CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
Nurses: 1.00 Nursing contact hour
Physicians: maximum of 1.00 AMA PRA Category 1 Credit™
Pharmacists: 1.00 contact hour (0.1 CEUs)
Released: February 22, 2024
Expiration: February 21, 2025
Sickle Cell Disease Overview
SCD is an inherited hematologic disorder associated with early mortality, increased healthcare resource utilization, and poor quality of life (QoL).1,2 In SCD, “sickle hemoglobin” polymerization can lead to red blood cell (RBC) deformation and RBC clumping in the vasculature, which in turn can lead to vaso-occlusion, organ damage and pain, and cerebrovascular disease and cognitive impairment―particularly in children. The highest rates of SCA are found in people from sub-Saharan Africa (Angola, Democratic Republic of Congo, Kenya, Uganda), where up to 2% of newborns are estimated to have SCA.
In patients with SCA, the associated symptoms of anemia are often managed with RBC transfusions and antimetabolites. Hydroxyurea is an antimetabolite approved by the FDA that is used to reduce the frequency of RBC transfusion and incidence of painful vaso-occlusive crises in people with SCA.3
At ASH 2023, we saw key advances presented for the management of SCD and its associated symptoms of anemia. I would like to start off by talking about a few of the most prominent and interesting abstracts presented at the meeting.
Dose-Optimized HU for Pediatric SCA in Sub-Saharan Africa (REACH Long-term Analysis): Study Design
A key study presented during the plenary session of ASH 2023 involved a long-term analysis from the international, open-label, 2-stage phase I/II REACH trial evaluating dose‑optimized hydroxyurea therapy in pediatric patients (aged 1-10 years) with SCA in sub‑Saharan Africa (N = 606; NCT01966731).4 In this trial, there was a screening phase and a 6‑month fixed-dose phase where the patients received either 15 or 20 mg of hydroxyurea/kg/day orally. Then there was a dose-escalation phase where the dose of hydroxyurea was escalated by 5 mg/kg/day every 8 weeks up to the MTD. Afterwards, there was a dose-optimization phase where the dose of hydroxyurea at the MTD was further optimized for weight gain and increases were guided by CBC parameters. The primary safety endpoint was the incidence of hematologic dose‑limiting toxicities (DLTs) in the first 3 months of treatment in the first 133 patients enrolled at each site. The secondary endpoints included feasibility of enrollment, retention, and adherence to treatment. The REACH study investigators also looked at safety parameters (dose level, toxicity, and incidence of malaria) and benefits seen through laboratory values, SCD-related events, need for transfusions, and patient survival. The report from ASH 2023 had a special focus on the long-term laboratory values, clinical outcomes, and DLTs across 4 dose phases.
REACH Long-term Analysis: Baseline Characteristics, Patient Disposition, and Dosing
When we look at the patient characteristics in the REACH study, the average age at enrollment was 5.4 years, mean hemoglobin level was 7.3 g/dL, mean hemoglobin F was 11 g/dL, and mean absolute neutrophil count was 6.8 x 109/L─which was within the normal range. A total of 606 patients started treatment, there were 44 patient deaths, and 40 patients exited the study. In total, 86% of patients remained on the study at the time of this report. The average treatment duration was approximately 85 months and at the time of analysis there were more than 4300 patient-years of hydroxyurea therapy.
REACH Long-term Analysis: Clinical Events
Clinical events of interest, which included events per 100 patient-years, were compared for fixed-dose vs MTD including vaso‑occlusive painful events 72.7 vs 43.6 (P <.001), acute chest event 10.0 vs 2.1 (P <.001), primary stroke 0.35 vs 0.18 (P <.55), secondary stroke 18.6 vs 4.5 (P <.061), development of malaria 32.8 vs 18.8 (P <.001), nonmalarial infections 124.9 vs 64.8 (P <.001), serious adverse events (AEs) 7.7 vs 3.1 (P <.0003), and death events 1.3 vs 0.9 (P <.50). Of importance, hemoglobin values increased from baseline and were sustained through Year 8 of the study.
Overall, when we look at the events per 100 patient-years on the fixed-dose vs the MTD dose, for many of the important metrics in patients with SCD we see a greater benefit without a significant difference in serious AEs or death with the MTD dose.
