Influence of detection of pretreatment cytogenetic abnormalities on first complete remission and survival in adult acute lymphoblastic leukemia

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.

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Clinical and biological importance of cytogenetic abnormalities in childhood and adult acute lymphoblastic leukemia

Annals of Medicine ◽

10.1080/07853890410018808 ◽

2004 ◽

Vol 36 (7) ◽

pp. 492-503 ◽

Cited By ~ 38

Author(s):

Bertil Johansson ◽

Fredrik Mertens ◽

Felix Mitelman

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Cytogenetic Abnormalities ◽

Biological Importance ◽

Adult Acute Lymphoblastic Leukemia

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Clinical Significance of Cytogenetic Abnormalities in Adult Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v91.11.3995 ◽

1998 ◽

Vol 91 (11) ◽

pp. 3995-4019 ◽

Cited By ~ 229

Author(s):

Stefan Faderl ◽

Hagop M. Kantarjian ◽

Moshe Talpaz ◽

Zeev Estrov

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Clinical Significance ◽

Lymphoblastic Leukemia ◽

Cytogenetic Abnormalities ◽

Adult Acute Lymphoblastic Leukemia

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Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia

Blood ◽

10.1182/blood-2014-09-599894 ◽

2015 ◽

Vol 125 (16) ◽

pp. 2486-2496 ◽

Cited By ~ 134

Author(s):

Nathalie Dhédin ◽

Anne Huynh ◽

Sébastien Maury ◽

Reza Tabrizi ◽

Kheira Beldjord ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Complete Remission ◽

Lymphoblastic Leukemia ◽

Adult Patients ◽

Key Points ◽

First Complete Remission

Key Points SCT in first complete remission is associated with 69.5% 3-year overall survival in high-risk ALL adult patients treated with intensified pediatric-like protocol. Poor early MRD response is a powerful tool to select patients who may benefit from SCT in first complete remission.

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Expression of the multidrug resistance-associated P-glycoprotein (P- 170) in 59 cases of de novo acute lymphoblastic leukemia: prognostic implications [see comments]

Blood ◽

10.1182/blood.v81.9.2394.2394 ◽

1993 ◽

Vol 81 (9) ◽

pp. 2394-2398 ◽

Cited By ~ 160

Author(s):

JE Goasguen ◽

JM Dossot ◽

O Fardel ◽

F Le Mee ◽

E Le Gall ◽

...

Keyword(s):

Multidrug Resistance ◽

Acute Lymphoblastic Leukemia ◽

Complete Remission ◽

De Novo ◽

Lymphoblastic Leukemia ◽

Survival Rates ◽

Glycoprotein P ◽

Kaplan Meier ◽

Prognostic Implications ◽

First Complete Remission

Abstract Immunocytochemical detection of the multidrug resistance (MDR)- associated membrane protein (P-170) was performed at time of diagnosis in a series of 36 children and 23 adults with acute lymphoblastic leukemia (ALL) using two monoclonal antibodies JSB1 and C219. Immunophenotypes were obtained in all cases and karyotypes were analyzed in 37 cases. Detection with JSB1 or with C219 led to similar results in terms of positive cells and cases, but the intensity of staining was higher with JSB1. In the populations studied, the rate of first complete remission differed between MDR-positive and MDR-negative in adult patients only (56% v 93%, respectively, P = .05). Of the 16 MDR-positive patients who had presented a first complete remission, 13 (81%) relapsed, compared with 13 of 35 (37%) MDR-negative (P = .008) patients. A higher rate of relapse among MDR-positive compared with MDR- negative patients was observed in adults and in children taken separately (adults 100% v 46%; children 73% v 32%, respectively). The survival rates (Kaplan-Meier method) were significantly higher in MDR- negative compared with MDR-positive populations as a whole (P = .002) and among children (P = .05) and adults (P = .03) taken separately. Event-free survival curves followed this trend. The percentage of second complete remission was very low in the MDR-positive group (15%) compared with 38% for the MDR-negative group. These results were shown by multivariate analysis to be independent of age, immunophenotypes, and karyotypes and clearly show the importance of MDR phenotype detection in ALL.

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Autologous Transplantation of Non-Cryopreserved Bone Marrow for the Treatment of High-Risk Adult Acute Lymphoblastic Leukemia in First Complete Remission.

Blood ◽

10.1182/blood.v106.11.5492.5492 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5492-5492

Author(s):

Jerzy Holowiecki ◽

Sebastian Giebel ◽

Malgorzata Krawczyk-Kulis ◽

Maria Sadus-Wojciechowska ◽

Lucja Kachel ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Complete Remission ◽

Hospital Stay ◽

Lymphoblastic Leukemia ◽

Autologous Transplantation ◽

Hematopoietic Stem ◽

Long Term Outcome ◽

First Complete Remission

Abstract Autologous hematopoietic stem cell transplantation (HSCT) is a recognised option of post-consolidation therapy for adults with high-risk acute lymphoblastic leukemia (ALL) not having a donor. G-CSF-stimulated peripheral blood SCT results in faster recovery compared to cryopreserved bone marrow transplantation (BMT) and is currentlly used by the majority of centres. In the current study we analyze the feasibility of a new technique of autologous BMT, which does not require cryopreservation. 115 adult patients (median age 24.5 (16–53) years) with high-risk ALL in first complete remission (CR) were treated with autologous BMT between 1991–2004 in a single center using uniform standard operating procedures. Immune phenotype was as follows: proB 17%, preB 9%, common 44%, mature B 1%, preT 9%, mature T 19%. Initial WBC was >30 G/l in 30% of patients. 8% of patients were bcr/abl(+), 38% required >1 course of induction to achieve CR. Bone marrow was collected in general anaesthesia and further stored for 72 hours in 4degC without any processing and reinfused 24 hours after completion of myeloablative therapy. Conditioning regimen (CAV) consisted of cytarabine 2x1000 mg/m2 d. −3, −2, −1, etoposide 800 mg/m2 d. −3, −2, cyclophosphamide 60 mg/kg d. −3, −2. Median NC dose was 2.0 (0.9–10.8)x10e8, CD34+cell dose − 1.6 (0.4–15)x10e6/kg. Median recovery of ANC>0.5 G/l equaled 16(11–45) days, PLT>50 G/l – 16(10–53) days (11% patients received cytokines to stimulate NC recovery). Median duration of hospital stay since the date of BMT was 19(13–51) days. The OS rate at 10 years (median follow-up 6.5 years) equaled 57% (+/−5%), LFS rate − 47% (+/−5%). Three patients died within 100 days after ABMT of septic infections (non-relapse mortality rate − 2.6%). None of the analysed factors (age, WBC at diagnosis, immonophenotype, time to achieve CR) was found to influence the long-term outcome. We conclude that autologous transplantation of non-cryopreserved bone marrow after CAV conditioning is feasible for adults with high-risk ALL. The method is characterized by fast recovery, short hospital stay and low non-relapse mortality, and may constitute good alternative to autologous PBSCT.

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

Blood ◽

10.1182/blood.v114.22.2303.2303 ◽

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.

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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 ◽

10.1182/blood.v122.21.231.231 ◽

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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