Survival in aplastic anemia has markedly improved in recent decades. In multivariate analysis, the introduction of newer antifungal agents and a decrease in fungal infections were independent predictors for survival in the months following immunosuppression among patients with persistent neutropenia.
Background. Persistent neutropenia associated with severe aplastic anemia (SAA) is an important risk factor for development of life-threatening infections. Earlier studies underscored the high mortality associated with invasive fungal infections (IFIs) in SAA. However, little is known about the current patterns of infections and the impact of advances in anti-infective therapy on survival in SAA.
Methods. We reviewed the records of 174 patients with SAA admitted to the Hematology Branch at NHLBI from 1989 to 2008 who were unresponsive to initial immunosuppressive therapy (IST) at 6 months. Three patient groups determined by IST protocol and time interval were compared: group 1 (43 patients; December 1989–October 1996), group 2 (51 patients; November 1996–October 2002), and group 3 (80 patients; November 2002–April 2008). Outcome variables included infections, patterns of resistance, survival, and infection-related mortality.
Results. During the past 2 decades, infection-related mortality decreased from 37% in group 1 to 11% in group 3 (P<.001), and the frequency of IFIs decreased from 49% in group 1 to 8% in group 3 (P<.001). Overall 5-year survival for all patients (n = 420) increased from 64% in group 1 to 79% in group 3 (P<.001). Among non-responders (n = 174), it increased from 23% in group 1 to 57% in group 3 (P<.001). In multivariate analysis, younger age, absolute neutrophil count >200 cells/μL before IST, absence of IFIs, and use of voriconazole were independently predictive of survival.
Conclusion. During the past 2 decades, there has been a significant decrease in IFIs, infection-related mortality, and overall mortality in patients with SAA unresponsive to initial IST.
Over 15 years, 42 children aged 2-14 years were diagnosed as having acquired aplastic anaemia. Adequate clinical details were available for 38 children who were categorised as very severe (n = 13), severe (n = 16), or nonsevere (n = 9) by the modified Camitta criteria. Treatment varied over the study period. Seven children received a bone marrow allograft from a full match family donor and three a matched unrelated donor transplant after failed treatment with antilymphocyte globulin. The remainder were treated with antilymphocyte globulin (n = 11), antilymphocyte globulin and oxymetholone (n = 4), oxymetholone with or without prednisolone (n = 12), or supportive treatment alone (n = 1). With a minimum follow up of one year since treatment, the five year survival was 70% for bone marrow transplantation with a family donor, 30% for antilymphocyte globulin, and 25% for oxymetholone. All three children with a matched unrelated donor transplant died. The prognosis of acquired aplastic anaemia remains poor for most children and new approaches to treatment are urgently required.
To investigate the efficacy and safety of granulocyte transfusion combined with granulocyte colony stimulating factor (G-CSF) in severe infection patients with severe aplastic anemia (SAA).
Fifty-six patients in severe infections with SAA who had received granulocyte transfusions combined with G-CSF from 2006 to 2012 in our department were analyzed. A retrospective analysis was undertaken to investigate the survival rates (at 30 days, 90 days and 180 days), the responses to treatment (at 7 days and 30 days, including microbiological, radiographic and clinical responses), the neutrophil count and adverse events after transfusion.
All SAA patients with severe infections were treated with granulocyte transfusions combined with G-CSF. Forty-seven patients had received antithymocyte globulin/antilymphocyte globulin and cyclosporine A as immunosuppressive therapy. The median number of granulocyte components transfused was 18 (range, 3–75). The survival at 30 days, 90 days and 180 days were 50(89%), 39(70%) and 37(66%) respectively. Among 31 patients who had invasive fungal infections, the survival at 30 days, 90 days and 180 days were 27(87%), 18(58%) and 16(52%) respectively. Among the 25 patients who had refractory severe bacterial infections, the survival at 30 days, 90 days and 180 days were 23(92%), 21(84%) and 21(84%) respectively. Survival rate was correlated with hematopoietic recovery. Responses of patients at 7 and 30 days were correlated with survival rate. Common adverse effects of granulocyte transfusion included mild to moderate fever, chills, allergy and dyspnea.