REACH Long-term Analysis: Safety Summary
If we look at safety-related events per 100 patient-years, total DLTs (24.1 vs 22.0 vs 23.2), hemoglobin levels (8.7 vs 5.8 vs 5.9), neutrophil counts (3.0 vs 4.3 vs 3.9), reticulocyte counts (5.7 vs 5.2 vs 6.6), and platelet counts (6.7 vs 6.6 vs 6.8), we can see that except for slightly lower hemoglobin there were no significant differences between the fixed-dose phase, the dose-escalation phase, or the maintenance phase (P ≥ .46 for all).
REACH Long-term Analysis: Conclusions and Takeaways
In the long‑term analysis from the REACH study, the investigators concluded that extended MTD hydroxyurea therapy was well-tolerated and effective in children aged 1 to 10 years with SCA and living in sub‑Saharan Africa. We also saw that there were improved clinical outcomes and the benefit in laboratory values were sustained when hydroxyurea was dose-escalated to MTD followed by dose-optimization according to body weight and CBC. Of importance, dose optimization was not associated with any increase in laboratory toxicities and CBC monitoring was only necessary once the patient had reached a stable dose―which was approximately 2 to 3 times a year.
My takeaway is that the results from the REACH trial are important as we try to translate the experience in sub‑Saharan Africa to our patient populations here in the United States. The challenges that we may encounter in our clinics have to do with patient compliance, patient follow-up, and concerns about quickly addressing toxicities if a patient is not able to easily get to us for frequent monitoring. The REACH study demonstrated that we can safely prescribe hydroxyurea, particularly in children, at a MTD without being overly concerned about having to monitor laboratory values every month.
In my opinion, the phase I/II REACH trial supports integrating hydroxyurea treatment at an optimal dosing into SCD programs in sub‑Saharan Africa and also informs our practice on the safety of escalating the hydroxyurea dose with less frequent monitoring.
Efficacy, Safety, and Health-Related QoL of Lovo-cell Gene Therapy in Patients With SCD: Study Design
Next, I would like to cover some of the newer therapeutic interventions for SCD in the form of gene therapy.
At ASH 2023, Dr Kanter and colleagues reported results of the pooled analysis from a single-arm, multicenter phase I/II HGB-206 (group C) trial and phase III HGB-210 trials evaluating the efficacy, safety, and health‑related QoL outcomes of lovotibeglogene autotemcel (lovo‑cel), a gene therapy consisting of a single infusion of autologous hematopoietic stem and progenitor cells transduced with a modified β-globin gene that produces modified antisickling hemoglobin A (HbAT87Q),5 in patients with SCD (NCT04293185).6
The trial enrolled patients 12 to 50 years of age with SCD (genotype βS/βS, βS/β0, or βS/β+) who had experienced ≥4 vaso‑occlusive events within the 24 months prior to informed consent. Patients had either failed hydroxyurea or were intolerant to hydroxyurea and had a Karnofsky performance status of ≥60.
Patients were placed on a premobilization transfusion regimen where stem cells were mobilized with plerixafor and collected with apheresis. Collected stem and progenitor cells were transfected with the HbAT87Q coding lentivirus. The patients received myeloablative conditioning and then a single lovo‑cel infusion. Following lovo-cel infusion, patients underwent a 2-year or 13‑year long‑term follow‑up study. The primary endpoint was complete remission from vaso‑occlusive events (timeframe: 6-18 months). The secondary endpoint was remission from severe vaso‑occlusive events, also from 6-18 months. Other endpoints included globin response, HbAT87Q levels, hemolysis markers, safety, and patient-reported outcomes (PROs) per Patient-Reported Outcomes Measurement Information System-57.
Lovo-cel Pooled Analysis: Baseline Characteristics
The median age of patients enrolled in the trials (pooled analysis) was 23 years (range: 12-38). Patients older than age 18 represented approximately 79% of the total population, and 8% overall had a history of overt stroke. The annualized number of vaso‑occlusive events was 3.5 (range: 0.0-16.5). The annualized number of severe vaso‑occlusive events was 3.0 (range: 0-13). The annualized number of packed RBC transfusions was 3 (range: 0.0-17.0). The median follow-up after infusion was 35.5 months with an overall exposure of approximately 126 patient-years.
Lovo-cel Pooled Analysis: Patient Disposition and Mobilization, Gene Tx, and Engraftment Characteristics
Overall, 59 patients initiated mobilization, 4 of them were pending lovo-cel infusion, 8 discontinued before infusion (due to physician decision, patient withdrawal, or stem cell mobilization failure).
