Berlin-Frankfurt-Münster Research Articles

Costs and Cost-Effectiveness of Allogeneic Stem Cell Transplantation in Children Are Predictable

The overall costs of pediatric stem cell transplantation (SCT), including donor search and costs during the first year post-SCT, were calculated in a cohort of 141 consecutive children undergoing SCT in a single institution. Costs were correlated with patient and transplantation characteristics and with a risk score for transplantation-related mortality. Cost-effectiveness was calculated based on the overall cost per surviving patient. Life-years gained were extrapolated from overall survival, and the costs per expected life-year gained were calculated. The overall median cost was €136,382 (175,815$), with a wide range, of €26,897 (34,679$) to €601,348 (775,343$). Increased costs were significantly associated with age, use of donors other than matched siblings, and advanced disease. There was a strong correlation of costs with a simple transplantation-related mortality risk score; median total costs were €89,550 (115,463$) for a score of 0, €127,349 (164,179$) for a score of 1, €156,578 (201,861$) for a score of 2, and €274,915 (354,499$) for a score of 3 (P < .001). Cost-effectiveness decreased with increasing transplantation-related mortality risk score; costs per survivor increased from €93,209 (120,200$) for a score of 0 to a maximum of €1,216,348 (1,568,579$) for a score of 3. Costs associated with pediatric SCT vary substantially; however, the combination of variables such as age, disease, and donor type is predictive of costs and cost-effectiveness. Costs per life-year gained are within the broadly accepted range in life-threatening hemato-oncologic diseases, even in the most cost-intensive patient cohort.

Profile of thrombin generation in children with acute lymphoblastic leukemia treated by Berlin–Frankfurt–Münster (BFM) protocols

Treatment with L-asparaginase is associated with coagulation disturbances with deep venous thrombosis being the most common clinical consequence. Use of the calibrated automated thrombogram allows precise estimation of thrombin generated in vitro. We show the first data on thrombin generation, measured by calibrated automated thrombography (CAT), in children with acute lymphoblastic leukemia treated with L-asparaginase. Thrombin generation was measured by means of CAT in 23 children treated for acute lymphoblastic leukemia. Samples were obtained at predefined time points during the induction and reinduction phase of acute lymphoblastic leukemia-intercontinental Berlin-Frankfurt-Münster (BFM) 2000 or Associazione Italiana Ematologica Oncologia Pedaitrica Interim BFM 2000 protocols. Antihrombin and fibrinogen were measured on the same sample. Twenty-eight sets of thrombin generation measurements were collected from 23 patients. We observed no significant effect of antithrombin deficiency and/or hypofibrinogenemia on thrombin generation. Endogenous thrombin generation and peak thrombin were significantly higher during induction than in the reinduction phase (P < 0.001). Four patients with severe infection experienced an increase in thrombin generation, reaching maximum in a median of 7.5 days after the onset of infection. Two of those patients developed deep venous thrombosis at the time of peaked endogenous thrombin generation. Thrombin generation in children with acute lymphoblastic leukemia treated according to BFM protocols is significantly higher during the induction phase compared with reinduction and is not substantially affected by hypofibrinogenemia and/or antithrombin deficiency. Severe infection during the induction phase enhances thrombin generation with subsequent risk of thrombosis.

Pediatric Non-Hodgkin Lymphoma: A Retrospective 14-Year Experience with Berlin-Frankfurt-Münster (BFM) Protocols from a Tertiary Care Hospital in Serbia

Use of current intensive chemotherapy protocols in pediatric non-Hodgkin lymphoma (NHL) in high-income countries resulted in event-free survival (EFS) rates ranging from 80 to 90%. The results are inferior in less privileged countries with limited resources for medical care. There are no reports about comprehensive data analysis in pediatric NHL in Serbia. A retrospective study was carried out at University Children's Hospital, Belgrade, in children aged less than 18 years diagnosed with non-Hodgkin lymphoma from 1997 to 2011. Fifty-seven children were eligible for analysis. Fourteen were diagnosed with lymphoblastic lymphoma, 38 with mature B-cell NHL (B-NHL), and 5 with anaplastic large-cell lymphoma. Mean age at diagnosis was 9.2 years, with male to female ratio 2.35:1. Children were treated according to Berlin-Frankfurt-Münster (BFM) protocols. With median follow-up of 59.3 months, 5-year probability of EFS was 84.1% for all patients, whereas overall survival was 93%. These results with BFM protocol administration, although inferior to leading international groups, reflect good treatment outcome in our patients. To the best of the authors’ knowledge, this article presents the first results regarding treatment and survival of childhood NHL in Serbia.

