Jan 15, 2009 - Severe aplastic anemia (SAA) is a rare and life-threatening disorder in children and adults. The current standard of care for definitive therapy of ...
Pediatr Blood Cancer 2009;52:626–630
Tacrolimus as an Alternative to Cyclosporine in the Maintenance Phase of Immunosuppressive Therapy for Severe Aplastic Anemia in Children Abdulrahman Alsultan, MD,* Neil A. Goldenberg, MD, PhD, Nicole Kaiser, Douglas K. Graham, MD, PhD, and Taru Hays, MD Objective . 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. Methods . Eight patients with SAA diagnosed between 2003 and 2008 for whom no human leukocyte antigen (HLA)-matched sibling donor was identified underwent tacrolimusbased 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. Results . Complete response (CR) rate was 88% for tacrolimus and 85% for CsA. Median time to CR was approximately 7 months in
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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 ¼ 1) at 2 years for tacrolimus and 0% at 2 years and 23% (n ¼ 3) at 5 years for CsA; no significant difference in relapse-free survival was detected between the two groups (P ¼ 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. Conclusion . 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. Pediatr Blood Cancer 2009;52:626–630. ß 2009 Wiley-Liss, Inc.
children; immunosuppressive therapy; severe aplastic anemia; tacrolimus
INTRODUCTION Severe aplastic anemia (SAA) is a rare and life-threatening disorder in children and adults. The current standard of care for definitive therapy of SAA in children is matched-sibling hematopoietic stem cell transplantation (HSCT). When a human leukocyte antigen (HLA)-matched sibling donor is not available, immunosuppressive therapy (IST) is a therapeutic alternative. In recent years, antithymocyte globulin (ATG) and the calcineurin inhibitor cyclosporine (CsA) have typically been used as principal agents for IST. The response to these agents supports the hypothesis that the pathogenesis of SAA involves T cell-mediated modulation of hematopoietic progenitor cells in bone marrow [1]. While CsA in IST is generally well tolerated, untoward effects include hirsutism and gingival hyperplasia, which can lead to reduced compliance to therapy. Other potential toxicities of CsA with variable frequencies include nephrotoxicity, hypertension, electrolyte disturbance, dyslipidemia, and neurotoxicity [2]. Another calcineurin inhibitor, tacrolimus, has become increasingly employed as an alternative to CsA in settings such as HSCT [3,4] and solid organ transplantation [5–7], with comparable observed rates in the aforementioned toxicities. However, hyperlipidemia, hypertension (HTN), hirsutism, and gingival hyperplasia are more common with CsA and headache, tremor, glucose intolerance, and diarrhea are more frequent with tacrolimus [2]. The use of tacrolimus in SAA has not been previously reported. We have previously reported favorable preliminary outcomes for IST in pediatric SAA, in which CsA served as the principal agent in the maintenance phase following acute administration of equine ATG and corticosteroid [8]. In 2003, in order to improve compliance and decrease adverse effects commonly associated with CsA (particularly hirsutism and gingival hyperplasia), we substituted tacrolimus for CsA in a uniform IST regimen for SAA in children. This represented, to our knowledge, the first use of tacrolimus for IST in either adult or pediatric SAA. We therefore sought in the present work to describe our institutional experience with the use of tacrolimus-based IST in pediatric SAA, and to compare outcomes
ß 2009 Wiley-Liss, Inc. DOI 10.1002/pbc.21926 Published online 15 January 2009 in Wiley InterScience (www.interscience.wiley.com)
with those of our preceding series of CsA-treated patients, for whom continued follow-up data were available.
PATIENTS AND METHODS Inclusion Criteria Patients diagnosed with SAA between January 1, 2003 and March 1, 2008 who underwent tacrolimus-based IST at The Children’s Hospital, Denver were included in this comparative retrospective study. No new patients were treated with CsA-based IST during this time period. The research was approved by the Institutional Review Board (COMIRB #08–0248), and conducted in accordance with the Declaration of Helsinki. SAA diagnostic criteria were: (1) cytopenias characterized by at least two of the following: absolute neutrophil count (ANC) 500/ml, reticulocyte count 1% (corrected for hematocrit), and platelet count (platelets) 20,000/ml; and (2) bone marrow cellularity 500/ml. All patients received irradiated and leukocyte-depleted blood products. Packed red blood cell (PRBC) transfusion of 10–15 ml/kg was given for hemoglobin (Hgb) 11 g/dl, and platelets >100,000/ml on two consecutive complete blood counts performed at least 1 week apart; time to CR; partial response (PR), defined as transfusion independence with
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ANC >500/ml; time to PR; time to transfusion independence; failure to respond, as defined by no CR or PR achieved within 6 months following initiation of IST; clinical relapse, defined as a decline in hematologic indices to levels no longer meeting criteria for CR or PR in patients who had achieved CR or PR, respectively, in the absence of development of a PNH clone; and development of PNH clone, as defined by findings of deficient CD55 or CD59 expression during surveillance of subjects with PR or as part of the evaluation for clinical relapse.
