Abstract 1508
The long term prognosis of ETV6/RUNX1 -positive acute lymphoblastic leukemia (ALL) remains to be evaluated with regard to the frequency of late relapses and the possible existence of a ...preleukemic stem cell. We performed a retrospective study based on a long-term follow up of the FRALLE 93 ALL relapses to address the issue of the outcome of ETV6/RUNX1 -positive ones.
1395 patients aged 0 to 20 years with untreated ALL (except L3) were included between 01-Jan-1993 and 31-Dec-1999. From 1995, children were systematically screened for four fusion transcripts (ETV6-RUNX1, BCR-ABL, E2A-PBX1, MLL-AF4). The FRALLE 93 study population was stratified into three groups (low-risk LR, intermediate-risk IR, and high-risk HR) based on the following prognostic factors: age, white-cell count at diagnosis, haemoglobin level, immunophenotype, karyotype, and response to steroids. Patients received an initial treatment comprised of a prednisone prophase and a triple-drug intrathecal injection. Induction treatment then included prednisone, vincristine, L-asparaginase, daunorubicin (except for the LR group), and one or two more triple-drug intrathecal injections (TIT). The main treatment features of the SR and IR protocol were induction, consolidation, delayed intensification, and maintenance (total treatment duration of 26 and 38 months for girls and boys respectively). Treatment of the HR patients consisted of induction, consolidation, two delayed intensifications, and maintenance with a total treatment time of 2 years. Depending on subgroups, CNS-directed therapy included intrathecal injections +/− high-dose methotrexate +/− cranial irradiation. Following factors influencing survival after first relapse were analyzed: age, leukocytosis, gender, duration of first remission (CR1), risk groups defined in the REZ-BFM 95/96 study, sites of relapse and post CR2 consolidation treatment (AlloSCT or not).
Results. ETV6/RUNX1 status was defined for 724 patients B lineage ALL. Overall, 162 of the 713 children who reached CR1 (45 % of boys) relapsed, including 43 with t(12;21). Cumulative incidence of relapses did not differ between ETV6/RUNX1 -positive and negative ALL (p=0.94), with a 5-year estimate at 19.4% and 19.9%, respectively nor according to gender and type of relapse. Nevertheless, 11 out of 26 relapses in the ETV6/RUNX1 -positive ALL males (43%) were testicular (4 testis isolated) versus 16 out of 70 (23%) in ETV6/RUNX1 -negative ALL cases (p= 0.04). Thirty three (77%) had been stratified as LR (n=6) or IR (n=27) group and 32 displayed good early response at initial diagnosis. Thirty five (81.4%) patients were classified as S1/S2 and 8 (18.6%) as S3/S4. All but three received second line salvage therapy (37/40 were included in the COOPRALL 97) and 16 underwent an AlloSCT (6 S3/S4). Based on univariate analyses, the overall survival of ETV6-RUNX1 -positive ALL after relapse was significantly affected by the duration of the first remission with a OS that was significantly improved when relapse occurred after 36 months (5-year OS: 80.6+/−7.9% versus 34.7+/− 12.3, p=0.002). Female gender was also associated with a poor survival (p= 0.015), whereas the site of relapse (p= 0.13), age at initial diagnosis (p= 0.81), leukocytosis (p=0.42), and consolidation strategy (p=0.18) had no affect on survival. In multivariate Cox-regression analysis, only the duration of first remission remained associated with the outcome (Figure 1).
We found a high rate of testicular relapse without any increase of other extramedullary sites and an excellent outcome for ETV6/RUNX1 -positive leukemia relapses occurring over 36 months post-diagnosis. These findings highlight the interest of a primary treatment able to cross the testicular barrier. They also support the hypothesis that ETV6/RUNX1 “late relapses” are due to a novel leukemic clone, sensitive to a novel cycle of ALL chemotherapy. Display omitted
No relevant conflicts of interest to declare.
