2018.3.29.

Catholic Hematology Hospital

The Catholic University of Korea

Kim, Yoo-Jin, MD, PhD

Hypomethylating Therapy in Stem Cell Transplantation

for MDS

대한혈액학회 Korean Society of Hematology

COI disclosure

Name of author ： Yoo-Jin Kim

I currently have, or I have had in the past two years, an affiliation or financial

interest with business corporation(s):

(1) Consulting fees, patent royalties, licensing fees ： No

(2) Research fundings： Yes,

Celgene, Janssen, Sanofi-Aventis

(3) Others No

Overview 1

Possible roles of HMA in transplant settings

Pre-transplant bridging therapy Post-transplant maintenance therapy

GVL effects GVHD control Separation of GVL effects and GVHD

Overview 1

2 HMA Before HSCT

-Practical issues in clinics -Disease stabilization or tumor reduction -Efficacy in poor cytogenetic risk group -Lower toxicity profile -Delayed response and lower CR rate

-Questions -Do HMA affect transplant outcomes? -Who may benefit from bridging therapy? -Optimal time to proceed to HSCT during HMT?

BBMT

2012;18:1211

BMT

2010; 45: 255

Lee Moffitt cancer center

AZA vs no treatment

HMA treatment prior to HSCT seemed to be a feasible option.

No harm by pre-transplant HMT

AZA vs induction chemotherapy

Fred Hutchinson CRC

J Clin Oncol

2012;30:4533

French study

Influences of HMT response upon transplant outcomes

Catholic BMT Center

56 consecutive patients receiving HSCT (2006-2010) following HMA

Median 4 cycles (range, 1-13) of HMA (49 AZA, 4 DAC, 3 both)

Conventional donors 45, alternative donors 11

Response to pre-transplant HMA seems to affect transplant outcomes.

Yahng et al. Eur J Haematol 2013;90:111

INT-2/high (n=39) at HMA INT-1 (n=17) at HMA

Suggestions and questions

1. Poor transplant outcomes in patients with disease progression

2. Needs for differential approach according to risk groups

3. Influences of marrow CR in higher risk group?

Better transplant outcome with pre-transplant marrow response after hypomethylating treatment in higher-risk MDS with excess blasts

Yahng et al. Oncotarget 2017;8:12342

Marrow response was identified to be a predictor of DFS.

• Presence of PB blast was a predictor of HMT response.

1. Transplant outcomes could be affected by the response type following

HMA.

2. Disease progression during HMA showed poor transplant outcomes, while

marrow response was an independent favorable predictor for 4 major

outcomes in patients with EB.

3. By identifying predictive factors for marrow response, selection of

bridging therapy could be individualized.

Overview 1

2

3 HMA After HSCT

HMA Before HSCT

-Salvage treatment -Preemptive treatment -Immune modulatory or stimulatory effects

Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial

Leukemia 2012; 26: 381

- Preemptive AZA for imminent relapse (CD34 chimerism <80%)

- AZA (75mg/m2/day for 7 days) while in CHR

- Response: 80% (increasing CD34 50%, stabilization 30%)

- Delayed relapse with a median of 231 days (range, 56–558)

Azacitidine and DLI as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation (AZARELA trial)

Leukemia 2013; 27: 1229

Overall response rate: 30% (CR 23%, PR 7%).

Best response: 79 days & 3 cycles

aGVHD: 37%)

Model-based adaptive phase I trial design of post-transplant decitabine maintenance in myelodysplastic syndrome (PODAC study)

Screening for enrollment

SCT for HR-MDS or MDS/AML

Screening for eligibility to receive

Decitabine (staring at D42-90 every 4 weeks)

To find optimal dose and maximum schedule within 12 cycles

Individual dose titration Cohort dose titration

Cohort

2

(n=3)

Modeling and simulation to avoid grade 4 toxicities of

neutrophil and platelet

Cohort

3

(n=3)

Cohort

4~

(n=3)

Clinical observation and exploratory evaluations

Cohort 1

5mg/BSA

5days

Every 28d

(n=3)

Han S et al. J Hematol Oncol. 2015;8:118

• 5 mg/m2/day is considered to be the most appropriate starting dose for the regimen studied.

• 6 weeks interval could be better. • Chronic GVHD: none 10, mild 6, moderate 3 • 10 of 19 completed 12 cycles and 12 patients are still

alive.

