Severe Aplastic Anemia in a Patient with Erythropoietic Protoporphyria Successfully Treated by Avatrombopag

Abstract Abstract 1091 Poster Board I-113 Introduction Aplastic anemia (AA) is a syndrome of bone marrow failure characterized by peripheral pancytopenia and marrow hypoplasia. In the past, AA was considered to be a fatal disease; however, current therapies, including bone marrow transplantation or immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine (CSA), are curative in the majority of patients. IST is effective at restoring hematopoietic stem cell production, but relapse and evolution to myelodysplastic syndromes remain clinical challenges. Additionally, there is no real consensus regarding optimal CSA levels, duration of CSA treatment, or the optimal use of growth factors and their relationship to the development of clonal disease. Objectives The primary objective was to review treatment management for severe AA in pediatric patients in order to elucidate treatment differences and review morbidity and mortality as they relate to treatment variation. Study Design/Methods A retrospective review of pediatric patients treated at the Children's Hospital of Philadelphia for AA (both severe and moderate) over a 23 year period was performed. Results A total of 70 patients with AA were treated at our institution from 1985 to July 2008. Exclusions included: 6 patients who received some type of initial treatment at outside institutions, 4 patients who had missing records, and 2 patients who had a diagnosis of moderate AA. Thus, a total of 58 patient records were included in the analysis. Of the total patients reviewed, 60% were male and 40% were female. 34.5% of patients were African-American, and 57% were diagnosed in 2000 or later. The mean age at diagnosis was 9.5±5.8 years. 52% fell into the category of very severe AA based on published diagnostic criteria, 45% had severe AA, and 2 patients (3%) had moderate AA. 15.5% of patients developed AA in the setting of acute hepatitis. More than half of the patients treated with IST had a complete response (CR). The average time to CR was 15±15 months. Average duration of CSA treatment was 15±13 months and 8.6±10.7 months for growth factor. Two patients (3.5%) died, one from complications unrelated to AA and one from infectious complications post-BMT after initial IST failure. Average time to transfusion independence for all patients was 8±11 months (with a range of 0-54 months). Not surprisingly, the time to transfusion independence was significantly associated with IST failure (p=0.010). Patients who failed treatment had an average time to transfusion independence of 17±16 months as compared to those who were complete responders who had an average time to transfusion independence of 3±3 months. Additionally, there was a significant association between IST failure and CSA levels (p=0.014). Patients who had nontherapeutic CSA levels overall had an increased rate of treatment failure. Of those patients who were nontherapeutic, 56% were noncompliant with CSA administration. There was no significant association between IST failure and bone marrow cellularity (p=0.251). PNH was diagnosed in 5% of patients; there were no patients with evidence of myelodysplastic syndrome (MDS). Two of the 3 patients with PNH failed initial IST. Another 2 patients had evidence of a cytogenetic abnormality (16q deletion), but never progressed to MDS. (Note: averages presented as mean±SD) Conclusions/Methods With current IST regimens, AA is curative in the majority of pediatric patients. IST failure was associated with nonadherence to CSA treatment. For patients with confirmed clonal disease, it is possible that IST failure and the ultimate development of clonal disease are related. Disclosures No relevant conflicts of interest to declare.

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Significant Benefit of Everolimus In a Patient With Urothelial Bladder Cancer Harboring A Rare M1043I Mutation of PIK3CA

10.21203/rs.3.rs-216259/v1 ◽

2021 ◽

Author(s):

Shouhua Pan ◽

Si Li ◽

Mingzhe Xiao ◽

Dongsheng Chen ◽

Junlong Li

Keyword(s):

Bladder Cancer ◽

Treatment Options ◽

Complete Response ◽

Significant Benefit ◽

Urothelial Bladder Cancer ◽

Multiple Tumor ◽

First Line Therapy ◽

First Case ◽

Potential Biomarker ◽

Urothelial Bladder

Abstract Urothelial bladder cancer (UBC) is a common malignancy with significant mortality worldwide. However, treatment options of UBC were mainly chemotherapy and immunotherapy since few targeted agents had shown efficacy in UBC. In recent studies, everolimus has showed antitumor activity in patients harboring aberrations in PI3K/Akt/mTOR pathway in multiple tumor types. Here we report a patient with metastatic UBC harboring a rare M1043I mutation of PIK3CA detected by DNA based next-generation sequencing. The patient received everolimus as first-line therapy after palliative transurethral resection. Within one months, the residual lymph node metastases achieved complete response and no more ostealgia was reported. To our knowledge, this is the first case reporting a significant benefit from everolimus in PIK3CA mutant UBC, suggesting the rare M1043I mutation variant may be a potential biomarker of sensitivity to everolimus. Further mechanism insights and clinical studies are needed to clarify the effectiveness of everolimus in patients with PIK3CA M1043I mutation.