A step towards the cure of Burkitt's lymphoma in developing countries

The outcome of sporadic Burkitt's lymphoma (BL) in high-income countries may be considered excellent due to its overall cure rate of roughly 90%(1-4). Three major US and European childhood cancer groups [Lymphoma malignancy B-cell (LMB), BerlinFrankfurt-Munster (BFM), Children's Cancer Group/Children Oncology Group (CCG/COG)] contributed to the most effective treatment strategies to date. Nevertheless, the treatment has pronounced toxic effects such as long periods of mucositis, hematological toxic effects as well as the potential risk of severe infection. Assuredly, the improvement of supportive care has contributed to these better outcomes(1-4). On the other hand, in low-income countries, therapeutic schemes need to be modified in accordance with local conditions in order to avoid unacceptable treatment-related mortality(5). In this issue Cunha et al.(6) present a retrospective study of 50 cases of BL in children and adolescents who were treated with chemotherapy regimens containing intermediate methotrexate doses (500 mg/m2). The probability of overall survival was 73% (median follow-up of35 months). The data show a favorable step with improvement in the results of BL treatment in Brazil even considering the high mortality rate (23.8%) observed in the study. Reinforcing the predicted tumor burden value in the prognosis of BL patients, survival was significantly lower for patients with uric acid levels > 7 mg/dL. In addition, these results may also show that the impact of methotrexate on the overall success may be of less importance in patients with lower tumor load compared with those with larger tumor masses(7). Thus, the efficacy of treatment may depend as much on the number of drugs used (at least 4-6 drugs systemically) as on their doses and so lower dose multidrug regimens may improve outcome without comparable increases in toxicity(8). Although the study by Cunha et al.(6) provides important information on the approach to BL care in Brazil, there are still several areas to be addressed. Differences among survival rates in a large country such as Brazil are worthy of comment. The mean tumor burden at diagnosis has an important impact on the outcome(9). Even though the Brazilian Government Healthcare System (SUS - Sistema Unico de Saude) covers most chemotherapy drug costs, primary healthcare should be improved for earlier diagnosis. Moreover, supportive care facilities remain inadequate in some Brazilian regions where resources are limited. Enhancement of laboratory monitoring, aggressive hydratation and the use of urate oxidase in patients with high risk of tumor lysis syndrome will result in fewer toxic events and better treatment outcomes(10). The availability of rituximab in the SUS to treat B-cell lymphomas in adult patients has ledto the possibility of obtaining excellent results in children with less toxicity by combining thisdrug with chemotherapy. However, there is a question as to whether rituximab is an effectivedrug in pediatric B-cell non-Hodgkin lymphoma (B-NHL). This drug was tested in a phaseII short-window study showing that it can be safely added to a pediatric chemotherapeuticregimen(11). Even so, only controlled clinical trials will allow an evaluation of the role of thisdrug in the treatment of pediatric B-NHL. Taking these considerations into account, results like those of high-income countries may be achieved by directing research towards designing protocol regimens in formal clinical trials with chemotherapy tailored by tumor burden. The primary goal of therapy studies in developing countries today is to define risk groups as accurately as possible, so that the patients receive therapy consistent with the best possible outcome while further reduction of acute and chronic toxicity may be achieved.

TREATMENT Toxicity in Adolescents and Young ADULT (AYA) PATIENTS COMPARED with Younger PATIENTS TREATED for HIGH RISK B-Precursor ACUTE LYMPHOBLASTIC LEUKEMIA (HR-ALL): A REPORT From the CHILDREN'S Oncology GROUP STUDY AALL0232

Abstract 1510Historically, AYA patients (>16yrs of age) with HR-ALL have lower event free survival and overall survival compared to younger patients (1–15 yrs of age) with HR-ALL. This inferior outcome is related to both a higher relapse rate and increased toxicity of therapy. Several underlying factors have been identified that may contribute to these differences including leukemia biology, host pharmacodynamics, relative intensity of treatment protocols, adherence to therapy, and supportive care measures, although their relative importance is largely unknown.AALL0232 was a Phase 3 randomized trial for patients 1–30 years old with newly diagnosed B-precursor HR-ALL that utilized a 2 × 2 factorial design with an augmented intensity Berlin- Frankfurt-Münster (BFM) backbone. Patients were randomized to receive dexamethasone versus prednisone during Induction and high dose methotrexate versus escalating Capizzi methotrexate during Interim Maintenance I. The study accrued 3051 eligible, evaluable, non-Down Syndrome patients between January 2004 and January 2011. AYA patients comprised 20% of study enrollments (n=601) with 555 patients in the 16–21 year range and 46 patients in the 22–30 year range. Toxicities were graded using Common Terminology Criteria for Adverse Events (CTCAE version 4.0) and all grades 3 and 4 are reported. Bone toxicities including avascular necrosis are not included in this analysis.During Induction, AYA patients when compared to younger patients had lower rates of febrile neutropenia (7.0% versus 13.4%, p<0.0001), higher rates of hyperglycemia (22.0% versus 15.4%, p=0.0002), hyperbilirubinemia (6.7% versus 3.7%, p=0.0022), but comparable rates for other measured toxicities including pancreatitis and thrombosis. There was no significant difference in Induction mortality between AYA patients and younger patients (2.2% versus 1.7%, p=0.39).Post-induction, AYA patients experienced higher rates of oral mucositis secondary to methotrexate during Interim Maintenance I (18.5% versus 11.3%, p=0.0002), and higher rates of peripheral motor neuropathy during protocol therapy (11.5% versus 7.4%, p=0.0015). Despite lower rates of febrile neutropenia throughout protocol therapy (35.6% versus 48.6%, p<0.0001), AYA patients had a significantly greater likelihood of death during remission. The 5-year cumulative incidence of remission death for AYA patients was 4.4 + 1.1% compared to 1.8 + 0.4% for younger patients (p=0.0015). Of the 16 remission deaths in AYA patients, 11 occurred within one year post-induction and the remaining within 3 years post-induction. Of the 29 remission deaths in younger patients, 22 occurred within one year post-induction, 6 occurred between 1–3 years, and one between 4–5 years. Infectious complications were responsible for 11 of 16 (69%) of the remission deaths in AYA patients compared to 15 of 29 (52%) of the remission deaths in younger patients.In conclusion, AYA patients experienced higher rates of hyperbilirubinemia and hyperglycemia during Induction, oral mucositis during Interim Maintenance I, and peripheral motor neuropathy throughout protocol therapy. Importantly, AYA patients experienced a higher rate of death during remission, predominantly due to infectious etiologies. Further analyses are needed to determine reasons for the increase in treatment related mortality, including, an evaluation of the responsible organisms, identification of periods of increased vulnerability because of concomitant mucositis, neutropenia, and/or delivery of specific chemotherapeutic agents. Disclosures:No relevant conflicts of interest to declare.

