to deplete graft T-cells. GVHD prophylaxisconsisted 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-sevenpatients (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 neutrophilcount of$500/ml was 15 days, and themedian time to an unsupported platelet count of$20,000/ml was24 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. 2 shows the cumulative incidence of grade 2–4 aGVHD was 27%, grade 3–4 aGVHD was 5% andchronic GVHD was 13%. This coincides with the data previously reported in the 67 patients, which hadshown 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 transplantationwithpost-transplantation cyclophosphamide.

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

Ashley T. Munchel et al. / Best Practice & Research Clinical Haematology 24 (2011) 359–368364

GVHD







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 cyclophosphamideSelective depletion of alloreactive T-cells

JSCT Haplo13 StudyThis 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 JohnsHopkins, Fred Hutchinson Cancer Research Center, or BMT Group of Georgia and HahnemannUniversity Hospital. Donors were first-degree relatives who were identical at one HLA-haplotype andmismatched at one or more loci of an unshared haplotype. Of the 210 patients, 149 were male. Themedian age of the patients at transplantation was 52 (range, 1-73). Eligible diagnoses included acuteleukemia 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) withduration of remission< 6months after chemotherapy or high risk features; multiple myeloma (MM) inresistant 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 otherthan CML. The two leading indications for transplantation were non-Hodgkin lymphoma (n ¼ 66) andacute myeloid leukemia (n ¼ 43).

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

The donor graft contained amedian of 3.7" 108mononuclear cells, of which 10%were Tcells 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 fiveconsecutive 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 depletedof red-blood cells and plasma but therewas nomanipulation to deplete graft T-cells. GVHD prophylaxisconsisted 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-sevenpatients (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 neutrophilcount of$500/ml was 15 days, and themedian time to an unsupported platelet count of$20,000/ml was24 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

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 Hopkins1BM

(n=210)

US/UK/AU2PBSC(n=53)

Haplo133PBSC(n=31)

Conditioning

regimenFlu/CY/TBI Flu/CY/TBI Flu/CY/TBI

+BU(6.4mg/kg)GVHD

prophylaxisPTCy+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-IV28%

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 regimenFlu (90mg/m2) + TBI (12Gy)

Myeloablative conditioning (MAC)

Flu (150mg/m2) + ivBU (6.4mg/kg) + TBI (4Gy) 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.

12

Patient characteristics (n=47)Median Age (range) 43 (18-70)

GenderMaleFemale

31 (66%)16 (34%)

DiagnosisAMLALLMDSLymphomaOthers

21 (45%)11 (23%)6 (13%)5 (11%)4 ( 9%)

Disease status1st CR2nd CR-non CR

19 (40%)7 (15%)

21 (45%)Allogeneic Transplantation

1st Transplantation2nd or 3rd Transplantation

38 (79%)10 (21%)

��

Flu (150mg/m2) + ivBU (12.8mg/kg) + TBI (4Gy) BU based regimen (n=7)

TBI based regimen (n=12)Flu (90mg/m2) + TBI (12Gy)


Flu (150mg/m2) + ivBU (6.4mg/kg) + TBI (4Gy) BU based regimen (n=28)


��

Peripheral blood stem cell (PBSC)CD34: 5.4 x 106/kg (2.4-9.9)CD3 : 1.5 x 108/kg (0.5-3.8)

Donor relationship ParentSiblingChildOther

13 (28%)16 (34%)16 (34%)2 ( 4%)

��

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

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

+Tacrolimus (day5-)

+MMF (15 mg/kg x 3, day5-)

0 5 10 15 20 25 30

0.0

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0.6

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ive

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ence

Neutrophil engraftment 100%median day14 (12-25)

Engraftment

0 20 40 60 80 100

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ence

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III-IV: 2%

13

0 200 400 600

0.0

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0.4

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chronic GVHD


Cum

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ence

all grade: 27%

mod-sev: 20%

0 100 200 300 400 500 600 700

0.0

0.2

0.4

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Probability


OS 78%

DFS 56%

OS�DFS�NRM

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0 200 400 600

0.0

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0.4

0.6

0.8

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Cum

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ive

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ence

Relapse

39%

0 100 200 300 400 500 600 700

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Prob

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ty


OS (disease risk index)90%

71%

54%

highintermediate

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 SummaryEngraftment 100%

(median day14)

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%

14

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

Conclusionsn 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 UniversityTakanori TeshimaDaigo HashimotoMasahiro OnozawaSouichi ShiratoriEiko Hayase

Tomoyuki EndoKaoru KahataMasao NakagawaHideki GotoKohei Okada

15

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

ĢBackgroundģ

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. ĢMethodsģ

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. ĢResultsģ

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. ĢConclusionģ

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.

16

24/Aug/2017 ICBMT

T-cell depletion effects of minimal low-dose antithymocyteglobulin 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 COIName 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 acurable treatment for patients with hematological malignancies, butgraft-versus-host disease (GVHD) remains a major problem afterHSCT.

�Compared to bone marrow transplantation (BMT), peripheral bloodstem cell transplantation (PBSCT) is a risk for severe acute GVHDand chronic GVHD

�Recent randomized controlled trials indicate that antithymocyteglobulin (ATG) reduces severe acute GVHD and chronic GVHD afterPBSCT, however, doses of ATG differ between studies and optimaldose of ATG need to be determined.

24/Aug/2017 ICBMT

Introduction




24/Aug/2017 ICBMT

Introduction

Extensive chronic GVHDGrade 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

PBSCT

BMT

(Nagafuji K, Int J Hematol, 2010)

17

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 n e w e ngl a nd j o u r na l o f m e dic i n e

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/NEJMoa1506002Copyright © 2016 Massachusetts Medical Society.

BACKGROUNDChronic 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.

METHODSWe 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.

RESULTSAfter 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).

CONCLUSIONSThe 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.)

A BS TR AC T

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 Downloaded from nejm.org at HOKKAIDO UNIVERSITY on January 7, 2016. For personal use only. No other uses without permission.

Copyright © 2016 Massachusetts Medical Society. All rights reserved.

n engl j med 374;1 nejm.org January 7, 201650

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

A B

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.17

No. at RiskATGNon-ATG

8372

7867

6161

5860

5558

5256

18

4954

21

4754

3335

ATG

Non-ATG

C

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.21


8372

7667

6161

5860

5558

5256

18

4954

21

4754

3335

ATG

Non-ATG

D

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.46


8372

7868

7064

6363

6261

5860

18

5459

21

5356

3635

ATG

Non-ATG

E F

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.005


8372

7667

4732

4221

3719

3517

18

3416

21

3415

228

ATG

Non-ATG

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.60


8372

7868

7064

6363

6261

5860

18

5459

21

5356

3636

ATG

Non-ATG

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P<0.001


6347

5843

4923

4318

4118

3918

18

3717

21

3716

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



ATG

non ATG

Extensive cGVHD



A B

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.17


8372

7867

6161

5860

5558

5256

18

4954

21

4754

3335

ATG

Non-ATG

C

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.21


8372

7667

6161

5860

5558

5256

18

4954

21

4754

3335

ATG

Non-ATG

D

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.46


8372

7868

7064

6363

6261

5860

18

5459

21

5356

3635

ATG

Non-ATG

E F

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.005


8372

7667

4732

4221

3719

3517

18

3416

21

3415

228

ATG

Non-ATG

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.60


8372

7868

7064

6363

6261

5860

18

5459

21

5356

3636

ATG

Non-ATG

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P<0.001


6347

5843

4923

4318

4118

3918

18

3717

21

3716

249

ATG

Non-ATG






cGVHD free relapse free survival











A BS TR AC T







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+sMTXConditioning

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 achievedCR and 1 patient achieved PR only by an increase in dose ofcalcineurin 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. Statisticalanalyses 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)

18

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


Alive in CR

Alive with disease relapse

Alive in CR

Alive in CR

Alive in CR

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



Alive in CR

Alive with disease relapse

Alive in CR

Alive in CR

Alive in CR



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 ATG0%

20%

40%

60%

80%

100%

120%

140%

ATG no ATG

CD4+ T cell fractions

Naive CD4+ T cellsMemory/effector CD4+ T cells

Cytokine-secreting CD4+ T-cellsRegulatory T-cells

Naive CD8+ T cellsMemory CD8+ T cellsEffector CD8+ T cells

** *

*p < 0.05; **p < 0.01


19

24/Aug/2017 ICBMT

Results

0

100

200

300

0

100

200

300

400

500

(/µl)(/µl)

Total CD4+ T cellsTotal CD3+ T cells

0

100

200

300

400(/µl)

Total CD8+ T cells

ATG no ATGATG 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 ATG0

50

100

150

200

250(/µl)

Memory/effector T cells

ATG no ATG

2

4

6

ATG no ATG0

5

10

15

ATG no ATG

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

(/µl)

CD4+ T cellpopulations

** *

* *

*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 ATG0

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 PBSCTshowed that frequencies of naïve CD4+ and CD8+ T-cell fractions weredistinctively less in patients with low-dose ATG-T than those without it.

�Absolute numbers of total CD3+, CD4+, and CD8+ T cells weresignificantly less in patients with low-dose ATG-T than those without it.

�ATG-T also decreased in absolute numbers of all T-cell subsetsevaluated in this study, and in particular, naïve CD4+ and CD8+ T-cellswere shown the most significant decrease in patients with low-doseATG-T.

�Clinical course of the patients enrolled in this study also indicated theinhibitory 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 cellsNaive CD4+ T cells

20

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 mayresult in reduction of acute and chronic GVHD.

�Now we are conducting a prospective, multicenter, phase IIstudy to evaluate the efficacy of 2 mg/kg of ATG-T containingGVHD prophylaxis for HLA-matched PBSCT (UMIN-CTRUMIN000018645).

24/Aug/2017 ICBMT

Acknowledgement

Department of HematologyHokkaido University Faculty of Medicine

Eiko HayaseKohei OkadaHideki GotoJunichi SugitaMasahiro OnozawaMasao NakagawaKaoru KahataDaigo HashimotoTomoyuki EndoTakeshi Kondo


Japan Study Group for Cell Therapyand Transplantation (JSCT)

21

2017N12m 59th 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

22

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.

