A Study Evaluating the Safety and Efficacy of Lovo-cel in Severe Sickle Cell Disease

Genetix Biotherapeutics Inc.54 enrolled

Overview

This is a non-randomized, open label, multi-site, single dose, Phase 1/2 study in approximately 50 adults and adolescents with severe SCD. The study will evaluate hematopoietic stem cell and progenitor stem cell (collectively referred to as hematopoietic stem and progenitor cells or HSPCs) transplantation using lovo-cel.

Subject participation for this study will be 2 years post-transplant. Subjects who enroll in this study will be asked to participate in a subsequent long-term follow up study that will monitor the safety and efficacy of the treatment they receive for an additional 13 years for a total of 15 years post-drug product infusion.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Sickle Cell Disease

Interventions

lovo-celGENETIC

lovo-cel is administered by IV infusion following myeloablative conditioning with busulfan.

Eligibility

Sex: ALLMin age: 12 YearsMax age: 50 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Be ≥12 and ≤50 of age at time of consent. 2. Diagnosis of sickle cell disease (SCD), with either βS/βS or βS/β0 or βS/β+ genotype. 3. Have severe SCD. i.e., in the setting of appropriate supportive care measures for SCD (e.g., pain management plan), have experienced at least 4 severe VOEs in the 24 months prior to informed consent. For the purposes of this study, a severe VOE is defined as an event with no medically determined cause other than a vaso-occlusion, requiring a ≥ 24-hour hospital or Emergency Room (ER) observation unit visit or at least 2 visits to a day unit or ER over 72 hours with both visits requiring intravenous treatment. Exception: priapism does not require hospital admission but does require a medical facility visit; 4 priapism episodes that require a visit to a medical facility (without inpatient admission) are sufficient to meet criterion. Severe VOEs include: 1. an episode of acute pain with no medically determined cause other than a VOE 2. Acute chest syndrome (ACS), defined by an acute event with pneumonia-like symptoms (e.g., chest pain, fever \[\> 38.5°C\], tachypnea, wheezing or cough, or findings upon lung auscultation) and the presence of a new pulmonary infiltrate consistent with ACS and requiring oxygen treatment and/or blood transfusion. 3. Acute hepatic sequestration, defined by a sudden increase in liver size associated with pain in the right upper quadrant, abnormal results of liver-function test not due to biliary tract disease, and reduction in Hb concentration by at least 2 g/dL below the baseline value 4. Acute splenic sequestration, defined as sudden enlargement of the spleen and reduction in Hb concentration by at least 2 g/dL below the baseline value. 5. Acute priapism: defined as a sustained, unwanted painful erection lasting more than 2 hours and requiring care at a medical facility (with or without hospitalization) 4. Karnofsky performance status of ≥ 60 (≥16 years of age) or a Lansky performance status of ≥60 (\<16 years of age). 5. Have either experienced hydroxyurea (HU) failure at any point in the past or must have intolerance to HU (defined as patient being unable to continue to take HU per PI judgement). 6. Have been treated and followed for at least the past 24 months prior to Informed Consent in medical center(s) that maintained detailed records on SCD history. Exclusion Criteria: 1. Positive for presence of human immunodeficiency virus type 1 or 2 (HIV-1 and HIV-2), hepatitis B virus (HBV), or hepatitis C (HCV). 2. Clinically significant and active bacterial, viral, fungal, or parasitic infection. 3. Inadequate bone marrow function, as defined by an absolute neutrophil count of \< 1000/µL (\< 500/µL for subjects on HU treatment) or a platelet count \< 100,000/µL. 4. Any history of severe cerebral vasculopathy: defined by overt or hemorrhagic stroke; abnormal transcranial Doppler \[≥200 cm/sec\] needing chronic transfusion; or occlusion or stenosis in the polygon of Willis; or presence of Moyamoya disease. Subjects with radiologic evidence of silent infarction in the absence of any of the above criteria would still be eligible 5. Baseline oxygen saturation \< 90% without supplemental oxygen (excluding periods of SCD crisis, severe anemia or infection). 6. Baseline carbon monoxide diffusing capacity (DLCO) \< 50% (corrected for Hb) in the absence of infection. If DLco cannot be assessed due to age or cognition-related restrictions, there must be a normal respiratory exam, chest radiograph without pulmonary infiltrates, and oxygen saturation by pulse oximetry ≥ 90% on room air. 7. Baseline left ventricular ejection fraction (LVEF) \< 45% measured by cardiac echography. 8. Clinically significant pulmonary hypertension at baseline, as defined by the requirement for ongoing pharmacologic treatment or the consistent or intermittent use of supplemental home oxygen. 9. Baseline estimated glomerular filtration rate (eGFR) \< 70 mL/min/1.73 m2, as determined using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (see http://www.kidney.org/professionals/kdoqi/gfr\_calculator.cfm). 10. Advanced liver disease, defined as: 1. Persistent aspartate transaminase, alanine transaminase, or direct bilirubin value \>3× the upper limit of normal (ULN), or 2. Baseline prothrombin time or partial thromboplastin time \>1.5× ULN, suspected of arising from liver disease, or 3. Magnetic Resonance Imaging (MRI) of the liver demonstrating clear evidence of cirrhosis, or 4. MRI findings suggestive of active hepatitis, significant fibrosis, inconclusive evidence of cirrhosis, or liver iron concentration ≥15 mg/g require follow-up liver biopsy in subjects ≥18 years of age. In subjects \<18 years of age, these MRI findings are exclusionary, unless in the opinion of the Investigator, a liver biopsy could provide additional data to confirm eligibility and would be safe to perform. If a liver biopsy is performed based on MRI findings, any evidence of cirrhosis, bridging fibrosis, or significant active hepatitis will be exclusionary. 11. For subjects who have history of iron overload or serum ferritin levels \> 1000 ng/mL, a cardiac MRI is required. Cardiac T2\* \< 10 ms results in exclusion. 12. Contraindication to anesthesia. 13. Any contraindications to the use of plerixafor during the mobilization of hematopoietic stem cells and any contraindications to the use of busulfan and any other medicinal products required during the myeloablative conditioning, including hypersensitivity to the active substances or to any of the excipients. 14. Any prior or current malignancy or immunodeficiency disorder, except previously treated, non-life threatening, cured tumors such as squamous cell carcinoma of the skin. 15. Prior receipt of an allogeneic transplant. 16. Immediate family member with a known or suspected Familial Cancer Syndrome. 17. Diagnosis of significant psychiatric disorder of the subject that, in the Investigator's judgment, could seriously impede the ability to participate in the study. 18. Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile subjects. 19. Participation in another clinical study with an investigational drug within 30 days of Screening. 20. Prior receipt of gene therapy. 21. An assessment by the Investigator that the subject or parents/caregivers (as required) will not be able to comply with the study procedures outlined in the study protocol. 22. Patients needing therapeutic anticoagulation treatment during the period of conditioning through platelet engraftment (patients on prophylactic doses of anticoagulants not excluded per this criteria). 23. Unable to receive Red Blood Cell (RBC) transfusion. 24. Any other condition that would render the subject ineligible for hematopoietic stem cell transplant (HSCT), as determined by the attending transplant physician. 25. Applicable to subjects \< 18 years of age only: Availability of a willing, matched HLA-identical sibling hematopoietic cell donor.

