Prognostic impact of persistent cytogenetic abnormalities at complete remission in adult patients with acute lymphoblastic leukemia

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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Secondary Cytogenetic Abnormalities and Outcome in Children with TEL-AML1-Positive Acute Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v106.11.1450.1450 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1450-1450

Author(s):

Oussama A. Abla ◽

Johann Hitzler ◽

Charles Ye ◽

Mohamed Abdelhaleem ◽

Ronald Grant ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Fusion Gene ◽

Lymphoblastic Leukemia ◽

Prognostic Significance ◽

Prognostic Indicator ◽

Similar Rate ◽

Chromosome 21 ◽

Prognostic Impact ◽

Extra Copy ◽

Cytogenetic Abnormalities

Abstract The t(12;21) translocation, which results in the fusion of the TEL (ETV6) and AML1 (RUNX1) genes, is present in ~25% of pediatric B-precusor acute lymphoblastic leukemia (ALL) patients. Although initially thought to be a favorable prognostic indicator, the t(12;21) was associated with a similar rate of relapse as t(12;21)-negative pre-B ALL in subsequent studies. While secondary cytogenetic abnormalities are often present, their prognostic significance is unknown. The objective of this study is therefore to examine the type, frequency and prognostic impact of secondary cytogenetic abnormalites in t(12;21)-positive blasts of children with ALL. We studied retrospectively 56 patients diagnosed with t(12;21)-positive ALL at the Hospital for Sick Children between 2000–2005. The mean age at diagnosis was 4.9 years (range <1 to 12 years). Nine patients (16%) presented with a white blood cell count of greater than 50 × 109/L. Cytogenetic studies consisted of a combination of FISH, G-banding and spectral karyotyping. The most frequent secondary cytogenetic changes in patients with t(12;21)-positive ALL were: the deletion of the non-translocated TEL allele (38%), an extra copy of the TEL-AML1 fusion gene (14%). Additional numerical abnormalities were seen in approximately one-third of the cases, with the most common being a gain of chromosome 21(13%). Recurrent deletions of chromosomal regions 6q and 11q were observed (14%). A surprising degree of karyotypic complexity was noted. Three or more additional chromosome abnormalities, two abnormal clonal lines, and complex structural rearrangements involving TEL-AML1 were detected in 28%, 21%, and 9% of patients, respectively. Five children (9%) in this cohort have developed a relapse of ALL. The 5-year event-free survival (EFS) was 83±7%. The 5-year EFS for patients with a deleted second TEL allele or an extra TEL-AML1 fusion was not statistically different. Of note, 4 of the children who relapsed had high-risk features at presentation (NCI criteria). All were treated with chemotherapy protocols developed for lower risk ALL. The realization that TEL-AML1 does not always predict excellent prognosis indicates that an on-going study of patients and their survival, with detailed analysis of complex genetic changes, is necessary for a reliable assessment of the prognostic value of the t(12;21) in pediatric ALL.

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Pharmacogenetics of Response to Glucocorticosteroids in Adults with Acute Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v108.11.2609.2609 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2609-2609

Author(s):

Krzysztof Jamroziak ◽

Ewa Balcerczak ◽

Zofia Szemraj ◽

Aleksandra Salagacka ◽

Olga Grzybowska-Izydorczyk ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Complete Remission ◽