23

Tabl

e1:

Pat

ient

s ch

aras

teris

tics

N =

20

Age

med

ian

(ran

ge)

54 (3

0-65

) M

ale

: Fem

ale

9:11

B

ody

surfa

ce a

rea

(BS

A)

med

ian

(ran

ge)

1.66

(1

.41-

2.08

) D

isea

se (N

) D

LBC

L 14

FL

1

AIT

L 2

ALC

L 2

ATLL

1

Clin

ical

sta

ge (N

)

4

6

3

7 In

tern

atio

nal P

rogn

ostic

Inde

x (IP

I) (N

) Lo

w

6 Lo

w-in

term

edia

te

8 H

igh-

inte

rmed

iate

4

Hig

h 1

Unk

now

n 1

Che

mot

hera

py re

gim

en (N

) C

HO

P 13

D

eVIC

2

ES

HA

P 2

DH

AP

1 E

PO

CH

1

HD

-Ara

C

1

Feasibilityand

kine.

csofC

D34+hem

atop

oie.

ccellsm

obiliza.o

n

bylow-dosepe

gfilgras.minlymph

omapa

.ents

Administra.

onof3.6m

gpe

gfilgras.monda

y7

inthe

cou

rse

ofche

mothe

rapycan

mob

ilize

CD34+

cellsto

perip

heralbloo

dwith

outan

ysevereadverseevents.

Hide

kiGoto1,D

aisukeHidaka1,SatoshiYam

amoto2,KojiH

ayasaka3,R

ieM

ichimata3,IkukoKagaw

a3,KanaSunagoya

3 ,HiroakiIijima4,EikoHa

yase

1 ,SouichiShiratori1,Koh

eiOkada

1 ,JunichiSugita

1 ,

Masahiro

Ono

zawa1,D

aigoHashimoto1,KaoruKahata1,KatsuyaFujim

oto1,Tom

oyukiEnd

o1,ChikaraShimizu

3 ,Takano

riTeshim

a1

Con

clus

ion

1) H

okkaidoUniversity

Hospital,De

partmen

tofH

ematology,Sappo

ro,Japan2)Sappo

roCity

Gen

eralHospital,De

partmen

tofH

ematology,Sappo

ro,Japan

3)H

okkaidoUniversity

Hospital,Divisio

nofLaboratoryandTransfusionMed

icine,Sappo

ro,Japan4)Ho

kkaido

University

Hospital,ClinicalResearchandMed

icalInno

vaQo

nCe

nter,D

epartm

ento

fBiostaQ

sQcs,Sappo

ro,Japan

Res

ults

Figure2.A)KineQ

csofpe

riphe

ralb

lood

CD

34+cell.B)Spaghe

VplotsofCD

34+

cell.

020

40

60

80

100

120

140

160

Day

1112

1314

CD34+cells×106/L

233×10

6 /L

onday14

0510

15

20

25

Day

14

714

11~

21

WBC

×109/L

Figure1.Kine

Qcso

fperiphe

ralblood

white

bloo

dcell(W

BC).

Successfulm

obilizaQo

nwasachievedin

19ofthe20paQ

ents(95%).Meannu

mbe

r(SD)ofW

BC(

109 /L)oneachdaybetween

day11and

day14was5.4(3

.7),11.4(9

.1),

14.2(9

.1)a

nd13.9(7.4),respecQvely(Figure

1).M

eannu

mbe

r(SD

)ofC

D34+cells(

106 /

L)oneachdaybetweenday11and

day14

was20.3(22.5),3

8.0(35.7),4

0.3(39.8),and

40

.1(53.5),

respecQv

ely.Th

e98

.75%

confi

dence

interval[CI]

ofCD

34+

cells

(10

6 /L)oneachdaybetweenday11and

da

y14

was[6.39-34

.22],[16.16

-60.25

],[15.77-64.97]and[7.09-73.16],respe

cQvely

(Figure2).The

num

bero

fCD3

4+cellson

day

12or13sho

wed

significantly

highe

rthan

1010

6 /LCD

34+cell(One

-sam

plet-test:

P=0.0022and

0.0030,re

specQvely:

)

Hematop

oieQ

cstem

cellrescue

with

autologou

spe

riphe

ralbloo

dstem

cells

(PBSC)

followinghigh-dosechem

othe

rapyh

asb

een

used

forthe

treatmen

toflym

phom

aand

myeloma.Granu

locytecolon

y-sQmulaQ

ngfactor(G-CSF)isused

forPBSCmob

ilizaQo

nbu

tdataonPB

SCm

obilizaQo

nbypegfilgrasQm

islimite

d.Recen

tstudiessho

wed

successfulPBSC

harvestbys

ingle

doseo

fpe

gfilgrasQmg

iven

at6m

gor1

2mg

with

in6

days

ajer

chem

othe

rapyinpa

Qents

with

maligna

ntlymph

oma1

) .Ho

wever,ad

ministraQo

nof

pegfilgrasQmearlyaje

rchem

othe

rapytreatmen

tindu

cesovershoo

tofneu

trop

hils,w

hich

mayresultinrapidplasm

aclearanceofG

-CSFdue

tointernaliza

Qonofthe

G-CSF/G

-CSF

receptorcom

plexesviaend

ocytosisinneu

trop

hils.Previou

sstudiesdem

onstratedthatday7

injecQon

ofp

egfilgrasQm

inth

ecourseofche

mothe

rapym

iQgatedthene

utroph

ilovershoo

tcomparedtoday4in

jecQon

ofp

egfilgrasQm

.Wehypo

thesize

dthatday7adm

inistraQo

nof

lowerdose3.6m

gpe

gfilgrasQmcou

ldavoidneu

trop

hilo

versho

otand

efficien

tlym

obilize

PBSCs.Hereweshow

thekine

Qcso

fCD3

4+PBSCmob

ilizaQo

naj

er3.6mgpe

gfilgrasQmgiven

on

day7inth

ecourseofche

mothe

rapy.1)M

GKimeta

lBon

eMarrowTransplantaQo

n2015;50:523-530

Met

hods

Stu

dy d

esig

n

Bac

kgro

und

Day

17

1112

1314

Start

chem

othe

rapy

Pegfi

lgras.m

3.6m

gs.c.

CD34cou

nt①

②③

④

Enrollm

ent

CD34+cellcoun

ts

(Periphe

ralblood

)

Nextcou

rse

ofche

mothe

rapy

Follo

w-uppe

riod

21

BetweenFebruary2016andMay2017,twen

typaQ

entsw

ithm

alignantlym

phom

aen

rolledinth

isstud

y.

A

llpaQe

ntsreceived

cytotoxicche

mothe

rapyonday1and3.6m

gofpegfilgrasQm

was

administered

sub

cutane

ously

onday7.Periphe

ralb

lood

CD3

4+cellc

ountswereanalyzed

from

day11to14aj

erche

mothe

rapybyflo

wcytometricanalysisusin

gsin

gleplao

orm

metho

dbasedon

ISHA

GEguide

line.Successfulm

obilizaQo

nwasdefi

nedasto

achievem

ore

than10

106/L

periphe

ralblood

CD3

4+cellson

anyQmepo

intsbetweenday11and

14.

The

prim

aryob

jecQveisto

clarifythekine

Qcsofperiphe

ralb

lood

CD3

4+cellswith

out

harvesQn

ginterven

Qon.The

mainsecond

aryob

jecQvesaretofind

peakpo

into

fCD3

4+cell

coun

tsaje

reachche

mothe

rapyregim

enand

the

feasibilityofp

egfilgrasQm

adm

inistraQo

non

day7.

CD3

4+value

soneachQmepo

intiss

taQsQcallyte

sted

usin

gon

e-samplet-test.Tovisu-

alize

the

prim

aryresult,bargraph

with

meananditscon

fiden

cein

tervaloneachdayis

represen

tedwith

thereferenceline.AllpaQe

ntswereassessed

fortoxicityaccordingto

the

NaQ

onalCancerInsQtuteCo

mmon

Toxicity

Criteria,versio

n4.0.Thisstud

ywasapp

rovedby

theinsQtuQo

nalreviewboardand

con

ducted

inaccordancewith

theDe

claraQ

onofH

elsin

ki.

Confl

icto

fInterest:Researchfund

ingwasprovide

dbyKyowaHa

kkoKirin

.

ThePaQe

ntswho

receivedplaQ

num

containingregim

en,C

D34+cellsfailedto

reachthepe

akbeforeday14be

causeof

prolon

ged

myelosupp

ression

(Figure

3).

The

numbe

rofprior

chem

othe

rapy

regimen

(0

vs1

-2)wasn

otassociated

with

thekine

QcsofCD3

4+cells(p=0.35)

(Data

not

show

n).

There

wasno

re

laQon

shipbe

twee

nCD

34+

cell

mob

ilizaQo

nandBSA(Figure4).B

ackpain

andLD

HelevaQ

on(Grade1-2)w

erethe

main

adve

rse

even

tsre

late

dto

pegfilgrasQmadm

inistraQo

n.W

ehadno

tde

tected

an

yseveread

verse

even

ts

(Table2).

Prio

r che

mot

hera

py re

gim

en n

umbe

r (N

) 0 13

1

or 2

7

Prio

r aut

olog

ous

stem

cel

l tra

nspl

anta

tion

(N)

Yes

0 N

o 20

010

20 0510

Day11

1213

14

CD34+cells×106/L

×109/L

DHAP

ESHA

P

WBC

010

20 0510

Day11

1213

14

Figure3.Kine

Qcsofperiphe

ralb

lood

CD3

4+

cell(A,B

)and

WBC

(C,D

)inatreatm

entw

ith

plaQ

numcon

tainingregimen

.

Tabl

e2:

Adv

erse

Eve

nts

010

20

30

40

50

60

70

80×1

06/L

Day

1112

1314

N=20,M

ean,98.75%CI

CD34+cells

Res

ults

Mean,SD

Figure4

.P

earson

correlaQo

ncoeffi

cien

t(r)

and

p-value

(p)

betw

eenCD

34+cellm

obilizaQo

nandBSA.

