3 Bench to Bedside: Innovations in Hemoglobinopathy Treatment
3.1 Session Overview
| Session | Bench to Bedside: Innovations in Hemoglobinopathy Treatment [slide p.1] |
| Speakers | Payal Desai, MD; Prantar Chakrabarti, MD, DNB, DM [slide p.2] |
| Affiliations | Levine Cancer Institute, Atrium Health, Winston-Salem, NC, USA; Sugah Healthcorp (Chief Medical Director), Chennai, and ex-Professor and Head of Hematology, NRS Medical College, Kolkata, India [slide p.2] |
| Time | Day 1, 11:00–11:45 a.m. |
This dual-speaker session is structured around a longitudinal case — a 22-year-old Thai woman with HbE/β-thalassemia presenting first to a US primary-care center (Dr. Desai) and then re-imagined as a Bengali patient at NRS Medical College, Kolkata (Dr. Chakrabarti) — to contrast the therapeutic frontier with the global access reality [slide p.10, p.74]. Dr. Desai builds the Western toolkit: phenotypic breadth of NTDT, iron overload, hydroxyurea in pregnancy (ESCORT-HU), pyruvate kinase activation with mitapivat (ENERGIZE-T), osivelotor as the successor to voxelotor, luspatercept meta-analysis, and the maturing gene therapy data (exa-cel CLIMB THAL-141 / SCD-151 in ages 5–11, BMT CTN 1507 haploidentical transplant) [slide p.16, p.29, p.36, p.48, p.43, p.54, p.59]. Dr. Chakrabarti then re-centers the conversation on Asia-Pacific: ~80% of the world’s hemoglobinopathy patients live in South and Southeast Asia, blood supply is critically imbalanced, and thalidomide — off-label in most jurisdictions but extensively validated in Indian HbE/β-thalassemia cohorts — is an accessible, affordable fetal hemoglobin inducer [slide p.6, p.86, p.98, p.101]. A recurring closing slide frames five unresolved dilemmas: to transfuse or not, how to source safe blood, how much to transfuse, which adjunctive agents to use, and how to chelate iron [slide p.75].
3.2 Speaker Spotlight
Payal Desai, MD is a hematologist at Wake Forest University School of Medicine specializing in adult SCD comprehensive care. Her work spans health equity, novel therapeutic clinical trials, and the delivery of multidisciplinary care for adults with SCD. She brings a clinical trials perspective on the post-withdrawal SCD treatment landscape.
Prantar Chakrabarti, MBBS, MD, DNB, DM is based at Zoho for Healthcare in India and brings extensive expertise in hemoglobinopathies in the Indian subcontinent. His work addresses the challenges of thalassemia management at scale, including digital healthcare and telemedicine solutions for chronic disease monitoring in resource-limited settings.
3.3 What’s New in 2025–2026
3.3.1 Setting the Stage: The Asia-Pacific Epicenter
Over 80% of global hemoglobin-disorder patients outside Africa are born and live in the South-East Asia and Western Pacific regions, with overlapping α-thalassemia, β-thalassemia, HbE, and SCD distributions [slide p.6]. India carries an estimated 100–150k β-thalassemia patients, 125k SCD patients, and ~15,000 new affected births per year; Thailand reports ~100k transfusion-dependent and >400k total thalassemia patients with HbE carrier rates of 5–50%; Indonesia has >13,612 registered patients and >6,000 affected newborns annually; Malaysia has 9,342 registered patients (5,442 TDT, 3,900 NTDT) [slide p.7]. HbE/β-thalassemia alone accounts for 46–58% of hemoglobin disorders in parts of the region, and the coexistence of α⁰-thalassemia with non-deletional mutations creates severe HbH disease and fatal hydrops fetalis [slide p.8]. Red-cell unit availability is drastically uneven (33.15 units per 1,000 in Thailand vs 11.18 in Indonesia vs 2.56 in Timor-Leste) and only 1–3% regular voluntary donation would meet need [slide p.9, p.86].
