Myelodysplastic syndrome unrelated to lentiviral vector in a patient treated with gene therapy for sickle cell disease

Hsieh, Matthew M.; Bonner, Melissa; Pierciey, Francis J.; Uchida, Naoya; Rottman, James B.; Demopoulos, Laura A.; Schmidt, Manfred; Kanter, Julie; Walters, Mark C.; Thompson, Alexis A.; Asmal, Mohammed; Tisdale, John F.

doi:10.1182/bloodadvances.2019001330

Cited by 113 publications

(81 citation statements)

References 31 publications

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“…32 Of note, an earlier case of MDS was also reported in a sickle cell patient but multiple independent assays demonstrated the absence of vector integration in the CD341 blasts and excluded lentiviral vectormediated oncogenesis as the MDS cause. 33 Several other gene insertion approaches and vectors have also been evaluated in animal models and validated for clinical investigation. A phase 1/2 trial (TIGET-BTHAL, NCT02453477) in TDT patients with β 0 or severe β+ mutations using an intrabone administration of HSCs transduced with the lentiviral vector GLOBE showed transfusion reduction in three adults and complete independence in 3/4 evaluated children.…”

Section: Gene Insertionmentioning

confidence: 99%

2021 update on clinical trials in β‐thalassemia

Musallam¹,

Bou‐Fakhredin

Cappellini

et al. 2021

American J Hematol

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The treatment landscape for patients with β-thalassemia is witnessing a swift evolution, yet several unmet needs continue to persist. Patients with transfusiondependent β-thalassemia (TDT) primarily rely on regular transfusion and iron chelation therapy, which can be associated with considerable treatment burden and cost.Patients with non-transfusion-dependent β-thalassemia (NTDT) are also at risk of significant morbidity due to the underlying anemia and iron overload, but treatment options in this patient subgroup are limited. In this review, we provide updates on clinical trials of novel therapies targeting the underlying pathology in β-thalassemia, including the α/non-α-globin chain imbalance, ineffective erythropoiesis, and iron dysregulation. | INTRODUCTIONThe β-thalassemias are a group of inherited disorders of hemoglobin (Hb) synthesis characterized by chronic anemia of varying severity.The degree of anemia relies on several genetic and environmental factors and determines the need for regular transfusion therapy. It is now common practice to classify patients as having transfusion-The TDT patients (β-thalassemia major and severe forms of HbE/β-thalassemia) are those who commonly present in early childhood with severe anemia and require lifelong transfusion therapy for survival. 1 Although the introduction of transfusions improved survival in TDT patients, it did not come without its own side-effect, systemic iron overload leading to end-organ damage and increased mortality from cardiac or hepatic disease. [2][3][4] Advances in iron chelation therapy and the introduction of MRI techniques to detect organ-specific iron overload have led to improved management and patient outcomes. 5,6 Still, TDT comes with considerable burden to the patient, clinician, and overall healthcare system owing to persistent morbidity and high healthcare utilization, poor access to optimal care and high treatment cost especially in resource-limited countries, and several unmet needs in terms of efficacy, safety and adherence to conventional therapies. 7 Allogeneic hematopoietic stem-cell transplantation (HSCT) has been used successfully for the past few decades to offer curative therapy for patients with TDT, but is only available to a minority of patients with compatible donors. 1 Patients with NTDT (β-thalassemia intermedia and mildmoderate forms of HbE/β-thalassemia) usually present later in childhood or even in adolescence with mild-moderate anemia that does not require immediate placement on a regular transfusion program. 1,8 Progress made over the past few decades has indicated that the diagnosis of NTDT carries greater morbidity than previously recognized.Ineffective erythropoiesis and anemia have been linked to an array of morbidities stemming from chronic hypoxia and an established hypercoagulable state. 1 Patients with Hb levels < 10 g/dl are at an increased risk of morbidity development, and variations of 1 g/dl can change a patient's morbidity risk. 9,10 There are currently no approved agents for the management of anem...

