ALBERT

Description: The efficacy of conventional and intensified chemotherapy in infant acute lymphoblastic leukemia (ALL) is limited worldwide particularly because of the high early relapses and treatment related mortality. We hypothesized that all-trans retinoid acid (ATRA) may participate in the differentiation of infant leukemic cells to normal progenitors with a consequent loss of malignant features and enhanced antiproliferative effects of chemotherapy. Our prospective multicenter non-randomized MLL-Baby/ALL-MB 2002 trial evaluated whether the novel recently developed ATRA based regimen, MLL-Baby is safe and more effective in the prevention of very early relapses comparing to ALL-MB 2002 - a well established protocol in Russia and Belarus. The trial was approved by Ethics Committees and parents’ informed consent was signed in all cases. The decision to receive MLL-Baby or ALL-MB 2002 was judged by the treating physician. The major difference between the 2 treatment approaches was the addition of ATRA in the MLL-Baby protocol. Patients were equally distributed of patients (pts.) between the two groups according to risk: only pts. with t(4;11) and/or MLL/AF-4 or without complete remission (CR) achieved on days 36/43 were subjects for the high risk group (HRG). The remaining pts were stratified to an intermediate risk group (IRG). Treatment schedules were also similar in both regimens except for CNS-disease prophylaxis: in MLL-Baby, cranial irradiation 12 Gy was retained only for HRG pts with initial CNS involvement who were older than 12 months and substituted by 5 additional intrathecal treatments, while all pts. allocated to ALL-MB 2002 1year of age underwent cranial irradiation 12 Gy, regardless of their initial CNS status and risk group. In MLL-Baby pts, the initial ATRA pulse in daily dose 25 mg/m2 was given after debulking of the main tumor from day 36 to day 43, followed by 12 in IRG and 16 in HRG 2-weeks of ATRA courses alternating with chemotherapy. Between September 2003 and November 2006, 40 pts. aged 1–12 months were enrolled onto MLL-Baby (n=19) and ALL-MB 2002 (n=21) protocols. Both groups were balanced for median age 8 (1–12) and 6 (2–12) months, p=0.47; initial WBC 115,5 (1,2–450) and 105,5 (2.6–350) per microliter, p=0.76; initial CNS disease 3 vs. 5, p=0.5; 11q23/MLL translocations 12 vs. 10 pts., including t(4;11) - 6 vs. 7 pts, p=0.74 and BI phenotype 9 and 4 cases correspondingly, p=0.37, respectively. No significant differences were observed between MLL-Baby and ALL-MB 2002 with respect to rates of induction deaths: 1 vs. 3 cases, CR rates 94.7% vs. 85.7%, deaths in CR 1 vs. 0; whereas the early relapse rate was higher with ALL-MB 2002 compared to MLL-Baby: RFS was 0.24±0.13 vs. 0.94±0.05 (p=0.02) with a median of follow-up 20 months (1–55). EFS differed significantly: 0.21±0.11 vs. 0.84±0.08 (p=0.03). Most relapses on ALL-MB 2002 (n=11) and MLL-Baby (n=1) developed very early: 7 of 11 pts. and 1 of 1 pt. respectively and were localized only to bone marrow in most cases: 6 of 11 pts. and 1 of 1 pt. correspondingly. Our data indicate that ATRA administration contributes positively towards early relapse-free outcome in infants with ALL. A prospective randomized clinical trial with longer follow-up is needed to confirm these results.