Locations (11)

Unnamed facility

Birmingham, Alabama, United States

Unnamed facility

Oakland, California, United States

Unnamed facility

Atlanta, Georgia, United States

Unnamed facility

Chicago, Illinois, United States

Outcomes

Primary Outcomes

Percentage of Group C Participants Who Achieved Complete Resolution of Vaso-occlusive Events (VOE-CR)

VOE-CR was defined as complete resolution of adjudicated VOEs between 6 months and 18 months post lovo-cel infusion. All reported VOEs were also adjudicated by an independent Event Adjudication Committee for purposes of endpoint analysis. VOEs were determined by adjudication committee after referring to protocol VOE. The committee was responsible for VOE assessment and determining whether an event met criteria for a VOE for all reported events.

Time frame: From 6 months to 18 months post lovo-cel infusion

Secondary Outcomes

Percentage of Group C Participants With Complete Resolution of Severe VOEs (sVOE-CR)

sVOE-CR was defined as the complete resolution of sVOEs, in the 6 to 18 months post lovo-cel infusion. All reported VOEs (including sVOEs) were adjudicated by an independent Event Adjudication Committee for purposes of endpoint analysis (referred to as Adjudicated sVOEs). sVOE were determined by adjudication committee after referring to protocol definition of sVOE. The committee was responsible for VOE assessment and determining whether an event met criteria for an sVOE for all reported events.

