Relapse occurs in 30–40% of newly diagnosed AML patients, with long-term survival in 20%. Aiming ... more Relapse occurs in 30–40% of newly diagnosed AML patients, with long-term survival in 20%. Aiming at improved outcome, we initiated a prospective, randomised study for relapsed AML, excluding AML M3 and those >18 years of age at initial diagnosis. FLAG is being used for 2 consecutive courses: fludarabine 30 mg/m2/day x 5, cytarabine 2 g/m2/day x 5, G-CSF 200 μg/m2/dose for 6 days, starting day -1. Liposomal daunorubicin (DaunoXome, DNX) is a new anthracycline with potentially less cardiotoxicity. Therefore, DNX at 60 mg/m2/day on days 1, 3 and 5 was randomly added or not to the first course of FLAG. Main objectives are to determine the efficacy and toxicity of DNX when added to FLAG, and the long-term outcome in a large group of relapsed AML patients. Thirteen groups worldwide are enrolling patients. More than 400 patients were registered by March 2006. This planned 2nd interim analysis with blinded efficacy data concerns 322 eligible and evaluable patients with first relapsed AML, of whom 250 (78%) were actually randomised. Fifty-two percent of patients relapsed early (<1 year from initial diagnosis). The majority (84%) concerned isolated bone marrow relapse, with central nervous system involvement in 6% of all patients. Dominating FAB types are M2 with auer rods, M4 without eosinophils and M5. Poor response to the 1st course of therapy (>20% of blasts in the BM shortly before the 2nd course), was seen in 23% of patients, more often in early relapses (31%) than in late relapses (15%). Early death occurred in 6% of patients. Complete remission (CR) was achieved in 63% of patients after 2 courses, and they have a probability of survival at 3 years (3-yr pSurv.) of 47% compared to 33% for the total group and 8% for patients not achieving CR. Compared to early relapses, patients with late relapse had higher CR rates (76 vs 51%), and higher 3-yr pSurv.: 42% vs 23%. Similarly, patients with either t(8;21) or inv(16) had a significantly better outcome. Death in continuous CR occurred in 8.6% of 322 patients, without excess of deaths in one treatment arm. Nearly all patients in CR have been transplanted, the majority with a matched unrelated donor. There was significant grade III/IV toxicity, but no unexpected toxicity, and no clinically relevant differences between the arms with and without DNX, especially not in cardiotoxicity. In conclusion, it is feasible to perform a large randomised pediatric study in a very international setting. DNX added to FLAG does not result in major additional toxicity, but follow-up of cardiotoxicity should be extended as planned in this protocol. Late relapses do better in terms of CR and overall survival, as well as patients with t(8;21) or inv(16), but early relapses achieving CR have a realistic chance of survival as well with currently 23% of them in continuous CR. The study is ongoing until 360 eligible and fully evaluable patients have been randomised, to answer the question whether liposomal daunorubicin improves outcome in pediatric relapsed AML.
Apoptosis-related proteins are important molecules for predicting chemotherapy response and progn... more Apoptosis-related proteins are important molecules for predicting chemotherapy response and prognosis in adult acute myeloid leukemia (AML). However, data on the expression and prognostic impact of these molecules in childhood AML are rare. Using flow cytometry and western blot analysis, we therefore investigated 45 leukemic cell samples of children with de novo AML enrolled and treated within the German AML-BFM93 study for the expression of apoptosis-regulating proteins (CD95, Bcl-2, Bax, Bcl-xL, Procaspase-3, XIAP, cIAP-1, Survivin). XIAP (p<0.002) but no other apoptosis regulators showed maturation-dependent expression differences as determined by FAB morphology with the highest expression levels observed within the immature M0/1 subtypes. XIAP (p<0.01) and Bcl-xL (p<0.01) expression was lower in patients with favorable than intermediate/poor cytogenetics. After a mean follow-up of 34 months, a shorter overall survival was associated with high expression levels of XIAP {30 (n=10) vs. 41 months (n=34); p<0.05} and Survivin {27 (n=10) vs. 41 months (n=34); p<0.05}. We conclude that apoptosis-related molecules are associated with maturation stage, cytogenetic risk groups and therapy outcome in childhood de novo AML. The observed association of XIAP with immature FAB types, intermediate/poor cytogenetics and poor overall survival should be confirmed within prospective pediatric AML trials.
