The second therapeutic trial for children with hematological malignancies who relapsed after their first allogeneic SCT: Long-term outcomes

Nishikawa T, Inagaki J, Nagatoshi Y, Fukano R, Nakashima K, Ito N, Sawa D, Kawano Y, Okamura J. The second therapeutic trial for children with hematological malignancies who relapsed after their first allogeneic SCT: Long‐term outcomes. Abstract: The impact of a second all‐SCT on the long‐term outcomes of children who relapse after allo‐SCT has been unclear. We retrospectively analyzed the long‐term outcomes of different salvage treatments for such children. Sixty‐six children with hematological malignancies (40 ALL, 22 AML, three MDS, and one CML) who relapsed after a first allo‐SCT received either a second allo‐SCT (n = 16) or CTx and/or DLI (n = 50). The median follow‐up for all children was 9.1 yr. The five‐yr OS after relapse was significantly better in patients who underwent a second allo‐SCT (42.9%) than in patients treated with CTx and/or DLI (11.8%) (p < 0.05). However, this advantage diminished with increasing time. The eight‐yr OS for these groups of patients were 21.4% and 11.8%, respectively (p = n.s.). Among the 16 patients who received a second allo‐SCT, two died more than five yr after the second allo‐SCT. A second allo‐SCT can therefore lead to a prolonged OS in patients who relapse after allo‐SCT. However, a second allo‐SCT should be selected carefully. This is because the mortality rate is still high, even when there is an extensive duration of time following the second allo‐SCT.     

Physical and emotional well‐being of survivors of childhood and young adult allo‐SCT – A Danish national cohort study

The aim of this investigation was to examine, within a population‐based study of a national cohort comprising Danish survivors of allo‐SCT (n = 148), the long‐term effects of allo‐SCT in children and young adults. Physical and emotional well‐being was assessed using the Short Form 36 (SF‐36) and the HADS. Allo‐SCT‐related data were obtained from the participants' medical records. The study includes 148 patients, with an 89% response rate (n = 132). For comparison purposes, norm data from Danish (1994, n = 6000), Swedish (2006, n = 285), and British (2001, n = 1792) population samples were used. Factors negatively influencing the SF‐36 subscales included female gender; TBI; stem cells derived from PB; older age at time of questioning; and living alone. Factors significantly (p < 0.05) influencing HADS were transplantation with stem cells derived from PB and being underweight at time of questioning (median values were within normal range). Overall scores of allo‐SCT patients were similar to norm data. In conclusion, this national cohort study shows that patients treated with SCT in early life (<25) and whose survival period extended beyond 10 yr (mean) from SCT, showed similar levels of anxiety, depression, and physical and emotional well‐being to those of the normal population.     

Haploidentical hematopoietic stem cell transplantation for paediatric high‐risk T‐cell acute lymphoblastic leukaemia

Paediatric HR T‐cell ALL demonstrates dismal prognosis with chemotherapy, and poor outcomes could be improved with allo‐SCT. HID‐SCT is an almost immediately available choice; however, few studies have focused on the outcomes of HID‐SCT for paediatric HR T‐ALL. Forty‐eight consecutive HR T‐ALL children who underwent HID‐SCT were included. Survival outcomes and factors predictive of outcomes were retrospectively analysed. Of the 48 patients, 35 were in CR1, 10 in CR2, and three in relapse. The cumulative incidence of grade 3/4 aGVHD was 10.4% and that of extensive cGVHD was 28.4%. The CIR at three yr was 30.8% and that of NRM at three yr was 14.7%. At a median follow‐up of 20.0 (range 2.5–124.2) months, the three‐yr LFS was 54.4%. Children who received transplants during CR1 had a better LFS (65.7% vs. 26.0%, p = 0.008) and a lower relapse rate (19.8% vs. 56.7%, p = 0.014) compared to those during non‐CR1. HID‐SCT is feasible for HR T‐ALL children, and survival outcomes are better when performed in CR1 compared to non‐CR1. Prospective clinical trials would be needed to confirm that.     