Time frame: From 6 months to 18 months post lovo-cel infusion

Percentage of Group C Participants Who Achieved Globin Response

Globin Response is defined as meeting the following criteria for a continuous period of at least 6 months post lovo-cel infusion (starting at least 60 days after last packed red blood cell \[pRBC\] transfusion): 1. Weighted average HbAT87Q percentage of non-transfused total Hb \>=30% AND 2. Weighted average non-transfused total Hb increase of \>=3 g/dL compared to baseline total Hb OR weighted average non-transfused total Hb \>=10 g/dL

Time frame: From at least 60 days after last pRBC transfusion up to Month 24 post lovo-cel infusion

Percentage of Group C Participants Who Meet the Definition of Globin Response at Month 24

Globin Response at Month 24 was defined as continuously meeting the following criteria from the first date of globin response initiating to Month 24 assessment post lovo-cel infusion: 1. Weighted average HbAT87Q percentage of non-transfused total Hb \>=30% AND 2. Weighted average non-transfused total Hb increase of \>=3 g/dL compared to baseline total Hb OR weighted average non-transfused total Hb \>=10 g/dL

Data from ClinicalTrials.gov

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Unnamed facility

Bethesda, Maryland, United States

Unnamed facility

Hackensack, New Jersey, United States

Unnamed facility

New Hyde Park, New York, United States

Unnamed facility

New York, New York, United States

Unnamed facility

Chapel Hill, North Carolina, United States

Unnamed facility

Philadelphia, Pennsylvania, United States

...and 1 more locations

Time frame: From first date of Globin Response to Month 24 post lovo-cel infusion

Duration of Globin Response in Group C Participants

Duration of Globin Response is the time period from the first date of Globin Response initiating to the date of last high pressure liquid chromatography (HPLC) assessment such that the weighted average HbAT87Q (%) in non-transfused total Hb and non-transfused total Hb continuously meet Globin Response criteria. 1. Weighted average HbAT87Q percentage of non-transfused total Hb \>=30% AND 2. Weighted average non-transfused total Hb increase of \>=3 g/dL compared to baseline total Hb OR weighted average non-transfused total Hb \>=10 g/dL

Time frame: From first date of Globin Response to Month 24 post lovo-cel infusion

Change From Baseline in the Annualized Number of VOEs in Group C Participants

Change from baseline in the annualized number of VOEs was assessed from 24 months post lovo-cel infusion compared to the 24 months prior to Informed Consent. All reported VOEs were also adjudicated by an independent event adjudication committee for purposes of outcome analysis. VOEs were determined by adjudication committee after referring to protocol definition of VOE. The committee was responsible for VOE assessment and determining whether an event met criteria for a VOE for all reported events.

Time frame: From Baseline up to 24 months post lovo-cel infusion

Change From Baseline in the Annualized Number of sVOEs in Group C Participants

Change from baseline in the annualized number of sVOEs was assessed from 24 months post lovo-cel infusion compared to the 24 months prior to Informed Consent. All reported VOEs (including sVOEs) were adjudicated by an independent Event Adjudication Committee for purposes of endpoint analysis. sVOE were determined by adjudication committee after referring to protocol definition of sVOE. The committee was responsible for VOE assessment and determining whether an event met criteria for an sVOE for all reported events.

Time frame: From Baseline up to 24 months post lovo-cel infusion

Percentage of Group C Participants With Complete Resolution of VOE Between 6 and 24 Months Post Lovo-cel Infusion (VOE-CR24)

VOE-CR24, defined as complete resolution of VOE between 6 months and 24 months post lovo-cel infusion. All reported VOEs were also adjudicated by an independent Event Adjudication Committee for purposes of outcome analysis. VOEs were determined by adjudication committee after referring to protocol definition of VOE. The committee was responsible for VOE assessment and determining whether an event met criteria for a VOE for all reported events.

Time frame: From 6 months to 24 months post lovo-cel infusion

Percentage of Group C Participants With Complete Resolution of sVOEs Between 6 and 24 Months Post Lovo-cel Infusion (sVOE-CR24)

sVOE-CR24, defined as complete resolution of sVOEs in 6 to 24 months post lovo-cel infusion compared to the 24 months prior to Informed Consent. All reported VOEs (including sVOEs) were adjudicated by an independent Event Adjudication Committee for purposes of outcome analysis. sVOE were determined by adjudication committee after referring to protocol definition of sVOE. The committee was responsible for VOE assessment and determining whether an event met criteria for an sVOE for all reported events.

