Clinical Updates in Use of Umbilical Cord Blood Treatments: Shifting the Paradigm in BMT Juliet Barker, MBBS Attending Physician & Director, CBT Program Adult Bone Marrow Transplant Service, MSKCC Professor of Medicine, Weill Cornell Medical College Co-chair, ASBMT CB SIG
Acknowledgements MSKCC Staff, NMDP, NYBC, HRSA University of Minnesota colleagues National & international CBT colleagues.
Disclosures Consultancy for Gamida, Angiocrine and NOHLA. Clinical trial funding by Angiocrine.
Current Landscape: Patient Triage Non-transplant therapy1 or autologous transplant2
Stem Cell Source: • HLA-identical sibling3 • 8/84 or 7/8 URD5 • Cord blood6 • Haplo-identical donor7
Conditioning High dose, midi, RIC, mini
-7
0
+28
Everyone has a donor
+100
+180
+1 year
Patient Factors: Older (up to ~75 years) & more co-morbidities.
New therapies to get to transplant or be combined with transplant. Increasingly complicated: 7 treatment alternatives. Impacts patient triage & urgency: this will impact transplant outcomes.
“Everyone has a donor� (nearly) but donor access remains complicated. Management needs to be further optimized.
African n=22 Middle Eastern (3%) n=8 (1%) White Hispanic n=29 (4%) Asian n=29 (4%)
European Mix n=166 (24%) Southern European n= 54 (8%)
Non-European Mix n=39 (6%) Northwest European n=188 (28%)
8/8 URD Transplants (n = 683)
8/8 URDs predominantly serve Europeans: major racial disparity in access. 2018 MSK analysis: disparity not improving. Eastern European n=148 (22%)
Non-European Mix n=12 (6%) Middle Eastern n=2 (1%)
Northwest European n=33 (17%)
7/8 URD Transplants (n = 193)
African n=23 (12%) White Hispanic n=20 (10%)
Eastern European n=27 (14%)
Asian n=11 (6%)
European Mix n=41 (21%)
Southern European n=24 (12%)
NonEuropeans more likely to get a mismatched URD.
Non-European Mix n=20 (7%) Middle Eastern n=11 (4%)
African n=56 (18%)
Northwest European n=22 (7%) Eastern European n=30 (10%)
CB Transplants (n = 301)
Southern European n=45 (15%)
White Hispanic n=29 (10%) Asian n=46 (15%)
European Mix n=42 (14%)
CB extends transplant access to all. Of African patients, 47% received CBT.
Non-European Mix n=4 (7%)
Northwest European n=1 (2%)
Southern European n=7 (13%) European Mix n= 2 (4%) Asian n=1 (2%)
White Hispanic n=8 (15%) African n=30, (57%)
No 7-8/8 URD or CB graft (n = 53) Majority of patients without 7-8/8 URD or CB grafts are nonEuropeanespecially African ancestry.
Q: Many pts will not have an 8/8 URDcan a matched URD be predicted at search initiation? A: Yes
A novel Search Prognosis patient categorization based on Haplogic can accurately predict 8/8 HLA-allele matched URD likelihood at search initiation. Poor, very poor, or futile searches can be rapidly recognized. Facilitates immediate pursuit of alternative grafts.
Q: Does everyone have a haplo-identical donor & CB graft? A: No.
CB graft availability by patient ancestry if no 8/8 URD (n = 89 patients evaluated). Ancestry (N, % of total patients) European (n = 38, 43%) African (n = 20, 22%) Other Non-European (n = 31, 35%)
N (%) of Group with Suitable CB Graft 36/38 (95%) 13/20 (65%) 27/31 (87%)
P Value 0.0127
Kosuri et al, BBMT 2017
Haplo graft availability* per patient ancestry if no 8/8 URD (n = 81 patients evaluated) Ancestry (N, % of total patients) European (n = 37, 46%) African (n = 16, 20%) Other Non-European (n = 28, 34%)
N (%) of Group with Suitable Haplo Graft 31/37 (84%) 7/16 (44%) 23/28 (82%)
P Value 0.008
Limitation: donor must be medically, socially & psychologically fit to donate. Also consider: Speed of donor clearance, delay if use extended family, possible limitations with children. * Minors not considered as donors but donors targeted by recipient DSA allowed.