Description: Background Studies have shown that the incidence of inhibitor development varies between FVIII concentrates, with some suggesting that recombinant FVIII (rFVIII) concentrates produced in hamster cell lines pose a greater risk of inhibitor development than plasma-derived (pd) von Willebrand factor (VWF)-containing FVIII (pdFVIII/VWF) products. In the SIPPET study, the cumulative incidence of high-titer inhibitorswith hamster-cell derived rFVIII products was 28.4% vs 18.6% for pdFVIII/VWF (Peyvandi F et al. N Engl J Med 2016; 374:2054-2064). These studies did not include new generation rFVIII products produced in human cell lines. Nuwiq® (Human-cl rFVIII) is the first and only new-generation rFVIII produced in human cells without chemical modification or protein fusion. The pharmacokinetics, efficacy and safety of Nuwiq® have been examined in previously treated patients (PTPs) with severe hemophilia A, and no inhibitors have been reported in 201 PTPs. The immunogenicity, efficacy and safety of Nuwiq® in previously untreated patients (PUPs) with severe hemophilia A is currently being assessed in the ongoing NuProtect study. Methods The NuProtect study was initiated in 2013 and is being conducted in 17 countries and 38 centers worldwide. One hundred evaluable (110 enrolled) male PUPs of all ages and ethnicities are being studied for 100 exposure days (EDs) or a maximum study participation of 5 years. The patients were to have received no treatment with FVIII concentrates or other blood products containing FVIII prior to study entry. The primary objective of the NuProtect study is to assess the immunogenicity of Nuwiq® by determining inhibitor activity (≥0.6 BU) using the Nijmegen modified Bethesda assay in a central laboratory. Intensive screening for inhibitors is scheduled every 3-4 EDs until 20 EDs, then every 10-12 EDs until 100 EDs, and every 3 months until study completion. Secondary endpoints include assessment of hemostatic efficacy in prophylaxis, in the treatment of bleeds and in surgical prophylaxis, as well as safety and tolerability. All patients undergo F8 gene mutation analysis. Results Data from 85 treated PUPs have been included in the first pre-planned interim analysis (May 2016) of which 66 PUPs had ≥20 EDs (by which time the majority of inhibitors are likely to have arisen). The median age at first treatment was 13 months (range: 3-135). Of the 59 patients with available F8 gene mutation analysis, 1 (1.7%) had no identifiable mutation, 44 (74.6%) had mutations conferring a high risk of inhibitor development and 47 (81.0%) had null mutations. Data analysis in May 2016 showed that only 8 of the 66 PUPs treated with Nuwiq® for ≥20 EDs had developed a high-titer inhibitor after a median of 11.5 EDs (range 6-24). Five of the 66 PUPs developed a low-titer inhibitor, 4 (80%) of which were transient. Only 2 patients developed an inhibitor (1 high-titer) after 20 EDs. The cumulative incidence of high-titer inhibitors in PUPs treated with Nuwiq® is 12.8% (95% CI: 4.49-21.15) (Figure 1). The cumulative incidence of low-titer inhibitors was 8.4% (95% CI: 1.28-15.59) and of all inhibitors was 20.8% (95% CI: 10.68-30.95). No patient developed an inhibitor after 25 EDs. The incidence has remained consistent since the start of the study in 2013. Twelve of 13 patients who developed inhibitors had the causative F8 gene mutation detected, all of which were null, and all but one were high-risk. Conclusions PUPs treated with Nuwiq® for ≥20 EDs had 12.8% cumulative incidence of high-titer inhibitorsat the time of interim analysis (8 of 66 PUPs) despite the fact that 81% of patients had gene mutations known to be associated with increased inhibitor risk (e.g. null mutations). These interim data support the low rate of inhibitor development in PUPs treated with Nuwiq® - a human-cell derived (not chemically modified or protein fused) recombinant FVIII. Final data from the NuProtect study are expected in 2018 and will provide further insights into the development of inhibitors in PUPs with severe hemophilia A. Figure 1. Cumulative incidence of inhibitor development Figure 