Outcome of hematopoietic stem cell transplantation of children with very high risk acute lymphoblastic leukemia in first complete remission

Schechter T, Ishaqi KM, Rojas M, Irina Z, Doyle JJ, Gassas A. Outcome of hematopoietic stem cell transplantation of children with very high risk acute lymphoblastic leukemia in first complete remission.
Pediatr Transplantation 2010:14: 377–382. © 2009 John Wiley & Sons A/S. Abstract: Approximately 10% of children with ALL present at diagnosis with VHR for relapse if treated with chemotherapy alone. They may benefit from allogeneic HSCT in CR1. We have reviewed the outcome of this population in our institution. Forty‐three patients (median age: 8.9 yr) with VHR ALL in CR1 underwent HSCT from October 1994 to April 2006. VHR features included Philadelphia chromosome (n = 17), induction failure (n = 9), hypodiploidy (n = 6), MLL gene rearrangement (n = 5), and others (n = 6). All patients received TBI (1200 cGy) with either CY and/or etoposide. Stem cell source was unrelated (n = 24) and related (n = 19). Incidence of grade III‐IV acute GVHD and chronic extensive GVHD were 25% and 16%, respectively. Twelve patients relapsed (eight received related HSCT). Eleven patients died due to transplant‐related mortality (eight received unrelated HSCT). For a median follow up of 39 months (range 11–110), the event free survival and OS were 0.49 (95% CI: 0.31–0.67) and 0.53 (CI: 0.44–0.71), respectively. Outcomes of children with VHR ALL receiving HSCT in CR1 remain unsatisfactory. Relapse, mainly after related HSCT, and TRM, mainly after unrelated HSCT, continue to be major problems.     

Outcome of allogeneic hematopoietic stem cell transplantation for children with acute myelogenous leukemia in second complete remission: Single center experience

Abstract: We reviewed 26 consecutive patients with AML who were transplanted in second CR2 between 1994 and 2005. The most common conditioning regimen was CY and TBI. Median age at transplant was 8.9 yr (range 2.2–18.2). Nine patients received related donor, 16 patients received unrelated donors, and one patient received unrelated cord stem cells. Acute grade III–IV and chronic extensive GVHD occurred in eight (30%) and nine (35%) patients, respectively. Six patients (23%) relapsed, four of them died. Six patients (23%) died from TRM. Estimate of three‐yr EFS was 0.53 (95% CI; 0.34–0.72). Including the two relapsed patients who were salvaged by DLI and second transplantation, three‐yr OS was 0.61 (95% CI; 0.41–0.78) with a median follow‐up of three and a half yr (range 1.5–11.2 yr). When entering remission, children with relapsed AML have a reasonable survival with HSCT, but relapse and TRM remain a concern.     

Treatment of childhood acute myelogenous leukemia with allogeneic and autologous stem cell transplantation during the first remission: a report from the Kyushu-Yamaguchi Children's Cancer Study group in Japan

A total of 64 newly diagnosed acute myelogenous leukemia patients (except FAB M3 and/or Down syndrome) under 18 years of age were consecutively enrolled into the study. Patients having an HLA-identical sibling (allo group) were assigned to undergo allogeneic bone marrow transplantation (allo BMT) in the first complete remission (CR). Others (non-allo group) were assigned to undergo autologous peripheral blood stem cell transplantation (PBSCT) or autologous BMT (auto BMT). Conditioning regimen was busulfan + melphalan for all transplantation. Of 64 patients (allo group 24; non-allo group 40), 59 (92.2%) achieved a CR. Eighteen relapses occurred (allo group 4; non-allo group 14) and 6 died during the first CR. The 5-year event-free survival (EFS) rate was 53.3 +/- 6.4% at a median follow-up period of 45 months. The 5-year EFS rates of allo and non-allo groups were 70.8 +/- 9.3% and 43.0 +/- 8.1%, respectively (p = .08). The EFS rates at 5 years post-transplant for allo BMT from an HLA-identical sibling (n = 18), PBSCT (11), and auto BMT (6) were 88.1 +/- 7.9%, 41.6 +/- 19.7%, and 83.3 +/- 15.2%, respectively. The outcome of allo BMT was superior to that of autograft. Auto BMT rather than PBSCT might contribute to a long-term survival in case of no available HLA-identical siblings.     

Improved overall survival for pediatric patients undergoing allogeneic hematopoietic stem cell transplantation – A comparison of the last two decades

