Refractory Severe Aplastic Anemia Research Articles

Treatment of relapsed/refractory severe aplastic anemia in children: Evidence-based recommendations.

Severe aplastic anemia (SAA) is a rare potentially fatal hematologic disorder. Although overall outcomes with treatment are excellent, there are variations in management approach, including differences in treatment between adult and pediatric patients. Certain aspects of treatment are under active investigation in clinical trials. Because of the rarity of the disease, some pediatric hematologists may have relatively limited experience with the complex management of SAA. The following recommendations reflect an up-to-date evidence-based approach to the treatment of children with relapsed or refractory SAA.

Comparison of hematopoietic stem cell transplantation and repeated intensified immunosuppressive therapy as second-line treatment for relapsed/refractory severe aplastic anemia.

The optimal treatment for patients with severe aplastic anemia (SAA) who fail an initial course of antithymocyte globulin (ATG) plus cyclosporine has not yet been established. We compared the effectiveness of allogeneic hematopoietic stem cell transplantation (allo-HSCT) (n = 36) with repeated immunosuppressive therapy (IST) (n = 33) for relapsed/refractory SAA between 2007 and 2022. In the IST group, patients were retreated with ATG (n = 16) or high-dose cyclophosphamide (n = 17). The overall response rate was 57.6% at 6 months and 60.6% at 12 months. In the allo-HSCT group, patients received a transplant from a matched sibling donor (n = 6), matched unrelated donor (n = 7), or haploidentical donor (n = 23). All patients achieved neutrophil engraftment, and there were no cases of primary graft failure. The cumulative incidences (CIs) of grades II-IV and III-IV acute graft-versus-host disease (GVHD) were 36.1% ± 0.7% and 13.9% ± 0.3% at day +100, respectively. The 4-year CI of chronic GVHD (cGVHD) was 36.2% ± 0.7%, with moderate to severe cGVHD at 14.9% ± 0.4%. Compared with IST, HSCT recipients showed much higher hematologic recovery rate at 3, 6, and 12 months (63.9%, 83.3%, and 86.1%, respectively, p < 0.001). The estimated 4-year overall survival (OS) (79.8% ± 6.8% vs. 80.0% ± 7.3%, p = 0.957) was similar; however, the failure-free survival (FFS) was significantly better in the HSCT group (79.8% ± 6.8% vs. 56.6% ± 8.8%, p = 0.049). Of note, children in the HSCT cohort were all alive without treatment failures, exhibiting superior OS (100% vs. 50.0% ± 17.7%, p = 0.004) and FFS (100% vs. 50.0% ± 17.7%, p = 0.004) than children in the IST cohort. Subgroup analysis revealed that younger patients (age ≤ 35 years), especially children, and those with refractory SAA benefited more from HSCT. Therefore, for these patients, salvage HSCT may be more preferable than a second course of IST.

Effectiveness and Safety of Hetrombopag-Containing Therapy in Patients with Severe Aplastic Anemia: A Multicenter Real-World Study

Background: In recent years, immunosuppressive therapy (IST) in combination with thrombopoietin receptor agonist (TPO-RA) with or without other hematopoietic interventions has emerged as the first-line treatment option for patients with severe aplastic anemia (SAA) who are not eligible for hematopoietic stem cell transplantation. Hetrombopag, an innovative orally administered, non-peptide, small-molecule TPO-RA, has shown impressive efficacy and safety as a monotherapy for managing patients with relapsed or refractory SAA. Despite these promising findings, there is a lack of comprehensive real-world evidence on the benefit of hetrombopag in combination with IST-based therapy for patients with SAA. This study aims to fill this knowledge gap by evaluating the effectiveness and safety of hetrombopag-containing therapy for patients with SAA in a real-world setting. Methods: In this multicenter, real-world study, the clinical records of SAA patients who underwent hetrombopag-containing therapy were retrospectively reviewed in six hematological medical centers across China from August 2021 to November 2022. The therapeutic regimen encompassed cyclosporine (CsA) and hetrombopag, with the optional addition of anti-thymocyte globulin (ATG) and/or stanozolol according to the patients' condition. Hetrombopag was initially administered at a daily dose of either 5 or 7.5 mg, which could be escalated to a maximum of 15 mg daily. CsA was introduced at a preliminary dosage of 3-5 mg/kg/day, later tailored to sustain a trough concentration between 150 and 250 μg/L. ATG was given at doses of 2.5-3.5 mg/kg/day for rabbit ATG, or 20-30 mg/kg/day for pig ATG, over five days. Stanozolol was administered at 2-6 mg/day. Hematologic response (HR) was characterized based on evaluations of platelet (PLT), hemoglobin (HGB), and neutrophil (ANC) counts. PLT response was defined as an elevation to 20×10 9/L above the baseline or maintenance ≥20×10 9/L without transfusion for ≥8 weeks. HGB response was defined as an increase by 1.5 g/dL above the baseline, or for those receiving transfusions, an absolute decrease of ≥ 4 units of transfusions over an unbroken 8-week period, relative to that in the 8 weeks preceding treatment. ANC response was classified as a doubling from the baseline, or an increment in ≥ 0.5×10 9/L. Fulfillment of all three response criteria was classified as a complete response (CR), whereas meeting at least one of the three was considered an HR. Results: Our study comprised thirty-two patients diagnosed with SAA, of which 18 were treatment-naive, and 14 were refractory to previous IST. These patients were administered a median dose of hetrombopag of 7.5 mg (range: 5-15 mg) daily for a median duration of 8 months (range: 3-13 months). In treatment-naive SAA patients, the HR and CR rates after three months of hetrombopag-containing therapy were 44.4% and 16.7%, respectively. These rates increased to 87.5% for HR and 25.0% for CR after six months. Meanwhile, refractory SAA patients exhibited HR and CR rates of 50.0% and 14.3% respectively, after three months of therapy, and these rates improved to 60.0% and 40.0% at the six-month mark. Significantly, no patients developed hepatic or renal toxicity of grade 3 or higher. Additionally, no cases of clonal evolution or serious adverse events were documented throughout the treatment period. Conclusions: The hetrombopag-containing therapy demonstrated remarkable effectiveness in both treatment-naïve and refractory SAA patients in the real-world setting, with manageable safety profile. Most notably, the response rates and depth of remission in SAA patients significantly improved over time, signifying the ongoing therapeutic advantage of extended hetrombopag-containing therapy.