1. Cumulative incidence of inhibitor development Disclosures Liesner: CSL Behring: Consultancy, Honoraria, Research Funding; Biogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; SOBI: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; BPL: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Cangene: Research Funding; Baxalta Innovations GmbH, now a part of Shire: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria. Altisent:Baxalta: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Grifols: Consultancy; Pfizer: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; Octapharma: Consultancy. Belletrutti:Shire Pharmaceuticals (formerly Baxalta): Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; NovoNordisk: Other: Travel support. Borel-Derlon:LFB: Other: Reference expert and national coordinator for VWD; Shire - Baxalta: Research Funding; Octapharma: Research Funding; NovoNordisk: Other: Expert for scientific committee. Ducore:CSL Behring: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; LFB: Membership on an entity's Board of Directors or advisory committees; Octapharama: Membership on an entity's Board of Directors or advisory committees; Baxalta (Shire): Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Sigaud:Shire - Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Acute lymphoblastic leukemia (ALL) in infants (less than 1 year old) is a unique tumor with distinct biological features and poor outcome even when modern treatment schemes are used. Rearrangementsof MLL-gene, located in 11q23 region, are detected in approximately 75-80% of infants with ALL and lead to treatment resistance and high relapse rate. Nevertheless patients with germline MLL also demonstrate inferior outcome compared to ALL in older children. Thus additional risk factors implementation is one of the crucial points in infant ALL management. Minimal residual disease (MRD) measurement by multicolor flow cytometry (FCM) or various PCR technics is a well-standardized method of treatment response evaluation in childhood ALL, although in infants MRD data is not so widely applied. The aim of the study was to evaluate the relapse prediction feasibility in infant ALL by FCM MRD assessment during remission induction of MLL-Baby protocol. Methods. Totally 89 infants aged from 5 days to 11 months were enrolled in the present study. In 23 cases (25.8%) MLL gene was germline (MLL-g group), 33 patients (37.1%) had MLL-AF4 fusion while in remaining 33 cases (37.1%) other types of MLL-rearrangements were found. All patients were diagnosed as B-cell precursor ALL and all were treated by well established in Russia and Belarus MLL-Baby protocol, which is specially designed for infant ALL management. MRD was measured by 6-10-color FCM in bone marrow (BM) samples obtained at day 15 and at the end of remission induction (day 36). The availability of samples at at least one of these time-points was the only criteria for study group completion. In 43 patients with known types of MLL-rearrangements MRD was also assessed by fusion gene transcript (FGT) detection in RQ-PCR after first consolidation or first high risk block (for intermediate risk and high risk groups respectively). Relapse risk was investigated by cumulative incidence of relapse (CIR) estimation. Median of follow-up was 3 years 10 months. Results. Finally at day 15 MRD was studied in 71 cases. 17 patients (23.9%) were tested MRD-negative while remaining ones displayed various levels of MRD-positivity: 8 cases (11.3%) - from 0.01% to 0.1%; 14 (19.7%) - from 0.1% to 1%; 22 (31.0%) - from 1% to 10%; 10 (14.1%) - more than 10%. Proportion of MRD-positivity was lower in MLL-g group compared to MLL-rearranged (MLL-r) patients (58.8% and 81.5% respectively, p=0.06). Prognostic impact of day 15 MRD differed due to MLL-status. In MLL-r group significant differences between MRD(+) and MRD(-) patients were observed (n=10, CIR 0.28(0.18) and n=37, CIR 0.67(0.08) respectively, p=0.025). At the same time in MLL-g group these outcome differences were not significant (n=7, CIR 0 and n=9, CIR 0.22(0.14) correspondingly, p=0.197). Interestingly, in patients carrying