Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell ...transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.
A total of 156 patients (age range 1.3-18.0 years, median 13.2 years; 91 (58.3%) male) with newly diagnosed CML (N = 146 chronic phase (CML-CP), N = 3 accelerated phase (CML-AP), N = 7 blastic phase ...(CML-BP)) received imatinib up-front (300, 400, 500 mg/m
, respectively) within a prospective phase III trial. Therapy response, progression-free survival, causes of treatment failure, and side effects were analyzed in 148 children and adolescents with complete data. Event-free survival rate by 18 months for patients in CML-CP (median follow-up time 25 months, range: 1-120) was 97% (95% CI, 94.2-99.9%). According to the 2006 ELN-criteria complete hematologic response by month 3, complete cytogenetic response (CCyR) by month 12, and major molecular response (MMR) by month 18 were achieved in 98, 63, and 59% of the patients, respectively. By month 36, 86% of the patients achieved CCyR and 74% achieved MMR. Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response or intolerance (N = 9). In all, 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N = 3) or SCT-related complications (N = 2). This large pediatric trial extends and confirms data from smaller series that first-line imatinib in children is highly effective.
Summary
Relapse remains the major cause of treatment failure in children with high‐risk acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem‐cell transplantation (allo‐SCT). ...Prognosis is considered dismal but data on risk factors and outcome are lacking from prospective studies. We analysed 242 children with recurrence of ALL after first allo‐SCT enrolled in the Berlin‐Frankfurt‐Munster (BFM) ALL‐SCT‐BFM 2003 and ALL‐SCT‐BFM international 2007 studies. Median time from allo‐SCT to relapse was 7·7 months; median follow‐up from relapse after allo‐SCT until last follow‐up was 3·4 years. The 3‐year event‐free survival (EFS) was 15% and overall survival (OS) was 20%. The main cause of death was disease progression or relapse (86·5%). The majority of children (48%) received salvage therapy without second allo‐SCT, 26% of the children underwent a second allo‐SCT and 25% received palliative treatment only. In multivariate analyses, age, site of relapse, time to relapse and type of salvage therapy were identified as significant prognostic factors for OS and EFS, whereas factors associated with first SCT were not statistically significant. Combined approaches incorporating novel immunotherapeutic treatment options and second allo‐SCT hold promise to improve outcome in children with post allo‐SCT relapse.
Purpose
Results of the prospective trial “CML-PAED-II” assessing treatment efficacy and side effects in children and adolescents with newly diagnosed chronic myeloid leukemia (CML) are reported.
...Patients and Methods
156 patients (age range 1.3-18.0 years, 91 male) with newly diagnosed CML (N= 146 chronic phase (CML-CP), N= 3 accelerated phase (CML-AP), N= 7 blastic phase (CML-BP)) received imatinib upfront (300 mg/m², 400 mg/m², 500 mg/m², respectively). Therapy response, progression-free survival, causes of treatment failure and proportion of patients undergoing stem cell transplantation were analyzed in 148 patients with complete data.
Results
Event-free survival rate at 18 months for pediatric patients diagnosed in CML-CP (median follow-up time 25 months, range: 0.1-120) was 97% (95% CI, 94.2%-99.9%). According to the 2006 ELN-criteria complete hematologic response at month 3, complete cytogenetic response (CCyR) at month 12, and molecular response (MR3.0) at month 18 were achieved in 98%, in 63%, and 59% of the patients, respectively. At month 36 on continuous first line imatinib or 2nd generation tyrosine kinase inhibitor treatment, 86% of the patients achieved CCyR and 74% achieved MR3.0.
66% of the patients experienced at least one side effect. Imatinib-related anemia was the most frequent toxicity observed if all grades were considered (N=98; 66%) while neutropenia was the most frequently reported grade 3/4 hematologic adverse effect (N=22; 15%). Among non-hematologic toxicities, all grades of gastrointestinal toxicity were observed most frequently (N=57, 38%), however, it occurred at lower grades 1/2 in all but one patient. Higher grade 3/4 musculoskeletal pain was also frequent (N=53, 36%). Twenty-seven patients (18%) had to discontinue treatment temporarily while nine patients permanently terminated imatinib due to non-tolerable side effects (neutropenia N= 4, muscle cramps N= 3, skin N= 1, liver N= 1).
Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response (N= 27) or intolerance (N= 9). 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N=3) or SCT-related complications (N=2).
Conclusion
This large pediatric trial provides evidence confirming that first line imatinib in children is highly effective. Observed adverse effects are acceptable and mainly comprise hematological side effects. Long term outcome and effects of a potentially life-long TKI treatment have to be registered in cooperation with adult hematologists in extended surveillance follow-up studies.