Granulocyte transfusions combined with G-CSF could be an adjunctive therapy for treating severe infections of patients with SAA.
Critically short telomeres produce apoptosis, cell senescence and chromosomal instability in tissue culture and animal models. Variations in telomere length have been reported in severe aplastic anemia (SAA) but their clinical significance is unknown.
To investigate the relationship between telomere length and clinical outcomes in SAA.
Design and Setting
Single institution analysis of SAA patients treated in sequential prospective protocols at NIH from 2000 to 2008.
We retrospectively analyzed pre-treatment leukocyte age-adjusted telomere length in 183 patients with SAA consecutively enrolled into immunosuppression protocols with anti-thymocyte globulin plus cyclosporine for correlation with clinical outcomes.
Main Outcomes Measures
The outcomes studied were hematologic response, relapse, clonal evolution and survival.
There was no relationship between hematologic response and telomere length with response rates of 56.5%, 54.3%, 60%, and 56.5% in the first (n=46), second (n=46), third (n=45), and fourth quartiles (n=46), respectively. In multivariate analysis, telomere length was associated with relapse, clonal evolution, and mortality. Evaluated as a continuous variable, telomere length inversely correlated with the probability of hematologic relapse (HR=0.16; 95% CI, 0.03–0.69; p=0.01). The rate of clonal evolution was higher in patients in the first quartile (24.5%; 95% CI, 8.7%–37.5%) compared to quartiles 2–4 (8.4%; 95% CI, 3.2%–13.3%; p=0.009), and evolution to monosomy 7 or complex cytogenetics was more common in the first quartile (18.8%; 95% CI, 3.5%–31.6%) compared to quartiles 2–4 (4.5%; 95% CI, 0.5%–8.2%; p=0.002). Survival between these two groups differed, with 66% (95% CI, 52.9%–82.5%) surviving 6 years in the first quartile compared to 83.8% (95% CI, 77.3%–90.9%) in quartiles 2–4 (p=0.008).
In a cohort of patients with severe aplastic anemia receiving immunosuppressive therapy, telomere length was unrelated to response, but was associated with risk of relapse, clonal evolution, and overall survival.
Although recent advances in therapy offer the promise for improving survival in patients with severe aplastic anemia (SAA), the small size of the patient population, lack of a mechanism in North America for longitudinal follow-up of patients and inadequate cooperation among hematologists, scientists, and transplant physicians remain obstacles to conducting large studies that would advance the field. In order to address this issue, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) convened a group of international experts in March 2010 to define the most important questions in the basic science, immunosuppressive therapy (IST), and bone marrow transplantation (BMT) of SAA and propose initiatives to facilitate clinical and biologic research. Key conclusions of the working group were: 1) new patients should obtain accurate, expert diagnosis and early identification of biological risk; 2) a population-based SAA outcomes registry should be established in North America to collect data on patients longitudinally from diagnosis through and after treatment; 3) a repository of biologic samples linked to the clinical data in the outcomes registry should be developed; 4) innovative approaches to unrelated donor BMT that decrease graft vs. host disease are needed, and 5) alternative donor transplantation approaches for patients lacking HLA-matched unrelated donors must be improved. A partnership of BMT, IST and basic science researchers will develop initiatives and partner with advocacy and funding organizations in order to address these challenges. Collaboration with similar study groups in Europe and Asia will be pursued.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for severe aplastic anemia (SAA). However, graft failure and graft-versus-host disease (GVHD) are major causes of the early morbidity in Allo-HSCT.
To reduce graft failure and GVHD, we treated fifteen patients with SAA using high- dose of HSCT with both G-CSF mobilized PB and BMSCs from HLA-identical siblings to treat patients with SAA.
All patients had successful bone marrow engraftment. Only one patient had late rejection. Median time to ANC greater than 0.5 × 109/L and platelet counts greater than 20 × 109/L was 12 and 16.5 days, respectively. No acute GVHD was observed. The incidence of chronic GVHD was 6.67%. The total three-year probability of disease-free survival was 79.8%.