Optimized Rabbit Antithymocyte Globulin Protocol Plus Sequential Cyclosporine and Levamisole Regimen for Newly Diagnosed Severe Aplastic Anemia: A Single-Arm, Single-Centre, Prospective, Phase 2 Trial

Background The inferior effect of rATG is due to the early fatal blow caused by the more potent immunosuppression. In order to retain its sustainable immunosuppression while weakening the early fatal blow. We explored a modifying schedule of administration of rATG by prolonging the course of rATG administration based on the equality of total dose, and then reported the better response and survival in severe aplastic anemia (SAA). And previously, we reported the encouraging effectiveness of cyclosporine alternately combined with levamisole (CSA and LMS regimen) in moderate AA, refractory or relapsed SAA, and SAA. We aim to establish whether the optimized rATG protocol plus sequential CSA and LMS regimen could improve SAA outcomes. Methods We conducted a single-arm, prospective, phase 2 trial at The Institute of Hematology &amp; Blood Diseases Hospital, Chinese Academy of Medical Science &amp; Peking Union Medical College (CAMS &amp; PUMC). Patients aged 6 years or older with confirmed, newly diagnosed SAA were eligible. Patients received optimized rATG administration (1.97 mg/kg/d for 9 days) based on the equality of total does with standard protocol (3.55 mg/kg/d for 5 days). And then CSA and LMS were alternatively administrated every other day from day 14. The initial dose of CSA was 3mg/kg/day in adults and 5mg/kg/day in children (6-18 years old). Oral LMS was alternatively administrated at a dose of 150 mg per day in adults and 2.5 mg/kg per day in children (&amp;lt; 40 kg) in three divided doses. The primary endpoint was overall response rate at 6 months. The trial is registered at www.clinicaltrials.gov as NCT02203396. Results: Between Aug 1, 2014 and Sep 30, 2017, 40 patients with newly diagnosed SAA were treated (median age 24 years [range 7-57 years]; 19 [47.5%] male; 18 [45%] VSAA; 1[2.5%] post-hepatitis). All of these patients were transfusion dependent. Demographic data and clinical characteristics of these patients are outlined in Table 1. The 3-month overall response rates (ORRs) was 40.0%, including 2.5% CR and 37.5% PR. The ORRs increased to 60% (15% CR and 45% PR) at 6 months and 72.5% (42.5% CR and 30% PR) at 12 months. With a median follow-up of 77 months (range 0.1-97 months), estimated 8-year OS rate and event-free survival rate were 84.9% (95% CI, 69.35-92.9%) and 66.5 (95%CI, 49.1-79.1%), respectively. No patient discontinued therapy because of treatment-related toxicity. There were two deaths-one due to infection and another due to cerebral hemorrhage. In this cohort, 4/40 patients (5.7%) evolved to clonal disorders. Of the 4 patients, 1 patients progressed to overt PNH, 2 MDS and 1 acute myeloid leukemia (AML). Cytogenetic abnormalities involved chromosome 7 occurred in one cases with AML. A total of 2 (7.1%) patients relapsed at 33 and 79 months after initial response. Both of the 2 relapsed patients acquired response again with the administration of CSA. Conclusions: Front-line sequential optimized rATG protocol with CSA and LMS regimen resulted in encouraging long-term survival. Future randomized studies should evaluate the optimized IST regimen in the treatment of patients with SAA.

Efficacy and safety of eltrombopag in Chinese patients with refractory or relapsed severe aplastic anemia

For patients with severe aplastic anemia (SAA) in China who have had an insufficient response to the first-line treatment with hematopoietic stem cell transplantation or immunosuppressive therapy, there is no established standard of care other than transfusion support and treatment of infections. This non-randomized, open-label, Phase II multicenter trial investigated the efficacy and safety of eltrombopag in 20 adult Chinese patients with refractory or relapsed (r/r) SAA. The primary endpoint of hematologic response rate at Week 26, defined as the proportion of patients who met any of the International Working Group criteria, was observed in 70% (14/20) of patients, with more than 50% of these having at least bi-lineage response. Reduced red blood cell and platelet transfusion at Week 26 were observed in 57% (8/14) and 80% (8/10) of patients, respectively. Safety findings were consistent with the established safety profile of eltrombopag and no new safety signals were reported. None of the patients discontinued eltrombopag because of safety concerns. Although the sample size was small, this is the first prospective study to show that eltrombopag is efficacious and has a favorable safety profile in a Chinese patient population with r/r SAA.Trial registration: This trial is registered on ClinicalTrials.gov (NCT03988608); registered 17 June 2019.

