Kim Vettenranta

Risk group assignment differs for children and adults 1–45 yr with acute lymphoblastic leukemia treated by the NOPHO ALL‐2008 protocol

The prognosis of acute lymphoblastic leukemia is poorer in adults than in children. Studies have indicated that young adults benefit from pediatric treatment, although no upper age limit has been defined.

Molecular and Clinical Heterogeneity in CLCN7-dependent Osteopetrosis: Report of 20 Novel Mutations

The “Osteopetroses” are genetic diseases whose clinical picture is caused by a defect in bone resorption by osteoclasts. Three main forms can be distinguished on the basis of severity, age of onset and means of inheritance: the dominant benign, the intermediate and the recessive severe form. While several genes have been involved in the pathogenesis of the different types of osteopetroses, the CLCN7 gene has drawn the attention of many researchers, as mutations within this gene are associated with very different phenotypes. We report here the characterization of 25 unpublished patients which has resulted in the identification of 20 novel mutations, including 11 missense mutations, 6 causing premature termination, 1 small deletion and 2 putative splice site defects. Careful analysis of clinical and molecular data led us to several conclusions. First, intermediate osteopetrosis is not homogeneous, since it can comprise both severe dominant forms with an early onset and recessive ones without central nervous system involvement. Second, the appropriateness of haematopoietic stem cell transplantation in CLCN7‐dependent ARO patients has to be carefully evaluated and exhaustive CNS examination is strongly suggested, as transplantation can almost completely cure the disease in situations where no primary neurological symptoms are present. Finally, the analysis of this largest cohort of CLCN7‐dependent ARO patients together with some ADO II families allowed us to draw preliminary genotype‐phenotype correlations suggesting that haploinsufficiency is not the mechanism causing ADO II. The availability of biochemical assays to characterize ClC‐7 function will help to confirm this hypothesis.

Complying with the European Clinical Trials directive while surviving the administrative pressure – An alternative approach to toxicity registration in a cancer trial

The European Clinical Trials Directive of 2004 has increased the amount of paper work and reduced the number of initiated clinical trials. Particularly multinational trials have been delayed. To meet this challenge we developed a novel, simplified, fast and easy strategy for on-line toxicity registration for patients treated according to the Nordic/Baltic acute lymphoblastic leukaemia protocol, NOPHO ALL 2008, for children and young adults, including three randomisations. We used a risk-assessment based approach, avoiding reporting of expected adverse events and instead concentrating on 20 well-known serious, but rarer events with focus on changes in therapy introduced in the treatment protocol. This toxicity registration strategy was approved by the relevant regulatory authorities in all seven countries involved, as compliant within the EU directive of 2004. The centre compliance to registration was excellent with 98.9% of all patients being registered within 5weeks from the requested quarterly registration. Currently, four toxicities (thrombosis, fungal infections, pancreatitis and allergic reactions) have been chosen for further detailed exploration due to the cumulative fraction of patients with positive registrations exceeding 5%. This toxicity registration offers real-time toxicity profiles of the total study cohort and provides early warnings of specific toxicities that require further investigation.

The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse

Drug doses, blood levels of drug metabolites and myelotoxicity during 6-mercaptopurine/methotrexate (MTX) maintenance therapy were registered for 59 adolescents (⩾10 years) and 176 non-adolescents (<10 years) with B-cell precursor acute lymphoblastic leukemia (ALL) and a white blood cell count (WBC) <50 × 109/l at diagnosis. Event-free survival was lower for adolescents than non-adolescents (pEFS12y:0.71 vs 0.83, P=0.04). For adolescents staying in remission, the mean WBC during maintenance therapy (mWBC) was related to age (rS=0.36, P=0.02), which became nonsignificant for those who relapsed (rS=0.05, P=0.9). The best-fit multivariate Cox regression model to predict risk of relapse included mWBC and thiopurine methyltransferase activity, which methylates mercaptopurine and reduces the intracellular availability of cytotoxic 6-thioguanine nucleotides (coefficient: 0.11, P=0.02). The correlation of mWBC to the risk of relapse was more pronounced for adolescents (coefficient=0.65, P=0.003) than for non-adolescents (coefficient=0.42, P=0.04). Adolescents had higher mean neutrophil counts (P=0.002) than non-adolescents, but received nonsignificantly lower mercaptopurine and MTX doses during maintenance therapy. Red blood cell MTX levels were significantly related to the dose of MTX among adolescents who stayed in remission (rS=0.38, P=0.02), which was not the case for those who developed a relapse (rS=0.15, P=0.60). Thus, compliance to maintenance therapy may influence the risk of relapse for adolescents with ALL.

The incidences of malignant gonadal and extragonadal germ cell tumors in males and females: a population-based study covering over 40 years in Finland.

PurposeGerm cell tumors (GCTs) comprise a heterogeneous group of tumors derived from primordial germ cells. The incidence of malignant testicular GCTs has increased in recent decades, but little is known about possible changes in malignant female GCTs. Population-based data covering all malignant GCTs in both sexes remain limited.MethodsAll cases of malignant GCTs in 1969–2008 were collected from the Finnish Cancer Registry and their age-adjusted annual incidences calculated.ResultsThe overall incidence of malignant GCTs was 2.56 per 100,000 person-years in males and 0.34 per 100,000 in females. The incidence of gonadal GCTs increased from 2.27 to 8.36 per 100,000 in males between 15 and 44xa0years of age. Moreover, the incidence of all histological subtypes of gonadal GCTs increased in males. In females, the only increase was seen in the incidence of ovarian non-dysgerminoma (from 0.07 to 0.29/100,000). The incidence of extragonadal GCTs did not change during the study period, being 0.18 and 0.10 per 100,000 in males and females, respectively.ConclusionsThe incidence of gonadal GCTs in males increased significantly during the 40-year study period, whereas in females, no such change was observed. There were significant gender differences regarding the distribution of histological subtypes and patients’ ages. However, the incidence of extragonadal GCTs remained low in both sexes. The differences in the incidences of gonadal GCTs derived from the same population suggest that the risk factors of these malignancies differ between the two sexes.