In the efficacy and safety analysis pool, a total of 47 patients have received infusion of the lovo-cel product and 9 were not yet evaluable for efficacy at the data cutoff. A total of 38 patients were evaluable for globin response and 34 were evaluable for vaso‑occlusive events.
The median days to neutrophil engraftment (n = 44) was approximately 20 days (range: 12-35). Median days to platelet engraftment was 35 days (range: 19-136). Of importance, the median duration of hospitalization was 36 days (range: 26-65).
Approximately 85% of patients needed fewer than 2 mobilization cycles and the peripheral blood vector copy number remained stable throughout the follow-up period.
Lovo-cel Pooled Analysis: Complete Resolution of All VOEs From 6-18 Mo (Primary Endpoint)
Complete resolution of all vaso‑occlusive events from 6 to 18 months was achieved by 88.2% of patients who received single-infusion lovo-cel gene therapy. Looking specifically to the adolescent patient population (ages 12 to ≤18), 100% achieved complete resolution of vaso‑occlusive events. All patients with a vaso-occlusive event at baseline experienced a 50% or greater reduction in vaso-occlusive events following treatment.
Lovo-cel Pooled Analysis: Complete Resolution of Severe VOEs From 6-18 Mo (Key Secondary Endpoint)
Complete resolution of all severe vaso‑occlusive events from 6 to 18 months was achieved in 94.1% of patients who received single-infusion lovo-cel gene therapy. Of interest, 100% of the adolescent patient population (ages 12-≤18) achieved complete resolution of severe vaso‑occlusive events. Moreover, from 6 months after infusion through the last follow-up (median follow-up: 36.3 months), 85.3% of patients had no vaso‑occlusive event–related hospitalizations.
Lovo-cel Pooled Analysis: PROs, Globin Response, and Laboratory Evaluations
Patients reported significant improvements in pain and fatigue intensity scores. No post‑treatment strokes were observed in any patient with a history of stroke. Regarding globin response and laboratory evaluations, 86.8% of patients achieved a globin response and 100% had durable globin response through the last follow-up.
Hemoglobin A levels remained stable in all patients from 6 months to the last follow-up, and hemoglobin A comprised a median of 40% or greater of nontransfused hemoglobin.
Markers of hemolysis (eg, reticulocytes, indirect bilirubin, lactate dehydrogenase [LDH]) trended towards normal levels in these patients following single-infusion lovo-cel.
Lovo-cell Pooled Analysis: Safety Summary
Regarding the safety of lovo-cel, any grade AEs were reported in all 47 patients in the transplant population. Grade ≥3 AEs were reported in approximately 94% of patients.
Lovo-cel–related AEs (8.5%) as assessed by trial investigators included anemia (4.3%), abdominal discomfort (2.1%), blood pressure decrease (2.1%), myelodysplastic syndromes (MDS) (2.1%), and nasal congestion (2.1%). Few serious AEs were deemed to be lovo‑cel related. There was 1 death attributed to SCD‑related cardiopulmonary disease, which was present at baseline and deemed unrelated to the lovo‑cel therapy.
Most treatment‑emergent AEs occurred within 1 year of lovo-cel therapy and appear closely related to the safety profile for busulfan conditioning. No patients had veno-occlusive disease of the liver, graft failure, or graft-vs-host disease (GVHD).
There was no oncogenesis or vector‑mediated replication‑competent lentivirus observed. However, 2 patients, 1 with βS/βS and another with α-thalassemia trait (-α3.7/-α3.7), developed severe anemia and myelodysplasia. The patient with MDS was a 16-year-old and was diagnosed 30 months after the lovo-cel infusion.
Conclusion and Takeaways
My takeaways from this pooled safety study of single-infusion lovo-cel gene therapy for SCD is that the vast majority of patients had a very good response with regards to complete resolution of vaso‑occlusive events (88%) and severe vaso-occlusive events (94%). All 10 adolescent patients had a complete resolution of their vaso‑occlusive events. After a median follow-up of approximately 36 months, most patients continue to be free of vaso‑occlusive events.
There were clinically meaningful improvements in pain and fatigue, and the investigators mentioned that these were consistent with previous reports.5
For our practices, this is an exciting novel therapeutic option to consider for our patients with SCD. It also brings home some concepts that we need to be thinking about when treating these patients earlier in their disease process, particularly to avoid any of the chronic consequences of living with SCD.