Pediatric protocols for allogeneic hematopoietic SCT have been altered during the last two decades. To compare the outcomes in children (<18 yr old), who underwent SCT at our center during 1992–2002 (P1) and 2003–2013 (P2). We retrospectively analyzed 188 patients in P1 and 201 patients in P2. The most significant protocol changes during P2 compared with P1 were a decrease in MAC protocols, particularly those containing TBI, an increase in RIC protocols, and altered GvHD prophylaxis. In addition, P2 had more patients with nonmalignant diagnoses (p = 0.002), more mismatched (MM) donors (p = 0.01), and more umbilical CB grafts (p = 0.03). Mesenchymal or DSCs were used for severe acute GvHD during P2. Three‐yr OS in P1 was 58%, and in P2, it was 78% (p < 0.001). Improved OS was seen in both malignant disorders (51% vs. 68%; p = 0.05) and nonmalignant disorders (77% vs. 87%; p = 0.04). Multivariate analysis showed that SCT during P2 was associated with reduced mortality (HR = 0.57; p = 0.005), reduced TRM (HR = 0.57; p = 0.03), unchanged relapse rate, similar rate of GF, less chronic GvHD (HR = 0.49; p = 0.01), and more acute GvHD (HR = 1.77, p = 0.007). During recent years, OS has improved at our center, possibly reflecting the introduction of less toxic conditioning regimens and a number of other methodological developments in SCT.     

Possible Benefits of High-Dose Chemotherapy as Intensive Consolidation in Patients with High-Risk Rhabdomyosarcoma Who Achieve Complete Remission with Conventional Chemotherapy

The authors reviewed their single-center experience with autologous stem cell transplantation (SCT) in 22 patients with advanced rhabdomyosarcoma. Pathological subtypes included alveolar ( n = 7) and embryonal types ( n = 15). The conditioning regimen primarily consisted of etoposide, carboplatin, and melphalan. Fourteen, five, and three patients underwent SCT in CR, PR, and PD, respectively. Eight patients are currently alive without evidence of disease. The overall survival rate at 5 years was 70% for 14 patients who were in CR at the time of SCT. This limited experience warrants the examination of SCT in a prospective study.     

Possible benefits of high-dose chemotherapy as intensive consolidation in patients with high-risk rhabdomyosarcoma who achieve complete remission with conventional chemotherapy

The authors reviewed their single-center experience with autologous stem cell transplantation (SCT) in 22 patients with advanced rhabdomyosarcoma. Pathological subtypes included alveolar ( n = 7) and embryonal types ( n = 15). The conditioning regimen primarily consisted of etoposide, carboplatin, and melphalan. Fourteen, five, and three patients underwent SCT in CR, PR, and PD, respectively. Eight patients are currently alive without evidence of disease. The overall survival rate at 5 years was 70% for 14 patients who were in CR at the time of SCT. This limited experience warrants the examination of SCT in a prospective study.     

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.     

The effectiveness of busulfan‐based conditioning regimens for stem cell transplantation against lymphomas in children,adolescents, and young adults in Japan

Conditioning regimens for stem cell transplantation (SCT) involving total body irradiation (TBI) are generally preferred over busulfan (BU)‐based ones for lymphoid malignancies. However, reports of favorable results using BU against lymphomas have recently emerged. This study sought to compare the effectiveness of BU and TBI regimens for SCT against lymphomas. We retrospectively analyzed 893 lymphoma patients who underwent primary SCT in Japan between 1980 and 2015. The median age of all patients was 18 years (range, 0–30 years) with 589 males, 303 females, and 1 patient whose sex was unknown. Overall survival (OS) was not different between those receiving BU and TBI (P = 0.672). OS in patients receiving autologous SCT was significantly better with BU over TBI regimens (P = 0.038), particularly in children (0–15 years) (P = 0.024). Conversely, OS in adolescents and young adults (AYAs; 16–30 years) receiving allogeneic SCT was significantly worse with BU over TBI regimens (P = 0.035). Overall, BU regiments had comparable effectiveness to TBI conditioning regimens, and, although less effective for AYAs with allogeneic SCT, were particularly more effective than TBI regimens for children who received autologous SCT.     

Retrospective analysis of children with high‐risk acute myeloid leukemia who underwent allogeneic hematopoietic stem cell transplantation following complete remission with initial induction chemotherapy in the AML‐05 clinical trial

In the AML‐05 clinical trial conducted by the Japanese Pediatric Leukemia/Lymphoma Group from 2006 to 2010, children with high‐risk acute myeloid leukemia (HR AML) received allogeneic hematopoietic stem cell transplantation (allo‐HSCT) at first complete remission (CR1). The aim of this study was to investigate the impact of allo‐HSCT on the outcome of HR AML. Patients with either monosomy 7, 5q?, t(16;21), Ph1, FLT3‐ITD, or induction failure after the first course of chemotherapy were eligible for transplant. Of 53 children with HR AML, 51 received allo‐HSCT—45 in CR1, five in CR2, and one with non‐CR. t(8;21), t(9;11), and t(16;21) abnormalities were identified in eight, five, and four patients, respectively. The stem cell sources varied—bone marrow in 30 patients, peripheral blood in three, and cord blood in 18. The median follow‐up was 62 months. The overall survival (OS) rates at 3 years were 73% and 25% for patients who received transplant at CR1 and ≥CR2, respectively. Multivariable analysis showed that patients with chronic graft‐versus‐host disease (cGVHD) had better OS. This study supports that allo‐HSCT is a suitable treatment for HR AML in CR1. The favorable outcome associated with cGVHD indicates that a graft‐versus‐leukemia effect might be occurring.     

