Pure red cell aplasia after hematopoietic stem cell transplantation - experimental therapeutic approaches

KEYWORDS:

• Pure red cell aplasia – stem cell transplantation – anemia - ABO system

1. Introduction

Pure red cell aplasia (PRCA) is a rare syndrome that is defined by normocytic, normochromic anemia, severe reticulocytopenia and major reduction or even absence of erythroid precursors in the bone marrow [1]. The condition can be congenital or acquired and may be one of the more frequent reasons for acquired erythroblastopenia [2]. Acquired PRCA is further classified as primary or secondary, the latter due to other conditions such as lymphoproliferative disorders, viral infections or pharmacologic agents including recombinant erythropoietin (EPO) [1]. Finally, PRCA is a known complication related to ABO mismatched allogenic hematopoietic stem cell transplantation (allo-HSCT). PRCA after allo-HSCT may cause impaired quality of life as patients may become transfusion dependent for long periods due to anemia [3]. In addition, the patients are at risk of developing alloantibodies, transfusion reactions, and iron overload. To date, there is no standardized treatment, though recent reports have contributed to elucidate certain aspects which may prove helpful in future management.

2. PRCA in the setting of allo-HSCT

In allo-HSCT, it is important to ensure human leucocyte antigen compatibility between donor and recipient. However, ABO mismatch is not considered a contraindication to allo-HSCT, occurring in 27–50% of transplantations [4–6]. Mismatches are either defined as a major, minor, or bidirectional (Table 1), and it has been estimated that 7.5–13% of patients receiving major or bi-directional ABO-incompatible allo-HSCT develop PRCA requiring red cell transfusions [6,7]. Several studies have reported no effects of ABO-mismatches on overall survival in patients with PRCA after allo-HSCT [3,6,8], although the issue remains controversial as discussed in a recent review by Migdady et al [9]. Interestingly, data from a relatively large retrospective cohort study with 46 PRCA patients showed a decreased overall survival in the treatment group, with infections related to corticosteroid treatment accounting for 7 of 11 deaths [10].

Table 1. a) A minor ABO mismatch is defined as an ABO incompatibility where the donor produces anti-recipient ABO antibodies. b) A major ABO mismatch is defined as an ABO incompatibility where the recipient produces anti-donor ABO antibodies. c) A bidirectional mismatch is defined as an ABO incompatibility where both donor and recipient have anti-ABO antibodies against each other.

RECEPIENT DONOR	A	B	AB	O
A	ABO match	Bidirectional	Minor	Major
B	Bidirectional	ABO match	Minor	Major
AB	Major	Major	ABO match	Major
O	Minor	Minor	Minor	ABO match

The pathophysiology of PRCA in the setting of allo-HSCT is not fully understood. It is believed to be mediated by the presence of recipient isoagglutinins against donor ABO antigens, which then inhibit the proliferation and growth of early erythroid stages via mechanisms still not clear [8,11,12]. Complement-mediated inhibition and destruction of erythroid precursor cells are probably important [13,14]. Certain risk factors have been reported, mostly associated with the presence of recipient isoagglutinins to donor antigen. The risk factors proposed include reduced intensity conditioning regimen such as busulfan/fludarabine treatment [3,6,15], transplants from sibling donors [16], and absence of graft-versus-host disease [3,16]. Reports have showed that the most important risk factor for developing PRCA and duration beyond 2–3 months post-transplant, was elevated pre-transplant isoagglutinin titers [3,17,18]. In two cases, Martino et al report persisting and rising isoagglutinin titers post-transplantation, suggesting an immune response. Moreover, the disappearance rate of the isoagglutinin has been hypothesized to be is associated with the degree of genetic dissimilarity between donor and recipient, implying a graft-versus-plasma cell effect [16]. In cases of spontaneous remission, the titers usually reside after approximately 60 days post-transplantation, while it persists beyond 90 days in patients with prolonged PRCA [3,10,17]. In summary, the presence of residual anti-donor isoagglutinins in the host and production via persisting host B cells appears to play a central role in the development of the condition. The identified risk factors seem to be related to the lack of host B-cells or isoagglutinin eradication.

3. New pharmacological agents

Several therapeutic approaches have been attempted in post-transplant PRCA (Table 2). The therapeutic approaches involve immunomodulation either by immunosuppression or inducing an immune response against host B-cells, enhancing erythropoiesis, or removal of residual isoagglutinins either prior to- or after transplantation. Yet, no standard treatment has been established as the responses have been varying [8]. In the most extensive review to date, Marco-Ayala et al. found that none of the current treatment regimens seemed superior [8].

Table 2. Pros and cons of interventions in post allo-HSCT PRCA.

Intervention	Pros	Cons	Estimated response rates
Watchful waiting	Spontaneous resolution in many patients. No additional adverse effects of drugs	Prolonged transfusion dependence and transfusion-related complications, reduced quality of life	Spontaneous remission 38–100% after a median of 98–255 days [6,8,10,22]
Immunological interventions
Apheresis therapy (IA, PE, DFPP)	Few adverse effects	Requires substantial logistics, varying effect reported	16/30 (53%) [8]
Donor lymphocyte infusion	Few adverse effects	Requires substantial logistics, risk of GVHD, varying effect reported, few reports	4/8 (50%) [8]
Pharmacological interventions
Erythropoietin	Commonly available, few adverse effects	Varying effect reported	9/35 (35%) [8]
Thrombopoietin receptor agonists	Commonly available, few adverse effects	Few reports	4/4 (100%) [8,20,21]
Corticosteroids (high dose and low dose)	Widespread use, commonly available, long experience with the drug, easy administration via tablets.	Decreased overall survival, adverse effects of corticosteroids, increased risk of infection, varying effect reported.	14/34 (41%) [8]
Bortezomib	Well tolerated, commonly available.	Adverse effects, increased risk of infection, varying effect reported. Few reports (9 cases)	3/9 (33%) [8]
Rituximab	Well tolerated, commonly available.	Adverse effects, infusion reactions, increased risk of infection, expensive, varying effect reported.	9/29 (31%) [8]
Daratumumab	Promising results in published case reports.	Adverse effects, increased risk of infection, highly expensive, few reports.	9/9 (100%) [8,17,25,26]

A selection of interventions used in post allo-HSCT PRCA and their potential pros and cons. Abbreviations: IA Immunoadsorptions, PE plasma exchange, DFPP double filtration plasmapheresis.