Early death (ED) refers to deaths in study patients before onset of therapy or in protocol patien... more Early death (ED) refers to deaths in study patients before onset of therapy or in protocol patients within the first six weeks of therapy.
Grundlagen fur das Konzept der »Qualitat« der medizinischen Versorgung wurden bereits 1966 gelegt... more Grundlagen fur das Konzept der »Qualitat« der medizinischen Versorgung wurden bereits 1966 gelegt (Donabedian 1966) und ihre Eigenstandigkeit 1996 in einschlagigen medizinischen Zeitschriften formuliert (Schrappe 2001). Hinsichtlich der Gewahrleistung dieser Versorgungsqualitat besteht gegenwartig noch eine deutliche Lucke zwischen den gesetzlichen Vorgaben zur Qualitatssicherung, die zuletzt im Jahr 2003 in §§ 135a und 137 SGBV verstarkt wurden, und der tatsachlichen Verbreitung von Qualitatsmanagementsystemen, die uber einzelne qualitatssichernde Masnahmen hinausgehen.
Introduction: Although rare, acute myeloid leukemia (AML) in children and adolescents is the most... more Introduction: Although rare, acute myeloid leukemia (AML) in children and adolescents is the most frequent treatment-related malignancy in children and adolescents. Both, chemotherapy and irradiation, but also predisposing inherited syndromes might be involved in leukemogenesis. The overall prognosis is generally poor and curative treatment requires allogeneic stem cell transplantation (alloSCT) in almost all cases. Methods: In clinical trials or registries of the AML‐BFM Study group, between 1993 and 2018 145 children and adolescents (f=70; m=75) with tAML have been enrolled. T‐AML was defined according to the WHO 2016 classification. Patients were included if the initial malignancy occurred before their 18th birthday. Thirteen patients were excluded due to the lack of data concerning the primary malignancy. Whereas between 1993 and 2003, full AML-BFM treatment with double induction and two consolidation elements prior to SCT was recommended (AML-BFM 93 / AML-BFM 98), since 2004 only double induction and direct alloSCT have been applied. AlloSCT should be performed in 1st CR but also in case of no evidence of blasts (NEL), e.g. hematological regeneration was not required. Results: The median age was 10.6 years old and ranged from 1.4 to 26.6 years. The median percentage of BM blasts was 68% (range 11 ‐ 95%), the median WBC of 10,100/ μl (range 1,100 ‐ 201,000/μl) and hemoglobin 9.6 g/dl (range 6.5‐13.1 g/dl) According to the FAB classification, FAB M4/M5 (66%) was the largest group, followed by FAB M0/M1/ M2 (25%), FAB M6/M7 (6%) and others (6%). This corresponded to genetics: t(9;11) 32% and other MLL rearranged AML ((10;11); t(11;19), t(4;11); 15%, normal (n=13; 13%), or complex karyotype (n=10; 10%). Other patients had different findings such as n‐ras (n=8; 8%), trisomy 8 (n=5; 5%), t(8;21); 1%, inv(16), 2%, monosomy 7 (n=2; 2%), WT1 (n=4;4%) or NPM1, c‐kit, CEBPαdm, FLT3‐ITD (n=1 each). Twenty-eight different primary malignancies were reported, the median interval between primary malignancy and tAML was 2.6 years (range 1.3 to 22 years). Acute lymphoblastic leukemia (n=37, 28%) was the most frequent primary malignancy, however in total tAML occurred in 47% of the patients following solid tumors (n=68; Ewing-sarcoma n=11, 8%, osteosarcoma n=12; 9%, neuroblastoma n=13, 10%, rhambomyosarcoma n=7; 5%, nephroblastoma n=5; 4%), in 40% following systemic malignancies (ALL, non-Hodgkin lymphoma n=7; 7%, Hodgkin-lymphoma (n=6, 4%) and in 13% following brain tumors (medulloblastoma n=6, 4%; others n=8, 9%).The 5yrs‐overall survival (OS) rate of the complete cohort was 28 ± 4%, increasing from 19 ± 5% (n=70 1993‐2003) to 34±7% (n=41, 2004‐2011) up to 45±9% (n=34 2012‐2018; p log rank <0.03). The OS is similar for solid tumors (28±6%) and systemic malignancies (37±6%) but inferior for patients with a previous brain tumor (6±6%; p<0.002). Early death was recorded in 20/145 patients (14%). Children with tAML, who achieved CR (47%) or at least no evidence of leukemia (NEL; 39%) had an OS 60±7% and 32±11%, respectively. By contrast, 10 out of 11 patients with persistence blasts at time of alloSCT died. Conclusions: T‐AML in pediatric patients is still associated with a poor prognosis due to poor response, increased toxicities and unfavorable genetic aberrations. T-AML following brain tumors as 1st malignancy showed the worst prognosis. The reduction to two treatment elements prior to alloSCT and proceeding to SCT without CR might contribute to the improvement of survival. Disclosures Reinhardt: BlueBirdBio: Membership on an entity's Board of Directors or advisory committees; CLS Behring: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; CElgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding.