Time frame: From 6 months to 24 months post lovo-cel infusion

Percentage of Group C Participants With At Least 75% Reduction in Annualized sVOEs (sVOE-75)

sVOE-75, defined as at least a 75% reduction in annualized sVOEs in the 24 months post lovo-cel infusion compared to the 24 months prior to Informed Consent. All reported VOEs (including sVOEs) were adjudicated by an independent Event Adjudication Committee for purposes of outcome analysis. sVOE were determined by adjudication committee after referring to protocol definition of sVOE. The committee was responsible for VOE assessment and determining whether an event met criteria for an sVOE for all reported events.

Time frame: Up to 24 months post lovo-cel infusion

Change From Baseline in Annualized VOE-related Hospital Admissions in Group C Participants

Change from baseline was calculated as annualized number of VOE-related hospital admissions during post-drug product infusion discharge through the last study visit minus annualized number of VOE related hospital admissions at baseline. Baseline was annualized number of VOE-related hospital admissions in 24 months prior to the Informed Consent.

Time frame: From post hospital discharge to Month 24

Change From Baseline in Annualized VOE-related Total Days Hospitalized in Group C Participants

Change from baseline was calculated as annualized number of VOE-related hospital days during post-drug product infusion discharge through the last study visit minus annualized number of VOE related hospital days at baseline. Baseline was annualized number of VOE-related hospital days in 24 months prior to the Informed Consent.

Time frame: From post hospital discharge to Month 24

Weighted Average of Non-transfused Total Hb in Group C Participants

Non-transfused total Hb was the total g/dL of HbS + HbF + HbA2 + HbAT87Q for participants without beta + allele or HbS + HbF + HbA2 + HbAT87Q + HbA for participants with beta + allele.

Time frame: At Month 6, 12, 18, and 24 post lovo-cel infusion

Weighted Average of HbS Percentage (%) in Non-transfused Total Hb in Group C Participants

HbS % in non-transfused total Hb = (HbS/ non-transfused total Hb)\*100.

Time frame: At Month 6, 12, 18, and 24 post lovo-cel infusion

Percentage of Group C Participants Who Achieved <= 70%, <= 60%, and <= 50% Weighted Average of HbS % in Non-transfused Total Hb

HbS % in non-transfused total Hb = (HbS/ non-transfused total Hb)\*100. The denominator of the percentage is based on the total number of participants who have non-missing value at the Visit.

Time frame: At Month 6, 12, 18, and 24 post lovo-cel infusion

Weighted Average of HbAT87Q % in Non-transfused Total Hb in Group C Participants

HbAT87Q % in non-transfused total Hb was calculated as: HbAT87Q / non-transfused total Hb \*100.

Time frame: At Month 6, 12, 18, and 24 post lovo-cel infusion

Weighted Average of Non-HbS % in Non-transfused Total Hb in Group C Participants

Non-HbS percentage in non-transfused total Hb = \[(HbF + HbA2 + HbAT87Q)/ non-transfused total Hb\] \*100. For participants with beta + allele, HbA was also included in the calculated for "non-HbS" for samples taken \>= 60 days after last pRBC transfusion.

Time frame: At Month 6, 12, 18, and 24 post lovo-cel infusion

Non-transfused Total Hb (g/dL) Over Time

Non-transfused total Hb was the total g/dL of HbS + HbF + HbA2 + HbAT87Q for participants without beta + allele or HbS + HbF + HbA2 + HbAT87Q + HbA for participants with beta + allele.

Time frame: From infusion up to Month 24

HbS % in Non-transfused Total Hb Over Time

HbS (%) in non-transfused total Hb = (HbS / non-transfused total Hb)\*100.

Time frame: From infusion up to Month 24

HbAT87Q % in Non-transfused Total Hb Over Time

HbAT87Q (%) in Non-transfused total Hb = (HbAT87Q / non-transfused total Hb)\*100.

Time frame: From infusion up to Month 24

Non-HbS % of Non-transfused Total Hb Over Time

Non-HbS % in non-transfused total Hb = \[(HbF + HbA2 + HbAT87Q)/ non-transfused total Hb\] \*100.

