Recent progress in the treatment of infant acute lymphoblastic leukemia

Treatment of infants with acute lymphoblastic leukemia (ALL), especially those with mixed lineage leukemia (MLL) rearrangement (MLL‐r), which account for approximately 80% of cases, is still a major challenge for pediatric hematologists and oncologists worldwide. Continuing efforts by collaborative clinical study groups in Europe, North America, and Japan have rescued approximately half of the MLL‐r ALL patients with intensive chemotherapy with or without allogeneic hematopoietic stem cell transplantation. Recent progress has clarified the unique mechanism of MLL‐r ALL: the aberrant methylation and histone modifications via DOT1L and other related molecules by MLL fusion proteins lead to leukemogenetic gene expression, thus to overt leukemia. In order to overcome this dismal subtype of ALL, novel targeted therapy based on leukemia biology is urgently needed. Due to the extreme rarity of the disease, collaboration between the study groups in Europe (Interfant), North America (Children's Oncology Group), and Japan (Japanese Pediatric Leukemia/Lymphoma Study Group) is under way.     

High-dose chemotherapy and blood stem cell autografts for children with first relapsed acute lymphoblastic leukemia: A pilot study of the children's cancer and leukemia study group of Japan (CCLSG)

This study was performed to determine the value of high-dose chemotherapy and peripheral blood stem cell autografts (PBSCT) in the treatment of children with first relapsed acute lymphoblastic leukemia (ALL). Eighteen children underwent PBSCT during the second complete remission (CR) and had a minimum 10 month follow-up. The median age of the patients was 11 yr (range, 2–17 yr). Fifteen patients received the “MCVAC” regimen, one received high-dose MCNU + busulfan therapy, one received high-dose melphalan + VP-16, and one received melphalan + carboplatin + cytosine arabinoside + MCNU. None of these regimens included total body irradiation. Eight patients developed recurrence of the disease at 1 to 19 mo (median, 3 mo) after PBSCT. Patients in whom the first relapse occurred sooner, that is, within 16 mo of initial therapy, tended to have a better survival rate than those who developed relapse after 30 mo (six of seven survived versus four of 11; not significant). Although the preliminary data provided little conclusive information, it did suggest that incorporation of PBSCT in the salvage protocol of relapsed childhood ALL can be justified. © 1994 Wiley-Liss, Inc.     

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.     

Impact of pretransplant minimal residual disease on the post‐transplant outcome of pediatric acute lymphoblastic leukemia

There are few reports on the clinical significance of MRD before HSCT in pediatric ALL. We retrospectively analyzed the clinical significance of FCM‐based detection of MRD (FCM‐MRD) before allogeneic HSCT in pediatric ALL. Of 38 pediatric patients who underwent allogeneic HSCT for the first time between 1998 and 2014, 33 patients were in CR and five patients were in non‐CR. The CR group was further divided into two groups based on the pretransplant FCM‐MRD level: the MRD^neg (<0.01%; 30 patients) group and the MRD^pos (≥0.01%; three patients) group. There were significant differences in the three‐yr event‐free survival rates between the CR and non‐CR group, and between the MRD^neg and MRD^pos group. The three‐yr cumulative RI in the MRD^neg group were 27.3% ± 8.8%, whereas two of the three patients in the MRD^pos group relapsed within one yr after HSCT. The clinical outcome of the MRD^pos group was as poor as that of the non‐CR group in pediatric ALL. Therefore, an improvement in pretransplant treatment that aims to achieve a more profound remission would contribute to reducing the risk of relapse.     

