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HEMATOPOIETIC STEM CELL TRANSPLANTATION IN 2024:

WHAT EVERY HEMATOLOGIST NEEDS TO KNOW

RICHARD W. CHILDS M.D.

BETHESDA MD

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To Update the State of the Art of Allogeneic Transplantation in 2025

Key components to a successful transplant outcome
Improvements in preventing transplant complications
Improvements in managing transplant complications
Widening application of transplant that don’t use HLA-matched donors
New approaches to preventing relapse after allogeneic HCT
Explosion of new treatments to manage GVHD

Learning Objectives

GVHD= Graft vs host disease

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Data from the CIBMTR 2024

Annual Number of Transplants Performed in the United States

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Transplants Dramatically Safer Over Past 2 Decades

Death After Transplant

Day 200 NRM

2003-2007 vs 2013-2017

34% reduction in NRM
24% reduction in cancer relapse

Wong F.L. et al JNCI 2020 (112:11)

McDonald G.B. et al Annals Int Med 2020:Ann Intern Med. 2020;172:229-239.

AML and Allogeneic Transplant:

Survival Improving

Survival AML Pts

After Allo HCT

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Improvements in Allogeneic Transplants

First FDA approved drugs to treat GVHD

Ruxolitinib 73% response for SR acute GVHD- FDA approved 2019
Rezurock – 74%-77% response rate- FDA approved 2021 for pts who have received ≥ 2 lines of systemic therapy
Axatilimab- 74% response rate in pts with cGVHD failing >2 lines of prior therapy- FDA approved
Remestemcel- 70% response rate in Steroid-refractory acute GVHD- FDA approved December 2024 for pediatric SRGVHD

Letermovir approved (2017) to prevent CMV reactivation post-HCT

Reduced risk of CMV reactivation from 41% to 17% compared to placebo

Maribavir- FDA approved 2022 for patients with post-transplant refractory CMV infection

57% viral clearance rate compared to best standard therapies
No marrow suppression or renal toxicity

CMV Reactivation

41%

17.5%

Death any cause

Wolff D. et al. NEJM 2024

Cutler C. et al, Blood 2021

Maertens J. et al, NEJM 2019: 381(12)

Marty F. et al. NEJM Dec 2017

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Sib

Data from the CIBMTR 2024

Donor Allograft Sources: Change in Use Over the Past 10 Years

MMUD

Haplo

Cord

MUD

Slide 3: Upon further stratifying the number of allogeneic transplants recipients in the US by donor type, recipients of unrelated donor transplants represent the largest group. The number of unrelated donor (URD) transplants has surpassed the number of allogeneic transplants from related donors after 2006 and the gap between these two types of approaches continues to grow. After 2013, the number of HLA-identical sibling transplants has shown a downward trend in absolute numbers. URD transplants plateaued from 2013-2016 but began rising again after 2016. Transplants performed using alternative donors are increasing. From 2003 to 2011, there was a steady increase in the numbers of transplants using umbilical cord blood (UCB) as a result of several published studies demonstrating its benefit in both children and adults, after which URD UCB transplant activity declined. From 2012 onward, there has been an increase in the numbers of transplants from ‘Other Relatives’, likely due to the use of haploidentical donors with post-transplant cyclophosphamide strategy. After 2014, the numbers of transplants using ‘Other Relatives’ surpassed the total numbers of UCB transplants performed in the US. This trend has continued to rise with these transplants representing 21% of transplants and nearing numbers of HLA-identical sibling transplants which represent 23% of allogeneic transplants in the US in 2019.

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Increase in Reduced Intensity Transplants Over

Myeloablative Transplants

Most Common Conditioning Regimens

MAC vs RIC/NMA

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Data from the CIBMTR 2024

25% of Allogeneic Transplants Performed in

Adults > 65 Years of Age

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GVHD Prophylaxis- Growing Use of Post Transplant

Cyclophosphamide (PTCy) Outside the Haplo Transplant Setting

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Increase In Proportion of Minorities Undergoing

Allogeneic Transplantation

Relative Proportion of Allogeneic Transplants in US by Race

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Little Change in The Relative Proportion of MUD Transplants

in US by Race

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Relative Proportion of Haplo Transplants in US by Race

Haplo Transplants Particularly Useful For Racial Groups That

Are Least Likely to Have MUD Donors Available

47% Haplo HCTs

Asian
Hispanic
Black or

African American

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Allogeneic Transplants in U.S. For Black or African

American By Donor Type

HAPLOs

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Fact: In transplants from HLA matched donors (related and unrelated), best outcomes are associated with

Donors that have the best HLA match
Donors who are younger (<30 years MUD)
Avoiding a female donor into a male recipient (results in less GVHD)

