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.     

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.     

伴t(8;21)/AML1-ETO的儿童急性髓系白血病的临床研究

目的探讨伴t(8;21)/AML1-ETO的儿童急性髓系白血病(AML)的临床及生物学特征。方法52例初治患儿,男34例,女18例,中位年龄12(4~18)岁,均进行了遗传学和/或AML1-ETO融合基因检测。诱导缓解治疗采用HA/DA/HAD方案,缓解后进行异基因造血干细胞移植或7~12疗程的联合化疗。结果24%的儿童AML伴t(8;21)/AML1-ETO,男女比例1·9,FAB分型为M250例(96%);初诊时伴中枢神经系统浸润7·7%(4/52);WBC17·2(1·8~146·3)×109/L,初诊时WBC大于10×109/L者50·0%(26/52),大于50×109/L者3·8%(2/52),血清乳酸脱氢酶升高者85·7%(36/42);细胞免疫分型CD19(44·4%),CD56(58·9%);单独为t(8;21)异常的13例(28·9%),Y染色体丢失22例,占男性患儿的64·7%;X染色体丢失3例,占女性患儿的16·7%,del(9q)6例;1疗程及2疗程完全缓解(CR)率分别为71·8%(28/39)和94·4%(34/36),4年的EFS率、DFS率和OS率分别为(25·4±9·6)%、(28·4±10·4)%和37·9±10·3)%。结论近1/4的儿童AML伴t(8;21)/AML-ETO,多见于FAB分型的M2型,男性居多,年长儿多发,易发生髓外浸润;高白细胞者少见,血清乳酸脱氢酶增高,细胞免疫分型较多表达CD19和CD56;细胞遗传学检查常伴有性染色体丢失和del(9q);诱导缓解治疗完全缓解率高,应用联合化疗进行巩固强化远期疗效好     

Improved outcome in childhood acute myeloid leukemia in Singapore with the MRC AML 10 protocol

BACKGROUND: The introduction of the United Kingdom Medical Research Council's 10th AML trial (MRC AML 10) protocol incorporating high-dose anthracycline therapy has improved outcome of children with acute myeloid leukemia (AML). In this study, we review the results of childhood AML therapy in a Singapore university hospital over the last 17 years emphasizing toxicity and outcome. PROCEDURE: Retrospective analysis revealed 34 children with AML between 1988 and 2003. Prior to September 1996, therapy consisted of: POG-8498 (n = 10), others (n = 9). From September 1996, all but one of 15 children received MRC AML 10 treatment. RESULTS: At the time of analysis, 17 had died from disease, and 17 patients were alive among whom 2 had relapsed. MRC AML 10-treated patients (n = 14) had significantly better 3-year overall, event-free, and disease-free survival (74% vs. 35%, 77% vs. 20%, 83% vs. 31%; P = 0.019, P = 0.002, and P = 0.010, respectively) and were likelier to achieve complete remission (CR) than non-MRC AML 10 patients (P = 0.102). Among patients who achieved CR, MRC AML 10-treated patients were significantly more likely to achieve CR after only one cycle of chemotherapy (P = 0.016). Hematologic toxicity was similar among the different regimens (P = 0.9). CONCLUSIONS: These findings suggest that MRC AML 10 treatment results in significantly superior survival, without excess toxicity. Future studies should attempt to elucidate the relative importance of individual MRC AML 10 components and reduce the high cumulative anthracycline dose without compromising outcome.     

Adoptive immunotherapy as consolidation of remission in pediatric AML relapsing post-transplant

Treatment of acute leukemia relapse following an allogeneic transplantation is a challenge. We reinduced three pediatric patients with acute myeloid leukemia (AML) relapsing after a marrow transplantation from a sibling donor into remission with chemotherapy and used donor lymphocyte infusions (DLIs) as consolidation. In two of the cases, the allogeneic recognition was enhanced through the use of interferon in the absence of clinical graft vs. host disease (GVHD). Subsequently, all the three developed (acute grade III-IV or chronic extensive) GVHD and remain in remission with a good quality of life 19, 15 and 14 months post-relapse. We consider an active approach in the treatment of pediatric AML relapsing post-transplant justified.     

