Treatment of young children with CNS‐positive acute lymphoblastic leukemia without cranial radiotherapy

Background

Due to the long‐term sequelae of cranial radiotherapy (CRT), contemporary treatment protocols for children with acute lymphoblastic leukemia (ALL) aim to limit the use of prophylactic CRT. For patients with central nervous system (CNS) involvement with ALL at diagnosis, the use of CRT remains common. Children <5 years of age are a particularly challenging subgroup in whom the consequences of CRT can be devastating.

Procedure

This study retrospectively describes the overall (OS) and event‐free survival (EFS) of young children (1–5 years) who were treated for CNS‐positive ALL at the Hospital for Sick Children between 2000 and 2013.

Results

Of a total of 19 patients, two were treated with upfront CRT, both as part of the conditioning regimen prior to HSCT. All patients received intensification of CNS‐directed chemotherapy by triple intra‐thecal chemotherapy (84.2%), use of dexamethasone in induction (57.9%) and maintenance (66.7%), and high‐dose methotrexate (77.8%). The OS was 84.2 ± 8.4% and EFS was 79.0 ± 9.4% with a median follow‐up time of 4.3 years (range, 2.6–8.2). The cumulative incidence of CNS relapse was 5.2 ± 5.1%.

Conclusions

We conclude that omission of CRT from the treatment of young children with ALL involving the CNS is associated with acceptable survival and avoids potentially devastating late effects in this group. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.     

The utility of performing the initial lumbar puncture on day 8 in remission induction therapy for childhood acute lymphoblastic leukemia: TCCSG L99-15 study

Background

Traumatic lumbar puncture with leukemic blasts (TLP+), which has been reported to occur 5–10%, in the previous studies, adversely affects the outcome of children with acute lymphoblastic leukemia (ALL). Based on the results from our previous study, we deferred the initial lumbar puncture until day 8 in remission induction therapy in order to reduce the frequency of cases with TLP+.

Procedure

The study was conducted as a prospective cohort study within the Tokyo Children's Cancer Study Group (TCCSG) L99‐15 study. Between April 1999 and June 2003, 754 children with newly diagnosed ALL enrolled. The patients received the initial intrathecal chemotherapy after 7 days of prednisolone treatment. The incidence of central nervous system (CNS)‐positive (the presence of leukemic blasts in cerebrospinal fluid or cranial nerve palsy) including TLP+ cases and cumulative incidence of CNS relapse were examined.

Results

The incidence of CNS‐positive and TLP+ was 2.9% (n = 22) and 0.8% (n = 6), respectively. These incidences were much lower than those in the representative study groups employing the initial IT on day 1. Of 22 patients with CNS‐positive, only one patient relapsed in CNS, whereas 22 of the remaining CNS‐negative 723 patients suffered from CNS relapse. Overall, event‐free survival at 4 year was 78.2 ± 1.6%. Four‐year cumulative incidence of any CNS relapse was 3.3 ± 0.7%, which improved from our previous study in spite of limiting the use of cranial irradiation.

Conclusions

Our strategy reduced the frequency of CNS‐positive patients who required reinforcement of CNS‐directed therapy without compromising overall outcome. Pediatr Blood Cancer 2012; 58: 23–30. © 2011 Wiley Periodicals, Inc.     

Identifying causes of variability in outcomes in children with acute lymphoblastic leukemia treated in a resource‐rich developing country

Background

The outcome of children with acute lymphoblastic leukemia (ALL) in developing countries is less favorable than in developed countries, primarily due to resource constraints. However, it is unknown whether the therapeutic results differ. Thus, we hypothesized that outcomes in resource‐rich developing countries would be similar to those in industrialized regions.

Procedure

We performed a retrospective analysis of 224 consecutive children with ALL, who were treated according to the Children's Cancer Group (CCG) protocols between January 2001 and December 2007. High‐risk (HR) and standard‐risk (SR) patients were treated with modified CCG‐1961 and CCG‐1991 protocols, respectively. Modifications included substitution of dexamethasone for prednisone in HR patients and addition of two intrathecal methotrexate treatments for CNS2 patients during induction. All patients received double delayed intensification with two interim maintenance phases.

Results

Five‐year overall survival (OS), event‐free survival (EFS) and disease‐free survival (DFS) were 84.7 ± 2.4%, 77.0 ± 2.9%, and 81.4 ± 2.7%, respectively. Remission was achieved in 98.1% of the patients. Induction failure and relapse rates were 1.9% and 15.1%, respectively. Death as the first event occurred in 6.4% of cases, of which 2.7% and 3.7% involved deaths in induction and remission, respectively. Interestingly, a significant reduction in induction deaths was observed over time.