MaxCD34+cell

Bodysu

rfacearea

×106/L

r=-0

.0073

p=0.976

24

2018N2m 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

1Hokkaido University 2Kyushu University 3Niigata University 4Kurume University 5Sapporo Hokuyu Hospital 6Nagaoka Red Cross Hospital 7Akita University 8Japanese Red Cross Nagoya First Hospital 9Aichi Cancer Center Research Institution 10Toranomon Hospital 11Karatsu 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

25

others (MAC; n=6, RIC; n=3). Twentyfour patients (48%) and 45 patients (58%) in the MAC group and RIC group, respectively, were not in remission, and 30 patients (42%) in the RIC group had a history of prior alloSCT. Neutrophil engraftment was achieved in 98% and 94% with a median of 17 and 18 days in the MAC group and RIC group, respectively (P=0.10). The cumulative incidence of grades II IV and IIIIV acute GVHD at days 100 were 18%, 8% in the MAC group, and 14%, 5% in the RIC group, respectively (IIIV; P=0.52, IIIIV; P=0.52). All grade and moderate to severe chronic GVHD at 1 year were 30%, 14% in the MAC group, and 23%, 17% in the RIC group, respectively (all grade; P=0.37, moderate to severe; P=0.71). Overall survival (OS) and event free survival (EFS) at 1 year were significantly superior in the MAC group (OS: 76% vs 54%, P=0.01, EFS: 68% vs 44%, P=0.02). There was no significant difference in NRM and relapse rate (RR) at 1 year between the groups (NRM: 8% vs 18%, P=0.08, RR: 28% vs 39%, P=0.33). In a subgroup analysis of patients who had no history of prior alloSCT, there was no difference in OS, EFS, NRM, and RR between the MAC and RIC groups (OS: 76% vs 60%, P=0.11, EFS: 68% vs 53%, P=0.27, NRM: 8% vs 19.1%, P=0.07, RR: 28% vs 30%, P=0.77). In a subgroup analysis of patients in remission, there was also no difference in OS, EFS, NRM, and RR between the groups (OS: 89% vs 74%, P=0.16, EFS: 77% vs 69%, P=0.59, NRM: 8% vs 13%, P=0.55, RR: 15% vs 22%, P=0.88). Our results suggest that MAC PTCy haploPBSCT and RIC PTCyhaplo PBSCT produce comparable rates of engraftment, acute and chronic GVHD, and NRM.

� �

26

Myeloablative versus reduced-intensity conditioning in HLA-haploidentical peripheral blood stem cell

transplantation using posttransplant cyclophosphamide

Junichi Sugita1, Yusuke Kagaya2, Toshihiro Miyamoto3, Yasuhiko Shibasaki4,Koji Nagafuji5, Shuichi Ota6, Tatsuo Furukawa7, Miho Nara8, Keitaro Matsuo9,Koichi Akashi3, Shuichi Taniguchi10, Mine Harada11, Takanori Teshima1, onbehalf of the Japan Study Group for Cell Therapy and Transplantation(JSCT)1Hematology, Faculty of Medicine, Hokkaido University, Sapporo, Japan, 2Hematology, Japanese Red Cross NagoyaFirst Hospital, Nagoya, Japan, 3Hematology/Oncology, Kyushu University Hospital, Fukuoka, Japan, 4Stem CellTransplantation, Niigata University Medical and Dental Hospital, Niigata, Japan, 5Hematology and Oncology, KurumeUniversity School of Medicine, Kurume, Japan, 6Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan, 7Hematology,Nagaoka Red Cross Hospital, Nagaoka, Japan, 8Hematology/Nephrology / Rheumatology, Akita University Hospital,Akita, Japan, 9Molecular and Clinical Epidemiology, Aichi Cancer Center Research Instituteivision, Nagoya, Japan,10Hematology, Toranomon Hospital, Tokyo, Japan ,11Karatsu Higashimatsuura Medical Center, Karatsu, Japan

COI disclosureName of first author � Junichi Sugita

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

BM

PBSCRelated

BM

PBSC

CB

Unrelated

Allogeneic SCT in Japan

JOHNS HOPKINS, Baltimore

GVHD







GVHD







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.

BMTNon-myeloabative conditioning

PBSCT

iv BU 3.2 mg/kg/day

Sugita J, Biol. Blood Marrow Transplant. 2015.

JSCT Haplo13 Study(prospective multicenter phase II study)

Challenge of this study: �PBSCT is a risk for GVHD

27

Johns Hopkins1BM

(n=210)

US/UK/AU2PBSC(n=53)

Haplo133PBSC(n=31)

Conditioning

regimenFlu/CY/TBI Flu/CY/TBI Flu/CY/TBI

+BU(6.4mg/kg)GVHD

prophylaxisPTCy+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-IV28%

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.

JSCT Haplo14 MAC

JSCT Haplo14 Study(two parallell, prospective, multicenter phase II studies)

JSCT Haplo14 RIC

HaploPBSCT following Myeloablative conditioning (MAC)

HaploPBSCT following reduced-inteinsity conditioning (RIC)

Challenge of this study: �HLA-mismatch�Myeloablative Worst risk for GVHD�PBSCT Jagasia: BLood 2012


day -6 -5 -4 -3 -2 -1 0 5 10 20 30 40 50 60 180

Flu (30 mg/m2/day) CY (50 mg/kg/day)

TBI (12 Gy)

PBSCT

G-CSF

MMF

Tacrolimus

day -6 -5 -4 -3 -2 -1 0 5 10 20 30 40 50 60 180


iv BU (3.2 mg/kg/day)TBI (4 Gy)

PBSCT

G-CSF

MMF

Tacrolimus

BU based regimen

TBI based regimen


day -6 -5 -4 -3 -2 -1 0 5 10 20 30 40 50 60 180


iv BU (3.2 mg/kg/day)

TBI (4 Gy)

PBSCT

G-CSF

MMF

Tacrolimus

BU based regimen

JSCT Haplo13

JSCT Haplo14 RIC

Flu + CY + BU + TBI (2Gy)

Flu + CY + BU + TBI (4Gy)

Results of Haplo14 study

MAC (n=50) RIC (n=77) P-valueAge at transplant

Median (range), years17-5050-65

36 (17-60)41 (82%)9 (18%)

58 (22-65)26 (34%)51 (66%)

<0.01

<0.01

Sex, no (%)MaleFemale

41 (82%)9 (18%)

48 (62%)29 (38%)

0.028

DiagnosisAMLALLMDS/MPNLymphomaOthers

23 (46%)11 (22%)6 (12%)6 (12%)4 (8%)

34 (44%)14 (18%)12 (16%)14 (18%)3 (4%)

0.72

Patient characteristics

28

MAC (n=50) RIC (n=77) P-valueDisease status

CR1CR2-Not in remission

15 (30%)11 (22%)24 (48%)

17 (22%)15 (20%)45 (58%)

0.48

refined DRIlowintermediatehighvery high

2 ( 4%)22 (44%)14 (28%)12 (24%)

3 ( 4%)22 (29%)25 (33%)27 (35%)

0.34

HCT-CI, no (%)01-2≥3

37 (74%)9 (18%)3 ( 8%)

43 (59%)24 (31%)10 (13%)

0.14

History of prior allo-SCT, no(%)NoYes

50 (100%)-

47 (61%)30 (39%)

<0.01

Patient characteristics Donor and graft characteristicsMAC (n=50) RIC (n=77) P-value

HLA match, no.(%)(GVH direction)

4/85/86/87/8

(HVG direction)4/85/86/87/88/8

28 (56%)16 (32%)6 (12%)

-

31 (62%)16 (32%)2 (4%)

-1 (2%)

33 (43%)33 (43%)10 (13%)1 (1%)

38 (49%)27 (35%)11 (14%)1 (1%)

-

0.44

0.13

Donor relationship, no (%)ParentSiblingChildOthers

14 (28%)25 (50%)8 (16%)3 (6%)

6 (8%)25 (33%)46 (60%)

-

<0.01

Donor and graft characteristicsMAC (n=50) RIC (n=77) P-value

D/R gender mismatch, no. (%)MatchFemale to MaleMale to Female

26 (52%)21 (42%)3 (6%)

48 (62%)17 (22%)12 (16%)

0.033

D/R CMV serostatus, no.(%)D+R+D-R-D+R-D-R-NA

34 (71%)9 (19%)4 (8%)1 (2%)2 (4%)

49 (71%)15 (22%)4 (6%)1 (1%)8 (12%)

0.91

CD34 (x106/kg) of PBSCsmedian (range)<4.0≥4.0

4.0 (2.0-11.4)25 (50%)25 (50%)

4.2(1.4-11.1)33 (43%)44 (57%)

0.36

0.47

Cytokine release syndrome (CRS)

0 1 2 3 4 5 6 736

37

38

39

40

41

0 1 2 3 4 5 6 736

37

38

39

40

41MAC RICCyclophosphamide Cyclophosphamide

48 (96%) of 50 patiens developed CRS 72 (94%) of 77 patiens developed CRS

EngraftmentMAC: 98%

RIC: 94%

P=0.10

MAC: 84%

RIC: 74%

P=0.32

Neutrophil engraftment Platelet engraftment

median day 17 median day 18

median day 31 median day 37

acute GVHD

MAC: 18%

RIC: 14% P=0.52

MAC: 8% RIC: 5%

P=0.52

grade II-IV acute GVHD grade III-IV acute GVHD

29

chronic GVHDall grade chronic GVHD moderate to severe chronic GVHD

MAC: 36%

RIC: 27%

P=0.24

MAC: 20% RIC: 20%

P=1.0

NRM・Relapse

MAC: 10%

RIC: 20%

P=0.15

MAC: 36%

RIC: 45%

P=0.32

NRM relapse

OS・EFSOS EFS

MAC: 68%

RIC: 44%

P=0.02

MAC: 54%

RIC: 35%

P=0.04

OS・EFSOS EFS

MAC: 68%

RIC (1st SCT): 52%

P=0.04

RIC (≥2nd SCT): 31%

MAC: 54%

RIC (1st SCT): 44%

RIC (≥2nd SCT): 21%

P=0.02

OS stratified by DRIMAC RIC

low/int : 87%(n=24)

high/very high : 50%(n=26)

low/int: 67%(n=25)

high/very high: 33%(n=52)

P<0.01 P<0.01

Cause of death MAC

(n=28) RIC

(n=43)Relapse 13 (72%) 28 (65%)

Non-relapse mortality (NRM) 5 (28%) 15 (35%)Infection 3 6Graft failure 3Graft-versus-host disease (GVHD) 2Sinusoidal obstruction syndrome (SOS) 1 1Acute Respiratory Distress Syndrome (ARDS) 1Interstitial pneumonia 1Multiple organ failure (MOF) 1 1

