tacrolimus and Anemia--Aplastic

Severe aplastic anemia (SAA) has a poor prognosis in the absence of treatment. Current accepted therapeutic strategies include allogeneic stem-cell transplantation and immunosuppression, both resulting in long-term survival in the majority of patients. Although human leukocyte antigen (HLA)-matched sibling stem-cell transplantation is highly effective, the 25% probability of finding a suitable sibling donor within a family renders this approach available to only a minority of patients. Transplantation using HLA-matched, unrelated donors carries a high risk of treatment failure along with considerable toxicity. While combined immunosuppression with both antithymocyte globulin (ATG) and cyclosporine A (CSA) produces hematologic improvement in most patients, relapse is common. Late evolution of aplastic anemia to other serious hematologic disorders, including paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia, and acute leukemia, is also a significant problem following treatment with ATG/CSA. Recently, results of immunosuppression in SAA with another potent immunosuppressive agent, cyclophosphamide, were reported in a small number of patients. The overall response rate was similar to that seen with ATG/CSA, but relapse and late clonal disease were not observed during a long period of follow-up. A larger randomized trial comparing sustained hematologic response rates to either conventional immunosuppression with ATG/CSA or high-dose cyclophosphamide and CSA is now underway; secondary end points include response duration, event-free survival, and overall survival. Additionally, a number of protocols designed to test the efficacy of alternative immunosuppressive or immunomodulatory agents are being developed.

Topics: Anemia, Aplastic; Antibodies, Monoclonal; Cyclophosphamide; Humans; Immunosuppressive Agents; Mycophenolic Acid; Receptors, Interleukin-2; Sirolimus; Tacrolimus

This trial compared eltrombopag (EPAG)+tacrolimus and EPAG monotherapy in patients with refractory/relapsed acquired aplastic anaemia (AA). Patients with refractory/relapsed AA were randomly assigned to receive either EPAG+tacrolimus or EPAG monotherapy at a ratio of 2:1. Patient response, safety, clonal evolution and survival were compared. In total, 114 patients were included in the analysis, with 76 patients receiving EPAG+tacrolimus and 38 receiving EPAG only. With a median follow-up of 18 (6-24) months, the overall response rate (ORR) for patients treated with EPAG+tacrolimus and EPAG alone was 38.2% vs. 31.6% (P = 0.490) at the 3

Topics: Anemia, Aplastic; Clonal Evolution; Humans; Middle Aged; Prospective Studies; Tacrolimus

Hematopoietic cell transplantation is an effective treatment for patients with nonmalignant diseases and for many is the only known cure. Conventional myeloablative regimens have been associated with unacceptably high early transplant-related mortality (TRM), particularly in patients with comorbid conditions. This prospective multicenter trial was designed to determine the safety and engraftment efficacy of treosulfan-based conditioning in patients with nonmalignant diseases. Thirty-one patients received HLA-matched related (n = 4) or unrelated (n = 27) grafts after conditioning with treosulfan (total dose, 42 g/m(2)), fludarabine (total dose, 150 mg/m(2)), ± thymoglobulin (6 mg/kg; n = 22). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. All patients engrafted. Day-100 TRM was 0%. With a median follow-up of 2 years, the 2-year survival was 90%. Three patients died of GVHD, recurrent hemophagocytic lymphohistiocytosis, and a surgical complication, respectively. The cumulative incidences of grades II to IV and III to IV acute GVHD at day 100 and chronic GVHD at 2 years were 62%, 10%, and 21%, respectively. Patients who received thymoglobulin had a significantly lower incidence of grades III to IV acute GVHD (0% versus 33%; P = .005). These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with low toxicity and improved survival in patients with nonmalignant diseases and support the need for future disease-specific clinical trials.

Topics: Adolescent; Adult; Anemia, Aplastic; Antilymphocyte Serum; Antineoplastic Agents, Alkylating; Busulfan; Child; Child, Preschool; Fanconi Anemia; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Male; Methotrexate; Myeloablative Agonists; Prospective Studies; Tacrolimus; Transplantation Conditioning; Unrelated Donors; Vidarabine

Given the paucity of data on the use of agents other than cyclosporine (CsA) in the maintenance phase of immunosuppressive therapy (IST) for severe aplastic anemia (SAA) in children, we sought to describe our experience with tacrolimus in pediatric SAA, and to compare outcomes with a preceding series of patients who received CsA.. Eight patients with SAA diagnosed between 2003 and 2008 for whom no human leukocyte antigen (HLA)-matched sibling donor was identified underwent tacrolimus-based IST. These children were compared with a previously described series of 13 patients who had undergone CsA-based IST at our institution between 1990 and 2003. All patients initially received equine antithymocyte globulin (ATG) and corticosteroids.. Complete response (CR) rate was 88% for tacrolimus and 85% for CsA. Median time to CR was approximately 7 months in both groups. Median follow-up duration was 2.4 years for tacrolimus and 8.4 years for CsA. Among responders with de novo SAA, relapse rate was 25% (n = 1) at 2 years for tacrolimus and 0% at 2 years and 23% (n = 3) at 5 years for CsA; no significant difference in relapse-free survival was detected between the two groups (P = 0.07). Paroxysmal nocturnal hemoglobinuria was seen in one patient on tacrolimus who had relapsed after CsA-based IST. Tacrolimus-based IST was well-tolerated.. These data provide evidence that tacrolimus may be a suitable alternative to CsA as part of an IST regimen for SAA in children who lack an HLA-matched sibling and may have a more favorable profile of side effects than CsA.