Time frame: From infusion up to Month 24

Change From Baseline in Absolute Reticulocyte Count in Group C Participants

Reticulocytes are immature RBCs that develop in the bone marrow and circulate in the bloodstream for about a day before developing into mature RBCs. Due to the loss of mature RBCs during hemolysis, there is usually a high demand to produce new RBCs in subjects with SCD, resulting in higher than normal absolute reticulocyte counts. For this outcome Baseline is the first assessment on or after Informed Consent but before initiation of stem cell collection.

Time frame: Baseline, Month 12 and Month 24

Change From Baseline in Percent (%) Reticulocyte/Erythrocytes in Group C Participants

Reticulocytes are immature RBCs that develop in the bone marrow and circulate in the bloodstream for about a day before developing into mature RBCs. The fraction of reticulocytes/erythrocytes in the blood is normally 0.5% to 2.5%, and is increased when there is peripheral hemolytic anemia. Due to the loss of mature RBCs during hemolysis, there is usually a high demand to produce new RBCs in subjects with SCD, resulting in higher than normal reticulocyte counts. For this outcome, Baseline is the first assessment on or after Informed Consent but before initiation of stem cell collection.

Time frame: Baseline, Month 12 and Month 24

Change From Baseline in Total Bilirubin in Group C Participants

Reduction of red blood cell sickling with lovo-cel has the potential to reduce or eliminate downstream complications, including hemolysis. Total Bilirubin is a marker of RBC hemolysis and so increases in Total Bilirubin levels suggests increased hemolysis. For this outcome, Baseline is the first assessment on or after Informed Consent but before initiation of stem cell collection.

Time frame: Baseline, Month 12 and Month 24

Change From Baseline in Haptoglobin in Group C Participants

Reduction of red blood cell sickling with lovo-cel has the potential to reduce or eliminate downstream complications, including hemolysis. Haptoglobin is a marker of RBC hemolysis and so increases in Haptoglobin levels suggests increased hemolysis. For this outcome, Baseline is the first assessment on or after Informed Consent but before initiation of stem cell collection. It should be noted that Baseline haptoglobin levels may be impacted by a range of factors that result in variability, including (but not limited to) other therapies that a participant receives (such as blood transfusions or hydroxyurea), which limit interpretability of these data.

Time frame: Baseline, Month 12 and Month 24

Change From Baseline in Lactate Dehydrogenase (LDH) in Group C Participants

Reduction of red blood cell sickling with lovo-cel has the potential to reduce or eliminate downstream complications, including hemolysis. Lactate Dehydrogenase is a marker of RBC hemolysis and so increases in LDH levels suggests increased hemolysis, For this outcome, Baseline is the first assessment on or after Informed Consent but before initiation of stem cell collection.

Time frame: Baseline, Month 12 and Month 24

Change From Baseline in Cardiac T2* on MRI in Group C Participants

Particulate intracellular iron causes shortening of the magnetic resonance relaxation parameter T2 due to microscopic magnetic field inhomogeneity. A myocardial T2 value of 40 msec, which equates to 0.50 mg/g of dry weight iron has widely been used as the normal mean. Myocardial T2. Values below 20 msec are considered abnormal, and values below 10 msec indicate high risk of cardiac morbidity and mortality. For this outcome, Baseline was defined as the first assessment on or after Informed Consent but before initiation of stem cell collection. If no records at screening, the last assessment prior to Informed Consent was used. Note: while data are provided for this outcome measure, the results for this outcome are not anticipated to be fully mature until extended participant long-term follow-up in Study LTF-307 has been achieved. The results presented below should be interpreted in that context.

Time frame: Baseline, Month 24

Change From Baseline in Serum Ferritin in Group C Participants

Serum ferritin is commonly used for an indirect estimation of body iron stores. Although sensitive, it is not specific for iron overload as it can be elevated in a variety of infectious and inflammatory states, and in the presence of cytolysis. For this outcome, Baseline was the first assessment on or after Informed Consent but before initiation of stem cell collection. Note: while data are provided for this outcome measure, the results for this outcome are not anticipated to be fully mature until extended participant long-term follow-up in Study LTF-307 has been achieved. The results presented below should be interpreted in that context.