儿童急性淋巴细胞性白血病ALL-2005方案治疗失败病例分析

目的分析ALL-2005方案治疗儿童急性淋巴细胞性白血病(ALL)失败的原因。方法将初治ALL失败病例分为诱导治疗失败、复发和依从失败以及治疗相关死亡三类,回顾性分析失败的原因。结果 2005年5月1日至2009年4月30日,共388例初治ALL患儿,随访时间中位数48个月(24～72个月)。101例患儿治疗失败,总失败率为26.0%;其中诱导治疗失败6例,复发69例,依从失败17例,治疗相关死亡9例。骨髓复发率为13.2%,单纯中枢神经系统复发率为2.4%,男性患儿睾丸复发率为3.9%。388例ALL患儿中,300例B系ALL患儿在诱导治疗第35天监测微小残留病(MRD),MRD≤0.01%患儿的复发率为15.4%,而MRD>0.01%患儿为28.8%,两者间差异有统计学意义(χ2=5.818,P=0.016)。结论复发是导致ALL-2005方案治疗ALL失败的主要原因,诱导治疗第35天MRD水平可以预测患儿的预后。     

T-cell acute lymphoblastic leukemia relapsing as acute myelogenous leukemia

We present the unusual case of a 16-year-old girl with T-cell acute lymphoblastic leukemia (ALL) with an early thymocyte immunophenotype without myeloid markers, who after 13 months of complete hematological remission relapsed as acute myelogenous leukemia (AML) with minimal differentiation and died of her disease. Whether the AML represented a relapse with lineage switch of the original immature T-cell clone or a new secondary malignancy, could not be proven due to the absence of molecular or clonal markers. This report suggests that a subset of CD7+ T-cell leukemias without mature T-cell antigens (CD4-, CD8-) are minimally differentiated and can relapse as AML.     

Treatment‐related mortality in relapsed childhood acute lymphoblastic leukemia

1 Background

Treatment of relapsed childhood acute lymphoblastic leukemia (ALL) is particularly challenging due to the high treatment intensity needed to induce and sustain a second remission. To improve results, it is important to understand how treatment‐related toxicity impacts survival.

2 Procedure

In this retrospective population‐based study, we described the causes of death and estimated the risk for treatment‐related mortality in patients with first relapse of childhood ALL in the Nordic Society of Paediatric Haematology and Oncology ALL‐92 and ALL‐2000 trials.

3 Results

Among the 483 patients who received relapse treatment with curative intent, we identified 52 patients (10.8%) who died of treatment‐related causes. Twelve of these died before achieving second remission and 40 died in second remission. Infections were the cause of death in 38 patients (73.1%), predominantly bacterial infections during the chemotherapy phases of the relapse treatment. Viral infections were more common following hematopoietic stem cell transplantation (HSCT) in second remission. Independent risk factors for treatment‐related mortality were as follows: high‐risk stratification at relapse (hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.3–3.9; P < 0.01), unfavorable cytogenetic aberrations (HR 3.4; 95% CI 1.3–9.2; P = 0.01), and HSCT (HR 4.64; 95% CI 2.17–9.92; P < 0.001). In contrast to previous findings, we did not observe any statistically significant sex or age differences. Interestingly, none of the 17 patients with Down syndrome died of treatment‐related causes.

4 Conclusions

Fatal treatment complications contribute significantly to the poor overall survival after relapse. Implementation of novel therapies with reduced toxicity and aggressive supportive care management are important to improve survival in relapsed childhood ALL.     

Hematopoietic stem cell transplantation in pediatric patients with acute myeloid leukemia without favorable cytogenetics

Intensified chemotherapy, HSCT, and supportive care improve the survival of pediatric patients with AML. However, no consensus has been reached regarding the role of HSCT in patients without favorable cytogenetics. We evaluated OS and EFS according to prognostic factors that affect clinical outcomes, including cytogenetics risk group, conditioning regimen, donor type, disease status at the time of HSCT, and number of chemotherapy cycles prior to HSCT in 65 pediatric patients with AML without favorable cytogenetics who underwent HSCT. Fifteen of the 65 patients died: three of TRM and 12 of disease‐related mortality. The 5‐year OS and EFS were 78.0% and 72.0%, respectively, and the 5‐year cumulative relapse and TRM rates were 26.9% and 5.1%, respectively. Survival rates were not influenced by cytogenetic group (intermediated vs. poor), donor type (related vs. unrelated), transplant type (myeloablative vs. reduced‐intensity conditioning), or number of pretransplant chemotherapy cycles (≤3 vs. >3 cycles). The low TRM rate and encouraging outcomes suggest that HSCT may be a feasible treatment for pediatric patients with AML without favorable cytogenetics.     

