conditioning regimen for haplo transplant

05/01/2023 B.S. Andersson

Optimized Induction in Haplos; MAC vs RIC

AUBHO 2015August 28-29, 2015

Borje S. Andersson, MD, Ph.D.Molecular Pharmacology and Translat.

Drug Development Program,Department of Stem Cell Transplantation

UT MD Anderson Cancer Center.


Myeloablative vs Non-Myeloablative (RIC) Conditioning Regimens

Dose Intensity

FC± RBEAM +/-R2-5

5-10

MF

Non-Ablative RIC

Oral Bu/Cy2, -4>10

TBI/± Cy/ ± F /± TT /± VP16

Oral Bu8/F/± ATG

Ablative

TBI 2GyCyThymicXRT/TLI

100

Day

s , T

RM

%

FlagIda Flu- IV Bu -2, -3 Clo-+/Flu - IV Bu4

Gen. Trend


What have we learned?

1. Engraftment rate improves with intensive conditioning2. Disease control improves with intensive conditioning3. TRM not necessarily directly related to the intensity of

the conditioning – GFs contribute to TRM. 4. Rational use of mechanistic cytotoxicity information at

the molecular level can be used to design improved conditioning therapy.

Author Conditioning Graft GF (%) TRM (%) EFS (%)

Raiola TT-Bu-Flu BM 4 18 68/37(n=50) Flu-TBI-10Gy

Bashey Cy-Flu-Bu or BM/PBSC n/a 4 60(n=53) Flu-Cy-TBI-2Gy

Ciurea TT-Mel-Flu BM 6 16 50(n=32)

Luznik Flu-Cy-TBI-2Gy BM 13 15 26(n=68) (2 Yrs.)

Wang Ara-C-Bu-Cy- BM/PBSC 1 18 ~60(n=756) MeCCNU (3 Yrs.) (5 Yrs.)

Haplo-Identical SCT for (mainly) Hematological Malignancies


General Problems with highly HLA-disparate grafts, aka Haplos

1. Treatment- /Regimen-Related Toxicity (“TRM”)2. Graft failure3. Recurrent Disease

Busulfan - Cyclophosphamide Metabolic Interactions

GSTM1

CYP2B6CYP2C9

Sulfolane

CYPsFMO?

-3 -2 -1-4-6 -5 +14 +21 +100 >1800

Graft

Conditioning

Supportive Care

GVHD prophylaxis and therapy

Patient(age, gender, CMV, comorbidities…)

12

3 5

6

4

DiseaseFeatures

Malignant vs.“Non-Malignant”

How to (Optimize Conditioning to) Improve outcome?

1. Nucleoside Analogs (NA) do not utilize CYP450 or GSH/GST-conjugation in their metabolism.

2. Further, when the NA (e.g. fludarabine) is properly time-sequenced with IV busulfan, the conditioning reliably facilitates engraftment of MRD and MUD BM and PBPC grafts in (adult) recipients.

3. NAs and AAs (here, Busulfan) kill primarily by induction of apoptosis and terminal differentiation.

De Lima M., et al. Blood. 2004; 104(3):857-64.

NAs cause histone modifications; enhanced with an alkylator

Valdez et al. Biochem Pharmacol. 2011 Jan 15;81(2):222-32


[Clof+Flu+Bu] combo activates DNA damage response through the ATM-CHK2 pathway in AML cell line

P -ATM (Ser1981)

ATM

γ -H2AX

P -SMC1(Ser957)

P -CHK2 (Ser33/35)

β -ACTIN

P -ATM (Ser1981)

ATM

-H2AX

P -SMC1(Ser957)

P -CHK2 (Ser33/35)

-ACTIN

P -ATM (Ser1981)

ATM

γ -H2AX

P -SMC1(Ser957)

P -CHK2 (Ser33/35)

β -ACTIN

P -ATM (Ser1981)

ATM

-H2AX

P -SMC1(Ser957)

P -CHK2 (Ser33/35)

-ACTIN

Suggested mechanism of synergisticcytotoxicity of NAs and AAs

Valdez & Andersson. Environ Mol Mutagen. 2010; 51:659-668.

Histone modificns

Chromatin remodelingDNA cross-

linking

DNA damage

Loop of death

DNA alkylating agents (AAs)

DNA synthesis/repair

Nucleoside analogues (NAs)

Apoptosis


Optimized Conditioning, (Haplos).

RIC or MAC ???


Normal OrganToxicity

Tumor Load; PK-Guided, Individualized / Standardized Therapy Should Improve Treatment Outcome.

“Therapeutic Windows”

Num

ber

of p

atie

nts

Blue: Fixed-DosingGreen: PK-Guided Dosing in high-risk patients - MAC.Orange: PK-guided dosing - RIC

Leukemia ProgressionCR Pats

aGVHD

Leukemia Progression “Refr. Pats.”

