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  • 1
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    Impact of Minimal Residual Disease (MRD) on Prognosis in Children with Philadelphia Positive Acute Lymphoblastic Leukemia (ALL) Treated in the AIEOP-BFM ALL 2000 Study.
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 1511-1511
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 1511-1511
    Abstract: Introduction: The International “Berlin-Frankfurt-Münster” Study Group (I-BFM-SG) pioneered the evaluation of minimal residual disease (MRD) based on Immunoglobulin and T-cell Receptor gene rearrangements as PCR targets. The prospective AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica)-BFM ALL 2000 study is the largest in which standardized quantitative assessment of PCR-MRD at two time points (TP) was used for stratification in 127 centers. Objective: To assess whether PCR-MRD levels discriminate outcome in patients with childhood Philadelphia positive (Ph+) ALL treated with intensive chemotherapy. Material and Methods: Between 07–2000 and 07–2006, 79 Ph+ patients were enrolled in the AIEOP-BFM ALL 2000 study. They were eligible for the high risk (HR) treatment arm and treated with Induction (protocol IA + IB), poly-chemotherapy blocks, reinduction (by one or more Protocols II or III), followed by maintenance therapy. BM samples obtained at day 33 (Time Point 1, TP1) and 78 (TP2) of induction therapy were used for MRD analysis by patient specific PCR targets. At least one or two sensitive markers (≥ 1 × 10−4) could be determined in 62 (78.5%) and 54 (68.4%) patients, respectively. MRD-Standard Risk (SR) was defined by MRD-negative at both TP1 and TP2; MRD-HR by MRD ≥1×10−3 at TP2; MRD-Intermediate Risk (IR): all others. Median follow-up was 3 years; 5-year survival and event-free survival (EFS) (SE) estimates are given. Results: Out of 79 registered patients, 3 (3.7%) died during Induction phase, 15 (19.2%) were Prednisone-poor responders (PPR), 12 (19.2%) were resistant to phase IA and 75 (94.9%) achieved CR. Forty-six patients (58.2%) underwent hematopoietic stem cell transplantation (HSCT). Overall, EFS and Survival (SE) were 44.3%(6.5) and 61.5%(6.2), respectively. Sixty-two patients were stratified by MRD (i.e. they were alive and valuable at day 78 and had at least one sensitive PCR marker). Eleven patients (17.7%) were at MRD-SR: 8 remained in CCR (4 after BMT), 1 died in CCR and 2 relapsed at 2.7 and 5.7 years from diagnosis; 28 (45.2%) were at MRD-IR: 18 remained in CCR (14 after BMT), 1 died in CCR and two for TRM after HSCT; 7 relapsed after 0.6 to 5.1 years; 23 (37.1%) were at MRD-HR and only 4 remained in CCR (all after BMT). The relapse rate was 18% in MRD-SR, 25% in MRD-IR and 61% in MRD-HR. Of note, within the Prednisone good-response subgroup (n=61), the evaluation of MRD identified those patients (MRD-HR, n=12 out of 51 PGR, MRD stratifiable) at very high risk of relapse (6/12: 50%). Conclusions: PCR-MRD is a strong predictor for outcome in Ph+ ALL patients treated with BFM therapy. MRD response detected by PCR can tailor the selection of the best treatment (Imatinib or other tyrosine kinase inhibitors and chemotherapy with or without transplant). The prognosis in the subgroup of Ph+ALL as defined HR according to PCR-MRD detection is still very poor even after HSCT and accordingly new therapeutic strategies are needed.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.1511.1511
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 2
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    Repeated Bone Marrow Aspiration At the End of Induction Therapy: Implications for Treatment Stratification in Paediatric Acute Lymphoblastic Leukaemia
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 756-756
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 756-756
    Abstract: Abstract 756FN2 Bone marrow (BM) aspiration at the end of induction therapy plays a crucial role for the evaluation of remission and the minimal residual disease (MRD), both critical for treatment stratification in modern treatment protocols for paediatric acute lymphoblastic leukaemia (ALL). However, the aspiration is repeated in 15–20% of patients, either due to non-representative morphology or to insufficient material needed for MRD analysis. We prospectively analysed 320 paediatric ALL patients treated according to ALL-BFM 2000 (n=301) or ALL IC-BFM 2002 (n=19) protocols with repeated BM aspiration at the end of induction therapy, on treatment day 33. Fourteen patients had more than one re-puncture. The median follow-up was 69 months, 45 (14%) patients had an event (relapse/death). The cause for the repeated BM aspiration was non-representative morphology (32%), insufficient material for MRD analysis (33%) or both (35% cases). In order to evaluate prognostic significance of the re-punctures and to determine which of the repeated samples should be used for