Outcome after first relapse in children with acute lymphoblastic leukemia: a report based on the Dutch Childhood Oncology Group (DCOG) relapse all 98 protocol

Background

We report on the treatment of children and adolescents with acute lymphoblastic leukemia (ALL) in first relapse. The protocol focused on: (1) Intensive chemotherapy preceding allogeneic stem cell transplantation (SCT) in early bone marrow relapse; (2) Rotational chemotherapy in late relapse, without donor; (3) Postponement of cerebro‐spinal irradiation in late isolated CNS relapse; and (4) Treatment in very late bone marrow relapse with chemotherapy only.

Methods

From January 1999 until July 2006 all 158 Dutch pediatric patients with ALL in first relapse were recorded. Ninety‐nine patients were eligible; 54 patients with early and 45 with late relapse. Eighteen patients had an isolated extra‐medullary relapse; 69 patients had bone marrow involvement only.

Results

Five‐years EFS rates for early and late relapses were 12% and 35%, respectively. For early relapses 5 years EFSs were 25% for patients transplanted; 0% for non‐transplanted patients. For late relapses 5 years EFS was 64% for patients treated with chemotherapy only, and 16% for transplanted patients. For very late relapses EFS was 58%.

Conclusions

Our data suggest the superiority of SCT for early relapse patients. For late relapses a better outcome is achieved with chemotherapy only using the rotational chemotherapy scheme. The most important factor for survival was interval between first CR and occurrence of the first relapse. Pediatr Blood Cancer 2011; 57: 210–216. © 2011 Wiley‐Liss, Inc.

     

异基因造血干细胞移植治疗儿童急性髓系白血病临床研究

目的评估应用异基因造血干细胞移植(allo-HSCT)治疗儿童急性髓系白血病(AML)的临床疗效及相关影响因素。方法回顾分析2002年1月至2017年11月49例确诊中、高危及复发AML行allo-HSCT患儿的临床资料,分析危险度分级、HLA分型、移植前状态、移植方式、干细胞来源及急慢性移植物抗宿主病(GVHD)等对allo-HSCT治疗效果的影响。结果 49例患儿中男35例、女14例,中位年龄9岁。三年总体存活率(OS)为(59.2±7.3)%,无白血病存活率(LFS)为(50.9±7.4)%。其中第1次缓解状态移植、非血缘移植、外周血干细胞移植、中危组移植的三年LFS分别为69.8%、69. 2%、73. 7%、65. 8%。19例死亡,分别为复发13例、严重感染5例、多器官衰竭1例。COX回归模型结果显示,急性GVHD是影响移植OS的独立危险因素(RR=3. 16,95%CI:1. 23～8. 09,P=0. 017),移植前状态为部分缓解及未缓解是影响移植LFS的独立危险因素(RR=4.76,95%CI:1.52～14.94,P=0.008;RR=5.28,95%CI:1.68～16.58,P=0.004)。结论移植前状态及急性GVHD是影响Allo-HSCT治疗儿童AML疗效的关键因素;白血病复发及感染是导致死亡的主要原因。     

Pharmacokinetics of high-dose etoposide administered in combination with fractionated total-body irradiation as conditioning for allogeneic hematopoietic stem cell transplantation in children with acute lymphoblastic leukemia

Etoposide (VP-16) is one of the most widely used antitumor agents in pediatric oncology as well as chemotherapeutic agents used in conditioning regimen prior to allo-HSCT for childhood ALL. This study included 21 children with ALL who underwent allo-HSCT after conditioning with FTBI and high-dose of VP-16 (60 mg/kg) given intravenously as single four-h infusion on day -3 (n=2) or day -4 (n=19) prior to allo-HSCT. Blood samples were collected at defined time intervals until 120 h elapsed from the end of infusion. VP-16 plasma concentrations were determined using validated HPLC method. Three-compartment model was assumed for assessing PK parameters of VP-16. The median value of VP-16 C(max) measured at the end of infusion was 188.0 μg/mL (range 148.0-407.0 μg/mL). Out of 21 studied children, VP-16 was still detectable in 17 patients 72 h (median concentration 0.31 μg/mL) and in eight patients 96 h (median concentration 0.31 μg/mL) after the end of infusion. VP-16 concentration 96 h after the end of infusion was positively correlated with VP-16 AUC and negatively correlated with VP-16 CL normalized to body weight.     