3.3.2 Dr. Desai: The Expanding Western Toolkit
3.3.2.1 Thalassemia is a Spectrum, and NTDT is not “Never Transfused”
Thalassemia extends across a continuum from thalassemia minor through non-transfusion-dependent thalassemia intermedia (NTDT) to transfusion-dependent thalassemia major, with β-thalassemia intermedia, HbE/β-thalassemia, deletional and nondeletional HbH, and E/F Bart’s disease all falling in the intermittently transfused middle [slide p.13]. In a 3-center US cohort of 82 adults with NTDT (Cheng et al., Abstract #1141: UCSF, Weill Cornell, Penn), 38% had ferritin >800 ng/mL with only 22.6% on chelation, 50% had liver iron content (LIC) >5 mg/g dry weight with only 24% on chelation, and 3 patients had cardiac T2* <20 msec without any chelation — iron overload in NTDT is common and under-treated [slide p.17]. Over follow-up, 49% were recommended to initiate regular transfusions, most commonly for symptomatic anemia/fatigue (49%) or extramedullary hematopoiesis / ineffective erythropoiesis (40%) [slide p.18], reinforcing that NTDT classification is fluid and ~13% of patients phenoconvert to TDT within a decade [slide p.80].
3.3.2.2 Hydroxyurea in SCD Pregnancy (ESCORT-HU)
The ESCORT-HU and ESCORT-HU Extension studies are prospective European multicenter cohorts (France, Germany, Greece, Italy) initiated at the request of EMA, with >15,000 patient-years of safety data from 3,145 enrolled SCD patients [slide p.25]. Among 245 pregnancies in 183 women, 207 were exposed to hydroxyurea (84%) — most commonly stopped in the first trimester (61.8%), with 9.3% exposed throughout [slide p.26, p.27]. Live-birth rates were identical between HU-exposed and non-exposed pregnancies (74% vs 74%), with no maternal deaths, 17% prematurity, and only a single congenital anomaly (pyelocalyceal junction abnormality in an exposure limited to the first 2 weeks) [slide p.28]. Conclusion: pregnancy outcomes are not worse with HU exposure; in low-resource settings without transfusion access, continuing HU may be less harmful than feared [slide p.29]. For thalassemia pregnancy, Dr. Desai’s targets are Hb >10 g/dL, stopping iron chelation 3 months before conception and holding until late second trimester, with screening for diabetes, thrombosis, and cardiopulmonary status [slide p.23].
3.3.2.3 Mitapivat: Pyruvate Kinase Activation Extends to Thalassemia
Mitapivat and etavopivat are oral PK-R activators that increase ATP and decrease 2,3-DPG, improving RBC membrane integrity and (in SCD) reducing HbS polymerization [slide p.31]. In the ENERGIZE-T phase 3 double-blind trial (mitapivat 100 mg BID vs placebo 2:1 for 48 weeks in adult transfusion-dependent α- or β-thalassemia), mitapivat reduced transfusion burden across TRR, TRR2, TRR3, and TRR4 endpoints [slide p.33, p.35]. In the α-thalassemia subgroup, 77.8% met the primary endpoint (≥50% reduction with ≥2-unit decrease in any 12-week window) versus 0% on placebo [slide p.35]. In the overall ENERGIZE-T population, 17/171 (9.9%) mitapivat-treated patients achieved protocol-defined transfusion independence (≥8 consecutive transfusion-free weeks) versus 1/87 (1.1%) on placebo [slide p.38]. In the open-label extension, the 17 TI responders had a mean transfusion-free duration that grew from 21.69 weeks in the DBP to 30.49 weeks in DBP+OLE (maximum 84.3 weeks), translating to a 56% reduction in annualized transfusion visits (~50.2 hours saved/year) and a 63.6% reduction in PRBC units transfused (~2,802 mg less transfusional iron/year) [slide p.40, p.41, p.42]. Mitapivat was approved for TDT and NTDT in December 2025 [slide p.52].