Kosuri et al, BBMT 2017
Q: Does CB has availability advantage? A: Yes. Relevance: Urgent patients. Also CBT after myeloid CARs or new expansion technologies with enhanced GVL.
Slide courtesy of Dr M. Scaradavou, NCBP, NYBC.
2018 Donor Algorithm Suitable Matched SIB
Majority of pts
Evaluate for 8/8 URD
Very Good/ Good Search: 8/8 URD transplant Urgent
Fair Search
Poor/ V. Poor/ Futile Search
Pursue potential 8/8s & alternative donors.
Abandon 8/8 URD
Alternative Donors Cord Blood Rapid availability esp. if domestic
Haplo
MM URD
Can have availability limitations
Only need 8 allele typing
Q: Are the outcomes of adult CBT improving, & in some patients could CBT be the best type of transplant in hematologic malignancies? A: Yes
MSKCC Midi Prep: Cy 50/ Flu 150/ Thio 10/ TBI 400 + Double Unit CBT
• Adults < 65 years. • High risk heme malignancies.
-6
0
30
1 yr
CSA/ MMF (no ATG).
Politikos, ASBMT 2018
Cy/ Flu/ Thio/ TBI 400 Midi dCBT (n = 154)
Characteristic Median Age (range) Median Weight (range) Ancestry (%) European Non-European CMV seropositive (%) N (%) Diagnosis Acute leukemia* MDS/ MPD* Lymphoma (B-cell & HL) Median (range) HLA-match Median (range) CD34+ cell dose (infused 105/kg/unit) Supplement with haplo-CD34+ cells
Value 51 years (23-65) 79 kg (range 48-136) 74 (48%) 80 (52%) 90 (58%) 115 (75%) 24 (16%) 15 (10%) 5/8 (2-8) 1.1 (0.2-8.6) 58 (38%)
* â&#x2030;¤ 10% blasts pre-CBT
Politikos et al, ASBMT 2018
Midi Double Unit CBT (n = 154) Outcome Day 45 neutrophil engraftment
0.2
0.4
0.6
0.8
3 yr PFS: 66% (95%CI: 59-75)
0.0
Progression-free Survival (%)
1.0
(median survivor follow-up: 2.9 years)
0
6
12 18 24 Months from dCBT
30
Value 96%
Day 180 grade III-IV aGVHD
20%
3 yr cGVHD
9%
Day 180 TRM
11%
2 yr relapse
13%
36
Low TRM & low relapse & chronic GVHD rates.
Midi dCBT: 3-year PFS by aaHCT-CI (n = 154)
0.6
0.8
Day 180 TRM: 3% vs 16%
0.2
0.4
aaHCT-CI 3-9 (n = 95): 58% (49-70) (median score 4, range 3-9). Median age 53 yrs (25-66). P = 0.011
0.0
Progression-free Survival (%)
1.0
aaHCT-CI 0-2 (n = 59): 79% (69-91). (Median age 46 yrs (23-63).
0
6
12
18 24 Months from dCBT
30
36
Politikos et al, 2018 ASBMT
1.0 0.8
aaHCT-CI 0-2 0-2 (n = 59)
0.6
aaHCT-CI 3 (n = 33)
0.2
0.4
aaHCT-CI 4+ (n = 62)
p = 0.018
0.0
Progression-free Survival (%)
Midi dCBT: 3-year PFS by aaHCT-CI (n = 154)
0
6
12
18 24 Months from dCBT
30
36
Politikos et al, 2018 ASBMT
1.0 0.8
Low-Intermediate rDRI (n = 119): 69% (61-79)
0.6
Supports robust GVL
0.2
0.4
High-V. High rDRI (n = 35): 56% (40-77)
P = 0.135
0.0
Progression-free Survival (%)
Midi dCBT: 3-year PFS by Disease Risk (rDRI, n = 154)
0
6
12
18 24 Months from dCBT
30
36
Politikos et al, 2018 ASBMT
Midi Double Unit CBT (n = 154): Recent 3-year PFS (70%) Improving Variable Patient age: < 51 yrs, N = 72 >/= 51 yrs, N = 82 Period of CBT: Earlier yrs, (N = 64) Recent: 2014-2016, (N = 90)
3-yr PFS 70% 63% 63% 70%
Day 180 TRM, relapse or 3-yr PFS: no association with CMV serostatus, ancestry, addition of haplo cells, 8 allele & infused CD34+ dose of dominant unit.