The importance of the cellular pharmacokinetics of cytarabine triphosphate (ara-CTP) with regard ... more The importance of the cellular pharmacokinetics of cytarabine triphosphate (ara-CTP) with regard to therapeutic efficacy is well established. In vitro and in vivo monitoring of pharmacokinetic parameters of leukemic blast cells were initiated in order to contribute to the pharmacological basis of optimal ara-C treatment strategies. Peripheral or bone marrow blast cells from 66 leukemic patients [51 acute myelogenous leukemia (ALL), 15 acute lymphoblastic leukemia (AML) were separated and incubated with ara-C for 1 hour and in ara-C-free medium for another 3 hours, and the intracellular formation and retention of ara-CTP was measured. In eight children who received continuous ara-C infusion for induction treatment, the ara-CTP concentration in circulating blast cells was monitored in vivo. The in vitro values observed in this assay corresponded to the cellular levels monitored in vivo. The ara-CTP retention differed clearly among the individual groups, as classified by immunophenotype at the time of the initial diagnosis: non-T-ALL 67+/-25% (x+/-SD, n=33), T-ALL 37+/-15% (n=8), and AML 34+/-18% (n=14). The difference in ara-CTP retention between non-T-All and AML (P<0.05) as well as T-ALL (P<0.05) was significant. There was a tendency toward lower ara-CTP retention in relapsed as compared with newly diagnosed ALL, but the difference was not significant. The maximal accumulation of ara-CTP (after 1 hour incubation) was comparable in AML, T-ALL, non-T-ALL, and blast cells from children in relapse. The observed similarity of cellular accumulation in all groups and the significantly more rapid decrease in T-ALL and AML provide the pharmacokinetic rationale supporting the prolonged infusion duration for ara-C in these subgroups as an alternative to the intensification by high-dose ara-C schedules with short-term infusion.
BACKGROUND: Long-term survival in pediatric acute myeloid leukemia (AML) improved remarkably duri... more BACKGROUND: Long-term survival in pediatric acute myeloid leukemia (AML) improved remarkably during the last decades. However, children with refractory disease or relapsed AML still suffer from exceedingly poor outcome, especially those who relapse within one year of diagnosis with very limited treatment options. Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody linked to calicheamicin, a potent cytotoxic agent. Developed for targeted treatment of CD33-positive AML, studies in adults showed its efficacy in relapsed and refractory AML. We performed this retrospective analysis of patients with highly advanced pediatric AML, receiving GO as compassionate use. PATIENTS AND METHOD: In total, 96 children <18 years diagnosed from 1995 to 2014 with multiple relapsed or refractory AML received GO as compassionate use. Eighty-eight patients had sufficient data available for this retrospective analysis, evaluation of adverse effects during first cycle of GO was based on medical reports of 83 patients. Sixty-one patients were treated in refractory disease or early first relapse, but also including 7 patients with 2 relapses within the first year after diagnosis. Nine patients were in 2nd relapse (>1year from diagnosis) and one patient in 3rdrelapse, four children had AML as secondary malignancy. Fourteen children have been already transplanted once, one child twice before GO therapy. Fourty-seven children received monotherapy with GO, 35 children were treated combined with cytarabine and 3 children received other combinations with other agents (3 unknown). Fifty-three patients received one cycle, 34 received 2 cycles of GO, however one patient received 4 cycles of monotherapy. Of note, eight patients have been previously reported elsewhere (Zwaan et al., Br J Haematol. 