1. به نام او که زیبا آفرید

2. Hematopoietic stem cell transplantation (cord or haploidentical) in aplastic anemia دکتر بایزید قادری هیئت علمی دانشگاه علوم پزشکی کردستان

3. Disease severity  AA is classified according to disease severity based on bone marrow cellularity and peripheral blood cytopenia.

4. Severe AA (sAA) is characterized: marrow cellularity <25 percent of normal, which varies by age, and at least two severe peripheral cytopenia, absolute neutrophil count [ANC] <500 cells/microL , platelet count <20,000/microL,  absolute reticulocyte count <20,000 cells/microL.

5. very severe AA (vsAA) is characterized by  bone marrow cellularity <10 percent and ANC <200/microL,  

6. Severe AA — Severe AA requires definitive therapy due to its extremely high mortality rate. The decision between HCT and IST must balance the relative toxicities and long-term efficacy of the therapies, which differ over time (eg, higher up-front mortality but greater chance of cure with HCT) and according to patient age.

7. Ages 20 to 50 — The approach to adults 20 to 50 years of age is shifting due to improvements in HCT outcomes, For patients ages 20 to 50 who are otherwise in good health (ie, without other major comorbidities), we suggest HCT. However, some patients may choose  eltrombopag plus IST due to the up-front risks of HCT, which may be greater than for children and adolescents. 

8. Over age 50 — Patients over the age of 50 years with AA experience increased toxicities of treatment compared with younger patients with AA. However, in many cases eltrombopag plus IST is appropriate.  

9. INITIAL IMMUNOSUPPRESSIVE THERAPY — Immunosuppressive therapy (IST) is often used to treat severe AA, especially in patients for whom the risks of hematopoietic cell transplantation (HCT) are considered too great or for whom a suitable donor cannot be identified. The addition of eltrombopag to IST has been shown to improve cytopenias.

10. Eltrombopag plus IST using (ATG) and cyclosporin A (CsA) has been demonstrated to improve counts in a large proportion of patients, However, follow-up is relatively short (eg, two years). It is not known whether these responses are more durable than responses to IST alone. .

11. If a donor cannot be found in a timely manner, the search should continue as long as HCT is considered to be a potentially effective therapy for that patient Immunosuppressive therapy sometimes may be used during this period because the search for an unrelated donor may take a long time (eg, four months or more).

12. Evidence for efficacy — Outcomes with HCT to be superior to immunosuppressive therapy. Randomized trials comparing HCT with immunosuppression in AA are lacking. Two meta-analyses that evaluated available evidence (7955 and 302 patients, respectively) found that overall survival either was greater with HCT or was no different from immunosuppressive therapy

13. Immunosuppressive therapy versus haploidentical transplantation in adults with acquired severe aplastic anemia Zheng-Li Xu1 ● Ming Zhou2 ● Jin-Song Jia1 ● Wen-Jian Mo2 ● Xiao-Hui Zhang1 ● Yu-Ping Zhang2 ● Yu Wang1 ● Yu-Miao Li2 ● Xiao-Jun Huang 1,3,4 ● Shun-Qing Wang2 ● Lan-Ping Xu1 Received: 13 May 2018 / Revised: 8 November 2018 / Accepted: 10 November 2018 © Springer Nature Limited 2019

14. The medical records of 113 SAA adults who received IST, including rabbit ATG and cyclosporin (N = 37), or HID HSCT (N = 76) within 6 months of diagnosis at two institutions were retrospectively reviewed. Estimated 8-year overall survival (OS) was comparable between the IST and HID HSCT groups (75.6 vs. 83.7%, respectively, P = 0.328), but failure free survival (FFS) was significantly lower in IST group than HID HSCT group (38.5 vs. 83.7%, respectively, P = 0.001).

15. At the last follow-up, patients in HSCT group achieved better Karnofsky Performance Status (KPS) than those in IST group (100 [20– 100] vs. 90 [20–100], P = 0.002). In terms of blood count, 83.1% (54/65) of patients in HSCT group showed complete recovery compared to only 38.2% (13/34) in IST group (P < 0.001). These data suggest that HID HSCT could be an effective alternative treatment option for SAA adults, and additional prospective studies are necessary.

16. refractory aplastic anemia Refractory aplastic anemia (AA) is defined as a lack of response to first-line immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporin and is manifested as persistence of severe cytopenias at 6 months after IST.

17. Management of the refractory aplastic anemia patient: what are the options? Judith C. W. Marsh1,2 and Austin G. Kulasekararaj1,2 1King’s College Hospital, and 2King’s College London, London, United Kingdom (Blood. 2013;122(22): ) Hematopoietic stem cell transplantation is indicated if refractory AA patients are fit and have a suitably matched donor, either a sibling or unrelated donor.