MSKCC Cy/ Flu/Thio/ TBI Midi Based New Trials CB #1
dCBT + IL-6 receptor blockade to abrogate PES & severe aGVHD
Unmet needs: - Slow engraftment. - aGVHD incidence/ morbidity. - CMV infection.
EC-based dCBT + Ex-vivo expansion.
sCBT + 3rd party offthe-shelf Notch-expanded CB-derived myeloid progenitors
If patient CMV seropositive: Letermovir prophylaxis
Perspective
Multiple series in hematologic malignancies that demonstrate: Mortality: • CB same as HLA-matched URD & better than HLA-mismatched URD. Brunstein 2010, Ponce 2015, Milano 2016. Relapse: • Relapse lower after CB than HLA-matched or mismatched URD. Brunstein 2010, Ponce 2015, Milano 2016.
Q: Is CBT rising in popularity? A: No. Reasons: Cost of CB units/ early hospital stay Complexity of CBT.
Q: What can be done to prevent decline of CBT? A: Improve inventory of large units*. Reduce unit price. Make CBT easier: optimize practices. New technologies. * Barker et al: CD34+ content of NMDP U.S. inventory, ASBMT 2018
Q: Is BMT CTN Non-myeloablative dCBT vs Haplo Randomized Trial Going to Inform Field about the Value of CBT. A: No Need to increase conditioning regimen intensity & optimize practices for both HSC sources.
Promote optimal practices Interact with public banks: promote quality products Interact with NMDP/ HRSA/ other agencies to promote banking/ CBT
CB SIG websitemembership, communication
Interact with other SIGs
Promote clinical, translational & lab research
ASBMT CB SIG Interact with organizations eg CBA, AABB, ISCT, EBMT
Collaboration with foreign centers: UK/ Europe/ other
On behalf of NMDP & ASBMT CB SIG, Barker et al, 2017, BBMT
Optimize CBT with Optimal Practices Thaw &quality assessment .
Optimized graft selection: • Single unit. (children with adequate single unit)
Novel conditioning
-6
• Efficient searches: consider CB search if no URD predicted at search initiation. • Conditioning: consider diagnosis & HCT-CI.
• Double unit. (if inadequate single or intermediate/ NMA conditioning). 0
30
1 yr
• Early assessment of engraftment. • Optimize immune suppression to prevent severe aGVHD & enhance immune recovery. • Prompt therapy of PES. • Early diagnosis & therapy of GVHD . • Optimized infection prophy/ monitoring. Barker et al, BBMT 2017
Guidelines: More in the Works • Donor selection: NMDP URD/ CB review. • CB unit selection: practical examples. • Thaw and infusion: practical examples. • Infections: collaboration with ASBMT ID SIG.
CBT Collaborating Centers Facilitate rapid collaborations, information exchange, publications, trials.
Most important test of effective immune system post-allograft is protection against relapse. Biology underlying GVHD vs GVL in CBT not understood. Obtaining funding to study CBT is now difficult-and yet now great interest in agents to prevent relapse post-allograft.
Paradigm Shifts Should Include Recognition of: • 1) Racial disparity in access to 8/8 URDs will not be resolved by increased registry size. Important: 7/8 URDs are inferior. • 2) There are limitations in access to both CB & haplo grafts. • 3) Poor searches that will not result in an 8/8 URD can be immediately recognized –can be acted upon at search initiation. • 4) Haplo transplants have limitations: access & relapse. • 5) CB rapid availability major advantage-esp if start CB search early. • 6) Pediatric CBT outcomes very good. Adult CBT is improving: reduced TRM & good GVL - without graft manipulation: if low comorbidity score CB transplant of choice? • 6) Optimize CBT practices & promote collaboration: improves outcomes & reduces costs. AND creates platform for optimal application of new cellular therapy technologies.