Conclusions

Despite the encouraging results observed in the present study, our patients displayed significantly lower survival outcomes compared to subjects treated in major clinical trials conducted by leading leukemia cooperative groups. Furthermore, this work underscores the need for targeted interventions to reduce death as the first event in developing regions. Pediatr Blood Cancer 2015;62:945–950. © 2014 Wiley Periodicals, Inc.     

Prevalence and predictors of anthracycline cardiotoxicity in children treated for acute myeloid leukaemia: retrospective cohort study in a single centre in the United Kingdom

Background

Anthracycline cardiomyopathy is of concern in children treated for acute myeloid leukaemia (AML), but there are few data on the incidence and natural history of cardiotoxicity after AML treatment in the United Kingdom, where regimens have included high anthracycline exposure.

Procedure

Prevalence and predictors of cardiotoxicity were retrospectively reviewed in 124 children treated on the MRC AML 10 and AML 12 trials in a single, large centre from November 1987 to September 2004. Subclinical cardiotoxicity was defined as a shortening fraction of less than 28% and clinical cardiomyopathy as evidence of heart failure, and both were classified as late cardiotoxicity 1 year after completing first line therapy.

Results

Cumulative survival was 61% at 10 years. The prevalence of early and late cardiotoxicity was 13.7% (95%‐CI: 8.2–22.0%) and 17.4% (95%‐CI: 10.9–26.8%), respectively. Early cardiotoxicity was a strong predictor (OR = 9.18; 95%‐CI: 2.10–40.11; P < 0.005) and children who received salvage therapy following relapse showed a trend towards increased late cardiotoxicity (OR = 3.53; 95%‐CI: 0.86–14.48; P < 0.08). Subclinical cardiotoxicity resolved spontaneously in all but one case, but clinical cardiomyopathy always required continuing therapy. Two children died of cardiomyopathy and six remained on medical therapy.

Conclusions

Anthracycline cardiotoxicity remains a major concern for survivors of childhood AML and correlates with early cardiotoxicity and treatment intensity. Long‐term follow‐up is required to fully determine the outcome for children with subclinical cardiotoxicity. Pediatr Blood Cancer 2011;56:625–630. © 2011 Wiley‐Liss, Inc.     

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.     

Evolving of therapeutic strategies for CNS‐PNET

Background

A protocol for the intensive treatment of non‐cerebellar PNET (CNS‐PNET) combining chemotherapy and radiotherapy was launched in 2000. Efforts were subsequently made to improve the prognosis and to de‐escalate the treatment for selected patient groups.

Procedure

Twenty‐eight consecutive patients were enrolled for a high‐dose drug schedule (methotrexate, etoposide, cyclophosphamide, and carboplatin ± vincristine), followed by hyperfractionated accelerated CSI (HART‐CSI) at total doses of 31–39 Gy, depending on the patient's age, with two high‐dose thiotepa courses following CSI. After the first 15 patients had been treated, craniospinal irradiation (CSI) was replaced with focal radiotherapy (RT) for selected cases (non‐metastatic and not progressing during induction chemotherapy). Eight of the 28 children received the same chemotherapy but conventionally fractionated focal RT at 54 Gy.

Results

The 5‐year progression‐free survival (PFS), event‐free survival (EFS), and overall survival (OS) rates were 62%, 53%, and 52%, respectively, for the whole series, and 70%, 70%, and 87% for the eight focally irradiated children. Residual disease and metastases were not prognostically significant. In children with residual disease, response to RT was significant (5‐year PFS 59% vs. 20%, P = 0.01), while the total dose of CSI was not. There were three treatment‐related toxic events. Relapses were local in seven cases (including two of the eight focally irradiated patients), and both local and disseminated in 2.

Conclusions

This intensive schedule enabled treatment stratification for the purposes of radiation, thereby sparing some children full‐dose CSI. Local control is the main goal of treatment for CNS‐PNET. Pediatr Blood Cancer 2013;60:2031–2035. © 2013 Wiley Periodicals, Inc.     

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.

     

Results of AIEOP LNH-97 protocol for the treatment of anaplastic large cell lymphoma of childhood

Background

Anaplastic large cell lymphoma (ALCL) represents approximately 15% of all pediatric non‐Hodgkin lymphomas (NHL). It has distinct clinical features, including frequent involvement of extranodal sites and rare localization to the central nervous system (CNS). Despite varying treatment approaches the outcome of patients with ALCL has not significantly improved during the last two decades.