30

Rates of off-immunosuppressants

83% at 2yr

65% at 1yr56% at 1yr

86% at 2yr

in patients who survived at last follow-up without relapse (MAC:n=26, RIC:n=27)

MAC RIC

NRMHR (95%CI) P-value

RelapseHR (95%CI) P-value

Conditioning regimenMACRIC

11.13 (0.33-3.84) 0.85

10.81 (0.41-1.58) 0.53

Age at transplant<50≥50

13.39 (0.95-12.0) 0.06

- -

refined DRIlow/Inthigh/very high

- - 13.09 (1.60-5.97) <0.01

History of prior allo-SCTNoYes

- - 12.01 (1.02-3.97) 0.04

Multivaliate analysis

OSHR (95%CI) P-value

EFSHR (95%CI) P-value

Conditioning regimenMACRIC

10.85 (0.41-1.75) 0.66

10.73 (0.39-1.38) 0.34


12.12 (1.18-3.84) 0.01

12.15 (1.26-3.65) <0.01


13.42 (1.82-6.43) 0.01

12.87 (1.67-4.95) 0.01


12.43 (1.26-4.67) <0.01

12.38 (1.30-4.33) <0.01

Multivaliate analysis Johns Hopkins1

BM(n=210)

Haplo14 MACPBSC(n=50)

Haplo14 RICPBSC(n=77)

Condtioningregimen

Flu/CY/TBI Flu/TBIFlu/BU4/TBI

Flu/BU2/TBI

GVHDprophylaxis

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

Engraftment 87%day15(11-42)

98%day17(12-39)

94%day18(13-50)

Acute GVHDII-IVIII-IV

27%5%

18%8%

14%5%

Chronic GVHDallmod-sev

13%-

36%20%

27%20%

NRM 18% 10% 20%

1) Munchel AT, Best Pract Res Clin Haematol. 2011;24:359–368.

n We presented outcomes of two parallel prospective, multicenter, phase II studies of MAC and RIC based PTCy-haploPBSCT in Japan.

n In the multivaliate analysis, recipient age at transplant, DRI, and history of piror allo-SCT were independent risk factors for OS and EFS.

n Our results indicate that both MAC and RIC are valid options for PTCy-haploSCT for adults with hematological malignancy. Ideally, more precise comparison of MAC and RIC should be studied further in the setting of a randomized trial.

ConclusionDepartment of Hematology, Faculty of Medicine, Hokkaido University

Takanori TeshimaDaigo HashimotoMasahiro OnozawaHideki GotoSouichi ShiratoriKohei OkadaEiko HayaseReiki OgasawaraTakahide Ara

Acknowledgement



Japan Agency for Medical Research and Development(AMED, JP17ek0510012)

31

) ) . )

7

HLA J II

11 21 31 41 51 61

71 81 91 21 101 111

1 1: , 2:

, 3: , 4: , 5: , 6:

/ / , 7: , 8: , 9: S

, 10: J , 11:

HLA‒haploidentical stem cell transplantation using post‒transplant cyclophosphamide (PTCy‒haploSCT) after nonmyeloablative conditioning ensures good GVHD controls and low non‒relapse mortality (NRM), however, relapse remains a major problem. We conducted a prospective, multicenter, phase II study to evaluate the safety and efficacy of PTCy‒haploPBSCT using myeloablative conditioning (MAC: JSCT Haplo14 MAC, UMIN000014406). The primary endpoint of this study was 1‒year event‒free survival (EFS). Myeloablative conditioning regimen were fludarabine (Flu, 90mg/m2) plus total body irradiation (TBI, 12Gy), or Flu (150mg/m2), busulfan (12.8mg/kg), and 4Gy TBI. GVHD prophylaxis consisted of Cy (50 mg/kg/day on days 3 and 4) and tacrolimus plus mycophenolate mofetil starting on day 5. Fifty‒patients with a median age of 36 (range, 17 to 60) were enrolled between 2014 and 2015. Diagnoses included AML/MDS (n=27), ALL(n=11), lymphoma (n=6), and others (n=6). Neutrophil engraftment was achieved in 98% of patients with a median of 17 days. The cumulative incidence of grades II‒IV and III‒IV acute GVHD and chronic GVHD at 1 year were 18%, 8%, and 32%, respectively. Overall survival, EFS, relapse rate, and NRM were 76%, 64%, 28%, and 8%, respectively, at 1 year. EFS 64% (95%CI: 49%‒76%) was over the threshold (30%). EFS and relapse rate at 1year were 77% and 15% in remission patients, and 50% and 42% in patients with active disease. Our results suggest that PTCy‒haploPBSCT after MAC achieved low incidences of GVHD and NRM with an acceptable relapse rate, particularly in remission patients.

32

骨髄破壊的前治療による移植後シクロホスファミドを用いた血縁者間HLA半合致末梢血幹細胞移植の第II相試験JSCT-Haplo14 MAC （UMIN000014406）杉田純一1), 宮本敏浩2), 長藤宏司3), 加賀谷裕介4), 町田真一郎5), 奈良美保6), 宮崎泰彦7), 柴崎康彦8), 松尾恵太郎9), 赤司浩一2), 谷口修一11), 原田実根12), 豊嶋崇徳1)1) 北海道大学大学院医学研究院血液内科学教室2) 九州大学病院血液・腫瘍・心血管内科3) 久留米大学病院血液・腫瘍内科4) 名古屋第一赤十字病院血液内科5) 東海大学医学部付属病院血液腫瘍内科6) 秋田大学医学部附属病院血液内科/腎臓内科/リウマチ科7) 大分県立病院血液内科8) 新潟大学医歯学総合病院高密度無菌治療部9) 愛知県がんセンター研究所遺伝子医療研究部11) 虎の門病院血液内科12) 唐津東松浦医師会医療センター


日本血液学会}� ~開示

筆頭発表者名：杉田純一

■すべての共同発表者を代表し、本発表演題に関連して開示すべきCOI 関係にある企業などはありません。

■本研究は北海道大学病院および各参加施設においてIRB の承認を得ています。

Introduction・Johns Hopkins のLuzunikらにより移植後シクロホスファミドを用いたHLA半合致骨髄移植の報告がなされ、GVHD抑制効果に優れ、非再発死亡が少ないことが報告されている。

・一方で再発率に課題が残ることから、前治療強化や末梢血幹細胞を用いる試みなど欧米では多くの臨床研究が進行中である。

・我々は過去にJohns Hopkinsの原法にBusulfan (6.4mg/kg) を追加し、移植片を末梢血幹細胞への変更を行った多施設共同第II相試験 (Haplo13) を実施し、欧米からの報告と同様にGVHD抑制効果に優れ、非再発死亡が少ないことを報告した。

・今回我々は骨髄破壊的前治療を用いた血縁者間HLA半合致末梢血幹細胞移植の第II相試験 (Haplo14 MAC) を実施したのでその結果を報告する。

Luznik L, BBMT. 2008;14:641–650.

Solomon SR, BBMT. 2012;18:1859–1866. Raiola AM, BBMT. 2013;19:117–122.

Sugita J. BBMT. 2015;21:1646–1652.

154��604��C15oh

154��654��C15z�yoc

Haplo14 MAC Haplo14 RIC

Haplo13 Sugita J, BBMT 2015;21:1646–1652.

Haplo16 MAC Haplo16 RIC

154��704��C15z�yoc

154��604��C15oh

PTCY�*oh (50mg/kg, day3,4)MMFq(+:8{�3T/�9{Y��9qH�

PTCY8U (40 mg/kg, day3,4)MMFq(+:8{�3T/�9{Y��9qH�

Flu+BU4+TBI(4Gy)Flu+TBI(12Gy)

Flu+BU2+TBI(4Gy)

Flu+CY+BU2+TBI(2Gy)

Haplo17 MAC Haplo17 RICPTCY�*oh (50mg/kg, day3,4)MMF8U (15mg/kg, 1'2�, day5-30)Tacq(+�3 (day90�Xq�3)

PTCY8U (40 mg/kg, day3,4)MMF8U (15mg/kg, 1'2�, day5-30)Tacq(+�3 (day90�Xq�3)

E40�SNFLC1�(-�) ��

Methods・多施設共同第Ⅱ相試験（JSCT研究会）

・登録症例数：53例 (2014/08 ‒ 2015/09)解析症例数：50例不適格1例：HLA一致度6/8移植中止2例：原病増悪、採取細胞数不足

・観察期間中央値: 705日 (369-957)

・主要評価項目移植後1年時点での無イベント生存率（EFS）

・副次評価項目移植後100日、移植後1年、移植後2年時点での生着達成割合、急性GVHD、慢性GVHD、再発率、全生存率、無病生存率など

移植前治療・GVHD予防

day -6 -5 -4 -3 -2 -1 0 5 10 20 30 40 50 60 180


TBI (12 Gy)

PBSCT

G-CSF

MMF

Tacrolimus

day -6 -5 -4 -3 -2 -1 0 5 10 20 30 40 50 60 180


iv BU (3.2 mg/kg/day)TBI (4 Gy)

PBSCT

G-CSF

MMF

Tacrolimus

BU based regimen

TBI based regimen

33

Results

Median age, y (range) 36(17-60)Sex (M:F) 41:9Diagnosis

AMLALL/LBLMDS/MPNLymphomaOthers

23 (46%)11 (22%)6 (12%)6 (12%)4 ( 8%)

Disease status1st CR2nd CR or 3rd CRnon CR

15 (30%)11 (22%)24 (48%)

Refined Disease Risk Index (DRI)

LowIntermediateHighVery High

2 ( 4%)22 (44%)14 (28%)12 (24%)

Patient characteristics

Donor relationshipParentSiblingChildOther

14 (28%)25 (50%)

8 (16%)3 ( 6%)

CMV serostatusD+R+D-R+D+R-D-R-NA

34 (68%)9 (18%)4 ( 8%)1 ( 2%)2 ( 4%)

Cell doseCD34 (x106/kg) 4.0 (2.0-11.4)

Donor and graft characteristics Engraftment

好中球生着: 98%, 中央値 day17 血小板生着: 84%, 中央値 day31

GVHD急性GVHDII-IV: 18%, III-IV: 8%

慢性GVHDall grade: 30%(1y),33%(2y)moderate-severe: 14%(1y),17%(2y)