Glucocorticoid Receptor ◽

Induction Chemotherapy ◽

Direct Sequencing ◽

Lymphoblastic Leukemia ◽

Receptor Gene ◽

Prognostic Impact ◽

Functional Polymorphisms ◽

Glucocorticoid Receptor Gene

Abstract Glucocorticoids are crucial components of standard chemotherapy regimens used for the treatment of adult acute lymphoblastic leukemia (ALL). However, little is known on significance of the inherited genetic background for response to steroids in adult ALL. We hypothesized that functional single nucleotide polymorphisms (SNPs) in genes important for steroid pharmacokinetics and pharmacodynamics may contribute to sensitivity or resistance to steroids. In this study we investigated whether analysis of common functional SNP in drug transporter P-glycoprotein gene (MDR1 or ABCB1), phase I cytochrome P450A metabolizing enzymes genes (CYP3A4 and CYP3A5) and glucocorticoid receptor gene NR3C1 can be useful to predict response to induction chemotherapy and survival of adult ALL patients. Sixty-two uniformly treated adult ALL patients were investigated for 6 common SNPs affecting steroid pathway including MDR1 exon 26 C3435T, CYP3A4*1B, CYP3A5*3, CYP3A5*6, NR3C1 bcl I and NR3C1 N363S polymorphisms. Genotypes were identified using direct sequencing or restriction fragment length polymorphism (RFLP) method. In the genotyped cohort 60% patients achieved complete remission after first induction chemotherapy. The analysis of the prognostic impact of the genotyped SNPs on treatment response showed that carriers of the glucocorticoid receptor NR3C1 gene 363S allele had a significantly greater probability of achievement of complete remission as compared to the non-carriers, odds ratio(OR)=1.23, 95% confidence interval (95%CI) = 1.02 −1.47, p=0.042). None of the analyzed polymorphic variants showed significant impact on probability of progression-free and overall survival of the included patients. In conclusion, we found that glucocorticoid receptor NR3C1 gene N363S polymorphism contributes to the response to steroids in patients with adult ALL. Inherited functional polymorphisms in pharmacokinetic pathways of anti-leukemic drugs should be considered as determinants of response potentially useful for individualization of chemotherapy of adult ALL of in the future.

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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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Crebbp HAT Domain Mutations Are Frequently Detected in Adult Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v120.21.1419.1419 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1419-1419

Author(s):

Kenji Tokunaga ◽

Shunichiro Yamaguchi ◽

Eisaku Iwanaga ◽

Tomoko Nanri ◽

Taizo Shimomura ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

B Cell ◽

Pediatric Patients ◽

Lymphoblastic Leukemia ◽

Genetic Alterations ◽

Adult Patients ◽

Prognostic Impact ◽

Pediatric All ◽

Crebbp Gene

Abstract Abstract 1419 Aims: Molecular pathogenesis of acute lymphoblastic leukemia (ALL) has largely been verified in pediatric patients and the identification of genetic alterations have contributed to stratifying therapeutic applications. In adult patients with ALL, cytogenetic and genetic abnormalities have not sufficiently been elucidated and therapeutic improvement has been hindered. CREB binding protein (CREBBP) is a transcriptional coactivator that interacts with a diverse range of transcription factors and regulates transcription by histone acetylation in hematopoiesis. Mutations of the CREBBP gene are recently found in approximately 2–4% of pediatric patients with ALL. Especially in relapsed cases, the mutations prevail (18–63%) and are possible markers for prediction of relapse in pediatric ALL. In adult patients with ALL, the clinical significance of CREBBP mutations remains to be determined. Here we examined adult ALL patients in an attempt to determine the incidence, clinical characteristics and prognostic impact of the CREBBP mutations. Methods: We investigated 71 adult patients with newly diagnosed ALL treated with JALSG protocols between 1986 and 2010. Age ranged from 15 to 86 years, with a median of 54 years. CREBBP mutations are dominantly identified in histone acetyltransferase (HAT) domain. HAT domain in the CREBBP gene was amplified with RT-PCR using RNA isolated from the peripheral blood or bone marrow mononuclear cells at diagnosis and was subjected to direct sequencing. We compared clinical profiles between patients with and without CREBBPHAT domain mutations. This study was approved by the Institutional Review Boards and informed consent was obtained from each patient according to guidelines based on the revised Declaration of Helsinki. Results: CREBBP HAT domain mutations were detected in 8 of 71 (11.3%) patients: one nonsense mutation, five insertion mutations with frameshifts, and five missense mutations. Two patients harbored biallelic mutations. The mutations at diagnosis in adult patients were seen more frequently than those in pediatric patients ever reported. Such mutations were not completely identical to those detected in pediatric ALL, but were seen in the region within the HAT domain, indicating that such mutations are loss-of-function mutations. The mutations were found in both B-cell (6/53: 11.3%) and T-cell (1/9: 11.1%) ALL, and distributed in patients harboring IKZF1 alterations (3/31: 9.7%) or the BCR-ABL fusion gene (2/19: 10.5%). There were no statistical difference in age, sex, leukocyte, platelet counts and complete remission rate between patients with and without the CREBBP HAT domain mutations. Patients with the mutations had a trend with worse cumulative incidence of relapse (P=0.4637), relapse-free survival (P=0.4195) and OS (P=0.2349) compared to patients lacking the mutations, but statistical significance was not detected in this small cohort. Conclusions: CREBBP HAT domain mutations at diagnosis in adult ALL are found more frequently than in pediatric ALL. This may be one of the mechanisms that adult ALL has been associated with poor OS compared with pediatric ALL. In this study, CREBBP HAT domain mutations were observed in various subtypes of ALL: both B-cell and T-cell ALL, and both Philadelphia chromosome positive and negative ALL. In pediatric ALL, CREBBP mutations were frequently seen in relapsed patients but not in previously untreated patients. These observations suggest that CREBBP mutations play an important role in an additional late event(s) leading to the development and progression of ALL. Our study implies the possibility that mutations of the CREBBP gene are associated with the pathogenesis and prognostic marker of adult ALL and represent specific epigenetic modifiers in adult ALL, serving as potential therapeutic targets. Disclosures: No relevant conflicts of interest to declare.

