Double allogeneic peripheral blood stem cell transplantation in a 9-year-old patient with relapsed acute lymphoblastic leukemia: case report

A 9-year-old female patient with relapsed leukemia that was refractory to conventional reinduction chemotherapy was successfully treated with double allogeneic peripheral blood stem cell transplantation. The conditioning regimen for the first transplantation consisted of busulfan, etoposide, and melphalan, and that for the second transplantation was total body irradiation and thiotepa. Neither severe regimen-related toxicity nor graft-versus-host disease was observed. The patient is in complete remission without major complications for 5 years. Double transplantation should be considered as one of the possible treatments for refractory acute lymphoblastic leukemia.     

Childhood relapsed acute lymphoblastic leukemia: Biology and recent treatment progress

Acute lymphoblastic leukemia (ALL) is the most frequent cancer in children. Despite remarkable improvement in the prognosis of childhood ALL over the past few decades, the treatment of relapsed ALL is still challenging. The prognosis of first ALL relapse is associated with time of relapse after initial therapy, sites of relapse, and immunophenotype. More recently, response to treatment, which is evaluated by assessment of minimal residual disease (MRD), has been found to be clinically significant in relapsed ALL as well as in the initially diagnosed disease. Utilizing these factors, risk‐oriented treatment stratification for first ALL relapse has been established. In the standard‐risk group for first ALL relapse, intensification of conventional ALL‐type therapy can provide a cure in approximately 70% of patients. It is important to assess MRD after reinduction therapy to determine the indications for stem cell transplantation in the standard‐risk group. In contrast, no standardized therapy has been established for the high‐risk group, which accounts for more than half of relapsed ALL patients. Recent studies have shed light on the clonal origin of relapsed ALL, which usually exists as a minor subclone at the time of initial diagnosis. Clonal selection and evolution take place during chemotherapy, resulting in distinct genetic and epigenetic characteristics of relapsed ALL, some of which are linked to drug resistance, a common and problematic feature of ALL after relapse. To overcome resistance to standard ALL‐type therapy, and considering the heterogeneous biological background of high‐risk relapsed ALL, innovative therapies using new agents are necessary.     

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.     

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.     

Isolated breast relapse after allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia

Unusual sites of relapses following bone marrow transplantation (BMT) for childhood acute lymphoblastic leukemia (ALL) are rarely reported. We report the case of a 16-year-old girl who presented with an isolated right breast relapse 8 months after allogeneic BMT for ALL in second remission. Biopsy showed an ALL infiltrate. Bone marrow and CSF were normal. The girl never showed before extramedullary involvement. She was treated with local radiotherapy and mild systemic chemotherapy. Nine months after breast relapse, she presented an isolated central nervous system relapse. The treatment of isolated extramedullary relapses following BMT is still controversial.     

Phase II study of gemcitabine in children with relapsed acute lymphoblastic leukemia or acute myelogenous leukemia (ADVL0022): a Children's Oncology Group Report

BACKGROUND: To determine the response rate and toxicity to gemcitabine administered as 10 mg/m2/min x 360 min weekly for 3 weeks in children with relapsed acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). Gemcitabine is a deoxycytidine analog that inhibits DNA synthesis and repair and has a broad spectrum of antitumor activity. PROCEDURE: From April 2001 to April 2003, 23 male and 9 female eligible patients were recruited for the Children's Oncology Group (COG) phase II study of Gemcitabine (ADVL0022). RESULTS: One of 20 evaluable patients with ALL and none of 10 evaluable patients with AML had complete responses to gemcitabine; there were no partial responses. Grade 3 or 4 hematologic toxicity and liver toxicity were common during therapy. Only one patient was alive 1 year after entry. The estimated 1-year overall survival probability for the 32 patients was 4% (SE = 3%). CONCLUSIONS: Gemcitabine at the dose and schedule in this trial was not effective for children with relapsed AML or ALL.     

T‐cell‐rich HLA‐haploidentical hematopoietic stem cell transplantation for relapsed/refractory pediatric Philadelphia chromosome‐positive acute lymphoblastic leukemia without posttransplant tyrosine kinase inhibitor therapy

Intensive chemotherapy with tyrosine kinase inhibitor (TKI) improves the prognosis of patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph‐ALL). However, the prognosis of cases of relapsed or refractory Ph‐ALL remains poor. Here, we aimed to assess the efficacy of T‐cell‐rich HLA‐haploidentical hematopoietic stem cell transplantation (TCR‐haplo‐HSCT) in eight patients with relapsed or refractory pediatric Ph‐ALL. Transplant‐related mortality was observed in two patients. All patients discontinued TKI after receiving TCR‐haplo‐HSCT. The 3‐year probability of overall survival and event‐free survival was 75.0 and 62.5%, respectively. These results indicate the efficacy of TCR‐haplo‐HSCT for relapsed/refractory pediatric Ph‐ALL.     

