Gritta E. Janka-Schaub

Contemporary classification of histiocytic disorders

Pathologists and pediatric hematologist/ oncologists of the World Health Organizations Committee on Histiocytic/Reticulum Cell Proliferations and the Reclassification Working Group of the Histiocyte Society present a classification of the histiocytic disorders that primarily affect children. Nosology, based on the lineage of lesional cells and biological behavior, is related to the ontogeny of histiocytes (macrophages and dendritic cells of the immune system). Dendritic cell-related disorders of varied biological behavior are dominated by Langerhans cell histiocytosis, but separate secondary proliferations of dendritic cells must be differentiated. Juvenile xanthogranuloma represents a disorder of dermal dendrocytes, another dendritic cell of skin. The hemophagocytic syndromes are the most common of the macrophage-related disorders of varied biological behavior. Guidelines for distinguishing the exceedingly rare malignant diseases of histiocytes from large cell lymphomas through the use of a battery of special studies are provided.

Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia.

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study

BACKGROUND Genetic subtypes of acute lymphoblastic leukaemia (ALL) are used to determine risk and treatment in children. 25% of precursor B-ALL cases are genetically unclassified and have intermediate prognosis. We aimed to use a genome-wide study to improve prognostic classification of ALL in children. METHODS We constructed a classifier based on gene expression in 190 children with newly diagnosed ALL (German Cooperative ALL [COALL] discovery cohort) by use of double-loop cross-validation and validated this in an independent cohort of 107 newly diagnosed patients (Dutch Childhood Oncology Group [DCOG] independent validation cohort). Hierarchical cluster analysis with classifying gene-probe sets revealed a new ALL subtype, the underlying genetic abnormalities of which were characterised by comparative genomic hybridisation-arrays and molecular cytogenetics. FINDINGS Our classifier predicted ALL subtype with a median accuracy of 90.0% (IQR 88.3-91.7) in the discovery cohort and correctly identified 94 of 107 patients (accuracy 87.9%) in the independent validation cohort. Without our classifier, 44 children in the COALL cohort and 33 children in the DCOG cohort would have been classified as B-other. However, hierarchical clustering showed that many of these genetically unclassified cases clustered with BCR-ABL1-positive cases: 30 (19%) of 154 children with precursor B-ALL in the COALL cohort and 14 (15%) of 92 children with precursor B-ALL in the DCOG cohort had this BCR-ABL1-like disease. In the COALL cohort, these patients had unfavourable outcome (5-year disease-free survival 59.5%, 95% CI 37.1-81.9) compared with patients with other precursor B-ALL (84.4%, 76.8-92.1%; p=0.012), a prognosis similar to that of patients with BCR-ABL1-positive ALL (51.9%, 23.1-80.6%). In the DCOG cohort, the prognosis of BCR-ABL1-like disease (57.1%, 31.2-83.1%) was worse than that of other precursor B-ALL (79.2%, 70.2-88.3%; p=0.026), and similar to that of BCR-ABL1-positive ALL (32.5%, 2.3-62.7%). 36 (82%) of the patients with BCR-ABL1-like disease had deletions in genes involved in B-cell development, including IKZF1, TCF3, EBF1, PAX5, and VPREB1; only nine (36%) of 25 patients with B-other ALL had deletions in these genes (p=0.0002). Compared with other precursor B-ALL cells, BCR-ABL1-like cells were 73 times more resistant to L-asparaginase (p=0.001) and 1.6 times more resistant to daunorubicin (p=0.017), but toxicity of prednisolone and vincristine did not differ. INTERPRETATION New treatment strategies are needed to improve outcome for this newly identified high-risk subtype of ALL. FUNDING Dutch Cancer Society, Sophia Foundation for Medical Research, Paediatric Oncology Foundation Rotterdam, Centre of Medical Systems Biology of the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research, American National Institute of Health, American National Cancer Institute, and American Lebanese Syrian Associated Charities.

