Acute Lymphoblastic Leukemia in Children and Adolescents
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Although the majority of children and adolescents with acute lymphoblastic leukemia (ALL) are curable with current chemotherapy regimens, poor outcome persists in some individuals (Eckert et al. 2011; von Stackelberg et al. 2011; Schrappe et al. 2012).
Although the majority of children and adolescents with acute lymphoblastic leukemia (ALL) are curable with current chemotherapy regimens, poor outcome persists in some individuals (Eckert et al. 2011; von Stackelberg et al. 2011; Schrappe et al. 2012). Allo-HSCT is the most established treatment to control leukemia by means of the GVL effect. During the last decade, it was demonstrated in prospective trials that HSCT from HLA-MSD and from HLA-MURD results in similar outcomes.
Standardized MAC for paediatric patients with high relapse risk produced a low incidence of TRM and effective control of leukemia (Mann et al. 2010; Pulsipher et al. 2011; Peters et al. 2015). Currently, also HSCT from HLA haplo-identical family donors or mismatched CB gives promising results (Rocha et al. 2009; Luznik et al. 2012; Ruggeri et al. 2012; Berger et al. 2016; Klein et al. 2017; Locatelli et al. 2017).
To offer the patients the best available treatment options, a close collaboration between international therapy study groups and transplant consortia are necessary. This is realized within the big treatment consortia for childhood leukemia (e.g. IBFM-SG, IntReALL, NOPHO, UKALL, AIEOP, FRALLE and others) and the paediatric transplant community (e.g. EBMT-PD WG, IBFM-SC SCT, GETMON, GITMO). The study groups for ALL treatment evaluate outcome according to their chemotherapy protocols and stratify patients to relapse standard-risk, medium-risk and high-risk groups. In contrast to adult patients, only patients with high-relapse risk are eligible for allo-HSCT to protect children from the potential long-term consequences of myeloablation and GVHD.
72.2 Prognostic Factors and Indications for HSCT
HSCT indications have to be defined prospectively and must be re-evaluated and reconfirmed at intervals dependent on modifications and improvements in non-transplant approaches for both front-line and relapse protocols. Some risk factors conveying a dismal prognosis in childhood ALL can be identified even at diagnosis (Moorman 2016; O’Connor et al. 2018). Additionally, response to induction treatment measured by MRD has a strong predictive value and defines nowadays many indications or HSCT (Bader et al. 2009; Conter et al. 2010; Schrappe et al. 2011; Eckert et al. 2013).
72.2.1 Indications: CR1
Indications for allogeneic HSCT in CR1 according to AIEOP-BFM ALL 2009-trial
No MRD result
MRD TP2 ≥ 10−3 to <10−2
MRD TP2 ≥ 10−2
No CR d33
Hypodiploidy < 44 chromosomese
PPR + T-ALL
None of the above featuresf
72.2.2 Indications: CR2 and Later
Indication for HSCT according to IntReALL SR 2010 and HR protocol criteria
Relapse risk group
Time of relapse
Site of relapse
I-BM, C-BM, I-EM
MSD, MD, MMD
I-BM, C-BM, I-EM
If patients achieve a third or higher remission, allo-HSCT should be considered if the physical state allows such a procedure. Patient not in morphological remission should not receive allografts except in extraordinary experimental situations.
72.3 Donor Selection and Stem Cell Source
OS and incidence of NRM have constantly improved; however it has been shown that in children, a BMT from a HLA-identical sibling results in quicker myeloid engraftment, immunoreconstitution and less severe infections and should be therefore the preferred option (Peters et al. 2015). As only 25% of patients have a MSD, HSCT from other donors is the most applied method. Several groups have demonstrated that HSCT from unrelated donors, identified by HLA high-resolution typing and matching, has similar outcome results as MSD-HSCT (Zhang et al. 2012; Fagioli et al. 2013; Burke et al. 2015).