Intravenous 6-mercaptopurine decreases salvage after relapse in childhood acute lymphoblastic leukemia: a report from the Children's Cancer Group study CCG 1922

PURPOSE: To compare outcomes of patients with NCI standard risk acute lymphoblastic leukemia (ALL) who relapsed after being randomized to receive either oral or intravenous 6-mercaptopurine (6MP) in the Children's Cancer Group study CCG 1922. PATIENTS AND METHODS: CCG 1922 accrued patients from March 1993 to August 1995. A total of 1,060 patients were randomly assigned to four treatment groups: oral 6MP plus prednisone (OP), intravenous 6MP plus prednisone (IP), oral 6MP plus dexamethasone (OD), and intravenous 6MP plus dexamethasone (ID). During the 2nd through 4th month of therapy groups OP and OD were treated with 75 mg/m(2)/day of oral 6MP for 70 days and groups IP and ID with 1,000 mg/m(2)/week of intravenous 6MP over 10 hr for 11 doses. All patients received a single delayed intensification and all received oral 6MP in maintenance. RESULTS: Patients randomized to oral 6MP had significantly better 5-year overall survival (96 +/- 1% vs. 92 +/- 1%; P = 0.008). There was, however, no statistically significant difference in the event-free survival (EFS). Of the 179 patients who relapsed, 84 had a second or later event and 68 have died. Forty of the 84 second events were a death. Survival after relapse was significantly greater for patients randomized to oral 6MP during consolidation than those receiving intravenous 6MP (P = 0.002, log rank test) with 4-year survival post-relapse of 67 +/- 6% vs. 48 +/- 6%. The steroid randomization had no influence on outcome. Post-relapse therapy details are not available and if different between groups may have influenced the outcome. CONCLUSION: Treatment with intravenous 6MP during a brief period of total therapy had a significant negative impact on the prognosis in childhood ALL even though oral 6MP was used during maintenance.     

Intrahepatic cholangiocarcinoma as a rare secondary malignancy after allogeneic hematopoietic stem cell transplantation for childhood acute lymphoblastic leukemia: A case report

Secondary malignancies are a significant cause of non‐relapse mortality in patients who undergo allogeneic HCT. However, secondary liver cancer is rare, and ICC following HCT has never been reported in the literature. Secondary solid cancers typically have a long latency period, and cholangiocarcinoma is classically a malignancy occurring in older individuals. Here, we report the first case of secondary ICC, which presented just 3 years after HCT in a young adult with a history of childhood ALL. A 26‐year‐old male with history of precursor B‐cell ALL presented with asymptomatic elevated liver function tests 3 years after HCT. Laboratories were indicative of biliary obstruction. ERCP showed focal biliary stricturing of the common and left hepatic ducts. MRCP revealed left intrahepatic duct dilatation, suggestive of intrahepatic obstructing mass. Additional workup lead to a clinical diagnosis of ICC. The patient underwent left hepatectomy with extrahepatic bile duct resection and portal lymphadenectomy. Surgical pathology was consistent with moderately differentiated cholangiocarcinoma. Our case illustrates a rare SMN following HCT for ALL. It is the first case report of ICC occurring as a secondary cancer in this patient population. Although cholangiocarcinoma is characteristically diagnosed in the older population, it must remain on the differential for biliary obstruction in post‐HCT patients.     

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.     

Comparison of idarubicin to daunomycin in a randomized multidrug treatment of childhood acute lymphoblastic leukemia at first bone marrow relapse: A report from the Children's Cancer Group

The outcome of children with acute lymphoblastic leukemia (ALL) and bone marrow relapse has been unsatisfactory largely because of failure to present subsequent leukemia relapses. Ninety-six patients were enrolled and received vincristine, prednisone, L-asparaginase, and an anthracycline as reinduction therapy. Ninety-two patients were randomized to receive either daunomycin (DNR) or idarubicin (IDR). After achievement of second complete remission (CR2), maintenance chemotherapy included the same anthracycline, IDR or DNR, high-dose cytarabine, and escalating-dose methotrexate. Compared to DNR (45 mg/m²/week × 3), IDR (12.5 mg/m²/week × 3) was associated with prolonged myelosuppression and more frequent serious infections. Halfway through the study, the dose of IDR was reduced to 10 mg/m². Overall, second remission was achieved in 71% of patients. Reinduction rate was similar for IDR and DNR. Reasons for induction failure differed; none of 15, 1 of 5, and 5 of 7 reinduction failures were due to infection for DNR, IDR (10 mg/m²), and IDR (12.5 mg/m²), respectively. Two-year event-free survival (EFS) was better among patients who received IDR (12.5 mg/m²) (27 ± 18%) compared to DNR (10 ± 8%, P = 0.05) and IDR (10 mg/m²) (6 ± 12%, P = 0.02). However, after 3 years of follow-up, late events in the high-dose IDR group result in a similar EFS to the lower-dose IDR and DNR groups. In conclusion, IDR is an effective agent in childhood ALL. When used weekly at 12.5 mg/m² during induction, the EFS outcome during the first 2 years of treatment appears better than lower-dose IDR or DNR (45 mg/m²), although this difference was not sustained at longer periods of follow-up. Increased hematopoietic toxicity seen at this dose might be reduced through the use of supportive measures, such as hematopoietins and intestinal decontamination. © 1996 Wiley-Liss, Inc.     

Standard and intermediate risk acute lymphoblastic leukemia in Poland: A report of the Polish Children's Leukemia/Lymphoma Study Group

A total of 527 children with acute lymphoblastic leukaemia (ALL) from the most frequent risk groups: standard risk group (SRG) and intermediate risk group (IRG) were treated between 1987 and 1991 according to an intensified treatment program (based on the BFM protocol) including the use of an intermediate dose of methotrexate in the IRG. A comparison of the treatment results in this group from 513 children treated between 1981 and 1987 indicates that the chance for a 6 year event-free survival has increased to 73% (previously 55%).