18. Patients lacking a fully matched donor should be considered for a second course of antithymocyte globulin plus cyclosporin, although response in the refractory setting is only ∼30% to 35%. Response may also occur with alemtuzumab or the thrombopoietin mimetic eltrombopag in refractory AA. The emerging data for alternate donor (cord or haploidentical) transplantation in AA has provided additional therapeutic choices to consider in refractory disease.

20. Allogeneic HCT: For most patients under age 50 with severe or very severe AA who have an available donor, proceeding directly to allogeneic HCT rather than pursuing a course of immunosuppressive therapy.

21. The rationale for early transplantation includes improved outcomes with HCT, especially in younger patients.

22. Outcomes from HCT historically have been better in younger patients, especially individuals who are ≤20 years of age. However, outcomes have continued to improve in individuals between 20 and 50 years.

23. HCT is the treatment of choice for patients with SAA <40 to 50 years old who have an HLA-matched related donor (typically a sibling) and lack significant medical comorbidities. HCT may also be appropriate for selected patients older than 50 years with excellent performance status who have an available HLA-matched donor.

24. Preferred stem cell source — For the majority of individuals undergoing HCT for AA, we recommend bone marrow rather than peripheral blood as the source of hematopoietic stem cells. In patients with AA, HCT using bone marrow has been demonstrated to provide excellent outcomes and a lower risk of GVHD.

25. Haploidentical related donor — Evidence is limited regarding the use of haploidentical related donors in AA. However, use of a haploidentical donor may be appropriate for a patient for whom HCT is indicated and an HLA-matched donor is not available.

26. A matched related donor (typically, a sibling) is preferable to an unrelated donor, and a human leukocyte antigen (HLA)-matched unrelated donor is preferable to a haploidentical related donor.  

27. Comparable Outcome with a Faster Engraftment of Optimized Haploidentical Hematopoietic Stem Cell Transplantation Compared with Transplantations from Other Donor Types in Pediatric Acquired Aplastic Anemia Hyery Kim1, Ho Joon Im1,*, Kyung-Nam Koh1, Sung Han Kang1,2, Jae Won Yoo1,3, Eun Seok Choi1, Young-Uk Cho4, Seongsoo Jang4, Chan-Jeoung Park4, Jong Jin Seo1 1 Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Korea 2 Department of Pediatrics, Korea University College of Medicine, Seoul, Korea 3 Department of Pediatrics, Chungnam National University School of Medicine, Daejeon, Korea 4 Department of Laboratory Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, KoreaARTICLE IN PRESS Biol Blood Marrow Transplant 000 (2019) American Society for Blood and Marrow Transplantation.

28. Sixty-seven patients who underwent transplantation between 1998 and 2017 were included. Fourteen patients received grafts from matched sibling donors, 21 from suitable unrelated donors, and 32 from haploidentical family donors. Ex vivo CD3+ or ab+ T celldepleted grafts were used for haploidentical transplantation. Sixty-five patients (97.0%) achieved neutrophil engraftment at a median of 11 days. Haploidentical transplantation resulted in significantly faster neutrophil engraftment at a median of 10 days, compared with 14 days in cases of matched sibling donors and 12 days in cases of unrelated donor recipients. Nine patients experienced graft failure, and 5 of 7 who underwent a second transplantation are alive.

29. There was no difference in the incidence of acute or chronic graft-versus-host disease based on donor type. The 5-year overall survival and failure-free survival rates were 93.8% and 83.3% respectively, and there was no significant survival difference based on donor type. The survival outcomes of haploidentical transplantation in patients were comparable with those of matched sibling or unrelated donor transplantation. Optimized haploidentical transplantation using selective T cell depletion and conditioning regimens including low-dose total body irradiation for enhancing engraftment may be a realistic therapeutic option for pediatric patients with severe aplastic anemia.

30. Clinical evaluation of haploidentical hematopoietic combined with human umbilical cord‑derived mesenchymal stem cells in severe aplastic anemia Lixin Xu1†, Zhouyang Liu1†, Yamei Wu1, Xueliang Yang1, Yongbin Cao1, Xiaohong Li1, Bei Yan1, Songwei Li1, Wanming Da2 and Xiaoxiong Wu1*Xu et al. Eur J Med Res (2018) 23:12

31. Cotransplantation of haplo-HSCs and UC-MSCs was performed in 24 SAA patients. The conditioning regimens consisted of rabbit anti-human T-lymphocyte immunoglobulin (ATG), cyclophosphamide, and fludarabine with or without busulfan. GVHD was prevented using cyclosporine A, ATG, anti-CD25 monoclonal antibody, and mycophenolate material. The incidence of acute GVHD was 50%. Upon follow-up for a median of 13 months, 5 of the 24 patients (20.8%) were dead. The survival rates at 3 and 6 months in all patients were 87.5% (21/24) and 83.3% (20/24), respectively. Conclusion: Cotransplantation of haplo-HSCs combined with UC-MSCs was an effective and safe approach for the treatment of patients with SAA.