Topics: Adolescent; Anemia, Aplastic; Child; Child, Preschool; Cyclosporine; Disease-Free Survival; Humans; Immunosuppressive Agents; Tacrolimus; Treatment Outcome; Young Adult

Hepatitis-associated aplastic anemia (HAAA) is a potentially life-threatening diagnosis without clear treatment guidelines. The goal of the study was to characterize the presentation, evaluation, histopathology, and outcomes of therapy in children with HAAA to guide future research and to develop standardized care guidelines for this rare disease.. Retrospective chart review of 4 patients with HAAA who presented to Children's Hospital Colorado between 2016 and 2019 was conducted. Patient presentation, evaluation, bone marrow and liver pathology, interventions, and clinical course were collected. Immunohistochemistry of liver biopsies was performed.. We treated 4 patients with HAAA without liver failure. All had evidence of systemic hyperinflammation and CD8+ T cell predominant liver tissue infiltration. One had a genetic mutation predisposing him to immune-mediated disease, but all other genetic testing was negative. In 3 of the 4 patients, hepatitis was poorly responsive to standard therapy with steroids, azathioprine, or tacrolimus; however, sustained biochemical remission of hepatitis was induced after more aggressive immunosuppressive therapies including Anti-Thymocyte Globulin (ATG) at standard immunosuppressive therapy (IST) dosing for severe Aplastic Anemia (sAA). Two patients underwent hematopoietic stem cell transplant (HSCT); 1 as first line therapy and 1 for refractory sAA.. We found that ATG-based IST induced remission of hepatitis in patients with steroid-refractory HAAA. This is also an appropriate initial treatment for severe Aplastic Anemia, though may not prevent the need for HSCT. We propose that equine ATG based IST at standard dosing regimen for sAA is a therapy that in select cases can be considered early on in the treatment course and could lead to a sustained remission of both hepatitis and sAA. This should be considered in collaboration with a pediatric hematologist.

Topics: Anemia, Aplastic; Animals; Child; Colorado; Hepatitis; Horses; Humans; Immunosuppressive Agents; Male; Retrospective Studies; Tacrolimus; Treatment Outcome

The impact of calcineurin inhibitor types and anti-thymocyte globulin (ATG) in conditioning on overall survival (OS) and GVHD-free, relapse-free survival (GRFS) has not yet been analyzed in detail for aplastic anemia. We herein examined 517 adult patients with aplastic anemia who underwent BMT from HLA-matched sibling donors (MSD, n = 255) and unrelated donors (UD, n = 262) and were treated with cyclosporine A (CSA) + methotrexate (MTX) (n = 258) and tacrolimus (TAC) + MTX (n = 259). In total, 330 patients received ATG in conditioning. CSA + MTX versus TAC + MTX did not have a significant impact on acute and chronic GVHD, OS, or GRFS in each donor type. The use of ATG in conditioning reduced the risk of grade II-IV acute GVHD in the MSD and UD cohorts (HR 0.42, P = 0.014, and HR 0.3, P < 0.001, respectively); however, a differential impact on GRFS was identified, namely, better GRFS in MSD recipients (HR 0.56, P = 0.016), but not in UD recipients (HR 1.1, P = 0.657). In conclusion, CSA + MTX and TAC + MTX were similar as GVHD prophylaxis regardless of the donor type, and ATG in conditioning increased GRFS in MSD transplants, but not in UD transplants.

Topics: Adolescent; Adult; Aged; Anemia, Aplastic; Antilymphocyte Serum; Cohort Studies; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Graft vs Host Disease; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Pre-Exposure Prophylaxis; Retrospective Studies; Survival Rate; Tacrolimus; Transplantation Conditioning; Young Adult

First-line treatment of aplastic anemia(AA) and for AA patients ineligible for hematopoietic stem cell transplantation (HSCT) has consisted of antithymocyte globulin (ATG), the calcineurin inhibitor cyclosporine A (CsA), and more recently eltrombopag. However, at our institution, we have successfully substituted another calcineurin inhibitor, tacrolimus, as a part of immunosuppressive threatment (IST) for AA due to more favorable toxicity profile. Since there is limited data on the use of tacrolimus in aplastic anemia, we conducted a retrospective review of twenty patients treated with tacrolimus-based immunosuppressive therapy (IST) as a first- or second-line treatment. The overall response rate was comparable to that of patients treated with CsA (18 patients). However, there were no cutaneous side effects observed in patients receiving tacrolimus, a relatively common finding with CsA use. Our data suggest that tacrolimus-based IST is a potential option in AA and might have a more favorable toxicity profile compared to CsA.

Topics: Adult; Aged; Anemia, Aplastic; Antilymphocyte Serum; Benzoates; Cyclosporine; Drug Eruptions; Female; Gingival Hypertrophy; Hirsutism; Humans; Hydrazines; Immunosuppressive Agents; Male; Middle Aged; Pyrazoles; Retrospective Studies; Tacrolimus

Hepatitis-associated aplastic anemia (HAAA) is an acquired bone marrow failure syndrome that develops after seronegative fulminant hepatitis. Abnormal cytotoxic T-cell activation with cytokine release is a possible pathophysiology. We present the case of a 16-month-old Japanese male who developed HAAA following living-donor liver transplantation for fulminant hepatitis. His aplastic anemia was successfully treated with immunosuppressive therapy. He had been administered tacrolimus for prophylaxis against hepatic allograft rejection. Ten years after the HAAA onset, the patient's bone marrow was found to be slightly hypoplastic. Tacrolimus may be effective in controlling abnormal immune reactions that can cause recurrent impaired hematopoiesis.