AML1-ETO阳性的儿童急性髓系白血病疗效分析

目的探讨儿童急性髓系白血病m2型伴AML1-ETO阳性患儿的疗效及预后相关因素。方法2003年1月至2008年12月收住AML1-ETO阳性儿童m233例,并对患儿进行总结分析、随访。了解患儿临床特征,免疫分型,染色体核型治疗及疗效,生存情况及影响治疗的因素。结果33例AML1-ETO阳性儿童第一疗程诱导缓解率为63.5%,中位随访时间32个月,目前仍处于CR状态25例占75.5%,5例患儿骨髓复发,复发率为15.1%,高白细胞数,多脏器受累,免疫表型CD5＋6以及第一疗程诱导治疗未达缓解者预后不良,并伴有较低的生存率。结论儿童急性髓系白血病M2伴有AML1-ETO阳性患儿预后是好的。强烈化疗高剂量阿糖胞苷能帮助提高疗效。提高生存率。高白细胞计数,累及多脏器以及CD56标记阳性和初次诱导治疗的缓解不佳,影响总的生存率。     

Hypocellular acute myeloid leukemia treated with bone marrow transplantation

Hypocellular acute myeloid leukemia (AML) mainly occurs in elderly patients, and is extremely rare in childhood. There is still no established treatment for hypocellular AML. We report the case of an 11‐year‐old boy with hypocellular AML who was treated successfully with allogenic bone marrow transplantation (allo‐BMT). He presented with fever, pallor and pancytopenia. Bone marrow aspiration and biopsy confirmed a diagnosis of hypocellular AML. Although low‐dose cytarabine induced reduction of blasts, it did not lead to complete remission. He subsequently received myeloablative conditioning and allo‐BMT. Graft‐versus‐host disease (GVHD) prophylaxis included short‐course methotrexate and cyclosporine. Neutrophil engraftment (>5 × 10⁸/L) and platelet recovery (>10 × 10¹⁰/L) were achieved on days 13 and 27, respectively. He developed acute GVHD of the skin (grade 2), which responded well to treatment with prednisolone. He has remained in complete remission for 5 years since allo‐BMT. We consider allo‐BMT to be feasible for children with hypocellular AML.     

Ex vivo chemopurging of autologous bone marrow with 4-hydroperoxycyclophosphamide to eliminate occult leukemic cells. Laboratory and clinical observations

The application of autologous bone marrow transplantation (ABMT) in treating acute leukemias in children has been limited by the presence of residual occult viable leukemic cells in the marrow cell suspension. One approach to this problem is the ex vivo treatment ("purging") of the autograft to eradicate these tumor cells yet spare the normal lymphohematopoietic stem cells. Initial studies of acute myeloid leukemia (AML) in a rodent model demonstrated that incubation with 4-hydroperoxycyclophosphamide (4HC), a congener of cyclophosphamide and an active alkylating agent in aqueous solution, could effectively eliminate viable AML cells from marrow cell suspensions without apparent toxicity to normal stem cells. We have conducted clinical trials of ABMT with 4HC-treated marrow in children with acute leukemia in remission; marrow was collected, treated ex vivo with 4HC (100 micrograms/ml), and cryopreserved in liquid nitrogen until reinfusion. Children received pre-ABMT conditioning with either high-dose cyclophosphamide and total body irradiation (CY-TBI) for acute lymphocytic leukemia (ALL) or high-dose busulfan and cyclophosphamide (BU-CY) for AML. Of nine children who underwent ABMT with 4HC-treated marrow for ALL in second complete remission (CR2), all relapsed (eight in the marrow, one in the central nervous system) at a median of 5 months (range, 2-17) after ABMT and all have died with relapsed ALL or as a consequence of its treatment. Twenty-nine children with AML (five in CR1, 24 in CR2) received autografts with chemopurged marrow at a median remission duration of 3 months (range, 2-15). Three patients died from sepsis during aplasia; 10 children (one in CR1 and nine in CR2) relapsed with AML at a median of 7 months (range, 2-23) after ABMT, for an actuarial relapse rate of 47%. Sixteen patients with AML (four in CR1, 12 in CR2) are in unmaintained remission at a median of 16 months (range, 6-102) after ABMT, for an actuarial disease-free survival of 49%. Although ABMT with 4HC-treated marrow appears to have a limited role in the treatment of children with ALL who lack a suitable related donor, the results in AML are encouraging and compare favorably with both syngeneic and allogeneic BMT in similar groups of patients.     

Therapy of acute myeloid leukemia in children--results of the AML II/87 multicenter study]

Fifty seven patients entered the cooperative study AML II/87 of the working group "Pediatric Hematology and Oncology" of East Germany. Two patients with initial hyperleukocytosis died prior therapy. 13 patients died within the first 4 weeks of therapy, 3 patients did not respond to therapy, and one patient is not yet in remission. 38 patients (70%) attained a complete remission. 15 patients get a bone marrow transplantation in first CR (10 autologous BMT without purging, 5 allogenous BMT). 12 of them are living and well 3 to 34 months after BMT. 9 of the 23 patients under chemotherapy relapsed, one patient is lost to follow up. 13 patients are living in continuous complete remission. The life table probabilities 48 months after the start of the protocol are 0.43 for disease free survival (DFS) and 0.60 for event free interval (EFI). The respective results of the former protocol AML I/82 were 0.34 for DFS and 0.47 for EFI.     