3.3.2.4 Luspatercept Across the β-Thalassemia Spectrum
A meta-analysis of 4 prospective trials (n=393) across TDT and NTDT β-thalassemia confirmed luspatercept as a first-in-class erythroid maturation agent (TGF-β superfamily ligand trap, SMAD2/3 attenuation) [slide p.44]. Pooled TDT efficacy: 74% achieved ≥33% and 27% achieved ≥50% transfusion-burden reduction (BELIEVE patients were ~6× more likely to achieve ≥33% reduction vs placebo, OR 5.8) [slide p.45]. Pooled NTDT efficacy (BEYOND): 78% achieved ≥1.0 g/dL and 54% achieved ≥1.5 g/dL hemoglobin increase (77.1% vs 0% for placebo at ≥1.0 g/dL) [slide p.45]. Safety: 98% any-grade TEAEs, 24% grade ≥3; most common AEs were musculoskeletal pain, headache, and arthralgia, with no new safety signals [slide p.45].
3.3.2.5 Osivelotor: A Second-Generation HbS Polymerization Inhibitor
Following voluntary withdrawal of voxelotor in September 2024 for an excess-mortality imbalance in post-marketing data, osivelotor — a next-generation HbS polymerization inhibitor — was presented in a 12-week phase 2 randomized (1:1) dose-finding study in 54 adults with HbSS or HbSβ⁰ (Hb 5.5–10.5 g/dL, ≤10 VOCs in prior year), with open-label extension [slide p.48, p.49]. At week 12, the 150 mg arm achieved a least-squares mean Hb rise of 3.35 g/dL (95% CI 2.81–3.89) and the 100 mg arm 2.58 g/dL (95% CI 2.05–3.11); >70% of patients had >2 g/dL Hb increase sustained into the OLE, hemolysis markers improved, and a trend toward fewer pain crises was observed [slide p.50]. AEs were mostly grade 1–2, supporting ongoing development [slide p.51].
3.3.2.6 Exa-cel Extends to Pediatric Patients (Ages 5–11)
Exagamglogene autotemcel (Casgevy, the first approved CRISPR/Cas9 gene-editing therapy) is currently approved for patients ≥12 years with TDT or SCD with recurrent VOCs, via non-viral ex vivo editing of the BCL11A erythroid-specific enhancer in CD34⁺ HSPCs to reactivate HbF [slide p.55]. The CLIMB THAL-141 (TDT) and CLIMB SCD-151 (SCD) studies in children aged 5–11 years (follow-up >2 years, data cut July 2025) demonstrated: 6/6 (100%) evaluable TDT participants achieved TI12 with transfusion-free durations of 2.3–22.5 months; 4/4 (100%) evaluable SCD participants achieved VF12 and HF12, with no VOCs observed in any pediatric SCD participant post-infusion [slide p.56, p.59]. Pancellular HbF rose to mean >40% in SCD and normalized total Hb to age-adjusted ranges in both diseases, with similar efficacy to the 12–17-year cohort [slide p.60, p.61]. Children 5–11 required fewer mobilization/apheresis cycles than adults aged 18–35 [slide p.61].
3.3.2.7 Haploidentical Transplant: BMT CTN 1507 Pediatric Stratum
In the pediatric stratum (n=39, median age 12.5 years, 92.3% Black, 97.4% HbSS) of BMT CTN 1507 using reduced-intensity conditioning for haploidentical BMT, the 2-year EFS was 79.3% (95% CI 62.8–89.1%) with 2-year OS 94.5% [slide p.65, p.66]. Eight qualifying events occurred: 2 deaths (both during GVHD treatment: adenoviral infection and fungal/respiratory failure), plus 2 primary and 4 secondary graft failures [slide p.65, p.66]. Cumulative incidence of grade II–IV acute GVHD was 15.5%; any chronic GVHD reached 30.6% by 2 years [slide p.67]. 59% of patients experienced infections (25 bacterial, 33 viral, 3 fungal) and 76.9% had at least one hospital re-admission, with 41% re-admitted beyond day 100 [slide p.68, p.69]. OS appeared similar to HLA-identical sibling BMT and better than URD BMT, but unacceptable graft failure and disease recurrence in children (consistent with prior Vanderbilt data) support an urgent need to lower graft failure, infection, and GVHD before widespread adoption [slide p.70].