the final treatment stratification we analysed MRD levels and MRD stratification, morphology, leukocyte count (WBC) and the length of treatment delay caused by waiting for the repeated aspiration. MRD data were collected and interpreted according to the EuroMRD guidelines in one central reference laboratory per each participating country. Morphology was evaluated centrally using an own scoring system (with a max value of 26 points). Treatment delay between the original and the last aspiration was one-third longer in patients with subsequent event compared to patients remaining in complete remission (CR) (median 8 (range 2 – 21) vs. 6 (1 - 28) days, respectively; p=0.020). Patients with a subsequent event had significantly higher WBC at the time of the last repeated BM aspiration, compared to patients without event (p=0.019), while there was no difference relative to the original aspiration (p=0.9). Analysis of the BM morphology at the original aspiration showed no significant difference between patients with an event vs. those in CR. However, the repeated aspiration of patients with a subsequent event had significantly better morphology (median 18.5/26 vs. 15/26 points, p=0.0012) mainly due to higher cellularity (p=0.003) and number of megakaryocytes (p=0.048). MRD levels were identical or decreased in 88% and increased in 12% of cases comparing the original aspiration to the repeated aspiration. In 63 patients (20%) the different MRD levels would lead to different treatment stratification. Higher MRD was associated with treatment failure; the best predictive values for subsequent event were obtained using the MRD results of the original aspiration (p=3.1e-07) or the highest of the detected MRD levels (p=6.0e-07). The last aspiration before proceeding with treatment had the lowest, though still a highly significant predictive value (p=8.6e-06). Corresponding results are obtained when MRD levels are substituted by final MRD risk stratification into standard, medium or high risk (p 〈 0.0001, p=0.0005 and p=0.0008 for the prediction of treatment failure using the MRD level in the original, the highest and the last aspiration, respectively). In conclusion, our data show that the original BM aspiration – independently of the quality of morphology – is not inferior for MRD treatment stratification, and that it actually has the best predictive value. In cases where sample quality precludes MRD analysis, the repeated sample with the highest MRD level should be used for stratification in order to not underestimate the putative risk of treatment failure. Longer treatment delay caused by waiting for a more representative sample seems to worsen the outcome. Notion that patients with a subsequent event need more time for BM regeneration is not justified, as their cellularity, overall morphology and also WBC before proceeding with treatment are better than in patients remaining in long-term CR. Any decision to perform a re-puncture at the end of induction therapy due to a non-representative morphology should be critically weighed. If possible, any unnecessary prolongation of treatment delay should be avoided unless being inevitable for other reasons, and therapy should be continued as soon as possible. Support: Deutsche Krebshilfe, Germany (Projects 50–2698 Schr1; 50–2722 BA6/7); St. Anna Kinderkrebsforschung, Austria; MSM0021620813; IGA NS/1000-4. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.756.756
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 3
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    IKZF1 Deletion Is An Independent Predictor of Outcome In Pediatric Acute Lymphoblastic Leukemia Treated According to the ALL-BFM 2000 Protocol
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 409-409
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    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 409-409
    Abstract: Abstract 409 Alteration of the IKZF1 gene – encoding the transcription factor IKAROS, a key player in lymphoid development and tumor suppression – has been reported to be associated with a poor outcome in pediatric precursor B-cell ALL, especially in cases positive for the BCR-ABL1 fusion gene. In order to assess the prognostic value of IKZF1 deletions in a representative cohort of pediatric ALL patients treated on the German ALL-BFM 2000 study protocol, we screened 409 patients by applying a multiplex ligation-dependent probe amplification (MLPA) assay covering all eight IKZF1 exons (P335-A3 ALL-IKZF1 probemix; MRC-Holland, Amsterdam, The Netherlands). In ALL-BFM 2000, risk group stratification (standard, SR; intermediate, MR; high, HR) was based on minimal residual disease (MRD) analysis at two different time points (TP) and required two MRD targets with sensitivities of ≤10−4 (Flohr et al. Leukemia 2008). SR patients were MRD-negative on treatment days 33 (TP1) and 78 (TP2). HR patients had residual disease (≥10−3) at TP2. MRD MR patients had