What are the promising stem cell therapies with backed evidence for various medical conditions, including blood cancers, graft-versus-host disease, osteoarthritis, heart failure, and neurodegenerative diseases?

Stem Cell Therapies with Evidence-Based Support

Hematopoietic Stem Cell Transplantation (HSCT) for Blood Disorders

Hematopoietic stem cell transplantation is the only stem cell therapy with robust, guideline-supported evidence for clinical use, primarily indicated for blood cancers, thalassemia major, sickle cell disease, and graft-versus-host disease management. 1

Blood Cancers and Hematologic Malignancies

Allogeneic HSCT is standard of care for:

• Acute myeloid leukemia (AML) with FLT3-ITD mutation: All patients except those with low allelic ratio (<0.5), concurrent NPM1 mutation, and confirmed MRD negativity should undergo allogeneic HSCT in first complete remission (CR1) 1
• High-risk acute leukemias: Patients with poor prognostic features benefit from allogeneic HSCT, though only 6% of allogeneic transplant indications are supported by randomized controlled trials 1
• Myelodysplastic syndromes (MDS): Allogeneic HSCT is indicated for intermediate and high-risk MDS, with donor selection following standard HLA-matching protocols 1

Autologous HSCT is standard for:

• Multiple myeloma: Autologous transplantation following high-dose chemotherapy remains standard consolidation therapy 2, 3
• Hodgkin's and non-Hodgkin's lymphoma: Autologous HSCT is established for relapsed/refractory aggressive B-cell lymphomas and Hodgkin's lymphoma 2
• AL amyloidosis: Autologous transplantation is a treatment option for eligible patients 2

Notably, 41% of autologous transplant indications have randomized trial support, compared to only 6% for allogeneic procedures, yet both are widely accepted as standard of care based on historical precedent and observational data 1

Thalassemia Major

HSCT should be performed as soon as possible after diagnosis of transfusion-dependent thalassemia major when an HLA-identical sibling donor is available. 1

Donor selection hierarchy:

• First choice: HLA-identical sibling bone marrow or cord blood (if adequate cell dose >3.5×10⁷ nucleated cells/kg) 1
• Second choice: Allelic-matched unrelated donors, but only in patients without iron-related tissue damage and with well-controlled iron overload 1
• Avoid: Haploidentical and HLA-mismatched family donors outside controlled trials 1

Critical pre-transplant requirements:

• Assess Pesaro risk score (based on age, hepatomegaly, and portal fibrosis) before proceeding 1
• Control iron overload through adequate chelation therapy; this is the primary determinant of transplant outcomes 1
• Patients with >20 units of RBC transfusions should receive iron chelation prior to conditioning 1

Outcomes by risk class:

• Low-risk children <14 years with HLA-matched sibling: 96% disease-free survival, 5% transplant-related mortality 1
• Adults and high-risk patients: Should only undergo HSCT within controlled trials due to 25% transplant-related mortality 1

Sickle Cell Disease (SCD)

Allogeneic HSCT is recommended for symptomatic SCD patients with an HLA-identical sibling donor, performed as early as possible. 1

Indications for HLA-identical sibling HSCT:

• Any symptomatic manifestation of SCD (stroke, recurrent acute chest syndrome, recurrent vaso-occlusive crises) 1
• Over 90% of pediatric patients achieve cure with HLA-identical sibling transplantation 1

Alternative donor options:

• Matched unrelated donors: Conditional recommendation for patients meeting specific severity criteria (stroke, recurrent acute chest syndrome, or other severe complications) 1
• Haploidentical donors: Only within controlled clinical trials 1
• Cord blood: HLA-identical sibling cord blood is preferred over bone marrow when available with adequate cell dose and viability 1

Conditioning regimens:

• Standard: IV busulfan, cyclophosphamide, and anti-thymocyte globulin (ATG) 1
• Reduced-intensity conditioning: Only within controlled trials 1

Critical limitation: Less than 20% of US patients with SCD have an HLA-identical sibling or matched unrelated donor, restricting access to this curative therapy 1

Post-Transplant Management

For FLT3-ITD AML patients post-HSCT:

• Initiate sorafenib maintenance therapy at 400 mg/day (divided doses) as soon as possible after engraftment, particularly for MRD-positive patients 1
• Continue for minimum 2 years, temporarily discontinuing only for active acute GVHD requiring systemic corticosteroids 1
• MRD-positive patients may receive 800 mg/day adjusted for tolerance 1

For MDS patients with declining donor chimerism:

• Rapidly taper immunosuppression when mixed chimerism (<90% donor cells) or increasing recipient chimerism (>10%) is detected 1
• Follow with prophylactic donor lymphocyte infusions if no GVHD is present 1
• Azacitidine combined with donor lymphocyte infusions shows promising results for relapsed MDS, with 66% two-year survival 1

GVHD management post-HSCT:

• First-line: Methylprednisolone 1-2 mg/kg/day IV for Grade II-IV acute GVHD 4
• Continue or escalate calcineurin inhibitors (tacrolimus or cyclosporine) 4
• Steroid-refractory disease: Anti-thymocyte globulin as second-line option 4

Therapies Lacking Sufficient Evidence

No other stem cell therapies currently have guideline-level evidence supporting their use outside of hematopoietic stem cell transplantation. 1

The following conditions are frequently marketed for stem cell therapy but lack adequate evidence:

• Osteoarthritis: No guideline support; requires demonstration of cellular replacement or paracrine repair mechanisms in properly controlled trials 1
• Heart failure: Insufficient evidence for clinical recommendation; mechanism of action (cellular replacement vs. paracrine signaling) remains poorly defined 1
• Neurodegenerative diseases: No established efficacy; CNS applications face unique challenges regarding immune privilege and delivery systems 1

Key regulatory considerations:

• Stem cell trials must demonstrate safety and efficacy profiles superior to standard of care in preclinical studies 1
• Phase 1 trials should use dose-escalation protocols with phased enrollment 1
• Cell production must follow current Good Manufacturing Practices with stringent quality control 1
• Trials should be properly funded by sponsors, not by patients themselves 1

Common Pitfalls to Avoid

• Do not delay HSCT in young thalassemia patients with HLA-matched siblings waiting for iron overload to develop; early transplantation before complications yields 96% disease-free survival 1
• Do not use peripheral blood stem cells from matched siblings in thalassemia outside experienced centers, as three of four studies show increased chronic GVHD risk 1
• Do not perform unrelated cord blood transplantation for thalassemia outside controlled trials at expert centers; registry data shows only 21% disease-free survival with 52% graft failure 1
• Do not withhold HSCT from SCD patients based solely on availability of disease-modifying medications (hydroxyurea, voxelotor, crizanlizumab); HSCT remains the only curative option 1
• Do not pursue "stem cell therapy" for conditions lacking cellular deficiency mechanisms (osteoarthritis, heart failure, neurodegenerative diseases) outside properly designed clinical trials with clear mechanistic rationale 1