Topics: Anemia, Aplastic; CD4-CD8 Ratio; Hepatitis; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Lymphocyte Activation; Male; Tacrolimus

Stem cell transplantation (SCT) from an unrelated donor (URD) is often considered in patients with severe aplastic anemia (SAA) whom immunosuppressive therapy failed and matched sibling donor is not available. To reduce the incidence of graft-versus-host disease (GVHD) in URD SCT, introducting antithymocyte globulin (ATG) into the conditioning regimen has been proposed. Although ATG was shown to play a role in reducing GVHD in a cohort with diverse hematologic diseases, its role in SAA remains uncertain. The aim of this study was to determine the efficacy and toxicity of ATG in URD SCT for adult patients with SAA. We investigated 83 adult patients with SAA who underwent URD SCT between 2003 and 2014. The transplantation strategy consisted of total body irradiation (total 800 cGy) and cyclophosphamide (total 100 mg/kg to 120 mg/kg), followed by tacrolimus and a short-term methotrexate. We divided patients into 2 groups: group 1 (n = 25), which received HLA-matched (8/8) bone marrow (BM) without ATG, and group 2 (n = 58), which received SCT from either an HLA-mismatched donor or peripheral blood (PB). Thereafter, group 2 was subdivided according to ATG use into group 2A (without ATG, n = 26), which served as a historical cohort, and group 2B (with ATG, n = 32). Rabbit ATG (Thymoglobulin; Genzyme-Sanofi, Lyon, France) was used in group 2B at a dose of 2.5 mg/kg. The median age of all patients was 30 years (range, 17 to 59 years). The incidence of GVHD was significantly lower in group 2B than group 2A, as demonstrated by the rate of grade II to IV acute GVHD at day 100 (31.2% versus 61.5%, P = .003) and the rate of chronic GVHD at 3 years (21.9% versus 65.4%, P = .002). The overall survival rates of the 3 groups were similar. However, GVHD-free, failure-free survival (GFFS) was significantly higher in group 2B than group 2A (P = .034). A multivariable model identified use of ATG as an independent factor affecting grades II to IV acute GVHD (hazard ratio [HR], 2.902; 95% confidence interval [CI], 1.417 to 5.942; P = .004), chronic GVHD (HR , 3.005; 95% CI, 1.279 to 7.059; P = .012), and GFFS (HR, 2.363; 95% CI, 1.162 to 4.805; P = .014). Toxicities, including infectious complications, were not different among the 3 groups. In conclusion, low-dose ATG (2.5 mg/kg) can reduce the incidence of acute and chronic GVHD and improve the quality of life in patients with SAA who receive stem cells from either an HLA-mismatched donor or PB; importantly, these benefits are

Topics: Acute Disease; Adolescent; Adult; Anemia, Aplastic; Antilymphocyte Serum; Cyclophosphamide; Drug Administration Schedule; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Methotrexate; Middle Aged; Myeloablative Agonists; Retrospective Studies; Severity of Illness Index; Siblings; Survival Analysis; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Unrelated Donors; Whole-Body Irradiation

Topics: Adult; Allografts; Anemia, Aplastic; Bone Marrow Transplantation; Chronic Disease; Graft vs Host Disease; Humans; Immunosuppressive Agents; Influenza Vaccines; Infusions, Intravenous; Lymphohistiocytosis, Hemophagocytic; Male; Methylprednisolone; Prednisolone; Tacrolimus; Treatment Outcome

Combinations of cyclosporine (CSP) with methotrexate (MTX) have been widely used for immunosuppression after allogeneic transplantation for acquired aplastic anemia. We compared outcomes with tacrolimus (TAC)+MTX versus CSP+MTX after transplantation from HLA-identical siblings (SIB) or unrelated donors (URD) in a retrospective cohort of 949 patients with severe aplastic anemia. Study endpoints included hematopoietic recovery, graft failure, acute graft-versus-host disease (GVHD), chronic GVHD, and mortality. TAC+MTX was used more frequently in older patients and, in recent years, in both SIB and URD groups. In multivariate analysis, TAC+MTX was associated with a lower risk of mortality in URD recipients and with slightly earlier absolute neutrophil count recovery in SIB recipients. Other outcomes did not differ statistically between the 2 regimens. No firm conclusions were reached regarding the relative merits of TAC+MTX versus CSP+MTX after hematopoietic cell transplantation for acquired aplastic anemia. Prospective studies would be needed to determine whether the use of TAC+MTX is associated with lower risk of mortality in URD recipients with acquired aplastic anemia.

