Summary
As treatments for second relapsed and refractory first relapsed paediatric AML transition from purely palliative to more commonly curative in nature, comparative data is necessary for ...evaluating the effectiveness of emerging treatment options. Furthermore, little is known about predictors of prognosis following third‐line therapy. From 2004 until 2019, 277 of the 869 patients enrolled in NOPHO‐DB SHIP consortium trials experienced a first relapse and, of these patients, 98 experienced refractory first relapse and 59 a second relapse. Data on patient and disease characteristics within this cohort of 157 patients was analysed to determine probability of overall survival (pOS) and to identify factors influencing survival. Data on early treatment response and complete remission were not available. One and 5‐year pOS were 22 ± 3% and 14 ± 3%, respectively. There was no statistically significant difference in survival between refractory first relapsed and second relapsed AML. Factors influencing prognosis included: late relapse, type of third‐line treatment, FLT3 mutational status, and original treatment protocol. These data provide a baseline for evaluating the effectiveness of emerging therapies for the treatment of children with refractory first relapsed and second relapsed paediatric AML and evidence that select patients receiving third‐line therapy can be cured.
In pediatric relapsed acute myeloid leukemia (AML), optimal reinduction therapy is unknown. Studies suggest that liposomal daunorubicin (DNX; DaunoXome; Galen, Craigavon, United Kingdom) is effective ...and less cardiotoxic, which is important in this setting. These considerations led to a randomized phase III study by the International Berlin-Frankfurt-Münster Study Group.
Patients with relapsed or primary refractory non-French-American-British type M3 AML who were younger than 21 years of age were eligible. Patients were randomly assigned to fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) or to FLAG plus DNX in the first reinduction course. The primary end point was status of the bone marrow (BM) sampled shortly before the second course of chemotherapy (the day 28 BM). Data are presented according to intention-to-treat for all 394 randomly assigned patients (median follow-up, 4.0 years).
The complete remission (CR) rate was 64%, and the 4-year probability of survival (pOS) was 38% (SE, 3%). The day 28 BM status (available in 359 patients) was good (≤ 20% leukemic blasts) in 80% of patients randomly assigned to FLAG/DNX and 70% for patients randomly assigned to FLAG (P = .04). Concerning secondary end points, the CR rate was 69% with FLAG/DNX and 59% with FLAG (P = .07), but overall survival was similar. However, core-binding factor (CBF) AML treated with FLAG/DNX resulted in pOS of 82% versus 58% with FLAG (P = .04). Grade 3 to 4 toxicity was essentially similar in both groups.
DNX added to FLAG improves early treatment response in pediatric relapsed AML. Overall long-term survival was similar, but CBF-AML showed an improved survival with FLAG/DNX. International collaboration proved feasible and resulted in the best outcome for pediatric relapsed AML reported thus far.
Background
In addition to treatment response, cytogenetic and molecular aberrations are the most important prognostic factors in children with de novo acute myeloid leukemia (AML). However, little is ...known about cytogenetics at the time of relapse.
Methods
This international study analyzed the prognostic value of cytogenetic profiles and karyotypic changes in pediatric relapsed AML in relation to the probability of event‐free (pEFS) and overall survival (pOS). For this purpose, cytogenetic reports from all patients registered on the Relapsed AML 2001/01 Study were reviewed and classified.
Results
Cytogenetic information at relapse was available for 403 (71%) of 569 registered patients. Frequently detected aberrations at relapse were t(8;21)(q22;q22) (n = 60) and inv(16)(p13.1q22)/t(16;16)(p13.1;q22) (n = 24), both associated with relatively good outcome (4‐year pOS 59% and 71%, respectively). Monosomy 7/7q−, t(9;11)(p22;q23), t(10;11)(p12;q23), and complex karyotypes were associated with poor outcomes (4‐year pOS 17%, 19%, 22%, and 22%, respectively). Of 261 (65%) patients for whom cytogenetic data were reliable at both diagnosis and relapse, pEFS was inferior for patients with karyotypic instability (n = 128, 49%), but pOS was similar. Unstable karyotypes with both gain and loss of aberrations were associated with inferior outcome. Early treatment response, time to relapse, and cytogenetic profile at time of relapse were the most important prognostic factors, both outweighing karytoypic instability per se.
Conclusion
The cytogenetic subgroup at relapse is an independent risk factor for (event‐free) survival. Cytogenetic assessment at the time of relapse is of high importance and may contribute to improved risk‐adapted treatment for children with relapsed AML.