positive MRD detection at either one and or both time points but at a level of 〈 10−3 at TP2. Although MRD-based stratification criteria were introduced in ALL-BFM 2000, established high-risk parameters were also retained: patients with prednisone poor-response or ≥5% leukemic blasts in the bone marrow on day 33 or positivity for a t(9;22) or t(4;11) or their molecular equivalents (BCR/ABL1 or MLL/AF4 fusion RNA) were stratified into the high-risk group independent of their MRD results. First results on MRD and outcome were published earlier (Conter et al. Blood 2010). Out of the 409 patients analyzed in our study, 46 (11%) displayed a deletion in at least one of the eight IKZF1 exons. Forty-three out of the 46 cases showed heterozygous deletions, while 3 patients displayed homozygous loss of IKZF1 exons. MLPA results of 11 patients were validated with results derived from copy number/LOH analyses using Affymetrix SNP 6.0 arrays. IKZF1 deletion was significantly more common in precursor B compared to T cell ALL (13% vs. 4%, P = 0.03) and less frequent in TEL/AML1-positive ALL (3% vs. 13%, P = 0.004). Out of 11 BCR/ABL1-positive samples, only two were characterized by an IKZF1 deletion. Forty-four patients with IKZF1-deleted ALL had results of MRD analyses available for both informative time points (day 33 after induction and day 78 after consolidation). Despite a trend towards increasing incidence of IKZF1 deletion in patients with slow response, the distribution of IKZF1-deleted ALL patients over the risk groups was not significantly different from non-deleted ALL (SR: 40.9 vs. 41.9; MR: 45.5 vs. 52.3; HR: 13.6 vs. 5.7%; P = 0.153). Regarding treatment outcome, patients with an IKZF1 deletion had a significantly lower 5-year event-free survival (EFS) compared to non-deleted patients (0.78±0.06 vs. 0.86±0.02; P = 0.015). This result was due to a higher cumulative incidence of relapses in IKZF1-deleted patients (0.16±0.05 vs. 0.10±0.02; P = 0.031). In multivariate Cox regression analyses including known prognostic variables (gender, immunophenotype, WBC count at diagnosis, TEL/AML1 status, risk group criteria of ALL-BFM 2000), IKZF1 deletion conferred a risk of 2.16 (95% confidence interval 1.14 – 4.10; P = 0.018) for an event when compared to non-deleted patients. We conclude that IKZF1 deletion is an independent predictor of treatment outcome for patients enrolled on the ALL-BFM 2000 protocol and represents a candidate marker to be integrated in future algorithms for early risk stratification in pediatric ALL. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.409.409
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 4
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    Dexamethasone in Induction Can Eliminate One Third of All Relapses in Childhood Acute Lymphoblastic Leukemia (ALL): Results of An International Randomized Trial in 3655 Patients (Trial AIEOP-BFM ALL 2000)
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 7-7
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 7-7
    Abstract: From 07/2000 to 06/2006, 4741 eligible pts with ALL (age range 1–17 years) were enrolled in the trial AIEOP-BFM ALL 2000 (registered at http://clinicaltrials.gov with identifiers NCT 00430118 (BFM) and NCT 00613457 (AIEOP)). 3655 patients from Germany, Italy, Austria, and Switzerland entered the randomized comparison of dexamethasone (DEX) at 10 mg/m2/d vs prednisone (PDN) at 60 mg/m2/d (both given daily from d8 to d29 of induction plus 9 days tapering after a 7d prednisone prophase). Induction therapy also comprised vincristine (1.5 mg/m2) and daunorubicine (30 mg/m2) both given on d8, 15, 22, 29, as well as L-asparaginase given at 5,000 IU/m2 x8 q3d from d12. I.T. methotrexate was given thrice (in CNS-2 and CNS-3 patients for 5 times) in induction. Post-induction therapy was derived from trial ALL-BFM 95 (A. Möricke et al, BLOOD 2008) but stratification and subsequent treatment intensity was based on early response as measured by prednisone response (on d8) and MRD quantification on d33 and d78. With a median follow-up of 4.4 years, 6-year event-free survival (6y-EFS) was 84.1% (SE 1%) and 79.1% (1%) for patients randomized to receive DEX or PDN, respectively (log-rank p=0.0083). The 6-year cumulative incidence (CI) of relapse was 11% (1%) and 18% (1%) for patients randomized to receive DEX or PDN, respectively (Gray p 〈 0.001). The difference between the two groups was observed for isolated BM relapses (8% vs 12%), CNS-relapses (2% vs 4%) and other relapses (2% vs 3%). Higher toxicity was observed in patients treated with DEX: CI for death in induction was 2.0% for DEX and 0.9% for PDN (p=0.003). The latter value was similar to that of study ALL-BFM 95 (0.7%). CI for death in remission was similar being 2.0% and 1.6% for DEX and PDN groups. In each arm, only 0.2% did not achieve CR after intensive consolidation. Severe toxicities, mainly infections, were recorded for DEX