scholarly journals Clinical Implication of BCR/ABL Fusion Transcript Monitoring in Addition to Ig/TCR Gene Rearrangement-Based Minimal Residual Disease in Philadelphia Chromosome-Positive Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2258-2258
Author(s):  
Kirsten Bleckmann ◽  
Julia Alten ◽  
Anja Moericke ◽  
Andishe Attarbashi ◽  
Andrea Teigler-Schlegel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Fusion Transcript ◽  
Minimal Residual

Abstract Background: Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) accounts for about 3% of pediatric ALL and has a poor prognosis. Advances of treatment due to the tyrosine kinase inhibitor imatinib have improved the cure rates. According to recent guidelines in the amended European intergroup trial on Ph+ ALL (EsPhALL), patients with rapid minimal residual disease (MRD) response and negativity during further treatment are no longer eligible for allogeneic stem cell transplantation (alloSCT). This down-grading of therapy in a circumscribed patient cohort with favorable prognosis is a desirable development as stem cell transplantation still implies a considerable risk of toxicity. These guidelines refer to MRD by immunoglobulin/T-cell receptor (Ig/TCR) gene rearrangements and do not consider monitoring of the BCR/ABL fusion transcript as long as informative results for Ig/TCR MRD are available. However, discrepancies between the results of the two methods occur. This complicates the decision on alloSCT indication if Ig/TCR MRD becomes negative while the BCR/ABL fusion transcript remains detectable. Objectives/Methods: We therefore evaluated the prognostic relevance of this specific combination of findings, i.e. the continuous negativity for Ig/TCR MRD and persistently positive results for BCR/ABL after the second intensive consolidation block or later, in 16 pediatric patients with Ph+ ALL. They were identified among 139 German and Austrian Ph+ patients treated in the ALL-BFM 2000 or EsPhALL trial from August 1, 1999 to July 31, 2013. Twelve out of the 16 patients received imatinib in first-line treatment intermittently as previously described in the EsPhALL protocol (Biondi A et al Lancet Oncol. 2012) or continuously as recommended by the amended EsPhALL protocol. Results: Eight of the 16 identified patients received an alloSCT in first complete remission (1st CR), whereas the remaining eight patients were treated with chemotherapy only. Of the eight patients with alloSCT, seven are in first continuous complete remission (1st CCR) with median EFS of 7.6 years, one patient died after second relapse. In the group of eight patients without alloSCT three are in 1st CCR with a median EFS of 2.6 years, four patients are in 2nd CR after relapse (3/4 had alloSCT in 2nd CR, median EFS 4.7 years), and one patient with Down syndrome died of an infectious complication. Remarkably, two patients of the latter group (both with M-BCR) showed a protracted increase of BCR/ABL copy numbers over several years with neither morphological signs of relapse nor Ig/TCR MRD based reappearance. One of them eventually suffered a relapse 5 years after diagnosis, one is still in 1st CCR with EFS of 5.2 years. Conclusion: The data suggest that patients with Ig/TCR MRD negativity and persistently detectable BCR/ABL fusion transcript have a high risk of relapse when treated with chemotherapy only and may benefit from alloSCT. However, patient numbers are currently too small to deduce recommendations from this observation. Further investigation of a larger cohort with longer follow-up is needed to confirm the prognostic importance of BCR/ABL fusion transcript monitoring in addition to Ig/TCR MRD, especially considering a potential additional impact of the recently implemented continuous imatinib treatment. One additional patient would have met the diagnostic inclusion criteria of this analysis. He had an extensive increase of BCR/ABL fusion transcript at the end of maintenance treatment while being in morphological remission and negative for Ig/TCR MRD. This patient proved to be BCR/ABL positive in granulocytes revealing a chronic myeloid leukemia (CML) misdiagnosed as ALL during initial blast crisis. This indicates that an underlying CML might be taken into consideration also in other patients of the analyzed cohort. In consequence, BCR/ABL in granulocytes is now tested in all newly diagnosed Ph+ ALL patients in Germany to ensure the differentiation of BCR/ABL positive ALL vs. CML in blast crisis. Disclosures No relevant conflicts of interest to declare.

Monitoring of Minimal Residual Disease After Allogeneic Stem-Cell Transplantation in Relapsed Childhood Acute Lymphoblastic Leukemia Allows for the Identification of Impending Relapse: Results of the ALL-BFM-SCT 2003 Trial

2015 ◽  
Vol 33 (11) ◽  
pp. 1275-1284 ◽  
Author(s):  
Peter Bader ◽  
Hermann Kreyenberg ◽  
Arend von Stackelberg ◽  
Cornelia Eckert ◽  
Emilia Salzmann-Manrique ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Event Free Survival ◽  
Free Survival ◽  
Minimal Residual