Haploidentical bone marrow transplantation in patients with relapsed or refractory severe aplastic anaemia in the USA (BMT CTN 1502): a multicentre, single-arm, phase 2 trial

Relapsed severe aplastic anaemia is a marrow failure disorder with high morbidity and mortality. It is often treated with bone marrow transplantation at relapse post-immunosuppressive therapy, but under-represented minorities often cannot find a suitably matched donor. This study aimed to understand the 1-year overall survival in patients with relapsed or refractory severe aplastic anaemia after haploidentical bone marrow transplantation. We report the outcomes of BMT CTN 1502, a single-arm, phase 2 clinical trial done at academic bone marrow transplantation centres in the USA. Included patients were children and adults (75 years or younger) with severe aplastic anaemia that was refractory (fulfilment of severe aplastic anaemia disease criteria at least 3 months after initial immunosuppressive therapy) or relapsed (initial improvement of cytopenias after first-line immunosuppressive therapy but then a later return to fulfilment of severe aplastic anaemia disease criteria), adequate performance status (Eastern Cooperative Oncology Group score 0 or 1, Karnofsky or Lansky score ≥60%), and the presence of an eligible related haploidentical donor. The regimen used reduced-intensity conditioning (rabbit anti-thymocyte globulin 4·5 mg/kg in total, cyclophosphamide 14·5 mg/kg daily for 2 days, fludarabine 30 mg/m2 daily for 5 days, total body irradiation 200 cGy in a single fraction), related HLA-haploidentical donors, and post-transplantation cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis. Additionally, for GVHD prophylaxis, mycophenolate mofetil was given orally at a dose of 15 mg/kg three times a day up to 1 g three times a day (maximum dose 3000 mg per day) from day 5 to day 35, and tacrolimus was given orally or intravenously from day 5 to day 180 as per institutional standards to maintain a serum concentration of 10-15 ng/mL. The primary endpoint was overall survival 1 year after bone marrow transplantation. All patients treated per protocol were analysed. This study is complete and is registered with ClinicalTrials.gov, NCT02918292. Between May 1, 2017, and Aug 30, 2020, 32 patients with relapsed or refractory severe aplastic anaemia were enrolled from 14 centres, and 31 underwent bone marrow transplantation. The median age was 24·9 years (IQR 10·4-51·3), and median follow-up was 24·3 months (IQR 12·1-29·2). Of the 31 patients who received a transplant, 19 (61%) were male and 12 (39%) female. 13 (42%) patients were site-reported as non-White, and 19 (61%) were from under-represented racial and ethnic groups; there were four (13%) patients who were Asian, seven (23%) Black, one (3%) Hawaiian/Pacific Islander, and one (3%) more than one race, with seven (23%) patients reporting Hispanic ethnicity. 24 (77%) of 31 patients were alive with engraftment at 1 year, and one (3%) patient alive with autologous recovery. The 1-year overall survival was 81% (95% CI 62-91). The most common grade 3-5 adverse events (seen in seven or more patients) included seven (23%) patients with abnormal liver tests, 15 (48%) patients with cardiovascular changes (including sinus tachycardia, heart failure, pericarditis), ten (32%) patients with gastrointestinal issues, seven (23%) patients with nutritional disorders, and eight (26%) patients with respiratory disorders. Six (19%) deaths, due to disease and unsuccessful bone marrow transplantation, were reported after transplantation. Haploidentical bone marrow transplantation using this approach results in excellent overall survival with minimal GVHD in patients who have not responded to immunosuppressive therapy, and can expand access to bone marrow transplantation across all populations. In clinical practice, this could now be considered a standard approach for salvage treatment of severe aplastic anaemia. Attention to obtaining high cell doses (>2·5 × 108 nucleated marrow cells per kg of recipient ideal bodyweight) from bone marrow harvests is crucial to the success of this approach. US National Heart, Lung, and Blood Institute and US National Cancer Institute.

PB1941: PRELIMINARY EXPLORATION OF PROLONGED USE OF ELTROMBOPAG IN PATIENTS WITH NAÏVE SEVERE APLASTIC ANEMIA IN THE REAL WORLD: DURATION AND EFFICACY