Abstract▪2100▪This icon denotes a clinically relevant abstract
Autoimmune hemolytic anemia (AIHA) in children is in more than half cases characterized by a severe course, with prolonged need of ...immunosuppressive therapy. Rituximab is a chimeric anti-CD20 monoclonal antibody increasingly used for treating severe autoimmune diseases. Paediatric experience in AIHA is only made of case reports and short series. The Rare Disease Plan gave us the opportunity to conduct national studies on those rare pediatric diseases.
At the end point of August 1, 2011, data from the CEREVANCE French national prospective cohort of auto-immune cytopenia were extracted, and a retrospective study of children who underwent rituximab for isolated AIHA was conducted. Patients with post bone marrow transplantation AIHA or underlying characterised primitive immune deficiency were excluded. Medical data and procedures were checked from patients' medical records. Complete remission (CR) was defined by haemoglobin count of more than 11 g/dL and reticulocytes count of less than 120 G/L, continuous complete remission (CCR) was defined as CR with no relapse or treatment for at least one year (Aladjidi et al, Haematologica 2011). Efficiency, safety and immunologic tests were evaluated after therapy.
Rituximab was administered in 42 children with isolated AIHA between 1999 and 2010. Associated immunologic disorders were noticed in 16 children before AIHA or during the follow-up. The median age at rituximab initiation was 5.4 years (0.1 to 17.5), with 15 children being younger than 2. The median duration of AIHA before rituximab was 6.2 months (0.1 to 74). The number of lines of treatments before rituximab varied from 1 (steroids alone for 23 children) to 5. Nineteen children received 4 weekly doses of 375 mg/m2, 6 received less than 4 courses and 7 received more than 4 courses (6 to 12). Rituximab allowed CR obtention in 85% of evaluable children, and all immunosuppressive treatment cessation in 67%. For failure or relapse, 21 children required 1 to 3 further lines of treatments. Systematic intravenous immunoglobulin (IVIg) substitution was administered in 55% of children, for a median duration of 18 months (1–140). Rituximab was well tolerated and severe neutropenia with sepsis happened in one child 6 months after rituximab. With a median follow-up of 3.6 years (0.2 to 11.3) after rituximab treatment, 22 children were in CCR, 7 children were in CR without treatment, 10 children were in CR with continuous treatment, 2 children were not in remission, 1 child died from associated giant cell hepatitis. Six children still required IgIV substitution at the last follow up, mainly younger and heavily treated children.
Comparisons with rituximab efficiency and tolerance in chronic ITP and in AIHA/Evans syndrome are available from this national cohort.
This collaborative national study confirms the excellent benefit-risk ratio of rituximab for childhood refractory AIHA. Early introduction could allow avoiding prolonged steroid treatments. However, the benefit of more than 4 courses was not demonstrated in this cohort. AIHA and chronic ITP are different diseases: the prolonged IVIg substitution required in 14% of children imposes to carefully search prior underlying immune deficiency before beginning an anti-CD20 treatment.
Acknowledgments to the Association Française pour le Syndrome d’Evans (AFSE), the GIS-Institut des Maladies Rares-INSERM, and the French Health Ministry (Programme Hospitalier de Recherche Clinique 2005, Rare Diseases Plan 2007).
No relevant conflicts of interest to declare.
Purpose. The prognosis of relapses of ETV6/RUNX1-positive acute lymphoblastic leukemia remains to be evaluated, particularly with regards to the frequency of late relapses. We performed a long term ...follow-up a retrospective study to address the outcome of ETV6/RUNX1-positive leukemia relapses.Design and Method. Among the 713 children tested for ETV6/RUNX1 enrolled into the FRALLE 93 protocol, 43 ETV6/RUNX1-positive patients relapsed (19.4%). Most were initially stratified as low or intermediate risk groups. Median follow-up after relapse was 54.2 months. All but three received a second-line salvage therapy and 16 underwent an allogeneic transplantation.Results. ETV6/RUNX1 greatly impacted on overall survival after relapse (3 year-survival= 64.7 % for positive versus 46.5 % for negative cases) (p= 0.007). The 5-year cumulative incidence of relapse was 19.4% and testes were more frequently involved in ETV6/RUNX1-positive relapses (p=0.04). 81.4 % were late relapses, early combined or isolated extramedullar relapses. The 5-year survival rate of ETV6-RUNX1-positive acute lymphoblastic leukemia relapses reached 80.6% when relapse occurred after 36 months (vs 34.9%). In univariate analysis, female gender was associated with a poor survival, whereas site of relapse, age at diagnosis, leukocytosis and consolidation strategy had no effect. In multivariate analysis, only the duration of first remission remained associated with outcome.Conclusions. We found an excellent outcome for ETV6/RUNX1-positive leukemia relapses occurring over 36 months post-diagnosis. Duration of first complete remission may thus be a guide to define the treatment strategy of ETV6/RUNX1-positive leukemia relapse.