treated patients more frequently. Three years into the trial, the DSMC and the TSC decided to halt the randomization for patients aged 10 years or older. CI for relapse/death in induction in this age group is now at 15%/4.5% for DEX, and 20%/2.4% for PDN (p=0.09/0.13). In patients less than 10 years of age, the CI for relapse/death in induction was 11%/1.4% if treated with DEX, and 18%/0.5% if treated with PDN (p 〈 0.001/0.01). If specific biological subgroups were analyzed, a significantly lower CI of relapse for patients randomized to receive DEX was observed in T-ALL as well as TEL/AML1 positive and negative pcB-ALL patients. The reduction was most pronounced in T-ALL patients with good prednisone response after the prophase: CI for relapse in DEX treated patients (n=135) was only 6% (SE 2%) as compared to 20% (SE 4%) in PDN treated patients (n=138; p=0.003). Four patients died in the DEX arm, 3 in the PDN arm for toxicity. In TEL/AML1-positive patients with good prednisone response, the CI for relapse was 4% (SE 1%) in the DEX group and 13% (SE 2%) for PDN treated patients (p 〈 0.001). This large difference became most evident only more than 2 years from diagnosis. The percentage of patients found negative for MRD at d33 was very similar between the randomized groups: It was 47.9% for patients treated with DEX, and 45% for patients treated with PDN. Interestingly, patients with pcB-ALL found MRD negative at d33 had significantly less subsequent relapses if treated with DEX in induction (p(Gray)=0.012). In conclusion, the use of DEX at the same dosage as applied in delayed intensification (10 mg/m2/d for 3 weeks) although associated with a greater risk of severe toxicity leads to a marked reduction of the risk of relapse, translating this into a significant benefit in terms of EFS. This was most evident in patients with in vivo sensitivity to the prednisone prephase, while the efficacy of DEX in poor responding patients was not convincing. In the future, more intensive clinical monitoring and early anti-infective interventions could render the advantage of using DEX even more evident. Moreover, other potentially toxic agents such as anthracyclines may be limited in induction for carefully selected subgroups of patients with the aim of limiting early or late toxicities.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.7.7
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 5
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    Prognostic Impact of Minimal Residual Disease (MRD) in Children Is Different in B or T Lineage Acute Lymphoblastic Leukemia: Results of Trial AIEOP-BFM ALL 2000.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 1425-1425
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    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 1425-1425
    Abstract: Slow early response indicates poor prognosis in childhood ALL. We aimed to evaluate if post-induction MRD levels had different prognostic impact in precursor B-cell (pB) or T-cell ALL. From 07/2000 to 06/2006, 4730 pts with ALL were enrolled in trial AIEOP-BFM ALL 2000. MRD levels were centrally measured by real-time quantitative polymerase chain reaction using the identification of clone-specific T-cell receptor and immunoglobulin gene rearrangements. MRD study time-points (TP) were treatment day 33 (TP1, end of induction) and day 78 (TP2, after consolidation). To define MRD negativity, two markers with a sensitivity of at least 10−4 were required. Patients were treated with BFM induction (protocol I-A), consolidation (I-B), extra-compartment/intensified consolidation (HD-MTX in non-high-risk patients, pulses in high-risk patients), reinduction, and maintenance. MRD analysis at one or two time points suceeded in 3707 pts; the immunophenotype was available from 3636 pts. MRD levels and corresponding estimated 5-year event-free survival (5y-pEFS) comparing pB- and T-ALL are shown in Table 1 (3yrs median follow-up). MRD response in T-ALL was slower than in pB-ALL resulting in a higher percentage of pts with high MRD load in T-ALL. In pB-ALL as well as T-ALL, high MRD levels at TP2 were well predictive to identify pts with poor prognosis. For prediction of good prognostic subgroups, TP1 was more appropriate identifying a subgroup with excellent 5y-pEFS of & gt;90% in case of MRD negativity. Specificity of TP1 was poor in T-ALL if the pB-ALL criteria of MRD negativity were applied. If MRD low positive and MRD negative T-ALL pts were combined, the discrimination was as good as in pB-ALL. The optimal choice of MRD evaluation time points depends on biological factors and treatment, and is most relevant for MRD-based risk stratification. Table 1 pB-ALL T-ALL n % 5y-pEFS % (SE) n % 5y-pEFS % (SE) all 3177 100% 82.3 (1.0) 459 100% 77.2 (2.2) MRD TP1     neg 1399 44.1 92.5 (1.0) 75 16.4 94.3 (2.8)     10E-4/−5 1122 35.4 81.9 (1.7) 116 25.4 91.2 (2.8)     10E-3 393 12.4 66.4 (3.5) 110 24.1 75.3 (4.6)     ≥10E-2 256 8.1 53.2 (4.3) 156 34.1 59.8 (4.5) MRD TP2     neg 2464 77.6 87.7 (1.0) 220 47.9 91.9 (2.0)     10E-4/−5 523 16.5 68.9 (2.9) 143 31.2 76.6 (3.9)     10E-3 107 3.4 56.3 (6.5) 58 12.6 50.2 (8.1)     ≥10E-2 82 2.6 38.0 (7.3) 38 8.3 33.2 (8.3)