Background: Eltrombopag (E-PAG) plus the immunosuppressive therapy (IST) consisted by antithymocyte immunoglobulin (ATG) and cyclosporin (CsA) has been reported with better efficacy in both refractory and naïve severe aplastic anemia (SAA) patients than IST alone. E-PAG was used up to 6 months in clinical trials. Patients with refractory SAA who remained on E-PAG with a median duration of 12 months showed further hematological improvement. Aims: To explore whether patients with naïve SAA could benefit from continuous use of E-PAG beyond 6 months and when E-PAG should be withdrawn in patients with no response. Methods: From February 2018 to November 2021, we collected 57 Chinese adult patients with naïve SAA who were treated with rabbit-ATG based IST (r-ATG, 3.5mg/kg/d × 5d and CsA 3-5 mg/kg/d) combining with E-PAG at dose of 75mg per day in the China Eastern Cooperation Group for Anemia (Clinical trials: ChiCTR2100045895). All patients were treated with E-PAG at least 6 months, and then whether to continue treatment was decided by the attending doctor according to patients’ situation. The dosage of E-PAG would be tapered gradually at 3 months after complete remission (CR) or 6 months after stable partial remission (PR). Results: Clinical and laboratory characteristics of patients were listed in Table 1. The median time from diagnosis to treatment was 3 weeks (1 week to 291 weeks). The median follow-up time was 17 months (1 month to 44 months) and overall survival rate was 98%. The overall response rates were 35% (20 of 57), 67% (36 of 54), 84% (42 of 50) and 95% (41 of 43) at 1, 3, 6 and 12 months, and CR rates were 17% (9 of 54), 24% (12 of 50) and 35% (15 of 43) at 3, 6 and 12 months. The first response was observed at 2 weeks after treatment, and the median time to remission during the first 6 months was 11 weeks (2 weeks to 25 weeks). 11% of patients achieved efficacy between 7 and 12 months. In patients with NR after continuous use of E-PAG for 12 months, no more patients met criteria for PR by extending the treatment of E-PAG. The cumulative effect curve showed that 88 percent of all 12 months responses occurred within 6 months, and the efficacy reached a peak at 6 months (Figure 1). 11 patients (22%, 11 of 50) who achieved CR within 6 months were under steady state with the exception of 1 patient converting to paroxysmal nocturnal hemoglobinuria at 12 months after treatment. In 30 patients achieved PR at 6 months, 5 patients (17%, 5 of 30) discontinued E-PAG after 6 months and 25 patients had a continuous exposure to E-PAG, while the efficacy of 13 patients (52%, 13 of 25) were improved to CR within median extended usage time of 9 months (2 to 31 months) of E-PAG, and the dose of E-PAG was tapered gradually in 6 patients (24%, 6 of 25), maintained at 75mg per day in 7 patients (28%, 7 of 25). The other 12 patients (48%, 12 of 25) were in stable PR. In 8 patients (16%, 8 of 50) were ineffective at 6 months, 1 patient died early at 1 month; 2 patients achieved PR at 12 months by E-PAG continuously; 5 patients treated with CsA alone latter; and 2 patients achieved CR at 12 months, 3 patients still were in NR in CsA alone group. Image:Summary/Conclusion: It was suggested that E-PAG was used at least 6 months. Continuous administration of E-PAG could improve the hematological response of PR patients to CR. No patient with NR taking effect after 12 months, new options should be considered with caution for them.

Eltrombopag for Post-Transplant Poor Graft Function in East Asian Patients.

Poor graft function (PGF) is a serious, potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. Eltrombopag has shown multilineage responses in patients with refractory severe aplastic anemia, supporting the idea that it may improve cytopenia in patients with PGF. This retrospective, single center analysis included 8 Korean patients receiving eltrombopag for PGF. Median interval between transplant and eltrombopag treatment was 73 days, and the median duration treatment was 3.5 weeks. With median maximum daily dose of 50 mg, the time to best response was 93 days. Median hemoglobin increased from 8.2 g/dL to 10.9 g/dL, platelet from 18.5 × 109/L to 54 × 109/L, and absolute neutrophil count from 1.25 × 109/L to 3.32 × 109/L. In conclusion, eltrombopag is a good option for PGF in Korean patients, even at a lower dose compared to western patients.

Intensive Immunosupressive Therapy Combining with Eltrombopag for Adult Chinese Patients with Severe Aplastic Anemia