One of the most used treatments, EPO, is aimed at stimulating the maturation of erythroid precursors to compensate for the suppressed erythropoiesis. In the successful cases, intervention was mostly started after day 250 post allo-HSCT but there were also patients without response [3,8]. Corticosteroid therapy has often failed, either as monotherapy or in combination with other treatments, and is also associated with complications and decreased overall survival as previously mentioned [10].

Eltrombopag, a thrombopoietin receptor agonist used in chronic immunological trombocytopeni (ITP) and severe aplastic anemia, have been successfully used in four case reports in post allo-HSCT PRCA refractory to other treatments [19–21]. The multilinear effect is hypothesized to be due to stimulation of hematopoietic stem cells despite inhibition mediated by proinflammatory cytokines present after allo-HSCT such as interferon-γ (IFN-γ) [19,21]. However, in the reports eltrombopag was initiated after day 100 and time to response varied from one to two months, which makes it difficult to rule out the possibility of spontaneous remission.

Based on the current knowledge regarding the pathophysiology, treatment to suppress residual host B-cells appears as a rational approach. However, rituximab, donor lymphocyte infusion (DLI), and plasmapheresis have all shown varying responses with no clear evidence of effect [3,8]. Regarding plasmapheresis, the levels of isoagglutinins seem to decrease transiently, but transfusion dependency remains in many patients [8]. Also, pre transplantation, plasmapheresis has varying effect [22,23]. Promising results in a patient with PRCA refractory to rituximab and DLI was reported after treatment with bortezomib, a proteosome inhibitor used in multiple myeloma (MM) [24]. However, a lack of response has later been reported in several other cases [8]. Recently, another MM agent, the CD38 antibody daratumumab, has emerged as a novel agent with promising clinical results in PRCA post allo-HSCT (Figure 1). To our knowledge, there are nine cases reported to date, all of which were successful, and the majority had an early and lasting response [8,17,25,26].

Figure 1. Possible mecahism of action for CD38 antibody daratumumab in PRCA.

4. Future perspective and expert opinion

Even though our understanding of post allo-HSCT PRCA has increased the last decades, many aspects remain unclear. The assessment of treatment efficacy has proven challenging due to the self-limiting nature in many patients with a spontaneous resolution after a median of 98–255 days post allo-HSCT [6,8,10,22]. Validation of treatment regimen is difficult as the interventions were introduced 100–200 days post allo-HSCT, and responses with remission were reported long after treatment initiation [8]. Hence, it is unclear whether this implies a more heterogenous condition than previously thought, or if several successful treatments reported represent cases of spontaneous remission. As the condition is not associated with a decreased overall survival and complications of immunomodulating treatment may lead to fatal complications, several questions should be discussed. Do patients with PRCA need treatment, and if so, when and how?

There is a need for developing methods to identify patients at risk of developing prolonged PRCA and patients who will benefit from treatment. High isoagglutinin titers prior to allo-HSCT have been reported to be associated with increased occurrence of PRCA with high sensitivity (96%), and high negative predictive value (99%) [3]. Additionally, as newly demonstrated by Martino et al. persistently high titers especially in combination with rising titers may prove a timely treatment indication, as spontaneous remission is hence less likely to occur [17]. In cases where measuring of isoagglutinin titers is not feasible, a watch and wait strategy seems appropriate the first six months based on the available reports. In the future, other potential prognostic biomarkers should be explored. In primary PRCA, various recurring cytogenetic aberrations have been associated with poor treatment response [27].

The choice of treatment should be based on an individual assessment of the patient’s disease burden, other risk factors, comorbidities, and potential future biomarkers. Commonly used and less aggressive treatment such as EPO has been recommended as initial treatment [8]. However, considering the varying response and the recent study by Longval et al., EPO seems ineffective in the management of PRCA, and may delay the initiation of better treatment options. A Eltrombopag is a safe option, but more data are needed to consider this to be a valid treatment of choice. The varying effects of rituximab and bortezomib underline the uncertainties regarding the pathophysiology of PRCA. However, plasma cells seem to play a key role in the pathophysiology as daratumumab have shown promising results. Although the mechanisms are yet to be elucidated, Daratumumab targets CD38 which has been shown to be expressed in high levels in plasma cells under normal conditions, and in low levels in myeloid and lymphoid cells [28]. Further studies regarding daratumumab are needed, as it may prove an effective treatment and potentially provide new insight in disease mechanisms. Future studies should focus not only on treatment responses, but also on timing and duration of treatment, pathophysiological aspects, and evolution of biomarkers with both prognostic and therapeutic relevance. The main goal should be to reliably identify patients who will benefit from treatment interventions. Only then, can we improve our care for patients with PRCA after ABO mismatched allo-HSCT.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was supported by the Helse Vest, Rakel and Otto Kristian Bruuns fund, the Øyvind Mølbach Petersens fund, and the Norwegian Society of Internal Medicine.