Matching criteria according to HLA typing/matching and stem cell source for children and AYAs with ALL
HLA-genotypically matched sibling, or 10/10 allelic match (if parental haplotypes unknown)
6/6 or 8/8, 5/6 or 7/8a
9/10 or 10/10 allelic matched related or unrelated
5–6/6 unrelated or 6–7-8/8 unrelated
Less than 9/10 matched
Less than 5/6 or 6/8 UCB
Donor hierarchy—further selection criteria
Patient CMV IgG positive
Donor CMV IgG positive
Donor CMV IgG negative
Patient CMV IgG negative
Donor CMV IgG negative
Donor CMV IgG positive
Male or female (preferentially not allo-immunized by prior pregnancy) donor
Female (preferentially not allo-immunized by prior pregnancy) donor
Younger donor if body weight enables sufficient SC harvest
Stem cell source
HSCT from MSD or MD
PPBSC (CAVE: adjust GvHD-prophylaxis for matched siblings)
Cord blood with sufficient cell number (>3 × 107 NC/kg)
HSCT from MMD: possible options
BM, 8/10 matches, unmanipulated
PBSC, haploidentical, CD3/CD19 depleted, α/β depleted
CB, sufficient stem cell dose
PBSC, haploidentical, CD34+ selection
72.4 Conditioning Regimen
Most children receive a MAC. This consists either of TBI and VP and/or CY or—especially for children below 4 years of age—of BU-/FLU-containing regimen, often combined with TT. An increasing use is recognized for TREO which results also in myeloablation but seems to have less toxic side effects (Wachowiak et al. 2011; Boztug et al. 2015; Lee et al. 2015; Peters et al. 2015).
To reduce acute organ toxicity, the interval between the end of the last chemotherapy and the start of conditioning is 3 or at most 6 weeks. If infection or toxicity requires a delay of conditioning, patients receive risk-adjusted chemotherapy to bridge the time until transplantation. Currently, a multinational trial comparing TBI/VP with either FLU/TT/BU or FLU/TT/TREO investigates in a randomized study the value of both conditioning regimens (FORUM study: allogeneic HSCT for children and AYAs with ALL comparing TBI with myeloablative chemo-conditioning) (Willasch et al. 2017).
72.5 GVHD Prophylaxis
Children transplanted with BM from matched sibling donors might benefit from an augmented GVL effect if only single and short GVHD prophylaxis is given (Locatelli et al. 2000). However careful monitoring and rapid treatment intervention are crucial to prevent severe GVHD. After HSCT from non-sibling donors, a combination of CNI and ATG with or without short MTX is given in most patients (Veys et al. 2012; Peters et al. 2015).
72.6 Post-transplant Follow-Up and Interventions
72.6.1 Mixed Chimerism (MC) and MRD
Mixed chimerism (MC) and MRD strongly predict risk for relapse in children (Bader and Kreyenberg 2015).
Preemptive immunotherapy, e.g. withdrawal of IS or DLI guided by chimerism and MRD monitoring, can prevent impending relapse. However, the dynamic of leukaemic reappearance hampers the final success of these methods. Therefore, new post-transplant intervention strategies with less risk for severe complications like bi-specific antibodies or CAR-T-cell interventions may expedite the control of impending relapse (Handgretinger et al. 2011; Maude et al. 2018).
72.6.2 Children with Ph+
Children with Ph + should receive post-transplant TKIs: Whether the prophylactic approach (all Ph + patients will receive TKIs) or a preemptive therapy (only patients with a Ph + signal peri-HSCT) is more effective has to be prospectively proven (Schultz et al. 2010; Bernt and Hunger 2014). Both TKI options are currently under investigation.
22.214.171.124 The Amended EsPhALL Recommendation
Administration of imatinib prophylaxis post HSCT when more than 50,000 platelets are reached. Duration, 365 days after HSCT.
126.96.36.199 TKI According to MRD Result
Administration of imatinib post HSCT for all MRD-positive patients until two negative results are achieved. FACS- and PCR-MRD analyses are accepted.
Only children and adolescents with very high or high relapse risk should be candidates for allo-HSCT. The definition of relapse risk depends on the leukaemic phenotype, response to chemotherapy and—if applicable—time and site of relapse.
MRD levels during chemotherapy but also pre- and post-HSCT are powerful predictors for outcome after HSCT.
Patients who are not in morphological remission before conditioning should not undergo allogeneic HSCT except in extraordinary situations.
MAC is recommended for children with ALL. Whether TBI is necessary to control leukemia is subject of a prospective randomized EBMT/IBFM trial.
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