Promising therapy results for lymphoid malignancies in children with chromosomal breakage syndromes (Ataxia teleangiectasia or Nijmegen‐breakage syndrome): a retrospective survey

Children with chromosomal instability syndromes have an increased risk of developing lymphoma and leukaemia. The treatment of these malignancies is hampered by therapy-associated toxicity and infectious complications. This retrospective analysis evaluated the therapy outcome of 38 children with Ataxia teleangiectasia or Nijmegen-breakage syndrome with acute lymphoblastic leukaemia (ALL, n = 9), Non-Hodgkin lymphoma (NHL, n = 28) and Hodgkin lymphoma (HL, n = 1). All patients with NHL or ALL were treated in accordance to Berlin-Frankfurt-Münster (BFM)- or Co-operative study group for childhood ALL (CoALL)-oriented chemotherapy schedules. 22 patients received significantly reduced-intensity chemotherapy. After a median follow-up of 3·7 years the 10-year overall survival was 58%. Dosage-reduction of chemotherapeutic drugs seemed to have no disadvantages and reduced toxic side effects. On the other hand, reduced-intensity chemotherapy did not prevent second malignancies, which occurred in ten patients with a 10-year incidence of 25%. After individual treatment approaches three of these patients with second malignancies were in complete clinical remission for more than 5 years. We conclude that BFM- or CoALL-oriented chemotherapy is effective and can be administered in children with AT or NBS. Moreover, we show that even second lymphoid malignancies can successfully be treated in these patients.

Comparison of high-dose methotrexate (HD-MTX) with Capizzi methotrexate plus asparaginase (C-MTX/ASNase) in children and young adults with high-risk acute lymphoblastic leukemia (HR-ALL): A report from the Children’s Oncology Group Study AALL0232.

3 Background: Although EFS continues to improve for children and young adults with HR-ALL, central nervous system (CNS) disease has become an increasing site of treatment failure. AALL0232 was designed to test the safety and efficacy of interventions targeted to enhance CNS control including comparisons of HD-MTX versus Capizzi escalating methotrexate plus PEG asparaginase (C-MTX/ASNase) during interim maintenance-1 (IM-1) and dexamethasone (DEX) versus prednisone (PRED) during Induction. Methods: AALL0232 was a Phase III, randomized trial for patients 1-30 years old with newly diagnosed NCI high risk B-precursor ALL that utilized a 2 x 2 factorial design with an augmented intensity Berlin-Frankfurt-Münster (BFM) backbone. Patients were randomized to receive DEX versus PRED during induction and HD-MTX (5gm/m2 biweekly x 4) versus C-MTX/ASNase during IM-1. To date 2104/3156 AALL0232 patients have completed IM-1. Results: Planned interim monitoring showed 5-year EFS for patients randomized to receive HD-MTX (N=1,209) was 82 + 3.4% versus 75.4 + 3.6% for the C-MTX/ASNase (N=1,217) regimen, p=0.006. Because this difference crossed a pre-defined boundary, enrollment was halted and patients were crossed over from C-MTX/ASNase to HD MTX when feasible. There were fewer marrow and CNS relapses in the HD-MTX versus C-MTX/ASNase arms (42 and 22 versus 68 and 32). The incidence of febrile neutropenia was lower with HD-MTX compared to the C-MTX; 5.2% vs 8.2%, respectively, p=0.005. There were no statistically significant differences in acute neurotoxicity, osteonecrosis, or other clinically relevant toxicities between the two regimens. Conclusions: HD-MTX administered in place of C-MTX, during the IM-1 phase of augmented BFM therapy is associated with superior EFS, with no increase in acute toxicity, in children and young adults with HR-ALL.