2010). Time of database lock was 07/2016 with a median follow-up of 9.8 years for the surviving patients. RESULTS: Safety profile was comparable to other pediatric studies. Adverse effects during first cycle of treatment consisted mostly of fever in neutropenia (n=49), less frequently infections (n=9) or allergic reactions (n=18). A few patients reported about mild gastrointestinal symptoms, which was not clearly related to GO due to combination therapy. Two patients suffered from sepsis. Veno-occlusive disease (VOD) of the liver occurred in three patients, one of those had a previous VOD, but all of them have been treated successfully with defibrotide. No lethal event was observed during treatment with GO. One patient developed a VOD during subsequent transplantation despite of prophylactic use of defibrotide. Sixty patients were evaluable for response assessment of the bone marrow. Twenty-eight children showed a response with a blast reduction to 5% or less in the bone marrow samples after treatment (46%). Fourteen out of these patients, received GO combined with cytarabine, 12 patients had monotherapy, and two other combinations. Subsequently, 53 children proceeded to stem cell transplantation (SCT) (one patient unknown). Of note, 13 out of those, received further chemotherapy before HSCT was performed. In details, 47 patients proceeded to first SCT, whereas 5 patients received 2ndSCT (one unknown). Time to transplantation varied (<3 weeks, n=14; 3 to 6 weeks, n=28; >6 weeks, n=11 patients [median time to transplantation after GO: 30 days]). The probability of 4-year overall survival after treatment with GO of all patients (n=88) was 21±4%. In patients treated with monotherapy it was 18±6%. Eighteen patients of this cohort are still alive at time of database lock. CONCLUSION: To our knowledge, this analysis is the largest pediatric cohort of patients, treated with GO in a very advanced disease. The results of this retrospective trial indicate efficacy of GO, while having an acceptable toxicity profile, even in heavily pretreated patients. It can induce blast reduction and even survival in patients, who have no further conventional treatment options. Further randomized studies are necessary to learn more about efficacy and side effects in a relapse setting, especially for therapeutic implications in future. Disclosures Rasche: Jazz Pharma: Other: Travel accomodation. Zwaan:Pfizer: Research Funding; Pfizer: Consultancy. Reinhardt:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Jazz Pharma: Other: Travel Accomodation.
The prognostic significance of Auer rods in predicting response rate and remission duration was i... more The prognostic significance of Auer rods in predicting response rate and remission duration was investigated in 257 patients of the two West German acute myelogenous leukemia (AML) studies BFM‐78 and ‐83. Auer rods were found in 129 children (50%) in the initial bone marrow smear. The incidence was higher in myeloid subtypes M1 (63%) and M2 (78%) compared with subtypes M4 (47%) and M5 (5%) with monocytic differentiation. In both studies, the remission rate was significantly higher in patients with Auer rods (P = 0.01), and in the study AML‐BFM‐83 a significantly longer remission duration was evaluated for Auer rodpositive patients (P = 0.007). In the M1 type, Auer rods were of high prognostic significance regarding both the induction success (P = 0.003) and the remission duration (P = 0.004), whereas no significant differences between Auer rodpositive and ‐negative patients in other subtypes were found. Occurrence of Auer rods was independent of hyperleukocytosis, the most powerful prognostic parameter in the studies AML‐BFM‐78 and ‐83, whereas absence of Auer rods was associated with the AML risk group M5. In the M1 type, Auer rod‐negative leukemias appeared to represent cases of poorly differentiated AML. Auer rods were therefore useful in differentiating between patients with a poor and a more favorable prognosis, particularly in the M1 type.
Over a period of 10 years the bone marrow of 38 children with secondary leukemia was cytogenetica... more Over a period of 10 years the bone marrow of 38 children with secondary leukemia was cytogenetically analyzed. After comparison of all karyotypes, chromosomes 5, 7, and 11 were found to be most frequently involved in numerical or structural aberrations. Whereas in ANLL chromosomes 5 and 7 predominated, chromosome 11 was found in all groups, but mainly in ALL. The breakpoints of different rearrangements were always located in band 11q23.