Procedure

From October 1997 to beginning of 2000, newly diagnosed ALCL patients were enrolled into AIEOP LNH‐97 protocol for ALCL. Thereafter and until 2007, only CNS positive patients were included. AIEOP LNH‐97 was based on the BFM‐95 schema for ALCL and included six high‐dose chemotherapy courses. CNS prophylaxis was obtained with one intrathecal injection of chemotherapy in each course, whereas treatment of CNS involvement included three intrathecal injections without irradiation.

Results

Thirty‐two patients were eligible for the study. Lymph‐node disease was the most frequent localization (69% of the cases), followed by mediastinal (25%), CNS (22%), bone marrow (16%), and skin (13%) involvement. Probabilities of overall survival (OS) and of event‐free survival (EFS) at 5 years for the whole population were 87% (SE 6%) and 68% (SE 8%), respectively.

Conclusions

This study confirmed that short pulse chemotherapy is an efficacious treatment option for first line therapy of pediatric ALCL, and that dose intensity may have some relevance for outcome, but not in all of the patients. Refinement and optimization of therapy strategies for ALCL may originate from a combination of clinical and biological prospective studies, as those in the pipeline of current international collaboration. Pediatr Blood Cancer 2012; 59: 828–833. © 2012 Wiley Periodicals, Inc.     

Augmented therapy improves outcome for pediatric high risk acute lymphocytic leukemia: results of Children's Oncology Group trial P9906

Background

The augmented BFM regimen improves outcome for children with NCI high acute lymphoblastic leukemia (ALL). Patient age, sex, and presenting white blood cell count (WBC) can be used to identify a subset of approximately 12% of children with B‐precursor ALL that had a 5‐year continuous complete remission (CCR) rate of only about 50% on earlier Pediatric Oncology Group (POG) trials.

Procedures

Children's Oncology Group trial P9906 evaluated a modified augmented BFM regimen in 267 patients with particularly high risk B‐precursor ALL. Minimal residual disease (MRD) was assessed in blood at day 8 and in marrow at day 29 of induction and correlated with outcome.

Results

The 5‐year CCR probability for patients in P9906 was significantly better than that observed for similar patients on POG trials 8602/9006 (62.2 ± 3.7% vs. 50.6 ± 2.4%; P = 0.0007) but similar to POG 9406 (63.5 ± 2.4%; P = 0.81). Interim analysis showed poor central nervous system (CNS) control, especially in patients with initial WBC ≥100,000/microliter. Day 29 marrow MRD positive (≥0.01%) vs. negative patients had 5 year CCR rates of 37.1 ± 7.4% vs. 72.6 ± 4.3%; day 8 blood MRD positive vs. negative patients had 5 year CCR rates of 57.1 ± 4.6% vs.83.6 ± 6.3%. End induction marrow MRD predicted marrow but not CNS relapse. In multivariate analysis, day 29 MRD > 0.01%, initial WBC ≥ 100,000/µl, male gender, and day 8 blood MRD > 0.01% were significant prognostic factors.

Conclusions

Augmented BFM therapy improved outcome for children with higher risk ALL. Day 8 blood and day 29 marrow MRD were strong prognostic factors in these patients. Pediatr Blood Cancer 2011; 57: 569–577. © 2011 Wiley‐Liss, Inc.

     

Cost-effectiveness of treatment of childhood acute lymphoblastic leukemia with chemotherapy only: the influence of new medication and diagnostic technology

Background

Survival for childhood acute lymphoblastic leukemia (ALL) has reached 80–90%. Future improvement in treatment success will involve new technologies and medication, adding to the pressure on limited financial resources. Therefore a retrospective cost‐effectiveness analysis of ALL treatment with chemotherapy only according to the two most recent Dutch Childhood Oncology Group treatment protocols was performed. The most recent protocol ALL10 included more expensive medication (pegasparaginase) and implemented a new diagnostic technique (minimal residual disease levels) compared to the previous ALL9 protocol.

Procedure

Fifty children from a single center cohort were included. All direct medical costs made during treatment, including those in satellite hospitals, were determined. Costs per life year saved (LYS) were calculated. The cost‐effectiveness ratio of the most recent treatment protocol was determined. LYS were calculated based on national 5‐year event‐free survival.