In sight of different pharmacokinetics between races, the recommended dose is 75mg/d for Asian using eltrombopag [1]. However, the efficacy and safety of antithymocyte immunoglobulin (ATG) and cyclosporin A (CsA) with eltrombopag are still largely unknown for adult Asian patients with severe aplastic anemia (SAA).From May 2014 to March 2021, 121 Chinese adult patients with SAA were treated with IST (r-ATG, 3.5mg/kg/d × 5d and CsA 3-5 mg/kg/d) or in conjunction with eltrombopag (75mg/d, from day 1 to 6 months) prospectively and non-randomly. The adverse events (≥3 grades) referring to Common Terminology Criteria for Adverse Events version (CTCAE) 5.0 within 6 months.In pretreatment evaluation of clinical and laboratory characteristics. Median age (39 years and 40 years) was comparable. The complete blood count with differential and quantification of CD4/CD8 T-cell subsets were similar in both groups, but median time from diagnosis to treatment (16 d and 28 d, P=0.038) was different significantly (Table 1).The Chi-Squared test was used to compare the efficacy. The overall response rates (ORR) of IST alone or in combination with eltrombopag in the 1st, 3rd, 6th and 12th month after IST were 12% vs 35% (P=0.002), 44% vs 64% (P=0.028), 61% vs 85% (P=0.006) and 73% vs 91% (P=0.031), respectively. The complete response (CR) rates in the 3rd, 6th and 12th month after IST are 7% vs 17% (P=0.069), 14% vs 27% (P=0.11) and 33% vs 32% (P=0.92) (Table 2).We analyzed factors associated with the efficacy at 6 months by the Binary-Logistic regression model. Elements would be listed in multivariate analysis whether the factors might impact on the efficacy or had P value lower than 0.2 in univariate analysis. It was suggested that ORR was significantly related with the use of eltrombopag (P=0.011, OR=3.600, 95%CI 1.345-9.638) (Table 3).The overall survival (OS) and factors related to survival were analyzed by Kaplan-Meier method and Cox regression model. The OS in IST combined with eltrombopag group was 98% compared to 88% for IST alone (P=0.078). No significant intergroup differences were noted in multivariate analysis of OS.The nonhematologic adverse events (≥3 grades) were infrequent, occurring in 16% patients. 8 in IST plus E-PAG cohort and 11 in IST alone cohort (15% vs 16%, P=0.80). Hepatic injury was prevalent complication (6% vs 8%, P=0.96), relatively. But none showed significant difference between two groups.DiscussionIt has been reported that eltropopag promoted the response of megakaryocytic or even three lineages in refractory SAA [2]. The 6th month CR rate and ORR of our study are lower than the results of Townsley's research with 35% and 94% in the cohort of IST plus eltrombopag [1]. But the CR rate ORR is comparable to De Latour's results with 21.9% and 59.4% in the 3rd month [3]. Median age and dosage of eltrombopag needs to be considered with caution between different researchs, whist the efficacy of horse ATG (hATG) and rATG remained a subject of some debate [4]. Townsley et al. had reported that hepatic impairment (≥3 grades) was 18% [1], but our research showed lower rate of liver impairment with 6%. We should increase the sample volume to analyze the adverse events.Reference[1] Townsley DM, et al. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia [J]. N Engl J Med, 2017, 376 (16): 1540-1550.[2] Desmond R, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug [J]. Blood, 2014, 123 (12): 1818-1825.[3] De Latour, RP, et al. Results of the EBMT SAAWP Phase III Prospective Randomized Multicenter RACE Study of Horse ATG and Ciclosporin with or without Eltrombopag in naive SAA patients. EBMT 2020 abstract O018.[4] Vallejo, C., et al., Rabbit antithymocyte globulin versus horse antithymocyte globulin for treatment of acquired aplastic anemia: a retrospective analysis. Annals of Hematology, 2015. 94(6): p. 947-954. [Display omitted] DisclosuresHe: F. Hoffmann-La Roche Ltd.: Consultancy; LongBio Pharma: Consultancy, Research Funding.

Combined haploidentical and cord blood transplantation for refractory severe aplastic anaemia and hypoplastic myelodysplastic syndrome

Umbilical cord blood (UCB) transplantation is a potentially curative treatment for patients with refractory severe aplastic anaemia (SAA), but has historically been associated with delayed engraftment and high graft failure and mortality rates. We conducted a prospective phase 2 trial to assess outcome of an allogeneic transplant regimen that co-infused a single UCB unit with CD34+ -selected cells from a haploidentical relative. Among 29 SAA patients [including 10 evolved to myelodysplastic syndrome (MDS)] who underwent the haplo cord transplantation (median age 20years), 97% had neutrophil recovery (median 10days), and 93% had platelet recovery (median 32days). Early myeloid engraftment was from the haplo donor and was gradually replaced by durable engraftment from UCB in most patients. The cumulative incidences of grade II-IV acute and chronic graft-versus-host disease (GVHD) were 21% and 41%, respectively. With a median follow-up of 7·5years, overall survival was 83% and GVHD/relapse-free survival was 69%. Patient- and transplant-related factors had no impact on engraftment and survival although transplants with haplo-versus-cord killer-cell immunoglobulin-like receptor (KIR) ligand incompatibility had delayed cord engraftment. Our study shows haplo cord transplantation is associated with excellent engraftment and long-term outcome, providing an alternative option for patients with refractory SAA and hypoplastic MDS who lack human leucocyte antigen (HLA)-matched donors.

Paediatric severe aplastic anaemia treatment: where to start?

Paediatric severe aplastic anaemia treatment: where to start?

Current evidence and the emerging role of eltrombopag in severe aplastic anemia

Acquired aplastic anemia (AA) is characterized by a reduced stem cell reserve. Several preclinical studies have confirmed the beneficial effect of thrombopoietin (TPO) on the expansion and maintenance of hematopoietic stem cells (HSCs). Thus, TPO receptor agonists seem to be an ideal therapeutic agent for AA to augment marrow function. First studies with eltrombopag as a single agent at 150 mg/day showed an overall response rate of 40–50% in patients with refractory severe AA (rSAA). Subsequent studies examined the first-line use of eltrombopag together with horse antithymocyte globulin and cyclosporine, reaching response rates up to 94%. Although used at high doses, known adverse events in the form of skin, gastrointestinal, or hepatic impairment are feasible in AA, however first data show a relatively high rate of clonal evolution in the form of karyotypic aberrations in patients with rAA. Nonetheless, there is a strong rationale that eltrombopag can contribute to restoring hematopoiesis in SAA by stimulating HSCs. Further studies are needed to decide if eltrombopag is clearly superior to current established treatments and to determine optimal treatment duration, dosage, and long-term effects.

Acquired aplastic anemia: Is bystander insult to autologous hematopoiesis driven by immune surveillance against malignant cells?