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Total Marrow Irradiation (TMI) Based T- Replete Myeloablative Haploidentical Stem Cell Transplantation in Adult Patients with Acute Lymphoblastic Leukemia in Second Complete Remission: A Single Center Experience of Two Cases

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2015.11.776 ◽

2016 ◽

Vol 22 (3) ◽

pp. S308

Author(s):

Neelesh Jain ◽

Amitabh Ray ◽

Amrita Chakravarti ◽

Kasturi Sengupta ◽

Joydeep Chakrabartty

Keyword(s):

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

Complete Remission ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Lymphoblastic Leukemia ◽

Adult Patients ◽

Single Center ◽

Single Center Experience ◽

Total Marrow Irradiation

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Analysis of outcomes following autologous stem cell transplantation in adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia during first complete remission

Haematologica ◽

10.3324/haematol.2014.108712 ◽

2014 ◽

Vol 99 (11) ◽

pp. e228-e230

Author(s):

H. Kato ◽

T. Kawase ◽

S. Kako ◽

S. Mizuta ◽

M. Kurokawa ◽

...

Keyword(s):

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

Complete Remission ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Autologous Stem Cell Transplantation ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Adult Patients ◽

First Complete Remission

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Structure and significance of cytogenetic abnormalities in adult patients with Ph-negative acute lymphoblastic leukemia

Terapevticheskii arkhiv ◽

10.26442/terarkh201890730-37 ◽

2018 ◽

Vol 90 (7) ◽

pp. 30-37 ◽

Cited By ~ 2

Author(s):

I S PISKUNOVA ◽

T N OBUKHOVA ◽

E N PAROVICHNIKOVA ◽

S M KULIKOV ◽

V V TROITSKAYA ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Structural Changes ◽