Results

Mean total costs were between $115,858 (ALL9) and $163,350 (ALL10) per patient. Hospital admissions (57%) and medication (11–17%) were important drivers of overall costs, and were higher in the most recent protocol ALL10. Costs per LYS were $1,962 (ALL9) and $2,655 (ALL10) and the cost‐effectiveness ratio was $8,215.

Conclusion

Treatment of childhood ALL with chemotherapy only is well within accepted ranges of cost‐effectiveness. The use of new technology and more expensive medication in the most recent protocol ALL10 lead to higher costs but more LYS. In future (ALL) treatment protocols, costs in relation to effects should be taken into account in order to establish more cost‐effective disease management without jeopardizing survival and quality of life. Pediatr Blood Cancer 2011; 57: 1005–1010. © 2011 Wiley‐Liss, Inc.     

Viral surveillance using PCR during treatment of AML and ALL

1 Background

While viral surveillance of cytomegalovirus (CMV), Epstein–Barr virus (EBV), and adenovirus using PCR is routine in patients undergoing hematopoetic stem cell transplant and solid organ transplant, the utility in the nontransplant pediatric leukemia population is unknown. Our institution screens patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) for viral DNAemia by PCR as part of clinical care.

2 Procedure

This retrospective chart review included patients treated for newly diagnosed or relapsed AML or ALL between April 2010 and September 2014. We retrieved data for viral PCR screening, detection and quantification, duration of positivity, and prophylaxis or treatment.

3 Results

One hundred eleven patients were included in analyses. Forty (36.0%) had at least one blood PCR positive for EBV, CMV, or adenovirus. Patients with ALL had significantly higher rates of persistent viral detection and treatment than those with AML (P < 0.02, P < 0.01, respectively). International patients had significantly higher rates of viral detection (P < 0.01), persistence (P < 0.01), any treatment (P < 0.03), and antiviral treatment (P < 0.01); 16.9% of patients who received intravenous immunoglobulin (IVIG) prophylactically had viral detection compared to 63% of patients who did not receive prophylactic IVIG (P = 0.0008).

4 Conclusions

Patients with ALL were more susceptible than those with AML to viral reactivation that was persistent or resulted in treatment. Patients with relapsed ALL, refractory ALL, or infantile ALL are most likely to benefit from asymptomatic screening for CMV and adenovirus. International patients are at higher risk for reactivation and may merit screening. EBV reactivation was not significant and does not warrant screening.     

U.S. childhood cancer survival, 1973–1987

The surveillance, epidemiology, and end-results (SEER) data on 5-year relative survival rates (1973-1987) for the most common pediatric tumors (ages 0–14) were analyzed. The SEER data are population based, so the observed progress in survival from childhood cancer represents the real impact that development in cancer treatment had on the population followed by the registry. The greatest increase in survival rate from 1973 until 1987 has been achieved in hematopoietic tumors such as acute lymphocytic leukemia (ALL), in which survival increased from 47.6% (1973–1977) to 60.8% (1983–1987), and Burkitt's lymphoma in which survival increased from 27.6% (1973–1977) to 68.7% (1983–1987). Solid tumors showed a less steep, but steady increase in survival rates. Flattening in the survival rates since 1978–1982 has been observed for acute leukemia, astrocytoma, medulloblastoma, and osteosarcoma. Females have better survival rates for most pediatric tumors, except Hodgkin's disease. Analysis of race of childhood leukemia confirmed that black children have worse survival than white. When solid tumors were analyzed by stage at presentation, there was no indication that diagnosis in earlier stages of disease accounted for the improved survival. Observed flattening in the survival rates since 1978–1982 of leukemia and some solid tumors warrants further follow-up. © 1994 Wiley-Liss, Inc.     

