Treatment-free survival to bortezomib combined with dexamethasone in patients with refractory/relapsed pure red cell aplasia: a prospective clinical study.

Introduction

Acquired pure red cell aplasia (aPRCA) is a rare anemia due to the failure of erythropoiesis, characterized by severe reticulocytopenia and a significant reduction of erythroid precursors in the bone marrow [ 1 ]. Although the underlying mechanism of aPRCA remains unclear, recent studies indicated that autoimmune disorder, mediated either by autoantibodies or T-lymphocyte dysregulation, plays a critical role in the dysfunction of erythroid precursors [ 2–4 ].

Although cyclosporine A (CsA) could achieve a satisfactory efficacy with an overall response rate of approximately 80% [ 2 , 5 , 6 ], and still 30% of them experience relapse upon tapering or discontinuing CsA [ 7 ]. Furthermore, some patients are intolerant to CsA, particularly due to its long-term hepatotoxicity and nephrotoxicity. Second-line treatment options for those who experience CsA failure or severe side effects are limited, including cyclophosphamide, methotrexate, rituximab, and alemtuzumab, which yield an ORR of approximately 51.8-66.7% [ 1 , 4 , 8 ]. Recently, several studies have underscored the potential benefits of sirolimus, a mammalian target of rapamycin (mTOR) inhibitor in patients who are refractory or CsA intolerant [ 9 , 10 ]. However, concerns remain regarding prolonged maintenance and the incidence of infections during sirolimus treatment. Consequently, there is a pressing clinical need for effective salvage therapies that can induce a maintenance-free hematologic response.

Bortezomib, a potent inducer of apoptosis in plasma cells, is the most commonly used proteasome inhibitor and has been proved to be effective in plasma cell dyscrasia. Previous reports have shown bortezomib successfully used in monoclonal gammopathy-associated PRCA, possibly due to its immunomodulatory effects and partial clearance of plasma cells and immunoglobulins that inhibit erythropoiesis [ 11–15 ]. Additionally, bortezomib-based regimens have exhibited promising efficacy in conjunction with long-term maintenance in refractory PRCA secondary to ABO-mismatched hematopoietic stem cell transplantation (HSCT) [ 16–20 ]. Our prior study indicated the beneficial effects and long-term treatment-free survival (TFS) of bortezomib in two patients with refractory and recurrent aPRCA [ 21 ]. Here, we initiated a prospective, single-arm clinical trial ( NCT04423367 ) to evaluate bortezomib combined with dexamethasone as an alternative therapy for those who were refractory/relapsed or intolerant to previous immunosuppressive therapies.

Methods

In this prospective cohort study ( NCT04423367 ), we assessed the safety, efficacy and treatment-free survival (TFS) of bortezomib combined with dexamethasone (BD regimen) as a second-line therapy for patients with refractory or relapsed aPRCA. Out of 19 patients screened for eligibility, one was excluded based on the exclusion criteria. Therefore, 18 patients were enrolled finally, and all completed the designed treatment.

Patients

Patients with refractory or relapsed aPRCA at Institute of Hematology & Blood Diseases Hospital were recruited. The diagnosis of aPRCA was confirmed based on bone marrow smear and biopsy [ 1 , 2 ], along with thorough differential diagnosis to rule out other diseases. Enrollment criteria included: (1) age over 18 years old; (2) fulfillment of aPRCA diagnostic criteria; (3) refractory or recurrent to first-line treatment, including at least four months of full dose CsA with or without corticosteroids; relapse after prior treatment; or unable to tolerant previous treatments because of severe side effects; (4) Eastern Cooperative Oncology Group score ≤ 2; (5) well-functioning organs; (6) consent to participate and signed the informed consent form.