HSCT with both G-CSF mobilized PB and BMSCs is a promising approach for heavily transfused and/or allo-immunized patients with SAA.
One of the major obstacles of immunosuppressive therapy (IST) in children with severe aplastic anemia (SAA) comes from the often months-long unpredictability of bone-marrow (BM) recovery. In this prospective study in children with newly diagnosed very severe AA (n=10), who were enrolled in the therapy study SAA-BFM 94, we found a dramatically reduced diversity of both CD4+ and CD8+ BM cells, as scored by comprehensive V-beta chain T-cell receptor (TCR) analysis. Strongly skewed TCR V-beta pattern was highly predictive for good or at least partial treatment response (n=6, CD8+ complexity scoring median 35.5, range 24–73). In contrast, IST in patients with rather moderate reduction of TCR V-beta diversity (n=4, CD8+ complexity scoring median 109.5, range 82–124) always failed (P=0.0095). If confirmed in a larger series of patients, TCR V-beta repertoire in BM may help to assign children with SAA up-front either to IST or to allogeneic stem-cell transplantation.
aplastic anemia; T-cell receptor V-beta chain repertoire; children
Patients with severe aplastic anemia (SAA) over 40 years of age are often not offered treatment with hematopoietic cell transplantation (HCT) because of concerns about transplant-related morbidity or mortality. To evaluate this risk, we analyzed outcomes after allogeneic HCT from HLA-identical sibling donors for all older patients with SAA at our center since 1988. The 23 consecutive patients ranged in age from 40 to 68 years. The conditioning regimen was cyclophosphamide (200 mg/kg) and horse anti-thymocyte globulin. Methotrexate and cyclosporine were given for post-grafting immunosuppression. The cumulative incidences of grades II, III and IV acute graft-versus-host-disease (GVHD) were 30%, 4%, and 0%, respectively; that for chronic GVHD was 26%. With a median follow-up of 9.1 years, overall survival was 65%. Documented infections within 1 month before HCT were significantly associated with risk of early transplant-related mortality (p<0.001). The median time to discontinuation of post-transplant immunosuppression was 6.2 (range, 5.9–92.0) months. Three patients developed superficial basal cell carcinoma between 5.5 and 15 years after HCT. Our data favor a practice of extending HLA-identical sibling HCT for treatment of SAA in patients older than 40 years of age who are without significant medical comorbidities.
aplastic anemia; older age; human leukocyte antigen-matched bone marrow transplantation; cyclophosphamide/antithymocyte globulin conditioning
Severe aplastic anemia (SAA) patients without an HLA-matched sibling donor need alternative treatment options. Umbilical cord blood transplantation (UCBT) has become an alternative means for treating various diseases, but it has not been proved to be a satisfactory method to treat SAA. Here, we report the case of a girl who underwent successful two-unit UCBT after engraftment failure with a single unit. Two-unit UCBT is proposed to have better engraftment potential and to offer a better chance of survival, according to some reports. Increased cell dose and graft-versus-graft reaction could contribute to these advantages. With this promising result, two-unit UCBT could be an alternative treatment option for patients with SAA without an HLA-matched donor.
Anemia, Aplastic; Cord Blood Stem Cell Transplantation; Two-unit
To evaluate the efficacy of enhanced, intensive, immuno-suppressive therapy with umbilical cord blood support for severe aplastic anemia (SAA).
A total of 25 patients with SAA received enhanced, intensive, immuno-suppressive therapy and a cord blood transfusion. Therapy protocol: Anti-thymocyte globulin (ATG) 2.5 mg/(kg•d) × 5d; Cyclophosphamide 50 mg/(kg•d) × 2d; cyclosporin A (CsA) maintenance therapy.
25 patients were enrolled. 18 underwent a complete recovery, 4 made significant improvements, 1 did not respond, and 2 died. Therefore, the efficacy rate was 88%. The median follow-up time was 35 months (range 13-47 months), and the 3-year overall survival rate was 92%. Patients rapidly achieved reconstitution of hematopoiesis. The median time to neutrophil ANC > 0.5 × 109/L was 18 days (range 8-36), platelets >20 × 109/L was 34 days (range 12-123), and Hb > 100 g/L 95 dyas (range 35-173).