Abstract 135▪▪This icon denotes a clinically relevant abstract
From December 2000 to June 2010, 1201 children with SR-BCP-ALL (age: 1–9 years, WBC<50 G/L, CNS-, no MLL rearrangement, no BCR-ABL, no ...Down syndrome) were included in the FRALLE 2000-A multicenter protocol. At a MFU of 60 months, 1195 patients are evaluable. An ETV6-RUNX1 fusion transcript was documented in 28% of the pts (329 out of 1173 evaluable pts). Induction regimen: prednisone prephase +IT MTX, dexamethasone (DEX) 6 mg/m2/d, vincristine (VCR), native E.coli L-asparaginase ASPA: 6000 IU/m2 × 9 infusions). Response was assessed at D8 (blood, good if < 1000 blasts/mm3), D21 (bone marrow morphology, good if less than 5% blasts, so-called M1) and end of induction D35 (bone marrow morphology and DNA-based PCR for Ig/TCR rearrangements MRD). A D21 M1 marrow was observed in 1132 pts (94.7%). Out of these, 1128 pts were randomized to receive daunorubicin (DNR; 40 mg/m2 at D22 and D29) 560 DNR(+) pts or not 568 DNR(-) pts. Pts with D21 M2/M3 marrow (n= 61; 5%) were not randomized and received two infusions of DNR. Two pts died before D21. Pts with D21 M1 marrow (A1 group) received after induction a 12 week-consolidation based on VCR, DEX, mercaptopurine (6-MP) and oral methotrexate (MTX), followed by a 1st delayed intensification (reduced “Protocol II”, including a total of 75 mg/m2 of doxorubicin), an interphase therapy (VCR, DEX, 6-MP, MTX), and a triple drug only-2nd delayed intensification (DI°2) (VCR, MTX 100 mg/m2, ASPA 20000 IU/m2; 4 cycles). A 24-month maintenance was then applied, including 12 VCR-DEX pulses the first year. A total of 18 intrathecal injections of MTX was given. Only the rare patients with D21 M3 marrow and/or EOI MRD level ≥1% (n= 47, 4%)(A3 group) received an intensified treatment after CR with 3 block-consolidation, intensified interphase with 6 cycles of MTX 5 g/m2 and a second DI (“reduced protocol II”). No pt received CNS irradiation.
Results:
No leukemic induction failure was observed; 4 induction deaths (0.3%) occurred leading to a 99.7% CR rate. Only 30 out 1097 evaluable pts (2.7%) had a decisional EOI MRD ≥ 1%. Eighty-two relapses have been observed (BM: 47, CNS+: 24, BM+CNS: 9, testis: 2). For the whole population 5-year EFS is 91.5% (95%CI: 89.8–93.3), 5-year OS is 97.4% (95%CI: 96.4–98.4). 5-yr EFS and OS for the A1 and A3 groups are 93.1% vs. 61.2% (p<0.0001), and 98.3% vs. 84.2% respectively (p<0.0001). Five-year DFS of the 30 pts with MRD ≥1% is 58.8% (95%CI: 41.7–82.8). Five-year EFS of the children with ETV6-RUNX1 fusion transcript is 96.6% (95%CI: 94.4–98.8).
5 non leukemic deaths have been observed after CR (0.4%). Other main toxicities were attributable to ASPA (CNS thrombosis: 1.5%, grade 3–4 pancreatitis: 0.8%, allergic reaction-all grades- during DI °2: 70%). Six cases of secondary neoplasms were observed (AML: 5 pts, astrocytoma: 1 pt).