32. Outcome of combination of HLA-haploidentical hematopoietic SCT with an unrelated cord blood unit for 127 patients with acquired severe aplastic anemia]. Liu LM1, Zhang YM, Zhou HF, Wang QY, Qiu HY, Tang XW, Han Y, Fu CC, Jin ZM, Sun AN, Miao M1, Wu DP. Author information The clinical data of 127 SAA patients [including 74 male and 53 female patients, 65 very severe aplastic anemia (vSAA), the median age as 23.5(3-54) years] received HID-HSCT from September 2011 to April 2017 were analyzed retrospectively. The median interval from SAA diagnosis to transplantation was 2 ( ) months. The conditioning was modified Bu/Cy+ATG/ALG-based (Busulfan + cyclophosphamide + antithymocyte immunoglobulin/antilymphocyte immunoglobulin) regimen. Cord blood units were selected based on the results of HLA typing and cell doses evaluated before freezing. Units with at least 4/6 matched HLA loci became the candidates. Prophylaxis for graft-versus host disease (GVHD) was by cyclosporine (CsA), mycophenolate mofetil (MMF) plus short-term methotrexate (MTX).

33. The median values of absolute nucleated cell counts were 10. 87 (3
The median values of absolute nucleated cell counts were ( )×10(8)/kg in the haploidentical grafts and 2.22 ( )×10(7)/kg in the cord blood units, respectively. The median doses of CD34(+) cells infused were 3.49( ) ×10(6)/kg in the haploidentical grafts and 0.56 ( ) ×10(5)/kg in the cord blood units, respectively. Of the 127 patients, 5 patients occurred early death, one patient occurred primary graft failure. All 121 surviving patients attained complete haploidentical engraftment. The median durations of myeloid engraftment were 11 (9-28) days and 15 (9-330) days for platelets, with a cumulative platelet engraftment incidence of 96.1%.

34. The incidence of infection was 58. 27% (74/127)
The incidence of infection was 58.27% (74/127). During a median follow-up of 20.5 (4-60) months, the incidence of grade Ⅱ-Ⅳ acute GVHD was 24.79% (30/121), moderate-severe chronic GVHD was 14.15% (15/106), 4-year estimated overall survival was (78.5±4.3) %, 4-year estimated failure-free survival was (77.4±4.3) %, respectively. Conclusion: Combination of HID-HSCT and an unrelated umbilical cord blood unit was a feasible choice with favorable outcome for SAA patients without matched donors.

35. Alternative donor transplants for severe aplastic anemia. Bacigalupo A1. © 2018 by The American Society of Hematology. When a matched sibling is not available, one can search for a matched unrelated donor or a cord blood unit (CB) in the international registries or, more recently, for an HLA haploidentical (HAPLO) family member. International guidelines call for a course of antithymocyte globulin (ATG) and cyclosporine before a patient with SAA receives a transplant from a donor other than an HLA identical sibling, but whether this is necessary for patients age <20 years is less clear.

36. Here I will examine the rapid increase in HAPLO transplantations for SAA, showing encouraging early results both in children and young adults. Graft-versus-host disease prophylaxis remains of primary importance in patients with SAA, and in vivo T-cell depletion with either ATG or alemtuzumab offers a significant survival advantage. © 2018 by The American Society of Hematology.

37. Unrelated cord blood transplants This is the largest cohort of UCB grafts in patients with acquired SAA. The review includes 71 patients who received a single UCB transplant (n ¼ 57,80%)or double UCB (n ¼ 14,20%) . More than 50% of patients were children (medianage,13years).Most patients (69%) received reduced-intensity conditioning regimens that were fludarabine-based. The cumulative incidence of neutrophil recovery at day 60 was 51% . GvHD grade II–IV was seen in 20% of patients and 11/34 at risk developed chronic GVHD. The estimated probability of 3-year overall survival was 38% .

38. There are no published randomized studies comparing HLA-haploidentical HCT versus umbilical cord blood transplantation.

39. Conclusion: A matched related donor (typically, a sibling) is preferable to an unrelated donor, and a human leukocyte antigen (HLA)-matched unrelated donor is preferable to a haploidentical related donor. a haploidentical donor may be appropriate for a patient for whom HCT is indicated and an HLA-matched donor is not available. Cotransplantation of haplo-HSCs combined with UC-MSCs was an effective and safe approach for the treatment of patients with SAA.