Topics: Age Factors; Anemia, Aplastic; Cyclosporine; Drug Therapy, Combination; Female; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Living Donors; Male; Methotrexate; Proportional Hazards Models; Retrospective Studies; Tacrolimus; Transplantation Conditioning; Treatment Outcome

To evaluate the outcomes of allogeneic hematopoietic stem cell transplantation（allo-HSCT）for paroxysmal nocturnal haemoglobinuria（PNH）and aplastic anemia（AA）- PNH syndrome.. The clinical data of 18 PNH or AA-PNH patients, including 4 classic PNH and 14 AA-PNH, received allo-HSCT from Dec 2007 to Feb 2015 were analyzed retrospectively. Nine patients received HLA-haploidentical donor HSCT（1 patient received salvage HLA-haploidentical donor HSCT after the graft failure of double cord blood transplantation）, 7 patients received HLA-identical sibling donor HSCT, and 2 HLA-identical unrelated donor HSCT. The conditioning regimens were as follow: 13 patients received modified BU/CY- based regimens, 5 non- myeloablative regimens ［fludarabine （Flu） + antithymocyte globulin（ATG）+ cyclophosphamide（CY）or busulfan（BU）］. Prophylaxis for graft- versushost disease（GVHD）: the patients with HLA-identical sibling donor received cyclosporine（CsA）plus short-term methotrexate（MTX）, the patients with HLA -haploidentical donor or HLA-identical unrelated donor received CsA or tacrolimus（FK506）+ mycophenolate mofetil（MMF）+ short- term methotrexate （MTX）.. All patients were engrafted successfully（1 patient engrafted by haploidentical donor after the graft failure of double cord blood transplantation）. The median days of neutrophils（ANC）above 0.5 × 109/L and platelets （PLT） more than 20 × 10⁹/L were 11（10- 26）days and 15（11- 120）days, respectively. Three patients（17.6%）developed acute GVHD（aGVHD）, 2 for grade Ⅱ aGVHD, 1 for grade Ⅳ aGVHD. Of 16 patients, 2 occurred limited chronic GVHD（cGVHD）. After a median follow-up of 14.6（2.0-86.7）months, 3 patients（17.6%）died, out of which one died of severe aGVHD, one died of severe pulmonary infection, one pulmonary infection with transplant- associated thrombotic microangiopathy. The 5- year estimated disease free survival was（80.5 ± 10.2）%. No patient relapsed.. Allo-HSCT is an effective and curable therapy for PNH or AA-PNH with improved prognosis, and offers a valid therapeutic option for these patients before humanized monoclonal antibody against C5 are widely used clinically.

Topics: Anemia, Aplastic; Antilymphocyte Serum; Busulfan; Cyclophosphamide; Cyclosporine; Disease-Free Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hemoglobinuria, Paroxysmal; Humans; Methotrexate; Mycophenolic Acid; Retrospective Studies; Siblings; Tacrolimus; Transplantation Conditioning; Treatment Outcome; Unrelated Donors; Vidarabine

Severe aplastic anemia (SAA), which is considered to be an immune-mediated destruction of bone marrow stem cells with pancytopenia and hypoplasia, can be successfully treated with immunosuppressive therapy or hematopoietic stem cell transplantation (HSCT). Between January 2009 and December 2012, thirteen patients diagnosed with SAA were treated with tacrolimus plus rabbit antithymocyte globulin (ATG)-based immunosuppressive therapy (IST). The outcomes were then compared with our previous data for twenty-four patients administered with cyclosporine (CsA) plus rabbit ATG-based IST. All 37 cases accepted methylpredenisolone and recombinant human granulocyte colony-stimulating factor (rhG-CSF) from the first day that rabbit ATG was initiated. A total of 7 (54%) of the 13 patients in the tacrolimus group and 10 (42%) of the 24 cases in the ATG+CsA group achieved the criteria for complete response (CR); the partial response (PR) rate was 31% in the tacrolimus group and 33% in the ATG+CsA group. The median follow-up duration of the tacrolimus group and ATG+CsA group patients was 28 months and 27 months, respectively. Two patients in the tacrolimus group who were red blood cell- and platelet transfusion-dependent died, one of sepsis and the other of cerebral hemorrhage, whereas one patient died from serious infection on the 5th day after ATG was initiated in the ATG+CsA group. No clonal transformation to paroxysmal nocturnal hemoglobinuria (PNH) was observed in either group. Our data provide a possibility of using tacrolimus as part of an IST regimen for SAA in adults who have no opportunity of HSCT from human leukocyte antigen (HLA)-matched sibling donors.

Topics: Adolescent; Adult; Anemia, Aplastic; Antilymphocyte Serum; Blood Component Transfusion; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Severity of Illness Index; Tacrolimus; Treatment Outcome; Young Adult

We report a case of a 57-year-old woman with type I diabetes who had received a simultaneous pancreas-kidney (SPK) transplant maintained on tacrolimus, mycophenolic acid (MPA) and prednisolone. Her renal allograft failed 6 years post-transplant but she continued to have a normal functioning pancreatic allograft. Over the course of 5 years, she developed progressive bone marrow failure with repeat bone marrow aspirates demonstrating an evolution from erythroid hypoplasia to hypocellular marrow and eventual aplastic anaemia despite discontinuation of MPA and reduction of tacrolimus. She was transfusion-dependent and had frequent admissions for sepsis. Despite treatment with antithymocyte globulin and cyclosporine for aplastic anaemia, she developed fatal invasive pulmonary aspergillosis within 3 weeks of treatment. Even though the cause of aplastic anaemia is likely multifactorial, this case highlights the difficulty in balancing the need for versus the risk of ongoing immunosuppression in a SPK transplant recipient who continues to have normal pancreatic graft function.