MLL-AF4 fusion, known to be one of the most adverse types of MLL-rearrangements, day 15 MRD-negativity predicted low relapse incidence (n=5, CIR 0 and n=16, CIR 0.68(0.12) respectively, p=0.045). Thus day 15 MRD-negativity allows to detect low-risk MLL-r infants but it is not applicable in MLL-g group. It was previously shown that any detectable level of FGT after first consolidation or first high risk block predicts very poor outcome in MLL-r cases (G. Tsaur et al, ASH-2011). In current series RQ-PCR data in patients, FCM MRD(+) at day 15, distinguished groups of intermediate and very high relapse risk (n=17, CIR 0.51(0.13) and n=18, CIR 0.84(0.09) respectively, p=0.017). At day 36 FCM MRD was assessed in 82 infants. Among them 35 (42.7%) were tested negative while remaining 47 (57.3%) were MRD(+) at various levels. Prognostic value of day 36 FCM MRD data in MLL-r group was not significant: MRD(+) patients (n=23) had CIR of 0.71(0.08) while in MRD(-) cases (n=33) CIR was 0.49(0.12), p=0.153. Conversely, in MLL-g group low end-induction MRD (less than 0.1%) lead to excellent outcome compared to patients with higher MRD (n=14, CIR 0 and n=7, CIR 0.22(0.20) respectively, p=0.010). Conclusions. Thus FCM MRD data could distinguish infants with low risk of ALL relapse, but in MLL-r and MLL-g groups different time-points are prognosticaly significant. In MLL-g patients tandem application of FCM at early time-point and RQ-PCR later could help to define groups with low, intermediate and high relapse risk. MRD data could be added to MLL-Baby protocol risk group stratification, which is currently based on type of MLL-rearrangement. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 2731 Background. Despite many attempts worldwide treatment results for infants with MLL rearrangements and especially MLL-AF4 remain unsatisfied. MLL-Baby protocol was developed for infant acute lymphoblastic leukemia (ALL). In this treatment approach conventional chemotherapy is augmented by administration of all-trans retinoic acid (ATRA). This treatment program is successfully applied for infant ALL within Russian Federation and Republic of Belarus (L. Fechina et al, ASH 2007 #2828). Minimal residual disease (MRD) is a strong tool for risk-adapted treatment. Majority of infants carry MLL rearrangements, so in this group MRD monitoring by quantification of fusion gene transcripts (FGt) is fast, easy and cost-effective approach. Objective. To evaluate the prognostic significance of MRD monitoring by FGt measurements in MLL-rearranged infant ALL, enrolled into MLL-Baby study. Methods. Twenty three infants with defined MLL translocation partner genes who received at least two ATRA courses were included in the current study. Median of follow-up period in the observed group was 41 months. Presence of MLL rearrangements was detected by FISH and confirmed by long-distance inverse PCR (C. Meyer et al, 2005). MRD detection in bone marrow (BM) was performed by real-time quantitative PCR and qualitative nested reverse-transcriptase PCR as previously described (A. Borkhardt et al.,1994, J. van Dongen et al., 1999, N. Palisgaard et al., 1998, J. Gabert et al, 2003) with sensitivity 1E–05. MRD-negativity was defined as absence of FGt in both assays. Among 23 infants there were 13 MLL-AF4-positive patients (pts), 4 MLL-MLLT10-positive pts, 3 MLL-EPS15-positive pts, 2 MLL-MLLT1-positive pts and one MLL-MLLT3-positive patient. BM samples were obtained at the time of diagnosis, on day 15 of remission induction (time point (TP) 1), at the end of remission induction (TP2) and after each course of ATRA administration (TP3-TP9). Informed consent was obtained in all cases. Results. All patients were MRD-positive at TP1. At TP2 two MLL-MLLT10-positive patients became MRD-negative. At TP3 other 4 pts (3 MLL-AF4-positive and 1 MLL-MLLT1-positive) converted to MRD-negativity. By TP4 18 pts were MRD-negative, while FGt were detected in 5 pts. 2 pts became MRD-negative before protocol II (at TP9), while 3 pts never achieved MRD-negativity. Retrospectively, we compared prognostic significance of MRD at each TP. TP4 was the earliest TP when