An evaluation of corynebacterium parvum during remission maintenance therapy in pediatric patients with acute lymphoblastic leukemia

The biologic impact and clinical toxicity of Corynebacterium parvum administered at a dose of 5 mg/M² by intravenous or subcutaneous routes were evaluated in 18 children receiving combination chemotherapy for maintenance of acute lymphoblastic leukemia (ALL) in remission. Several nonspecific immunologic and hematologic parameters were evaluated. Patients were also monitored for changes in cutaneous sensitivity to histamine. No changes in any parameter were observed in patients after only one course of C parvum injection. However, after 6-10 courses, glass-adherent peripheral blood leukocytes of C parvum-treated patients augmented the response of PHA-stimulated autologous lymphocytes. In all nine patients studied who received C parvum injection subcutaneously for at least six months, there were significant increases in the mean bone marrow myelocyte-erythrocyte (ME) volumes compared to pretreatment values. These results suggest that periodic evaluations are desirable in patients receiving repeated administration of C parvum, since changes in immunologic and hematologic responses may be demonstrable only after several injections. In contrast to the reported experience in adults, subcutaneous C parvum administration in children was not well tolerated, whereas intravenous infusion was generally well tolerated.     

Treatment and biology of pediatric acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. In the past ALL was intractable but now the survival probability is as high as 80–90%. Improved supportive care, treatment stratification based on relapse risk, biological features of leukemic cells, and optimization of treatment regimens by nationwide and international collaboration have contributed to this dramatic improvement. While including traditional risk factors (e.g. age and leukocyte count at diagnosis), the treatment has been modified based on biological characteristics (aneuploidy and translocation) and treatment response (assessed by minimal residual disease). Treatment for pediatric ALL typically consists of induction therapy with steroids, vincristine, and asparaginase with or without anthracycline, followed by multi‐agent consolidation including high‐dose methotrexate and re‐induction therapy. After consolidation, less intensive maintenance therapy is required for 1–2 years to maintain event‐free survival. Recently, using advanced genomic analysis technology, novel sentinel genomic alterations that may provide more precise stratification or therapeutic targets, were identified. Moreover, in the last decade germline variations have been recognized as similarly important contributors to understanding the etiology and sensitivity of ALL to treatment. A more individualized approach based on genomic features (somatic and germline) and treatment response, the introduction of newly developed agents such as molecular targeted drugs or immunotherapy, and social support including long‐term follow up are required for further improvement.     

��ͯ����T�ܰ�ϸ����Ѫ���ٴ���Ч��Ԥ���������73������

??Objective??To analyze the clinical characteristics and prognosis of pediatric acute T lymphoblastic leukemia. Methods??Clinical characteristics of 73 children with acute T lymphoblastic leukemia and T-cell lymphoblastic lymphoma involving the bone marrow treated in Peking University People’s Hospital from March 2003 to March 2014 were retrospectively analysed?? and the prognosis factors were analyzed. Results??Of the 73 patients?? 25 children relapsed and 3 died from complications during chemotherapy or transplantation. Their 5-year CRF was ??37.89±6.02??% and 5-year EFS was ??58.74±6.01??%. The 5-year EFS decreased significantly when the initial onset age was more than 13. The 5-year CRF increased significantly when the initial onset size of spleen was bigger than 9 cm under the costal margin or the IgH rearrangement was positive. The 5-year CRF decreased significantly and 5-year EFS increased significantly when average peak methotrexate ??MTX?? blood concentration was more than 40 μmol/L during high-dose MTX chemotherapy. Conclusion??The treatment result of children with T-ALL is unsatisfactory. Initial onset age ≥13 and huge spleen indicate poor prognosis. Positive IgH rearrangement may be associated with high risk of recurrence. T-ALL patients can benefit from high-dose MTX therapy.