Systemic Drug Exposure

“Safe Upper Limit”, Syst.Exposure

0 10 20 30 40 50 60 70 80

Months Post Transplant

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0C

umul

ativ

e P

ropo

rtion

Sur

vivi

ng P

rogr

essi

on F

ree Active Disease at Transplant

Adjusted, N=40

Fixed, N=46

P 0.03

Progression-Free Survival, Active Dx - Patients

0 10 20 30 40 50 60 70 80

Months Post Transplant

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cum

ulat

ive

Pro

porti

on S

urvi

ving

Pro

gres

sion

Fre

e

Adjusted, N=71

Fixed, N=68

P 0.4Remission at Transplant

Progression-Free Survival, CR- Patients


Successful Conditioning includes several components:

1. Killing malignant cells2. A. Killing cell populations that are mediate (acute)

graft rejection (T-cells and other) , B. Killing immature, progenitor/stem cells that can mediate regeneration of ancillary immuno-competent cells that mediate secondary graft failure.

3. Removal of reproductively dead, yet still functional cell subpopulations that mediate rejection


Normal Organ

ToxicityNum

ber

of p

atie

nts

Blue: Fixed-DosingGreen: PK-Guided Dosing, high-risk patients.

aGVHD


Leukemia Pats. Immunosuppressed

Hemglobinopathies/ e.g. Thalassemia Immunocompetent Pat.

“Immuno-ablative Therapeutic Interval”


SCID


Optimizing Pretransplant Conditioning.

We suggest, that one should pay close attention to:

1. Time-Sequence of the drugs in the conditioning program,

2. Consider adding either (a) cytotoxic agent(s) that provide a radiomimetic, “interphase-death-inducing”, effect on the T-cells, such as Thiotepa, low-dose TBI, or

3. use of “early” ATG to eliminate mature host T-cells.


“Genetic Diseases and Haplo Tx” !(Hemoglobinopathies)

- Intact, (hyper-) active immune system- Iron overload/subclinical organ failure- “Benign hemoglobinopathy”

-3 -2 -1-4-6 -5 +14 +21 +100 >1800

Graft

Conditioning



12

3 5

6

4

Diseasefeatures

Hypothesis: Personalized Conditioning Improves outcome !


Optimizing Pretransplant Conditioning Therapy.

We suggest, that one should pay close attention to:

1. Time-Sequence of the drugs in the conditioning program,

2. Consider adding either (a) cytotoxic agent(s) that provide a radiomimetic, “interphase-death-inducing”, effect on the T-cells, such as Thiotepa, low-dose TBI, or

3. use of “early” ATG to eliminate mature host T-cells.4. To further promote engraftment of highly HLA-

disparate grafts (“haplos”) consider using pharmacological Pretransplant ImmunoSuppression Therapy (“PTIS”) in the pre-conditioning phase.


Normal Organ

ToxicityNum

ber

of p

atie

nts

Blue: Fixed-DosingGreen: PK-Guided Dosing, MAC.Orange: PK-guided dosing, RIC

aGVHD


Hemglobinopathies/ e.g. Thalassemia Immunocompetent Pat.

“Immuno-ablative Therapeutic Intervals”


Thalassemia After PTIS.


Thalassemia (Pre-) Transplant Platform

Day -56 -54 -52 -28 -26 -24 -21 -14 -12 -10 -8 -7 -6 -5 -4 -3 -2 -1 0 +3 +4

Modifying the Conditioning Platform


1 2 3,45

Flu - Bu ± ATG HSC Post Tx – Cy

Clinical Consideration Points

1. Pre – “PTIS” 2. + “Early ATG” alt. “Necrosis-inducing agent”3. PK-TDM new standard4. Post Tx Intervention, Post-Cy, demethylating agents, vaccines, etc.

Modifying the Platform, Post-Tx-Cyclophosphamide.

Platform Technology

Summary, RIC vs MAC/RTC

1. Malignant Disease, - Tumor Load: CR: RIC = MAC

Active Dx: RIC < MAC

- Engraftment: Consider pretreatment level of immunosuppression, need to modify?

2. Genetic Disease (hemoglobinopathy vs SCID):Immunol. active/hyperactive/suppressed: May need modified (pre-) conditioning to secure engraftment, otherwise RIC since no malignancy.

-3 -2 -1-4-6 -5 +14 +21 +100 >1800

Graft

Conditioning

Supportive Care



12

3 5

6

4

Diseasefeatures

Summary: Personalized Conditioning Improves outcome !


CollaboratorsUT MD Anderson

Clinical:EJ Shpall Roy Jones Yago Nieto Partow Kebriaei Muzaffar Qazilbash Chitra Hosing Laura Worth Dean Lee Richard Champlin Lab:Ben Valdez, Guiyun Wang Yan Liu Yang LiBiostatistics: Peter F. Thall

Ramathibodi Hospital, Bangkok, Thailand: Suradej Hongeng

Institut Paoli Calmette, Marseille, France: Didier Blaise

Karolinska Institute, Stockholm, Sweden: Moustapha Hassan

U Alberta, Calgary, AB, CA: James Russell


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