Relapse occurs in 30–40% of newly diagnosed AML patients, with long-term survival in 20%. Aiming ... more Relapse occurs in 30–40% of newly diagnosed AML patients, with long-term survival in 20%. Aiming at improved outcome, we initiated a prospective, randomised study for relapsed AML, excluding AML M3 and those >18 years of age at initial diagnosis. FLAG is being used for 2 consecutive courses: fludarabine 30 mg/m2/day x 5, cytarabine 2 g/m2/day x 5, G-CSF 200 μg/m2/dose for 6 days, starting day -1. Liposomal daunorubicin (DaunoXome, DNX) is a new anthracycline with potentially less cardiotoxicity. Therefore, DNX at 60 mg/m2/day on days 1, 3 and 5 was randomly added or not to the first course of FLAG. Main objectives are to determine the efficacy and toxicity of DNX when added to FLAG, and the long-term outcome in a large group of relapsed AML patients. Thirteen groups worldwide are enrolling patients. More than 400 patients were registered by March 2006. This planned 2nd interim analysis with blinded efficacy data concerns 322 eligible and evaluable patients with first relapsed AML, of whom 250 (78%) were actually randomised. Fifty-two percent of patients relapsed early (<1 year from initial diagnosis). The majority (84%) concerned isolated bone marrow relapse, with central nervous system involvement in 6% of all patients. Dominating FAB types are M2 with auer rods, M4 without eosinophils and M5. Poor response to the 1st course of therapy (>20% of blasts in the BM shortly before the 2nd course), was seen in 23% of patients, more often in early relapses (31%) than in late relapses (15%). Early death occurred in 6% of patients. Complete remission (CR) was achieved in 63% of patients after 2 courses, and they have a probability of survival at 3 years (3-yr pSurv.) of 47% compared to 33% for the total group and 8% for patients not achieving CR. Compared to early relapses, patients with late relapse had higher CR rates (76 vs 51%), and higher 3-yr pSurv.: 42% vs 23%. Similarly, patients with either t(8;21) or inv(16) had a significantly better outcome. Death in continuous CR occurred in 8.6% of 322 patients, without excess of deaths in one treatment arm. Nearly all patients in CR have been transplanted, the majority with a matched unrelated donor. There was significant grade III/IV toxicity, but no unexpected toxicity, and no clinically relevant differences between the arms with and without DNX, especially not in cardiotoxicity. In conclusion, it is feasible to perform a large randomised pediatric study in a very international setting. DNX added to FLAG does not result in major additional toxicity, but follow-up of cardiotoxicity should be extended as planned in this protocol. Late relapses do better in terms of CR and overall survival, as well as patients with t(8;21) or inv(16), but early relapses achieving CR have a realistic chance of survival as well with currently 23% of them in continuous CR. The study is ongoing until 360 eligible and fully evaluable patients have been randomised, to answer the question whether liposomal daunorubicin improves outcome in pediatric relapsed AML.
Apoptosis-related proteins are important molecules for predicting chemotherapy response and progn... more Apoptosis-related proteins are important molecules for predicting chemotherapy response and prognosis in adult acute myeloid leukemia (AML). However, data on the expression and prognostic impact of these molecules in childhood AML are rare. Using flow cytometry and western blot analysis, we therefore investigated 45 leukemic cell samples of children with de novo AML enrolled and treated within the German AML-BFM93 study for the expression of apoptosis-regulating proteins (CD95, Bcl-2, Bax, Bcl-xL, Procaspase-3, XIAP, cIAP-1, Survivin). XIAP (p<0.002) but no other apoptosis regulators showed maturation-dependent expression differences as determined by FAB morphology with the highest expression levels observed within the immature M0/1 subtypes. XIAP (p<0.01) and Bcl-xL (p<0.01) expression was lower in patients with favorable than intermediate/poor cytogenetics. After a mean follow-up of 34 months, a shorter overall survival was associated with high expression levels of XIAP {30 (n=10) vs. 41 months (n=34); p<0.05} and Survivin {27 (n=10) vs. 41 months (n=34); p<0.05}. We conclude that apoptosis-related molecules are associated with maturation stage, cytogenetic risk groups and therapy outcome in childhood de novo AML. The observed association of XIAP with immature FAB types, intermediate/poor cytogenetics and poor overall survival should be confirmed within prospective pediatric AML trials.