Prognostic impact of t(1;19)/ TCF3–PBX1 in childhood acute lymphoblastic leukemia in the context of Berlin–Frankfurt–Münster-based protocols

Historically, t(1;19)(q23;p13.3) has been related to pre-B acute lymphoblastic leukemia (ALL) and associated with a poor prognosis. Current treatments have overcome this dismal outcome, but advantages in survival for the unbalanced group have been reported. We compared the outcome of balanced and unbalanced der(19)t(1;19) cases and also patients with t(1;19)/TCF3–PBX1 versus patients without this translocation, to assess its prognostic value. From January 1990 to December 2010, t(1;19)(q23;p13)/TCF3–PBX1 was detected in 48 cases. Patients were treated with Berlin–Frankfurt–Münster (BFM)-based protocols and classified into balanced (n = 17) and unbalanced (n = 23) groups. The probability of event-free survival (pEFS) (standard error) of patients with t(1;19)/TCF3–PBX1 was 85% (6%), for the unbalanced group 78% (10%), and 88% (8%) for the balanced. The pEFS of patients with t(1;19)/TCF3–PBX1 was significantly superior to that of patients without t(1;19)/TCF3–PBX1 (p-value <0.0001). Patients with t(1;19)/TCF3–PBX1 presented a good outcome with no differences between balanced and unbalanced subgroups. Thus, risk-adjustment therapy would not be necessary for cases with t(1;19)/TCF3–PBX1.

Different outcome in older children with acute lymphoblastic leukemia with different treatment protocols in the Netherlands

From 1991 until 2004 children with acute lymphoblastic leukemia (ALL) in the Netherlands were treated according to protocols ALL-8 and ALL-9 which were based on different principles. An earlier study showed that the outcome of adolescents highly differed on these protocols. In this retrospective study, we analyzed whether the outcome of older children 10-15 years of age at diagnosis differed between the Berlin-Frankfurt-Münster (BFM)-based ALL-8 regimen and the ALL-9 regimen. Two hundred fifty-four older children who were treated according to protocol ALL-8 (n = 82) or ALL-9 (n = 172) were included in the analysis. A higher 5-year event-free survival (EFS) rate was found for patients treated according to ALL-8 compared to ALL-9 (79 ± 5% vs. 65 ± 4%, P = 0.02). Patient characteristics did not differ except for a slightly higher age in ALL-8. Therefore, additional analyses were done including only patients who were 12-15 years of age. In this age group there was also a difference in the 5-year EFS (82 ± 5% vs. 61 ± 5%, P = 0.00) as well as in the 5-year overall survival rate; 89 ± 4% compared to 68 ± 5%, respectively (P = 0.01). Major difference between protocols was the use of a consolidation and reinduction/intensification course and higher cumulative doses of asparaginase, methotrexate, and anthracyclines in ALL-8. Children 10-15 years of age have been undertreated with the ALL-9 regimen and benefit by intensive treatment components as used in ALL-8. We recommend using BFM-based protocols for these older children with ALL.

Acute Neurotoxicity In Children with Acute Lymphoblastic Leukemia: An Association with Day-36 Intrathecal Methotrexate In Delayed Intensification

AbstractAbstract 3224 Background:Methotrexate (MTX), both intrathecal (IT) and intravenous (IV) may induce acute neurotoxicity, typically manifested as seizures or stroke-like encephalopathy. The FRALLE 93 trial reported exposure to high-dose (HD) MTX as an independent risk factor for acute neurotoxicity in univariate analysis 1. Pediatric Oncology Group (POG) trial 9005 showed an association between IV MTX and acute neurotoxicity2. We investigate risk factors associated with acute neurotoxicity in children treated according to recent Children's Oncology Group (COG)-modified Berlin-Frankfurt-Munster (BFM)-based protocols, specifically whether number of doses of IT MTX therapy given during delayed intensification (DI) is an independent predictor. Patients and Methods:A retrospective cohort of 167 children ages 1–21 years with ALL treated at our institution according to COG-modified BFM-based therapy between January 2001 and December 2007 with complete records available were reviewed. Patients who received bone marrow transplant in first remission or died prior to DI were excluded. In patients who relapsed, only data regarding therapy prior to relapse was reviewed.Baseline characteristics between patients with acute neurotoxicity (n= 11) and patients without acute neurotoxicity (n= 156) were assessed for differences using the two-tailed student's t-test for continuous variables and the Chi-squared test or Fisher's exact test for categorical variables. Logistical regression analysis was performed using age, diagnosis (pre-B versus T-cell ALL), administration of HD MTX, administration of cranial irradiation (cXRT) and doses of IT MTX (two, on days 1/29, vs. three, on days 1/29/36) administered during DI as predictor variables. Interaction between doses of IT MTX and administration of HD MTX or cXRT was not able to be reliably assessed because of the rarity of the outcome event. Results:4/136 (3%) patients who received two doses of IT MTX during DI experienced acute neurotoxicity either during DI or thereafter compared with 7/31 (23%) patients who received three doses of IT MTX (p = 0.0008). Univariate analysis showed no significant differences in diagnosis, administration of HD MTX, cranial radiation and relapse rate between patients with acute neurotoxicity vs. those without. Patients with acute neurotoxicity were more likely to be older (p = 0.05) and have received three doses of IT MTX during DI than patients without an event (see table). [Display omitted] In multivariate analysis, patients who received three doses of IT MTX during DI were at increased risk of acute neurotoxicity (OR = 7.6, 95% confidence interval 1.7–33.7) adjusted for age, diagnosis, administration of HD MTX and cXRT. Older age was no longer a significant predictor of acute neurotoxicity (OR = 1.1, 95% confidence interval 0.94–1.3). Conclusion:In children with ALL treated per COG-modified BFM-based protocols at our institution, three doses of IT MTX during DI (Days 1/29/36) was associated with a higher risk for acute neurotoxicity compared to two IT MTX doses on Days 1/29. The association between Day 36 IT MTX and acute neurotoxicity was seen in both univariate and multivariate analysis adjusted for age, diagnosis, administration of HD MTX and cXRT. This association should be explored in a larger patient cohort, and if confirmed, warrants consideration of eliminating IT MTX on Day 36 of DI.1. Dufourg NM et al. Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE 93 trial for acute lymphoblastic leukemia in children. Leukemia 2007; 21:238-47.2. Mahoney DH et al. Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: an association with intermediate-dose intravenous methotrexate and intrathecal triple therapy – a Pediatric Oncology Group study. J Clin Oncol 1998; 16:1712-22. Disclosures:No relevant conflicts of interest to declare.