discriminative data was obtained. According to the qualitative MRD results at this TP pts were divided into MRD-positive and MRD-negative groups. The first group consisted of 18 pts with different MLL translocation partner genes, while the second group included 5 MLL-AF4-positive pts, who remained MRD-positive at TP4. Groups did not differ in age at diagnosis, sex distribution, initial WBC count, immunophenotype, type of MLL partner gene, number of blast cells at day 8 of dexamethasone prophase, BM status on day 15, CNS disease, and achievement of hematological remission at day 36. Number of relapses was significantly higher in the second group (p=0.017). Odds ratio was 20.00 with 95% CI 1.61–247.99. In the first group there were 3 relapses (in one MLL-AF4-positive case and two MLL-EPS15-positive cases) while in the second group 4 relapses occurred. Cumulative incidence of relapse for pts who achieved MRD-negativity by TP4 was 0.17, for MRD-positive pts 0.80 (p=0.005). 7-years event-free survival in the first group was 0.82±0,09, in the second group 0.20±0.17 (p=0.008) (fig 1). Conclusions. MRD monitoring by FGt measurements has significant prognostic value in infants with MLL-rearranged ALL treated by MLL-Baby protocol. In our series achievement of MRD-negativity by TP4 corresponds to favorable outcome in infant ALL with MLL rearrangements treated by MLL-Baby protocol. Persistence of MRD-positivity at TP4 allows to define group with high incidence of relapse. Disclosures: No relevant conflicts of interest to declare.

Description: Acute lymphoblastic leukemia (ALL) in infants is a relatively rare disease with peculiar biological features, high frequency of KMT2A gene rearrangements and grim prognosis. Even with new therapeutic approaches, event-free survival (EFS) in infants with ALL does not exceed 50%. Currently large cooperative studies of infant ALL have been promoted by the Interfant and MLL-Baby networks. Minimal residual disease (MRD) monitoring is considered a strong tool for optimizing management of childhood ALL. In contrast to older children in this age group the prognostic impact of MRD detected by multicolor flow cytometry (MFC) is still unclear. Aim of the present study was to evaluate the prognostic value of MFC MRD measurement during induction in infants with ALL treated with Interfant-99 and Interfant-06 protocols in AIEOP centers in Italy as well as MLL-Baby protocol in Russia and Belarus. Patients and methods. Two independent groups of patients were investigated: study cohort of 139 consecutive infants with newly diagnosed ALL enrolled between September 2003 and April 2016 in Russian and Belorussian centers with MLL-Baby protocol and validation group of 146 ones enrolled in AIEOP centers in Interfant trials during the same period. By availability of MFC MRD data obtained at day 15 and/or end of induction (EOI), 81 and 86 patients of study and validation cohorts respectively were selected for outcome evaluation. In 61 MLL-Baby patients (75.3%) and 61 AIEOP cases (70.9%) different types of KMT2A gene rearrangements were identified. All patients were diagnosed as BCP-ALL, except one with cortical T-ALL. Overall, day 15 samples were studied in 64 MLL-Baby patients and 73 AIEOP cases while EOI samples in 75 and 63 cases respectively. MRD detection was performed in Reference Laboratories in Ekaterinburg, Minsk and Padua according the BFM AIEOP FLOW Network SOP. MRD negativity was defined as

Description: Abstract 1515 Treatment achievements in infant's acute lymphoblastic leukemia (ALL) are still very modest. Despite of many attempts, the creation of novel, based on the molecular mechanisms, clinically approved and safe therapy strategies for this group of patients (pts) seems to be slow, so far. We also have developed a new treatment approach for infants with acute leukemia – MLL-Baby protocol, which includes 1 or 2 weeks ATRA consecutive courses at the dosing schedule of 25 mg/m2/d adjusted to age, started immediately after induction completion, alternating with standard chemotherapy and/or simultaneously applied with re-inductions. Rationale for ATRA application and