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.1425.1425
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 6
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    Prognostic Factors in CD10 Negative Precursor B-Cell Acute Lymphoblastic Leukemia in Children: Data from Three Consecutive Trials ALL-BFM 86, 90, and 95.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 1957-1957
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    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 1957-1957
    Abstract: The overall unfavorable prognosis of CD10 negative (CD10−) precursor B-cell acute lymphoblastic leukemia (BCP-ALL) is well known. We analyzed 4473 pediatric patients (pts) 〈 18 years (y) with BCP-ALL and immunophenotyping of CD10 enrolled from 1986 to 2000 in three consecutive ALL-BFM trials to explore prognostic factors in the CD10− subset. CD10 negativity was defined by CD10 expression in 〈 20% of blasts. 233 pts (5.2%) were CD10−. In comparison to CD10 positive (CD10+) BCP-ALL pts, CD10− pts comprised more infants (age 〈 1y 34% vs. 1%, p(X2) 〈 0.001), more cases with hyperleukocytosis (WBC ≥100/nl 43% vs. 6%, p 〈 0.001), more CNS involvement (CNS positive 10% vs. 2%; p 〈 0.001) and an impaired treatment response (prednisone poor response (PPR) 22% vs. 5%, p 〈 0.001; induction failure 6% vs. 1%, p 〈 0.001). Estimated probability of 5 years event free survival (5y-pEFS) was significantly lower in pts with CD10− as compared to CD10+ BCP-ALL (49±3% vs 81±0.6%, p(log-rank) 〈 0.001). Cox regression analysis including age, WBC, prednisone response (PR) and MLL/AF4 status as covariables revealed CD10 negativity as independent prognostic factor (RR 1.5, 95% confidence interval (CI) 1.1–2.1, p=0.01). Further analyses were performed within the CD10− group: 83% of infants and 60% of pts ≥1y were successfully analyzed for MLL/AF4. MLL/AF4 was detected in 55% of pts 〈 1y and 27% of pts ≥1y. The well known risk factors for BCP-ALL (sex, age, WBC, CNS involvement, MLL/AF4 and PPR) also had prognostic impact within the CD10− group: n* 5y-pEFS* (%) SE (%) p (log-rank) *5 pts w/o reinduction were excluded sex female 109 55 5 0.022 male 119 40 5 age 〈 1y 78 25 5 〈 0.001 ≥1y 150 62 4 WBC 〈 100/nl 128 62 4 〈 0.001 ≥100/nl 100 33 5 CNS neg 181 54 4 0.011 pos 21 33 10 MLL/AF4 neg 95 53 5 0.001 pos 61 29 6 PR good 170 57 4 〈 0.001 poor 50 30 6 Out of a number of immunophenotypic markers, analyzed at different expression cut-off points, CD24 at missing or weak expression of 〈 40% and CD65 at high expression of ≥40% were significantly correlated with unfavorable clinical characteristics and worse outcome within the CD10− group. Significant correlation with PR could only be demonstrated for expression of CD24, which is presumed to act as negative regulator in B-cell development through mediation of apoptosis. age 〈 1y* WBC ≥100/nl* MLL/AF4 pos* PPR# pEFS§ n/total (%) n/total (%) n/total (%) n/total (%) % ±SE * all p(X2) 〈 0.01, #CD24 p=0.01, CD65 n.s., §all p(log-rank] 〈 0.001 CD24 〈 40% 37/77 (48) 52/77 (68) 33/56 (59) 24/73 (33) 32 ±5 CD24 ≥40% 34/122 (28) 35/122 (29) 18/76 (24) 20/119 (17) 59 ±5 CD65 〈 40% 56/180 (31) 67/180 (37) 39/120 (33) 39/175 (22) 30 ±7 CD65 ≥40% 22/44 (50) 32/44 (73) 21/34 (62) 10/41 (24) 54 ±4 Including age, WBC, PR and MLL/AF4 status as covariables, out of the analyzed markers only CD65 proved to be an independent prognostic factor in CD10− BCP-ALL (Cox regression analysis: RR 1.5, 95% CI 1.1–2.9, p=0.018). The identification of additional prognosis associated immunophenotypic markers may contribute to further refinement of treatment strategies for CD10− BCP-ALL pts.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.1957.1957
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
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  • 7
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    Thirty Percent Long Term Survival In Children with Acute Leukemia and Complications Requiring Mechanical Ventilation
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 3243-3243
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    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3243-3243