Purpose To elucidate the impact of minimal residual disease (MRD) after allogeneic transplantation, the Acute Lymphoblastic Leukemia Berlin-Frankfurt-Münster Stem Cell Transplantation Group (ALL-BFM-SCT) conducted a prospective clinical trial. Patients and Methods In the ALL-BFM-SCT 2003 trial, MRD was assessed in the bone marrow at days +30, +60, +90, +180, and +365 after transplantation in 113 patients with relapsed disease. Standardized quantification of MRD was performed according to the guidelines of the Euro-MRD Group. Results All patients showed a 3-year probability of event-free survival (pEFS) of 55%. The cumulative incidence rates of relapse and treatment-related mortality were 32% and 12%, respectively. The pEFS was 60% for patients who received their transplantations in second complete remission, 50% for patients in ≥ third complete remission, and 0% for patients not in remission (P = .015). At all time points, the level of MRD was inversely correlated with event-free survival (EFS; P < .004) and positively correlated with the cumulative incidence of relapse (P < .01). A multivariable Cox model was fitted for each time point, which showed that MRD ≥ 10−4 leukemic cells was consistently correlated with inferior EFS (P < .003). The accuracy of MRD measurements in predicting relapse was investigated with time-dependent receiver operating curves at days +30, +60, +90, and +180. From day +60 onward, the discriminatory power of MRD detection to predict the probability of relapse after 1, 3, 6, and 9 months was more than 96%, more than 87%, more than 71%, and more than 61%, respectively. Conclusion MRD after transplantation was a reliable marker for predicting impending relapses and could thus serve as the basis for pre-emptive therapy.

Allogeneic hematopoietic stem cell transplantation contributes to eradication of minimal residual disease in adult Philadelphia chromosome-positive acute lymphoblastic leukemia patients treated with dasatinib.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7024-7024
Author(s):  
Jeremy Chang ◽  
Mojtaba Akhtari
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Minimal Residual

7024 Background: Philadelphia Chromosome-Positive (Ph+) disease is associated with a poor prognosis in acute lymphoblastic leukemia (ALL). Recent studies have shown that the eradication of minimal residual disease (MRD) in this population leads to improved survival outcomes. While hematopoietic stem cell transplantation (HSCT) has demonstrated clinical benefits in Ph+ ALL patients treated with the tyrosine kinase inhibitor (TKI) imatinib, its role is less clear with the use of more potent, newer-generation TKIs such as dasatinib. Methods: This was a retrospective study analyzing the impact of allogeneic HSCT on MRD status in Ph+ ALL patients treated with dasatinib. Patients were divided into 2 groups: those treated with chemotherapy plus dasatinib followed by allogeneic HSCT and those who received chemotherapy plus dasatinib alone. All patients underwent bone marrow biopsy with MRD analysis following induction therapy and subsequent re-evaluation of MRD status at day 100 post-transplant in the HSCT group and after further cycles of chemotherapy plus dasatinib in the non-transplant group. MRD-negative disease was defined as the absence of a BCR-ABL1 transcript by real-time quantitative polymerase chain reaction (qRT-PCR) with a sensitivity of 0.01%. Results: A total of 51 adult Ph+ ALL patients with MRD-positive disease following induction therapy were included. Twenty-seven patients (53%) were male and the median age at time of diagnosis was 42 years (range 23-68). There were 29 patients in the transplant group and 22 patients in the non-transplant group. When analyzing rates of MRD eradication, 18 (62%) patients in the transplant group were found to have MRD-negative disease at day 100 post-transplant compared to 7 (32%) patients in the non-transplant group who only received further cycles of chemotherapy plus dasatinib (risk ratio 0.56, 95% confidence interval 0.32-0.96, p = 0.048). Conclusions: In the era of newer-generation TKIs, allogeneic HSCT continues to have notable benefits in Ph+ ALL such as a significantly higher rate of MRD eradication as demonstrated in this study.

Predictive Potential of Minimal Residual Disease Level after the First Imatinib Cycle on the Outcome of Allogeneic Stem Cell Transplantation in Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1098-1098
Author(s):  
Seok Lee ◽  
Yoo-Jin Kim ◽  
Chang-Ki Min ◽  
Byung-Sik Cho ◽  
Sung-Yong Kim ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Stem Cell Transplantation ◽  
Minimal Residual Disease ◽  
Allogeneic Stem Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Imatinib Therapy ◽  
Minimal Residual

Abstract Purpose: Previously, we demonstrated the positive impact of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation (SCT) in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) (Blood2005;105:3449). Here, we analyzed for risk factors that affect transplantation outcome, and focused particularly on the prognostic relevance of minimal residual disease (MRD) during treatment course. Patients and Methods: Fifty-two consecutive adults with Ph-positive ALL who completed SCT following imatinib therapy were enrolled in this prospective study. MRD assessment was performed using real-time quantitative polymerase chain reaction. Results: Forty-three (87.8%) of the 49 evaluable patients showed a decrease in MRD after imatinib therapy. Molecular remission rates were 18.4% and 44.4% after the first and second imatinib cycles, respectively. Forty-eight (92.3%) of the 52 patients received SCT during first complete remission. With a median follow-up of 42 months after SCT, the actuarial 3-year relapse and disease-free survival (DFS) rates were 22.9% ± 6.6% and 67.3% ± 7.2%, respectively. An MRD level of ≥ 10−3 after the first imatinib cycle was found to be the most powerful predictor of relapse (47.5% ± 14.3% versus 11.4% ± 6.4%, P = .009) and DFS (45.0% ± 13.2% versus 80.9% ± 8.0%, P = .016). The presence of chronic graft-versus-host disease was also found to be associated with a lower relapse (5.3% ± 5.1% versus 37.6% ± 10.8%, P = .029) and better DFS (82.0% ± 9.5% versus 62.4% ± 10.8%, P = .039). Conclusion: In the setting of allogeneic SCT following imatinib therapy, prospective MRD monitoring may allow us to identify subgroups of Ph-positive ALL patients at high risk of relapse at an earlier treatment stage.

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.

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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