Time frame: Baseline, Month 12 and Month 24

Change From Baseline in Liver Iron Concentration (LIC) by Magnetic Resonance Imaging (MRI) in Group C Participants

Liver Iron Concentration of greater than 15 mg per gram dry weight (mg/g) is associated with an increased risk of hepatic disease and cardiac toxicity, whereas levels between 7 to 15 mg/g enhance the risk of hepatic fibrosis and endocrine complications. Liver Iron Concentration of greater than 1.8 mg/g dry weight is considered abnormal; however, organ damage generally does not occur with levels less than 7 mg/g. For this outcome, Baseline was defined as the first assessment on or after Informed Consent but before initiation of stem cell collection. If no records at screening, the last assessment prior to Informed Consent was used. Note: while data are provided for this outcome measure, the results for this outcome are not anticipated to be fully mature until extended participant long-term follow-up in Study LTF-307 has been achieved. The results presented below should be interpreted in that context.

Time frame: Baseline, Month 24

Change From Baseline in Annualized Volume of pRBC Transfusions in Group C Participants

Change from baseline was calculated as annualized volume of pRBC transfusions in 6 to 24 months post lovo-cel infusion - annualized volume of pRBC transfusions at baseline. Baseline was the annualized volume of pRBC transfusion in the 24 months prior to the Informed Consent.

Time frame: From 6 months through 24 months post lovo-cel infusion

Change From Baseline in Annualized Number of Packed Red Blood Cell (pRBC) Transfusions in Group C Participants

Change from baseline was calculated as annualized number of pRBC transfusions in 6 to 24 months post lovo-cel infusion - annualized number of pRBC transfusions at baseline. Baseline was the annualized number of pRBC transfusion in the 24 months prior to the Informed Consent.

Time frame: From 6 months through 24 months post lovo-cel infusion

Change From Baseline in Erythropoietin Levels in Group C Participants

Erythropoietin is a hormone produced mainly by the kidneys in response to hypoxia, which can be caused by anemia. Patients with SCD typically produce higher than normal levels of serum erythropoietin. Baseline is the first assessment on or after Informed Consent but before initiation of stem cell collection.

Time frame: Baseline, Month 12 and Month 24

Change From Baseline in Cardiac-pulmonary Function Via Left Ventricular Ejection Fraction (LVEF) in Group C Participants

LVEF is the central measure of left ventricular systolic function. LVEF is the fraction of chamber volume ejected in systole (stroke volume) in relation to the volume of the blood in the ventricle at the end of diastole (end-diastolic volume). This was measured by ECHO. Baseline was the first assessment on or after Informed Consent but before initiation of stem cell collection. If no records at screening, the last assessment prior to Informed Consent was used. Note: while data are provided for this outcome measure, the results for this outcome are not anticipated to be fully mature until extended participant long-term follow-up in Study LTF-307 has been achieved. The results presented below should be interpreted in that context.

Time frame: Baseline, Month 24

Change From Baseline in Serum Transferrin Receptor in Group C Participants

Transferrin is a circulating iron carrier protein, delivering iron to cells via the transferrin receptor, and levels of serum transferrin receptor have been used as an indicator of excess iron in the body. Additionally, the transferrin receptor is highly expressed in erythroblasts, and increased levels of the soluble form (serum transferrin receptor) have been shown to be associated with increased levels of erythropoiesis. Baseline is the first assessment on or after Informed Consent but before initiation of stem cell collection.

Time frame: Baseline, Month 12 and Month 24

Change From Baseline in Renal Function as Measured by Estimated Glomerular Filtration Rate (eGFR) in Group C Participants

eGFR was calculated by chronic kidney disease epidemiology collaboration (CKD-EPI) formula for participants \>=18 years of age and Schwartz formula was used for participants \<18 years of age. Baseline is the first assessment on or after Informed Consent but before initiation of stem cell collection. If no records at screening, the last assessment prior to Informed Consent was used. Note: while data are provided for this outcome measure, the results for this outcome are not anticipated to be fully mature until extended participant long-term follow-up in Study LTF-307 has been achieved. The results presented below should be interpreted in that context.

Time frame: Baseline, Month 12 and Month 24

Number of Participants With Shift From Baseline in Cardiac-pulmonary Function Via Echocardiogram (Tricuspid Regurgitant Jet Velocity [TRJV]) in Group C Participants

TRJV over time for each participant was classified into 2 categories: \<2.5 m/sec versus \>=2.5 m/sec. Higher value of TRJV indicates worse result. A TRJV value of \>2.5 m/s was associated with a higher risk of complications, especially in participants with Sickle Cell Disease due to hemolysis and pulmonary hypertension. Baseline was the first assessment on or after Informed Consent but before initiation of stem cell collection. If no records at screening, the last assessment prior to Informed Consent was used. Note: while data are provided for this outcome measure, the results for this outcome are not anticipated to be fully mature until extended participant long-term follow-up in Study LTF-307 has been achieved. The results presented below should be interpreted in that context.