Enhanced, intensive, immuno-suppressive therapy with umbilical cord blood support may be an effective option for SAA therapy.
With improvements in hematopoietic cell transplantation (HCT) outcomes for severe aplastic anemia (SAA), there is a growing population of SAA survivors following HCT. However, there is a paucity of information regarding late effects that occur after HCT in SAA survivors. This study describes the malignant and non-malignant late effects in survivors with SAA following HCT. A descriptive analysis was conducted of 1,718 patients post-HCT for acquired SAA between 1995–2006 reported to the CIBMTR. The prevalence and cumulative incidences of late effects are reported for 1-year HCT survivors with SAA. Of the HCT recipients, 1,176 (68.5%) and 542 (31.5%) patients underwent a matched sibling donor (MSD) or unrelated donor (URD) HCT, respectively. The median age at the time of HCT was 20 years. The median interval from diagnosis to transplant was 3 months for MSD HCT and 14 months for URD HCT. The median follow-up was 70 months and 67 months for MSD and URD HCT survivors, respectively. Overall survival at 1 year, 2 years, and 5 years for the entire cohort was 76% (95% confidence interval [CI]: 74–78), 73% (95% CI: 71–75), and 70% (95% CI: 68–72). Among 1-year survivors of MSD HCT, 6% had one late effect and 1% had multiple late effects. For 1-year survivors of URD HCT, 13% had one late effect and 2% had multiple late effects. Among survivors of MSD HCT, the cumulative incidences of developing late effects were all less than 3% and did not increase over time. In contrast, for recipients of URD HCT, the cumulative incidence of developing several late effects exceeded 3% by five years: gonadal dysfunction 10.5% (95% CI: 7.3–14.3), growth disturbance 7.2% (95% CI: 4.4–10.7), avascular necrosis 6.3% (95% CI: 3.6–9.7), hypothyroidism 5.5% (95% CI: 2.8–9.0), and cataracts 5.1% (95% CI: 2.9–8.0). Our results indicated that all patients undergoing HCT for SAA remain at-risk for late effects and must be counseled about and should be monitored for late effects for the remainder of their lives.
hematopoietic cell transplant; allogeneic; survivorship; severe aplastic anemia; late effects
The current case report presents a patient with acute monocytic leukemia (AML-M5) occurring 14 years following the successful treatment of severe aplastic anemia (SAA) with immunosuppressants and androgens. The patient was treated with induction chemotherapy, but did not achieve remission. The patient succumbed to central nervous system bleeding 2 weeks following the first cycle of chemotherapy. Chromosomal examination revealed 47,XX,+21/46,XX. To the best of our knowledge the present case is the first to be reported of SAA 14 years preceding AML-M5 with acquired trisomy 21.
severe aplastic anemia; leukemia; trisomy 21
The HLA class II DRB1 antigen DR15 (common alleles *1501, *1502) is an important marker in the pathobiology of severe aplastic anemia (SAA). We studied 1204 recipients of HLA-matched sibling bone marrow transplantation for SAA to determine whether HLA-DR15 status (as determined by allele-level typing) affected hematopoietic recovery, graft-versus-host disease (GvHD) or overall survival. In multivariate analysis, secondary graft failure rate at 2-years was lower in patients who are HLA-DR15+ (hazard ratio 0.46, p=0.01). However, neutrophil recovery at day-28, platelet recovery at day-100, acute GvHD, chronic GvHD and overall mortality were independent of DR15 status. The 5-year probabilities of overall survival, after adjusting for age, race, performance score, transplant-conditioning regimen and year of transplantation, were 78% and 81% for patients who are HLA-DR15+ and HLA-DR15-, respectively (p=0.35). In conclusion, DR15 status is associated with secondary graft failure after HLA-matched sibling bone marrow transplantation for SAA but has no significant impact on survival.