Lymphoblastic Leukemia ◽

Adult Patients ◽

Long Term Results ◽

Serum Lactate Dehydrogenase ◽

Cytogenetic Abnormalities ◽

Fish Technique ◽

Study Results ◽

Cdkn2a Deletion

Objective. To evaluate occurrence, variety, structural peculiarities and prognostic meaning of cytogenetic abnormalities in adult patients with Ph-negative acute lymphoblastic leukemia (ALL) receiving therapy according to ALL-2009 protocol. Materials and methods. The study included 115 adult patients with firstly diagnosed Ph-negative ALL: 58 male and 57 female aged from 15 to 61 years (mean age 26.5 years), who underwent treatment from September 2009 to September 2015 in National Medical Research Center for Hematology MH RF (n=101) and in hematology departments of regional hospitals (n=14). All patients received therapy of ALL-2009 protocol (ClinicalTrials.gov, NCT01193933). The median follow-up was 24.5 months (0.2-94.4 months). As a part of the study results of a standard cytogenetic assay (SCA) were analyzed and fluorescence hybridization in situ (FISH) with the use of DNA-probes was performed on archived biological material for structural changes in gene locuses MLL/t(11q23), с-MYC/t(8q24), TP53/ deletion 17p13, CDKN2A/ deletion 9p21, translocation t(1;19)/E2A-PBX1 и t(12;21)/ETV6-RUNX1; iAMP21 identification. Results. Karyotype was defined using SCA in 86% of patients. Normal karyotype was found in 48.5% of them, chromosome aberrations in 51.5% (structural changes were found in 19.2%, hyperploidy in 27.2%, and hypoploidy in 5.1%). In 17.2% of patients complex karyotype abnormalities were found. With the use of FISH technique aberrations were found in 67% of patients: 9p21/CDKN2A deletion in 24.3%, MLL/t(11q23) gene abnormalities in 7.8%, 17p13/TP53 deletion in 5.2%, abnormalities of c-MYC/t(8q24) in 1.7%, t(1;19)/E2A-PBX1 in 0.8%, and iAMP21 in 0.8%, other abnormalities (additional signals/absence of signals from gene locuses) in 26.4%, t(12;21)/ETV6-RUNX1 was not found. FISH technique use in addition to SCA allows to increase aberrant karyotype location from 51.5 to 67%. A statistically significant correlation of 9p21/CDKN2A deletion with high serum lactate dehydrogenase activity (p=0.02); MLL/t(11q23) gene abnormalities - with leucocytosis and high blast cells level in blood (p=0.0016), hyperploidy - with normal leukocyte count (p=0.02) was shown. In groups with different cytogenetic abnormalities no statistically significant differences of treatment with ALL-2009 protocol were found (in terms of complete remission, early mortality and treatment resistance). When connection of cytogenetic abnormalities and their combinations with long-term results were analyzed according to ALL-2009 protocol, only two characteristics - MLL/t(11q23) and c MYC/t(8q24) gene abnormalities had a statistically significant influence on disease-free survival (HR - 176.9; p

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The significance of splenomegaly in 101 adults with acute lymphoblastic leukemia (ALL) at presentation and during remission

Blood ◽

10.1182/blood.v57.4.798.bloodjournal574798 ◽

1981 ◽

Vol 57 (4) ◽

pp. 798-801

Author(s):

A Friedman ◽

P Schauer ◽

R Mertelsmann ◽

C Cirrincione ◽

H Thaler ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Complete Remission ◽

Lymphoblastic Leukemia ◽

Clinical Status ◽

Prognostic Significance ◽

Response Rates ◽

Complete Response ◽

Adult Patients ◽

Leukemia Cells ◽

Prognostic Implications

One-hundred-one adult patients with ALL were analyzed to determine the prognostic implications of splenomegaly occurring at any time during the course of their illness. The clinical status of the spleen at presentation was not found to be of major prognostic significance. Complete response rates, remission durations, and survivals did not differ between patients with and without splenomegaly at presentation. An enlarged spleen accompanied relapse in four patients. In six additional patients, splenomegaly was present during complete remission, and splenectomies performed in five of these patients revealed no evidence of leukemia to account for the splenomegaly. Splenectomy does not appear to be detrimental, as all five patients are currently in complete remission from 20 to 63 mo after splenectomy. Evidence implicating the spleen as a source of an antibody directed against autologous leukemia cells in one patient is reviewed.

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