In A Nutshell: Hematopoietic Stem Cell Transplant for Inborn Errors of Immunity - Who & When?

Abstract

Allogeneic Hematopoietic Cell Transplant (HCT) offers potential cure for patients with inborn errors of immunity (IEI) but comes with its own set of complications and toxicities. In this nutshell article, we discuss factors that impact definitive therapy decisions in IEI patients.

Graphical Abstract

Hematopoietic stem cell transplantation (HCT) for patients with inborn errors of immunity (IEI) is influenced by donor, host and IEI-specific factors. Patient age and the known natural history and/or penetrance of a specific IEI must always be considered when discussing potential HCT. Factors that may indicate a positive outcome include patients that do not have active infections, available well-matched donors, preserved organ function and a well-defined genotype-phenotype. Control of inflammation pre-HCT is also critical to improve outcomes. Factors that may delay HCT include active infection and/or inflammation, limited donor options or significant end organ damage. For optimal outcomes, HCT for IEI must be considered from a complex multi-disciplinary standpoint to make sure the patient is optimized prior to the start of conditioning.

Introduction

Advances in molecular diagnostics and functional assays have increased the number and diversity of monogenic diagnoses of IEI across all ages.¹ IEI are broadly divided into primary immune deficiency (PIDs), predominantly characterized by an infectious phenotype, and primary immune regulatory disorders (PIRDs) which have a distinct autoimmune/autoinflammatory component.² Allogeneic HCT is curative for many of these disorders and outcomes continue to improve.³ As we continue to diagnose increasing numbers of patients with IEI, the major conundrum in the field for many of these disorders is who and when to transplant.

HCT for Classical PIDs and PIRDs

Severe Combined Immunodeficiency (SCID), a disorder of T cell (+/− B cell and/or NK cell) development and function, is the canonical PID. The incorporation of SCID testing in newborn screening by assessment of T-cell receptor excision circle (TRECs) has transformed the treatment paradigm and outcomes for these patients allowing diagnosis to be made prior to severe infections.⁴ The current practice in SCID is to pursue allogeneic HCT as soon as possible after a diagnosis is made.⁴ This is primarily due to the viral, fungal and bacterial infections that can be fatal in the first year of life or cause significant organ damage. Furthermore, multi-center data have demonstrated that proceeding to HCT in the absence of active infection significantly improves outcomes.⁵ Thus, for optimal outcomes in SCID, allogeneic HCT as early as possible and while patients are free from infection is critical. Similarly, data from other PIDs with extensive experience (ex: Wiskott Aldrich Syndrome and Chronic Granulomatous Disease) support superior outcomes for patients that receive HCT early in life.⁶

The emerging data from allogeneic HCT for PIRDs follows a similar pattern.⁷ For example, in the largest published series of patients with STAT1 GOF (n = 15) the overall survival (OS) was 60% for patients less than 12 years of age and 0% for those that were older.⁸ A complicating factor in patients with PIRDs is that uncontrolled inflammation, and particularly activation of the Interferon-γ (IFNγ) pathway, can cause graft rejection/failure and other HCT complications.⁹ Thus, in addition to pursuing HCT early in life, prior to end organ toxicity (a goal complicated in some cases by prolonged time to diagnosis), inflammation must be adequately controlled for optimal outcomes. Emapalumab (anti-IFNγ antibody; NCT05787574) and JAK inhibitors are two examples of targeted therapeutics that have been reported to effectively bridge patients with JAK/STAT gain of functions to HCT and are currently being investigated in clinical trials.^10,11