Time frame: Baseline, Month 24

Number of Participant With Shift From Baseline in Cardiac-pulmonary Function Via Pulmonary Function Tests (PFTs) in Group C Participants

PFTs over time of each participant were classified into one of the five categories: normal, obstructive, restrictive, mixed obstructive and restrictive and isolated low DLco (carbon monoxide diffusing capacity). Only non-zero values are reported here. Baseline was the first assessment on or after Informed Consent but before initiation of stem cell collection. If no records at screening, the last assessment prior to Informed Consent was used. Note: while data are provided for this outcome measure, the results for this outcome are not anticipated to be fully mature until extended participant long-term follow-up in Study LTF-307 has been achieved. The results presented below should be interpreted in that context.

Time frame: Baseline, Month 24

Change From Baseline in Meters Walked During 6-minute Walk Test in Group C Participants

The 6-minute walk test measures the distance in meters walked during 6 minutes and can be used to assess pulmonary function. Baseline was the first assessment on or after Informed Consent but before initiation of stem cell collection.

Time frame: Baseline, Month 12 and Month 24

Change From Baseline in Patient-reported Quality of Life as Measured by Patient Reported Outcomes Measurement Information System-57 (PROMIS-57): Domain (T- Score) in Group C Participants

The PROMIS-57 profile was a self-reported questionnaire assessing quality of life in various 7 domains (pain interference, physical function, sleep disturbance, Ability to participate in social roles and activities, anxiety, depression, and fatigue) in participants \>=18 years old.These 7 domains are scored on a 5-point Likert scale and converted into standardized T-scores with a mean of 50 and a standard deviation of 10 based on a US general population. The higher of the T-score: the better of physical function, satisfaction with participation in social roles, and ability of participate in social roles in activities; The higher of the T-score: the worse of anxiety, depression, fatigue, sleep disturbance, and pain interference. A negative value indicates improvement, and a positive value indicates no improvement in condition. Baseline was the first assessment on or after Informed Consent but before initiation of stem cell collection.

Time frame: Baseline, Month 24

Change From Baseline in Patient-reported Quality of Life as Measured by PROMIS-57: Pain Intensity Score in Group C Participants

The PROMIS-57 profile was a self-reported questionnaire assessing quality of life in various domains in participants \>=18 years old. Pain intensity was scored from 0 to 10, with higher scores indicating greater pain intensity. A negative value indicates improvement in pain intensity and a positive value indicates no improvement or worsening in pain intensity. Baseline was the first assessment on or after Informed Consent but before initiation of stem cell collection.

Time frame: Baseline, Month 24

Change From Baseline in Patient-reported Quality of Life as Measured by Patient Reported Outcomes Measurement Information System- 49 (PROMIS-49)): Domain (T- Score) in Group C Participants

The PROMIS-49 profile was a self-reported questionnaire assessing quality of life in various 6 domains (physical function mobility, peer relationships, pain interference, anxiety, depression, and fatigue) in participants \<=18 years old. These 6 domains are scored on a 5-point Likert scale and converted into standardized T-scores with a mean of 50 and a standard deviation of 10 based on a US general population. The higher of the T-score, the better of physical function mobility, and peer relationships; The higher of the T-score, the worse of anxiety, depression symptoms, fatigue, and pain interference. A negative value indicates improvement, and a positive value indicates no improvement in condition. Baseline was the first assessment on or after Informed Consent but before initiation of stem cell collection.

Time frame: Baseline, Month 24

Change From Baseline in Patient-reported Quality of Life as Measured by PROMIS-49: Pain Intensity Score in Group C Participants

The PROMIS-49 profile was a self-reported questionnaire assessing quality of life in various domains in participants \<=18 years old. Pain intensity was scored from 0 to 10, with higher scores indicating greater pain intensity. A negative value indicates improvement in pain intensity and a positive value indicates no improvement or worsening in pain intensity. Baseline was the first assessment on or after Informed Consent but before initiation of stem cell collection.

Time frame: Baseline, Month 24