We previously reported a serendipitous finding from a patient with refractory severe aplastic anemia who had gotten an unexpected hematological response to treatment with gut-cleansing preparations (GCPs). This patient experienced three recurrences over the ensuing one year of intermittent GCP treatments, with each recurrence occurring 7-8 wk from a GCP. After his third recurrence, he was prescribed successive treatment with rifampicin, berberine, and monthly administered GCP for 4 mo, and he developed an erythroid proliferative neoplasma and an overwhelming enteropathy, and eventually died of septic shock. Laboratory investigations had validated the resolution of myelosuppression and the appearance of malignant clonal hematopoiesis. From the treatment process and laboratory investigations, it is reasonably inferred that the engagement of gut inflammation is critically required in sustaining the overall pathophysiology of acquired aplastic anemia probably by creating a chronic inflammatory state. Incorporation of rifampicin, berberine, and monthly GCP into cyclosporine can enhance the immunosuppressive effect. In a subgroup of acquired aplastic anemia patients whose pathogenesis is associated with genotoxic exposure, the suppressed normal hematopoiesis may result from the bystander insult that is mediated by the soluble inflammatory cytokines generated in response to the immunogenic products of damaged hematopoietic cells in the context of chronic inflammatory state and may offer a protective antineoplastic mechanism against malignant proliferation.

Current insights into the treatments of severe aplastic anemia in China.

Recently, several studies have been conducted to generate considerable evidence regarding unique treatments for severe aplastic anemia (SAA) in China. Haploidentical donor hematopoietic stem cell transplantation (HID-HSCT) showed an overall survival rate (80.3-86.1%) comparable to those with immunosuppressive therapy (IST) and matched related donor (MRD)- and matched unrelated donor (MUD)-HSCT. Failure-free survival of HID-HSCT was also comparable (76.4-85.0%) to those of MRD- and MUD-HSCT and better than IST in patients < 40years. Although these results are promising, HID-HSCT should be regarded as a salvage therapy when young patients fail to respond to IST. Porcine anti-human lymphocyte immunoglobulin (pALG) showed similar or superior overall response at 6months compared to rabbit anti-human thymocyte immunoglobulin (rATG) (64.0-79.4% in the pALG-group vs.48.1-64.7% in the rATG-group) as a first-line IST. Promising hematological response (28.4-33.3%) was observed in patients with refractory AA following infusion of the mesenchymal stromal cells (MSCs) derived from the bone marrow of allogeneic donors. pALG can replace rATG as an immunosuppressive drug and MSCs infusion can be used as a second-line treatment for refractory SAA. We believe that this review contributes to refine the global practices for SAA treatment.

Effect of arsenic trioxide on the Tregs ratio and the levels of IFN-γ, IL-4, IL-17 and TGF-β1 in the peripheral blood of severe aplastic anemia patients.

Previous studies have suggested that the anticancer agent, arsenic trioxide (ATO), could attenuate T cell mediated immunity by not only inhibiting the proliferative response of T cells but by also increasing the frequency of regulatory T cells (Tregs). Furthermore, ATO represents a reasonable salvage treatment in some patients with refractory severe aplastic anemia (SAA). The current study aimed to evaluate the function of ATO on the Tregs percentage and cytokines changes in the peripheral blood mononuclear cells (PBMCs) of SAA patients.PBMCs were collected from 20 newly diagnosed SAA patients in Henan Cancer Hospital and treated with different concentrations of ATO (0, 1, 2.5, and 5 μmol/L). Then we investigated the efficacy of ATO on Tregs ratio and the levels of interferon (IFN)-γ, interleukin (IL)-4, IL-17 and transforming growth factor (TGF)-β1 in the peripheral blood of SAA patients in vitro.The results showed that ATO significantly increased the proportion of Tregs (P < .001) at 2.5 and 5 μmol/L concentrations, and the proportion of Tregs was increased with increasing ATO concentration (r = 0.524). At 1 (P = .03), 2.5 (P < .001) and 5 μmol/L (P < .001), ATO significantly up-regulated the expression levels of Foxp3 mRNA, which was positively and linearly correlated with the increase of Tregs cell-frequency (r = 0.52, 95%CI, 0.37–0.67). In addition, ATO significantly reduced the levels of IFN-γ (at 1, 2.5 and 5 μmol/L, P < .001), IL-4 (at 2.5 μmol/L, P = .009; at 5 μmol/L, P < .001), and IL-17 (at 2.5, P = .016; at 5 μmol/L, P < .001). ATO significantly reduced the levels of TGF-β1 at 5 μmol/L (P = .03), but showed no significant effects at 1 and 2.5 μmol/L (P > .05).ATO could mediate the immune regulation, which might contribute to improve hematopoietic recovery in SAA patients.

Eltrombopag treatment promotes platelet recovery and reduces platelet transfusion for patients with post-transplantation thrombocytopenia.

Post-transplantation thrombocytopenia (PT) is a common and severe complication which usually leads to poor prognosis. Eltrombopag (EPAG), a novel oral thrombopoietin (TPO) receptor agonist, has shown promising effects in thrombocytopenia due to immune thrombocytopenic purpura (ITP) and refractory severe aplastic anemia (rSAA), while the effectiveness of EPAG for PT patients still needs to be evaluated. A total of 32 PT patients receiving EPAG were retrospectively analyzed between September 2017 and July 2019, including 15 patients with poor graft function (PGF) and 17 patients with secondary failure of platelet recovery (SFPR). To date, 21 (65.6%) patients achieved overall recovery (OR) and 14 (43.8%) patients achieved complete recovery (CR). Among responders, 18 (85.7%) patients discontinued or tapered the drug and 16 (76.2%) patients successfully maintained their best response. During the EPAG treatment, responders received much lower median platelet transfusion units than non-responders (11 vs. 95, P < 0.001). After a median follow-up time of 364 days (range, 24-842), the overall survival in these patients was 78.1% (100% for responders and 36.4% for non-responders, P < 0.001). In the univariate and multivariate analysis, PGF was identified as the independent risk factor for OR (P = 0.041, HR = 5.333). Megakaryocyte (Megk) amounts (P = 0.025, HR = 14.638) and splenomegaly (P = 0.042, HR = 11.278) were identified as independent risk factors for CR. Besides, PGF patients tended to take a longer time to achieve PR and CR than SFPR patients. In conclusion, our data suggest that EPAG can promote platelet recovery and reduce platelet transfusion in PT patients.