Topics: Anemia, Aplastic; Antilymphocyte Serum; Cyclosporine; Diabetes Mellitus, Type 1; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Prednisolone; Tacrolimus

To explore the inhibitory effects of tacrolimus (FK506) on effector T cells in vitro and examine the relationship between effector T cells and clinical features in patients with severe aplastic anemia (SAA) to elucidate its immune mechanism.. The CD8(+) HLA-DR(+) cells, sorted by immunomagnetic separation from bone marrow mononuclear cells (BMMNC) of 16 SAA patients, were cultured in different concentrations of interleukin-2 (IL-2) alone or with FK506 for 72 hours. The proliferation effect was measured with methyl thiazolyl tetrazolium (MTT) method. The T lymphocytes were sorted from the SAA patients by lymphocyte separation medium and cultured alone or with IL-2 or with FK506 or FK506 plus cyclosporin A (CsA) for 18 hours. The expression of tumor necrosis factor-β (TNF-β) in CD8(+) HLA-DR(+) T cells was analyzed by flow cytometry. The relationship between the expression of TNF-β and the clinical data, including percentages of reticulocyte and lymphocytes in peripheral blood cell count and ratio of CD4(+) T cells and CD8(+)T cells, was also analyzed.. At the concentration of IL-2 greater than or equal to 20 U/ml, the cell proliferation (A values, 0.538 ± 0.142) were significantly higher than that in the blank culture hole (0.505 ± 0.153) (P < 0.05). The A values significantly decreased (0.386 ± 0.124) after the addition of FK506 (P < 0.05). Compared with control group, the expression of TNF-β was significantly higher in IL-2 group (73.36% ± 16.73% vs 66.61% ± 16.20%, P < 0.05), significantly lower in FK506 and FK506 plus CsA groups (P < 0.05). No significant differences existed between the FK506 and FK506 plus CsA groups (47.78% ± 20.09% and 42.23% ± 21.35%, P > 0.05). The expression of TNF-β in SAA was negatively correlated with the percentage of reticulocyte and the ratio of CD4(+) T cell and CD8(+) T cell, positively correlated with the percentage of lymphocyte in peripheral blood count (r = -0.86, -0.90, 0.77, all P < 0.05).. IL-2 can enhance the proliferation and expression of TNF-β of CD8(+)HLA-DR(+)T cells from SAA patients. Such an effect is inhibited by FK506. And FK506 and FK506 plus CsA have similar effects.

Topics: Adult; Aged; Anemia, Aplastic; CD4-CD8 Ratio; CD8-Positive T-Lymphocytes; Cell Proliferation; Cells, Cultured; Cyclosporine; Female; HLA-DR Antigens; Humans; Interleukin-2; Lymphotoxin-alpha; Male; Middle Aged; Tacrolimus; Young Adult

Hemophagocytic lymphohistiocytosis (HLH) is associated with hypercytokinemia in children. Although HLH can be also observed after hematopoietic stem cell transplantation (HSCT), the incidence and clinical features of HLH after HSCT remain obscure.. The clinical features of HLH after HSCT (post-HSCT HLH) were investigated in children with malignancies, immune deficiencies, or aplastic anemia. The HLH/Langerhans Cell Histiocytosis (LCH) Committee of the Japanese Society of Pediatric Hematology (JSPH) sent questionnaires to hospitals with JPSH members asking for details of cases in which HLH occurred after HSCT between 1998 and 2008.. Among 42 children who were diagnosed with post-HSCT HLH between 1998 and 2008 in Japan, 37 fulfilled our inclusion criteria; of these, 26 were classified as early-onset (onset <30 days after HSCT) and 11 were classified as late-onset (onset >30 days after HSCT). In the early-onset group, the presence of respiratory symptoms, high levels of total bilirubin, and triglycerides at onset and the lack of control of GVHD with tacrolimus were significantly associated with non-resolution of HLH (P < 0.05). The survival rate was significantly higher in patients with resolution of HLH than in those without resolution (59% vs. 14%, P < 0.05).. These findings suggest that early-onset post-HSCT HLH is a specific entity of HLH, and appropriate diagnosis and prompt management need to be established.

Topics: Anemia, Aplastic; Bilirubin; Child; Child, Preschool; Common Variable Immunodeficiency; Disease-Free Survival; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Japan; Lymphohistiocytosis, Hemophagocytic; Male; Neoplasms; Surveys and Questionnaires; Survival Rate; Tacrolimus; Transplantation, Homologous; Triglycerides

A 24-year-old man from Ecuador presents to your clinic with dyspnea on exertion, bruising, and petechiae. He is noted to be pancytopenic with ANC 430, hemoglobin 7.4 g/dL (reticulocyte count 0.9%), and platelets 18 000. His BM biopsy is hypocellular for age. Ultimately, he is diagnosed with severe aplastic anemia. He is the only child of 2 South American parents without any matches in the unrelated donor registry, including cord blood. He is red cell- and platelet transfusion-dependent. He has been recommended therapy with antithymocyte globulin and cyclosporine but declined it. He seeks recommendations about new alternatives to this regimen to improve his chance of response.

