Phase‐1 study of siplizumab in the treatment of pediatric patients with at least grade II newly diagnosed acute graft‐versus‐host disease

Brochstein JA, Grupp S, Yang H, Pillemer SR, Geba GP. Phase‐1 study of siplizumab in the treatment of pediatric patients with at least grade II newly diagnosed acute graft‐versus‐host disease.
Pediatr Transplantation 2010:14:233–241. © 2009 John Wiley & Sons A/S. Abstract: In a phase‐1 study, siplizumab, a humanized anti‐CD2 monoclonal antibody, was administered (0.012 or 0.04 mg/kg) to 10 pediatric patients with ≥ grade‐II newly diagnosed, non‐steroid‐refractory aGvHD after BMT or PBSCT. SAEs and other AEs including infections, and GvHD staging changes (overall, skin, liver, gut) were evaluated over 364 days. Patients reported a total of 121 AEs (19 grade‐3, 5 grade‐4 0.012 mg/kg group; 17 grade‐3, 17 grade‐4 0.04 mg/kg group) and 14 SAEs (five grade‐3, three grade‐4, 0.012 mg/kg group; three grade‐3, 0.04 mg/kg group); 15 AEs in five patients and four SAEs in three patients (fever, PTLD, adenoviral infection, and EBV lymphoma) were considered siplizumab‐related. Six deaths occurred (study days 17–267); two were considered siplizumab‐related: one from EBV‐associated PTLD (0.012 mg/kg) and one from adenoviral infection (0.04 mg/kg); the other four deaths could potentially be attributed in part to study drug Three patients (one, 0.012 mg/kg group; two, 0.04 mg/kg group) developed PTLD. By study day 12, GvHD grade decreased in 3/5 and 2/5 patients in the 0.012 and 0.04 mg/kg groups, respectively; remission (grade 0) occurred in one patient in each group. Four of five patients (0.012 mg/kg group) and one of four patients (0.04 mg/kg group) achieved grade 0 GvHD during the first 100 study days (55.6% response). While treatment with siplizumab was associated with improvement of GvHD and remission in some pediatric patients, the overall high morbidity, mortality, and occurrence of PTLD is of safety concern, not warranting further development of siplizumab for the treatment of aGvHD in children.     

Coronary artery involvement in chronic graft‐versus‐host disease presenting as sudden cardiac arrest

Graft‐versus‐host disease (GVHD) is related to considerable morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Cardiac complications associated with GVHD are uncommon, and coronary artery involvement is even more unusual. We report on a male pediatric patient with chronic GVHD who developed a fatal ventricular arrhythmia caused by coronary artery obstruction after HSCT. At 30 months after HSCT, he suddenly collapsed with ventricular fibrillation. After resuscitation, electrocardiography showed abnormal q‐wave and ST changes in the inferior leads, suggesting a coronary event. Coronary angiography revealed complete obstruction of the proximal left anterior descending artery, subtotal obstruction of the mid left circumflex artery, and mild narrowing at the right coronary artery. This boy had none of the risk factors for coronary artery disease, and the only possible explanation for the cardiac event is GVHD. Coronary artery disease only rarely occurs as a cardiac event in children. However, coronary artery involvement should be recognized as one of the important manifestations of chronic GVHD in children.     

Mycophenolate mofetil for treatment of steroid‐refractory acute graft‐versus‐host disease after pediatric hematopoietic stem cell transplantation

A standard treatment is yet to be established for steroid‐refractory acute aGVHD following HSCT. The effects of MMF have not been well studied in children with aGVHD. We evaluated the effectiveness of oral MMF in 14 children with steroid‐refractory aGVHD (grade II in one patient, grade III to IV in 13 patients). The median initial dose of MMF was 40 mg/kg/day (range, 30–74) and was increased by 1.5–2 times if manifestations of GVHD did not improve. Within four wk of treatment, seven patients (50%) achieved CR, and four (29%) had a PR. Within eight wk, 11 patients (79%) achieved CR without using additional agents. Overall, 12 patients are alive and in remission with a median follow‐up of 35 months (range, 14–86). The median maximum dose of MMF was 60 mg/kg/day (range, 34–107). No fatal toxicity was observed, including MMF‐related infections. MMF appears to be highly effective for steroid‐refractory aGVHD when used at a higher dose than has been described previously. Larger studies and pharmacokinetic analysis are required to evaluate its efficacy and toxicity and find the optimal dose of MMF in children.     