HLH‐94: A treatment protocol for hemophagocytic lymphohistiocytosis

In January 1995, the Hemophagocytic Lymphohistiocytosis (HLH) Study Group opened its first international treatment study dedicated to the hemophagocytic lymphohistiocytoses. The main intention of the study protocol is to offer affected children therapy with a wellestablished chemotherapeutic regimen (epipodophyllotoxin and corticosteroids) in combinationwith a newer approach, immunotherapy with cyclosporin A. Subsequent bone marrow transplantation (BMT) is recommended to all children with an available donor. The purpose of this communication is to describe this approach to management, that intends to prolong survival and increase the cure rate for children throughout the world with this highly lethal disease [1].

Standardized MRD quantification in European ALL trials : Proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008

Assessment of minimal residual disease (MRD) has acquired a prominent position in European treatment protocols for patients with acute lymphoblastic leukemia (ALL), on the basis of its high prognostic value for predicting outcome and the possibilities for implementation of MRD diagnostics in treatment stratification. Therefore, there is an increasing need for standardization of methodologies and harmonization of terminology. For this purpose, a panel of representatives of all major European study groups on childhood and adult ALL and of international experts on PCR- and flow cytometry-based MRD assessment was built in the context of the Second International Symposium on MRD assessment in Kiel, Germany, 18–20 September 2008. The panel summarized the current state of MRD diagnostics in ALL and developed recommendations on the minimal technical requirements that should be fulfilled before implementation of MRD diagnostics into clinical trials. Finally, a common terminology for a standard description of MRD response and monitoring was established defining the terms ‘complete MRD response’, ‘MRD persistence’ and ‘MRD reappearance’. The proposed MRD terminology may allow a refined and standardized assessment of response to treatment in adult and childhood ALL, and provides a sound basis for the comparison of MRD results between different treatment protocols.

Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements.

To assess the clinical heterogeneity among patients with acute lymphoblastic leukemia (ALL) and various 11q23 abnormalities, we analyzed data on 497 infants, children and young adults treated between 1983 and 1995 by 11 cooperative groups and single institutions. The substantial sample size allowed separate analyses according to age younger or older than 12 months for the various cytogenetic subsets. Infants with t(4;11) ALL had an especially dismal prognosis when their disease was characterized by a poor early response to prednisone (P=0.0005 for overall comparison; 5-year event-free survival (EFS), 0 vs 23±12% s.e. for those with good response), or age less than 3 months (P=0.0003, 5-year EFS, 5±5% vs 23.4±4% for those over 3 months). A poor prednisone response also appeared to confer a worse outcome for older children with t(4;11) ALL. Hematopoietic stem cell transplantation failed to improve outcome in either age group. Among patients with t(11;19) ALL, those with a T-lineage immunophenotype, who were all over 1 year of age, had a better outcome than patients over 1 year of age with B-lineage ALL (overall comparison, P=0.065; 5-year EFS, 88±13 vs 46±14%). In the heterogeneous subgroup with del(11)(q23), National Cancer Institute-Rome risk criteria based on age and leukocyte count had prognostic significance (P=0.04 for overall comparison; 5-year EFS, 64±8% (high risk) vs 83±6% (standard risk)). This study illustrates the marked clinical heterogeneity among and within subgroups of infants or older children with ALL and specific 11q23 abnormalities, and identifies patients at particularly high risk of failure who may benefit from innovative therapy.

Long-Term Outcome in Children With Relapsed ALL by Risk-Stratified Salvage Therapy: Results of Trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group 87