Potential risks common to curative and transformative therapies highlighted by Dr. Desai include chemotherapy toxicities (infertility, infection, VOD, secondary malignancy), clonal hematopoiesis (SCD is associated with early-onset clonal hematopoiesis involving DNA damage response pathway mutations per Abstract #0008), and GVHD [slide p.71].
3.3.3 Dr. Chakrabarti: Asia-Pacific Realities and Thalidomide
3.3.3.1 A Tale of Two Cities
Dr. Chakrabarti re-framed the same 22-year-old Thai patient as a Bengali woman at NRS Medical College, Kolkata: diagnosed with HbE/β-thalassemia, presenting with a massive undetected spleen and compressive myelopathy from a paraspinal extramedullary hematopoiesis mass, ultimately managed with low-dose radiotherapy (20–30 Gy in fractions) in addition to regular transfusion and hydroxyurea [slide p.74]. This case framed five recurring clinical dilemmas that return throughout his half of the session: whether to transfuse at all, how to source leukodepleted/phenotype-matched/irradiated units, how much to transfuse, which adjunctive agents are feasible, and how to chelate iron [slide p.75].
3.3.3.2 The Phenoconversion Phenomenon
An NTDT patient at steady-state Hb 9.0 g/dL is at high risk: sustained Hb <10 g/dL, and particularly <7 g/dL, marks a critical tipping point for severe morbidity and mortality [slide p.79]. Observational data show ~13% of NTDT patients phenoconvert to TDT over 10 years [slide p.80]. NTDT morbidity is dominated by extramedullary hematopoiesis with paraspinal pseudotumors, pulmonary hypertension, hypersplenism, chronic leg ulcers, and thromboembolic events [slide p.82]. Pregnancy is a critical catalyst: guidelines mandate maternal Hb >10 g/dL to prevent IUGR and preterm delivery, and in reality 56–57% of previously non-transfused NTDT women require transfusion during pregnancy [slide p.83]. Drivers include advancing age (declining erythropoietin response) and genetic modifiers — co-inherited α-thalassemia traits and BCL11A / XmnI polymorphisms regulating HbF act as internal shock absorbers [slide p.84]. Dr. Chakrabarti’s multidisciplinary shield is a two-phase cycle: longitudinal monitoring (routine CBC, annual echocardiography with tricuspid regurgitant velocity for pulmonary hypertension, MRI T2* for iron) followed by disease-modifying interception with hydroxyurea or luspatercept before irreversible damage [slide p.85].
3.3.3.3 The Blood Supply Crisis
The 5 critical challenges of transfusion in South-East Asia Region countries: suboptimal blood safety and processing, inadequate pre-transfusion hemoglobin targets (>58% of SEAR patients maintain Hb <9 g/dL), gaps in professional expertise and adherence to international guidelines, geographical and seasonal inequities (Jakarta shows +60% excess while West Papua shows a 96.3% shortage in the same country), and severe socio-economic burdens [slide p.86, p.89]. Regionally, 38.6% of patients receive inadequate, interrupted, or belated transfusion; 72.6% are unaware of how their blood was processed [slide p.88]. Dr. Chakrabarti’s NTDT transfusion targets: initiate at Hb <7 g/dL (or growth failure), standard pre-transfusion target 9.5–10.5 g/dL, suppression target >10 g/dL to reverse complications such as pulmonary hypertension, pregnancy target >10 g/dL, and acute-stress (surgery/infection) target 7–8 g/dL [slide p.91].