DR15; SAA; GvHD; Survival; Graft Failure
Acquired severe aplastic anemia (SAA) is a rare and progressive disease characterized by an immune-mediated functional impairment of hematopoietic stem cells. Transplantation of these cells is a first-line treatment option if HLA-matched related donors are available. First-line immunosuppressive therapy may be offered as alternative. The aim was to compare the outcome of these patients in controlled trials.
A systematic search was performed in the bibliographic databases MEDLINE, EMBASE, and The Cochrane Library. To show an overview of various outcomes by treatment group we conducted a meta-analysis on overall survival. We evaluated whether studies reported statistically significant factors for improved survival.
26 non-randomized controlled trials (7,955 patients enrolled from 1970 to 2001) were identified. We did not identify any RCTs. Risk of bias was high except in 4 studies. Young age and recent year of treatment were identified as factors for improved survival in the HSCT group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the IST group. In 19 studies (4,855 patients), summary statistics were sufficient to be included in meta-analysis. Considerable heterogeneity did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies.
Young age and recent year of treatment were identified as factors for improved survival in the transplant group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the immunosuppressive group. Considerable heterogeneity of non-randomized controlled studies did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies.
Acquired aplastic anemia (AA) is the typical bone marrow failure syndrome characterized by an empty bone marrow; an immune-mediated pathophysiology has been demonstrated by experimental works as well as by clinical observations.
Immunusuppressive therapy (IST) is a key treatment strategy for aplastic anemia; since 20 years the standard IST for AA patients has been anti-thymocyte globuline (ATG) plus cyclosporine A (CyA), which results in response rates ranging between 50% and 70%, and even higher overall survival. However, primary and secondary failures after IST remain frequent, and to date all attempts aiming to overcome this problem have been unfruitful. Here we review the state of the art of IST for AA in 2010, focusing on possible strategies to improve current treatments. We also discuss very recent data which question the equality of different ATG preparations, leading to a possible reconsideration of the current standards of care for AA patients.
aplastic anemia; immunosuppressive therapy.
High dose cyclophosphamide (HiCY) without stem cell rescue has been shown to induce remissions in patients with severe autoimmune disorders (SADS). However, up to 80% of these patients ultimately relapse. Here we review the outcomes of seven patients treated with two cycles and one patient treated with three cycles of HiCY. The diseases re-treated were scleroderma, multiple sclerosis, three patients with severe aplastic anemia (SAA), and three patients with myasthenia gravis (MG). All but two patients with SAA had received standard immunomodulatory therapy for their disease up front and had been refractory. All patients had complete hematologic recovery. Overall survival in this cohort was 100%. All patients relapsed after the initial cycle but event free survival thereafter was 93.3%. All are still in remission except two MG patients, one of whom relapsed after a severe GI infection requiring hospitalization, and the other relapsed 3 years after the second treatment and she did not respond to the third treatment. This shows that HiCY can be safely re-administered in patients with SAA and refractory SADS. The quality and duration of second remissions appears to be equal or superior to the first remission.
Autoimmunity; cyclophosphamide; severe autoimmune diseases
Immunosuppressive regimens, which include antithymocyte globulin (ATG), are widely used for the treatment of severe aplastic anemia (SAA). However, bradycardia has been reported only as a rare side effect of ATG therapy in the manufacturer's product information and, in rare cases, in the adult literature. We present an adolescent with SAA and preexisting bradycardia who underwent immunosuppression therapy with ATG, methylprednisolone, and tacrolimus and developed profound sinus bradycardia with successive doses of ATG.
antithymocyte globulin; aplastic anemia; Atgam; bradycardia
For children with severe aplastic anemia (SAA) who fail immunosuppressive therapy and lack an HLA-matched sibling donor, unrelated donors provide a source of hematopoietic stem cells. Data from 195 children with acquired SAA who underwent unrelated donor transplantation from 1989-2003 were analyzed. Neutrophil recovery (86% at day-28) was higher with TBI-containing conditioning regimen and in younger recipients (aged ≤16 years) receiving grafts from older donors (aged >40 years). Recovery was lower after mismatched transplants and transplantations prior to 1997. Mortality rates were higher after mismatched transplants, in recipients with a poor performance score, and when the interval between diagnosis and transplantation was longer than 4 years. When restricted to donor-recipient pairs with allele-level HLA typing (8-loci; N=118), mortality rates were also higher after mismatched transplants and older recipient receiving grafts from older donors; 5-year probabilities of overall survival after HLA A, B, C, DRB1 matched and mismatched transplants adjusted for donor and recipient age were 57% and 39%, respectively (p=0.008). The data suggest that unrelated donor transplantation is an acceptable alternative for children; early referral for transplantation and identification of an HLA-matched (allele-level) donor offers the best outcome.