Early death (ED) refers to deaths in study patients before onset of therapy or in protocol patien... more Early death (ED) refers to deaths in study patients before onset of therapy or in protocol patients within the first six weeks of therapy.
Grundlagen fur das Konzept der »Qualitat« der medizinischen Versorgung wurden bereits 1966 gelegt... more Grundlagen fur das Konzept der »Qualitat« der medizinischen Versorgung wurden bereits 1966 gelegt (Donabedian 1966) und ihre Eigenstandigkeit 1996 in einschlagigen medizinischen Zeitschriften formuliert (Schrappe 2001). Hinsichtlich der Gewahrleistung dieser Versorgungsqualitat besteht gegenwartig noch eine deutliche Lucke zwischen den gesetzlichen Vorgaben zur Qualitatssicherung, die zuletzt im Jahr 2003 in §§ 135a und 137 SGBV verstarkt wurden, und der tatsachlichen Verbreitung von Qualitatsmanagementsystemen, die uber einzelne qualitatssichernde Masnahmen hinausgehen.
Introduction: Although rare, acute myeloid leukemia (AML) in children and adolescents is the most... more Introduction: Although rare, acute myeloid leukemia (AML) in children and adolescents is the most frequent treatment-related malignancy in children and adolescents. Both, chemotherapy and irradiation, but also predisposing inherited syndromes might be involved in leukemogenesis. The overall prognosis is generally poor and curative treatment requires allogeneic stem cell transplantation (alloSCT) in almost all cases. Methods: In clinical trials or registries of the AML‐BFM Study group, between 1993 and 2018 145 children and adolescents (f=70; m=75) with tAML have been enrolled. T‐AML was defined according to the WHO 2016 classification. Patients were included if the initial malignancy occurred before their 18th birthday. Thirteen patients were excluded due to the lack of data concerning the primary malignancy. Whereas between 1993 and 2003, full AML-BFM treatment with double induction and two consolidation elements prior to SCT was recommended (AML-BFM 93 / AML-BFM 98), since 2004 only double induction and direct alloSCT have been applied. AlloSCT should be performed in 1st CR but also in case of no evidence of blasts (NEL), e.g. hematological regeneration was not required. Results: The median age was 10.6 years old and ranged from 1.4 to 26.6 years. The median percentage of BM blasts was 68% (range 11 ‐ 95%), the median WBC of 10,100/ μl (range 1,100 ‐ 201,000/μl) and hemoglobin 9.6 g/dl (range 6.5‐13.1 g/dl) According to the FAB classification, FAB M4/M5 (66%) was the largest group, followed by FAB M0/M1/ M2 (25%), FAB M6/M7 (6%) and others (6%). This corresponded to genetics: t(9;11) 32% and other MLL rearranged AML ((10;11); t(11;19), t(4;11); 15%, normal (n=13; 13%), or complex karyotype (n=10; 10%). Other patients had different findings such as n‐ras (n=8; 8%), trisomy 8 (n=5; 5%), t(8;21); 1%, inv(16), 2%, monosomy 7 (n=2; 2%), WT1 (n=4;4%) or NPM1, c‐kit, CEBPαdm, FLT3‐ITD (n=1 each). Twenty-eight different primary malignancies were reported, the median interval between primary malignancy and tAML was 2.6 years (range 1.3 to 22 years). Acute lymphoblastic leukemia (n=37, 28%) was the most frequent primary malignancy, however in total tAML occurred in 47% of the patients following solid tumors (n=68; Ewing-sarcoma n=11, 8%, osteosarcoma n=12; 9%, neuroblastoma n=13, 10%, rhambomyosarcoma n=7; 5%, nephroblastoma n=5; 4%), in 40% following systemic malignancies (ALL, non-Hodgkin lymphoma n=7; 7%, Hodgkin-lymphoma (n=6, 4%) and in 13% following brain tumors (medulloblastoma n=6, 4%; others n=8, 9%).The 5yrs‐overall survival (OS) rate of the complete cohort was 28 ± 4%, increasing from 19 ± 5% (n=70 1993‐2003) to 34±7% (n=41, 2004‐2011) up to 45±9% (n=34 2012‐2018; p log rank <0.03). The OS is similar for solid tumors (28±6%) and systemic malignancies (37±6%) but inferior for patients with a previous brain tumor (6±6%; p<0.002). Early death was recorded in 20/145 patients (14%). Children with tAML, who achieved CR (47%) or at least no evidence of leukemia (NEL; 39%) had an OS 60±7% and 32±11%, respectively. By contrast, 10 out of 11 patients with persistence blasts at time of alloSCT died. Conclusions: T‐AML in pediatric patients is still associated with a poor prognosis due to poor response, increased toxicities and unfavorable genetic aberrations. T-AML following brain tumors as 1st malignancy showed the worst prognosis. The reduction to two treatment elements prior to alloSCT and proceeding to SCT without CR might contribute to the improvement of survival. Disclosures Reinhardt: BlueBirdBio: Membership on an entity's Board of Directors or advisory committees; CLS Behring: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; CElgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding.