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Study of the Outcome of Pediatric Patients with Aplastic Anemia treated with Immunosuppressive Therapy at Ain Shams University Pediatric Hospital

QJM ◽

10.1093/qjmed/hcab113.052 ◽

2021 ◽

Vol 114 (Supplement_1) ◽

Author(s):

W Mohamed ◽

S Matboly ◽

N Morcy

Keyword(s):

Aplastic Anemia ◽

Immunosuppressive Therapy ◽

Alternative Therapy ◽

Patient Characteristics ◽

Complete Response ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Pediatric Age Group ◽

Best Response ◽

Life Threatening

Abstract Background Aplastic anemia (AA) is life threatening disorder in pediatric age group with an increasing incidence nowadays. Hematopoietic stem cell transplant being the 1st line therapy; immunosuppressive therapy (IST) is the alternative therapy and is the most commonly used modality of treatment especially in the developing countries. Aim of the Work to assess the outcome of IST in children with severe and very severe AA. Patients and Methods Data for 23 children treated with IST from January 201 0 to January 201 9 (10 years) were retrieved from clinic records. IST included rabbit anti thymocyte globulin (ATG) along with cyclosporine A and another group were treated by sandimmune alone. Results Patient characteristics included median age (9) with 73.9% male and 26.1% female. With median interval between diagnosis and start of IST 2(1 -5) months and around 30.4% with hepatitis A associated aplastic anemia. Complete response, and no response were seen in 4 (50%) patients and 4(50%) patients, respectively in patients received ATG and sandimune. While in patients received sandimune alone complete response, partial response and no response were seen in 7(46.7%) patients, 5 (33.3%) patients, and 3 (20%) patients respectively. The median time to best response in the whole cohort was 2 months. There was no difference in outcome related to severity of AA, or higher Hb or platelet level. There was a significantly better rate of response in both groups of patients with higher initial TLC count (p = 0.001) initial ANC (p = 0.002), initial ALC (p = 0.001), and initial ARC (p = 0.014) before start of IST. An overall response rate in both groups around of 43.47% reported a 5-year OS. With 45.5 of patients with complete response had HAAA. A delayed time to complete response with prolonged requirement of cyclosporine therapy was detected in the study. Conclusion In a developing country setting, IST with ATG and cyclosporine seems to be an alternative treatment for children with aplastic anemia lacking MRD.

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Activity of eltrombopag in severe aplastic anemia

Blood Advances ◽

10.1182/bloodadvances.2018020248 ◽

2018 ◽

Vol 2 (21) ◽

pp. 3054-3062 ◽

Cited By ~ 13

Author(s):

Phillip Scheinberg

Keyword(s):

Aplastic Anemia ◽

Single Agent ◽

Complete Response ◽

Severe Aplastic Anemia ◽

Transfusion Independence ◽

Thrombopoietin Receptor ◽

Cd34 Cells ◽

Insufficient Response ◽

Marrow Cellularity

Abstract Since the approval of horse antithymocyte globulin (ATG) decades ago, there was a long hiatus in therapies with activity in severe aplastic anemia (SAA). This scenario changed in 2014 when eltrombopag, a thrombopoietin receptor agonist, was approved for SAA after an insufficient response to initial immunosuppressive therapy (IST). The basis for this approval was the observation of single-agent activity of eltrombopag in this patient population, where 40% to 50% recovered blood counts at times involving >1 lineage. The achievement of transfusion independence confirmed the clinical benefit of this approach. Increase in marrow cellularity and CD34+ cells suggested a recovery to a more functioning bone marrow. Further in its development, eltrombopag was associated with standard horse ATG plus cyclosporine in first line, producing increases in overall (at about 90%) and complete response rates (at about 40%) and leading to transfusion independence and excellent survival. Interestingly, best results were observed when all drugs were started simultaneously. The cumulative incidence of clonal cytogenetic abnormalities to date has compared favorably with the vast experience with IST alone in SAA. Longer follow-up will help in define these long-term risks. In this review, the development of eltrombopag in SAA will be discussed.