IEI-specific Considerations for HCT

Despite these illustrative disorders, the decision to pursue allogeneic HCT is often challenging in many of the approximately 500 IEI, particularly for patients with recently discovered or ultra-rare IEI. Lack of data regarding the natural history of a particular disorder and/or lack of functional validation of variants in known or suspected IEI-related genes makes it difficult to consider allogeneic HCT early in life and decisions are typically delayed until patients have been observed to demonstrate repeated clinically significant and severe complications. These decisions are further complicated by the presence of somatic reversion in small subsets of patients with IEI.¹² Lack of penetrance data also affects consideration of allogeneic HCT. Penetrance can vary widely even amongst cohorts that have similar (or the same) genetic defect.¹³ While this makes consideration of HCT based solely on genetic diagnosis very difficult, there is emerging data that in specific gene defects such as those associated with primary hemophagocytic lymphohystiocytosis as well as XLP1, pre-emptive HCT based on presence of genetic mutations has had favorable outcomes.^14,15 A third complicating factor that impacts the decision to consider allogeneic HCT is the fact that some genetic IEI have effects on organs outside of the immune system that would not necessarily be corrected by HCT. As most IEI disorders lack validated predictive biomarkers of disease progression, the decision to pursue HCT early in life is complex requiring multiple specialists and ongoing discussions and shared decision making with families about upfront and long-term risks associated with either HCT or medical management. Increased risk of malignancy in certain IEIs also needs to be addressed as it may factor into when and who to transplant. A further complication is that each IEI manifests differently and each patient may therefore require different sub-specialty input for these complex therapeutic discussions. There is a critical unmet need for predictive biomarkers to assist in making these very difficult decisions about proceeding to early upfront HCT. Given the lack of ability to prognosticate many individual cases, there is a growing experience of allogeneic HCT in adult patients with IEI with improving outcomes.^16,17

The incorporation of targeted therapies into the treatment paradigm for IEI, though beneficial, has also further complicated the decision to pursue early upfront HCT. For instance, in patients with STAT1 GOF, a disorder characterized by mucocutaneous candidiasis, opportunistic infections and autoinflammatory complications, ruxolitinib, a JAK1/2 inhibitor, has been shown to ameliorate symptoms.¹¹ Long term risks and sustained efficacy, however, are still being investigated. For some patients with STAT1 GOF, ruxolitinib can ameliorate symptoms and patients are able to proceed with their everyday lives. For others, ruxolitinib is unable to control disease symptoms, and for still others, ruxolitinib can control symptoms temporarily but loses efficacy over time. Ruxolitinib changes the natural history of STAT1 GOF in that there is less end organ damage, less infection and less autoinflammatory complications.¹¹ This likely shifts the need to go to HCT early in life but by how long and in which patients remains a critical question.

HCT-intrinsic Considerations in IEI

Limitations regarding transplant procedures also influence decisions regarding allogeneic HCT. For patients with an available, unaffected matched family donor, the decision to proceed with allogeneic HCT early is easier because outcomes are expected to be optimal. Given the incomplete penetrance of many IEIs though, genetic testing for the known mutation should always be done prior to proceeding with a related donor. For patients with only alternative donor options (matched and mismatched unrelated, haploidentical, cord blood etc.) the decision is more complex given the increased risk of graft versus host disease, graft failure and subsequent morbidity and mortality.¹⁸ Modifications of conditioning regimens over time to optimize chemotherapeutic intensities and other improvements in anti-microbial options and GVHD prophylaxis and treatment have improved HCT outcomes, thus making it easier to consider allogeneic HCT in IEI disorders.^19,20 However, modern mortality risks still range from approximately 5–30% depending on the disorder and patient and transplant characteristics. Though we continue to reduce transplant related mortality, we are still learning and understanding the long-term side effects for patients with IEI that undergo HCT and a focus on appropriate interventions to mitigate long-term sequelae will help further improve outcomes.²¹ Continued advancements will likely continue to lower the threshold for consideration of allogeneic HCT over time.

In summary, experience with both PID and PIRDs demonstrates that approaching HCT at a young age, without infection, with minimal end organ damage and well controlled inflammation is critical for optimal outcomes. Transplant decisions are complicated by the lack of ability to prognosticate how each patient’s underlying disease will progress, lack of validated predictive biomarkers, desire to minimize and control pre-transplant inflammation and by transplant-related limitations such as donor availability and general transplant-related complications. The emergence of successful gene therapy/modification approaches for certain IEIs will add another layer of complexity in deciding which curative approach is best for each patient. Thus, there are many vital areas on which we should continue to refine our approach and given the rare nature of these disorders, efforts should include international collaborations, consortia, registries, standardized comprehensive data collection tools and multi-institutional trials to generate critical data and improve outcomes for patients with IEI.

• Allogeneic HCT offers a possible cure to patients with IEI

• Uncertainty regarding the natural history of patients with recently discovered or ultra-rare IEI impacts decision-making

• Targeted therapeutics can provide a bridge to HCT but also can change the natural history thereby complicating the decision when to pursue HCT

• Early HCT without active infection, end organ dysfunction, active autoimmunity or inflammation leads to optimal outcomes in IEI

• Many complex IEI cases benefit from a multi-disciplinary approach and discussion from the outset so that definitive treatment with allogeneic HCT is considered on an ongoing basis