The t(7;12)(q36;p13) (MNX1/ETV6) is not included in the WHO classification but has been described in up to 30% of acute myeloid leukemia (AML) in children <2 years and associated with a poor ...prognosis. We present the clinical and cytogenetics characteristics of AML cases with t(7;12)(p36;p13). A literature review identified 35 patients with this translocation, published between 2000 and 2015. Outcome data were available in 22 cases. The NOPHO‐AML (Nordic Society for Pediatric Hematology and Oncology) database contained 651 patients with AML from 1993 to 2014 and seven (1.1%) had the translocation. The t(7;12) was only present in patients <2 years of age (median age 6 months) but none was diagnosed as newborn. These patients constituted 4.3% of the patients <2 years of age. There was a strong association with trisomy 19 (literature: 86%, NOPHO: 100%) and +8 (literature: 19%, NOPHO: 14%). Seventeen of 22 patients from the literature with t(7;12) and four of seven patients from the NOPHO database suffered from relapse. The patients with t(7;12) had a 3‐year event free survival of 24% (literature) vs. 43% (NOPHO) and a 3‐year overall survival of 42% (literature) vs. 100% (NOPHO). None of the NOPHO patients was treated with hematopoietic stem cell transplantation (HSCT) in first complete remission. Relapse was frequent but the salvage rate using HSCT was high. We conclude that t(7;12)(q36;13) is a unique subgroup of childhood AML with presentation before 2 years of age with most cases being associated with +19.
Background
The prognostic significance of extramedullary leukemia (EML) in childhood acute myeloid leukemia is not clarified.
Procedure
This population‐based study included 315 children from the ...NOPHO‐AML 2004 trial.
Results
At diagnosis, 73 (23%) patients had EML: 39 (12%) had myeloid sarcoma, 22 (7%) had central nervous system disease, and 12 (4%) had both. EML was associated with young age (median age: 2.6 years), a high white blood cell count (median: 40 × 109/l), M5 morphology (40%), and 11q23/MLL (KMT2A) rearrangements (34%). No patient received involved field radiotherapy. Five‐year event‐free survival did not differ significantly between the EML and the non‐EML patients (54% vs. 45%, P = 0.57), whereas 5‐year overall survival (OS) was significantly lower in the EML group (64% vs. 73%, P = 0.04). The risk of induction death was significantly higher for EML patients (8% vs. 1%, P = 0.002). There was a trend toward a lower risk of relapse for EML patients (5‐year cumulative incidence of relapse 33% vs. 49%, P = 0.16). Traumatic lumbar puncture did not adversely affect survival in this cohort.
Conclusions
EML was associated with increased risk of induction death impacting the OS. No patients relapsed at the primary site of the myeloid sarcoma despite management without radiotherapy.
Allogeneic hematopoietic stem cell transplantation is curative for transfusion‐dependent thalassemia, but mixed chimerism (MC) may herald graft rejection. We report a child who failed bone marrow ...transplant (BMT) from matched unrelated donor (MUD) successfully salvaged with haploidentical peripheral blood stem cell transplant (PBSCT), but had MC in T‐lymphocyte compartment despite near‐complete donor chimerism in myeloid compartment. MC was successfully improved by repeated CD45RA‐depleted donor lymphocyte infusion (DLI). A 2‐year‐old Chinese girl with beta‐thalassemia major underwent 12/12‐MUD BMT with HU/AZA/Cy/Flu/Bu/TT conditioning resulted in graft rejection. As donor refused second donation, rescue haploidentical PBSCT was performed with alemtuzumab/fludarabine/treosulfan conditioning. Harvest product was CD3/CD45RA depleted with extra products cryopreserved. Split cell chimerism performed 1‐month after haplo‐transplant showed 97% mother, 3% MUD, and 0% host for granulocytes but 38% mother, 62% MUD, and 0% host for CD3 + T cells. In view of low haploidentical donor chimerism in T‐lymphocyte compartment, CD45RA‐depleted DLI using cryopreserved product was performed on day + 38, after thymoglobulin 3 mg/kg given as T‐cell depletion 3 days beforehand. T‐cell chimerism improved to 51% mother and 49% MUD post‐DLI. Second cryopreserved CD45RA‐depleted DLI was given 17 days after the first DLI (day + 55), and 100% full chimerism of mother's T cells was gradually established without significant graft‐versus‐host disease (GVHD) or viral reactivation. To conclude, split lineage chimerism determination is beneficial to guide management strategy. For MC in T‐cell compartment, CD45RA‐depleted DLI is a potential alternative to unselected T cells as it carries lower risk of GVHD and infection.