NRM{RelapseNRM: 8%(1y), 8%(2y) Relapse: 28%(1y), 38%(2y)

34

Overall survival (OS)76% (1y)

73% (2y)

Event-free survival (EFS)

68% (1y)

56% (2y)

Primary endpoint1 );lqEFS 68% (95%CI: 53%-79%)

Cause of death Relapse 11 (73%)

Non relapse mortality (NRM) 4 (27%)Infection 2

Sinusoidal obstruction syndrome (SOS) 1

Multiple organ failure (MOF) 1

Haploimmunostorm syndrome

0 1 2 3 4 5 6 736

37

38

39

40

41

Tem

pera

ture

(ºC

)


50例中48例(96%)で38ºC以上の非感染性発熱

Disease risk index

P<0.01 P<0.01

High, n=14Low/Int, n=24

Very high, n=12

OS EFS

Disease risk index High, n=14Low/Int, n=24

Very high, n=12

NRM Relapase

P<0.01P=0.99

35

Conditioning regimen Flu/BU4/TBI, n=23Flu/TBI, n=27

P=0.61 P=0.11

OS EFS

Conditioning regimen Flu/BU4/TBI, n=23Flu/TBI, n=27

NRM Relapase

P=0.11P=0.90

%K _

P=0.08 P=0.13

OS EFS

404��, n=30414��, n=20

%K _

404��, n=30414��, n=20

NRM Relapase

P=0.67P=0.01

Multivariate analysisOS

Hazard Ratio (95%CI) P-valueEFS

Hazard Ratio (95%CI) P-valueAge at PBSCT

404��414��

11.77 (0.58-5.5) P=0.32

11.20 (0.46-3.1) P=0.72

Conditioning regimenFlu/BU4/TBIFlu/TBI

10.93 (0.33-2.7) P=0.91

10.54 (0.21-1.4) P=0.20

Disease risk indexLow/IntHighVery high

13.31 (0.58-19.2)10.3 (2.1-49.6)

P=0.18P<0.01

12.52 (0.72-8.8)4.70 (1.54-14.2)

P=0.15P<0.01

Discussion

36

Johns Hopkins1

BM(n=210)

Haplo132

PBSC(n=31)

Haplo14 MACPBSC(n=50)

Condtioningregimen

Flu/CY/TBI Flu/CY/TBI+BU(6.4mg/kg)

Flu/TBIFlu/BU4/TBI

GVHDprophylaxis

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

Engraftment 87%day15(11-42)

87% (100%)day19(15-27)

98%day17(12-39)

acute GVHDII-IVIII-IV

28%4%

23%3%

18%8%

Chronic GVHD 13% 15% 30%NRM (1yr) 18% 23% (11%) 8%

1) Munchel AT, Best Pract Res Clin Haematol. 2011;24:359–368. 2) Sugita J, Biol. Blood Marrow Transplant. 2015;21:1646–1652.

Safety of PTCy-haploPBSCT

P<0.01 P<0.01

High, n=14Low/Int, n=24

Very high, n=12

OSLow/Int

High

Very high High

Very high

Low

Int

Armand P. Blood. 2014;123:3664–3671.

Efficacy of PTCy-haploPBSCT

Conclusion{]^B�A�7?z=ciNIKVHLA��M,0N!FLC1#q1 EFS|68%(95%CI: 49%-76%)lbv`Q�hiW�lbw30%z��jia

{GVHD@><`[�@6�<r]^B�A�7?z=ckt� pR�lfwG.lbjimJdwa

{��q2PlrOS`EFSp"\z�dw��rDisease risk indexqslbjie`Haplo16`Haplo17on�#ZDgxiuv�&lq2Pe$Olbwa

Acknowledgement北海道大学病院血液内科札幌医科大学附属病院第一内科札幌医科大学附属病院腫瘍･血液内科北楡会札幌北楡病院血液内科市立旭川病院血液内科秋田大学医学部附属病院輸血部･血液内科仙台医療センター血液内科宮城県立がんセンター血液内科東北大学病院血液･免疫科山形県立中央病院血液内科福島県立医科大学附属病院血液内科新潟大学医歯学総合病院高密度無菌治療部長岡赤十字病院血液内科長野赤十字病院血液内科信州大学医学部附属病院血液内科群馬県済生会前橋病院白血病治療センター獨協医科大学病院血液･腫瘍内科東京医科大学病院血液内科慶應義塾大学医学部小児科東京女子医科大学病院血液内科東京医療センター血液内科東京慈恵会医科大学病院腫瘍･血液内科NTT東日本関東病院血液内科虎の門病院血液内科がん･感染症C 都立駒込病院血液内科防衛医科大学校病院血液内科千葉大学医学部附属病院血液内科虎の門病院分院血液内科横浜市立大学附属市民総合医療C 血液内科神奈川県立がんセンター血液科

東海大学医学部付属病院血液腫瘍内科亀田総合病院血液･腫瘍内科成田赤十字病院血液腫瘍科埼玉医科大学総合医療センター血液内科名古屋第一赤十字病院血液内科名古屋大学医学部附属病院血液内科名古屋市立大学病院血液･膠原病内科浜松医療センター血液内科愛知医科大学病院血液内科岐阜大学医学部附属病院血液･感染症内科岐阜市民病院血液内科江南厚生病院血液･腫瘍内科三重大学医学部附属病院血液･腫瘍内科伊勢赤十字病院血液･感染症内科田附興風会医学研究所北野病院血液内科近畿大学医学部附属病院血液･膠原病内科高槻赤十字病院血液腫瘍内科和歌山県立医科大学附属病院血液内科天理よろづ相談所病院血液内科京都第二赤十字病院血液内科京都府立医科大学附属病院血液内科石川県立中央病院血液内科金沢大学附属病院血液内科富山県立中央病院血液内科神戸市立医療C中央市民病院免疫･血液内科先端医療センター病院細胞治療科神戸大学医学部附属病院腫瘍･血液内科山口大学医学部附属病院第三内科公立学校共済組合中国中央病院血液内科島根大学医学部附属病院腫瘍･血液内科

米子医療センター血液腫瘍科岡山大学病院血液･腫瘍内科川崎医科大学附属病院血液内科香川大学医学部附属病院血液内科徳島赤十字病院血液科徳島大学病院血液内科高知大学医学部附属病院血液内科松山赤十字病院内科愛媛県立中央病院血液内科愛媛大学病院第一内科原三信病院血液内科九州がんセンター血液内科九州大学病院血液･腫瘍内科浜の町病院血液内科九州医療センター血液内科JCHO 九州病院血液･腫瘍内科久留米大学病院血液･腫瘍内科聖マリア病院血液内科佐賀県医療センター好生館血液内科佐賀大学医学部附属病院血液･腫瘍内科佐世保市立総合病院血液内科長崎医療センター血液内科長崎大学病院血液内科熊本医療センター血液内科熊本大学医学部附属病院血液内科大分県立病院血液内科大分大学医学部附属病院血液内科宮崎県立宮崎病院血液科今村病院分院血液内科鹿児島大学病院血液･膠原病内科

37

) ) . )

A pilot study of minimal low-dose antithymocyte globulin for GVHD prophylaxis in HLA-matched allogeneic peripheral blood stem cell transplantation: NJHSG-ATG Souichi Shiratori1, Akio Shigematsu2, Mizuha Kosugi-Kanaya1, Satomi Matsuoka3, Shojiro Takahashi2, Kohei Okada1, Hideki Goto1, Junichi Sugita1, Masahiro Onozawa1, Masao Nakagawa1, Kaoru Kahata1, Katsuya Fujimoto1, Daigo Hashimoto1, Tomoyuki Endo1, Takeshi Kondo1, Takanori Teshima1, on behalf of North Japan Hematology Study Group 1 Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan 2 Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan. 3 Department of Hematology, Hakodate Municipal Hospital, Hakodate, Japan. Abstract Background: Incidence of graft-versus-host disease (GVHD) is higher after allogeneic peripheral blood stem cell transplantation (PBSCT) than after bone marrow transplantation. Antithymocyte globulin (ATG) has been shown to reduce GVHD after PBSCT, but its optimal dose remains to be determined. Methods: We conducted a pilot study to evaluate the safety of minimal low-dose rabbit ATG (Thymoglobulin; ATG-T) for GVHD prophylaxis in HLA-matched PBSCT. ATG-T was administered at a dose of 1 mg/kg on days -2 and -1 before PBSCT from an HLA-8/8 matched sibling or unrelated donor. The primary study objective was the incidence of cytomegalovirus (CMV) infection, hemorrhagic cystitis (HC), and posttransplant lymphoproliferative disorder (PTLD) at 1 year posttransplant. Flow cytometric analysis of T-cell subsets in peripheral blood after PBSCT were also performed. Results: Six patients were enrolled in this study. All patients achieved engraftment and no patient developed CMV infection, HC, or PTLD. No patient developed acute or chronic GVHD requiring systemic corticosteroids. Low-dose ATG-T significantly decreased in numbers of CD4+ and CD8+ T cells, and naïve T cell fractions on day 28 after PBSCT. Conclusion: Our study suggested that minimal low-dose ATG-T containing GVHD prophylaxis is safe in HLA-matched PBSCT in Japanese. Now we are conducting a prospective, multicenter, phase II study to evaluate the efficacy of this GVHD prophylaxis for HLA-matched PBSCT.