Statistical Analysis Descriptive analyses involved calculation of median values and ranges for continuous data and frequencies for categorical data. Distributions of continuous data were compared between groups using the Mann–Whitney U-test, and proportions were compared between groups via chi-squared testing. Event-free survival functions were calculated from time-to-event data by the Kaplan– Meier method. Cumulative probabilities of relapse among responders with de novo SAAwere compared between groups using the log-rank test. The analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC). All hypothesis-testing was two-tailed and employed an alpha of 0.05.
RESULTS Eight patients with SAA diagnosed between 2003 and 2008 for whom no 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 [8]. Perpatient baseline characteristics, tacrolimus treatment duration, and efficacy outcomes are given in Table II for the tacrolimus group. The average length of hospitalization was four days, and was indicative of the prescribed 4-day duration of ATG treatment. All patients who responded to tacrolimus were maintained on treatment for at least 1 month (median 3.9 months, range 1.3–8 months) after achieving CR. One patient initially achieved a PR with mild anemia and achieved CR 1 month after discontinuing tacrolimus. Group-wise baseline characteristics, including age, proportion of patients with idiopathic SAA, severity of cytopenias, and efficacy are summarized in Table III between CsA and tacrolimus groups. Overall, 15 (71%) of 21 patients had idiopathic SAA and the
TABLE I. Summary of Tacrolimus-Based IST Regimen Drug ATG (equine) Tacrolimusa Methylprednisolone Prednisone Diphenhydramine Acetaminophen Meperidine Nystatin (500,000 IU/ml) Pentamidine (nebulized)
Dose
Route
40 mg/kg 0.15 mg/kg 1 mg/kgb 1 mg/kgb 1 mg/kg 15 mg/kg 1 mg/kg 5 ml 300 mg
IV PO IV PO PO/IV PO IV Swish/swallow Inhaled
Frequency Qday BID BID BID QID QID q4hrs prn chills BID Q4 weeks
Duration Days 1–4 Days 1–180c Days 1–4 Days 5–11 (taper 12–13) Days 1–4 Days 1–4 Days 1–4 Day 1 until ANC >500 Day 4 until off tacrolimus
IST, immunosuppressive therapy; ATG, antithymocyte globulin; IV, intravenously; PO, by mouth; Qday, once-daily; BID, twice-daily; QID, four times daily; ANC, absolute neutrophil count. aDose adjusted to maintain serum trough level of 5–15 ng/ml; bMaximum dose is 40 mg/day; c Tacrolimus dose was reduced by 50% approximately 1 month following achievement of complete response, and was then discontinued approximately 2 months thereafter in the absence of a rebound cytopenias. Pediatr Blood Cancer DOI 10.1002/pbc
Pediatr Blood Cancer DOI 10.1002/pbc 1 AI hepatitis 13 8.2 30 6,000 0 13 5 8 14.7 1.7 1.4 7.6 No n/a 28.0
34.0 NR after 2nd course of ATG; successful UCBT subsequently. Currently in remission for >2 years
3
Idio 3 3.3 96 4,000 0.17 58 23 40 8.5 NR NR NR n/a n/a
2
30.0 Currently receiving tacrolimus in 2nd course of IST
Idio 16 3.9 342 15,000 0.95 13 5 3 6.7 0.7 0.4 7.4 Relapse 16.7
4
7.3 Currently receiving tacrolimus
Idio 3 6.7 350 10,000 0.64 40 3 6 7.3 2.0 0.9 6.0 No n/a
5 c
15.7
Idio 13 5.1 480 6,000 0.21 25 7 7 13.1 2.3 2.7 9.4 No n/a
6
22.4
Idio 7 6.5 378 9,000 1.20 31 2 2 12.6 3.4 0.9 10.4 No n/a
7 c
39.0 Currently undergoing UCBT
Idio 19 8.3 300 20,000 0.80 14 10 10 20.0 0.6 1.0 12.0 PNH 17.0
8
29 (7.3–39)
88% Idio 11.5 (3–19) 6.2 (3.3–8.3) 346 (30–626) 9500 (4000–20,000) 0.68 (0–1.2) 28 (13–151) 5 (2–23) 6.5 (2–40) 10.6 (6.7–20) 1.9 (0.6–3.4) 0.9 (0–2.7) 7.6 (2.8–12) 29% 16.9 (16.7–17)
Median (range) or %
Idio, idiopathic; AI hepatitis, autoimmune hepatitis; [Dx/Rx], lowest value prior to IST; ANC, absolute neutrophil count; Plt, platelets, retic, reticulocytes; Hct, hematocrit; Tfn, transfusion; ATG, antithymocyte globulin; UCBT, unrelated cord blood transplant; CR, complete response; NR, no response; PNH, paroxysmal nocturnal hemoglobinuria. aAmong responders; bAll patients had bone marrow cellularity