Therapeutic leukapheresis for hyperleukocytosis in acute myelocytic leukemia

Twenty-two patients with newly diagnosed acute myelocytic leukemia (AML) and white cell counts (WBC) greater than 100,000/μl received one, two, or three leukaphereses prior to induction chemotherapy with cytosine arabinoside (Ara-C) and daunorubicin (DNR). Fifteen of 22 (68%) achieved a complete remission. Greater than a 30% decrease in initial WBC was found to be an important predictor of response. Fifteen of 17 patients (88%) with greater than 30% reduction of initial WBC achieved remission, while none of 5 patients with less than a 30% reduction responded (P = 0.001).     

Chemokine/chemokine receptor interactions in extramedullary leukaemia of the skin in childhood AML: Differential roles for CCR2, CCR5, CXCR4 and CXCR7

Chemokine receptor/ligand interactions orchestrate the migration of cells to peripheral tissues such as the skin. We analysed chemokine receptor expression by acute myeloid leukaemic (AML) cells present in peripheral blood (n = 7), bone marrow (n = 6), or skin (n = 11) obtained from 15 paediatric AML patients with skin involvement and in 10 AML patients without skin involvement. High percentages of circulating CCR2^pos AML cells were only detected in patients with extramedullary disease. Skin‐residing AML cells displayed a different set of receptors in situ, namely: CCR5, CXCR4, CXCR7 and CX3CR1. These results suggest the involvement of different chemokine/chemokine receptor interactions in homing and retention of AML blasts in the skin. Pediatr Blood Cancer. 2010;55:344–348. © 2010 Wiley–Liss, Inc.     

Fludarabine, cyclophosphamide, doxorubicin (FCD), and rituximab: a remission induction therapy for aggressive pediatric post-transplant lymphoproliferative disease (PTLD)

Management of aggressive, usually late-occurring, post-transplant lymphoproliferative disorders (PTLDs), a life-threatening complication after solid organ transplants, remains controversial. Four children affected by aggressive CD20+ PTLDs received a chemo-immunotherapy regimen for remission induction based on fludarabine, cyclophosphamide, doxorubicin, and rituximab, associated with a rapid discontinuation of immunosuppression (IS). Subsequent consolidation chemotherapy consisted of Berlin-Frankfurt-Münster-modified blocks. All patients achieved a complete remission, which persisted for 25, 68+, 80+, and 103+ months after diagnosis. Therapy was well tolerated. No patients developed allograft rejection during PTLD treatment. Our experience suggests that this chemo-immunotherapeutic approach may be an effective treatment strategy while allowing for a concomitant discontinuation of IS.     

Unusual presentation of central nervous system relapse with oculomotor nerve palsy in a case of CD56-positive acute myeloid leukemia following allogeneic stem cell transplantation

Allogeneic stem cell transplantation (allo-SCT) plays an important role in the treatment of infants and children with acute myelogenous leukemia (AML). Leukemic relapse after allo-SCT is responsible for a high rate of treatment failure. Extra-medullary relapse (EMR), without involvement of bone marrow, is rare compared to medullary relapse. CD56, the neural cell adhesion molecule, may contribute to the higher frequency of CNS relapse in CD56-positive AML. We observed an isolated EMR on the oculomotor nerve of a 17-month-old girl 12 weeks after cord blood transplantation (CBT), who was transplanted because of CD56-positive AML. Diagnosis of relapse was suspected clinically and confirmed by magnetic resonance imaging (MRI), and fluorescence-activated cell sorter (FACS) and chimerism analysis of cerebrospinal fluid (CSF). Therapy consisted of intra-thecal chemotherapy, CNS irradiation, and systemic immunomodulation by cyclosporin A (CsA) and basiliximab withdrawal. Twenty-one months after relapse, the patient shows full remission of symptoms and previously described oculomotor nerve infiltration.     

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.     

Azacitidine as a bridge to allogeneic hematopoietic cell transplantation in a pediatric patient with Fanconi anemia and acute myeloid leukemia

HCT is the definitive therapy for patients with FA and AML. Conventional cytotoxic agents cause potential DNA damage, and currently, there is no established regimen for these patients prior to HCT. A 13‐year‐old male with FA and refractory AML was given azacitidine, achieved morphologic remission and underwent HCT. At 95 days after HCT, he relapsed. Azacitidine along with DLI was used as first salvage therapy. Azacitidine was overall well tolerated with minimal side effects. In patients with AML and FA, azacitidine can be considered an alternative to conventional chemotherapy.     