    Abstract: Abstract 3243 Objective: Previous reports indicated that short term prognosis for patients with malignant diseases and serious adverse events requiring mechanical ventilation (SAEV) is not dismal any more. The purpose of this study was to determine whether patients who survive such complications can also achieve long term cure from leukemia. It might influence end-of-live decisions on the intensive care unit if patients with an SEAV only survive intensive care to succumb to relapse. Patients and Methods: We report the outcome of children with SAEV treated in the multicenter studies ALL-BFM 95 and AML-BFM 98. Data from 1182 patients with acute lymphoblastic leukemia (ALL) and 332 patients with acute myeloid leukemia (AML) were analyzed. 88 patients (51 ALL; 37 AML) developed an SAEV. Results: The prognosis was almost identical in ALL and AML (50% survival of SAEV; 30% overall survival after 5 years). This was independent from the time between diagnosis of leukemia and SAEV. Even children who required hemodialysis (n=14) or cardiac resuscitation (n=16) achieved 20% long term survival but no patient survived (n=16) who fulfilled more than 3 out of 6 identified risk factors: age≥10 years, high risk leukemia, C-reactive Protein≥150mg/l, administration of inotropic infusion, cardiac resuscitation, and hemodialysis. Conclusions: To our knowledge, this is the first report about cure rates in a malignant disease after successful treatment of SAEV. Our results show that intensive care medicine contributes to short and long term survival of children with leukemia. Sixty percent of all children with acute leukemia who survive an SAEV achieve long term cure. However, we could also identify risk features that still indicate a devastating prognosis. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.3243.3243
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
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    Evaluation of Minimal Residual Disease As a Surrogate Endpoint for Event Free Survival in Childhood B-Lineage Acute Lymphoblastic Leukemia
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 759-759
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    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 759-759
    Abstract: Introduction The need to optimize clinical evaluation of new drugs stimulates researchers and regulatory bodies to consider novel endpoints that facilitate assessment of the efficacy of a new drug earlier in time than do traditional endpoints. To be a useful marker of efficacy, an early endpoint must be an accurate surrogate for the true clinical endpoint. Minimal residual disease (MRD) is a strong prognostic factor for Event Free Survival (EFS) in children with newly diagnosed acute lymphoblastic leukemia (ALL) and is used routinely to assess treatment response and stratify treatment intensity. However, it is not known whether or not early MRD response is an accurate surrogate endpoint for EFS in evaluating the efficacy of treatment interventions. This study addresses for the first time in childhood ALL the formal validation of surrogacy of MRD levels at the end of induction treatment by a meta-analytic approach on individual data from two large phase III trials with a randomized question on type of steroids in induction (dexamethasone 10mg/m2/day vs prednisone 60mg/m2/day). Material and Methods We performed a meta-analysis of individual data of 2955 B-ALL patients from AIEOP-BFM-ALL2000 (NCT00613457, NCT00430118), and 945 and 930 high risk B-ALL patients randomized for steroids after being allocated either to Capizzi or High-dose Methotrexate in COG AALL0232 (NCT00075725; separately considered due to the significant quantitative interaction between Methotrexate regimens and type of steroid). The trials included evaluation of MRD at day +33 (PCR-MRD) and +29 (flow-cytometry MRD), respectively, with a sensitivity of at least 10-4. The three categories MRD level (negative, low positive i.e. 〈 5x10-4 and positive ≥5x10-4), was assessed as surrogate for the EFS endpoint (time to event defined as resistance at the end of induction, relapse, death in remission, second malignancy). A two-level modelling approach was used to estimate the association between MRD and EFS and between the treatment effect on MRD (proportional odds model) and on EFS (proportional hazard model). The quality of the surrogate at the individual level was assessed on the basis of the bivariate Plackett copula model, with a parameter representing the global odds ratio. The quality of the surrogate at the trial level was assessed on the basis of the coefficient of determination R2trial from a linear regression through the estimated treatment effects. Results The main results on MRD and EFS by trial and treatment are in table 1. The meta-analytic approach shows that MRD at the end of induction is a poor surrogate for treatment effect on EFS (Figure 1) at the trial level, with R2trial=0.09 (95% CI: 0-0.29), while, at the individual level, it shows a considerable prognostic association with EFS, after adjusting for treatment, with a 3.9 odds ratio of failure for patients with higher compared to lower MRD levels (95% CI: 3.4-4.4). Additional sensitivity analyses on relevant subgroups generally confirmed the previous findings both at the trial and patient level association. Conclusions Using a meta-analytic approach, we found that MRD, in 3 categories defined according to standard cut-points, is