Haploidentical (half-matched) stem cell transplant with pre-transplant immunosuppression for sickle cell anemia

A Pilot Study of Pre-transplant Immunosuppressive Therapy for Haploidentical Transplants in Patients With Sickle Cell Disease

This study tests whether two short cycles of pre-transplant immune-suppressing drugs followed by a myeloablative half-matched (haploidentical) stem cell transplant can be done safely and achieve donor engraftment in people with severe sickle cell disease who lack fully matched donors.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 11 (estimated)
• Ages: 1 Year to 30 Years
• Sex: All
• Sponsor: City of Hope Medical Center (Academic / other)
• Drugs / interventions: chemotherapy, radiation, Cyclophosphamide, Fludarabine
• Locations: 1 site (Duarte, California)
• Trial ID: NCT03279094 on ClinicalTrials.gov

What this trial studies

This Phase 1 protocol gives two cycles of fludarabine plus dexamethasone before a myeloablative conditioning regimen that includes rabbit ATG, fludarabine, and busulfan, followed by an allogeneic haploidentical hematopoietic stem cell transplant. Graft-versus-host disease prevention uses post-transplant cyclophosphamide on days +3 and +4, plus tacrolimus and mycophenolate mofetil. The primary aim is to characterize safety and toxicity and to achieve consistent donor chimerism while expanding the donor pool to half-matched family members. Patients are enrolled based on severe sickle cell complications such as stroke, recurrent acute chest syndrome, frequent vaso-occlusive crises, priapism, osteonecrosis of multiple joints, or chronic transfusion dependence.

Who should consider this trial

Good fit: Adults with sickle cell anemia (HbSS or HbSβ0) who have severe complications—such as stroke, elevated transcranial Doppler velocity, recurrent acute chest syndrome, frequent vaso-occlusive crises, recurrent priapism, osteonecrosis of two or more joints, or dependence on regular transfusions—and who have an available haploidentical donor are the intended candidates.

Not a fit: People with milder sickle cell disease who do not meet transplant indications, those with significant organ dysfunction or other comorbidities that preclude myeloablative conditioning, or those without any suitable haploidentical donor are unlikely to benefit from this approach.

Why it matters

Potential benefit: If successful, this regimen could allow more people with severe sickle cell disease to receive potentially curative transplants from half-matched family donors with acceptable toxicity.

How similar studies have performed: Haploidentical transplants using post-transplant cyclophosphamide have produced promising results in blood cancers and early reports in sickle cell disease, but the specific pre-transplant immunosuppression plus myeloablative regimen remains investigational.

Eligibility criteria

Inclusion criteria

* Diagnosis: Patients with sickle cell anemia (Hgb SS or SB° Thalassemia) with baseline Hgb S more than 60%.
* Disease status:
* Significant neurologic event (stroke) or any neurological deficit lasting \> 24 hours; or increased transcranial Doppler velocity (\>200 m/s).
* History of one or more episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea).
* History of one or more severe vaso-occlusive pain crises per year in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea).
* Recurrent priapism requiring medical therapy.
* Osteonecrosis of two or more joints despite the institution of supportive care measures.
* Prior treatment with regular RBC transfusion therapy, defined as receiving 8 or more transfusions per year for \> 1 year to prevent vaso-occlusive clinical complications (i.e. pain, stroke, and acute chest syndrome)
* Echocardiograph finding of tricuspid valve regurgitation jet (TRJ) velocity ≥ 2.5 m/sec.
* Ages 1 to 30.
* Child Bearing Potential- Transplantation could be teratogenic and/or lethal to the developing fetus. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation. Should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately.
* Informed Consent/Assent: All subjects must have the ability to understand and the willingness to sign a written informed consent.
* The recipient must have a related donor who is genotypically haploidentical on HLA-A, B, C and DRB1 loci.
* No HLA matched sibling or 10/10 matched unrelated donor is available.

Exclusion criteria:

* Any uncontrolled illness including ongoing or active bacterial, viral or fungal infection.
* Patients may not be receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to any in the pre- or post-transplant regimen.
* Pregnant women are excluded from this study.
* Patients with any active malignancy are ineligible for this study, other than non-melanoma skin cancers.
* Medical problem or neurologic/psychiatric dysfunction which would impair patient ability to be compliant with the medical regimen and to tolerate transplantation or would prolong hematologic recovery which in the opinion of the principal investigator would place the recipient at unacceptable risk.
* Prior autologous or allogeneic transplant.
* Fully HLA-matched related or unrelated donor is available to donate.
* Non-Compliance: Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.

Where this trial is running

Duarte, California

• City of Hope Medical Center — Duarte, California, United States (Recruiting)

Study contacts

• Principal investigator: Anna B. Pawlowska, MD — City of Hope Medical Center
• Study coordinator: Anna B. Pawlowska, MD

Conditions Sickle Cell Disease; Hematopoietic stem cell transplantation; Haploidentical stem cell transplantation; Post-transplant Cytoxan