Persistent Low Level Epstein-Barr Virus DNAemia in Childhood Cancer Survivors

Background: Clinical observation of Epstein-Barr virus (EBV) status has not documented in childhood cancer survivors (CCSs) sustaining long-term remission of malignant diseases. Thus, the aim of this study was to evaluate the EBV status in children with various malignant diseases after they completed their treatments. Patients and Methods: Thirty consecutive children with various malignant diseases previously received treatment at the University of Tsukuba Hospital. Nine cases had acute lymphoblastic leukemia (ALL), 10 had solid tumors, 4 had lymphoma, 4 had CNS tumors, and 3 had acute myeloid leukemia (AML). EBV DNA in 328 whole blood samples were monitored by real-time QPCR for all cases after treatment. Clinical records and laboratory data were also reviewed. Results: There were 6/30 (20%) cases with continuous detection of EBV DNA while there were 24/30 (80%) cases without continuous EBV DNA. EBV DNAemia was persistently observed in 4/9 (44.4%) cases with ALL and in 2/4 (50%) cases with lymphoma. Persistent EBV DNAemia can be observed for >5 years without any EBV associated symptoms or diseases. Conclusions: Childhood cancer survivors have persistent EBV DNAemia more frequently, which is thought to be observed in cases with ALL and lymphoma with higher tendency for >5 years after treatment. Persistent EBV DNAemia is frequent in CCSs aged 5–10 years. Any immunological alteration is speculative in a pathophysiology of persistent EBV DNAemia.     

Outcome and toxicity of chemotherapy for acute lymphoblastic leukemia in children with Down syndrome

Background

Acute lymphoblastic leukemia (ALL) in children with Down syndrome (DS) presents with an increased incidence, higher frequency of adverse effects and inferior probability of survival. Attempts at improving outcomes face the dilemma posed by the need to avoid excessive toxicity while maintaining the efficacy of treatment. Dose reductions and avoidance of infusions of intermediate and high‐dose methotrexate are common in this group.

Procedure

In a matched pair analysis we compared adverse effects and survival after ALL chemotherapy using intermediate and high doses of methotrexate in children with and without Down syndrome.

Results

Following intermediate and high doses of methotrexate to treat primary ALL, children with DS did not require opiate analgesia and parenteral nutrition for severe mucositis more often than children without DS. Children with DS spent more days in hospital and missed more doses of maintenance chemotherapy. Chemotherapy dose reductions were common and in this study had no detectable adverse impact. Event‐free and overall survival (OS) of children with ALL was lower in the DS than the non‐Down syndrome (NDS) control group. The difference, however, was no longer significant during the recent treatment era.

Conclusions

The feasibility of all treatment elements that are efficacious in pediatric ALL needs to be carefully considered in children with DS. In addition to survival data, the prospective collection of data on both adverse events and treatment modifications is essential to strike a balance between the avoidance of adverse effects and the need for intensive therapy that will safely improve ALL outcomes in this group. Pediatr Blood Cancer 2009;52:14–19. © 2008 Wiley‐Liss, Inc.     

Pretransplant functional imaging and outcome in pediatric patients with relapsed/refractory Hodgkin lymphoma undergoing autologous transplantation

1 Background

Pretransplant functional imaging (FI), particularly a negative positron emission tomography (PET), is a strong predictor of outcome in adults with relapsed or refractory Hodgkin lymphoma (HL), but data in pediatrics are limited.

2 Methods

The medical records of 49 consecutive pediatric patients, who received autologous transplant at a single institution, were retrospectively analyzed. All patients had either gallium or PET scan before transplant and were conditioned with carmustine, etoposide, cytarabine, and melphalan (BEAM). Deauville scores were retrospectively assigned for patients with PET (score ≥ 4 positive).

3 Results

Of the 49 patients (median age, 16.2 years), 41 (84%) were pretransplant FI negative and eight (16%) were pretransplant FI positive, after first‐ to fourth‐line salvage therapy, and a median of two salvage cycles. Eighteen patients (37%) received posttransplant radiation. At a median follow up of 46 months, 45 patients (92%) were alive and disease free, and there were three nonrelapse deaths and only one relapse death (Deauville score of 5). The 4‐year progression‐free survival (PFS) for the entire cohort was 92% (95% confidence interval [CI]: 78–97), and PFS based on pretransplant disease status was 95% (95% CI: 82–99%) in the negative FI group versus 75% (95% CI: 31–93) if positive FI (P = 0.057).

4 Conclusion

Our analysis revealed outstanding outcomes for children and adolescents with relapsed/refractory HL. There were too few relapses to identify the predictive value of pretransplant metabolic status, but pediatric patients with relapsed/refractory HL and a negative pretransplant FI had excellent survival.     

Bone marrow minimal disseminated disease (MDD) and minimal residual disease (MRD) in childhood T‐cell lymphoblastic lymphoma stage III,detected by flow cytometry (FC) and real‐time quantitative polymerase chain reaction (RQ‐PCR)

Background

Despite overlapping features of T‐cell lymphoblastic lymphoma (T‐LLy) and T‐cell acute lymphoblastic leukemia (T‐ALL), which respond favorably to T‐ALL treatment, clinical and biological differences exist. We retrospectively assessed the prevalence of submicroscopic bone marrow (BM) minimal disseminated disease (MDD) at diagnosis and the early response to treatment (minimal residual disease—MRD) and their prognostic significance in 17 children with stage III T‐LLy treated according to Berlin‐Frankfurt‐Munster (BFM) non‐Hodgkin lymphoma protocols.