Reduced Intensity Haploidentical BMT in Adults With Severe SCD (BMT CTN 1507): Study Design
Another study presented at ASH 2023 for SCD that I wish to highlight is the single-arm, multicenter phase II BMT CTN 1507 trial of reduced intensity haploidentical bone marrow transplant (BMT) with posttransplant cyclophosphamide in adults with severe SCD.7 The trial enrolled patients aged 15 to 45 years with SCD and ≥2 episodes of acute chest syndrome or ≥3 episodes of vaso‑occlusive crisis in the preceding 2 years. Patients had to have had ≥8 transfusions per year for ≥1 year, or tricuspid valve regurgitant jet velocity ≥2.7. Patients also had a haploidentical first‑degree relative. In total, 42 patients received a transplant following conditioning regimen, followed by cyclophosphamide, and post-transplant mycophenolate mofetil and sirolimus. The primary endpoint was event‑free survival (EFS) at 2 years after haploidentical BMT and secondary endpoints were clinical and laboratory manifestations of SCD.
BMT CTN 1507 Adult Cohort: Baseline Characteristics
The median age of patients enrolled in this study was 22.8 years (range: 15.5-43.2). Approximately 60% were men, 92.6% were Black or African American, and 3.7% were Hispanic/Latino.
The median follow-up time at the time of this report was 24.4 months (range: 1.0-45.8). Indications for transplant included recurrent vaso‑occlusive pain episodes (60%), chronic use of RBC transfusion (38.1%), acute chest syndrome (16.7%), overt stroke (14.3%), and elevated tricuspid valve regurgitant jet velocity (2.4%).
Regarding human leukocyte antigen (HLA) match score, approximately 76% of patients were 4/8 match, 14.8% were 5/8 match, and 9.3% were 6/8 match.
BMT CTN 1507 Adult Cohort: Efficacy and Engraftment Characteristics
When we look at the data for the primary endpoint of EFS, we see that the estimated 2-year EFS was 88% (95% CI: 73.5-94.8). The 2-year estimate for overall survival was 95% (95% CI: 81.5-98.7).
Neutrophil recovery at 42 days was seen in approximately 93% (95% CI: 77.4-97.9) of patients. Platelet recovery at 60 days was observed in 88% (95% CI: 81.5-98.7) of patients and it was approximately 93% (95% CI: 77.4-97.9) after 100 days. Of importance, 88.1% of patients achieved full donor chimerism at Day 28. Low donor chimerism (defined as lower than 5%), was only seen in 4.8% of patients.
BMT CTN 1507 Adult Cohort: GVHD
Incidence of GVHD at Day 100 was low. The cumulative incidence for 2‑year chronic GVHD estimates was approximately 22%. Approximately 26% of patients (95% CI: 14.0-40.2) developed grade II-IV acute GVHD. Only 4.8% (95% CI: 0.9-14.4) of patients developed grade III-IV GVHD.
BMT CTN 1507 Adult Cohort: Complications and Deaths
In regard to complications and death following transplant, 13 patients experienced complications at 1 year (eg, idiopathic pneumonia syndrome [n = 1], central nervous system toxicities [n = 1], and infections [n = 11]).
SCD-related events of special interest were relatively infrequent and were reported at 6-month visit (n = 3), 1-year visit (n = 4), 1.5-year visit (n = 6), and 2-year visit (n = 2). A total of 4 patients died on study; 1 patient each from intracranial hemorrhage, organ failure, acute respiratory distress syndrome, COVID-19, and hemorrhagic shock related to COVID-19.
BMT CTN 1507 Adult Cohort: Conclusions and Takeaways
The BMT CTN 1507 study showed that reduced intensity haploidentical-BMT in adults was feasible and yielded a 2‑year estimated EFS of 88%, including with enduring donor engraftment and low mortality. We also saw a promising 2‑year EFS and overall survival that were similar to those reported after a myeloablative BMT.8-10
To me, these results suggest that we could consider utilizing haploidentical-BMT with post‑transplant cyclophosphamide as a potential curative therapy for adults with SCD and coexisting end-organ toxicities that might make them ineligible for clinical trials of myeloablative gene therapy or gene editing approaches. This trial gives us an important set of data that will potentially help expand available curative options for our patients with SCD.
Back
