scholarly journals Allogeneic Hematopoietic Stem Cell Transplantation for Children With Acute Lymphoblastic Leukemia: Shifting Indications in the Era of Immunotherapy

2021 ◽  
Vol 9 ◽  
Author(s):  
Tony H. Truong ◽  
Cristian Jinca ◽  
Georg Mann ◽  
Smaranda Arghirescu ◽  
Jochen Buechner ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Hematopoietic Stem Cell ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Poor Response ◽  
Cell Transplant ◽  
T Cell Therapy ◽  
Hematopoietic Stem

Pediatric acute lymphoblastic leukemia generally carries a good prognosis, and most children will be cured and become long-term survivors. However, a portion of children will harbor high-risk features at the time of diagnosis, have a poor response to upfront therapy, or suffer relapse necessitating more intensive therapy, which may include allogeneic hematopoietic stem cell transplant (HSCT). Recent advances in risk stratification, improved detection and incorporation of minimal residual disease (MRD), and intensification of upfront treatment have changed the indications for HSCT over time. For children in first complete remission, HSCT is generally reserved for those with the highest risk of relapse. These include patients with unfavorable features/cytogenetics who also have a poor response to induction and consolidation chemotherapy, usually reflected by residual blasts after prednisone or by detectable MRD at pre-defined time points. In the relapsed setting, children with first relapse of B-cell ALL are further stratified for HSCT depending on the time and site of relapse, while all patients with T-cell ALL are generally consolidated with HSCT. Alternatives to HSCT have also emerged over the last decade including immunotherapy and chimeric antigen receptor (CAR) T-cell therapy. These novel agents may spare toxicity while attempting to achieve MRD-negative remission in the most refractory cases and serve as a bridge to HSCT. In some situations, these emerging therapies can indeed be curative for some children with relapsed or resistant disease, thus, obviating the need for HSCT. In this review, we seek to summarize the role of HSCT in the current era of immunotherapy.

A Successful Re-Induction Regimen for Relapsed Pediatric Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 863-863
Author(s):  
Jason Ackerman ◽  
Douglas Hawkins ◽  
Karyn Brundige ◽  
Laura Eisenberg ◽  
Blythe Thomson
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Induction Therapy ◽  
Lymphoblastic Leukemia ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Induction Regimen ◽  
First Relapse

Abstract Background: Acute Lymphoblastic Leukemia (ALL) is the most common form of malignancy in children. Advances in treatments have made ALL the disease highly curable; however relapse is the most common form of treatment failure. The prognosis for relapsed ALL is poor, and the ability to achieve a durable second remission is influenced by the length of the initial remission and, potentially, the re-induction therapy chosen. We present a series of 60 pediatric ALL patients with first relapse (54 pre B-cell and 6 T-cell) treated with a standardized four-drug induction therapy followed by either intensification therapy or hematopoietic stem cell transplant (HSCT). Methods: Patients treated at Children’s Hospital and Regional Medical Center, Seattle, WA with a common re-induction regimen for first relapse ALL were reviewed in this IRB-approved retrospective study. Patients included isolated or combined bone marrow (BM) relapse, isolated central nervous system (CNS) relapse alone, or isolated testicular relapse. Re-induction consisted of a four-drug combination of dexamethasone (dex) (day 0-6, 14-20), vincristine (VCR) (weekly for 4 weeks), peg-aspargase (weekly for 4 weeks), and idarubicin (10 mg/m2/day × 2-3 doses) and intrathecal triple (ITT) drug therapy. After achieving second complete remission (CR2), patients proceeded to HSCT or continued chemotherapy at the discretion of the physician. Allogeneic HSCT was total body irradiation based and a variety of stem cell sources. Continuation chemotherapy was alternating blocks every 3 weeks for up to 8 courses: Block A, consisting of dex, VCR, 6-thioguanine (TG), peg-asparagase and methotrexate (MTX) and ITT, and Block B, consisting of etoposide and ifosfamide and ITT. Maintenance chemotherapy with MTX, VCR and TG with cranial, craniospinal or testicular radiation completed the two year regimen. Results: Among the 54 pre-B-cell patients, there were 32 with BM relapse (either isolated or with CNS), 16 CNS relapses, and 6 testicular relapses. CR2 was achieved in 96% of the patients. Two did not achieve remission, dying of toxicity during re-induction. BM (± CNS) Isolated CNS Testicular Duration of CR1 n 3 yr. EFS (95% CI) n 3 yr. EFS (95% CI) n 3 yr. EFS (95% CI) <18 months 5 0% (± 52%) 3 67% (± 54%) - - >18 months 27 39% (± 24%) 13 75% (± 26%) 6 67% (± 38%) Among the patients with BM relapse, the 3 year Event Free Survival (EFS) was 33.2% (95% CI: ± 20.8%). The 3 year EFS for the 18 who proceeded to HSCT was 35.0% (95% CI: ± 27.4%), while 3-year EFS for chemotherapy only patients was 31.7% (95% CI: ± 31.8%). There were 6 patients with T-cell relapsed disease, which were evaluated separately. Their EFS was 0% (95% CI: ±46%) at three years, and 2 failed to achieve CR2. Discussion: We present a large single institution series of patients treated with a common reinduction regimen followed by chemotherapy or HSCT. Although intensive, the regimen was tolerable (less than 4% toxic death rate) and highly successful in achieving CR2. Among the patients with later BM relapse, there was minimal difference in 3-year EFS between chemotherapy and HSCT, offering a reasonable continuation chemotherapy regimen to these patients. Our data confirmed the excellent outcome of isolated CNS and testicular relapse and the poor outcome of very early relapse and T cell disease.