Prognostic Impact of Specific Chromosomal Aberrations in a Large Group of Pediatric Patients With Acute Myeloid Leukemia Treated Uniformly According to Trial AML-BFM 98

Because cytogenetic data are essential for risk stratification of childhood acute myeloid leukemia (AML), the impact of chromosomal aberrations is crucial. Data of a large group of patients younger than 18 years treated according to study AML-Berlin-Frankfurt-Münster (BFM) 98 (n = 454), including their cytogenetics, were analyzed. The favorable outcome in the subgroups of patients with t(8;21), inv(16), and t(15;17), with an overall survival of 91% (SE, 4%), 92% (SE, 6%), and 87% (SE, 5%), respectively, was confirmed. Within this group, the 5-year probability of event-free survival (pEFS) of all 17 children with t(8;21) and additional aberrations apart from del(9q) or -X/-Y was 100%. As expected, the cytogenetic finding of a complex karyotype (n = 35; pEFS, 33%; SE, 8%) or a monosomy 7 (n = 12; pEFS, 17%; SE, 11%) was associated with a poor outcome. Compared with remaining patients with cytogenetic data (pEFS, 48%; SE, 2%), prognosis in patients with an MLL rearrangement (n = 91) was inferior (pEFS, 34%; SE, 5%; P = .0005). Particularly, children with t(9;11) and additional aberrations (n = 13; pEFS, 31%; SE, 14%) and MLL rearrangements other than t(9;11) and t(11;19) (n = 41; pEFS, 24%; SE, 7%) had an unfavorable outcome. Nine patients with aberrations in 12p showed an adverse prognosis (pEFS, 11%; SE, 10%). The outcome of patients with aberrations of chromosome 5 (n = 13) was better than expected (pEFS, 50%; SE, 13%). Because the prognostic value of rare recurrent chromosomal aberrations still has to be elucidated, these data will contribute to future risk stratification for the treatment of pediatric AML.

Acute leukaemias of ambiguous lineage in children: characterization, prognosis and therapy recommendations

Acute leukaemias of ambiguous lineage (ALAL) represent a rare type of leukaemia, expressing both myeloid and lymphoid markers. This study retrospectively analyzed data from 92 children (biphenotypic n = 78, bilineal n = 6, lineage switch n = 8) with ALAL registered in the Berlin-Frankfürt-Münster (BFM) acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) studies between 1998 and 2006 (2.4% of all cases with acute leukaemia). Our cohort of ALAL patients was characterized by comparatively high median age (8.9 years), high median white blood cell count (14.9 x 10(9)/l), as well as frequent hyperleucocytosis (18.5%) and central nervous system involvement (24.1%). The most frequent cytogenetic abnormalities were ETV6/RUNX1 fusion (16%) and trisomy 8 (14.6%). Complete remission rate was significantly lower than in ALL-BFM patients (91.8% vs. 99.1%, P < 0.001), but comparable to AML-BFM patients (87.9%). Event-free survival (EFS) and overall survival (OS) of ALAL patients were low, at 62 +/- 5%. 5-year probability of EFS was significantly worse than in ALL patients (80 +/- 1%, P < 0.001), but better than for AML patients (49 +/- 2%, P = 0.027). Our data suggest that an intensive therapy regimen including stem cell transplantation may be favourable for bilineal or lineage switch cases, whereas patients with ETV6/RUNX1 fusion, lymphoid morphology and patients with expression of cyCD22 and cyCD79a should be treated with an ALL-directed therapy.