Successful treatment with placenta‐derived decidual stromal cells in a pediatric patient with life‐threatening acute gastrointestinal graft‐versus‐host disease

Severe aGvHD is a life‐threatening complication after allogeneic HSCT. The GI tract is considered to play a key role in aGvHD, where the disease process can start and is one of the major target organs. Here, we present a case of a one‐year‐old child with a life‐threatening GI‐aGvHD stage IV, post‐HSCT, resistant to steroids and MMF for 4 weeks. He was successfully treated with placenta‐derived DSC.     

Non‐invasive biological quantification of acute gastrointestinal graft‐versus‐host disease in children by plasma citrulline

Clinical grading of GI involvement during acute GVHD remains a challenging issue, especially in children. Plasma citrulline, a non‐protein amino acid selectively produced and released by enterocytes, is a suitable surrogate endpoint for small intestinal epithelial cell mass, irrespective of the underlying cause of cell loss. Children referred for allogeneic bone marrow transplantation who were free from chronic malabsorption or constitutional disease involving the GI tract were consecutively included in this prospective study. Plasma citrulline and albumin concentration was measured every week between day 7 and day 28 of BMT until resolution of the aGVHD or occurrence of chronic GVHD. In total, 31 children were included between 2008 and 2011. After a CR, citrulline levels fell to a minimum level on day 7 and then increased to reach the initial value on day 28. After day 28, plasma citrulline but not albumin was strongly linked to the occurrence of GI GVHD, the threshold being set at 10 μmol/L. The correlation with clinical grade of GI‐aGVHD now needs to be assessed in larger populations. In pediatric patients, citrulline is valuable as a suitable non‐invasive marker of GI involvement in acute GVHD.     

Infusion‐related febrile reaction after haploidentical stem cell transplantation in children is associated with higher rates of engraftment syndrome and acute graft‐versus‐host disease

The clinical significance and prognostic impact of IRFR in pediatric recipients of haploidentical SCT are not clearly understood. Therefore, we attempted to determine how IRFR affects clinical outcomes in children. Clinical data from 100 consecutive pediatric patients (60 boys and 40 girls; median age, 12 yr [range, 2–18 yr] after haploidentical SCT between January 2010 and December 2012 were collected retrospectively. IRFR was described as unexplained fever (>38 °C) within 24 h after the infusion of haploidentical PBSCs. Thirty‐eight (38.0%) cases met the criteria for IRFR. ES was found in 24 (63.2%) of the 38 children with IRFR, with the median time of developing ES of +9 (7–16) days, while only 15 (25.4%) of the 59 children without IRFR were found with ES (p < 0.001). Similarly, the cumulative incidence rates of grade II–IV aGVHD were 50.0% in the IRFR group and 29.3% (p = 0.012) in the non‐febrile group. Multivariate analysis identified IRFR as the risk factor for ES and aGVHD. In the haploidentical setting, IRFR is associated with the development of ES and aGVHD. We attempted to determine how IRFR affects clinical outcomes in children after haploidentical SCT. Thirty‐eight children comprised the IRFR group, and 59 were in the control (non‐IRFR) group. High incidence of ES was observed in children with the occurrence of IRFR. Similarly, the incidence of stage I–IV and II–IV aGVHD was significantly higher in the febrile group. Multivariate analysis showed IRFR to be the risk factor for ES and aGVHD.     

Hepatitic pattern of graft versus host disease in children

BACKGROUND: Liver involvement by graft-versus-host disease (GVHD) is characterized histologically by bile duct damage, which may be severe. A different pattern, "hepatitic GVHD," has been described in adult patients. This pattern also shows marked lobular hepatitis and hepatocellular damage. We report the development of hepatitic GVHD in six pediatric patients. PROCEDURE: Clinical information and histologic features of liver biopsy samples were retrospectively reviewed. RESULTS: Patients' ages ranged from 3 to 11 years. Underlying diagnosis, pre-transplant conditioning and GVHD prophylaxis varied. Peripheral blood stem cells were the source of the allograft in four patients, matched sibling in one, and matched-unrelated donor in one. Hepatic GVHD was detected between 149 and 310 days post-transplant. Prior acute GVHD had developed in two patients, and involved the skin and/or gastrointestinal tract. No patients had significant ductopenia. Only one patient had significant lymphocytic infiltration of bile ducts (ductitis). Bile duct epithelial damage and significant portal/periportal inflammation were present in all patients. Lobular necro-inflammation was present in five patients. Five patients improved with immunosuppression and one died with progressive GVHD. CONCLUSIONS: This series focuses on hepatitic GVHD in pediatric patients. Clinical and histologic patterns are similar to what has been described in adults. Specific etiology and pathogenesis of this entity remain unclear.     