Results of NOPHO ALL2008 treatment for patients aged 1–45 years with acute lymphoblastic leukemia

Adults with acute lymphoblastic leukemia (ALL) do worse than children. From 7/2008 to 12/2014, Nordic and Baltic centers treated 1509 consecutive patients aged 1–45 years with Philadelphia chromosome-negative ALL according to the NOPHO ALL2008 without cranial irradiation. Overall, 1022 patients were of age 1–9 years (A), 266 were 10–17 years (B) and 221 were 18–45 years (C). Sixteen patients (three adults) died during induction. All others achieved remission after induction or 1–3 intensive blocks. Subsequently, 45 patients (12 adults) died, 122 patients relapsed (32 adults) with a median time to relapse of 1.6 years and 13 (no adult) developed a second malignancy. Median follow-up time was 4.6 years. Among the three age groups, older patients more often had higher risk ALL due to T-ALL (32%/25%/9%, P<0.001), KMT2A rearrangements (6%/5%/3%, P<0.001) and higher day 29 residual leukemia for B-lineage (P<0.001), but not T-ALL (P=0.53). Event-free survival rates (pEFS5y) were 89±1% (A), 80±3% (B) and 74±4% (C) with significant differences only for non-high risk groups. Except for thrombosis, pancreatitis and osteonecrosis, the risk of 19 specified toxicities was not enhanced by age above 10 years. In conclusion, a pediatric-based protocol is tolerable and effective for young adults, despite their increased frequency of higher risk features.

The use of plerixafor in harvesting autologous stem cells in the pediatric setting.

The mobilization of stem cells using the standard approach, chemotherapy and G‐CSF, may not be successful in all cases heavily pretreated. Plerixafor (AMD3100) has emerged as a viable option in attempts to mobilize stem cells among these patients. The use of plerixafor in the adult setting has been established, but data on pediatric use is scarce. We report on the use of plerixafor in eight pediatric cases either as add‐on to chemotherapy plus G‐CSF or in remobilization. Pediatr Blood Cancer 2012; 59: 197–198.

Individualized toxicity-titrated 6-mercaptopurine increments during high-dose methotrexate consolidation treatment of lower risk childhood acute lymphoblastic leukaemia. A Nordic Society of Paediatric Haematology and Oncology (NOPHO) pilot study.

This study explored the feasibility and toxicity of individualized toxicity‐titrated 6‐mercaptopurine (6MP) dose increments during post‐remission treatment with High‐dose methotrexate (HDM) (5000u2003mg/m2, ×3) in 38 patients with Childhood (ALL). Patients were increased in steps of 25u2003mg 6MP/m2 per day if they did not develop myelotoxicity within 2u2003weeks after HDM. 6MP could be increased in 31 patients (81%). Toxicity was acceptable and did not differ significantly between groups. Patients receiving 75u2003mg/m2 per day had significantly shorter duration of treatment interruptions of 6MP than the remaining patients (Pu2003=u20030·03). This study shows individualized toxicity‐titrated 6MP dosing during consolidation is feasible without increased risk of toxicity.

Use of intrathecal chemoprophylaxis in children after SCT and the risk of central nervous system relapse

Conflicting conclusions can be drawn from the available data concerning antileukemic efficacy and risks of intrathecal (i.t.) chemoprophylaxis to children after hematopoietic SCT (HSCT). To address this, we enrolled six transplantation centers with similar treatment and patient material. Of the 397 children included, 136 patients had received post-HSCT i.t. treatment (i.t. group) and 261 had not (non-i.t. group). The two groups were, apart from the i.t. therapy given or not given, at equal risk of post-HSCT central nervous system (CNS) relapse, which was the primary endpoint studied. Isolated CNS relapses were observed in 2 (1.5%) patients from the i.t. group and 2 (1%) from the non-i.t. group. Combined relapses, including CNS, involved 4 (3%) patients from the i.t. group and 6 (2%) from the non-i.t. group. Overall survival and the occurrence of neurological side effects did not differ significantly between the groups. There was no statistically significant difference in the incidence of isolated or mixed CNS relapses between the two groups, suggesting little or no benefit from i.t. therapy post-HSCT in children.

In vitro cellular drug resistance adds prognostic information to other known risk-factors in childhood acute lymphoblastic leukemia.

Leukemic cells from 230 children with newly diagnosed B-cell precursor ALL were tested for in vitro drug resistance to a panel of anti-cancer drugs. Minimal residual disease (MRD) was measured by RQ-PCR. During follow-up, 24 relapses occurred in the 159 children with MRD <0.1% day 29. The risk of any relapse was correlated to vincristine and doxorubicin resistance, with a relative risk of 3.7 (95% CI 1.3-10.5; p=0.016) for patients resistant to both drugs. There was a significant correlation also for the subgroup with extra-medullary relapses. Our findings indicate that analysis of drug resistance can add prognostic information to other known risk-factors including MRD.