The exclusion criteria were as follows: (1) age <18 years; (2) pregnancy or lactating; (3) active bacterial or parasitic infection; (4) secondary PRCA due to symptomatic multiple myeloma (one patient with smoldering multiple myeloma was also included, as anemia is considered a manifestation of aPRCA rather than a CRAB symptom of MM); (5) secondary PRCA resulting from ABO major mismatched hematopoietic stem cell transplantation (HSCT) or organ transplantation; (6) secondary PRCA caused by solid tumor except for thymoma; (7) secondary PRCA due to drugs or pregnancy or B19 virus; (8) contraindications for glucocorticoids, or inability to tolerate glucocorticoids due to comorbidities; (9) participation in other clinical trials within 4 weeks prior to enrollment; (10) previous treatment with proteasome inhibitors; (11) history of active hemorrhage condition, including gastrointestinal, respiratory tract and central nervous system within 2 months before enrollment; (12) history of malignant tumors; (13) coexisting mental disorders; and (14) refusal to sign the informed consent form.

Study design

This study was a single-center, prospective, open-label, phase II clinical trial. Enrolled patients underwent a comprehensive medical history review and physical examination. In addition to regular laboratory tests, other baseline evaluations including hepatitis viruses, cytomegalovirus, Epstein-Barr virus (EBV), and parvovirus B19 tests, together with immunological tests were conducted to rule out connective tissue diseases. To assess lymphoproliferative and other hematological diseases, T-cell receptor rearrangement, flow cytometry, serum protein electrophoresis and serum immunofixation electrophoresis were performed. Chest and abdominal CT scans were conducted to exclude thymoma, lymphoma, and other solid tumors. Patients received bortezomib at a dosage of 1.3 mg/m 2 and weekly dexamethasone at 40 mg for 12 weeks [ 11 , 13 , 16 , 17 , 19 ]. The primary endpoint was the overall response rate at 12 weeks, with secondary endpoints including adverse events rate during treatment and TFS. After 12 weeks of intensive treatment, no maintenance therapy was administered. Responders began regular follow-up, while non-responders were transitioned to alternative medications or supportive care. A detailed study diagram is shown in Figure 1 .

Blood transfusions were permitted if the hemoglobin (Hgb) levels fell below 60 g/L or based on clinical judgment. Patients were followed up every two weeks for the first three months and then monthly until relapse. During follow-up, symptoms, signs, and laboratory tests were recorded. Bone marrow smear, biopsy and chromosome tests were conducted after achieving the primary endpoint. Anti-infection treatment was allowed under necessary condition. Response was evaluated using the following criteria: complete remission (CR): Hgb > 120 g/L in males or Hgb > 110 g/L in females and lasted for at least 1 month; partial remission (PR): Hgb increased by more than 30 g/L from baseline or became transfusion-independent but did not reach the criteria of CR; no response (NR): didn’t meet the PR criteria; overall response (OR) included both CR and PR [ 2 ]. Relapse was defined as the reoccurrence of hemoglobin reduction, which required the initiation of treatment. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). All participants provided written informed consent form, including permission for the publication of clinical data for research purposes. The study was approved by the Ethics Committee of Institute of Hematology & Blood Diseases Hospital (Approval No. IIT2020010) and conducted in accordance with the Declaration of Helsinki. This study was registered at www.clinicaltrial.gov ( NCT04423367 ) in September 2020.

Statistical analysis

Statistical analysis was performed using SPSS software (version 22.0). Continuous data are shown as means ± standard deviations, and categorical variables are presented as absolute frequencies and percentages. Comparisons between two groups were conducted using the t test and Mann-Whitney test. Fisher’s precision test was utilized for comparisons of categorical data. The Kaplan-Meier method was used to calculate cumulative response rate. Graphs were generated using GraphPad Prism software (version 6.0). All statical tests were performed by a two-sided significance level of p < 0.05.

Results

Patient characteristics

From September 2020 to September 2023, nineteen patients were screened. One patient was excluded due to severe disease-related complications. Ultimately, eighteen patients were enrolled and completed the 12-week intensive treatment. Baseline clinical characteristics are summarized in Table 1 .