38

FìATGŚ�ĵŃ.oxÍQ´¿¬y��Ō9iÔ�.ŬŜŴŦŨ×ý

ż*jpÍ�§®�

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Ŷ.oxÍQ´¿¬yŸPBSCTŹŌøSōPı7'�0Ś©ľŇķŗįpæňō2010PŕŗõÍ¶ºïPBSCTœî=ĽřŃİ

Ŷ�hňPBSCTōįþÿ¬yŉ�ÞľŇŸ`\ŹGVHDŌ7'įķŕŎłřŋ�Ķ¬yWŌQOLŌ��Ĺ62ĽřŇĺŃİ

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Background T h e n e w e ngl a nd j o u r na l o f m e dic i n e










A BS TR AC T







Original Article





A B

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.17


8372

7867

6161

5860

5558

5256

18

4954

21

4754

3335

ATG

Non-ATG

C

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.21


8372

7667

6161

5860

5558

5256

18

4954

21

4754

3335

ATG

Non-ATG

D

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.46


8372

7868

7064

6363

6261

5860

18

5459

21

5356

3635

ATG

Non-ATG

E F

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.005


8372

7667

4732

4221

3719

3517

18

3416

21

3415

228

ATG

Non-ATG

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.60


8372

7868

7064

6363

6261

5860

18

5459

21

5356

3636

ATG

Non-ATG

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P<0.001


6347

5843

4923

4318

4118

3918

18

3717

21

3716

249

ATG

Non-ATG






ATG

non ATG

Extensive cGVHD



A B

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.17


8372

7867

6161

5860

5558

5256

18

4954

21

4754

3335

ATG

Non-ATG

C

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.21


8372

7667

6161

5860

5558

5256

18

4954

21

4754

3335

ATG

Non-ATG

D

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.46


8372

7868

7064

6363

6261

5860

18

5459

21

5356

3635

ATG

Non-ATG

E F

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.005


8372

7667

4732

4221

3719

3517

18

3416

21

3415

228

ATG

Non-ATG

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P=0.60


8372

7868

7064

6363

6261

5860

18

5459

21

5356

3636

ATG

Non-ATG

Patie

nts

(%)

100

80

60

40

20

00 3 6 9 12 15 24

Months since SCT

P<0.001


6347

5843

4923

4318

4118

3918

18

3717

21

3716

249

ATG

Non-ATG






ATG

non ATG

cGVHD free relapse free survival











A BS TR AC T







Original Article



(Kröger N et al, N Engl J Med, 2016)

ATG-F: 30mg/kg

InhibitionofGVHDbyATG

GRFS

MRD: no ATGMUD: ATG-T: 2.5 mg/kg

MUD: ATG

MRD: non ATG

(Bryant A et al, Biol Blood Marrow Transplant, 2017)


(Kuriyama K et al, Int J Hematol, 2016)

Extensive cGVHDGradeIII-IV aGVHD GRFS

ATGnon ATG

ATGnon ATG

ATG

non ATG

ATG-T: 1.5 mg/kg(1.0 - 4.0mg/kg)


39

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

ATG-T (Thymoglobulin®)1mg/kg/day

HLA-matched PBSCT

CsA/Tac+sMTXConditioning

Ĳ¢ ĳ

HLA-matched PBSCTŋDĿŘFìATGŚ�ĵŃGVHDñ�Ō?�\ŚzÕĿŘİ

ĕĒĐėďĄċĘď ħĨĩĝĬ

ėĨĩĝĬăħĜğĞĢě

Ĳåw4�ĳ

ŶDÛ�]Ŷ�nż

(a) [\�Í�ż°�œľĻō°@�CÑnİ(b) ^\ŲŵŬÄżè"CÑnœľĻō@�CÑn(c) þÿ�Va��¸żIPSSŋŇintermediate-IIŐŃōhighį

WPSSŋŇhighŐŃōvery highįŐŃōCÑWŌ��İŶPĂż15��į65��ŶHLAĹå-ľŃÍ¶įŐŃōõÍ¶oxÍQ´¿ũŪŷŚmĿŘŶPerformance status(PS) 0-2Ō]ºŶ�ÐÇ3ŸZį½įÃį¾ŹŌ�ÂĹ�ŃřŇĵŘ]º

Ĳ�ÐÖ�ö¢ĳ: ¬yW1PCMV_vį Í\ÆÀ�įPTLDŌ��

Ĳ¢~��fĳ: 6�

Ĳ�ínïĳ: 2PïŸ2013P11lŽ2015P11lŹ


PĂ/\#

52/M

61/M

65/M

31/M

38/M

58/M

�n

PR

SD

CR

CR

CR

SD

¬yŤŷŢ

Related

Related

Related

Unrelated

Related

Related

�]

MDS

MDS

AML

AML

ALL

MDS

¬y%�·

Flu 180mg/m2 + Bu 12.8mg/kg



CY 120mg/kg + TBI 12Gy

CY 120mg/kg + TBI 12Gy


CMV IgG(D/R)

ź/ź

ź/ź

ź/ź

ź/ź

ź/ź

ź/ź

1

2

3

4

5

6


aGVHD / ÝM

Ż / Ż

Ż / Ż

Ż / Ż

Ż / Ż

Ż / Ż

Grade I / CR

cGVHD / ÝM

Moderate / CR

Ż / Ż

Mild / CR

Ż / Ż

Mild / PR

Ż / Ż

CMV infection / HC / PTLD

Ż / Ż / Ż

Ż / Ż / Ż

Ż / Ż / Ż

Ż / Ż / Ż

Ż / Ż / Ż

Ż / Ż / Ż

1

2

3

4

5

6

�¥

Day 15

Day 12

Day 15

Day 14

Day 14

Day 17


��

Ż

Day 228

Ż

Ż

Ż

Day 84

ÝM

Alive in CR

Alive in CR after 2nd SCT

Alive with CR

Alive with CR

Alive with CR

Died at Day 251

by fungal infection

��c$&

Ō��

day902

NA

day419

day331

Ż

NA

1

2

3

4

5

6

2nd SCT

Ż

Haplo (PTCy)

Ż

Ż

Ż

Ż


Ŷ��ňþÿ¨8 %�·ĹiÎĽřįàŔĸŌ<��Ō�¥ĹXŖřŃİ

ŶGrade II��ŌaGVHDōØŒŖřŀįcGVHDō3�ŋőŖřŃĹįĵŀřœŝųšūűŷŲŵòBËŌÙgįGb��ŌőňşŵŨŴŷų,ÂňĴŅŃİ

ŶCMV_v�į Í\ÆÀ�įPTLDŌ��ōőŖřŊĸŅŃİ

Ŷ��ō2�ŋØŒŖřįĶń1�ňōPTCYŚ�ĵŃ2nd¬yĹiÎĽřCRĹXŖřŃİ


40


ĕěĭĪĞ ĘĄĜĞġġ ĝĞĥġĞĨĠĤģ īĠĨğ ċĘď




Naive CD8+ T cellsNaive CD4+ T cells


(Bosch M, Cytotherapy, 2012)

ATG-T: 4.5 mg/kg


ATG-T: 4.5 mg/kg

(Bosch M, Cytotherapy, 2012)


ŶUóňHLA-matched PBSCTĹiÎĽřŃ12�ŸLow-dose ATGd�¸ż5�įõd�¸ż7�ŹŋķĵŇį¬yW28j¢ŌT´¿ŠůţŦŨŚįŮŴŷŠŜŨŰŨŲŷ�ŋŇÑtľŃİ

ŶT´¿ŠůţŦŨōį�ÓŌA¹Ō�ŋ"úľŃİŶCD4 positive T cells: Naïve T cells: CD45RA+ Foxp3-

Memory/effector T cells: CD45RA- Foxp3-

Cytokine-secreting T cells: CD45RA- Foxp3dim

Regulatory T cells: Foxp3+

ŶCD8 positive cells: Naive T cells: CD45RA+ CD27+

Memory T cells: CD45RA- CD27+

Effector T cells: CD27-

ŶµÒ> ÑtōĎĚĖŸÉ�+«:>5�+�ţŵťŷŹŚ�ĵŃİ


41

0% 20% 40% 60% 80%

100% 120%

ATG noATG0%

20% 40% 60% 80%

100% 120% 140%

ATG noATG

Naive CD4+ T cellsMemory/effector CD4+ T cells

Cytokine-secreting CD4+ T-cellsRegulatory T-cells

Naive CD8+ T cellsMemory CD8+ T cellsEffector CD8+ T cells

** *

*p < 0.05; **p < 0.01


8.9%� 3.7%

29.5%� 13.7%


12.2%� 4.7%

28.6%� 17.1%

Naïve fraction

Mann-Whitney U-test


CD4+ Naive T cells CD8+ Naive T cells

0

20

40

60

(/µl)

ATG no ATG

**0

20

40

60

80(/µl)

ATG no ATG

**

**p < 0.01Mann-Whitney U-test


NJHSG-ATG studyįķŕŎ¬yWŌT´¿ŠůţŦŨŌÑtŋŕŗįHLA-matched PBSCTŋķĵŇįFìATGŚ�ĵŃGVHDñ�Śįŕŗ:ĺŊ%0ĺÈR×ýŉľŇâŒŇĵĻ4¡ŉŊŘŧŷťĹXŖřŃİ

ėĩĢĢěĦĬ

ĒėČĘĄċĘďĆĈ

eŭŨÁÅ´¿��ŞŴůŲŵŚ�ĵŃĐēċå-ũŪŷĸŖŌ.oxÍQ´¿¬yŌ9iÔ�.°đđ£×ýęĔđĕ×ýđčżęĔđĕąąąąĆĊĉćĈ

§®�ÏºżÚJIY §®Ü ºż�ā¼�

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Thymoglobulin 2mg/kg(day -2, -1: 1mg/kg)

Tac/CsA+sMTX(day 1: 10mg/m2, day 3, 6, (11): 7mg/m2)

Conditioning therapy

PBSCT from HLA-8/8 matched related/unrelated donor

6 7 8 9 10 11

Ÿ Ź

ĒėČĘĄċĘďĆĈ ħĨĩĝĬ

42

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43


強度減弱前治療による移植後シクロホスファミドを用いた血縁者間HLA半合致末梢血幹細胞移植の有効性と安全性の検討

JSCT-Haplo14 RIC杉田純一1), 加賀谷裕介2), 柴崎康彦3), 太田秀一4),古川達雄5), 藤崎智明6), 衛藤徹也7), 安藤寿彦8), 松尾恵太郎9), 赤司浩一10), 谷口修一11), 原田実根12),豊嶋崇徳1)1) 北海道大学大学院医学研究院血液内科学教室2) 名古屋第一赤十字病院血液内科3) 新潟大学医歯学総合病院高密度無菌治療部4) 札幌北楡病院血液内科5) 長岡赤十字病院血液内科6) 松山赤十字病院内科7) 浜の町病院血液内科8) 佐賀大学医学部附属病院血液･腫瘍内科9) 愛知県がんセンター研究所遺伝子医療研究部11) 虎の門病院血液内科12) 唐津東松浦医師会医療センター

Introduction・Johns Hopkins のLuzunikらにより移植後シクロホスファミドを用いたHLA半合致骨髄移植の報告がなされ、GVHD抑制効果に優れ、非再発死亡が少ないことが報告されている。

・本邦では多施設共同第II相試験 (Haplo13試験)において、Johns Hopkinsの原法にBusulfan (6.4mg/kg) を追加、移植片を末梢血幹細胞への変更を行い、欧米からの報告と同様にGVHD抑制効果に優れ、非再発死亡が少ないことを報告した。

・今回我々は強度減弱前治療を用いた血縁者間HLA半合致末梢血幹細胞移植の第II相試験 (Haplo14 RIC) を実施したのでその結果を報告する。

Luznik L, BBMT. 2008;14:641–650.