Suttorp:Novartis: Research Funding. Schrappe:JAZZ Pharma: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; SigmaTau: Consultancy, Research Funding; Medac: Consultancy, Research Funding. Thiede:Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Roche: Consultancy; Agendix: Employment.
BACKGROUND. Allogeneic hematopoietic stem cell transplantation (HSCT) is of benefit in pediatric patients with high-risk acute lymphoblastic leukemia (ALL) in first or further remission. Whether ...transplantation from unrelated donors could yield similar results to transplantation from HLA identical siblings is still to be assessed within countries running different frontline and relapse protocols.
AIM OF THE STUDY. A prospective study was initiated within the International BFM Study Group, in order to assess whether the outcome of HSCT from a 9 or 10 out of 10 HLA allelic matched compatible donor (MD) was inferior to the outcome of HSCT from a matched sibling donor (MSD) in children or young adults with ALL carrying very high risk eligibility criteria for transplantation. Primary endpoint was event-free survival (EFS) and secondary endpoints were non-relapse mortality (NRM) and incidence of acute and chronic graft-versus-host disease (aGVHD, cGVHD).
PATIENTS AND METHODS. Between 2007 and 2013, 10 countries (Czech Republic, Denmark, France, Israel, Italy, The Netherlands, Poland, Sweden, Slovakia, Turkey) participated into the ALL SCT I-BFM Study, coordinated by Peters in Vienna. 298 consecutive patients, 18 years old or younger (70% male, median age 9 years), affected with VHR ALL in complete remission (CR), were enrolled in the core arm of the Study (MD vs MSD). Of 298, 107 patients were transplanted from a MSD (50% in CR1, 47% in CR2, 4% >CR2) and 191 from a MD (44% in CR1, 48% CR2, 9% >CR2), either related (5%) or unrelated (95%), at a median of 189 and 197 days, respectively, after diagnosis/relapse. As per protocol, conditioning regimen consisted of TBI-etoposide, in patients older than 2 years, or busulfan-cyclophosphamide-melphalan, in patients 2 years or younger, and GVHD-prophylaxis consisted of cyclosporine (CSA) only for MSD and CSA/methotrexate/ATG for MD recipients. Median follow-up for alive patients was 3.1 years.
RESULTS. Three-year EFS was 67% (SE 5%) for MSD vs 61% (SE 4%) for MD recipients (p-value 0.254), overall survival (OS) 76% (SE 4%) vs 69% (SE 4%) (p-value 0.207), cumulative incidence of relapse (CIR) 24% (SE 4%) vs 22% (SE 3%) (p-value 0.935) and NRM 8% (SE 3%) vs 16% (SE 3%) (p-value 0.094), respectively. There was a trend for a higher risk NRM for MD patients, although no statistical significance was reached (HR 1.94, CI 0.85-4.41; p=0.114), after adjusting for risk profile and donor type. Being transplanted in CR2 was associated with lower EFS and higher NRM (p=0.001).
Grade II-IV acute GVHD occurred in 37% and grade III-IV in 16% of MSD vs 42% and 15% of MD recipients; 39% of the evaluable MSD and 19% of the MD recipients experienced chronic GVHD, which was severe in 24% and 10%, respectively. Cumulative incidence of developing chronic GVHD was 39% (SE 5%) and 17% (SE 3%), for patients grafted from MSD and MD, respectively (p=0.001). Being transplanted from a MD, compared with a MSD, was significantly associated with a reduced risk of developing chronic GVHD (HR 0.31, CI 0.18-0.54, p <0.001), despite a similar risk of relapse (HR 0.81, CI 0.47-1.39; p=0.440). Acute GVHD grade 3 or 4 had statistically significant impact on NRM (HR 4.76, CI 2.33-9.74; <0.001) and OS (HR 1.97, CI 1.14-3.42; p=0.016), after adjusting for risk profile and donor type.
CONCLUSIONS. Outcome of transplantation of MD pediatric recipients with VHR ALL in CR was not inferior to the outcome of MSD recipients in terms of EFS, OS, and CIR, with probability of chronic GVHD being lower for MD versus MSD recipients, which suggests the crucial role of serotherapy, and severe acute GVHD being associated with increased NRM and lower OS but similar CIR.
Dalle:Gilead: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Macopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Peters:Medac: Research Funding; Fresenius: Research Funding; Amgen: Research Funding; Jazz: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanovi: Research Funding; Pierre-Fabre: Research Funding.