SAA; unrelated donor BMT; hematopoietic recovery and survival
The present study represents an analysis of 96 patients with severe aplastic anemia (SAA) treated in Seoul National University Hospital, Seoul, Korea between 1990 and 1999. Twenty-two patients were treated by allogeneic bone marrow transplantation (BMT) from HLA identical sibling donors and 74 by immunosuppressive therapy (IS) with antithymocyte globulin (ATG) or antilymphocyte globulin (ALG). There was no statistical difference between the two treatment groups in age, sex, disease duration, and previous transfusion amount. In the BMT group, grade II-IV acute graft versus host disease (GVHD) developed in 10% and chronic GVHD occurred in 33% of patient. Only one patient died from complication of transplantation (veno-occlusive disease). Of 74 patients who received IS treatment, 45% achieved a complete or partial response. Twenty patients died among IS treatment group. Major causes of death were hemorrhage (40%) and infection (55%). In the BMT group, the 5-yr overall survival (OS) was 95% after a median follow-up of 42 months. In the IS group, the 5-yr OS was 70% after a median follow-up of 49 months (p=0.04). In conclusion, the long-term survival rates of SAA in Koreans receiving BMT or IS were excellent compared with the Western data. Further evaluation on the prognosis of aplastic anemia in Asians should be done.
Previous reports showed that outcome of rabbit antithymocyte globulin (rATG) was not satisfactory as the first-line therapy for severe aplastic anemia (SAA). We explored a modifying schedule of administration of rATG.
Design and Methods
Outcomes of a cohort of 175 SAA patients, including 51 patients administered with standard protocol (3.55 mg/kg/d for 5 days) and 124 cases with optimized protocol (1.97 mg/kg/d for 9 days) of rATG plus cyclosporine (CSA), were analyzed retrospectively.
Of all 175 patients, response rates at 3 and 6 months were 36.6% and 56.0%, respectively. 51 cases received standard protocol had poor responses at 3 (25.5%) and 6 months (41.2%). However, 124 patients received optimized protocol had better responses at 3 (41.1%, P = 0.14) and 6 (62.1%, P = 0.01). Higher incidences of infection (57.1% versus 37.9%, P = 0.02) and early mortality (17.9% versus 0.8%, P<0.001) occurred in patients received standard protocol compared with optimized protocol. The 5-year overall survival in favor of the optimized over standard rATG protocol (76.0% versus. 50.3%, P<0.001) was observed. By multivariate analysis, optimized protocol (RR = 2.21, P = 0.04), response at 3 months (RR = 10.31, P = 0.03) and shorter interval (<23 days) between diagnosis and initial dose of rATG (RR = 5.35, P = 0.002) were independent favorable predictors of overall survival.
Optimized instead of standard rATG protocol in combination with CSA remained efficacious as a first-line immunosuppressive regimen for SAA.
We investigated the efficacy of arsenic trioxide (ATO) in patients with refractory severe aplastic anemia (SAA). A total of 5 consecutive adults were enrolled. The patients received ATO at a dose of 0.15 mg/kg intravenously daily for 5 days every week for 8 weeks. If necessary, a second course was performed after an interval of one week. All patients achieved clinically significant responses to ATO. The overall complete response rate and overall response rate at 17 weeks were 60% (3/5) and 100%(5/5), respectively. So treatment with ATO may be a feasible approach in patients with refractory SAA.
