scholarly journals Superior survival of unmanipulated haploidentical haematopoietic stem cell transplantation compared with intensive chemotherapy as post‐remission treatment for children with very high‐risk philadelphia chromosome negative B‐cell acute lymphoblastic leukaemia in first complete remission

2019 ◽  
Vol 188 (5) ◽  
pp. 757-767 ◽  
Author(s):  
Yu‐juan Xue ◽  
Pan Suo ◽  
Xiao‐jun Huang ◽  
Ai‐dong Lu ◽  
Yu Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Haematopoietic Stem Cell Transplantation ◽  
Philadelphia Chromosome ◽  
Haematopoietic Stem Cell ◽  
Intensive Chemotherapy ◽  
Very High ◽  
First Complete Remission

Outcome of Allogeneic Hematopoietic Stem-Cell Transplantation in Adult Patients With Acute Lymphoblastic Leukemia: No Difference in Related Compared With Unrelated Transplant in First Complete Remission

2004 ◽  
Vol 22 (14) ◽  
pp. 2816-2825 ◽  
Author(s):  
Michael G. Kiehl ◽  
Ludwig Kraut ◽  
Rainer Schwerdtfeger ◽  
Bernd Hertenstein ◽  
Mats Remberger ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Hematopoietic Stem ◽  
First Complete Remission

Purpose The role of unrelated allogeneic stem-cell transplantation in acute lymphoblastic leukemia (ALL) patients is still not clear, and only limited data are available from the literature. We analyzed factors affecting clinical outcome of ALL patients receiving a related or unrelated stem-cell graft from matched donors. Patients and Methods The total study population was 264 adult patients receiving a myeloablative allogeneic stem-cell transplant for ALL at nine bone marrow transplantation centers between 1990 and 2002. Of these, 221 patients receiving a matched related or unrelated graft were analyzed. One hundred forty-eight patients received transplantation in complete remission; 62 patients were in relapse; and 11 patients were refractory to chemotherapy before transplant. Fifty percent of patients received bone marrow, and 50% received peripheral blood stem cell from a human leukocyte antigen–identical related (n = 103), or matched unrelated (n = 118) donor. Results Disease-free survival (DFS) at 5 years was 28%, with 76 patients (34%) still alive (2.2 to 103 months post-transplantation), and 145 deceased (65 relapses, transplant-related mortality, 45%). We observed an advantage regarding DFS in favor of patients receiving transplantation during their first complete remission (CR) in comparison with patients receiving transplantation in or after second CR (P = .014) or who relapsed (P < .001). We observed a clear trend toward improved survival in favor of B-lineage ALL patients compared with T-lineage ALL patients (P = .052), and Philadelphia chromosome–positive patients had no poorer outcome than Philadelphia chromosome–negative patients. Total-body irradiation–based conditioning improved DFS in comparison with busulfan (P = .041). Conclusion Myeloablative matched related or matched unrelated allogeneic hematopoietic stem-cell transplantation in ALL patients should be performed in first CR.

Prognostic Impact of Different High Risk Features in Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in First Complete Remission.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2303-2303
Author(s):  
Theis Terwey ◽  
Philipp Hemmati ◽  
Gero Massenkeil ◽  
Bernd Dörken ◽  
Renate Arnold
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Prognostic Impact ◽  
Very High ◽  
First Complete Remission

Abstract Abstract 2303 Poster Board II-280 Introduction: In acute lymphoblastic leukemia (ALL) specific clinical and biological features confer high relapse risk and inferior overall survival (OS) after treatment with conventional chemotherapy alone. The differential prognostic impact of these high risk features after treatment with allogeneic hematopoietic stem cell transplantation (HCT) has not been well studied. Patients and Methods: 79 adult ALL patients in first complete remission (CR) received allogeneic HCT at our center between 1995 and 2008. All patients were high or very high risk according to German Multicenter Study Group for Adult ALL (GMALL) criteria. Median age was 36 years (range: 17-68). Patients received high-dose conditioning consisting of 12 Gy total body irradiation ± etoposide ± cyclophosphamide (n=69, 87%) or reduced intensity conditioning (RIC) consisting of fludarabine/busulfan/ATG (n=10, 13%) and HSCT from related (n=34, 43%) or unrelated (n=45, 57%) donors. Bone marrow (n=17, 22%) or peripheral blood stem cells (n=62, 78%) were given. Graft-versus-host-disease prophylaxis was CSA/MTX for high-dose conditioning or CSA/MMF for RIC. Results: Patients were classified as high risk or very high risk due to Philadelphia chromosome-positive disease (Ph+) (n=30, 38%), leukocytosis>30/nl at diagnosis in B-ALL (n=25, 23%), late response to induction therapy in B-ALL (>week 4) (n=13, 16%), early or mature T-ALL (n=13, 16%), pro-B-ALL/t(4;11) (n=8, 10%), persistence of minimal residual disease (MRD) (>week 16) (n=8, 10%) or complex aberrant karyotype (n=6, 8%). 57 patients (72%) presented with one high risk feature, whereas 20 patients (25%) and 2 patients (3%) presented with two or three features, respectively. Currently, after a median follow-up of 56 months (7-169) 49 patients (62%) remain alive. Projected OS of the whole cohort at 1, 2 and 5 years was 78%, 70% and 55% and leukemia-free survival was 77%, 66% and 55%. Cumulative incidence of non-relapse mortality (NRM) and relapse mortality (RM) at 5 years was 23% and 18%, respectively. In multivariate Cox regression analysis, a non-significant trend for inferior OS was seen for patients with early or mature T-ALL (hazard ratio (HR): 2.03 (95%CI: 0.92-4.52), p=0.082), whereas no differential effect on OS, NRM or RM was seen for any other high risk feature (Table 1). In additional analyses, inferior OS (HR 1.81 (95%CI: 1.02-3.29), p=0.043) and increased RM (HR 2.17 (95%CI 1.16-4.05), p=0.015) was observed for patients with more than one high risk feature. Conclusions: In summary, this single center study on allogeneic HCT in high risk ALL found a negative prognostic trend for early or mature T cell immunophenotype. No differential prognostic impact on OS, NRM and RM was seen for other high risk features as defined by GMALL criteria, however this conclusion is limited by the low patient number in some of the subgroups. Overall survival for the whole cohort was 55% at 5 years, with inferior OS and higher RM being observed in patients with more than one high risk feature. Disclosures: No relevant conflicts of interest to declare.