Fact: Recipients of Haplo Transplants typically have many potential family donors to choose from

Choosing the best Donor:

PFS and survival not impacted by: gender, relationship of the donor to the recipient, degree of HLA mismatch or ABO incompatibility, prior donor pregnancy
Avoid DSA to Haplo Donor

Donors <30 have a sustainably lower chance of causing severe acute GVHD

Choosing the Best Haplo Transplant Relative

Im A, et al. Biol Blood Marrow Transplant. 2020 26(8)

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Inferior Survival Amongst Non-Hispanic Black or African

American Patients Following Following Allo BMT for AML

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Inferior Survival Amongst Non-Hispanic Black or African

American Patients Following Following HLA Matched Allo BMT

Slide 106: Among adult patients with AML receiving Matched related donor transplant between 2009 and 2019, the 3-year probabilities (95%CI) of survival following transplant with a Race and Ethnicity of Hispanic, Non-Hispanic White, Non-Hispanic Black or African American, Non-Hispanic Asian and Others were 55% (52-59%), 52% (51-53%), 48% (44-53%), 55% (50-60%), and 52% (43-63%), respectively.

Among adult patients with AML receiving Matched unrelated donor transplant between 2009 and 2019, the 3-year probabilities (95%CI) of survival following transplant with a Race and Ethnicity of Hispanic, Non-Hispanic White, Non-Hispanic Black or African American, Non-Hispanic Asian and Others were 54% (50-58%), 51% (50-52%), 38% (32-45%), 53% (48-59%), and 54% (45-64%), respectively.

Trend data only is presented and any significant p values reflect global differences between indicated groups and not any specific differences between indicated groups. Caution interpreting these univariate curves is important as adjustment for other relevant factors using multi-variable analyses has not been done.

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Comparable Survival Amongst Non-Hispanic Black or African

American Patients Following Haplo/Post Cy BMT for AML

Slide 106: Among adult patients with AML receiving Matched related donor transplant between 2009 and 2019, the 3-year probabilities (95%CI) of survival following transplant with a Race and Ethnicity of Hispanic, Non-Hispanic White, Non-Hispanic Black or African American, Non-Hispanic Asian and Others were 55% (52-59%), 52% (51-53%), 48% (44-53%), 55% (50-60%), and 52% (43-63%), respectively.

Among adult patients with AML receiving Matched unrelated donor transplant between 2009 and 2019, the 3-year probabilities (95%CI) of survival following transplant with a Race and Ethnicity of Hispanic, Non-Hispanic White, Non-Hispanic Black or African American, Non-Hispanic Asian and Others were 54% (50-58%), 51% (50-52%), 38% (32-45%), 53% (48-59%), and 54% (45-64%), respectively.

Trend data only is presented and any significant p values reflect global differences between indicated groups and not any specific differences between indicated groups. Caution interpreting these univariate curves is important as adjustment for other relevant factors using multi-variable analyses has not been done.

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Death After Allogeneic Transplant: Relapse�Continues To Be THE Major Cause

RELAPSE!!

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Post-Transplant Cytoxan to Reduce Relapse

after HLA-Matched Allogeneic HCT

Lower cyclosporine levels (AUCs) after transplant associated with lower risk of AML relapse (Craddock C. et al Haematologica 2010)

Post-Transplant Cytoxan after HLA matched Transplant may obviate the need for post-transplant CSA/Tacro

Potentially allows for increased graft-vs-leukemia effects decreasing relapse risk
CTN Phase III trial-Better RFS in leukemia patients receiving post HCT Cy compared to CSA/MTX or CD34 selected transplants

Luznik L. et al JCO 2022

Post Cy

CSA/MTX

CD34 selected

327 pts leukemia in remission randomized to post HCT CY vs CSA/MTX vs CD34 selection

Post Cy CSA/MTX

CD34 selected

Survival

Relapse

CD34 selected/CSA/MTX

Post Cy

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CRISPR Deletion of CD33 in Donor Stem Cells To Protect Them From Anti-CD33

Therapies Given Post Allo-HCT To Prevent AML Relapse

Condition

Infuse CD33 KO

Donor Allograft

CD33+

AML Patient

Infuse

Gemtuzumab Ozogamicin

Kill patient’s CD33+ AML Cells

Donor CD34+ Stem Cells Protected

From Mylotarg

CD33+ AML

Dies

x

CD33 neg donor stem

cells survive

Allo HCT

Concept: Donor CD34+ cells that have CD33 CRISPR’ed out

will not be susceptible to killing by anti-CD33 targeting therapies

given after an allogeneic HCT to prevent relapse

Dipersio J. et al Science Direct 2024 S237-244

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CRISPR/Cas9 Gene-Edited Allograft Lacking CD33