Aplastic anemia; Hematopoiesis; Arsenic trioxide; Adipocytes; Mesenchymal stem cells
PURPOSE: Incidence data for severe aplastic anaemia (SAA) in children are scanty and vary. Few population based studies have been reported. A retrospective and prospective study was conducted to determine the incidence and course of SAA. PATIENTS AND METHODS: All children with a diagnosis of SAA in the Nordic countries from 1982 through 1993 were registered and have been followed up since 1987. RESULTS: A total of 101 children were diagnosed with SAA. The mean annual child population was 4.31 million. A constant incidence of 1.95/million children/year was found: 2.4 for boys and 1.5 for girls. A non-significant increase of cases occurred from November to March. Possible aetiological agents were noted in 29%. The actuarial survival was 79% after one year and 68% after five years without significant difference between boys and girls. CONCLUSION: The incidence of SAA in the Nordic countries remains stable with a preponderance among boys. SAA has still a high initial mortality and a risk of late deaths.
Radiotherapy (RT) and concomitant/adjuvant therapy with temozolomide (Temodar) is a common treatment regimen for children and adults with glioma. Although temozolomide is generally well tolerated with temporary myelosuppression as the primary dose-limiting toxicity, irreversible bone-marrow aplasia after treatment with temozolomide has been reported. We report the case of an adolescent patient with a high-grade glioma who, after > 2 years of event-free survival, underwent successful bone marrow transplantation for treatment of temozolomide-induced severe aplastic anemia (SAA).
Purpose of review
Most acquired aplastic anemia (AA) is the result of immune-mediated destruction of hematopoietic stem cells causing pancytopenia and an empty bone marrow, which can be successfully treated with either immunosuppressive therapy (IST) or hematopoietic stem-cell transplantation (HSCT).
In AA, oligoclonally expanded cytotoxic T-cells induce apoptosis of hematopoietic progenitors. T-bet, a transcription factor that binds to the interferon-γ promoter region, is up-regulated in AA T-cells. Regulatory T-cells are significantly reduced in patients' peripheral blood and in an AA murine model, infusion of regulatory T-cells ameliorates disease progression. In a minority of cases, loss-of-function mutations in telomerase complex genes may underlie disease development. Long term survival, once strongly linked to response to immunosuppressive therapy, can now be achieved even among non-responders due to significant advances in supportive care and better salvage treatments.
Evidence has accumulated in the recent years further corroborating an immune-mediated process underlying AA pathogenesis. HSCT from a matched sibling donor is preferred for children and young adults with severe AA, and IST is employed when HSCT is not feasible due to age, lack of a histocompatible sibling, co-morbidities, or by patient choice.
aplastic anemia; anti-thymocyte globulin; bone marrow failure; stem cell transplantation; cyclosporine; pancytopenia
To retrospectively evaluate the outcome and toxicity of total lymphoid irradiation (TLI) based conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in severe aplastic anemia (SAA) patients who experienced an engraftment failure from prior HSCT or were heavily transfused.
Materials and Methods
Between 1995 and 2006, 20 SAA patients received TLI for conditioning of HSCT. All patients were multi-transfused or had long duration of disease. Fifteen (75%) patients had graft failure from prior HSCT. In 18 (90%) patients, the donors were human leukocyte antigen identical siblings. The stem cell source was the peripheral blood stem cell in 15 (75%) patients. The conditioning regimen was composed of antithymocyte globulin plus TLI with a median dose of 750 cGy in 1 fraction. The graft-versus-host disease (GVHD) prophylaxis used cyclosporine with methotrexate.
With a median follow-up of 10.8 years, graft failures developed in 6 patients. Among them, 3 patients received their third HSCT to be engrafted finally. The Kaplan-Meier overall survival rate was 85.0% and 83.1% at 5 and 10 years, respectively. The incidence of acute and chronic GVHD was 20% and 20%, respectively. None of the patients have developed a malignancy after HSCT.
In our study, TLI based conditioning in allogeneic HSCT was feasible with acceptable rates of GVHD in SAA patients who experienced graft failure from prior HSCT or was at a high risk of graft rejection. We achieved relatively better results of engraftment and survival with a long term follow-up.
Aplastic anemia; Total lymphoid irradiation; Hematopoietic stem cell transplantation