Infliximab for steroid refractory or dependent gastrointestinal acute graft‐versus‐host disease in children after allogeneic hematopoietic stem cell transplantation

Yang J, Cheuk DKL, Ha SY, Chiang AKS, Lee TL, Ho MHK, Chan GCF. Infliximab for steroid refractory or dependent gastrointestinal acute graft‐versus‐host disease in children after allogeneic hematopoietic stem cell transplantation. Abstract: aGVHD of the GI tract is common after allogeneic HSCT. Corticosteroids are the mainstay of treatment. Recent data suggest infliximab might be beneficial for steroid refractory aGVHD. We reviewed our experience in 10 pediatric patients who developed severe steroid refractory aGVHD (stage 3, n = 6; stage 4, n = 4), after an allogeneic matched unrelated HSCT for various hematological diseases (leukemia, n = 7; thalassemia, n = 3). The median age was 9.5 yr (range, 0.8–18.5 yr). All patients received 10 mg/kg infliximab weekly for 3–4 doses. Eight patients had CR and two had partial response. None of the patients developed therapy‐related adverse effects. All patients developed infections subsequently, which may or may not be related to infliximab. Five patients developed chronic GVHD (cGVHD) (four severe, one mild). Six patients died at 66–1451 days post‐transplant, from infection (n = 3), aGVHD (n = 1), lung cGVHD (n = 1), or idiopathic pneumonia (n = 1). Four patients were alive at 238–924 days post‐transplant, all of whom had an increase in BMI by six months post‐transplant. In conclusion, infliximab is well tolerated and appears effective in children with steroid refractory or dependent GI aGVHD. Infection is common and mortality remains high.     

Acute graft‐versus‐host disease in pediatric allogeneic hematopoietic stem cell transplantation. Single‐center experience during 10 yr

a‐GvHD may complicate allogeneic HSCT. In this retrospective single‐center study, we evaluated incidence and risk factors of a‐GvHD in 197 consecutive allogeneic pediatric HSCTs applying Glucksberg and NIH a‐GvHD classifications. Among 179 eligible transplants, the cumulative incidence of grade 0–I a‐GvHD was 48% and grade II–IV was 52%. None of the considered variables significantly influenced the incidence of grade II–IV a‐GvHD. Malignancy and myeloablation were associated with an increased risk of classic a‐GvHD (p < 0.01). Seventy‐two percentage of children are alive, with a significant difference in OS and TRM between grade 0 and I vs. grade II and IV a‐GvHD; this observation was reproduced in the non‐malignant setting, while only a disparity in TRM was evidenced in children with malignancy. In our experience, the incidence of a‐GvHD was similar, regardless of donor type. Myeloablation and malignant disease represented the only risk factors for classic a‐GvHD. Our results highlight the need for a better prevention of this complication in the non‐malignant setting.     

The successful use of alemtuzumab for treatment of steroid‐refractory acute graft‐versus‐host disease in pediatric patients

SR‐aGVHD remains a significant cause of morbidity and mortality in allogeneic HCT recipients. Alemtuzumab has been used with success in adult patients but has not been studied in the pediatric setting. To estimate the effectiveness of alemtuzumab for the treatment of SR‐aGVHD in pediatric patients, we retrospectively reviewed the charts of 19 patients (median age 4 yr, range 0.5–28 years) with grades II (n = 3), III (n = 10), or IV (n = 6) SR‐aGVHD who received alemtuzumab treatment. Patients received a median dose of 0.9 mg/kg alemtuzumab (range 0.3–2 mg/kg) divided over 2–6 days. Eighty‐nine percent of patients received additional courses. A complete response, defined as GVHD of grade 0 at four wk following the first alemtuzumab course, was observed in nine patients (47%). A partial response, defined as an improvement in grade after four wk, was observed in five patients (26%). There was no response in five patients (26%). The overall response rate at four wk was 73%. Infectious complications included bacteremia (47%), presumed or documented fungal infections (21%), adenovirus viremia (52%), EBV viremia (36%), and CMV viremia (36%). We conclude that alemtuzumab is effective for SR‐aGVHD in pediatric patients with a tolerable spectrum of complications.     