5y EFS and OS from randomization was 92.9% and 97.2% for D21 M1 pts DNR(+) versus 93.3% and 98.2% for D21 M1 DNR(-) pts (p= 0.89 and p= 0.85, respectively). Interestingly EOI MRD levels in the two arms were not different at the sensitivity cut-off of 10−2 (p=0.93) or 10−3(p= 0.74).
For the whole population, age < 6 years, WBC < 20.000/mm3, ETV6-RUNX1 positivity, as well as D21 marrow M1 and EOI MRD levels of 10−2 and 10−3 were all associated to EFS in univariate analysis. In multivariate analysis remain only WBC < 20.000/mm3 (p=.001), ETV6-RUNX1 positivity (p=.02), EOI MRD levels ≤ 10−3 (p=1.4×10−5). Considering only randomized pts (D21M1 pts) age <6 (p=.004), WBC < 20.000/mm3 (p=.04), ETV6-RUNX1 positivity (p=.01), EOI MRD levels ≤ 10−3(p=.002) remain as independent prognostic factors in multivariate analysis.
Very good results were obtained with this VCR-DEX-ASPA oriented protocol. SR-BCP ALL pts which represents around 55 % of all children with ALL can be cured with a modest dose of anthracyclin (75 mg/m2). A further decrease in therapy based on the identified prognostic factors could be proposed. Intensification of the chemotherapy for the rare SR pts with a very high MRD has salvaged half of these pts but the addition of new drugs and/or HSCT is now to be evaluated.
No relevant conflicts of interest to declare.
Abstract 1628▪▪This icon denotes an abstract that is clinically relevant.
Poster Board I-654
Since the cloning of the t(12 ;21) in 1995 the prognosis of children with ETV6-RUNX1(+)ALL seems to ...further increase in the current era. From december 2000 to july 2008, 1461 children and adolescents aged from 1 to 20 years with B cell lineage ALL have been treated according the FRALLE protocols: one for standard-risk (SR) ALL (age 1-9 y, WBC < 50 G/L, no extra medullary involvement) F2000-A; the other one FRALLE 2000-B for high and very high risk ALL (HR) (all other pts). The two protocols mainly differ by a larger use of dexamethasone and a reduced use of anthracyclins in F2000A and the use of HDMTX and a double delayed intensification in FRALLE 2000B. ETV6-RUNX1 presence has been assessed by RT-PCR in 1392 pts (i.e. 96%) and found positive in 321 pts, i.e. 23%. Initial features include a median age of 4.2 y (1.2-15.6), a sex ratio (M/F) of 1.2, a median WBC of 10 G/L(1-293). Both peripheral blood D8 response to prednisone (PRED) and D21 marrow response to chemotherapy were evaluable in 316 pts: 94% of the pts have a rapid early response at D8 and D21. Only 3% of the pts were qualified as D8 poor PRED responders and 3% slow marrow responders at D21. The D35-42 CR rate is 100%. End of induction (EOI) minimal residual disease (MRD) using Ig-TCR methods is known in 259 out of 321 pts (81%) pts. Only 4 pts (2%) had a very high (≥10-2) EOI-MRD. Five year EFS, DFS and OS are 95±2%, 95±2%, 98±1%, respectively. The 5y EFS is 96±2% for the 252 SR pts and 90±7% for the 69 HR pts, p=0.30. The 5y EFS is significantly better for children with ETV6-RUNX1(+)ALL compared to those with ETV6-RUNX1(-) B-lineage ALL: 95±2% vs 84±2%, respectively (p=.001). Nine relapses have been reported in the bone marrow (4) the testis (4), the CNS (1) after a median time of 44 m (25-68), i.e. significantly longer than in the ETV6-RUNX1(-) cases (28m (1-92), p=.01). More testis relapses are observed in boys with ETV6-RUNX1(+)ALL (4 out 7 relapses vs 2 out of 62 in boys with ETV6-RUNX1(-) ALL). These results represent a significant progress compared to the previous protocol F 93 (191 children) both in terms of EFS and overall survival (5y EFS: 95±2% vs 78±3%, p=.001; 5 y OS: 98±1% vs 92±2%, p=.001).
an excellent prognosis of children with t(12;21)/ETV6-RUNX1 positive acute lymphoblastic leukemia is now observed in the FRALLE 2000 protocol. The question of a cautious de-escalation in this subgroup will be envisaged in the next protocol.