Topics: Anemia, Aplastic; Antilymphocyte Serum; Cyclosporine; Drug Therapy, Combination; Humans; Male; Randomized Controlled Trials as Topic; Sirolimus; Tacrolimus; Young Adult

A 51-year-old woman developed very severe aplastic anemia complicated by chronic renal failure. She underwent ATG therapy, resulting in a transient effect. Thereafter, renal insufficiency progressed, followed by the induction of CAPD therapy. Although rabbit ATG (rATG) was administered as the next immunotherapy for aplastic anemia, pancytopenia persisted and she experienced repeated episodes of severe infection including MRSA and fungal infections. She was transplanted with peripheral blood stem cells from her HLA-haploidentical son after a reduced-intensity conditioning regimen that included cyclophosphamide (three days of 30 mg/kg), fludarabine (two days of 20 mg/m(2)) and rATG (three days of 2.5 mg/kg). FK506 (0.03 mg/kg/24H) was administered for the prophylaxis of GVHD. Prompt trilineage engraftment occurred, resulting in the improvement of infections. Three months after grafting, she succumbed to cerebrovascular disease, although there was no apparent GVHD and she had remained well with stable hematopoiesis.

Topics: Anemia, Aplastic; Animals; Antilymphocyte Serum; Cyclophosphamide; Female; Graft Survival; Haploidy; HLA Antigens; Humans; Immunosuppressive Agents; Middle Aged; Nuclear Family; Peripheral Blood Stem Cell Transplantation; Peritoneal Dialysis, Continuous Ambulatory; Rabbits; Severity of Illness Index; Tacrolimus; Transplantation Conditioning; Vidarabine

We retrospectively surveyed patients who received a second transplantation for graft failure (GF) after allogeneic hematopoietic stem cell transplantation (SCT) in hospitals participating in the Kanto Study Group for Cell Therapy. A second SCT was performed in 21 of 45 patients with primary GF and in 13 of 15 with secondary GF. The median time between the first and second SCT was 49 days (range, 18-1204 days). The diagnosis included 28 patients with hematologic malignancies and 6 with aplastic anemia. Non-myeloablative or reduced-intensity conditioning was performed in 30 patients. Cord blood was frequently used as the source of stem cells followed by related donor peripheral blood, and unrelated bone marrow. Engraftment was achieved in 23 patients (68%). Conditioning regimen including total body or total lymphoid irradiation, was significantly associated with a higher engraftment rate. Overall survival at 5 years in all patients who underwent second SCT was 34%. Prognostic factors for better survival after second SCT were a time to second SCT longer than 90 days, the performance status at second SCT with 0 or 1, and the administration of tacrolimus for GVHD prophylaxis. The major cause of death after second SCT was infection. Although the outcome of a second SCT for graft failure remains poor, these findings suggest that the selection of patients as well as transplant methods, such as conditioning and GVHD prophylaxis, may contribute to survival.

Topics: Adolescent; Adult; Anemia, Aplastic; Female; Graft Rejection; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Japan; Male; Middle Aged; Retreatment; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors; Transplantation Conditioning; Transplantation, Homologous; Young Adult

We report a 10-yr-old boy who developed CIPS after a second allogeneic BMT for severe aplastic anemia. He received the second BMT from the same HLA-matched sibling donor 16 months after the first BMT due to secondary graft failure. The preparative regimen for the second BMT consisted of fludarabine, cyclophosphamide, and anti-thymocyte globulin. Prophylaxis for acute GVHD was tacrolimus and oral PSL. Engraftment was achieved on day 15. On day 19, he suddenly complained of intermittent pain in the bilateral lower limbs. Electric shock-like pain continued for a few minutes in succession. This intractable pain was not ameliorated by various analgesic drugs including pentazocine. MRI demonstrated bone marrow edema with high T2 signal intensity in the femur. He was diagnosed as CIPS based on his symptoms and MRI findings. The trough concentration of tacrolimus (10.1 ng/mL) at the onset of CIPS was within the therapeutic range. Bouts of severe pain naturally resolved after day 43 without the discontinuation of tacrolimus. CIPS is a rare complication in HSCT. This is the first non-malignant, and the first pediatric, case who developed CIPS after HSCT.

Topics: Adult; Anemia, Aplastic; Antilymphocyte Serum; Bone Marrow Transplantation; Calcineurin Inhibitors; Child; Cyclophosphamide; Edema; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Middle Aged; Pain; Tacrolimus

Aplastic anemia (AA) is a rare disorder in children, usually treated with immunosuppressive therapy (IST) including antithymocyte globulin (ATG) and cyclosporin A. There are no current widely used alternative therapies with comparable efficacy. We describe a child with severe aplastic anemia (SAA), who developed severe gingival hyperplasia secondary to cyclosporin A, unresponsive to intensive dental intervention. When IST was changed to tacrolimus there was a significant improvement in the gingival hyperplasia, but equally important, he achieved complete response of his AA within several months. The use of tacrolimus in children with AA may be a potential modality of treatment.

Topics: Anemia, Aplastic; Anemia, Refractory; Child; Cyclosporine; Gingival Hyperplasia; Humans; Immunosuppressive Agents; Male; Tacrolimus

Tacrolimus (FK) and cyclosporine (CsA) have been shown to be effective in the prophylaxis of graft-versus-host disease (GVHD). However, no comparative studies have yet been conducted to examine the efficacy of FK/methotrexate (MTX) and CsA/MTX in patients with severe aplastic anemia (SAA) given unrelated donor bone marrow transplantation (U-BMT). We used matched-pair analysis to compare FK/MTX with CsA/MTX in patients with SAA who received U-BMT through the Japan Marrow Donor Program. Forty-seven pairs could be matched exactly for recipient age and conditioning regimens. Forty-five patients achieved engraftment in the FK group and 42 patients in the CsA group. The probability of grade II-IV acute GVHD (aGVHD) was 28.9% in the FK group and 32.6% in the CsA group (P=.558). The probability of chronic GVHD (cGVHD) was 13.3% in the FK group and 36.0% in the CsA group (P=.104). The 5-year survival rate was 82.8% in the FK group and 49.5% in the CsA group (P=.012). The study shows the superiority of FK/MTX over CsA/MTX in overall survival because of the lower incidence of transplantation-related deaths. A prospective randomized study comparing FK/MTX and CsA/MTX is warranted.

