At the beginning of December, world-renowned doctors gathered in San Diego (USA) for the most important and comprehensive congress in hematological oncology. More than 20,000 visitors took part in the congress and exchanged views on the latest research findings and the most important innovations in pathophysiology, diagnostics and therapy.
In principle, allogeneic hematopoietic stem cell transplantation has the potential to cure sickle cell disease (SCD). Event-free survival (EFS) in children with SCD is >90% after a bone marrow transplant (BMT) from a myeloablative matched sibling donor (MSD). Unfortunately, <15% of patients with SCD have an MSD and myeloablative conditioning can be prohibitively toxic in adults with SCD. HLA-haploidentical BMT with reduced intensity and post-transplant cyclophosphamide (PTCy) has been shown in small studies to expand the donor pool with encouraging results. Nevertheless, there are still concerns about graft failure and graft-versus-host disease (GVHD). A multicenter, single-arm, prospective phase II clinical trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) of haploidentical BMT with PTCy was conducted to assess survival at two years in adults with severe SCD [1]. SCD patients aged 15 to 45.99 years with previous stroke, recurrent ACS or pain, chronic transfusion regimen, or a tricuspid regurgitant jet velocity (TRJV) ≥2.7 m/sec were eligible. Participants had to have an HLA-haploidentical first-degree relative as a donor who was willing and able to donate bone marrow. The primary objective was survival (without primary or secondary graft failure or second infusion of stem cells) two years after haploidentical BMT. Secondary objectives included determining the impact on clinical and laboratory manifestations of SCD and other transplant outcomes.
A total of 54 eligible participants from 19 locations registered; 42 (78%) were transplanted. Of the enrolled participants, 59.3% are male, 92.6% are black and 3.7% are Hispanic. Ten participants started with the HU but did not move on to the BMT, and two started with neither the HU nor the BMT. The reasons included problems with the donor, withdrawal of consent, insurance cover, death and other reasons. 38/42 (90%) participants completed the study as planned. 87% of participants had hemoglobin SS disease, 74.1% had a Lansky/Karnofsky score of 90-100 at baseline, and 75.9% had an HLA match score of 4/8. The most common indications for transplantation were recurrent vaso-occlusive pain episodes (38.9%), acute chest syndrome (16.8%) and open stroke (16.7%). Only 13 (31%) participants reached the intended dosage of 30 mg/kg/day for HU preconditioning.
The estimated 2-year survival rate is 88%; all but one qualifying event occurred within 12 months. The 2-year overall survival (OS) after HU was 93.0% and the 2-year OS after transplantation was 95.0%. 2 (4.8%) participants had primary graft failure and 1 (2.4%) had secondary graft failure. There were two deaths in the first year after BMT (1-organ failure; 1-ARDS) and none in the second year; 33 (78.6%) participants reported at least one readmission after BMT, mainly due to bacterial infection or viral reactivation.
The results show a permanent donor transplant after two years with low mortality. The 2-year EFS and OS are comparable to the results reported after myeloablative MSD-BMT. These results support haploidentical BMT with PTCy as a suitable and tolerable curative therapy for adults with SCD and severe end-organ toxicity such as stroke and pulmonary hypertension, a population normally excluded from participation in myeloablative gene therapy and gene editing trials.
ERG as a predictor for hematologic malignancy
Knowledge about hereditary and sporadic causes of hematologic malignancy (HM) and bone marrow failure (BMF) is still incomplete and prevents optimal diagnosis, disease monitoring and treatment. ERG has now been discovered as a new predisposition gene for BMF and HM [2]. ERG is a known oncogene that typically leads to dysregulated ERG overexpressionin blood and solid cancers via gene fusions. A germline variant of the ERG ETS domain p.Y373C was identified that segregated in a mother who developed AML (age 27) and then therapy-related MDS (age 35), as well as in her two sons with thrombocytopenia. All three exhibited copy-neutral loss of heterozygosity of all or part of chromosome 21q, including the ERG locus, with the eldest son having at least two somatic genetic rescue (SGR) events. The possibility of causal RUNX1 variantswas ruled out because the smallest somatic cnLOH event started within the RUNX1 genebut did not encompass the RUNT domain, where most pathogenic missense variants are located. ERG is critical for definitive hematopoiesis, adult hematopoietic stem cell (HSC) function and platelet maintenance. An identical heterozygous germline variant (p.Y343C) in the homologous next gene of ERG, FLI1, causes a bleeding disorder of platelet type-21 (BDPLT21, OMIM #617443).
Through global collaboration, 15 heterozygous variants in the ERG genewere identified, including 13 missense and two truncating variants in 17 individuals with cytopenia and/or HM (mainly myeloid) or lymphedema. The onset of hematologic symptoms ranged from birth to 38 years for the variants with truncated and restricted ETS domains. Of these 15 variants, 12 were confirmed in the germline, 2 of them de novo. Only four meiotic transmissions were observed. None of the missense variants in the highly conserved ETS domain of ERG, which mediates DNA binding, protein-protein interactions and nuclear localization, are present in gnomAD.