No relevant conflicts of interest to declare.
From 06/93 to 12/99, 1395 children and adolescents were included in the FRALLE 93 protocol: group A (Very Low Risk): 182, B (Standard risk): 672 and C (High risk including T-ALL): 541. The median FU ...is 9.5 yr. Inclusion criterias in group B were: age between 1 and 15 yr, WBC< 100,000, BCP phenotype and no poor-prognosis cytogenetic feature (MLL rearrangement or Ph1). Group B pts were randomised in a 2-steps schedule: at inclusion: daunorubicin (DNR: 40 mg/m2 × 2) vs idarubicin (IDA: 8 mg/m2 × 2), and at consolidation: high-dose IV methotrexate (HD-MTX): 4 × 8g/m2 at D1, D15, D29 and D42, vs low-dose po MTX (LD-MTX): 4 × 25 mg/m2; the number of triple IT was the same for both arms (N = 18). Pts with CNS leukemia were not randomized for MTX. During induction, pts were also classified on D21 bone marrow aspiration according to the level of residual blasts: M1 (< 5%): n=555, M2 (6–25%): n=71 and M3 (> 25%): n=41; M2/M3 pts received 1 more antracyclin infusion at D22 and M3 pts were subsequently treated according to the HR group and not randomized for MTX. Both M1 and M2 pts who reached CR were randomized for MTX. The overall group B EFS, DFS and OS were respectively 80±2, 81±2, and 91±1%. Globally there is no statistically significant impact of 1st or 2nd randomization on the outcome of patients. When we look at the outcome according to the D21 status, the EFS are very different: M1: 84±2%, M2: 63±6% and M3: 74±7%. The very poor EFS of M2 pts, who can not actually be classified as SR pts, and the fact that M1 pts represent 90% of pts randomized for MTX led us to analyse separately M1 pts. For M1 pts there is no interaction between 1st and 2nd randomization for survival, EFS and relapse rate (Gail and Simon test, p = 0.51); therefore pts were pooled for 2nd randomization analysis. Among M1 pts, 271 pts were randomized for HD-MTX and 264 for LD-MTX; there is no difference regarding age or leucocytosis between the 2 arms. Results are as follows:
5-yr EFSRelapses CIiBM relapses CIOther relapses CI5-yr OSHD-MTX87.82±1.99%0.12±0.047.01±0.025.17±0.0295.20±1.30LD-MTX79.92±2.47%0.20±0.0610.6±0.039.10±0.0388.64±1.95Testlog-rankGrayGrayGraylog-rankp value0.0280.0370.160.180.07(EFS: event-free survival, CI: cumulative incidence, iBM: isolated bone-marrow, OS: overall survival)
At the contrary, among M2 pts there is no difference in EFS for pts treated with HD-MTX (61±7%) and LD-MTX (65±9%)
Conclusion:
HD-MTX seems to benefit to pts with standard-risk BCP-ALL and good early response to chemotherapy, and the benefit is associated with a reduction in the number of relapses.No benefit is demonstrated in M2 pts with SER who have a very poor outcome and do require a more intensive treatment; the better EFS of M3 patients treated with double delayed intensification is in favour of this hypothesis.
Standard treatment of localized intracranial germinoma is focal irradiation of the primary tumor (45-50 grays Gy) combined with craniospinal radiotherapy (RT). To decrease late effects related to ...extensive fields of RT, the French Society of Pediatric Oncology decided in 1990 to replace prophylactic RT with chemotherapy (CT) and to deliver focal RT at 40 Gy.