Severe lung injury and lung biopsy in children post‐hematopoietic stem cell transplantation: The differences between allogeneic and autologous transplantation

To review outcome of children post‐allogeneic (allo) and autologous (auto) SCT with severe lung injury who had lung biopsy and to determine whether the diagnoses provided by lung biopsy had an impact on outcome. Retrospective study was carried out from January 2000 to June 2010. Nine hundred and eighteen children (0–18 yr) received SCT (allo 476, auto 442), and 59 biopsies were performed in 48 patients. Most common result of lung biopsy was non‐infectious inflammation and recurrent disease in allo‐ and autorecipients, respectively. In a multivariate analysis, survival of allorecipients who had management change was inferior (p = 0.002; HR: 3.12). These patients were extremely sick, and management change was the last attempt to stabilize their respiratory status. There was a trend toward superior survival for children who had biopsy after 100 days following SCT (p = 0.09; HR: 0.55) and a trend toward inferior survival for those with proven infections within two wk of biopsy (p = 0.07; HR: 2.14). Only 31% of allorecipients and 25% of autorecipients survived. There were no biopsy‐related complications. Lung biopsy itself appears to be well tolerated, although requiring a biopsy seems to carry a poor prognosis; this seems to be due to different causes, auto (relapse), allo (non‐infectious inflammation).     

Outcomes in childhood AML in the absence of transplantation in first remission--Children's Cancer Group (CCG) studies 2891 and CCG 213

Background

The majority of childhood acute myeloid leukemia (AML) patients lack a matched‐related bone marrow transplant (BMT) donor in first remission.

Procedure

Disease‐free survival (DFS), overall survival (OS), relapse‐free survival (RFS), and post‐relapse outcome were evaluated for children with de novo AML on CCG 213 and the standard timing (ST) and intensive timing (IT) induction arms of CCG 2891 who were randomized to (intent‐to‐treat, ITT) or who received (as‐treated, AT) only chemotherapy intensification.

Results

Outcomes at 8 years post‐induction in ITT analysis of chemotherapy intensification were as follows: 31% DFS, 43% OS on CCG 213; 34% DFS, 51% OS on CCG 2891 ST; 48% DFS, 56% OS on CCG 2891 IT. All toxic deaths during and following Capizzi II chemotherapy intensification on both protocols were in patients >3 years of age (P ≤ 0.001). Black race was a significant poor prognostic factor for OS (P = 0.008, hazard ratio: 1.74, 95% CI: 1.15–2.61). Overall 48% of patients on both trials relapsed and 19.1% of patients who relapsed on these trials survived. CR1 >12 months portends a much better OS for patients who relapse. Post‐relapse treatment included BMT in 47% of patients.

Conclusions

OS on CCG 2891 was superior to CCG 213 but equivalent between ST and IT arms due to better salvage rates post‐relapse in ST patients. Overall survival for childhood AML in the absence of BMT in CR1 is influenced by duration of CR1 and by race. Pediatr Blood Cancer 2008;50:9–16. © 2007 Wiley‐Liss, Inc.     

Multimodal treatment including tandem high‐dose chemotherapy and autologous stem cell transplantation in children with anaplastic ependymomas

In this study, we evaluated the results of multimodal treatment that included tandem HDCT/auto‐SCT in children with anaplastic ependymomas. Fourteen patients with anaplastic ependymomas were enrolled from 2006 to 2014. Six cycles of induction chemotherapy were administered to all patients before they underwent tandem HDCT/auto‐SCT. Patients who were older than 3 years of age were administered RT after two cycles of induction chemotherapy. In patients under 3 years of age, RT was either omitted or delayed until they reached 3 years of age, if the patients experienced CR after tandem HDCT/auto‐SCT. All patients, including two who experienced disease progression during induction treatment, underwent the first HDCT/auto‐SCT, and 13 subsequently underwent the second HDCT/auto‐SCT. One patient died from hepatic VOD during the second HDCT/auto‐SCT; other toxicities occurring during tandem HDCT/auto‐SCT were manageable. Relapses or progression occurred in seven patients, and five of seven of them remain alive till date after salvage treatment, including surgery and RT. The 5‐year overall and event‐free survival rates were 85.1% ± 9.7% and 50.0% ± 13.4%, respectively. These findings suggest that multimodal treatment including tandem HDCT/auto‐SCT could be a feasible option for improving survival in children with anaplastic ependymomas.     