Prognostic relevance of TLX3 (HOX11L2) expression in childhood T‐cell acute lymphoblastic leukaemia treated with Berlin–Frankfurt–Münster (BFM) protocols containing early and late re‐intensification elements

TLX3 expression (TLX3+) in childhood T-cell acute lymphoblastic leukaemia (T-ALL) seems to be associated with a poor prognosis when treated with regimens that lack early and/or late re-intensification therapy elements. Because such elements are essential components of the ALL-BFM (Berlin-Frankfurt-Münster) protocols, we evaluated whether TLX3+ T-ALL patients benefit from this type of therapy. Thirty-one/131 childhood T-ALL cases (24%) enrolled into four population-based Austrian ALL-BFM therapy studies were TLX3+. The male to female ratio was 3.5:1 and median age and leucocyte count at diagnosis were 8.7 years and 58.9 x 10(9)/l, respectively. Twenty-four patients (77%) were good responders to prednisone. All were in complete remission after induction therapy. After a median observation time of 4.9 years (range 0.4-16.1 years) 28/31 TLX3+ cases remained in first complete remission after chemotherapy with one after additional stem cell transplantation. Although molecular disease was frequently present after a 4-drug induction therapy, final treatment outcome was excellent indicating that TLX3+ T-ALL cases may benefit from a BFM-type of ALL therapy with early and late re-intensification elements. Moreover, the fact that 2/3 relapses were also NUP214-ABL1+ suggests that these cases might represent the particular risk-prone TLX3+ subgroup that could benefit from a targeted tyrosine kinase inhibitor therapy.

Long-term results of Dutch Childhood Oncology Group studies for children with acute lymphoblastic leukemia from 1984 to 2004

The Dutch Childhood Oncology Group (DCOG) has used two treatment strategies for children with acute lymphoblastic leukemia (ALL) based on Pinkel's St Jude Total Therapy or the Berlin-Frankfurt-Münster (BFM) backbone. In four successive protocols, 1734 children were treated. Studies ALL-6 and ALL-9 followed the Total Therapy approach; cranial irradiation was replaced by medium-dose methotrexate infusions and prolonged triple intrathecal therapy; dexamethasone was used instead of prednisone. Studies ALL-7 and ALL-8 had a BFM backbone, including more intensive remission induction, early reinduction and maintenance therapy without vincristine and prednisone pulses. The 5-year event-free survival and overall survival increased from 65.4 to 80.6% (P<0.001) and from 78.7 to 86.4% (P=0.07) in ALL-7 and ALL-9, respectively. In ALL-7 and ALL-8 National Cancer Institute (NCI) high-risk criteria, male gender, T-lineage ALL and high white blood cells (WBCs) predict poor outcome. In ALL-9 NCI criteria, gender, WBC >100 x 109/l, and T-lineage ALL have prognostic impact. We conclude that the chemotherapy-only approach in children with ALL in Total Therapy-based strategies and BFM-backbone treatment does not jeopardize survival and preserves cognitive functioning. This experience is implemented in the current DCOG-ALL-10 study using a BFM backbone and minimal residual disease-based stratification.

Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000

Between 1981 and 2000, 6609 children (<18 years of age) were treated in five consecutive trials of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). Patients were treated in up to 82 centers in Germany, Austria and Switzerland. Probability of 10-year event-free survival (EFS) (survival) improved from 65% (77%) in study ALL-BFM 81 to 78% (85%) in ALL-BFM 95. In parallel to relapse reduction, major efforts focused on reducing acute and late toxicity through advanced risk adaptation of treatment. The major findings derived from these ALL-BFM trials were as follows: (1) preventive cranial radiotherapy could be safely reduced to 12 Gy in T-ALL and high-risk (HR) ALL patients, and eliminated in non- HR non-T-ALL patients, if it was replaced by high-dose and intrathecal (IT) MTX; (2) omission of delayed re-intensification severely impaired outcome of low-risk patients; (3) 6-month-less maintenance therapy caused an increase in systemic relapses; (4) slow response to an initial 7-day prednisone window was identified as adverse prognostic factor; (5) condensed induction therapy resulted in significant improvement of outcome; (6) the daunorubicin dose in induction could be safely reduced in low-risk patients and (7) intensification of consolidation/re-intensification treatment led to considerable improvement of outcome in HR patients.

Pediatric-Based Therapy for Young Adults with Newly Diagnosed Lymphoblastic Leukemia.