The importance of the cellular pharmacokinetics of cytarabine triphosphate (ara-CTP) with regard ... more The importance of the cellular pharmacokinetics of cytarabine triphosphate (ara-CTP) with regard to therapeutic efficacy is well established. In vitro and in vivo monitoring of pharmacokinetic parameters of leukemic blast cells were initiated in order to contribute to the pharmacological basis of optimal ara-C treatment strategies. Peripheral or bone marrow blast cells from 66 leukemic patients [51 acute myelogenous leukemia (ALL), 15 acute lymphoblastic leukemia (AML) were separated and incubated with ara-C for 1 hour and in ara-C-free medium for another 3 hours, and the intracellular formation and retention of ara-CTP was measured. In eight children who received continuous ara-C infusion for induction treatment, the ara-CTP concentration in circulating blast cells was monitored in vivo. The in vitro values observed in this assay corresponded to the cellular levels monitored in vivo. The ara-CTP retention differed clearly among the individual groups, as classified by immunophenotype at the time of the initial diagnosis: non-T-ALL 67+/-25% (x+/-SD, n=33), T-ALL 37+/-15% (n=8), and AML 34+/-18% (n=14). The difference in ara-CTP retention between non-T-All and AML (P<0.05) as well as T-ALL (P<0.05) was significant. There was a tendency toward lower ara-CTP retention in relapsed as compared with newly diagnosed ALL, but the difference was not significant. The maximal accumulation of ara-CTP (after 1 hour incubation) was comparable in AML, T-ALL, non-T-ALL, and blast cells from children in relapse. The observed similarity of cellular accumulation in all groups and the significantly more rapid decrease in T-ALL and AML provide the pharmacokinetic rationale supporting the prolonged infusion duration for ara-C in these subgroups as an alternative to the intensification by high-dose ara-C schedules with short-term infusion.
BACKGROUND: Long-term survival in pediatric acute myeloid leukemia (AML) improved remarkably duri... more BACKGROUND: Long-term survival in pediatric acute myeloid leukemia (AML) improved remarkably during the last decades. However, children with refractory disease or relapsed AML still suffer from exceedingly poor outcome, especially those who relapse within one year of diagnosis with very limited treatment options. Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody linked to calicheamicin, a potent cytotoxic agent. Developed for targeted treatment of CD33-positive AML, studies in adults showed its efficacy in relapsed and refractory AML. We performed this retrospective analysis of patients with highly advanced pediatric AML, receiving GO as compassionate use. PATIENTS AND METHOD: In total, 96 children <18 years diagnosed from 1995 to 2014 with multiple relapsed or refractory AML received GO as compassionate use. Eighty-eight patients had sufficient data available for this retrospective analysis, evaluation of adverse effects during first cycle of GO was based on medical reports of 83 patients. Sixty-one patients were treated in refractory disease or early first relapse, but also including 7 patients with 2 relapses within the first year after diagnosis. Nine patients were in 2nd relapse (>1year from diagnosis) and one patient in 3rdrelapse, four children had AML as secondary malignancy. Fourteen children have been already transplanted once, one child twice before GO therapy. Fourty-seven children received monotherapy with GO, 35 children were treated combined with cytarabine and 3 children received other combinations with other agents (3 unknown). Fifty-three patients received one cycle, 34 received 2 cycles of GO, however one patient received 4 cycles of monotherapy. Of note, eight patients have been previously reported elsewhere (Zwaan et al., Br J Haematol. 