PURPOSE Approximately 20% of children with acute lymphoblastic leukemia (ALL) suffer a relapse, and their prognosis is unfavorable. Between 1987 and 1990, the multicenter trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group (ALL-REZ BFM) 87 was conducted to establish a uniform treatment for these children in Germany and Austria. PATIENTS AND METHODS Of 207 registered patients, 183 patients were stratified into three groups according to the protocol: A, early bone marrow (BM) relapse (n = 56); B, late BM relapse (n = 101); C, isolated extramedullary relapse (n = 26). Treatment consisted of risk-adapted alternating short-course multiagent systemic and intrathecal chemotherapy, cranial irradiation, if indicated, and conventional maintenance therapy. Additionally, 24 patients with an exceptionally poor prognosis (early BM or any relapse of T-cell ALL) were treated with individual regimens. In 35 patients, stem-cell transplantation was performed. RESULTS The probability of event-free survival (EFS) and overall survival of all registered patients at 15 years was 0.30 +/- 0.03 and 0.37 +/- 0.03, respectively, with significant differences between the strategic groups (A, 0.18 +/- 0.05 and 0.20 +/- 0.05; B, 0.44 +/- 0.05 and 0.52 +/- 0.05; C, 0.35 +/- 0.09 and 0.42 +/- 0.10). Despite risk-adapted treatment, an early time point of relapse and T-lineage immunophenotype were significant predictors of inferior EFS in uni- and multivariate analyses. CONCLUSION With the ALL-REZ BFM 87 protocol, more than one-third of patients may be regarded as cured from recurrent ALL with second complete remissions lasting more than 10 years. Immunophenotype and time point of relapse are important prognostic factors that allow us to adapt more precisely treatment intensity to individual prognosis in future trials.

Risk factors for diabetes insipidus in langerhans cell histiocytosis

Diabetes insipidus (DI) is the most frequent central nervous system (CNS)‐related permanent consequence in Langerhans cell histiocytosis (LCH), which mostly requires life‐long hormone replacement therapy. In an attempt to define the population at risk for DI, 1,741 patients with LCH registered on the trials DALHX 83 and DALHX 90, LCH I and LCH II were studied.

Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH)-III tested risk-adjusted, intensified, longer treatment of multisystem LCH (MS-LCH), for which optimal therapy has been elusive. Stratified by risk organ involvement (high [RO+] or low [RO-] risk groups), > 400 patients were randomized. RO+ patients received 1 to 2 six-week courses of vinblastine+prednisone (Arm A) or vinblastine + prednisone + methotrexate (Arm B). Response triggered milder continuation therapy with the same combinations, plus 6-mercaptopurine, for 12 months total treatment. 6/12-week response rates (mean, 71%) and 5-year survival (84%) and reactivation rates (27%) were similar in both arms. Notably, historical comparisons revealed survival superior to that of identically stratified RO+ patients treated for 6 months in predecessor trials LCH-I (62%) or LCH-II (69%, P < .001), and lower 5-year reactivation rates than in LCH-I (55%) or LCH-II (44%, P < .001). RO- patients received vinblastine+prednisone throughout. Response by 6 weeks triggered randomization to 6 or 12 months total treatment. Significantly lower 5-year reactivation rates characterized the 12-month Arm D (37%) compared with 6-month Arm C (54%, P = .03) or to 6-month schedules in LCH-I (52%) and LCH-II (48%, P < .001). Thus, prolonging treatment decreased RO- patient reactivations in LCH-III, and although methotrexate added no benefit, RO+ patient survival and reactivation rates have substantially improved in the 3 sequential trials. (Trial No. NCT00276757 www.ClinicalTrials.gov).

Long-term results of large prospective trials in childhood acute lymphoblastic leukemia.

Much progress has been made in the biological characterization of acute lymphoblastic leukemia (ALL). Many biologic features with prognostic significance have been used together with clinical factors to define patient groups for risk-adapted therapy. However, it is well recognized that the prognostic significance of virtually all variables depends on the type and intensity of treatment. The differences in risk classification, eligibility (eg upper or lower age limit) and composition of ethnic or racial population have made it difficult to compare results between study groups. The comparison is further complicated by the inclusion of only subsets of patients in some publications. In October 1985, an international workshop (organized by R Mastrangelo) was held in Rome during which recommendations were made to report study results by common, easily available criteria (age and presenting leukocyte count); to collect prospectively information on organ involvement, immunphenotype, genetics and treatment response; and to use standard statistical methods to analyze data.4 Despite this effort, different risk classifications continue to be used, and a large number of clinical trials had been conducted on subgroups of ALL, especially in the USA. In 1993, the US National Cancer Institute organized a workshop for the US cooperative study groups and major institutions to develop uniform risk criteria. The recommendations published in 19965 were more widely accepted. The major groups defined by age and leukocyte count were identical to that of the Rome workshop (Table 1). While the importance of cytogenetics and molecular genetics were recognized, they were not included in the risk criteria because the tests were not widely available at that time. The