Immune reconstitution after autologous purged bone marrow transplantation in children

PURPOSE: Immune reconstitution was studied in 30 children who had received purged autologous bone marrow transplantation for neuroblastoma or acute myeloid leukemia (AML). METHODS: Patients with neuroblastoma received high-dose chemotherapy and total body irradiation, and patients with AML received chemotherapy alone. Marrows were purged ex vivo with either antineuroblastoma monoclonal antibodies (neuroblastoma) or 4-hydroperoxycyclophosphamide (AML). Lymphocyte subsets, mitogen stimulation studies, and immunoglobulin levels were studied every 4 months. RESULTS: There were no significant differences between the two groups of patients in lymphocyte number or subsets over time. In both groups, CD2+ and CD4+ cells were below normal in 33% of patients at 12 months. CD4+/CD8+ ratios were below normal for up to 8 months after transplantation and natural killer cells were elevated for up to 2 years in most patients. Median IgG and IgA levels were below the age mean even at 2 years after transplantation, although patients with AML had significantly higher IgG levels at 12 months compared with those with neuroblastoma. Lymphocyte proliferative responses to mitogens were markedly reduced at 4 months but returned to normal at 8 months. Despite the delay in immune reconstitution, there were no life-threatening infections. CONCLUSIONS: There appeared to be little difference in the overall kinetics of immune reconstitution between the children with neuroblastoma, who received total body irradiation and high-dose chemotherapy, and those with AML, who received high-dose chemotherapy alone as their pretransplant preparative regimen.     

Results of allogenic and autologous bone marrow transplantation in children with acute myeloid leukemia]

We report on our experience of bone marrow transplantation (BMT) in children with acute myeloblastic leukaemia (AML) and high risk of relapse (initial WBC greater than 20 x 10(9)/l, FAB M 5, M 6, M 7). 32 children were grafted between november 1982 and october 1991 at the Children's Hospital of the University of Jena. Two patients underwent an allogenous BMT in relapse and died from progressive disease. In 13 children an allogeneic BMT was performed in first complete remission. One patient relapsed, two patients died from severe acute graft-versus-host disease, and two patients died from encephalopathy and cardiomyopathy. Eight of the 13 patients are living and well 18 months to eight and a half year after BMT. Seventeen patients received an autologous (unpurged) BMT. Four of them relapsed four to seven months after BMT. The disease free survival (DFS) for the 29 patients grafted in remission was 0.65. There was no statistical significant difference in DFS between patients with allogeneic and autologous BMT. We conclude that in children with AML and high risk for relapse BMT offers a real chance for better survival. Autologous BMT avoids the problems of graft-versus-host disease and of finding suitable donors for allogeneic marrow transplantation.     

儿童急性巨核细胞白血病临床特点及预后分析

目的 研究儿童急性巨核细胞白血病（acute megakaryocytic leukemia,AMKL）的临床特点及急性髓系白血病（acute myeloid leukemia,AML）03方案的疗效及预后。方法 收集2011年5月至2019年12月确诊为AMKL的47例患儿的临床资料,分析其疗效及预后因素。采用Kaplan-Meier法及log-rank检验进行生存分析。结果 47例AMKL患儿中,22例非唐氏综合征AMKL患儿使用AML03方案治疗,中位随访时间为11.4个月。非唐氏综合征AMKL患儿诱导Ⅱ后骨髓细胞学缓解率为85%,微小残留病（minimal resident disease,MRD）阴性率为79%;2年总生存（overall survival,OS）率及无事件生存（event-free survival,EFS）率分别为50%± 13%和40%±12%。单因素分析提示：免疫表型标志物CD56阳性组2年EFS率、OS率均低于CD56阴性组（P < 0.05）;诱导Ⅱ后骨髓细胞学未缓解组2年EFS率及OS率均低于缓解组（P < 0.05）;诱导Ⅱ后MRD阳性组2年EFS率低于MRD阴性组（P < 0.05）;移植与非移植患儿2年OS率与EFS率比较差异无统计学意义（P > 0.05）。结论 儿童AMKL缓解率低,预后较差。免疫表型标志物CD56阳性、早期治疗反应中的骨髓细胞学及MRD结果是影响预后的重要因素。异基因造血干细胞移植对AMKL预后无显著影响。     

A trial of plerixafor adjunctive therapy in allogeneic hematopoietic cell transplantation with minimal conditioning for severe combined immunodeficiency

For infants with SCID, the ideal conditioning regimen before allogeneic HCT would omit cytotoxic chemotherapy to minimize short‐ and long‐term complications. We performed a prospective pilot trial with G‐CSF plus plerixafor given to the host to mobilize HSC from their niches. We enrolled six patients who received CD34‐selected haploidentical cells and one who received T‐replete matched unrelated BM. All patients receiving G‐CSF and plerixafor had generally poor CD34⁺ cell and Lin^‐CD34⁺CD38^?CD90⁺CD45RA^? HSC mobilization, and developed donor T cells, but no donor myeloid or B‐cell engraftment. Although well tolerated, G‐CSF plus plerixafor alone failed to overcome physical barriers to donor engraftment.