Non‐total body irradiation myeloablative conditioning with intravenous busulfan and cyclophosphamide in hematopoietic stem cell transplantation for malignant infantile osteopetrosis

HSCT is the only curative treatment for MIOP. We prospectively investigated the outcome of HSCT using intravenous busulfan‐based conditioning regimen from 2008 to 2013. Nineteen patients (median age = 17 months) underwent transplantation from HLA‐matched related donors (n = 14), HLA‐haploidentical related donors (n = 2), partially matched cord blood donors (n = 2), and HLA‐matched unrelated donor (n = 1). Bone marrow (n = 9), peripheral blood (n = 8), and cord blood (n = 2) were used as stem cell sources. All but one patient demonstrated primary engraftment. Two patients experienced secondary graft failure. During the follow‐up period, three patients showed mixed chimerism (45%, 45%, and 70% of donor cells were engrafted in each one of these patients) but are disease free. Two‐yr OS and DFS were 84.2% and 73.7%, respectively. Improvement of visual acuity and partial reversal of mild conductive hearing loss occurred in two and four patients, respectively. The causes of death among three patients were infection, GvHD, and disease progression. In conclusion, due to major side effects of MIOP such as visual and hearing loss, early treatment using myeloablative conditioning without irradiation HSCT is suggested. The use of an HLA‐matched related donor seems to be highly successful in this regard. Also, according to results of our study, mixed chimerism may be sufficient to resolve symptoms of disease.     

Autologous cord blood transplantation for metastatic neuroblastoma

Auto‐SCT is a common approach for metastatic neuroblastoma with the intention to rescue hematopoiesis after megadose chemotherapy. PBSC or BM is the usual stem cell source for auto‐SCT. Auto‐CBT for neuroblastoma has very rarely been performed. Currently, case reports are available for two patients only. We performed 13 auto‐SCTs for high‐risk neuroblastoma from 2007 to 2013, including four cases of metastatic neuroblastoma aged 11–64 months treated with auto‐CBT. All four patients had partial or CR to upfront treatments before auto‐CBT. Nucleated cell dose and CD34+ cell dose infused were 2.8–8.7 × 10⁷/kg and 0.36–3.9 × 10⁵/kg, respectively. Post‐thawed viability was 57–76%. Neutrophil engraftment (>0.5 × 10⁹/L) occurred at 15–33 days, while platelet engraftment occurred at 31–43 days (>20 × 10⁹/L) and 33–65 days (>50 × 10⁹/L) post‐transplant, respectively. There was no severe acute or chronic complication. Three patients survived for 1.9–7.7 yr without evidence of recurrence. One patient relapsed at 16 months post‐transplant and died of progressive disease. Cord blood may be a feasible alternative stem cell source for auto‐SCT in patients with stage 4 neuroblastoma, and outcomes may be improved compared to autologous PBSC or BM transplants.     

Hematopoietic stem cell transplantation from non‐sibling matched family donors for patients with thalassemia major in Jordan

There are limited data on the outcome of patients with thalassemia receiving HSCT from non‐sibling matched family donors. Of the 341 patients with thalassemia major that underwent donor search at our center from January 2003 to December 2011, 236 (69.2%) had fully matched family donor of which 28 patients (8.2%) had non‐sibling matched family donors identified. We report on seven patients with a median age of eight yr (4–21) who underwent myeloablative (n = 4) or RIC (n = 3) HSCT. The median age of the donors was 33 yr (4–47), three were parents, two first cousins, one paternal uncle, and one paternal aunt. All patients achieved primary neutrophil and platelet engraftment at a median of 18 (13–20) and 16 days (11–20), respectively. One patient developed grade II acute GVHD, and two patients developed limited chronic GVHD. One patient experienced secondary GF requiring a second transplant. At a median follow‐up of 69 months (7–110), all patients are alive and thalassemia free. Our data emphasize the need for extended family HLA typing for patients with thalassemia major in regions where there is high rate of consanguinity. Transplant from non‐sibling matched family donor can result in excellent outcome.