19 ERG variantswere functionally characterized, 12 potentially pathogenic, one known pathogenic mouse variant and 3 population controls. It was shown that most ETS domain missense variants have loss-of-function (LOF) properties that interfere with transcriptional transactivation, DNA binding and/or nuclear localization in vitro. Robust preliminary data from ex vivo models of ERG overexpressionin fetal mouse liver cells in tissue culture (cytokine-independent), from a mouse transplantation assay, and from previous germlinemutant ERG mouse models consistently show that the ETS domain missense variants are LOF compared to wild-type ERG and benign controls.
Taken together, these data provide clinical, in vitro and ex vivo functional studies implicating LOF variants in predisposition to hematologic disease. LOF ERG mutationsalso occur in sporadic cases of HM.
Prevention of iron overload in MDS
Iron overload (IO) in myelodysplastic syndromes (MDS) contributes to the deterioration of the osteo-hematopoietic niche (OHN), where hematopoietic and osteogenic progenitors interact to regulate hematopoiesis and bone metabolism. Excess iron exacerbates ineffective hematopoiesis, inflammation and bone loss through direct effects on resident hematopoietic and osteogenic progenitor cells. Iron chelation therapy (ICT) is associated with improved event-free survival in MDS patients, but does not address the underlying cause of IO and is a burden for patients due to tolerability and cost.
KER-050 is an investigational modified activin receptor type IIA ligand trap to inhibit selected ligands of the TGF-β superfamily and to promote differentiation and maturation of erythroid and megakaryocytic progenitors. KER-050 has the potential to reduce dependence on red blood cell transfusions and increase iron utilization via erythropoiesis, potentially attenuating IO at its source.
As previously reported in an ongoing Phase II study, treatment in participants with lower risk (LR) MDS resulted in rates of 51.4% for modified IWG 2006 Hematological Improvement-Erythroid (HI-E) and 42.3% for Transfusion Independence (TI), with a median decrease in ferritin (322 ng/mL at week 24) in HI-E and/or TI responders. Treatment with KER-050 also showed effects on osteogenic progenitor cells, including the prevention of bone loss in an MDS mouse model and the dose-dependent increase in bone-specific alkaline phosphatase (BSAP), a marker of bone formation observed in healthy postmenopausal women. Thus, KER-050 has the potential to address the multifaceted pathogenesis of MDS, including IO. New data show benefits of improving IO in MDS [3].
Participants’ baseline ferritin levels were generally elevated, while mean corpuscular hemoglobin and reticulocyte hemoglobin levels were in the normal range. After treatment with KER-050, a sustained decrease in serum ferritin was observed in participants with baseline levels of ≥1000 ng/mL, likely due in part to reduced transfusion burden in responders. The simultaneously observed increase in the soluble transferrin receptor (sTfR) suggests that increased erythropoiesis may also have contributed to this.
The mean decreases in ferritin observed in the non-transfused (NT) participants (-228 ng/mL at week 24) suggest that KER-050 may affect iron homeostasis by mechanisms other than reducing transfusions. In one NT participant receiving ICT, baseline ferritin decreased from 1632 ng/ml to <500 ng/ml over 32 weeks, leading to discontinuation of ICT and accompanied by an increase in hemoglobin (Hgb) from 9.2 g/dL at baseline to 11.3 g/dL over the same period. In another NT participant who did not receive ICT, ferritin decreased from 1094 ng/ml at baseline to 884 ng/ml and 583 ng/ml at weeks 24 and 68, respectively, while Hgb gradually increased from 9.94 g/dL at baseline to 10.7 and 12.2 g/dL at weeks 24 and 68.
Treatment with KER-050 was also associated with an increase in BSAP, a novel finding in this MDS population that is consistent with previous observations in preclinical studies and studies in healthy volunteers. Despite some heterogeneity, mean increases of 8.47% and 10.4% were observed at weeks 24 and 48, respectively; three participants with erythroid response had increases in BSAP of ≥30% at these time points. The observed changes in BSAP suggest that KER-050 also acts on the osteogenic progenitor cells, which could lead to functional improvements within the OHN.
Literature:
- Kassim AA, et al: Reduced Intensity Haploidentical Bone Marrow Transplantation in Adults with Severe Sickle Cell Disease: BMT CTN 1507. LBA-4. 12.12.2023. ASH 2023.
- Scott HS, et al: ERG Is a New Predisposition Gene for Bone Marrow Failure and Hematological Malignancy. LBA-6. 12.12.2023. ASH 2023.
- Chee LCY, et al: Treatment Reduced Iron Overload and Increased Bone Specific Alkaline Phosphatase in Participants with Lower-Risk MDS Supporting Potential to Restore Balance to the Osteohematopoietic Niche. 1089 Ker-050. 09.12.2023. ASH 2023.
InFo ONKOLOGIE & HÄMATOLOGIE 2024; 12(1): 28-29 (published on 12.3.24, ahead of print)
Cover picture: Rick Jan Kluitenberg, wikimedia