8 Patients Treated to Date (data on 6 above)
Transplanted CD34+ cells Median 87.5% CD33 negative
ANC Recovery median 10 days (9-11)
PLT recovery median 16 days (15-22)
GO dosing starting on day 60 is ongoing in a 3+3 dose escalation strategy starting at 0.5 mg/m² every 28d for 4-8 cycles.
Platform could be used to protect from other CD33-targeting therapies such as CD33 CART

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Axatilimab For cGVHD

cGVHD= Chronic graft vs host disease

Death After Day 100:

11% caused by cGVHD

Background- Preclinical data suggest colony-stimulating factor 1 receptor dependent monos/macros may drive cGVHD inflammation and fibrosis. Axatilimab is a CSF-1R mAb that targets monos and macro. Phase I data demonstrated activity of Axa in patients with cGVHD

Method: Phase 2 open label study of 3 different dosing schedules of Axatilimab in pts with relapses/refractory cGVHD. Primary outcome was ORR in the first 6 cycles

Outcomes:

241 pts enrolled at 121 study sites
Heavily pretreated cohort- Median 4 prior therapies for cGVHD
Activity seen at all dose levels with 0.3 mg/kg iv q 2 weeks most active
74% ORR rate observed in pts who had failed ruxolitinib (74%) and belumosidil (23%)
Drug discontinuation in 6% due to TRAEs ( infection)

Wolff D. et al. NEJM 2024

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AGAVE-201 Trial

Axatilimab is highly active in cGVHD including refractory fibrotic cGVHD
Adverse events generally transient and asymptomatic: Only 6% of pts discontinued therapy due to toxicity
Infection rate not different than historical controls developing cGVHD

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Refractory or relapsed (r/r) T-cell acute lymphoblastic leukemia has a dismal prognosis with 0%-25% 5 year survival
Survival of r/r T-cell acute lymphoblastic leukemia following allogeneic transplant is poor (14%-30%)
Current standard of care for r/r T-cell acute lymphoblastic leukemia pts achieving a CR is an allogeneic transplant
Anti CD7 CAR-T cells with or without CD7 CRISPR KO can induce MRD neg CRs in up to 95% of pts with r/r T-cell acute lymphoblastic leukemia

Life-threatening CD3 lymphopenia can occur in up to 60% of pts
Allogeneic HCT after CD7 CAR T can be used to

Resolve CD3 lymphopenia
Prevent disease relapse through a GVT effect

The impact of CD7 CAR T-cell treatment on transplant outcome is not yet known

Using Allogeneic HCT To Rescue Patients Treated with CD7 CAR T-cells

That Cause Life-Threatening Lymphopenias

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34 patients with r/r T-ALL/LBL who underwent allo-HSCT after achieving CR with autologous CD7 CAR-T therapy.
Outcome compared with 124 consecutive-ALL/LBL patients who received allo-HSCT in CR following chemotherapy alone.
r/r CAR-T recipients and chemotherapy cohorts in remission exhibited comparable posttransplant outcomes including similar outcomes 2-year overall survival (OS) (61.9% vs. 67.6%, p = 0.210), leukaemia-free survival (LFS) (62.3% vs. 62.0, p = 0.548), and relapse rates (8.8 vs. 15.8% [, p = 0.557

Disappearance of CD7 CAR T-cells

following allogeneic HCT

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34 patients with r/r T-ALL/LBL who underwent allo-HSCT after achieving CR with autologous CD7 CAR-T therapy.
Outcome compared with 124 consecutive-ALL/LBL patients who received allo-HSCT in CR following chemotherapy alone.
r/r CAR-T recipients and chemotherapy cohorts in remission exhibited comparable posttransplant outcomes including similar outcomes 2-year overall survival (OS) (61.9% vs. 67.6%, p = 0.210), leukaemia-free survival (LFS) (62.3% vs. 62.0, p = 0.548), and relapse rates (8.8 vs. 15.8% [, p = 0.557

Overall Survival

LFS Survival

Relapse

The median interval from CD7 CAR-T therapy to transplantation was 57.5 days.
No differences in the time to ANC, Plt recovery, or CD4 immune recovery between cohorts. Infection rates post HCT were comparable
No differences in aGVHD and cGVHD between the CD7 CAR-T and chemotherapy groups.
Remarkably LFS was 62.3% in the r/r T-cell acute lymphoblastic leukemia/lymphoma pts treated with CAR T-cells who went to allo HCT. This is much higher than the 14%–30% LFS typically observed with salvage transplantation in this cohort
In conclusion, this study supports the use of consolidation allo-HSCT post remission after CD7 CAR-T. Patients undergoing HSCT after achieving CR through CD7 CAR-T therapy demonstrated promising OS and LFS comparable to those who achieved CR1 via chemotherapy who went to allo HCT.