To determine whether early intensification with 12 courses of intravenous methotrexate and intravenous mercaptopurine (IVMTX/IVMP) is superior to 12 courses of repetitive, low-dose oral MTX with I.V. MP (LDMTX/IVMP) for prevention of relapse in children with lower-risk B-lineage acute lymphoblastic leukemia (ALL).Seven hundred nine patients were entered onto the study. Vincristine, prednisone, and asparaginase were used for remission induction. Patients were randomized to receive intensification with either IVMTX 1,000 mg/m2 plus IVMP 1,000 mg/m2 (regimen A) or LDMTX 30 mg/m2 every 6 hours for six doses with IVMP 1,000 mg/m2 (regimen B). Twelve courses were administered at 2-week intervals. Triple intrathecal therapy (TIT) was used for CNS prophylaxis. Continuation therapy included standard oral MP, weekly MTX, and TIT every 12 weeks for 2 years.Six hundred ninety-nine (99%) patients achieved remission. Three hundred forty-nine were assigned to regimen A and 350 to regimen B. The estimated 4-year continuous complete remission (CCR) rate for patients treated with regimen A is 80.3% (SE = 2.9%) and with regimen B is 75.9% (SE = 3.1%). By log-rank analysis, regimen A demonstrated superior CCR (P = .013). Transient neutropenia/thrombocytopenia, bacterial sepsis, neurotoxicity, stomatitis, and hospitalizations were more frequent among patients treated on regimen A.Intensification with IVMTX/IVMP is more effective than LDMTX/IVMP for prevention of relapse in children with B-precursor ALL at lower risk for relapse.
Abstract Three groups of children with acute lymphoblastic leukemia (ALL) were treated with intermittent cyclophosphamide, vincristine, cytosine arabinoside, and prednisone (COAP). Group A (no prior relapse) and Group B (prior single‐agent relapse) received COAP after 12 months on another chemotherapy regimen. Children in Group C (prior relapse on multiagent regimens) received COAP following A‐COAP (asparaginase plus COAP) reinduction. Median disease‐free survival after beginning COAP was not reached for Group A, but was only 7 months for Groups B and C. As of November 1976, there were 8 of 15 Group A patients, 1 of 12 Group B patients, and 1 of 28 Group C patients who had remained disease‐free from 38 to 60 (median 54.5) months and were off chemotherapy. COAP has activity in childhood ALL. However, effectiveness in markedly diminished in patients with prior bone marrow relapse.
Recent genome-wide screens have identified genetic variations in ARID5B associated with susceptibility to childhood acute lymphoblastic leukemia (ALL). We sought to determine the contribution of ARID5B single nucleotide polymorphisms (SNPs) to racial disparities in ALL susceptibility and treatment outcome.We compared the association between ARID5B SNP genotype and ALL susceptibility in whites (> 95% European genetic ancestry; 978 cases and 1,046 controls) versus in Hispanics (> 10% Native American ancestry; 330 cases and 541 controls). We determined the relationships between ARID5B SNP genotype and ALL relapse risk in 1,605 children treated on the Children's Oncology Group (COG) P9904/9905 clinical trials.Among 49 ARID5B SNPs interrogated, 10 were significantly associated with ALL susceptibility in both whites and Hispanics (P < .05), with risk alleles consistently more frequent in Hispanics than in whites. rs10821936 exhibited the most significant association in both races (P = 8.4 × 10(-20) in whites; P = 1 × 10(-6) in Hispanics), and genotype at this SNP was highly correlated with local Native American genetic ancestry (P = 1.8 × 10(-8)). Multivariate analyses in Hispanics identified an additional SNP associated with ALL susceptibility independent of rs10821936. Eight ARID5B SNPs were associated with both ALL susceptibility and relapse hazard; the alleles related to higher ALL incidence were always linked to poorer treatment outcome and were more frequent in Hispanics.ARID5B polymorphisms are important determinants of childhood ALL susceptibility and treatment outcome, and they contribute to racial disparities in this disease.
The CBC is more than a collection of numbers. Understanding its strengths and limitations provides more useful information. When used in conjunction with careful review of the peripheral smear and a limited number of other tests, the CBC can be a more effective diagnostic tool. Badanie morfologiczne krwi nie stanowi jedynie zbioru liczb. Poznanie jego zalet i ograniczeń umożliwia zdobycie wielu przydatnych informacji. Badanie wykonane wraz z dokładnym rozmazem krwi obwodowej oraz kilku innymi testami może być bardzo przydatnym narzędziem diagnostycznym.
Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ALL) occurs in 2–5% of paediatric ALL and is historically associated with a poor prognosis. Although 80–90% of children achieve remission, their event-free-survival (EFS) with conventional chemotherapy prior to tyrosine kinase inhibitors (TKI) was poor, with a 7-year EFS rate of 32% (Arico et al, 2010). The addition of imatinib as monotherapy appeared promising in initial treatment of adults with Ph+ALL, despite a high rate of relapse (Druker et al, 2001). Many relapsed adults on imatinib monotherapy were found to have a resistant mutation within the kinase domain of BCR-ABL1 (Jones et al, 2008). Other studies have shown that TKI's, such as imatinib or dasatinib, as monotherapy can select for TKI resistant clones, which may then be overcome by the addition of cytotoxic chemotherapy in the mouse model (Boulos et al, 2011). The Children's Oncology Group (COG) clinical trial, AALL0031, used imatinib (340 mg/m2/d) in conjunction with intensive chemotherapy to treat children and adolescents with Ph+ALL (Schultz et al, 2009). This dosage is equivalent to approximately 600 mg/d in adults and was well tolerated with minimal additional side effects as compared to the identical chemotherapy arm without imatinib. AALL0031 differed from adult protocols in several aspects: use of drug combinations not common in adult protocols, intensive dosing of imatinib that was given continuously for the majority of 2.5 years and no continuation of TKI after completion of therapy. Three-year EFS on this treatment was 84% (more than double those of patients treated in the pre-imatinib era). Thus far, it remains unknown whether patients that relapse following this treatment approach have recurred due to development of imatinib resistance. A 2-year-old male with Ph+ALL and initial white blood cell count of 117 × 109/l was initially treated with a standard four-drug induction of vincristine, asparginase, doxorubicin, and prednisone. At presentation he showed no evidence of extramedullary disease. He achieved complete morphological and cytogenetic remission at the end of induction. He then received post-induction therapy according to COG AALL0031 cohort 5 (not on study). His therapy included the intensive systemic regimen with central nervous system (CNS)-directed therapy without cranial radiation. Twenty-four months into treatment he presented with headaches and mental status changes caused by a CNS relapse. BCR-ABL1 sequence analysis of his cerebrospinal fluid (CSF) blasts identified a guanine substitution for adenine, producing the missense mutation methionine 244 to valine (M244V) (Fig 1A). Concomitant bone marrow aspiration showed no leukaemia by morphology, flow cytometry or by fluorescent in situ hybridization. However, sequence analysis of the marrow sample identified the same mutation found in his CSF. BCR-ABL1 sequencing of the bone marrow specimen from initial diagnosis identified no mutation (Fig 1A). A biological correlate study to AALL0031 was developed to determine whether or not BCR-ABL1 kinase domain mutations were present in medullary relapse samples from Ph+ALL patients. COG AALL0031 enrolled 93 patients with Ph+ALL aged 1–21 years from 2002 to 2006 (Schultz et al, 2009). From this study, nine relapsed bone marrow samples were available for sequence analysis (Table 1). Eight of the nine samples from imatinib-treated patients showed no BCR-ABL1 kinase domain mutation (Table 1). One sample, from a patient who relapsed 15 months after diagnosis, carried the histidine 396 to proline (H396P) mutation (Fig 1B). A bone marrow sample from initial diagnosis of this child identified no mutation (Fig 1B). These results further validate that BCR-ABL1 kinase domain mutations can occur after treatment of Ph+ALL with imatinib and intensive multiple chemotherapeutic agents. From these 10 samples we identified two resistant mutations from patients who received imatinib and combination chemotherapy for more than 1 year. This mutation rate appears to be less than previously published in adults treated with imatinib monotherapy (Jones et al, 2008) (15 of 17 relapsed patients) or with hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine) combination therapy (Ravandi et al, 2010) where mutations were observed in three of five relapsed patients. Neither mutation was detected in samples obtained at diagnosis suggesting that the vast majority of the leukaemic cells did not have the mutation. This does not preclude the concept of a low level of mutations at diagnosis, as previously shown (Pfeifer et al, 2007). M244V and H396 mutations have been shown to be more resistant to imatinib but both have been shown to be sensitive to second generation TKI's, such as nilotinib and dasatinib (O'Hare et al, 2005). Treatment with dasatinib has been shown to overcome H396R resistance in CML (Talpaz et al, 2006). Our results are the first to