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Section: Gene Insertionmentioning

confidence: 99%

2021 update on clinical trials in β‐thalassemia

Musallam¹,

Bou‐Fakhredin

Cappellini

et al. 2021

American J Hematol

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“…However, larger studies and longer follow-up are needed to carefully assess the clinical e cacy and safety of gene editing based approaches. The occurrence of a secondary tumor (myelodysplasia followed by leukemia) in one SCD patient treated with LV 27 , likely as a result of chemotherapy-induced mutagenesis on residual host cells as well as a bone marrow dysplasia observed in an ADA-SCID patient treated with γRV deriving from non-corrected cells 28 were not unexpected. Indeed, the risk of secondary tumors is reported to be 4% at 7 years after autologous HSCT, with a median onset of 2.5 years post-transplantation (range = 3 months-7 years).…”

Section: Discussionmentioning

confidence: 86%

Gene therapy with hematopoietic stem and progenitor cell for monogenic disorders: a systematic review and meta-analysis

Tucci

Galimberti

Naldini³

et al. 2021

Preprint

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To provide an assessment of the safety of ex-vivo gene therapy (GT) with hematopoietic stem and progenitor cells (HSPC), we reviewed in a systematic manner the literature on monogenic diseases to describe survival, genotoxicity and engraftment of gene corrected HSPC, across vector platforms and diseases. From 1995 to 2020, 55 trials for 14 diseases met inclusion criteria and 406 patients with primary immunodeficiencies (55.2%), metabolic diseases (17.0%), haemoglobinopathies (24.4%) and bone marrow failures (3.4%) were treated with gammaretroviral vector (γRV) (29.1%), self-inactivating γRV (2.2%) or lentiviral vectors (LV) (68.7%). The pooled overall incidence rate of death was 0.9 per 100 person-years of observation (PYO) (95%CI = 0.37–2.17). There were 21 genotoxic events out of 1504.02 PYO. All these events occurred in γRV trials (0.99 events per 100 PYO, 95%CI = 0.18–5.43) for primary immunodeficiencies. Pooled rate of engraftment was 86.1% (95%CI = 66.9–95.0%) for γRV and 99.0% (95%CI = 95.1–99.8%) for LV HSPC-GT (p = 0.002). A comprehensive meta-analysis on HSPC-GT showed stable reconstitution of haematopoiesis in most recipients with superior engraftment and safer profile in patients receiving LV-transduced HSPC.

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“…63 A case of MDS in a SCD patient treated in the HGB-206 trial, who did not have MDS before myeloablation, was also observed. 64 The absence of vector integration in CD34+ blasts excludes lentiviral vector-mediated oncogenesis. An even more recent press release from Bluebird bio on March 10, 2021, announced that, according to the analyses, lentiviral vector BB305 unlikely caused the AML.…”

Section: Gene Therapy and Gene Editingmentioning

confidence: 99%

Innovative Treatments for Rare Anemias

et al. 2021

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Rare anemias (RA) are mostly hereditary disorders with low prevalence and a broad spectrum of clinical severity, affecting different stages of erythropoiesis or red blood cell components. RA often remains underdiagnosed or misdiagnosed, and treatment options have been limited to supportive care for many years. During the last decades, the elucidation of the molecular mechanisms underlying several RA paved the way for developing new treatments. Innovative treatments other than supportive care and allogeneic bone marrow transplantation are currently in clinical trials for β-thalassemias, sickle cell disease (SCD), and congenital hemolytic anemias. Recently, luspatercept, an activin receptor ligand trap targeting ineffective erythropoiesis, has been approved as the first pharmacological treatment for transfusion-dependent β-thalassemia. L-glutamine, voxelotor, and crizanlizumab are new drugs approved SCD, targeting different steps of the complex pathophysiological mechanism. Gene therapy represents an innovative and encouraging strategy currently under evaluation in several RA and recently approved for β-thalassemia. Moreover, the advent of gene-editing technologies represents an additional option, mainly focused on correcting the defective gene or editing the expression of genes that regulate fetal hemoglobin synthesis. In this review, we aim to update the status of innovative treatments and the ongoing trials and discuss RA treatments' future directions. Interestingly, several molecules that showed promising results for treating one of these disorders are now under evaluation in the others. In the near future, the management of RA will probably consist of polypharmacotherapy tailored to patients' characteristics.

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Myelodysplastic syndrome unrelated to lentiviral vector in a patient treated with gene therapy for sickle cell disease

Abstract: Key Points Ability to accurately attribute adverse events post–gene therapy is required to describe the benefit-risk of these novel treatments. A SCD patient developed myelodysplastic syndrome post-LentiGlobin treatment; we show how insertional oncogenesis was excluded as the cause.

Cited by 113 publications

References 31 publications

2021 update on clinical trials in β‐thalassemia

2021 update on clinical trials in β‐thalassemia

Gene therapy with hematopoietic stem and progenitor cell for monogenic disorders: a systematic review and meta-analysis

Innovative Treatments for Rare Anemias

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