There were 12 (66.7%) males and 6 (33.3%) females, with a median age of 47 (range 27-70) years old. Of these patients, 10 (55.6%) had primary aPRCA, and 8 (44.4%) had secondary aPRCA associated with plasma dyscrasia. All 18 patients had received prior immunosuppressive treatment (IST), among them, seven patients were refractory to CsA-based regimen, which included CsA monotherapy or CsA combined with glucocorticoids (GCS) or CsA combined with androgen. Nine cases had achieved PR or CR to IST, and two patients were intolerant to CsA because of severe side effects. Consequently, the hematological response rate to CsA as prior treatment in our cohort was 56.3% (9/16).

Before the BD regimen, the Hgb level was 51 ± 13 g/L and the reticulocyte count was 7.99 ± 13.76 × 10 9 /L. Seventeen patients (94.4%) presented with severe anemia (Hgb < 60 g/L) and were dependent on red blood cell transfusion. All enrolled patients were screened for normal renal and liver function. The colony forming unit-erythroid (CFU-E) and burst forming unit-erythroid (BFU-E) were measured at 45.13 ± 23.02 and 21.38 ± 8.83 per 10 5 bone marrow mononuclear cells (BMMNCs), respectively. Each patient had detected STAT3 mutation, with 22.2% (4/18) exhibiting mutated STAT3. TCR rearrangement was also assessed in this cohort, with only one patient showing positive rearrangement of TCRγ.

Specifically, eight patients were diagnosed with secondary aPRCA related to plasma dyscrasia, comprising seven with monoclonal gammopathy of undetermined significance (MGUS) and one with smoldering multiple myeloma (SMM). Among them, five were IgGκ, two were IgGλ and one patient had biclonal gammopathy (IgAλ and IgGλ) ( Table 2 ). All patients had a normal karyotype and none of them suffered from hypercalcemia or skeleton lesion. Prior to BD treatments, the M protein level was 6.23 ± 2.71 g/L, and the plasma cell ratio was 2.88 ± 3.26%. No significant differences in clinical baseline characteristics were found between primary and secondary aPRCA, except for the M protein level ( Table 1 ).

Efficacy

All enrolled patients received subcutaneous bortezomib at 1.3 mg/m 2 in combination with dexamethasone 40 mg weekly for a total of twelve doses. Eleven patients (61.1%) achieved hematological response by the primary endpoint, including nine with CR and two with PR ( Figure 2A ). Additionally, among the patients initially evaluated as PR at the primary endpoint, one achieved CR after 1 month and the other achieved CR at 1.5 months after the treatment ended. The median time to hematological response was only 40 days (range 21-77 days) and the median time to CR was only 2.5 months (range 1-4.5 months).

There was no significant difference in the overall hematological response rate between primary and secondary aPRCA ( p = 0.914). In primary aPRCA, six patients (60%) achieved hematological response, including five with CR and one with PR. For aPRCA secondary to plasma dyscrasia, five patients (62.5%) were classified as responders at the primary endpoint, all achieving CR ( Figure 2B ).

Additionally, we explored whether there was a difference in hematological response between patients refractory to and relapsed after IST. Among the seven patients refractory to prior IST, four (57.1%) achieved CR following the BD regimen. For patients who relapsed after IST, five (55.6%) achieved a hematological response, including four with CR and one with PR ( Figure 2C ).

At the end of the primary endpoint, significant increases were observed in Hgb levels and reticulocyte counts (51 ± 13 vs. 97 ± 37 g/L, p = 0.0002; 7.99 ± 13.76 vs. 60.28 ± 58.97 × 10 9 /L, p = 0.005) ( Figure 3A,B ). The need for red blood cell transfusions significantly decreased (944 ± 345 vs. 472 ± 619 ml/month, p = 0.004) ( Figure 3C ). The counts of CFU-E and BFU-E also showed significant recovery (45.1 ± 23.0 vs. 62.1 ± 25.8 per 10 5 BMMNCs, p = 0.0005; 21.4 ± 8.8 vs. 35.8 ± 11.7 per 10 5 BMMNCs, p = 0.0002) ( Figure 3D,E ). In addition, EPO level (743.9 ± 66.4 vs. 375.4 ± 360.9 mIU/ml, p = 0.0007) was significantly decreased compared to baseline values ( Figure 3F ).