3.3.3.4 Thalidomide: An Accessible Fetal Hemoglobin Inducer
In resource-limited settings where luspatercept and mitapivat are unaffordable and gene therapy is not an option, thalidomide directly inhibits BCL11A and KLF1 (the primary developmental silencers of γ-globin), promotes histone H4 acetylation, activates ROS-mediated p38 MAPK signaling, and suppresses NF-κB [slide p.95]. In Dr. Chakrabarti’s own published pilot trial (Jain M, Chakrabarti P, et al., Blood Cells Mol Dis 2021), 45 HbE/β-thalassemia patients were randomized to thalidomide+folic acid vs hydroxyurea+folic acid vs folic acid alone: the thalidomide arm achieved a 100% response rate (≥1 g/dL Hb increment) with 66.67% major responders (≥2 g/dL), compared to 40% in HU and 0% in folate alone (p<0.0001), with 100% vs 34% transfusion reduction and no severe adverse events [slide p.96]. Larger-cohort data from the 532-patient Thal-Thalido study and meta-analyses show 76.7% transfusion independence at 6 months, mean Hb rise ≥2 g/dL, 85% overall response rate and 54% complete response across meta-analyses, with durable responses up to 30 months and 66.2% pediatric transfusion freedom [slide p.97]. Thalidomide is particularly valuable in HU-refractory TDT and severe phenotypes where HU is capped at ~44% refractoriness by severe β-mRNA deficiency; limitations are neurotoxicity (16% polyneuropathy, 35% motor), teratogenicity, and thrombosis [slide p.98].
HU (stress erythropoiesis, NO donation) and thalidomide (epigenetic BCL11A/KLF1 suppression) work through complementary mechanisms. Combination data show a 77.8% response rate, median Hb rising from baseline to 8.7–9.35 g/dL within 6 months, mean transfusion volume dropping from 1106 mL to 315 mL, and 80% of responders in combination trials were XmnI negative — a genetic rescue of patients who would not respond to HU alone [slide p.99, p.100]. Indian and Pakistani retrospective data (Shah 2020; Ansari 2022) report 63.4% overall response in previously HU-refractory TDT with significant Hb and ferritin reduction [slide p.101]. Off-label use: thalidomide is not approved for thalassemia in most countries [slide p.3].
Dosing protocol [slide p.102]: HU 10–20 mg/kg/day (pediatric <30 kg: 500 mg alternate days; >30 kg: 500 mg daily); thalidomide cautious start at 1–2.5 mg/kg/day (or 50 mg flat at bedtime), with low-dose aspirin 100 mg/day for thrombosis prevention (particularly post-splenectomy or platelets >500×10⁹/L). Reassess at 2–3 months; escalate thalidomide by 1 mg/kg increments to a maximum of 4–5 mg/kg/day or 150 mg/day. Once Hb >9–10 g/dL and transfusion-free for 12 months, taper to the minimum effective dose (maintenance as low as 25 mg daily or alternate-day). Mandatory monitoring: monthly CBC with ANC and pregnancy tests; quarterly ferritin, LFT, renal function, pediatric growth; biannual nerve conduction velocity [slide p.103].
3.4 Clinical Pearls
- NTDT is not “never transfused.” Approximately 13% of NTDT patients phenoconvert to TDT within 10 years, and 56–57% of previously non-transfused women need transfusion during pregnancy. Iron overload is common and under-treated — in a US adult NTDT cohort, 50% had LIC >5 mg/g while only 24% were on chelation [slide p.17, p.80, p.83].
- Hydroxyurea is safe enough in SCD pregnancy. ESCORT-HU (245 pregnancies, 207 HU-exposed) showed identical 74% live-birth rates, no maternal deaths, and no malformations attributable to HU. In low-resource settings without transfusion access, continuing HU may be less harmful than feared [slide p.28, p.29].
- The Western toolkit is broadening: mitapivat, luspatercept, osivelotor, exa-cel. Mitapivat achieved 77.8% primary-endpoint response in ENERGIZE-T α-thalassemia and was approved for TDT and NTDT in December 2025. Osivelotor 150 mg raised Hb by a mean 3.35 g/dL at 12 weeks. Exa-cel produced 100% transfusion independence in 6/6 TDT and 100% VOC freedom in 4/4 SCD children aged 5–11 [slide p.35, p.50, p.52, p.59].