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Response of Paroxysmal Nocturnal Hemoglobinuria Clone with Aplastic Anemia to Rituximab

Case Reports in Hematology ◽

10.1155/2012/106182 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5

Author(s):

Radha Raghupathy ◽

Olga Derman

Keyword(s):

Aplastic Anemia ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Cell Clone ◽

Allogeneic Bone Marrow Transplantation ◽

Allogeneic Bone ◽

Hematopoietic Stem ◽

First Case ◽

Life Threatening ◽

Anti Cd20 ◽

Pnh Clone

Paroxysmal nocturnal hemoglobinuria is caused by expansion of a hematopoietic stem cell clone with an acquired somatic mutation in the PIG-A gene. This mutation aborts the synthesis and expression of the glycosylphosphatidylinositol anchor proteins CD55 and CD59 on the surface of blood cells, thereby making them more susceptible to complement-mediated damage. A spectrum of disorders occurs in PNH ranging from hemolytic anemia and thrombosis to myelodysplasia, aplastic anemia and, myeloid leukemias. Aplastic anemia is one of the most serious and life-threatening complications of PNH, and a PNH clone is found in almost a third of the cases of aplastic anemia. While allogeneic bone marrow transplantation and T cell immune suppression are effective treatments for aplastic anemia in PNH, these therapies have significant limitations. We report here the first case, to our knowledge, of PNH associated with aplastic anemia treated with the anti-CD20 monoclonal antibody rituximab, which was associated with a significant reduction in the size of the PNH clone and recovery of hematopoiesis. We suggest that this less toxic therapy may have a significant role to play in treatment of PNH associated with aplastic anemia.

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Effective treatment with tacrolimus for patients with non-severe aplastic anemia refractory/ intolerant to cyclosporine A: a retrospective study

10.21203/rs.3.rs-41969/v1 ◽

2020 ◽

Author(s):

Yali Du ◽

Yuzhou Huang ◽

Wenzhe Zhou ◽

Xinjian Liu ◽

Fangfei Chen ◽

...

Keyword(s):

Aplastic Anemia ◽

Cyclosporine A ◽

Complete Response ◽

Treg Cells ◽

Severe Aplastic Anemia ◽

Hematopoietic Stem ◽

Independent Risk Factors ◽

Elevated Creatinine ◽

One Year

Abstract Background: For the symptomatic non-severe aplastic anemia (NSAA) patients who cannot afford anti-thymocyte globulin (ATG) or allogeneic hematopoietic stem cell transplantation (HSCT), tacrolimus (FK) was occasionally reported to be an option if they were not response or tolerant to the cyclosporine A (CsA). Method: We collected and analyzed respectively 101 NSAA patients refractory or intolerant to CsA with no chance of HSCT or ATG, and treated them with tacrolimus for at least 6 months and followed up for at least one year. Results: The overall response (ORR) was 38.6% (complete response: 9.9%; partial response: 28.7%) and the median time to optimal response was 6 (3～10) months. 32 (31.7%) cases had elevated creatinine level. 8 (7.9%) cases had elevation of AST/ALT. 25.6% (10/39) of patients relapsed at the end of follow-up. Age (P=0.0005), FK concentration (4.0~12ng/ml, P=0.0005) and intolerance to CsA (P=0.012) were the independent risk factors for ORR. Treg cells level pre-FK treatment was much lower than healthy controls (3.7±0.6% vs 6.8±0.7%, P=0.0004), but increased significantly after FK treatment (3.7±0.6% vs. 7.1±0.8%, P=0.0039). Conclusion: Our data provide a possibility of tacrolimus as a salvage treatment for patients with NSAA refractory or intolerant to CsA.

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Relapse of Children with Aplastic Anemia after Immunosuppressive Therapy

Blood ◽

10.1182/blood.v112.11.3098.3098 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3098-3098

Author(s):

Takuya Kamio ◽

Etsuro Ito ◽

Akira Ohara ◽

Yoshiyuki Kosaka ◽

Masahiro Tsuchida ◽

...