Risk Factors for Outcome after Haploidentical Hematopoietic Stem Cell Transplant in Children with Very High Risk Acute Lymphoblastic Leukemia: Impact of Centre Experience. A Survey on Behalf of the ALWP and PDWP of the EBMT.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 438-438 ◽  
Author(s):  
Thomas Klingebiel ◽  
Jacqueline Cornish ◽  
Myriam Labopin ◽  
Franco Locatelli ◽  
Adriana Balduzzi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Hematopoietic Stem Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Alternative Option ◽  
Significant Difference ◽  
Very High

Abstract In the absence of an HLA identical donor, T-cell depleted haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) is an alternative option to treat children with very high risk acute lymphoblastic leukemia (ALL). However, little data is available in children. We have analyzed 118 children (≤16 years old) with ALL transplanted with a myeloablative Haplo-HSCT from 1995 to 2004 in Europe. Only transplants with 2 or more HLA disparities out of 6 (A, B and DRB1) were included. The median age was 8.5 years and median follow-up 56 months (8–116). At transplant, 21 (18%) were in CR1, 72 (61%) in CR2 or CR3 and 25 (21%) in more advanced phase. The 3-year leukemia free survival was 32±10%, 28±5% and 0%, respectively. Therefore we restricted the analysis to patients in remission (n=93) transplanted in 30 EBMT centers. Thirty-four (37%) patients were treated in centres performing more than 10 Haplo-HSCT in the study period (3 centres). The median age of recipient and donor was 8.7 and 37 years, respectively. Fifty four (65%) received a full Haplo-HSCT and 95% of the donors were parental. Twenty seven (29%) had t(9;21) or t(4;11). The majority of patients did not receive drugs for GVHD prophylaxis, ATG/ALG was used in conditioning in 74%, and 73% received TBI. The Clinimacs® device was used in 74% of selections. The median number of CD34+ cells infused was 12.8 106/Kg. Cumulative incidence with competing risk and KM estimates were used to calculate outcome probabilities. The median days of neutrophil recovery was 15 days (8–55) and 90% of patients had signs of engraftment. Acute GVHD II–IV was observed in 24% of the patients. In univariate analysis for LFS there was a trend towards better results for patients receiving higher CD34 cell dose (p=0.08) and a significant difference for patients transplanted in centres performing more Haplo-HSCT (49% versus 17%, p=0.002). Relapse incidence (RI) and non relapse mortality NRM) tended to be different between the experienced and less experienced centres. In less experienced centres NRM was 41% vs 27% (p=0.13) and RI 41% vs. 24% (p=0.10). There were patient, donor and transplant related differences between less and more experienced centres, specifically related to donor sex, Philadelphia positivity, year of transplantation, use of TBI, ATG and DLI and previous autograft. In conclusion, Haplo-HSCT is an alternative option to treat children with very high risk ALL in the absence of HLA identical donor. Centres with more experience have better LFS.

Molecular Relapse of Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation Can Be Successfully Treated with Donor Lymphocyte Infusions.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5122-5122
Author(s):  
Alida Dominietto ◽  
Anna Maria Raiola ◽  
Raffaella Grasso ◽  
Anna Garuti ◽  
Carmen di Grazia ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Hematopoietic Stem Cell ◽  
Lymphoblastic Leukemia ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Donor Lymphocyte Infusions

Abstract Background. Hematologic relapse is seen in 20–40% of adult acute lymphoblastic leukemia (ALL) patients undergoing an allogeneic hematopoietic stem cell transplant (HSCT) and is usually non responsive to donor lymphocyte infusions (DLI). This has suggested a lack of graft vs leukemia effect (GvL) in ALL patients. It is currently possible to monitor minimal residual disease (MRD) post-HSCT and this may allow to identify patients at high risk of hematological relapse. Objectives. To monitor MRD in B-ALL patients post-HSCT and to treat MRD positive patients with DLI. Patients and Methods. MRD was evaluated on bone marrow samples using nested polymerase chain reaction (PCR) and real time PCR (RT-PCR) assay to analyze respectively IgH VDJ and BCR-ABL gene rearrangement. Molecular positivity/relapse was defined with two consecutive positive PCR assays. MRD monitoring was performed in 28 patients grafted from an HLA-identical sibling (n=19), family mismatched related donor (n=2) or matched unrelated donor (n=7). Median follow-up was 47 months (range 5–163). Sixteen patients (57%) were in early disease phase at the time of transplant. Results. We identified 3 groups of patients. A) 14 patients (50%) had no evidence of MRD after HSCT. B) 6 (21%) had a positive MRD and received escalating dose DLI, within 60 days and C) 8 (29%) had a positive MRD, but did not received DLI, because not available or because of an early hematological relapse. Median time from HSCT to molecular relapse was 139 days (range 46–1048). The median follow up was 1385 days (144 – 4877). Median number of infused CD3+ cells was 0.6x10^7/Kg of recipient body weight (range 0.01–7). Hematological relapse was seen in 0%, 0% and 88% respectively of group A,B,C (p=0.0001) and disease-free survival (DFS) was 100% , 67% , 12% (p=0.0001). Conclusions. This study shows that (1) MRD monitoring of ALL patients post-transplant identifies patients at high risk of hematologic relapse and (2) that treatment with DLI, on the basis of MRD positivity, significantly reduces the risk of leukemia relapse and may improve DFS. These data also confirm the existence of a GvL effect, previously shown in this disease (Weiden et.al NEJM, 300, 1068; 1979).

Sign in / Sign up

Export Citation Format

Share Document