Sugita J. BBMT. 2015;21:1646–1652.

・多施設共同第Ⅱ相試験（JSCT研究会, UMIN試験ID: UMIN000014408）

・登録症例数：77例 (2014/08 ‒ 2016/02)

・観察期間中央値: 740.5日 (365-1247)

・主要評価項目移植後1年時点での無イベント生存率（EFS）

・副次評価項目移植後100日、移植後1年、移植後2年時点での生着達成割合、急性GVHD、慢性GVHD、再発率、全生存率、無病生存率など

Methods

day -6 -5 -4 -3 -2 -1 0 5 10 20 30 40 50 60 180


TBI (4 Gy)

PBSCT

G-CSF

MMF

Tacrolimusiv BU (3.2 mg/kg/day)

移植前のCYを削除し、TBIを2Gyから4Gyに増量Haplo13からの変更点

Conditioning regimen & GVHD prophylaxisBU based regimen

Results

Patient characteristicsAge at transplant

Median (range), years17-5050-65

58(22-65)26 (34%)51 (66%)

Sex, no (%)

MaleFemale

48 (62%)29 (38%)

Diagnosis

AMLALLMDS/MPNLymphomaOthers

34 (44%)14 (18%)12 (16%)14 (18%)3 ( 4%)

Disease status

CR1CR2-Not in remission

17 (22%)15 (20%)45 (58%)

refined DRI

lowintermediatehigh

very high

3 ( 4%)22 (29%)25 (33%)

27 (35%)

HCT-CI, no (%)

01-2≥3

43 (59%)24 (31%)10 (13%)

History of prior allo-SCT, no(%)

NoYes

47 (61%)30 (39%)

44

Donor and graft characteristicsHLA match, no.(%)(GVH direction)

4/85/86/87/8

(HVG direction)4/85/86/87/8

33 (43%)33 (43%)10 (13%)

1 (1%)

38 (49%)27 (35%)11 (14%)1 (1%)

Donor relationship, no (%)ParentSiblingChild

6 (8%)25 (33%)46 (60%)

D/R gender mismatch, no. (%)MatchFemale to MaleMale to Female

48 (62%)17 (22%)12 (16%)

D/R CMV serostatus, no.(%)D+R+D-R-D+R-D-R-NA

49 (71%)15 (22%)

4 (6%)1 (1%)8 (12%)

CD34 (x106/kg) of PBSCsmedian (range)<4.0≥4.0

4.2(1.4-11.1)33 (43%)44 (57%)

0 1 2 3 4 5 6 736

37

38

39

40

41

Tem

pera

ture

ºC)


77例中72例(94%)で38ºC以上の非感染性発熱Cytokine release syndrome (CRS)

PTCY

EngraftmentNeutrophil engraftment

median day 37median day 18

94%

74%

Platelet engraftment

GVHDacute GVHD chronic GVHD

II-IV 14%III-IV 5%

all grade 27%moderate to severe 20%

NRM�RelapseNRM Relapse

20%

45%

Overall survival

1yr OS 52% (95%CI, 40-62%)

2yr OS 44% (95%CI, 33-55%)

45

Event-free survival

2yr EFS 35% (95%CI, 25-46%)

Primary endpoint1yr EFS 43% (95%CI 32%-54%)

Cause of death Relapse 28 (65%)

Non-relapse mortality (NRM) 15 (35%)Infection 6Graft failure 3Graft-versus-host disease (GVHD) 2Sinusoidal obstruction syndrome (SOS) 1Acute Respiratory Distress Syndrome (ARDS) 1Interstitial pneumonia 1Multiple organ failure (MOF) 1

Rates of off-immunosuppressants

56% at 1yr

86% at 2yr

In patients who survived at last follow-up without relapse (n=27)

History of prior allo-SCT NRM Relapse

No (n=47) Yes (n=30)

No: 22%

Yes: 16%P=0.67 P=0.01

No: 35%

Yes: 62%

History of prior allo-SCT OS EFS

No: 52%

Yes: 31%

P=0.04

No: 44%

Yes: 21%

P=0.02

No (n=47) Yes (n=30)

refined DRI NRM stratified by DRI Relapse stratified by DRI

high/very high: 21%

low/int: 17%P=0.51

low/int: 25%

high/very high: 55%

P=0.02

low/int (n=25) high/very high (n=52)

46

refined DRI OS stratified by DRI EFS stratified by DRI

low/int (n=25) high/very high (n=52)

low/int: 67%

high/very high: 33%

P<0.01

low/int: 59%

high/very high: 24%

P<0.01

1stSCT+ low/in (n=19)62%

≥2ndCT+ low/in (n=6)83%

1stSCT+ high/very high (n=28)46%

2ndSCT+ high/very high (n=24)15%

OS stratified by DRI and number of allo-SCT

Overall survivalHR (95%CI) P-value

Event-free suvivalHR (95%CI) P-value


11.76 (0.87-3.56) P=0.12

11.82 (0.95-3.49) P=0.07


12.82 (1.33-6.00) P<0.01

12.67 (1.35-5.36) P<0.01


12.22 (1.13-4.38) P=0.02

12.27 (1.21-4.25) P=0.01

Multivaliate analysis a��,��+0`.MR;68EHLA �:!$;�492%�X1�EFSb43%(95%CI: 32%-54%)UL\J@�QRF�UL]25%`��SRK

aGVHD1/-JG1)�-Y�<BIUL]Haplo13V�'WJ�WA�UP]5#ULSRV7N]K

a��D>"UYrefined DRIJ�32%(OJOSJEFSW�H`�N]��ULSRK�<QT<_^RHaplo14 MACVX*C`�ZJ��Y[\� �UX&?O�=UL]K

Conclusion

北海道大学病院血液内科札幌医科大学附属病院第一内科札幌医科大学附属病院腫瘍･血液内科北楡会札幌北楡病院血液内科市立旭川病院血液内科秋田大学医学部附属病院輸血部･血液内科仙台医療センター血液内科宮城県立がんセンター血液内科東北大学病院血液･免疫科山形県立中央病院血液内科福島県立医科大学附属病院血液内科新潟大学医歯学総合病院高密度無菌治療部長岡赤十字病院血液内科長野赤十字病院血液内科信州大学医学部附属病院血液内科群馬県済生会前橋病院白血病治療センター獨協医科大学病院血液･腫瘍内科東京医科大学病院血液内科慶應義塾大学医学部小児科東京女子医科大学病院血液内科東京医療センター血液内科東京慈恵会医科大学病院腫瘍･血液内科NTT東日本関東病院血液内科虎の門病院血液内科がん･感染症C 都立駒込病院血液内科防衛医科大学校病院血液内科千葉大学医学部附属病院血液内科虎の門病院分院血液内科横浜市立大学附属市民総合医療C 血液内科神奈川県立がんセンター血液科

東海大学医学部付属病院血液腫瘍内科亀田総合病院血液･腫瘍内科成田赤十字病院血液腫瘍科埼玉医科大学総合医療センター血液内科名古屋第一赤十字病院血液内科名古屋大学医学部附属病院血液内科名古屋市立大学病院血液･膠原病内科浜松医療センター血液内科愛知医科大学病院血液内科岐阜大学医学部附属病院血液･感染症内科岐阜市民病院血液内科江南厚生病院血液･腫瘍内科三重大学医学部附属病院血液･腫瘍内科伊勢赤十字病院血液･感染症内科田附興風会医学研究所北野病院血液内科近畿大学医学部附属病院血液･膠原病内科高槻赤十字病院血液腫瘍内科和歌山県立医科大学附属病院血液内科天理よろづ相談所病院血液内科京都第二赤十字病院血液内科京都府立医科大学附属病院血液内科石川県立中央病院血液内科金沢大学附属病院血液内科富山県立中央病院血液内科神戸市立医療C中央市民病院免疫･血液内科先端医療センター病院細胞治療科神戸大学医学部附属病院腫瘍･血液内科山口大学医学部附属病院第三内科公立学校共済組合中国中央病院血液内科島根大学医学部附属病院腫瘍･血液内科

米子医療センター血液腫瘍科岡山大学病院血液･腫瘍内科川崎医科大学附属病院血液内科香川大学医学部附属病院血液内科徳島赤十字病院血液科徳島大学病院血液内科高知大学医学部附属病院血液内科松山赤十字病院内科愛媛県立中央病院血液内科愛媛大学病院第一内科原三信病院血液内科九州がんセンター血液内科九州大学病院血液･腫瘍内科浜の町病院血液内科九州医療センター血液内科JCHO 九州病院血液･腫瘍内科久留米大学病院血液･腫瘍内科聖マリア病院血液内科佐賀県医療センター好生館血液内科佐賀大学医学部附属病院血液･腫瘍内科佐世保市立総合病院血液内科長崎医療センター血液内科長崎大学病院血液内科熊本医療センター血液内科熊本大学医学部附属病院血液内科大分県立病院血液内科大分大学医学部附属病院血液内科宮崎県立宮崎病院血液科今村病院分院血液内科鹿児島大学病院血液･膠原病内科

Haplo14 参加施設



Acknowledgement

Japan Agency for Medical Research and Development(AMED, JP17ek0510012)

47

AML J J

J

Prognostic factor of AML and the efficacy of allo-HSCT in Hokkaido Leukemia Net

( )

1 1

1 1 1(

1) 1 1

1 1 S 1

1 1 1

4 5 3 J 14 9 H “ (HLN)”