Keyword(s):

Aplastic Anemia ◽

Family Member ◽

Immunosuppressive Therapy ◽

Severe Disease ◽

Cord Blood Transplantation ◽

Complete Response ◽

Myelogenous Leukemia ◽

Unrelated Donor ◽

Second Line ◽

Hematopoietic Stem

Abstract Although the therapeutic outcome for acquired aplastic anemia (AA) has improved markedly with the introduction of immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine A (CyA), a significant portion of patients treated with IST subsequently relapse and require second-line therapy. However, detailed analysis of the relapse cases has not been reported. In this study, we assessed the relapse rate, response to second-line treatment after relapse and prognosis. From November 1992 to July 2007, 473 newly diagnosed AA children (213 female, 260 male) entered two consecutive prospective studies (AA-92 and AA-97). The median age was 8 years, ranging from 1 to 18 years. Patients with very severe (n = 210), severe (n = 149) and non-severe disease (n = 114) received initial IST consisting of ATG and/or CyA. At six months after the initial IST, 280 patients (59.2%) achieved CR (n = 94) or PR (n=186). Relapse is defined by conversion to no response (NR) from partial or complete response (PR/CR). Among the 280 patients who responded to IST, 49 (17.5%) relapsed. The cumulative incidence of relapse was 19.6% at 10 years and the median time to relapse was 18 months, ranging 7 to 138 months. Among the 49 patients who relapsed, 22 received a second round of IST with ATG and CyA. Fourteen patients (63.6%) responded to the second round. However, three relapsed, and two developed paroxysmal nocturnal hemoglobinuria. Eight patients received CyA after relapse. Four patients responded to CyA, but two relapsed subsequently. Hematopoietic stem cell transplantation (HSCT) was attempted in 26 patients who relapsed after initial responses. Before HSCT, nine received a second course of IST with ATG and CyA and two received CyA. Fifteen patients progressed directly to HSCT. Bone marrow transplantation (BMT) from an HLA-matched sibling (n =7), HLA-matched family member (n = 1), or HLA-mismatched family member (n = 2) was performed in 10 patients, and all are presently alive. BMT from an unrelated donor was attempted in 13 patients, and four died of complications related to BMT. Cord blood transplantation from an unrelated donor was attempted in two patients and two patients are alive. Of the 26 patients who received HSCT, 21 are alive and well, 22 to 137 months (median 72 months) following transplantation. There were seven deaths out of total 49 who initially relapsed. The causes of death were HSCT-related complications (n = 5), MDS/acute myelogenous leukemia (n = 1), bacteremia (n = 1). Eight of 9 patients who received HSCT following a second round of IST are alive and well. The present study suggests that a second round of IST should be offered to the patients who relapse, and HSCT should be considered for the patients who fail to respond to the second round of IST.

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Activity of eltrombopag in severe aplastic anemia

Hematology ◽

10.1182/asheducation-2018.1.450 ◽

2018 ◽

Vol 2018 (1) ◽

pp. 450-456 ◽

Cited By ~ 5

Author(s):

Phillip Scheinberg

Keyword(s):

Aplastic Anemia ◽

Single Agent ◽

Complete Response ◽

Severe Aplastic Anemia ◽

Transfusion Independence ◽

Thrombopoietin Receptor ◽

Cd34 Cells ◽

Insufficient Response ◽

Marrow Cellularity

AbstractSince the approval of horse antithymocyte globulin (ATG) decades ago, there was a long hiatus in therapies with activity in severe aplastic anemia (SAA). This scenario changed in 2014 when eltrombopag, a thrombopoietin receptor agonist, was approved for SAA after an insufficient response to initial immunosuppressive therapy (IST). The basis for this approval was the observation of single-agent activity of eltrombopag in this patient population, where 40% to 50% recovered blood counts at times involving >1 lineage. The achievement of transfusion independence confirmed the clinical benefit of this approach. Increase in marrow cellularity and CD34+ cells suggested a recovery to a more functioning bone marrow. Further in its development, eltrombopag was associated with standard horse ATG plus cyclosporine in first line, producing increases in overall (at about 90%) and complete response rates (at about 40%) and leading to transfusion independence and excellent survival. Interestingly, best results were observed when all drugs were started simultaneously. The cumulative incidence of clonal cytogenetic abnormalities to date has compared favorably with the vast experience with IST alone in SAA. Longer follow-up will help in define these long-term risks. In this review, the development of eltrombopag in SAA will be discussed.