Side effects

Adverse events with various severity were reported in four cases (22.2%) ( Table 3 ). These included hyperglycemia (2 cases, 11.1%), infection (1 case, 5.6%), constipation (1 case, 5.6%), deep venous thrombosis of the lower extremity (1 case, 5.6%), and liver injury (1 case, 5.6%). No serious infections or pancytopenia occurred during the BD regimen. All adverse events were managed effectively with dose adjustment or symptomatic treatment. No treatment-related deaths were reported. Although elevated creatinine is a common side effect of CsA, none of the participants experienced renal dysfunction during the treatment.

Relapse and final outcome

For the 11 patients who achieved a hematological response, none of them received any maintenance treatment related to aPRCA after discontinuation of BD regimen. Among these 11 responders, the median follow-up was 12 months (range 5-53 months), and five responders maintained their response at the last follow-up, with a median TFS of 12 months (range 2-50 months). The cumulative TFS rates were 90.9% at 3 months, 70.7% at 6 months, 56.6% at 12 months, and 37.7% at 24 months ( Figure 4A ). Additionally, similar relapse-free survival curves were observed for primary and secondary aPRCA, with no significant difference between the two groups (16.75 months vs. 24 months, p = 0.1797) ( Figure 4B ).

As previously mentioned, seven patients did not respond to BD regimen and were either switched to alternative therapies or remained dependent on red blood cell transfusions. Throughout the study period, no clonal evolution was detected during routine bone marrow follow-up, and no deaths were recorded. Additionally, the M protein level remained stable in the secondary aPRCA group (6.23 ± 2.71 vs. 6.20 ± 5.83 g/L, p = 0.715) ( Figure 3G ).

Discussion

Immunosuppressive therapies have been reported as first-line or second-line treatment due to the underlying autoimmune mechanisms of acquired PRCA. As the most frequently used immunosuppressant agent for first-line treatment of aPRCA, CsA could achieve a satisfactory response rate of approximately 65-87% [ 5 , 22 ]. Sirolimus has been shown to be an effective second-line option for patients with refractory or relapsed aPRCA, providing an ORR of 73.5% during a 12-month follow-up [ 9 ]. However, both CsA and Sirolimus require long-term maintenance, as early withdrawal of these drugs leads to rapid relapse [ 10 , 22 ]. Long-term IST carries an increased risk of serious complications, particularly drug-induced renal damage and infections. Thus, optimal salvage therapy that does not require prolonged maintenance is essential.

Recent studies have reported a series of plasma cell dyscrasia-associated PRCA patients who were initially refractory to standard ISTs, such as CsA and GCS [ 11–14 , 23 ]. Bortezomib, a proteasome inhibitor commonly used in multiple myeloma (MM), has shown promising results in this subgroup of aPRCA patients. Korde et al. [ 11 ] reported remarkable improvement of anemia and reticulocytopenia in patients with refractory PRCA secondary to smoldering MM when treated with a bortezomib-based regimen combined with long-term lenalidomide maintenance. Additionally, bortezomib has been effectively utilized to treat refractory PRCA following ABO-mismatched hematopoietic stem cell transplantation [ 16–20 ]. We previously administered bortezomib plus dexamethasone as salvage therapy for two patients with MGUS associated PRCA, both of whom achieved rapid remission and maintained TFS for at least 8 months after drug withdrawal [ 21 ]. Based on previous work, we conducted a prospective study, which was currently the largest study on the second-line use of bortezomib in aPRCA.