Abstract 2037Poster Board II-14Adolescents 14 to 21 years of age with de novo acute lymphoblastic leukemia (ALL) have improved outcomes if treated on pediatric chemotherapy regimens as opposed to adult regimens. Young adults with ALL may also benefit from chemotherapy modeled after pediatric regimens, though toxicities may be limiting. We report on 48 young adult patients between the ages of 12 to 40 years with de novo Philadelphia chromosome negative ALL treated with the augmented Berlin-Frankfurt-Munster (BFM) chemotherapy regimen. All patients have completed at least the initial 28 days of therapy (induction) consisting of high dose prednisone, pegylated asparaginase (PEG-asp), vincristine, daunorubicin and intrathecal treatments. The median age of the group was 20 yrs (14-36); 40 patients had pre-B ALL and 8 T-ALL, No infectious deaths were observed during induction. 45 (95%) patients achieved a remission by 29 days and 2 achieved remission after a 2 week extension of induction. One patient was refractory to therapy. 39 (81%) patients achieved a morphological marrow remission (<5% blasts) by day 15 of treatment (rapid early responders). Minimal residual disease (MRD) assessed by flow cytometry was negative at the end of induction for 30 (62%), positive in 10 (21%), suspicious in 6 (12%) and not available for 2 patients. In the 41 patients who completed 12 weeks of therapy, MRD was negative in 35 (85%) and positive in 6 (15%). 7 (15%) patients have relapsed or have refractory disease; 1 patient died in CR. Admission for fever of unknown origin with neutropenia occurred in 10 (21%) patients, an additional 10 (21%) patients had documented infections. Grade III-IV hepatic toxicity has been prominent: 22 (45%) increased transaminase, 14 (29%) hyperbilirubinemia. 9 (19%) patients had allergic reactions to PEG-asp, and 10 (21%) had thrombotic events. The majority of grade III-IV adverse events have been reversible. The median complete remission duration is 57 weeks (range 5-143). The overall survival at two years is 82%. In summary, this pediatric-based regimen for young adults with ALL effectively induces remission, both by morphology and by flow cytometry. Toxicity has been significant, but mostly transient and tolerable. Longer follow-up is needed to determine the long-term efficacy of this regimen in young adults with ALL. Disclosures:Rytting:Enzon: Speakers Bureau. Jabbour:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau.

Outcome for Adolescents and Young Adults (AYA) with the Hyper-CVAD (with or without Rituximab) Regimens for De Novo Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma.

Abstract 3084Poster Board III-21AYAs aged 16–20 yrs with de novo ALL or LL have superior outcomes when treated with intensive pediatric regimens; event-free survival rates range from 60–70% compared to 30–40% after conventional adult chemotherapy [Stock W, Blood 112:1646, 2008]. This is in part attributed to higher dose intensity (and cumulative dose) of the anthracycline, vincristine [VCR], corticosteroid and asparaginase components. The intensive hyper-CVAD regimen (fractionated cyclophosphamide, VCR, doxorubicin, dexamethasone alternating with methotrexate and cytarabine) was originally modeled after childhood therapy for Burkitt lymphoma, and had been applied as frontline adult ALL therapy without age restriction since 1992. In contrast to conventional adult or pediatric ALL regimens, asparaginase is not administered during induction or consolidation phases. Modifications to the regimen have included the addition of rituximab for CD20 positive precursor B-cell ALL owing to adverse influence of CD20 expression, particularly in the younger subgroup [Thomas D, Blood 113:6330, 2009]. An adapted augmented Berlin-Frankfurt-Munster (BFM) regimen modeled after the CCG experience was developed specifically as frontline therapy for adolescents and adults up to age 30 in lieu of the hyper-CVAD regimen at our institution; accrual is ongoing. We updated the previous comparative hyper-CVAD experience in this young adult subset. One hundred seventy-six pts aged 13 to 30 yrs (median 22 yrs) with de novo ALL (n=149) or LL (n=27) were treated with hyper-CVAD (n=96) or modified hyper-CVAD (25 with anthracycline intensification, 55 without; 32 overall with rituximab). Eighty-three (47%) were less than 21 years of age (median 19 yrs). Forty-nine (29%) were CD20 positive. Overall complete remission (CR) rate was 97%; overall 3-yr CR duration (CRD) and survival (OS) rates were 65% and 70%, respectively. Rates for 3-yr CRD and OS were 68% and 75% if age 21 yrs or less, compared with 60% and 66%, respectively, if age 22 to 30 yrs (p=NS). The addition of rituximab improved the 3-yr CRD rates from 26% to 65% (p=.001) and 3-yr OS rates from 47% to 75% (p=.05) for the CD20 positive precursor B-cell ALL subsets, partly accounting for the improvement in outcomes. There were no significant differences in outcome by regimen for the CD20 negative subsets (all 3-yr rates > 70%). Outcomes with the hyper-CVAD regimens in AYAs appear to more closely resemble those of the pediatric approaches than the conventional regimens; incorporation of pegylated asparaginase and intensification of vincristine/corticosteroids (e.g., augmented hyper-CVAD) may further improve the efficacy of this regimen in the frontline setting. Incorporation of rituximab or the novel CD20 antibodies such as ofatumumab into the pediatric regimens warrants consideration. DisclosuresNo relevant conflicts of interest to declare.

Diagnostic Cytogenetic Analysis in Pediatric Acute Myeloid Leukemia (AML): Evaluation of Methodological Issues with a Special Focus On Missing Data.