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Introduction: Most pediatric patients (pts) with ALL receive total body irradiation (TBI) for myeloablative conditioning of allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is ...unproven whether TBI can be replaced by chemotherapy (CHT).
Methods: To compare the outcomes of TBI- versus (vs.) CHT-based conditioning, we performed a retrospective EBMT-registry based study. Children between 2 and 18 years of age (y.) after myeloablative conditioning for first allo-HSCT of bone marrow (BM) or peripheral blood SC (PBSC) from matched sibling (MSD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to consider the covariate “distribution of TBI recipients” for pts who did not receive TBI.
Results: In total 3071 pts (CR1: 1504 (49%), CR2: 1567 (51%)) were included. CR1: 1045 pts (69%) received BM and 459 pts (31%) PBSC from MSD (760 (51%)) or UD (744 (49%)). CR2: 1067 pts (68%) received BM and 500 pts (32%) PBSC from MSD (675 (43%)) or UD (892 (57%)). Overall, conditioning was TBI- in 2647 (86%) and CHT-based in 424 pts (14%). Busulfan/Cyclophosphamide (Bu/Cy) and Bu/Cy/Etoposide (Bu/Cy/Eto) were the two most frequently applied CHT combinations in CR1 (68 (32%), 66 (31%)) and CR2 (68 (32%), 52 (25%)). The remaining conditionings included 5 different combinations of chemotherapeutics (other chemo).
1504 pts in CR1 were conditioned with TBI (1291), Bu/Cy/Eto (66) or other chemo (147) with a median follow-up of 4.4, 3.4 and 2.4 y. In weighted univariate analysis no significant differences were detected for LFS (5-y.-LFS, range: 62.4 to 67.5%) and relapse incidence (5-y.-RI, range: 24.0 to 29.0%). In pairwise testing, OS after Bu/Cy/Eto was significantly better compared with TBI (5-y.-OS, 78.7 vs. 66.8%, P=.006). Non-relapse mortality was significantly higher after other chemo (5-y.-NRM, 12.7%, P <.001) and TBI (12.5%, P <.001) compared with Bu/Cy/Eto (3.5%).
Other significant influencing factors on LFS were age (5-y.-LFS, 2-11 y. 65.8 vs. 12-18 y. 58.0%, P=.009), y. of HSCT (2008-2012 65.9 vs. 2000-2007 59.6%, P=.035) and donor type (MSD 64.9 vs. UD 59.5%, P=.007). RI was influenced by y. of HSCT (5-y.-RI, 2008-2012 21.7 vs. 2000-2007 26.8%. P=.026). OS was influenced by age (5-y.-OS, 2-11 y. 72.7 vs. 12-18 y. 61.7%, P <.001) and donor type (MSD 70.1 vs. UD 65.0%, P=.002). NRM was influenced by age (5-y.-NRM, 2-11 y. 9.0 vs. 12-18 y. 18.0%, P <.001), donor sex (male 10.9 vs. female 16.6%, P=.007) and donor type (MSD 8.5 vs. UD 17.8%, P <.001).
In weighted multivariable Cox model clustered on EBMT centers, TBI-based conditioning in CR1 was associated with lower RI (HR 0.70, P=.047), lower OS (HR 1.54, P=.017) and higher NRM (HR 3.97, P <.001).
1567 pts in CR2 were conditioned with TBI (1356), Bu/Cy (68) or other chemo (143) with a median follow-up of 3.9, 3.2 and 3.1 y. In weighted univariate analysis highly significant differences of survival were detected. TBI-based conditioning resulted in highest 5-y.-LFS of 52.2% (Bu/Cy 41.0%, other chemo 18.4%, P <.001), lowest 5-y.-RI of 33.2% (Bu/Cy 38.3%, other chemo 55.3%, P <.001), highest 5-y.-OS of 56.1% (Bu/Cy 43.6%, other chemo 23.6%, P <.001) and lowest 5-y.-NRM of 14.6% (Bu/Cy 20.8%, other chemo 26.2%, P <.001).
Other significant influencing factors on LFS were age (5-y.-LFS, 2-11 y. 53.5 vs. 12-18 y. 43.0%, P <.001), y. of HSCT (2008-2012 53.3 vs. 2000-2007 47.3%, P=.009) and SC source (BM 53.3 vs. PBSC 42.5%, P <.001). RI was influenced by SC source (5-y.-RI, BM 33.1 vs. PBSC 36.6%, P=.024). OS was influenced by age (5-y.-OS, 2-11 y. 59.3 vs. 12-18 y. 46.8%, P <.001), y. of HSCT (2008-2012 58.6 vs. 2000-2007 52.0%, P=.005), donor type (MSD 58.5 vs. UD 52.6%, P <.024) and SC source (BM 58.4 vs. PBSC 47.5%, P <.001). NRM was influenced by age (5-y.-NRM, 2-11 y. 12.5 vs. 12-18 y. 22.3%, P <.001), donor type (MSD 10.2 vs. UD 19.8%, P <.001) and SC source (BM 13.6 vs. PBSC 20.8%, P <.001).