J 7 2

4 5FLT3-ITD NPM1 CEBPA c-kit AML 315

2

4 5 180 135 2 17-89 57 2

0.1-113.7 15.4 2

107 34.0% 11 6 2 J 3 OS 47.4%

57.6% 6 2NCCN J 107

111 96 3 OS 67.4% 44.3% 29.7%

6 p 0.001 2 87 J OS J

H 8 J OS 2

4 5NCCN J J OS

6 2

48

8ÕĐõfÝìÔ��œĻĿţAMLŔ�k�ĦŔ�¾rƐ(®ēÇõÃŻŸŹŔÄ�ù�ŦďńŎƐ

�Ī FĊ1ƌTę· Ëj1ƌ£4 ±�1ƌÙ0 èd1ƌQ� Ê1ƌô· Ë�2ƌ

�X ¥�3ƌG¿ Ò�4ƌW� é5ƌ�� iL6ƌQ>Z |7ƌ@ Ą8ƌ

ĝăW ä�9ƌÍ0 �ē10ƌī· ��11ƌT� �12ƌY\ .13ƌ

ª] Ć.14ƌė� ?15ƌ²© #2ƌčô �1ƌĄ] [m1

1 (®ēFMÃĠ õ¯�Ó

2 (®ēFMÃĠ ��ċõĖ

3 vêÃĠ õ¯�Ó

4 �c( ÃĠ õ¯�Ó

5 _Ø�cÃĠ õ¯�Ó

6 _Ø�^ÃĠ õ¯�Ó

7 ěĈ%¸ÃĠ �Ó

8 _Ø�ħÃĠ õ¯�Ó

9 �,ÃĠ õ¯�Ó

10 &)+�HÃĠ õ¯�Ó

11 (®ēĽŧŴƆŶƈ õ¯�Ó

12 `g/½ÃĠ õ¯�Ó

13�c/½ÃĠ õ¯�Ó

14 (øć*JÃĠ �Ó

15 yÖ´��ÃĠ õ¯�Ó

(®ēÇõÃŻŸŹ

ē�Ŕ6�ýļš ÅÇõÃŔ��ŦĤŝŎĔ�Iù�ŦöŋŎĸţƍ

ÉÈ

• �Ģ�Sp��SpœŠţOïhŗŔĕ�

• ÂsƄŲųŹƂŔ¡Û

(®ēFMÃĠ

8u3lı ��ƉFax, E-mail)

Flt3−ITD,WT1á�A:Ɖ1đĞıE-mailƊ

Ä�tAA:��Ɖblast%,G-bandá�,E-mailƊ

1$�ý

��(EDTAÚ 2ml

�� 2ml)

Ìzĸŏ)Uŗ→��Pŗ��~�

<AML>

¥b�=AML→NPM1,CEBPAt(8;21),inv16→c-kit

<ALL>

IKZF1del�MRD�ÜƉ1-2đĞıE-mailƊ

õ¯�ÓÎ×PœŎ

��

MRDſƈŬƈĽķţB7ŽūƅƈůƆžƃĻŠŖÄ�àĒA:��

ë�

• Flt3-ITDŒőŔĔ�IÁbŦ9ŜƂųŭ�ĦĽNCCN(National

ComprehensiveCancerNetwork)şELN(EuropeanLeukemiaNet)

ļšA:łŤŎĻŢƌ�k�µœ�¾ŏķţƍ

• ŃļŃƌ8ÕÔ��œĻĸŎĔ�IÁbŦ9ŜƂųŭ�ĦĽ¤íŅţļŕ*�œ�ûłŤŎĸŒĸƍ

O’Donnel etal.JNatlCompr Canc Netw 2017;15:926-957

Dohner etal.Blood.2017;129(4):424-447

(®ēÇõÃŻŸŹŔÄ�ŦNCCNŔ�ĦŏV!'Ń�kŦ�ûŃŉƍ

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• 2007e10�ļš2017e5�Śŏœþ�łŤƌ(®ēÇõÃŻŸŹœÆĜłŤŉ ÅAML315�ŦSąœk�}�ù�Ŧöŋŉƍ

• 2017e5�ŚŏŔàĒ�œ8ÕÔ�ĽöťŤŉÄ�ŦĳÔ�åĴƌöťŤŒļŋŉÄ�ŦĳĥÔ�åĴŐŃŉƍ

• OverallSurvivalƉOSƊŕþ�ļš§ķţĸŕ�ÞŽūƅƈũŸžŚŏŔ�ĞŐŃƌŇŔüĎŕKaplan-Meier¬ƌåĞŔ¨ĉŕLogrank�NŦ¾ĸŉƍEDĚù�ŦCox¨�żŰƈź;a¬Ŧ¾ĸŎöŋŉƍâúŵŽŹŕEZR(ð«)ÓFM)Ŧ¾ĸŉƍ

NCCNGuidelinesVersion3.2017qrĨĩrÇõÃ

�ÿ³śŔÝìĔ�MÈxøĻŠŖ�IÁbœ?ōľƂųŭ�Ħ

İįĮĭDÁ

Ƌ�IÁbĽ��ŔÄ�ŕÝìĔ�MÈxøŔśŏ�ĦŃŉƋ TP53DÁŕ��û

49

sçë�

�sç(N=313)

Ô�å(N=107)

ĥÔ�å(N=206) p-valueƋ

eĬ�H� 56(17-89) 46.5(17-69) 63(18-89) <0.001

Àr 179 (57.2%) 60 (56.1%) 119(57.8%) 0.810

¥b�= 131(41.9%) 50(46.7%) 81(38.9%) 0.228

t(8;21) 40(12.8%) 16(15.0%) 24(11.5%) 0.476

inv(16) 25(8.0%) 5(4.7%) 20(9.6%) 0.131

t(15;17) 27(8.6%) 2(1.9%) 25(12.0%) 0.001

�k�ò�ó� 42(13.4%) 14(13.1%) 28(13.6%) 1.000

NCCNrisk

favorable 112(35.8%) 26(24.3%) 86(41.7%) 0.003

intermediate 119(38.0%) 47(43.9%) 72(35.0%) 0.141

poor 82(26.2%) 34(31.8%) 48(23.3%) 0.136

Ƌ Fisher¥Ð�N

Ĕ�IÁbžƅŽŨŪƃ

Ǝ¥b�=Ə

�sç(N=131)

Ô�å(N=50)


Flt3-ITDģr 39 (29.8%) 20(40.0%) 19(23.5%) 0.051

Flt3-ITDġrļŌNPM1DÁģr

16(12.2%) 2(4.0%) 14 (17.3%) 0.028

Flt3-ITDġrļŌCEBPA�ĘDÁģr

17(13.0%) 7(14.0%) 10(12.3%) 0.794

ƎCBFÇõÃƏ

�sç(N=65)

Ô�å(N=21)


c-kitDÁģr 11 (16.9%) 6(28.6%) 5(11.4%) 0.154

Ƌ Fisher¥Ð�N

8ÕÔ��Ŕ¹n ( ;Ô�œŌĸŎ)

Ô��eĬ

50¦ � 41(38.3%)

50¦�¶ 66(61.7%)

"�ã

ĨĩÏCÈ 56 (52.3%)

ĥĨĩÏCÈ 51(47.7%)

Ô�ŵƈų

Ĩĩ 53(49.5%)

��õ 29(27.1%)

î`õ 25(23.4%)

Ô��Ã�

CR 74(69.2%)

non-CR 29(27.1%)

ÅÄkàĒƉeƊ

p=0.0485

favorable

intermediate

poor

NCCNŔƂųŭ�ĦœŠţ OS

ĥÔ�åÔ�å

½K¼

p<0.0001

ÅÄkàĒƉeƊ

favorable

intermediate

poor

Ô�åŏŕ “poor risk”ļőĹļĽĘ÷

ÅÄkàĒƉeƊ

p=0.696

intermediate(ć)

NCCNŔƂųŭ�ĦœŠţ OS

Ô�åƉ�ó�ÁbŔśŏ�ĦƊ

½K¼

NCCNpoor

�k�ò�ó� (+)

ÅÄkàĒƉeƊ

¥b�=Flt3-ITD(+)p=0.345

favorable(ī)

poor

�ó�ÁbŊĿŏŕ�*�ƍFlt3-ITDŒőŔĔ�IÁbŔ�ÜĽo÷

ÅÄkàĒƉeƊ

p=0.0235

CR

non-CR

p=0.0062

ÅÄkàĒƉeƊ

½K¼

50¦ �

50¦�¶

eĬ Ô��Ã�

Ô�åœĻĿţ�Ŕ�k<IœŌĸŎ

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p=0.993

PB

BM

CB

p=0.558

ÅÄkàĒƉeƊ

½K¼

RIC

MAC

Ô�"�ã Ô�ŵƈų

Ô�åœĻĿţ�Ŕ�k<IœŌĸŎ

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Hazard ratio(95%CI) p-value Hazardratio(95% CI) p-value

50¦ �(v.s.50¦�¶)

2.26(1.24-4.13) 0.008 1.97(1.07-3.63) 0.030

Ô�� non-CR

(v.s.CR)2.00(1.09-3.69) 0.026 1.94(1.05-3.57) 0.034

NCCNriskpoor

(v.s.notpoor)2.14 (1.15-3.96) 0.016 1.92(1.02-3.62) 0.042

OSœSŅţ-DĚƇEDĚù�Ɖ8ÕÔ��ŔśƊ

æR

• Ô�åœĻĸŎƌfavorableŐintermediateĽŘřĘŒţá�ŐŒŋŉƍfavorableÄ�œĻĸŎŞƌDNAƀŷƃ'şųžƁŪűƆŮœğťţĔ�

IÁbĽ�k�ò<IŐŃŎ{�łŤŎĻŢƌŀŤšŦ�ŅţŠĹŒÄ�Ľ8ÕÔ�Ŧo÷ŐŃŉ5írĽķţƍ

Hemmati etal.Eur JHaematol 2016;98:160-168

Stricklandetal.Leuk Res2018;65:67-73

• ELNŔƂųŭ�ĦŦ8ÕÔ�sç

œĻĸŎ�ûŃŉA:œĻĸŎŞƌ�Ş�k�òŐłŤţ “Adverse”

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• NCCNpoorrisk,Ô��eĬşÃ�ĽŇŤňŤ»ØŃŉ�k�ò<Iŏķŋŉƍ

• Ĕ�IÁbŦ9ŜÂsƂųŭŐÔ��ŔºwŦßś7ťņŉ�ŉŒƂųŭ�ĦĽĘ÷ŐæĺšŤƌłšŒţ�ûĽo÷ŏķţƍ

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