Procedure

Four‐color flow cytometry (FC) was used for lymphoma associated immunophenotype and real‐time quantitative polymerase chain reaction (RQ‐PCR) for T‐cell receptor (TCR β/δ/γ) gene rearrangements with at least 0.01% sensitivity.

Results

Two markers per patient were identified in all cases using FC and in 80% using RQ‐PCR. BM MDD at diagnosis of ≥0.01% was detected by FC and RQ‐PCR in 88% and 80% of patients, respectively, and by at least one of the methods in all patients. A significant correlation was achieved between the methods by Pearson correlation analysis (P = 0.004). MRD levels significantly decreased to very low levels on day 33 in 9 out of 10 patients studied. The only patient that remained positive relapsed.

Conclusions

MDD was prevalent in stage III T‐LLy, for which we could not prove a prognostic significance in the context of ALL‐like treatment. This study shows that both FC and RQ‐PCR methods are efficient for MDD and MRD analyses in T‐LLy. Pediatr Blood Cancer 2009;52:20–25. © 2008 Wiley‐Liss, Inc.     

Development of acute lymphoblastic leukemia following treatment for acute myeloid leukemia in children with Down syndrome: A case report and retrospective review of Children's Oncology Group acute myeloid leukemia trials

Children with Down syndrome have a 150‐fold increased risk of developing acute myeloid leukemia (AML) and 20‐fold increased risk of developing acute lymphoblastic leukemia (ALL). Although the risk of developing AML and ALL is significantly increased in children with Down syndrome, the development of both malignancies in the same patient is very rare. We describe a patient with Down syndrome who developed ALL 6 years after being diagnosed with AML. We performed a literature review and Children's Oncology Group query and discovered eight published cases and five cases of ALL following AML in pediatric patients with Down syndrome, as well as six cases of ALL following AML in non‐Down syndrome patients. There was a similar cumulative incidence of ALL after treatment for AML in the Down syndrome and non‐Down syndrome populations. Overall survival in patients with Down syndrome who developed ALL after treatment for AML was comparable to overall survival for patients with Down syndrome with de novo ALL with an average follow‐up of 7 years after ALL diagnosis. Clinical data collected were used to discuss whether this phenomenon represents a secondary leukemia, second primary cancer, or mixed‐lineage leukemia.     

A strategy to improve treatment‐related mortality and abandonment of therapy for childhood ALL in a developing country reveals the impact of treatment delays

Background

Treatment‐related mortality and abandonment of therapy are major barriers to successful treatment of childhood acute lymphoblastic leukemia (ALL) in the developing world.

Procedure

A collaboration was undertaken between Instituto Nacional de Cancerologia (Bogota, Colombia), which serves a poor patient population in an upper‐middle income country, and Dana‐Farber/Boston Children's Cancer and Blood Disorders Center (Boston, USA). Several interventions aimed at reducing toxic deaths and abandonment were implemented, including a reduced‐intensity treatment regimen and a psychosocial effort targeting abandonment. We performed a cohort study to assess impact.

Results

The Study Population comprised 99 children with ALL diagnosed between 2007 and 2010, and the Historic Cohort comprised 181 children treated prior to the study interventions (1995–2004). Significant improvements were achieved in the rate of deaths in complete remission (13% to 3%; P = 0.005), abandonment (32% to 9%; P < 0.001), and event‐free survival with abandonment considered an event (47% to 65% at 2 years; P = 0.016). However, relapse rate did not improve. Medically unnecessary treatment delays were common, and landmark analysis revealed that initiating the PIII phase of therapy ≥4 weeks delayed predicted markedly inferior disease‐free survival (P = 0.016). Conversely, patients who received therapy without excessive delays had outcomes approaching those achieved in high‐income countries.

Conclusions

Implementation of a twinning program was followed by reductions in abandonment and toxic deaths, but relapse rate did not improve. Inappropriate treatment delays were common and strongly predicted treatment failure. These findings highlight the importance of adherence to treatment schedule for effective therapy of ALL. Pediatr Blood Cancer 2015;62:1395–1402. © 2015 Wiley Periodicals, Inc.