Our data showed that, at a median follow-up of 16.5 months (range 6-51 months), the overall response rate was 61.1%, with a complete response rate of 55.6%. Compared to sirolimus, which had a median time to response of 3 months (range 1-6 months), the BD regimen resulted in a quicker response, with a median time to response of only 40 days (range 21-77 days). Furthermore, our study confirms the efficacy of the BD regimen in treating refractory aPRCA with a response rate of 57.1%, comparable to that in relapsed patients. Thus, the BD regimen may serve as an effective salvage therapy for CsA-resistant aPRCA, suggesting an alternative pathogenetic mechanism. Although there was no statistically significant difference in the overall hematological response rate between primary aPRCA and secondary aPRCA related to plasma dyscrasia, all responders in the secondary aPRCA group achieved CR at 12 weeks, similar to previous studies [ 11 , 13 , 14 ]. Thus, the BD regimen is recommended, especially for patients with monoclonal gammopathy-associated aPRCA.

After discontinuing BD regimen, patients who responded did not receive any maintenance treatment, significantly alleviating the treatment burden. Although nearly half of the responders experienced relapse, the median time to relapse was over 6 months. Specifically, the median TFS was 7 months (range 2-48 months), with the estimated 12-month TFS being 56.6%. Therefore, patients may benefit from the BD regimen by achieving longer therapy-free remission with intensive short-term treatments. And further follow-up and larger cohorts are needed to confirm these findings.

Overall, the BD regime had minimal safety concerns, with primarily mild-to-moderate AEs and no treatment-related SAEs. The most common side effect was hyperglycemia (11.1%), which was effectively managed after symptomatic treatment. Notably, no instances of peripheral neuropathy were reported during the final follow-up, and only one patient experienced constipation related to bortezomib. Although most patients had previously been exposed to several immunosuppressive agents before enrollment, infections were infrequently observed during treatment, with only one case of varicella-zoster virus infection reported. Nevertheless, potential infections and hyperglycemia should be closely monitored. All adverse events were recoverable after the completion of therapy.

Previous studies have demonstrated that monoclonal protein inhibits erythropoiesis, resulting in a drastic reduction in CFU-E and BFU-E [ 3 , 22 , 24 , 25 ]. Sarathy et al. [ 14 ] reported maturation arrest of BFU-E in plasma cell dyscrasia-associated PRCA patients, with a twofold increase of BFU-E and clearance of serum light chains observed upon achieving remission. Our study also showed the decrease of M protein and immunoglobulin after treatment. Thus, we concluded that partially clearance of plasma and immunoglobulin may underlie treatment response; however, further research is needed to delineate the biologic mechanisms.

Conclusion

In summary, our results are promising, indicating that bortezomib combined with dexamethasone is a beneficial and well-tolerated alternative regimen for patients with refractory/recurrent/intolerant aPRCA, leading to a rapid response and potentially longer TFS.

Acknowledgements

All authors are very grateful to all the participants that contributed to this study. Special thanks to our colleagues for their valuable insights and collaboration throughout the research process. Shi J and Fang LW contributed to the conception and design of the research and reviewed the manuscript. Zhang LL and Shen YC performed data analysis and interpretation, participated in data visualization and manuscript drafting, as well as reviewing and editing the manuscript. Zhang LL also contributed to methodology development. Li RN was involved in data curation, project administration, validation, and investigation. Pan H, Gao Z, Li WW, Zhao JY, Liang Q participated in investigation and resource management. All authors have read and approved the final work.

Clinical trial

Bortezomib Plus Dexamethasone for Acquired Pure Red Cell Aplasia Failure or Relapse After First-line Treatment (BID-PERAL), NCT04423367 .

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethics approval statement

All patients signed written informed consent. Approval was obtained from the Ethics Committee of Institute of Hematology & Blood Diseases Hospital (approval no. IIT2020010) and this study was conducted in accordance with the Declaration of Helsinki.

Data availability

The data of this study are available from the corresponding author, Jun Shi, upon reasonable request.

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