Curative therapies for sickle cell disease

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Matt Hsieh, MD

March 2025

Disclosures

• none

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• off label use of medications for hematopoietic cell transplantation include: cyclophosphamide, fludarabine, alemtuzumab, abatacept

Objectives

• recognize recently approved medications for sickle cell include L-glutamine (Endari), crizanlizumab (Adakveo)
• discuss matched related donor HCT results in ablative and non-ablative regimens
• discuss haplo HCT results using post transplant cyclophosphamide (PTCy) and T cell depletion based regimens
• recognize recently approved autologous gene therapies include Lyfgenia (adding normal beta-globin; lovotibeglogene or lovo-cel) and Casgevy (reactivating fetal hemoglobin; exagamglogene or exa-cel)

Sickle cell is caused by a genetic mutation

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Acute and chronic sickle manifestations

Thein, Blood 2019

Cardinal features of SCD:

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Anemia*

Hemolysis*

Pain crises*

Acute chest syndrome*

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*reversible by hematopoietic

cell transplant (HCT)

Tisdale, Science 2020

Approved medications for SCD

• hydroxyurea: reactivate fetal hemoglobin (HbF) and reduce WBC
• increase HbF and total hemoglobin levels
• disease modifying medication
• L-glutamine: anti-oxidant like properties, prolong red cell survival
• no change in CBC, hemolysis labs
• voxelotor: increase oxygen binding to reduce sickle polymerization
• higher hgb
• recently withdrawn due to higher rates of VOC and possibly deaths
• crizanlizumab: p-selectin inhibitor, reduce red cell and plts adhering to blood vessel endothelium
• no change in CBC, hemolysis labs
• mitapivat (in clinical trials): pyruvate kinase activator, prolong red cell survival
• higher hgb
• other anti-sickling medication in various stages of development and clinical trials

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Key hematologic results with life-long compliance in taking medication

Modestly

reduce pain crisis

reduce hospitalization

Significantly

reduce pain crisis

reduce hospitalization

Higher hgb

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(withdrawn due to higher rates of VOC and possibly death)

Modestly

reduce pain

Fewer patients derive clinical benefits

HCT for SCD: matched related donors

• leukemia type conditioning regimen, myeloablative
• chemotherapy based (high intensity) 🡪 aiming for full replacement of marrow by donor cells (full donor chimerism)
• occasionally, as low as 10% donor chimerism still had hematologic benefit
• all in children and young adults (<25 yo)
• for older adults (>25 yo) or those with compromised heart, lung, liver, or renal function, non-ablative regimen
• antibody and low dose radiation based (low intensity)
• mixed chimerism (5-95% donor) was much more common

Walters et al, 2001; Bernaudin et al, 2008

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Examples of conditioning regimens for matched related donor HCT

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“Alem-300 TBI” – non-myeloablative (low intensity)

Transplant outcomes

Alzahrani M, BJH 2020; Bernaudin F, Haematologica 2019

Comparing nonablative vs ablative, MRD

• non-ablative (low intensity) regimen, e.g. alem-300 TBI
• applicable to patients with compromised organ function (cirrhosis, pulm HTN, or dialysis)
• stable lung, liver, kidney function post HCT
• low intensity 🡪 likely more fertility preservation
• ablative (high intensity), e.g. Bu4-Cy4-rATG
• typically for children and young adults
• in pre-pubertal children, spontaneous puberty observed post HCT
• although requires normal function pre-HCT, lung, liver, and kidney functions also remain stable post HCT

Initial report with improved haplo HCT with PTCy

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Haplo HCT, 2 broad categories

• the survival and success rates of haplo HCT have steadily improved
• there are many haplo conditioning regimens. They can be grouped
• post-transplant cyclophosphamide (PTCy)
• giving Cy after donor cell infusion 🡪 reduces total pool of donor lymph and expand Treg 🡪 reduce GvHD
• moderately high intensity
• sickle free survival >80%, aGVHD ranged from 0 to 25%
• ex vivo T depletion
• reduce the activated T cells in the donor cell graft 🡪 reduce GvHD
• moderately high intensity
• sickle free survival >80%, aGVHD ranged from 6 to ~30%

When an antigen presenting cell shows a ‘foreign’ antigen to T cell receptor (TCR), this activates signal 1 of the T cell activation cascade.

There are several other co-stimulatory signals (also known as signal 2) that further elaborate the T cell activation process.

Danese S et al, Gut, 2003

Ongoing improvements in haplo HCT

• better supportive care, antimicrobial prophylaxis
• thoughtful design of conditioning regimen (PT-Cy, T cell depletion)
• during pre-HCT testing, when recipient antibody to antigen on donor cells is detected (positive donor specific antibody)
• many chemo and antibody combo to reduce DSA
• improve engraftment
• co-stimulatory blockade
• Co-stimulatory signal is the second part of the T cell activation process. Blocking this step improves both engraftment and reduces GvHD
• Ngwube A et al, Blood Adv 2020; Jaiswal SR et al, BBMT 2020

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AUTOLOGOUS gene manipulation

• for MANY patients, there are no suitable matched related donors, but they have disease severe enough to consider a transplant
• their curative options are haplo vs auto gene therapy
• gene manipulation = gene therapy (general term)
• Gene addition: add one or more correct copies of the normal beta-globin gene (lovotibeglogene or lovo-cel, Lyfgenia)
• Gene edit: change an existing gene to alter production. There has been several studies to increase HbF production (exagamglogene or exa-cel, Casgevy)
• Gene correction: fix the actual sickle mutation in the beta-globin gene. Clinical trials planned

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Hematologic improvement after gene ADDition

J Kanter et al, NEJM 2022

FDA approved in 2023, Lyfgenia

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• lentiviral vector
• insert a normal beta-globin gene, modified to have additional anti-sickling property
• expression of T87Q sufficient to counter HbS 🡪 similar to sickle trait
• increase in total hgb, reduce VOC and hosp adm

Hematologic improvement after gene EDIT

H Frangoul et al, NEJM 2024

FDA approved in 2023, Casgevy

erythroid

enhancer

BCL11A

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CRISPR cut

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Reduce expression

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Reactivate gamma-globin expression

Chr 2

Chr 11

• high HbF dilutes HbS to reduce sickle polymerization
• similar to taking HU
• increase total hgb, reduce VOC and hosp adm

matched related HCT vs gene therapy vs haplo HCT?

FIRST CHOICE: matched related HCT

- longer history and more experience

- side effects, complications, success/failure rates are well known

• many transplant centers already offer this option
• age <30 and no comorbid conditions 🡪 ablative or reduced toxicity to aim full donor chimerism
• presence of comorbid condition 🡪 low intensity regimen

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SECOND CHOICE:

- although haplo = gene therapy, haplo is more prob accessible

- increasingly more transplant centers are offering haplo

• gene therapy more expensive (for now)
• sequence of treatment matters
• Gene therapy first, if unsuccessful, can salvage with haplo
• But if haplo first and unsuccessful, cannot salvage with gene therapy

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Life-long compliance in taking meds

One-time, intensive treatment

Every 4-6 weeks

Comparing key hematologic outcomes after various therapies