MLL-Baby details were introduced in our previous report (ASH 2007 Abstract #2828). We have described there a small group of 19 primary diagnosed ALL infants, who underwent MLL-Baby protocol treatment in comparison to the group treated by standard chemotherapy with 20 months (mo.) median of follow up. ATRA-containing regimen has been shown well tolerated and improved early relapse free survival (RFS) significantly. Aim. To re-assess the ATRA efficacy in more representative group of pts with longer time of follow up. From September 2003 108 pts with primary ALL younger 12 mo. were non-randomly allocated either to ATRA (+) treatment approach (MLL-Baby) – 75 pts or ATRA (-) standard chemotherapy (mainly ALL-MB) – 33 pts due to decision of the treating physicians from 24 participating clinics in Russia and Belarus. Parents' informed consent was signed in all cases. The trial was approved by Ethics Committees. Both ATRA (−) and ATRA (+) groups were similar by the initial characteristics: median age 6 (1–11) and 6 (0–11) mo.; m/f ratio 12/21 and 25/50; initial WBC 96,7 (0,7–940) and 83,9 (1,6–2058) per microliter respectively, although CNS involvement seems to be more frequent in ATRA (+) group: 4 (12%) and 18 (24%) pts correspondingly. MLL rearrangements (MLL pos.) were found in 15 (53,6%) from 28 examined ATRA (−) pts and in 53 (70,7%) from 75 ATRA (+) pts. BI phenotype predominance was evident in ATRA (+) group - 39 (52,7%) out of 74 examined pts. The number of pts who have achieved CR was equally high in both schedules: 28 (84,9%) and 67 (89,3%) but the relapses rates remains significantly different: 16 (57,1%) and 16 (23,8%) pts in ATRA (-) and ATRA (+) groups respectively (p=0,001). Eight years RFS is 0,36 ± 0,08 and 0,59 ± 0,06 (p=0,02); cumulative incidence of relapses (RCI) is 0,62 ± 0,01 and 0,31 ± 0,004 (p=0,03) in ATRA (−) and ATRA (+) groups correspondingly, although EFS: 0,54 ± 0,06 vs. 0,33 ± 0,08 (p=0,17) and OS: 0,59 ± 0,06 vs. 0,36 ± 0,08 (p=0,09), median of follow up - 36 mo. (2 - 105), did not differ significantly between 2 groups ATRA (+) and ATRA (−) respectively due to the high proportion of induction and remission deaths. Among 75 pts treated by MLL-Baby – 7 (9,3%) died in induction and 7 (10,4%) out of 67 pts who achieved CR died in remission with median time to death – 2 mo., mostly because of severe infections. Out of 46 MLL pos. pts from ATRA (+) group who achieved CR, 14 (30%) pts relapsed, RFS is 0,59 ± 0,08 and RCI 0,40 ± 0,007. In contrast, in ATRA (−) group the relapse incidence in MLL pos. pts was very high - 12 (80%) out of 15 pts who achieved CR (p=0,008), RFS is 0,20 ± 0,10 (p=0,01) and RCI 0,80 ± 0,01 (p=0,02) correspondingly. In univariate analysis the following risk-factors: age 〈 6 mo. (p=0,001); MLL rearrangements (p=0,004) and dexamethasone response on Day 8 (p=0,01) have a significant negative impact on EFS in group of pts treated by MLL-Baby. Cox-regression analysis confirms the negative value of the same risk-factors: MLL pos. status with Hazard Ratio (HR) 3,8 (95% CI 1,32-10,9) p=0,01; age HR 3,18 (95%CI 1,5–6,8) p=0,003 and Day 8 response HR 3,16 (95% CI 1,4–7,1) p=0,005. Conclusions. The updated results in our cohort of 75 patients demonstrated that ATRA confirms effectiveness in the relapses prevention in infants suffering from ALL, if used in combination with standard chemotherapy without any escalation and bone marrow transplantation. Although the molecular mechanisms of ATRA effect are still poorly understood and need to be deeply explored, it might be recommended for randomization within representative international studies, particularly to the MLL rearranged infant's ALL. Great efforts in non-relapse mortality reduction should be applied by all participating clinics. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 184 Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML Therapy Introduction: With improving initial antileukemic therapy, CNS disease might become more important in AML. We therefore evaluated the incidence of CNS involvement in a large series of children with first relapsed AML. In addition, clinical and biological features of children with and without CNS involvement at relapse were compared, and finally the prognostic significance of CNS involvement at relapse was studied. Materials and Methods: Patients were selected from those registered in the setting of study Relapsed AML 2001/01 (ISRCTN code 94206677), based on having first relapsed AML and precise information on the location of the relapse, and on the type of CNS involvement. The latter was distinguished in asymptomatic and symptomatic disease. The protocol prescribed intensive intrathecal triple chemotherapy in case of CNS disease: first dose immediately before start of reinduction course 1. Second and subsequent doses every 7 days until 1 week after complete blast clearance of the CSF or disappearance of radiological abnormalities. Then, 2 more doses were given, one immediately before the start of the second reinduction course, and the other at the start of consolidation treatment. Cranial radiotherapy was not generally recommended and was actually used in 18% of patients with CNS relapse. Systemic therapy consisted of FLAG with or without liposomal daunorubicin (1:1 randomisation), followed by FLAG and allogeneic stem cell transplantation. This clinical study also enrolled patients with a combined relapse, or an isolated extramedullary relapse, or a bone marow relapse (isolated or combined) with

Description: Objectives: A decade after being licensed for treatment of CML in minors, the TKI imatinib (IMA) is well known for it's inhibitory off-target effects on activity and proliferative capacity of osteoclasts and osteoblasts resulting in impaired bone remodeling (Vandyke K et al 2010 Blood 115:766; Tauer JT et al Blood 2011:118). This causes longitudinal growth retardation in not outgrown individuals (Millot F et al 2009 Blood 114:863; Shima H et al 2011 Pediatrics 159:676; Bansal D et al 2012 Ped Blood Cancer 59:481) which can be aggravated by a disrupted growth hormone:IGF-I axis as a possible additional off-target effect exerted by TKI treatment (Ulmer A et al 2013 Klin Padiatr 225:120; Bansal D et al 2012 Ped Blood Cancer 59:481). Starting a pediatric trial in the year 2006 which recruits approx. 15 pediatric patients (pts) with CML annually, we investigated to what extend growth is impaired depending on sex, age, and pubertal stage at start of IMA treatment in a pediatric cohort. Methods: 102 pts (54 male / 48 female; median age 12 years, range: 1-18 years) at diagnosis of CML receiving IMA as upfront treatment were enrolled retrospectively in this analysis from centers in Germany and participating countries during 02/2006 to 06/2014. Height standard deviation scores (SDS) were derived from WHO-AnthroPlus, version 1.04 software, a global growth-monitoring tool providing normal range values for the age cohorts from birth till 19 years. 81 out of 102 pts fulfilled the criteria for continuous assessment of growth scheduled at three months intervals during IMA exposure. 21 pts were analyzed at intervals ≠ 3 month. Pts excluded comprised individuals shifted to a 2nd generation TKI, or cumulative interruptions of drug intake exceeding 4 weeks, or pts undergoing stem cell transplantation. Results: The mean and median duration of IMA exposure was 12 months and 9 months, respectively (range: 0–98 month). 27/102 pts (13 male, 14 female) were prepubertal (age: 14 years; 18 male, 11 female). In comparison to mean SDS at diagnosis a mean decrease in height of 0.48 SDS per year was observed in the total cohort during the first three years of treatment, being more pronounced in prepubertal pts. In pts diagnosed shortly before or at puberty a mean reduction of 0.75 SDS per year during the first three years were observed. Older teenagers revealed no change in body height z-score during TKI treatment compared to height z-score at diagnosis. Discussion: Growth retardation is a significant adverse effect of IMA in children with CML affecting predominantly prepubertal children. Possible medical interventions still need to be investigated. Acknowledgment: Supported by grant DFG SU122-3/1 to MS. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.