Maintenance Therapy with Decitabine after Allogeneic Stem Cell Transplantation

for Acute Myelogenous Leukemia and Myelodysplastic Syndrome

Biol Blood Marrow Transplant. 2015;21:1761

• Washington University School of Medicine • 5 MDS & 17 AML • Decitabine: +50~+100 days, 5 day schedules every 6 week for a maximum 8 cycles • The primary goal was to determine the maximum tolerated dose (MTD) of decitabine,

defined as the maximum dose at which < 25% of patients experience DLT during the first cycle of treatment. DLT was defined as (1) ANC < 500/μL and/or platelet count < 30,000/ μL sustained for 2 consecutive weeks without platelet transfusions, (2) inability to achieve ANC ≥ 1000/ μL and platelet count ≥ 50,000/ μL after a delay of the second cycle by a maximum 2 weeks, or (3) grade 3 and 4 nonhematological toxicities related to decitabine.

5mg/m2 7.5mg/m2 10mg/m2 15mg/m2

Maintenance Therapy With Low-Dose Azacitidine After Allogeneic Hematopoietic Stem Cell Transplantation for Recurrent Acute

Myelogenous Leukemia or Myelodysplastic Syndrome

• MD Anderson Cancer Center

• AML or high-risk MDS(INT-2/High), aged 18 to 75 years, not in

first CR (CR1), not candidates for myeloablative regimen

• FluBuMylotarg ± ATG

• AZA dose/schedule finding study

– CR at D30 without G3/4 acute GVHD

– 5 dose (8, 16, 24, 32, or 40mg/m2) level for 5 days, every 6 wks up to 4 cycles

– Bayesian method

– Discontinuation: G3/4 non-hematological toxicities

PLT<10K, ANC 500 not responding to G-CSF

Cancer 2010;116:5420

Azacitidine 32 mg/m2 daily for 5 days in each of 4 cycles every 30 days is associated with acceptable toxicities when given after HSCT. This treatment may prolong EFS and OS, and more cycles may be associated with

greater benefit. The probability of developing chronic GVHD decreased significantly with the

number of azacitidine cycles, but was unaffected by dose.

Salvage therapy with azacitidine increases regulatory T cells in peripheral blood of patients with AML or MDS and early relapse

after allogeneic blood stem cell transplantation

Leukemia 2013;27:1910

Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML)

Blood 2012;119:3361

Upregulation of HLA-I by DEC

Clin Cancer Res 2007;13:3333

Induction of CTA by DEC

Blood 2003;101:4644

Cancer Immunol Immunother 2010;59:697

Tumor infiltrating CD11b cells

to differentiate into mature APCs by DEC

HMA, a sensitizer of donor lymphocyte infusion?

Experimental hematology 2011;39:1056

Immunostimulatory effects of HMA

Activation of DC by AZA

Decitabine and DLI

Mouse BMT model mimicking early relapse in mixed chemirism

A

B C BDF1 (H-2b/d)

C57BL/6 (H-2b) C57BL/6 (H-2b)

P815

1x106 (s.c)

D8

Vehicle or DAC

D9 D13 D14

BM cell : 1x107 (i.v)

D0

400 cGy

E D

*

Liver Skin Intestine

DLI only

DEC 0.1 + DLI

DEC 1.0 + DLI

**

CD3

CD4

CD8

CFSE

Vehicle DEC 1mg/kg DEC 0.1mg/kg

CD28

IFN-γ

Rag1

Control

DE

C 1

mg/k

g

**

IFN-γ

Mixed lymphocyte reaction using splenic DC

Genes involved in DC activation and maturation

CD28

C57BL/6 (H-2b) C57BL/6 (H-2b)

P815

1x106 (s.c)

D8

Vehicle or DAC

D9 D13 D14 D21

BM cell : 1x107 (i.v)

D0

400 cGy

• DEC-induced DC activation could be associated with GHVD aggravation. • Timing of DLI following DEC could be adjusted based on the activational

status of DC and INF-γ level may be a guide.

Overview 1

2

3 HMA After HSCT

HMA Before HSCT

Summary 4

- Influences of HMT response pattern on transplant outcomes could differ according to disease risk.

- Achievement of marrow response was a favorable predictor in patients having excess BM blasts.

- Predictive factors for marrow response should be identified for the selection of optimal bridging treatment option.

- HMA induced DC activation and might have potential to separate GVL effects from unwanted GVHD.