a poor surrogate for EFS at the trial level, thus indicating that the effect of the randomized steroids (dexamethasone vs. prednisone in induction) on the MRD level at the end of induction does not reliably predict the effect of the intervention on EFS. In contrast, the analysis shows a strong and highly significant association between end induction MRD level and EFS time for individual patients, regardless of treatment, confirming the prognostic effect of early MRD response on clinical outcome. This study shows, for the first time, the limitation of a strong prognostic factor in being a surrogate in the context of front line ALL treatments. The impact of type of steroid on MRD distribution at the end of induction is relatively limited and subsequent treatment complexity and intensity, partly tailored on MRD itself as a key criterion used to modulate the intensity of post-induction therapy, may dilute a potential surrogacy. These data suggest that clinicians and regulatory bodies should be cautious in using early MRD response in the context of complex multiagent therapy as an early surrogate endpoint to evaluate the effect of a randomized treatment intervention on long-term EFS. Disclosures Moricke: JazzPharma: Honoraria, Other: financial support of travel costs. Biondi:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; BMS: Membership on an entity's Board of Directors or advisory committees; Cellgene: Other: Advisory Board.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.759.759
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    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
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    Thiopurine Methyltransferase Genetics Is Associated with Treatment Outcome and Hepatic Toxicity in Pediatric Patients with Acute Lymphoblastic Leukemia: a Report From the ALL-BFM Study Group.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 2625-2625
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    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2625-2625
    Abstract: Abstract 2625 Poster Board II-601 The thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) play an essential role in treatment protocols for acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (TPMT) is a key enzyme in the metabolism of thiopurines and underlies phenotypically relevant genetic variation. Heterozygotes or homozygotes for TPMT genotypes conferring lower enzyme activity demonstrate thiopurine drug metabolic patterns distinct from those of TPMT wild-type individuals. Underlining its clinical importance, several studies have demonstrated a relationship between low TPMT enzyme activity and thiopurine-associated toxicity as well as decreased relapse risk. Here we report on a prospective evaluation of the role of TPMT genetics for survival and treatment-related toxicity in a cohort of 814 pediatric ALL patients. These 814 patients were initially selected based on availability of DNA and represent 85.1% of the entire patient population (n=956) enrolled in the German-Austrian-Swiss multi-center trial ALL-BFM 2000 from October 1999 to September 2002. Genotyping for TPMT was performed by a denaturing HPLC method and subsequent sequencing of variant alleles using DNA prepared from either leukemic or remission bone marrows. This analysis revealed 755 (92.8%) patients with TPMT wild-type, 55 (6.8%) with a heterozygous, and 4 (0.5%) with a homozygous variant genotype (*2/*3A, *3A/*3A [n=2], *3A/*11), respectively. Genotype frequencies were in Hardy-Weinberg equilibrium. Allele frequencies were as follows: TPMT*1 = 96.12%, TPMT*2 = 0.25%, TPMT*3A = 2.95%, TPMT*3C = 0.56%, TPMT*9 = 0.06%, and TPMT*11 = 0.06%. Patients (n=55) heterozygous for allelic variants of TPMT conferring lower enzyme activity demonstrated significantly better event-free survival (EFS) and a lower relapse rate compared to homozygous wild-type patients (n=755) (six-years pEFS; heterozygotes vs. wild-type, 95% (SE 3%) vs. 84% (SE 1%), p(log-rank) = 0.04; p(point estimate difference) = 〈 0.001, relapse incidence at six years, 4% (SE 3%) vs. 12% (SE 3%), p = 0.07). In a Cox regression analysis, adjusting for sex, age, presenting leukocyte count, immunophenotype and minimal residual disease the effect of TPMT genotype was still detectable, but lost statistical significance (hazard ratio for TPMT heterozygosity = 0.38, p = 0.10). An analysis stratified by minimal residual disease-defined risk groups will be presented. While TPMT heterozygotes did not demonstrate statistically significant differences when their toxicity data collected according to the National Cancer Institute's Common Toxicity Criteria were compared with wild-type patients for 6-MP-containing treatment phases, they had an increased risk of developing hepatic veno-occlusive disease associated with a two-week exposure towards 6-TG given during re-intensification. In conclusion, TPMT genotyping may contribute important information for clinical decision making in childhood ALL that goes beyond the prevention of toxicity in TPMT deficient patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.2625.2625
