Hematopoietic Cell Transplantation (HCT) for MDS · 2019-08-19 · Hematopoietic Cell...
Transcript of Hematopoietic Cell Transplantation (HCT) for MDS · 2019-08-19 · Hematopoietic Cell...
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Hematopoietic Cell Transplantation (HCT) for MDS
H.Joachim DeegFred Hutchinson Cancer Research Center,
University of Washington, [email protected]
MDS Patient conference, August 10, 2019
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The only treatment with curative potential for MDS.
Considerable progress, but problems remain.
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Basics of HCT
• Objective: Cure the disease• Method:
– Condition the patient– Infuse healthy donor cells
• Problems:– Donor cells react against the patient’s body
(GVHD)– Long-term complications
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Conditioning
• Why?– Suppress the immune system– Kill disease cells
• Potential problems– “Systemic” effects and toxicity
• Important– Coordinate conditioning with other therapy given
before transplantation
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Condtioning Intensity, Toxicity and GVL Effect
BU+CY+TBI*BU+TBI*
CY + TBI*FLU + AraC
BU + CY (± ATG)CY + BU
BU + MelphalanFLU + Melphalan
FLU + TreosulfanFLU + BU (3.2-16)
tbi† + FLU (90-250)tbi†
Intensity
Toxi
city
Required Contribution of Allogeneic GVL Effect
*TBI at ≥12 Gy; †2 -3 - 4.5 Gy; HJ Deeg
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TumorTumor
Total Body Irradiation Radioimmunotherapy
J.Pagel
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α-particle
Range: 40-90 μM
LET 100keV/ μM
β-particle
Range: 400-7000 μM
LET 0.8 keV/ μM
Normal tissue
Vessels
Characteristics of β -, α - emittersAnti-CD45 antibodyAnti-CD45 antibody
J.Pagel
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Cell Donors
• HLA* matched– Full siblings– Unrelated volunteers (NMDP etc)
• HLA mismatched– HLA haploidentical family members– Unrelated volunteers
• Umbilical Cord blood (unrelated or related)
* HLA = Human Leukocyte Antigen
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Family HLA Study
Parents
Children
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Sources of stem cells
• Bone marrow• Blood, after “mobilization” of cells from the
marrow (with G-CSF)• Cord blood cells
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Engraftment
• Definition:– Donor cells have established themselves and
produce new cells in the patient
• How do you know?– Rise in neutrophil (poly/ ANC) count– Rise in platelets– Rise in red blood cells (later)
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Graft Failure
• Infrequent• Donor cells fail to get established in the
marrow– Primary – neutrophils never rise appropriately– Secondary - Cells initially rise, but then decline
again
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GVHD
• Donor cells contain/produce immune cells, which recognize the new environment (the patient) and “get turned on”.
• These cells then can attack and damage the patient ‘s body → GVHD
• GVHD can be acute, chronic or both
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Tomblyn M et al. BBMT 2009
GVHD often associated with Infections
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GVHD Prevention
• Eliminate donor T cells before infusion, in vitro (in the laboratory)
• Eliminate donor T cells/T cell effects afterinfusion, in vivo, by treating the patient
• CSP, Tacrolimus, MTX, Sirolimus, ATG• Cyclophosphamide
• Change the patient’s microbiome (Bacteria in the gut)
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Risk Factors and Results
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Risk Parameters (in MDS)
• IPSS-R• Co-morbidities
– HCT-CI– Age
• Mutations
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Survival by IPSS-R risk*:
*Since meeting risk criteria
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Comorbidity Score
Arrhythmia 1Cardiac 1Inflammatory bowel 1Diabetes 1Cerebro-vascular 1Depression/anxiety 1Hepatic-mild 1Morbid obesity 1Infection 1
Rheumatologic 2Peptic ulcer 2Renal-moderate/severe 2Pulmonary-moderate 2Prior Solid tumor 3Heart Valve disease 3Pulmonary-severe 3Hepatic-moderate/severe 3
The HCT-CI
M. S
orro
r et a
l
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Risk and Survival in non-transplanted patients:
K. Naqvi et al. JCO 2011
↑ IPSSAge ≥ 65↑ Comorbidity
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Bejar R et al. N Engl J Med 2011;364:2496
Mutations and Survival in MDS (N=439)
EZH2TP53RUNX1ASXL1ETV6CBLNRASIDH2
TET2IDH1KRASNPM1JAK2
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Candidate GenesTET2ASXL1RUNX1TP53EZH2NRASJAK2ETV6CBLIDH2NPM1IDH1KRASGNASPTPN11BRAFPTENCDKN2A
R. Bejar et al, NEJM, 2011
Mutations, karyotype and survival (no transplants)
Mutations Mutations and Cytogenetics
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How does all this impact Transplant Outcome?