Topics: Anemia, Aplastic; Bone Marrow Transplantation; Cyclosporine; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Male; Matched-Pair Analysis; Methotrexate; Survival Rate; Tacrolimus; Tissue Donors

Gran versus Host Disease (GVHD) is a common complication in allogenic bone marrow transplants and in some cases, it involves the oral mucosa. Therefore, the appropriate diagnosis and timely treatment is essential to prevent local complications which interfere with normal oral functions and facilitate infection spread. We report a 17 years old woman with GVHD associated to lichenoid and ulcerative lesion in the oral mucosa, which responded to the topical administration of a 0.1% tacrolimus ointment.

Topics: Adolescent; Anemia, Aplastic; Bone Marrow Transplantation; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Mouth Diseases; Mouth Mucosa; Tacrolimus

Matched sibling donor (MSD) bone marrow transplantation is the treatment of choice for pediatric patients with severe aplastic anemia (SAA); however, only about 33% of patients will have an HLA-identical sibling. Alternative donor (AD) transplants may be an option for these patients, but such therapies have been associated with greater incidence of graft failure and graft-versus-host disease (GVHD). We retrospectively analyzed 36 pediatric patients who received 38 bone marrow or peripheral blood stem cell transplants (15 MSD and 23 AD) for SAA at our institution from April 1997 to October 2005. Nineteen AD recipients received reduced intensity conditioning with cyclophosphamide, low-dose total body irradiation, and antithymocyte globulin (ATG) or Campath. The 4-year overall survival for MSD recipients was 93% versus 89% for AD recipients treated with reduced intensity conditioning regimens at a median follow-up of 52 months (range, 6-99 months). No patient receiving Campath, compared with 3 of 9 patients receiving ATG, developed extensive, chronic GVHD. We conclude that, for children with SAA, AD transplantation is as effective as MSD transplantation. Further, compared with ATG, preparatory regimens containing Campath may be associated with a lower incidence of extensive, chronic GHVD.

Topics: Adolescent; Alemtuzumab; Anemia, Aplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antilymphocyte Serum; Bone Marrow Transplantation; Child; Child, Preschool; Cyclosporine; Female; Graft Survival; Graft vs Host Disease; Histocompatibility; Humans; Immunosuppressive Agents; Infant; Infections; Kaplan-Meier Estimate; Male; Methotrexate; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Retrospective Studies; Siblings; Survival Analysis; T-Lymphocyte Subsets; Tacrolimus; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Whole-Body Irradiation

Topics: Anemia, Aplastic; Cyclosporine; Female; Humans; Immunosuppressive Agents; Male; Melanoma; Remission Induction; Sirolimus; Tacrolimus

Topics: Adolescent; Adult; Anemia, Aplastic; Antilymphocyte Serum; Child; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Postoperative Complications; Prednisone; Tacrolimus

We studied clinical features of immunosuppressive (cyclosporine, tacrolimus) associated encephalopathy in bone marrow transplant patients. 378 cases of allogeneic bone marrow transplant recipients over fifteen years old of chronic and acute leukemia (CML, ANLL, ALL) (n = 311), myelodysplastic syndrome (MDS) (n = 42) and severe aplastic anemia (SAA) (n = 25) were investigated. Immunosuppressive associated encephalopathy occurred in 12 cases. The rate of incidence was significantly higher in SAA and MDS (7 cases) than in leukemia. The cases which showed typical radiological abnormality in MRI were limited in SAA and hypoplastic MDS. 10 cases died, which revealed worse than an overall survival rate of recipients without immunosupressive-associated encephalopathy. 5 of 7 cases in SAA and MDS had taken cyclosporine as treatment of the disease before bone marrow transplantation and that might influence the incidence of encephalopathy.

Topics: Acute Disease; Adolescent; Adult; Anemia, Aplastic; Bone Marrow Transplantation; Brain Diseases; Cyclosporine; Female; Humans; Immunosuppressive Agents; Leukemia; Male; Middle Aged; Myelodysplastic Syndromes; Tacrolimus

To discuss a comprehensive diagnostic approach to an active duty patient presenting with dyspnea on exertion, fatigue, and pallor. A 50-year-old active duty E-6 white male in Al Udeid, Qatar, presented with progressive dyspnea on exertion, fatigue, and new pallor. This case illustrates the course of events from Al Udeid to the Walter Reed Army Medical Center, where the final diagnosis was made. Along the way, questions with discussions explore the various diagnostic and management aspects of his case and highlight military relevant issues that include efficient diagnostic algorithms in the field and transfusion of scarce blood products.