describe BCR-ABL1 kinase domain mutations in paediatric patients with Ph+ALL treated with intensive chemotherapy and imatinib. We are also the first to report an imatinib-resistant BCR-ABL1 kinase mutation from a CNS recurrence in a paediatric patient. It has been previously shown that imatinib has low penetrance into the CNS, which implies that selective pressure occurred systemically followed by expansion in the sanctuary of the CNS. The two mutations identified here are predicted to be sensitive to second generation TKIs, suggesting that these TKIs may be effective reinduction therapy for relapse following treatment of Ph+ALL with chemotherapy and imatinib. Importantly, dasatinib penetrates the CNS, a property that may help to decrease the risk of CNS recurrence in Ph+ALL. These next generation TKI's may further decrease relapse rates when used for initial therapy of Ph+ALL. Many patients who experience a relapse with combination chemotherapy and a TKI do not appear to carry a TKI-resistant mutation, suggesting that other BCR-ABL1 independent pathways play critical roles in leukaemia cell survival. Other tyrosine kinases, such as HCK, FGR, and LYN, are essential for Ph+ALL transformation (Hu et al, 2004). Therefore, less selective inhibitors like dasatinib may play an important role in salvage therapy for these patients. The current and planned COG Ph+ALL trials combine dasatinib rather than imatinib with intensive chemotherapy. Future studies will address whether dasatinib-resistant BCR-ABL1 mutants develop in patients who relapse on these studies. COG samples were obtained through the ALL Cell Bank (#2004-04) with local Institutional Review Board approval. Portions of this research was funded by the National Childhood Cancer Foundation (NCCF Laura and Greg Norman Research Fellowship); Children's Oncology Group grants CA098543 (Chair's Award), U10 CA98413 supporting the COG Statistical Center, and U24 CA114766 supporting Human Specimen Banking in NCI Supported Cancer Trials. B.H.C. is supported in part by the Oregon Child Health Research Center (National Institute of Child Health and Development K12) and the St. Baldrick's Foundation. SPH is the Ergen Family Chair in Pediatric Cancer. BHC, SGW, LS, SPH, BJD, and KRS designed the research and analysed the data. BHC, SGW, LS, WLC, BMC, NJW, SPH, BJD, and KRS wrote the manuscript. BHC, SGW, LS, WLC, BMC, NJW and KRS have no competing financial interests. SPH is a member of the Bristol Myers Squibb Dasatinib Pediatric Advisory Committee (without compensation). His children own stock in Bristol Myers Squibb. B.J.D. has financial interest in MolecularMD and receives clinical trial funding from Novartis and Bristol Myers Squibb.
Children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) have a poor prognosis, and there is no consensus on the optimal treatment for this variant of ALL.We reviewed the medical records of patients with Ph-positive ALL who were treated with intensive chemotherapy, with or without bone marrow transplantation, by 10 study groups or large single institutions from 1986 to 1996. Data on 326 children and young adults, who ranged in age from 0.4 to 19.9 years (median, 8.1), were analyzed to determine the rate of complete remission and the probability of event-free, disease-free and overall survival according to standard prognostic factors and type of treatment.The 267 patients who achieved a complete remission after induction chemotherapy (82 percent) were stratified into three subgroups according to the age and leukocyte count at the time of diagnosis: those with the best prognosis (a leukocyte count of less than 50,000 per cubic millimeter and an age of less than 10 years; 95 patients); those with an intermediate prognosis (intermediate-risk features; 92 patients); and those with the worst prognosis (a leukocyte count of more than 100,000 per cubic millimeter; 80 patients). The estimates of disease-free survival at five years (+/-SE) were 49+/-5 percent) for patients with the best prognosis), 30+/-5 percent (for those with an intermediate prognosis), and 20+/-5 percent (for those with the worst prognosis) (P<0.001 for the overall comparison). We also found that transplantation of bone marrow from an HLA-matched related donor offered significantly greater benefit than intensive chemotherapy alone in terms of protecting patients from relapse or other adverse events (relative risk, 0.3; 95 percent confidence interval, 0.2 to 0.5; P<0.001). This finding was consistent in all three groups.Unlike the usual type of all, Ph-positive ALL is associated with a poor prognosis. Nevertheless, in some patients with favorable prognosis features, the disease can be be controlled by intensive chemotherapy. Transplantation of bone marrow from an HLA-matched related donor is superior to other types of transplantation and to intensive chemotherapy alone in prolonging initial complete remissions.