Twenty-nine patients with localized, biopsy proven germinoma were included in this study between January 1990 and December 1994. CT consisted of 2 cycles of carboplatin 600 mg/m2 on Day 1, etoposide 150 mg/m2 on Days 1-3, ifosfamide 1.8 g/m2 on Days 22-26, and etoposide 150 mg2 on Days 22-24, followed by RT delivered to the initial tumor volume (40 Gy).
The median age of the 19 boys and 10 girls was 12.8 years; 25 patients had a unifocal tumor in the pineal (13), suprasellar (10), or thalamic (2) area, and 4 patients had a bifocal tumor. Three patients initially had complete surgery. Of the 26 patients evaluable for CT response, 11 had a small amount of tumor residue and 15 no residue; no patient underwent surgery after CT or RT. One patient recurred 3 years after diagnosis and is in his second complete remission. Twenty-eight patients are in their first complete remission after a median follow-up of 32 months (range, 7-68 months); 9 of the 28 have a small amount of tumor residue that is considered nonevolving. Overall survival at 4 years is 100% and event free survival is 93.3% (+/- 6%) after a median follow-up of 32 months.
This treatment strategy avoids craniospinal RT and reduces focal RT, with results equivalent to those achieved with extensive RT. Thus, the authors consider it a valid treatment of nonmetastatic germinoma.
From January 2000 to July 2006, 580 BCR-ABL negative patients with HR/VHR-ALL (200 T-ALL and 380 BCP-ALL (age≥10 or WBC≥50 or CNS+ or MLL-R) were included in the FRALLE 2000-BT trials. Induction ...regimen is prednisone (PRED) prephase + IT MTX, VCR, L-Aspa, DNR 120mg/m2 cumulated dose or DNR 160mg/m2 + cyclophosphamide 1g/m2 (T-ALL and D21 M2M3 marrow or MLL-R BCP-ALL). MRD at EOI is quantitatively determined by DNA-based PCR for Ig/TCR rearrangements either competitive PCR with GeneScan analysis or RQ-PCR with clone specific primers (sensitivity ranges 0.5×10−3–10−3, and 10−3–10−5, respectively). MRD status at EOI are available for 425 out of 552 CR (77%). MRD results are reported as negative, positive <10−3, highly positive (10−3≤MRD<10−2), very highly positive (≥10−2). Patients with EOI MRD ≥10−2 were to receive an intensified treatment.
Results:
1.30% (89/293) of HR/VHR BCP-ALL and 34% (45/132) T-ALL have detectable MRD at EOI, NS. A high or very high MRD is encountered in 16% (47/293) of BCP-ALL and 21% (27/132) of T-ALL (NS).2.Surprisingly 57% (20/35) of the pts with BCP-ALL and D8 poor PRED response (PPR) and 71% (36/51) of the pts with D8 PPR T-ALL have a negative or slightly positive MRD (<10−3) at EOI, NS. 30% (7/23) of the pts with D21 M2M3 BCP-ALL and 46% (6/13) of the pts with D21 M2M3 T-ALL have also a negative or slightly positive MRD (<10−3) at EOI. By contrast, 11% of good early responders (D8 good PRED response and D21 M1) with BCP-ALL or T-ALL (27/245 and 11/74, respectively) have a high or very high positive MRD.3.Overall, 20 out of 449 (4.5%) HR/VHR pts in CR have received an intensified treatment due to a very high MRD only.4.3y DFS for pts with a highly positive or very highly positive MRD are 65±7% (BCP-ALL) and 64±9% (T-ALL), NS. 3y DFS for pts with a negative or slightly positive MRD (<10−3) are 94±2% (BCP-ALL) and 87±4% (T-ALL), p=.04.5.There is a statistically significant difference in term of DFS between pts with MRD≥10−3 and MRD < 10−3, p=.001 and p =.05 for BCP- and T-ALL, respectively.
Conclusions:
1.the incidence of high and very high MRD at EOI is identical in children with HR/VHR-BCP- and T-ALL.2.High and very high MRD levels are found in good early responders defined by morphology. Conversely, excellent molecular responses can be found in bad early responders.3.High or very high MRD values are associated to a comparable prognosis between BCP- and T-ALLs.
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