In Adult Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia, The Negative Prognostic Impact Of IKZF1, CDKN2A/B and PAX5 Deletions Is Not Abrogated By Allogeneic Stem Cell Transplantation In First Complete Remission

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 231-231
Author(s):  
Heike Pfeifer ◽  
Katharina Raum ◽  
Sandra Markovic ◽  
Stephanie Fey ◽  
Julia Obländer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
B Cell Development ◽  
Genome Wide ◽  
First Complete Remission

Abstract Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is traditionally considered the subtype with the worst prognosis, despite recent improvements in long-term survival brought about by the use of tyrosine kinase inhibitors (TKI) such as imatinib or dasatinib. Allogeneic stem cell transplantation (aSCT) remains the most effective curative post-remission therapy in adults but appears to be less critical in children, indicating a substantial clinical and biological heterogeneity within the subgroup of Ph+ ALL. The ability to segregate Ph+ ALL into subgroups with different prognosis on the basis of reductions of BCR-ABL1 transcript levels during therapy lends further support to the heterogeneity of this type of leukemia, for which the genetic basis is not known. Microarray-based genome-wide profiling studies conducted predominantly in pediatric ALL patients have recently revealed novel recurrent submicroscopic aberrations of genes involved in B-cell development and cell cycle regulation, such as CDKN2A/B, IKZF1, PAX5, ETV6, RB1, BTG1 and EBF1. Deletions of IKZF1, CDKN2A/B and PAX genes have received the most attention due to their high frequency particularly in BCR-ABL1-positive ALL and their association with an inferior prognosis in the setting of combined TKI and chemotherapy. Their prognostic relevance in the setting of allogeneic SCT for adult or pediatric high risk BCP-ALL is not known. We therefore examined whether the negative prognostic role of IKZF1 aberrations and other frequent microdeletions of genes associated with B-cell development can be overcome by allogeneic SCT in CR1. A total of 137 newly diagnosed Ph+ ALL pts. (median age 42 years, range 18-64y, 79 male 58 female) treated within the prospective multicenter GMALL study 07/03 were analyzed. 96 of these patients underwent aSCT in first complete remission (CR), 8 pts. were primary refractory, 12 CR pts. did not undergo aSCT and relapsed, 11 pts. died during induction. Genome-wide copy number analysis in search for acquired copy number alterations (CNA) was performed with Affymetrix SNP 6.0 arrays with anonymous references. Copy number polymorphisms were excluded from the data by comparison with known copy number polymorphisms registered in the UCSC genome browser http://genome.ucsc.edu/, (hg-18). Putatively acquired CNAs were validated by multiplex ligation-dependent probe amplification (MLPA) and germline matched SNP array analysis of n=20 samples within the study. Of the 96 pts. transplanted in CR1, 48 remain in CR (CCR), 30 pts. relapsed after aSCT and 7 died of treatment related causes, survival data only are available for one patient. CDKN2A/B genomic alterations were identified in 41% (40/97) of patients, deletions of IKZF1 and PAX5 were observed in 61% (59/97) and 39% (38/97) of pts., respectively. Univariate analysis of the complete cohort revealed that deletion of CDKN2A/B was the only aberration with a statistically significant negative effect on overall survival (OS) (p=0.003). Among patients transplanted in CR1, IKZF1-deletions were associated with inferior median time to relapse after SCT (56 mos vs. n.r., p=0.01), DFS from SCT (15.6 mos. vs. n.r.; p=0.024) and OS (median 40 mos. vs. not reached (n.r.) p=0.04) compared with the IKZF1 wildtype cohort. Similarly, the prognosis of pts. with CDKN2A/B deletions was inferior in terms of DFS (median 10.6 mos. vs. n.r.; p=0.022) and OS (median 25 mos. vs. n.r.; p=0.01), but not of remission duration from SCT. PAX5 (p=0.07) but not the combination of all three lesions (p=0.14) showed a trend to a worse prognosis. Of the more uncommon genetic aberrations BTLA, EBF1, ETV6, RB1 and BTG1, only the latter was associated with a lower probability of remaining in CR (0% vs. 67% at 5 years; p=0.012) or DFS (0% vs. 52% at 5 years; p=0.043), with a trend towards shorter OS (median 35 mos. vs. 87 mos; p=0.078). In conclusion, genomic lesions of IKZF1, CDKN2 and PAX5 identify a subgroup of Ph+ ALL pts. who have an inferior survival despite undergoing aSCT in CR1. Their poor outcome is attributable primarily to a high relapse rate after SCT, emphasizing the need to introduce additional treatment elements prior to and after aSCT. Disclosures: No relevant conflicts of interest to declare.

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