Objective
The aim of this study was to review clinical outcomes and prognosis of paediatric patients with acute lymphoblastic leukaemia (ALL) with TCF3‐PBX1 rearrangement.
Patients
All children in ...Hong Kong diagnosed with ALL with TCF3‐PBX1 rearrangement over the past two decades were included.
Methods
Six hundred and twenty‐four newly diagnosed patients with ALL from four consecutive studies were enrolled from 1997 to 2016. Patients carrying TCF3‐PBX1 rearrangement and patients at intermediate risk without the gene expression were compared for clinical characteristics, overall survival and event‐free survival (EFS).
Results
The TCF3‐PBX1 rearrangement was detected in 30 of 624 patients (4.8%). Results were consistent across the consecutive clinical trials employed in the past two decades. Compared with 239 intermediate risk patients without TCF3‐PBX1 rearrangement, the 5‐year overall survival and EFS for patients with TCF3‐PBX1 rearrangement was superior, with both at 100% (P = 0.12 and P = 0.029).
Conclusion
This population‐based study over the past 20 years demonstrated that patients with TCF3‐PBX1 rearrangement had favourable EFS compared with other intermediate risk patients treated with a similar chemotherapy backbone.
Background
Supportive‐care use of granulocyte colony‐stimulating factor (G‐CSF) in pediatric acute myeloid leukemia (AML) remains controversial due to a theoretical increased risk of relapse and ...limited impact on neutropenic complications. We describe the use of G‐CSF in patients treated according to NOPHO‐AML 2004 and DB AML‐01 and investigated associations with relapse.
Procedure
Patients diagnosed with de novo AML completing the first week of therapy and not treated with hematopoietic stem cell transplantation in the first complete remission were included (n = 367). Information on G‐CSF treatment after each course (yes/no) was registered prospectively in the study database and detailed information was gathered retrospectively from each center. Descriptive statistics were used to describe G‐CSF use and Cox regression to assess the association between G‐CSF and risk of relapse.
Results
G‐CSF as supportive care was given to 128 (35%) patients after 268 (39%) courses, with a large variation between centers (0‐93%). The use decreased with time—the country‐adjusted odds ratio was 0.8/diagnostic year (95% confidence interval CI 0.7‐0.9). The median daily dose was 5 μg/kg (range 3‐12 μg/kg) and the median cumulative dose was 75 μg/kg (range 7‐1460 μg/kg). Filgrastim was used in 82% of G‐CSF administrations and infection was the indication in 44% of G‐CSF administrations. G‐CSF was associated with increased risk of relapse—the adjusted hazard ratio was 1.5 (95% CI 1.1‐2.2).
Conclusions
G‐CSF as supportive care was used in a third of patients, and use decreased with time. Our results indicate that the use of G‐CSF may be associated with an increased risk of relapse.
Background
Children with acute myeloid leukemia (AML) treated similarly show different toxicity and leukemic responses. We investigated associations between neutrophil recovery time after the first ...induction course, infection and relapse in children treated according to NOPHO‐AML 2004 and DB AML‐01.
Procedure
Newly diagnosed patients with AML with bone marrow blast <5% between day 15 after the start of the treatment and the start of second induction course, and in complete remission after the second induction course were included (n = 279). Neutrophil recovery time was defined as the time from the start of the course to the last day with absolute neutrophil count <0.5 × 109/l. Linear and Cox regressions were used to investigate associations.
Results
Neutrophil recovery time after the first induction course was positively associated with neutrophil recovery time after the remaining courses, and longer neutrophil recovery time (≥25 days) was associated with increased risk of grade 3–4 infections (hazard ratio 1.4, 95% confidence interval CI, 1.1–1.8). Longer neutrophil recovery time after the first induction (>30 days) was associated with the increased risk of relapse (5‐year cumulative incidence: 48% vs. 42%, hazard ratio 1.7, 95% CI, 1.1–2.6) for cases not treated with hematopoietic stem cell transplantation in first complete remission.
Conclusion
Longer neutrophil recovery time after the first induction course was associated with grade 3–4 infections and relapse. If confirmed, this knowledge could be incorporated into risk stratification strategies in pediatric AML.
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