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Study of the Outcome of Pediatric Patients with Aplastic Anemia treated with Immunosuppressive Therapy at Ain Shams University Pediatric Hospital

QJM ◽

10.1093/qjmed/hcab113.066 ◽

2021 ◽

Vol 114 (Supplement_1) ◽

Author(s):

W Mohamed ◽

S Matboly ◽

N Morcy

Keyword(s):

Aplastic Anemia ◽

Immunosuppressive Therapy ◽

Alternative Therapy ◽

Patient Characteristics ◽

Complete Response ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Pediatric Age Group ◽

Best Response ◽

Life Threatening

Abstract Background Aplastic anemia (AA) is life threatening disorder in pediatric age group with an increasing incidence nowadays. Hematopoietic stem cell transplant being the 1st line therapy; immunosuppressive therapy (IST) is the alternative therapy and is the most commonly used modality of treatment especially in the developing countries. Aim of the Work to assess the outcome of IST in children with severe and very severe AA. Patients and Methods Data for 23 children treated with IST from January 201 0 to January 201 9 (10 years) were retrieved from clinic records. IST included rabbit anti thymocyte globulin (ATG) along with cyclosporine A and another group were treated by sandimmune alone. Results Patient characteristics included median age (9) with 73.9% male and 26.1% female. With median interval between diagnosis and start of IST 2(1 -5) months and around 30.4% with hepatitis A associated aplastic anemia. Complete response, and no response were seen in 4 (50%) patients and 4(50%) patients, respectively in patients received ATG and sandimune. While in patients received sandimune alone complete response, partial response and no response were seen in 7(46.7%) patients, 5 (33.3%) patients, and 3 (20%) patients respectively. The median time to best response in the whole cohort was 2 months. There was no difference in outcome related to severity of AA, or higher Hb or platelet level. There was a significantly better rate of response in both groups of patients with higher initial TLC count (p = 0.001) initial ANC (p = 0.002), initial ALC (p = 0.001), and initial ARC (p = 0.014) before start of IST. An overall response rate in both groups around of 43.47% reported a 5-year OS. With 45.5 of patients with complete response had HAAA. A delayed time to complete response with prolonged requirement of cyclosporine therapy was detected in the study. Conclusion In a developing country setting, IST with ATG and cyclosporine seems to be an alternative treatment for children with aplastic anemia lacking MRD.

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Allo-HSCT compared with immunosuppressive therapy for acquired aplastic anemia: Is superiority a one-sided understanding?

10.21203/rs.2.19154/v2 ◽

2020 ◽

Author(s):

Yangmin Zhu ◽

Qingyan Gao ◽

Jing Hu ◽

Dongrui Guan ◽

Xu Liu ◽

...

Keyword(s):

Aplastic Anemia ◽

Immunosuppressive Therapy ◽

Comprehensive Evaluation ◽

Clonal Evolution ◽

Meta Analysis ◽

First Line ◽

Hematopoietic Stem ◽

First Line Therapy ◽

Risk Of Disease

Abstract Acquired aplastic anemia (AA) is a rare hematologic disease characterized by a profound pancytopenia and hypocellular bone marrow. To comprehensively compare the efﬁcacy and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with immunosuppressive therapy (IST) as a front-line treatment for patients with AA. We searched the Medline, Embase, and Cochrane Registry of Controlled Trials databases from January 2000 to March 2019. Studies comparing allo-HSCT with IST as a first-line therapy for patients with AA were included. Fifteen studies including a total of 5336 patients were included in the meta-analysis. The pooled hazard ratio (HR) for overall survival (OS) was 0.4 (95% CI 0.074–0.733, P = 0.016, I2 = 58.8%) and the pooled HR for failure-free survival (FFS) was 1.962 (95% CI 1.43–2.493, P = 0.000, I2 = 0%). The pooled relative risk (RR) for overall response rate (ORR) was 1.691 (95% CI 1.433–1.996, P = 0.000, I2 = 11.6%). Although survival was significantly longer among AA patients undergoing first-line allo-HSCT compared to those undergoing first-line IST, the selection of initial treatment for patients with newly diagnosed AA still requires comprehensive evaluation of donor availability, patient age, expected quality of life, risk of disease relapse or clonal evolution after IST, and potential use of adjunctive eltrombopag.

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