Ibrutinib for the treatment of chronic graft‐vs‐host disease in pediatric hematopoietic stem cell transplant patients: A single‐center experience

cGVHD is a significant cause of morbidity and mortality after transplant. Ibrutinib has been studied as treatment for cGVHD in the adult population. Pediatric dosing and safety of ibrutinib are unknown. We conducted a retrospective review on the use of ibrutinib in 22 children with cGVHD at Cincinnati Children's Hospital Medical Center. All patients received a dose of 250 mg/m² orally, once daily. Responses were measured at 6 months after drug initiation using the 2014 NIH consensus panel response criteria. Twenty‐two patients of median age 13.5 years received ibrutinib. cGVHD grades were severe (n = 15), moderate (n = 6), and mild (n = 1). Eight patients stopped ibrutinib prior to 3 months due to adverse events or death and could not be evaluated for 6‐month response. Of the 14 evaluable patients, 12 achieved a partial response at 6 months and two patients had progressive disease. Seven evaluable patients with lung involvement had stable lung function at 6 months. One patient had EBV reactivation, and one patient developed pneumococcal sepsis despite appropriate prophylaxis while on ibrutinib therapy. No fungal infections occurred while on ibrutinib. Adverse events leading to discontinuation included recurrent fevers without a source, extensive bruising, oral bleeding, gastrointestinal distress, lower GI bleeding, dizziness, elevated transaminases, and pneumococcal sepsis. Ibrutinib administration of 250 mg/m² oral daily shows promising responses in pediatric cGVHD. Pediatric‐focused pharmacokinetic‐directed studies are needed to establish optimal dosing and define efficacy in children.     

Cord blood transplant in childhood ALL

BACKGROUND: Optimal therapy for high risk and relapsed acute lymphoblastic leukemia (ALL) remains uncertain. Wider availability of cord blood from related and unrelated donors has prompted studies of its use for hematopoietic stem cell transplant (HSCT). PROCEDURE: We evaluated 26 consecutive cord blood transplants (CBT) for ALL performed at our center from 1996 to 2002 on studies using consistent conditioning therapy and graft-versus-host disease (GVHD) prophylaxis. Median patient age was 8.5 years (range, 0.5-24 year). Cord blood (CB) was from unrelated donors in 25/26 cases. Median CB nucleated cell dose was 3.26e7/kg (range, 0.8-12.9). RESULTS: With median follow-up of 548 days, 16/26 patients (62%) are event-free survivors. Acute GVHD developed in 14/24 evaluable patients, reaching grade III-IV in 7 patients. Chronic GVHD occurred in 10/22 evaluable patients. Multivariate analysis showed higher total nucleated cell dose per kilogram to be the strongest predictor of event-free survival. CONCLUSIONS: We conclude that CBT can effectively treat ALL in children with high risk features and following relapse.     

Transplant‐related mortality following allogeneic hematopoeitic stem cell transplantation for pediatric acute lymphoblastic leukemia: 25‐year retrospective review

Background

Over the last 25 years, donor source, conditioning, graft‐versus‐host disease prevention and supportive care for children undergoing hematopoeitic stem cell transplantation (HSCT) have changed dramatically. HSCT indications for acute lymphoblastic leukemia (ALL) now include high‐risk patients in first and subsequent remission. There is a large burden of infectious and pre‐HSCT morbidities, due to myelosuppressive therapy required for remission induction. We hypothesized that, despite these trends, overall survival (OS) had increased.

Procedure

A retrospective audit of allogeneic pediatric HSCT for ALL was performed in our institution over 25 years. Outcomes for 136 HSCTs were analyzed in three consecutive 8‐year periods (Period 1: 1/1/1984–31/8/1992, Period 2: 1/9/1992–30/4/2001, Period 3: 1/5/2001–31/12/2009).

Results

Despite a significant increase in unrelated donor HSCT, event‐free and OS over 25 years improved significantly. (EFS 31.6–64.8%, P = 0.0027; OS 41.8–78.9%, P < 0.0001) Concurrently, TRM dropped from 33% to 5% (P = 0.0004) whilst relapse rate was static (P = 0.07). TRM reduced significantly for matched sibling and unrelated cord blood transplantation (UCT) in Period 3 compared with earlier periods (P = 0.036, P = 0.0098, respectively). Factors leading to improved survival in patients undergoing UCT include better matching, higher total nucleated cell doses, and significantly faster neutrophil engraftment. Length of initial HSCT admission was similar over time.

Conclusion

EFS and OS have increased significantly despite heightened HSCT complexity. This survival gain was due to TRM reduction. Contemporary patients have benefited from refined donor selection and improved supportive care. Overall rates of leukemic relapse post‐HSCT are unchanged, and remain the focus for improvement. Pediatr Blood Cancer 2013;160:1520–1527. © 2013 Wiley Periodicals, Inc.