In weighted multivariable Cox model clustered on EBMT centers, TBI-based conditioning in CR2 was associated with higher LFS (HR 0.48, P <.001), lower RI (HR 0.48, P <.001) and higher OS (HR 0.51, P <.001).
Conclusion: Conditioning by TBI demonstrated clear superiority in comparison to CHT for children with ALL undergoing HSCT in CR2. For pts in CR1, TBI- and CHT-based conditioning showed similar results. This retrospective data is currently re-evaluated in a prospective, randomized, international trial (ALL SCTped 2012 FORUM).
Büchner:Novartis Pharmaceuticals Corporation: Consultancy; Pfizer: Consultancy. Veys:Bellicum: Research Funding; Servier: Research Funding. Bader:Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding.
Bone marrow failure (BMF) syndrome is a group of rare hereditary or idiopathic disorders occurring at all ages. For BMF patients under 40 years of age and having an HLA-identical related donor, ...allogeneic bone marrow transplantation (HSCT) is indicated. The use of cord blood transplantation (CBT) from an HLA-identical sibling donor is of interest in non-malignant disease due to the low risk of graft-versus-host disease (GVHD) associated with this type of stem cell source and the absence of risk to the donor.
We analyzed outcomes of 122 children and young adults with inherited or acquired BMF syndrome, who received a CBT from an HLA-identical related donor. Patients were transplanted in EBMT centers between 1988 and 2014 and reported to Eurocord and EBMT.
Ninety-six patients had an inherited and 26 patients had an acquired BMF. The specific diagnosis were: Fanconi anemia (n=48), Diamond Blackfan anemia (n=25), Amegakariocytic thrombocytopenia (n=6), Kostmann syndrome (n=4), Dyskeratosis congenital (n=3), Schwachman-Diamond syndrome (n=2), and unclassified inherited BMF (n=8) for the inherited group and severe aplastic anemia (n=25), pure red cell aplasia (n=1) for the acquired group.
Eighty-nine patients received a single cord blood (CB) unit, whereas 33 patients received a combination of CB and bone marrow (BM) cells from the same sibling donor. The main reason for adding BM was due to the low cell dose of the single CB unit alone. Of patients receiving CB+BM, 6 had an acquired and 24 had an inherited BMF.
Median age at CBT was 6.7 (range 1-16) years (5.6 years for patients with acquired and 6.9 years for those with inherited BMF). Median interval between diagnosis and CBT was 21 (range 2-114) months for the acquired and 55 (range 2-160) months for the inherited group, respectively.
Fifty-nine patients (53%) received a reduced intensity conditioning (RIC) and 52 (47%) were treated with myeloablative regimens (MAC) (data available for 111 of 122 patients). Fludarabine-based regimens were used in 54 patients (44%). For patients receiving a RIC the most common regimen was cyclophosphamide and fludarabine (56%), and for MAC, cyclophosphamide and busulfan (46%). Total body irradiation was used in 8 patients (both in RIC and MAC settings).
GVHD prophylaxis consisted mainly of cyclosporine alone (CSA) in 53 patients (43%), CSA + micophenolate mofetil in 11 patients (9%) and CSA + methotrexate in 23 patients (19%).
The median number of total nucleated cells (TNC) infused was 6.2x107/Kg (1-24.2x107/Kg) for patients receiving a single CB unit and 26.8x107/Kg (5.3-41x107/Kg) for those receiving CB+BM (median TNC was 3x107/Kg in CB, and 22x107/Kg in BM graft).
Median follow up is 5 (range 0.6-25) years. The cumulative incidence (CI) of neutrophil recovery at day 60 was 91%+9%, and the median time to engraftment was 21 (range 7-100) days. The CI of platelets engraftment at day 180 was 89+3% with a median time of 35 (range 7-138) days. Thirteen patients experienced primary graft failure (PFG) (12 patients after a single CB and one after a CB+BM graft). For those patients with available information, treatment of graft failure was second BM-HSCT (n=6), and growth factors (n=1).