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
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    Prospective Evaluation of Thromboembolic Events During Chemotherapy of Childhood Acute Lymphoblastic Leukemia: Results of Randomized Trial ALL-BFM 2000.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 990-990
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 990-990
    Abstract: Abstract 990 Poster Board I-12 Thromboembolic events (TE) are common complications in association with acute lymphoblastic leukemia (ALL). The incidence, as reported in the literature, is 3.2% on average, but varies from 1.1% to over 30%, which might be explained by different definitions of the events (symptomatic/asymptomatic), diagnostic methods, study designs (prospective/retrospective) and treatment protocols. Pathogenesis and etiology of ALL-related TE have not yet been fully clarified so far and the existing data on the relevance of potentially influencing risk factors are quite inconclusive. The higher risk of TE in patients with ALL and under ALL treatment may be caused by the ALL itself and the applicated chemotherapy, first of all asparaginase but potentially in combination with other drugs, e.g. steroids. The chemotherapy leads to an imbalance of coagulation factors inducing a hypercoagulable state in the patient. Other modulating factors might be the preexistence of hereditary thrombophilia, the existence of an implanted central venous line (CVL) and the potential treatment with antithrombotic prophylaxis. Data on TE were prospectively collected from 2419 patients with ALL (age 1-18 years) enrolled from August 1999 to September 2005 into study ALL-BFM 2000 of the Berlin-Frankfurt-Münster group (Germany, Austria, Switzerland). Patients participating in the “Thrombotect” study (randomized study for evaluation of antithrombotic therapies in ALL) were excluded from the analysis. Among the analyzed patients, 104 TE were documented (4.3%); 41 TE were localized in the CNS (mainly sinus venous thromboses), 63 TE outside of the CNS (lower deep venous system, n=14; upper deep venous system n=40; cardiac, n=6; pulmonary embolisms, n=3). Nine TE were classified as life-threatening (7 cerebral, 2 non-cerebral), 1 patient died from a cerebral infarct with concomitant serious bleeding. About 62% of the TE (n=64) were diagnosed during the 5-week induction treatment with prednisone or dexamethasone, vincristine, daunorubicin, asparaginase, and intrathecal methotrexate, 14% (n=15) during the subsequent consolidation phase, and 24% during later treatment phases. Adolescent patients had a significantly higher risk to develop TE with a rate of 3.4% in patients 〈 10 years and 6.6% in patients ≥10 years of age (p=0.001). There was a trend to a higher TE rate in male patients (4.8% vs. 3.4% in females, p=0.077), which was evident in the younger age group only. TE rate in T-ALL patients was significantly higher than in non-T-ALL (7.0% vs. 3.8%, p=0.006), which was independent of the age group. After a 7-day prednisone prephase, patients were randomized to receive dexamethasone or prednisone for three weeks plus tapering during induction treatment. Incidence rate of TE was 5.2% in randomized patients treated in the prednisone arm (n=968) and 3.7% in the dexamethasone arm (n=857) (p=0.14). The impact of the time point of CVL implantation was analyzed in 1439 patients with available data on CVL implantation. Of these patients, 43% received their CVL during the first week of induction treatment, 19% during the second week, and 38% after the second week. Time point of CVL implantation did not influence the TE incidence with a rate of 4.0%, 5.2%, and 5.2% in the above mentioned three groups, respectively (p=0.59). However, nearly all patients (97%) had received their CVL by start of consolidation phase (protocol day 36). Therefore, no statement could be made about the TE incidence in patients without CVL throughout therapy. Several parameters which have potential impact on TE incidence are unknown in this study. These include anticoagulatory prophylaxis by institutional practice, preexisting hereditary thrombophilia as well as the coagulation status at time of diagnosis of ALL, under chemotherapy, and at diagnosis of TE. TE are a rather rare but potentially serious complication of contemporary ALL treatment. Risk factors are numerous. So far, besides age, immunophenotype, and treatment phases robust predictive factors are still missing. Prospective randomized studies are underway to identify risk factors and to develop preventive strategies. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.990.990
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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