Abstract 4688 BackgroundAcquired clonal chromosomal alterations are common and considered to have prognostic implications in acute myeloid leukemia (AML). Although bone marrow cytogenetic analysis is required for the classification of AML subtypes and is often used for guiding therapy, the prognostic relevance of the cytogenetic abnormalities in children with AML remains controversial, limiting their value in risk-stratified therapy. Hence we reviewed the reports published by four major pediatric AML study groups to assess the strength of their evidence for the use of cytogenetics as a predictor variable in risk stratification of children with AML, focusing closely on the impact of missing data. MethodsReports of consecutive phase III clinical trials published by cooperative study groups that used cytogenetic features for risk stratification of children with de novo AML were reviewed for their methods of assessing the predictive strength of diagnostic cytogenetic analysis (predictor variable) for clinical outcomes, as well as the extent and impact of missing data. We focused on publications by the North American [Pediatric Oncology Group (POG) and Children's Cancer Group (CCG)] and the European [United Kingdom Medical Research Council (UK MRC) and Berlin-Frankfurt-Munster (BFM) group] consortia as they represent major pediatric AML study groups in their respective continents and each of these groups has conducted several multicenter pediatric AML studies with large sample sizes. ResultsDuring the period 1979-2003, four large pediatric AML study groups conducted 12 Phase III studies evaluating diagnostic cytogenetics. In all, 20 publications reporting the results of these trials were studied to evaluate the impact of diagnostic cytogenetics on clinical outcome. Across all study groups, large amount of cytogenetic data were missing (mean ± SD 31.5% ±17.5%; range 5.3% to 58.1%), but neither the causes of “missingness” nor the methods used to handle the missing data were reported or discussed. In addition, we found a lack of uniformity in the assessment of the predictor variable and outcome measures, lack of a priori estimation of sample size to address the impact of diagnostic cytogenetics and the absence of a validation process. ConclusionsMissing data were a common but often unidentified problem in a series of large clinical trials testing various treatment strategies in children with AML. This problem, together with other methodological issues in the assessment of the predictor variable and clinical outcome measures, may have biased the estimates of the prognostic strength of diagnostic cytogenetic analysis. Disclosures:No relevant conflicts of interest to declare.

Induction death and treatment-related mortality in first remission of children with acute lymphoblastic leukemia: a population-based analysis of the Austrian Berlin-Frankfurt-Münster study group

In the management of the childhood acute lymphoblastic leukemia (ALL), 5% of failures are due to induction death and treatment-related deaths in first complete remission. We retrospectively analyzed the incidence, pattern and causes of death and its risk factors for 896 children with ALL enrolled into five Austrian (A) Berlin-Frankfurt-Münster (BFM) trials between 1981 and 1999. The estimated 10-year cumulative incidence of death significantly decreased from 6+/-1% (n=16/268) in trials ALL-BFM-A 81 and ALL-A 84 to 2+/-1% (n=15/628) in trials ALL-BFM-A 86, 90 and 95 (P=0.006). A significant reduction of death was evident during induction therapy (2.2% in trials ALL-BFM-A 81 and ALL-A 84 and 0.2% in trials ALL-BFM-A 86, 90 and 95, P=0.001). Of 31 patients, 21 (68%) patients died from infectious and 10 (32%) from noninfectious complications. Treatment in trial ALL-BFM-A 81, infant age and female gender were independent predictors of an enhanced risk for death. Conclusively, we found a progressive reduction of death rates that may be explained by the increasing experience in specialized hemato-oncologic centers and improved supportive and intensive care. We also identified a distinct subset of patients who are especially prone to death and may need a special focus when receiving intense chemotherapy.

Long‐term outcome of initially homogenously treated and relapsed childhood acute lymphoblastic leukaemia in Austria – A population‐based report of the Austrian Berlin‐Frankfurt‐Münster (BFM) Study Group

Relapsed acute lymphoblastic leukaemia (ALL) is the most common cause for a fatal outcome in paediatric oncology. Although initial ALL cure rates have improved up to 80%, the prognosis of recurrent ALL remains dismal with event-free-survival (EFS) rates about 35%. In order to analyse a population-based cohort with uniform treatment of initial disease, we examined the outcome of children suffering from relapsed ALL in Austria for the past 20 years and the validity of the currently used prognostic factors (e.g. time to and site of relapse, immunophenotype). Furthermore, we compared survival rates after chemotherapy alone with those after allogeneic stem cell transplantation (SCT). All 896 patients who suffered from ALL in Austria between 1981 and 1999 were registered in a prospectively designed database and treated according to trials ALL-Berlin-Frankfurt-Münster (BFM)-Austria (A) 81, ALL-A 84 and ALL-BFM-A 86, 90 and 95. Of these, 203 (23%) suffered from recurrent disease. One-hundred-and-seventy-two patients (85%) achieved second complete remission. The probability of 10-year EFS for the total group was 34 +/- 3%. Clinical prognostic markers that independently influenced survival were time to relapse, site of relapse and the immunophenotype. Additionally, a Cox regression model demonstrated that allogeneic SCT after first relapse was associated with a superior EFS compared with chemo/radiotherapy only (hazard ratio = 0.254; P = 0.0017).