2010). Time of database lock was 07/2016 with a median follow-up of 9.8 years for the surviving patients. RESULTS: Safety profile was comparable to other pediatric studies. Adverse effects during first cycle of treatment consisted mostly of fever in neutropenia (n=49), less frequently infections (n=9) or allergic reactions (n=18). A few patients reported about mild gastrointestinal symptoms, which was not clearly related to GO due to combination therapy. Two patients suffered from sepsis. Veno-occlusive disease (VOD) of the liver occurred in three patients, one of those had a previous VOD, but all of them have been treated successfully with defibrotide. No lethal event was observed during treatment with GO. One patient developed a VOD during subsequent transplantation despite of prophylactic use of defibrotide. Sixty patients were evaluable for response assessment of the bone marrow. Twenty-eight children showed a response with a blast reduction to 5% or less in the bone marrow samples after treatment (46%). Fourteen out of these patients, received GO combined with cytarabine, 12 patients had monotherapy, and two other combinations. Subsequently, 53 children proceeded to stem cell transplantation (SCT) (one patient unknown). Of note, 13 out of those, received further chemotherapy before HSCT was performed. In details, 47 patients proceeded to first SCT, whereas 5 patients received 2ndSCT (one unknown). Time to transplantation varied (<3 weeks, n=14; 3 to 6 weeks, n=28; >6 weeks, n=11 patients [median time to transplantation after GO: 30 days]). The probability of 4-year overall survival after treatment with GO of all patients (n=88) was 21±4%. In patients treated with monotherapy it was 18±6%. Eighteen patients of this cohort are still alive at time of database lock. CONCLUSION: To our knowledge, this analysis is the largest pediatric cohort of patients, treated with GO in a very advanced disease. The results of this retrospective trial indicate efficacy of GO, while having an acceptable toxicity profile, even in heavily pretreated patients. It can induce blast reduction and even survival in patients, who have no further conventional treatment options. Further randomized studies are necessary to learn more about efficacy and side effects in a relapse setting, especially for therapeutic implications in future. Disclosures Rasche: Jazz Pharma: Other: Travel accomodation. Zwaan:Pfizer: Research Funding; Pfizer: Consultancy. Reinhardt:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Jazz Pharma: Other: Travel Accomodation.
The prognostic significance of Auer rods in predicting response rate and remission duration was i... more The prognostic significance of Auer rods in predicting response rate and remission duration was investigated in 257 patients of the two West German acute myelogenous leukemia (AML) studies BFM‐78 and ‐83. Auer rods were found in 129 children (50%) in the initial bone marrow smear. The incidence was higher in myeloid subtypes M1 (63%) and M2 (78%) compared with subtypes M4 (47%) and M5 (5%) with monocytic differentiation. In both studies, the remission rate was significantly higher in patients with Auer rods (P = 0.01), and in the study AML‐BFM‐83 a significantly longer remission duration was evaluated for Auer rodpositive patients (P = 0.007). In the M1 type, Auer rods were of high prognostic significance regarding both the induction success (P = 0.003) and the remission duration (P = 0.004), whereas no significant differences between Auer rodpositive and ‐negative patients in other subtypes were found. Occurrence of Auer rods was independent of hyperleukocytosis, the most powerful prognostic parameter in the studies AML‐BFM‐78 and ‐83, whereas absence of Auer rods was associated with the AML risk group M5. In the M1 type, Auer rod‐negative leukemias appeared to represent cases of poorly differentiated AML. Auer rods were therefore useful in differentiating between patients with a poor and a more favorable prognosis, particularly in the M1 type.
Over a period of 10 years the bone marrow of 38 children with secondary leukemia was cytogenetica... more Over a period of 10 years the bone marrow of 38 children with secondary leukemia was cytogenetically analyzed. After comparison of all karyotypes, chromosomes 5, 7, and 11 were found to be most frequently involved in numerical or structural aberrations. Whereas in ANLL chromosomes 5 and 7 predominated, chromosome 11 was found in all groups, but mainly in ALL. The breakpoints of different rearrangements were always located in band 11q23.
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