Eltrombopag for patients with moderate aplastic anemia or uni-lineage cytopenias

AbstractThere is no standard or widely effective treatment of patients with moderate aplastic anemia (MAA) or hypo-productive uni-lineage cytopenias (UC). Eltrombopag (EPAG), a small molecule thrombopoietin mimetic, has previously been shown to result in durable multi-lineage hematologic responses with low toxicity in patients with refractory severe aplastic anemia (SAA). Its safety and efficacy in MAA are unknown. This prospective phase 2 study enrolled previously untreated and treated MAA and UC patients with clinically relevant cytopenias. EPAG was administered at doses escalating from 50 to 300 mg/d. Hematologic responses were assessed at 16 to 20 weeks. Responding patients were continued on EPAG until reaching defined robust or stable blood counts. EPAG was reinstituted for relapse. Thirty-four patients were enrolled between 2012 and 2017, including 31 with MAA and 3 with UC. Seventeen patients responded in at least 1 eligible lineage by the primary end point. A striking improvement in anemia was observed in a patient with Diamond-Blackfan anemia. EPAG was well tolerated, and it was discontinued for robust or stable blood counts in 12 of 17 patients after a median of 8 months. A majority required re-initiation of EPAG for declining counts, and all regained response. Two of 34 patients developed non–chromosome 7 bone marrow cytogenetic abnormalities while taking EPAG, without dysplasia or increased blasts. Somatic mutation allele frequencies in cancer genes did not increase overall on EPAG. EPAG is a well-tolerated oral treatment of cytopenias in patients with MAA/UC. This trial was registered at www.clinicaltrials.gov as #NCT01328587.

Eltrombopag, oral immunosuppressant and androgen combination therapy in twelve patients with refractory severe aplastic anemia

ABSTRACT Objective: Eltrombopag monotherapy or eltrombopag combined with immunosuppressant has achieved robust hematologic responses in severe aplastic anemia (SAA). In patients with refractory SAA, for whom hematopoietic stem cell transplantation is unavailable, we attempted to combine eltrombopag with oral immunosuppressant and androgen, to further improve hematologic response. Methods: We collected and analyzed data retrospectively from twelve refractory SAA cases who had received combination therapy of eltrombopag, oral immunosuppressant and androgen. All these patients had received intensive immunosuppressive treatment (IST) for more than 6 months and were evaluated as nonresponders. Results: A total of 12 SAA patients were treated with a combination of eltrombopag, an oral immunosuppressant (cyclosporine, N = 9; tacrolimus, N = 3) and androgen. The median maximum dose of eltrombopag was 75 mg/day (range, 75–150). After a median follow-up of 8.5 months (7–23), the overall response rate (ORR) was 42% (5/12, including trilineage, N = 4; hemoglobin + platelet, N = 1). Two of 5 responders reached normal blood counts. Optimal hematological response rates were reached at 6 months. The median increase in neutrophil, hemoglobin and platelet count were 1.64 × 109 /L (0.71–2.66), 53 g/L (25–66.5) and 25 × 109 /L (14–230), respectively. In general, the combination therapy was well tolerated; however, two patients suffered from non-lethal upper extremity venous thrombosis when they were platelet transfusion-dependent. Conclusion: Eltrombopag, oral immunosuppressant and androgen combination therapy in patients with IST-refractory SAA is feasible and could restore multi-lineage hematopoiesis. Thrombosis risk of eltrombopag still needs to be monitored.

The Path to Cure: Using Haploidentical (haplo) Donors and High-Dose Post-Transplant Cyclophosphamide (PTCy) for Treatment-Naïve and Refractory Severe Aplastic Anemia (SAA)