Topics: Algorithms; Anemia, Aplastic; Antilymphocyte Serum; Bone Marrow Examination; Cyclosporins; Decision Trees; Diagnosis, Differential; Drug Therapy, Combination; Dyspnea; Fatigue; Humans; Immunosuppressive Agents; Male; Middle Aged; Military Medicine; Military Personnel; Pallor; Qatar; Tacrolimus; United States

FK506 is a newly developed potent immunosuppressant for preventing rejection after organ transplantation. However, FK506 can induce central nervous system toxicity. Until now the pathogenic mechanism of FK506 neurotoxicity was unclear. We report the findings of diffusion-weighted MRI and apparent diffusion coefficient (ADC) mapping of a FK506 neurotoxicity patient who showed increased signal intensities in both parieto-occipital lobes on T(2) weighted images, diffusion-weighted images and ADC maps. These findings suggest that a vasogenic oedema rather than a cytotoxic oedema may play a pivotal role in FK506 neurotoxicity pathogenesis.

Topics: Adult; Anemia, Aplastic; Bone Marrow Transplantation; Brain Edema; Brain Mapping; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Tacrolimus

We report a 20-year-old-male with severe aplastic anaemia who was treated with nonmyeloablative haematopoietic stem cell transplantation (NSCT) from a sibling donor. As the patient presented with complications consisting of mental retardation, severe obesity, a bone fracture, and recurrent infections, we selected NSCT instead of a myeloablative regimen, to reduce regimen-related toxicity (RRT). Conditioning therapy consisting of busulfan, fludarabine, antithymocyte globulin and FK506 was used to obtain immune suppression. RRT was limited and he is now in complete remission 19 months after NSCT. On day 91, he developed chronic graft-vs.-host disease; it was resolved by the combination of FK506, corticosteroids, and mycophenolate mofetil. Our experience contributes to the growing interest in NSCT as a modality for treating not only malignant haematological disorders associated with complications, but also nonmalignant haematological diseases.

Topics: Adult; Anemia, Aplastic; Antilymphocyte Serum; Busulfan; Female; Fractures, Bone; Graft Rejection; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Intellectual Disability; Male; Methylprednisolone; Mycophenolic Acid; Obesity; Peripheral Blood Stem Cell Transplantation; Prednisolone; Remission Induction; Siblings; T-Lymphocytes; Tacrolimus; Tissue Donors; Transplantation Chimera; Transplantation Conditioning; Vidarabine

Topics: Anemia, Aplastic; Azithromycin; Cyclosporine; Female; Gingival Hyperplasia; Humans; Middle Aged; Tacrolimus

A 21-year-old woman with severe aplastic anemia received an allogeneic bone marrow transplant (allo-BMT) from an HLA-matched and ABO-matched sibling donor after conditioning with cyclophosphamide, rabbit ATG (Lymphoglobuline; Aventis-Pharma), and total lymphoid irradiation. She had a long history of cyclosporin A (CsA) therapy before conditioning. She complained of severe headache and convulsions on day 0, and findings on magnetic resonance images suggested CsA-induced encephalopathy. CsA was immediately stopped, and tacrolimus for prevention of graft-versus-host disease (GVHD) was started on day 2. Hematological engraftment was observed on day 14 without serious GVHD. Prompt diagnosis, replacement of immunosuppressive agents, and careful monitoring of serum drug concentrations are thought to have contributed to the patient's good clinical course, since CsA-induced encephalopathy tends to be recurrent but to improve completely without any sequelae.

Topics: Adult; Anemia, Aplastic; Anticonvulsants; Blood-Brain Barrier; Bone Marrow Transplantation; Brain Diseases; Brain Edema; Ceftazidime; Cerebral Hemorrhage; Cyclosporine; Diagnosis, Differential; Diuretics; Endothelium, Vascular; Epilepsy, Generalized; Female; Fluconazole; Graft vs Host Disease; Headache; Humans; Immunosuppressive Agents; Intracranial Hypertension; Magnetic Resonance Imaging; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous

Severe aplastic anemia (SAA) is a frequent complication of orthotopic liver transplantation for non-typeable viral hepatitis. Allogeneic bone marrow transplantation (BMT) may successfully reconstitute hematopoiesis but the optimal conditioning regimen and graft-versus-host disease (GVHD) prophylaxis in such patients are unknown. Allogeneic BMT was undertaken in an 8-year-old male patient who developed SAA 6 weeks after cadaveric orthotopic liver transplantation for fulminant hepatic failure secondary to presumed non-typeable viral hepatitis. The preparative regimen for his HLA genotypically identical sibling BMT consisted of cytoxan and anti-thymocyte globulin. Tacrolimus (FK506) and prednisone, used to prevent liver graft rejection, were supplemented with methotrexate on post-BMT days, 1, 3, 6 and 11 for GVHD prophylaxis. Engraftment proceeded promptly and without complications. Transfusion dependence resolved 6 weeks after BMT. The patient is alive and well 1 year after his BMT on FK506 and prednisone without any signs of GVHD or liver allograft rejection. This case is the first demonstration of the feasibility of continuing FK506 used for prevention of liver graft rejection as GVHD prophylaxis for allogeneic BMT.

Topics: Anemia, Aplastic; Bone Marrow Transplantation; Child; Graft Rejection; Humans; Immunosuppressive Agents; Liver Failure; Liver Transplantation; Male; Tacrolimus; Transplantation, Homologous

Topics: Adult; Anemia, Aplastic; Bone Marrow Transplantation; Cardiomyopathy, Hypertrophic; Humans; Immunosuppressive Agents; Male; Tacrolimus