- Haploidentical SCT in pediatric SCD still needs work. BMT CTN 1507 pediatric stratum showed 2-year EFS of only 79.3% with unacceptable graft failure and disease recurrence; strategies to lower graft failure, infections, and GVHD are needed before broad adoption [slide p.65, p.70].
- Thalidomide is the accessible HbF inducer for Asia. In Indian and Pakistani cohorts, thalidomide (often with HU) achieves ~76.7% transfusion independence at 6 months in TDT, with 80% of responders being XmnI-negative — a genetic rescue unavailable with HU alone. Serum ferritin underestimates iron overload in NTDT, so initiate chelation at ferritin ≥800 ng/mL rather than using TDT thresholds [slide p.97, p.100, p.113].
3.5 Key References
- Cheng A, Peslak S, Sheth S, Sayani F, Lal A. High morbidity in adults with non-transfusion-dependent thalassemia referred to U.S. specialty centers. ASH 2025 Abstract #1141 [slide p.14].
- Habibi A, et al. Outcomes of pregnancies in sickle cell patients treated with hydroxyurea: findings from the ESCORT-HU cohort studies. ASH 2025 [slide p.24].
- Lal A, Glenthøj A, Al-Samkari H, et al. Efficacy of mitapivat in patients with transfusion-dependent α-thalassemia: subgroup analysis from the ENERGIZE-T trial. ASH 2025 [slide p.30].
- Sheth S, Estepp JH, Price GM, et al. Long-term transfusion-free duration and impact on transfusion-related burdens: ENERGIZE-T open-label extension. ASH 2025 [slide p.30, p.42].
- Guntupalli Y, Yannakula V, Alluri A, et al. Luspatercept in β-thalassemia: meta-analysis of efficacy and safety across transfusion-dependent and non-transfusion-dependent populations. ASH 2025 [slide p.43].
- Saraf SL, Abdullahi SU, Akinsete AM, et al. Efficacy and safety of osivelotor in participants with sickle cell disease in a 12-week, phase 2 multicenter, open-label, dose-finding trial and extension study. ASH 2025 Abstract #4728 [slide p.47].
- Frangoul H, de la Fuente J, Algeri M, et al. First results of exagamglogene autotemcel in pediatric patients aged 5–11 years with TDT or SCD with recurrent VOCs. ASH 2025 Abstract abs25-8416 (CLIMB THAL-141 / CLIMB SCD-151) [slide p.54].
- Walters MC, Kassim A, Brodsky R, DeBaun M, et al. Reduced-intensity conditioning for haploidentical bone marrow transplantation in children with symptomatic sickle cell disease (BMT CTN 1507 pediatric stratum) [slide p.62].
- Weeks L, et al. Sickle cell disease is associated with early-onset clonal hematopoiesis involving DNA damage response pathway mutations. ASH 2025 Abstract #0008 [slide p.71].
- Jain M, Chakrabarti P, Dolai TK, et al. Comparison of efficacy and safety of thalidomide vs hydroxyurea in patients with HbE/β-thalassemia: a pilot study from a tertiary care centre of India. Blood Cells Mol Dis. 2021;88:102544 [slide p.96].
- Shah S, Sheth R, Shah K, Patel K. Safety and effectiveness of thalidomide and hydroxyurea combination in β-thalassemia intermedia and major: retrospective pilot study. Br J Haematol. 2020;188(3):e18–e21 [slide p.101].
- Ansari SH, Ansari I, Wasim M, et al. Evaluation of the combination therapy of hydroxyurea and thalidomide in β-thalassemia. Blood Adv. 2022;6(24):6162–6168 [slide p.101].
- Premawardhena AP, Ediriweera D, Sabouhanian A, et al. Survival and complications in patients with haemoglobin E thalassaemia in Sri Lanka: a long-term prospective longitudinal cohort study. Lancet Glob Health 2021 [slide p.93].
- Taher AT, Musallam KM, Cappellini MD. β-Thalassemias. N Engl J Med. 2021;384(8):727–743 [slide p.79–84; editorial].
- Global Thalassaemia Review 2024. Thalassaemia International Federation [slide p.86–89].