Of the 13 patients with graft failure, 11 died within in a median time of 1.9 (0.3 to 6) months after CBT. Two patients are alive after the second HSCT.
The 100-day CI of grade II-IV acute GVHD was 11+3% (15 patients: grade II, n=8; grade III, n=6; grade VI, n=1), and the 1-year CI of chronic GVHD was 12+4%.
The 1-year CI of transplant-related mortality was 13+3%, 17 patients died: 11 due to PGF (infections (n=6) hemorrhagic syndrome (n=1) and other causes (n=4)) and the remaining 6 of acute respiratory distress syndrome (n=1), and infections (n=5).
Five-year overall survival (OS) for the whole population was 87+3%. OS was 80+8% for patients with acquired BMF, 87+3% for Fanconi anemia patients, 95+4% for those with Diamond Blackfan, and 86+7% for other inherited BMFs.
In pediatric and young adult patients with either inherited or acquired BMF syndrome, CBT from an HLA-identical sibling donor is associated with excellent long-term outcomes with particular low rates of both acute and chronic GVHD, this latter observation being of particular importance for patients with non-malignant disorders. In case of inherited BMF, collecting cord blood unit at the birth of a new sibling is strongly recommended.
Dufour:Pfizer: Consultancy.
•Outcomes are similar in pediatric acute lymphoblastic leukemia after peripheral blood stem cell transplantation (PBSCT) with HLA-identical sibling donors and matched unrelated donors.•There is a ...higher incidence of chronic graft-versus-host disease (GVHD) in HLA-identical sibling donor transplant recipients.•There is a higher incidence of acute and chronic GVHD after PBSCT.•Severe acute GVHD is associated with lower relapse but is detrimental for event-free survival and survival.•Severe acute and chronic GVHD are associated with higher nonrelapse mortality.•Adolescents have worse chronic GVHD, higher nonrelapse mortality, and poorer survival.
Eligibility criteria for hematopoietic stem cell transplantation (HSCT) in acute lymphoblastic leukemia (ALL) vary according to disease characteristics, response to treatment, and type of available donor. As the risk profile of the patient worsens, a wider degree of HLA mismatching is considered acceptable. A total of 138 children and adolescents who underwent HSCT from HLA-identical sibling donors (MSDs) and 210 who underwent HSCT from matched donors (MDs) (median age, 9 years; 68% male) in 10 countries were enrolled in the International-BFM ALL SCT 2007 prospective study to assess the impact of donor type in HSCT for pediatric ALL.
The 4-year event-free survival (65 ± 5% vs 61 ± 4%; P = .287), overall survival (72 ± 4% versus 68 ± 4%; P = .235), cumulative incidence of relapse (24 ± 4% versus 25 ± 3%; P = .658) and nonrelapse mortality (10 ± 3% versus 14 ± 3%; P = .212) were not significantly different between MSD and MD graft recipients. The risk of extensive chronic (cGVHD) was lower in MD graft recipients than in MSD graft recipients (hazard ratio HR, .38; P = .002), and the risks of severe acute GVHD (aGVHD) and cGVHD were higher in peripheral blood stem cell graft recipients than in bone marrow graft recipients (HR, 2.06; P = .026). Compared with the absence of aGVHD, grade I-II aGVHD was associated with a lower risk of graft failure (HR, .63; P = .042) and grade III-IV aGVHD was associated with a higher risk of graft failure (HR, 1.85; P = .020) and nonleukemic death (HR, 8.76; P < .0001), despite a lower risk of relapse (HR, .32; P = .021). Compared with the absence of cGVHD, extensive cGVHD was associated with a higher risk of nonleukemic death (HR, 8.12; P < .0001).
Because the outcomes of transplantation from a matched donor were not inferior to those of transplantation from an HLA-identical sibling, eligibility criteria for transplantation might be reviewed in pediatric ALL and possibly in other malignancies as well. Bone marrow should be the preferred stem cell source, and the addition of MTX should be considered in MSD graft recipients.
Thiopurine methyltransferase (TPMT) is a key component in thiopurine metabolism. There is an insufficient evidence about the distribution of the genotype frequencies of TPMT variants and frequencies ...of TPMT alleles associated with intermediate and deficient activity in a healthy Slovak population and pediatric patients with inflammatory bowel disease (IBD). TPMT variant alleles (*1,*2, *3A, *3B, and *3C) were determined in 114 children treated for IBD and in 281 healthy volunteers. Mutant alleles were present in 9/114 (7.89%) in the IBD patients and in 23/281 (8.19%) of probands. The distribution of the most frequent variants of TPMT gene was similar in a healthy population and patients with IBD.
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