SAA is a life-threatening hematopoietic stem cell disorder that is often treated with bone marrow transplantation (BMT) to reconstitute hematopoiesis and eliminate clonality. Our group has shown that PTCy after related HLA-haplo BMT can facilitate engraftment and yield low rates of relapsed and refractory (R/R) SAA. Given the risk of relapse or secondary clonal disease following immunosuppressive therapy (IST) is &amp;gt; 50% at five years, we decided to implement this treatment paradigm in untreated SAA. Here, we review the haplo outcomes in SAA, with an update in R/R SAA patients and new results in treatment-naïve (TN) SAA patients using haplo donors and PTCy. Patients were eligible with SAA. Fanconi anemia and short telomere patients were excluded. R/R patients had ≥ one course of IST. The conditioning regimen included standard published haplo backbone of antithymocyte globulin, low dose CY, and total body irradiation (TBI). All R/R patients received 200cGy. The TBI dose for the TN cohort was modified after 3 graft failures (GF) in initial 7 patients treated at 200cGy; thus, the last 8 TN patients received 400cGy. After the marrow graft was infused on day 0, cyclophosphamide 50mg/kg/day IV on days +3,+4 post-transplant was administered. All received mycophenolate mofetil beginning day +5 through 35 and tacrolimus day +5 to 365. Engraftment definitions include: absolute neutrophil count &amp;gt;1.0 x10E9/L for three consecutive days; days from last red blood cell transfusion for hemoglobin and platelet count &amp;gt;50,000 for 7 days without transfusion. Thirty-five SAA patients received haplo BMT: 20 R/R and 15 TN. The median follow-up is 31 months (90% CI: 26.0, 45.4). The median age was 25 (range, 4-69) years, with 23 patients &amp;gt; age 20 and 57% were males. The median related haplo donor age was 34 years (range, 19-57), including three non-first degree relatives. Table 1 shows data by cohort. Median time to neutrophil recovery was 17 days (range 15-88), to red cell recovery 23 days (range 6-58) and to platelet recovery 28 days (range 15-108). At the time of BMT, 25 of 35 patients had evidence of clonality (mostly PNH clones). Four of 35 patients (11.4%) (95% CI: 3.2, 26.7%) experienced GF. There was one GF out of 20 patients in the R/R group (5%) (95% CI: 0.1, 24.9%) and 3 of 15 in the TN group 20% (95% CI: 4.3,48.1%, p= 0.20). OS for all patients (Figure 1) is 94% (90% CI: 88,100%) at one and two years, 100% in the R/R group and 86% (90% CI: 72, 100%) in the TN group. The cumulative incidence of grade II-IV aGVHD at day 100 is 9% (90% CI: 1, 17%). The cumulative incidence of chronic GVHD at 2 years is 9% (90% CI: 1,17%). All R/R patients are alive and well, and fully engrafted with 100% donor chimerism; patient with primary GF is 100% chimeric after 2nd transplant from different haplo donor. One patient has extensive cGVHD. Of the first 7 TN patients who received 200cGy TBI, 4 are fully engrafted and well; of the 3 with GF, 2 died from infection and one is now 100% chimeric using second haplo donor. After increasing the TBI dose to 400cGy, the subsequent 8 patients are alive with full donor chimerism. Nonmyeloablative haplo BMT with PTCy represents a potential cure in SAA, with all 20 R/R currently alive, disease-free (including eradication of clonal diseases), and no evidence of active GVHD. Extending this approach to TN patients was associated with higher GF rates. Perhaps this is not surprising given that the potential beneficial effect of front-line IST on engraftment is absent. The increase in TBI dose to 400cGy in TN patients appears to achieve more durable engraftment without early greater toxicity (infection, delayed engraftment, GVHD); more patients and longer follow up are required to understand rates of fertility and other survivorship issues. Alternative donor BMT (including haplo donors) should be offered to all SAA patients with R/R SAA who are fit enough to tolerate non-myeloablative conditioning. A potential advantage of haplo donors over unrelated donors is that the transplant center has full control and oversight of allograft quality, which can be especially important with the use of the preferred allograft source for SAA, bone marrow. Non-myeloablative haplo BMT in TN SAA could lead to a paradigm-shift in the field, such that essentially all children and fit adults can proceed quickly to a relatively safe, curative BMT. Disclosures DeZern: Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Cooke:Jazz pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Low Dose of Eltrombopag with Long-Term Response in Children with Severe Aplastic Anemia, Less Morbi-Mortality Better Quality of Life

Refractory severe aplastic anemia (RSAA) has poor prognosis. Eltrombopag is a therapeutic option in patients that failed to ATG+CyA; in countries with poor outcomes their use is limited. Described experience with low doses of Eltrombopag 25mg/d. CASE 1. Female 4 yo diagnosis SAA not responded after 2 cycles ATG, the first one with mesterolone for 6 months, continued pancytopenic with multiple transfusions (every 2/3 weeks) complicated by iron overload, and serious infections; presented CNS infection with secondary spastic paralysis, due chelation therapy development 2 cholestasis outbreak. Eltrombopag was started 25mg/d, after the first month, no more transfusion was needed with increase of neutrophils and platelet counts. After 7 months Eltrombopag for economic reasons was stopped with partial response. Hb &gt;10g/dL, CAN &gt;1000 m3 &amp; platelets 99 X103. For 4 years; until now; she is doing well, no infections and no transfusions needed. CASE 2. Male 2 yo, SAA not responded ATG course, he was inpatient during 8 months with multiple infections, bleeding complications and consequence transfusion was needed. Iron overload required iron chelation therapy, the medical orders and CyA was irregularly administrated, the parents not accept considered BMT, so Eltrombopag 25mg/d was started, 6 weeks later no more transfusion was required, the bleeding stopped and no mores infections were observed; after 7 months had a partial response Hb &gt; 11g/dL CAN &gt; 1000m3 &amp; platelets 45 x103, and Eltrombopag was stopped. This two patients use Eltrombopag as compassionate use, with good clinical results, in spite of low dose to get a partial hematological response. Low dose of Eltrombopag is useful to induce partial response rapidily with an excellent clinical results even when it is discontinued. Actually all patients with new SAA diagnostic are register in our Institution in a prospective protocol to receive ATG+CyA and start Eltrombopag 50mg/d with increase according to the response. The low dose could be a good option for patients with refractory aplastic anemia to get a partial response in development countries with less morbidity-mortality and a better quality of life. Disclosures No relevant conflicts of interest to declare.