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Transplant outcome by Transplant Risk
Della Porta et al., Blood, 2014
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IPSS-R plus Mutations
High risk mutations:IDH1,ASXL1,DNMT3A, CBL, TP53
H.A. Hou et al ,Blood Cancer Journal, 8:39, 2018
neg
pos
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Mutations and Outcome after Transplantation for MDS
Adjusted for blast %, conditioning regimen, HLA match and complex karyotype
Bejar et al, J Clin Onc 2014
Sur
viva
lR
elap
se/N
RM
TP53 mut
Rel.TP53 mut
Rel.TP53 wt
NRM
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Age and Transplant Outcome(various diagnoses andregimens, related or unrelated donors,
N=3,910)
Ch. Kyriakou et al, BBMT 24:86, 2019
Progression-free Survival
Overall Survival
18-50 ys51-65 ys
>65 ys
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Survival by gait speed
Michael A. Liu et al. Blood 2019;134:374-382©2019 by American Society of Hematology
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RIC in patients 60 – 70 ys of age(by IPSS risk)
Koreth J et al JCO 2013; 31: 2662
IPSS Low/Int-1
IPSS Int-2/High
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MRD by CYTO POS CYTO NEG
0,0
0,2
0,4
0,6
0,8
1,0
0 12 24 36 48 60 72 84 96 108 120 1320,0
0,2
0,4
0,6
0,8
1,0
0 12 24 36 48 60 72 84 96 108 120 132
LOW INTENSITY
HIGH INTENSITY HIGH INTENSITY
LOW INTENSITY
P< 0.0001p= 0.65
SUR
VIVA
L
0,0
0,2
0,4
0,6
0,8
1,0
0 12 24 36 48 60 72 84 96 108 120 132
Cumu
lative
Incid
ence
01
0,0
0,2
0,4
0,6
0,8
1,0
0 12 24 36 48 60 72 84 96 108 120 132
Cumu
lative
Incid
ence
01
LOW INTENSITY
HIGH INTENSITY
LOW INTENSITY
HIGH INTENSITY
REL
APSE
MRD and CONDITIONING Intensity(Patients in morphologic remission)
M. Festuccia et al, BBMT 2016
Typically used in older patients and withcomorbidities
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Conditioning Intensity and Survival
31
9.7% difference (95% CI: -0.9%, 20.3%) MAC vs RICP = .07 (18 months)
RIC 67.7%
0 6 123 9 15 18
1.0
0.8
0.6
0.4
0.2
0.0
Surv
ival
Pro
babi
lity
Months
MAC 77.4%
MAC 135 130 126 114 109 99 89RIC 137 129 117 102 96 89 82
Scott B. et al. J Clin Oncol. 2017;35:1154-1161
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D. Beelen et al, EBMT 2018
BU2/Flu vs Treosulfan/Flu
PFS
BU2/Flu
Treo/Flu
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HLA haploidentical HCT for MDS and AML with post-HCT CY
M. Slade et al, BBMT 23:1736, 2017
OS
Relapse
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Umbilical Cord Blood
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Cord Blood HCT(High intensity conditioning)
F.Milano et al NEJM 375: 944, 2016
CBT 71%
MURD 63%
MMURD 49%
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“Bridging” Treatment pre-Transplant?
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23.7%
21.5%
HR=1.12 (0.52-2.39) p=0.72
34.2%
56.6%
HR=2.1 (1.2-3.66) p<0.01
HR=1.88 (1.19-2.95) p<0.01
42%
22%
Post-HCT Outcomes after HMA Failure
M. Festuccia et al, BBMT 2017
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GVHD
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Acute and chronic GVHD with post-transplant CY
M. Mielcarek et al. Blood 27:1502, 2016©2016 by American Society of Hematology
Chronic
Chronic
Acute
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New Developments
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Intestinal Bacteria (microbiome) and GVHD
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Changing intestinal microbiota by fecal
transplants in patients
Kazuhiko Kakihana et al. Blood 2016;128:2083-2088
©2016 by American Society of Hematology
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Naïve T cell Depletion
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Selective TN depletion for GVHD reduction
No T cell depletion Complete T cell depletion Selective TN depletion
GVHD (TN)Pathogen-specific
T cells (TM)
GVHD GVHD
Immune reconstitution
Goal:
+
CD34+ stem cells
Immune reconstitutionImmune reconstitution
GVHD
M. Bleakley et. al JCI 2015
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TN-depleted HCT: Less/shorter treatment needed for GVHD
(Compared to T cell replete HCT, HLA = sibs conditioned with TBI-Cy, given Tacrolimus, MTX )M. Bleakley et. al JCI 2015
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Anti-CD117 antibody
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Summary
• Indications for Transplantation– Intermediate or higher risk MDS– Life threatening cytopenias– High risk mutations
• Relative contraindications– Comorbidities– Older age
• Choice of Conditioning Regimen– Based on underlying disease risk, stage and health of
patient
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Thanks to many colleagues – and our patients!