Long Term Outcomes of Adult Lymphoblastic Lymphoma Patients Treated with Pediatric Regimen in Brazil

Abstract Introduction: Lymphoblastic lymphoma (LBL) is a rare and aggressive neoplasm which is more common in children and young adults. The adoption of pediatric inspired regimens for acute lymphoblastic leukemia (ALL) increased response rates and improved overall survival (OS). Due to the rarity of this disease studies addressing specific outcomes of LBL, especially from Latin America, are lacking. Objectives: To report outcomes of adult newly diagnosed with LBL in our center, aiming to examine baseline factors associated with worse survival. Methods: Retrospective cohort study of patients diagnosed with LBL between 2002 and 2018 and treated with adapted-BFM (aBFM) regimen at Instituto do Cancer do Estado de São Paulo (ICESP). Patients with acute leukemia were excluded from this analysis. The aBFM protocol was based on the BFM-86 protocol and previously reported by our group (Pinheiro et al, 2006). Results: Over this period, 26 patients received aBFM protocol in our institution. Twenty patients had T-LBL (77%) and mostly male (n=18). Median age was 26 years (17-54). Fifty-four percent (n=9) had an advanced stage (III-IV) and 77% (n=20) had bulky disease at diagnosis, predominantly mediastinal (n=15). Bone marrow involvement occurred in 21% of cases (5/24) and CNS disease was found in 2 cases. Complete remission (CR) rate was 68% (17/25). Four out of 5 B-LBL cases did not achieve CR, showcasing the influence of immunophenotype on CR (p=0.04). Two patients died before response assessment. Nine patients underwent consolidation radiotherapy (RT), defined at the discretion of the physician. The remaining 2 cases received cranial RT for CNS involvement. At 5 years, overall survival (OS) was 47,3% (CI 95%, 29,5 - 75,6) and event-free survival (EFS) was 51,1% (CI 95%, 34,6 - 75,5). Univariate analysis showed that phenotype (B-cell, HR=4.3) and the hemoglobin level at the diagnosis (continuous, HR=0.78) were significantly associated with OS (Figure). Cumulative incidence of relapse was 36%, whereas non-relapse mortality was 12% in this cohort. Discussion: Current treatment of LBL is based on pediatric ALL protocols including CNS prophylaxis. Previous studies of LBL patients using pediatric inspired regimens had 3y OS of 69%, which is higher than that found in our study. Markedly, outcomes of patients with B-LBL were poor and notably, no genetic evaluation aiming to screen for BCR-ABL or Ph-like signature was performed in such cases. These genetic alterations are more common in Latin America and must be screened as they strongly impact on the management. Conclusions: Few studies encompassing adult LBL patients are available. To our knowledge, this is the first one from Brazil. Although this study carries several limitations, we can conclude that the use of aBFM is feasible and achieves acceptable response rates in the T-cell subset. By contrast, B-LBL cases fared poorly and further studies are needed to implement a better genetic characterization and newer treatment strategies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Landscape of driver mutations and their clinical impacts in pediatric B-cell precursor acute lymphoblastic leukemia

Blood Advances ◽

10.1182/bloodadvances.2019001307 ◽

2020 ◽

Vol 4 (20) ◽

pp. 5165-5173

Author(s):

Hiroo Ueno ◽

Kenichi Yoshida ◽

Yusuke Shiozawa ◽

Yasuhito Nannya ◽

Yuka Iijima-Yamashita ◽

...

Keyword(s):

Overall Survival ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Tp53 Mutation ◽

Lymphoblastic Leukemia ◽

Genetic Alterations ◽

Cell Precursor ◽

Tp53 Mutations ◽

Positive Correlations ◽

Panel Sequencing

Abstract Recent genetic studies using high-throughput sequencing have disclosed genetic alterations in B-cell precursor acute lymphoblastic leukemia (B-ALL). However, their effects on clinical outcomes have not been fully investigated. To address this, we comprehensively examined genetic alterations and their prognostic impact in a large series of pediatric B-ALL cases. We performed targeted capture sequencing in a total of 1003 pediatric patients with B-ALL from 2 Japanese cohorts. Transcriptome sequencing (n = 116) and/or array-based gene expression analysis (n = 120) were also performed in 203 (84%) of 243 patients who were not categorized into any disease subgroup by panel sequencing or routine reverse transcription polymerase chain reaction analysis for major fusions in B-ALL. Our panel sequencing identified novel recurrent mutations in 2 genes (CCND3 and CIC), and both had positive correlations with ETV6-RUNX1 and hypodiploid ALL, respectively. In addition, positive correlations were also newly reported between TCF3-PBX1 ALL with PHF6 mutations. In multivariate Cox proportional hazards regression models for overall survival, TP53 mutation/deletion, hypodiploid, and MEF2D fusions were selected in both cohorts. For TP53 mutations, the negative effect on overall survival was confirmed in an independent external cohort (n = 466). TP53 mutation was frequently found in IGH-DUX4 (5 of 57 [9%]) ALL, with 4 cases having 17p LOH and negatively affecting overall survival therein, whereas TP53 mutation was not associated with poor outcomes among NCI (National Cancer Institute) standard risk (SR) patients. A conventional treatment approach might be enough, and further treatment intensification might not be necessary, for patients with TP53 mutations if they are categorized into NCI SR.

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High-Dose Methotrexate and Early Intensification of Therapy Do Not Improve 3 Year EFS in Children and Adolescents with Disseminated Lymphoblastic Lymphoma. Results of the Randomized Arms of COG A5971

Blood ◽

10.1182/blood.v112.11.3610.3610 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3610-3610 ◽

Cited By ~ 13

Author(s):

Minnie Abromowitch ◽

Amanda Termuhlen ◽

Myron Chang ◽

Sherrie L. Perkins ◽

Thomas Gross ◽

...

Keyword(s):

Bone Marrow ◽

Lymphoblastic Leukemia ◽

Bone Marrow Involvement ◽

Disease Free Survival ◽

Lymphoblastic Lymphoma ◽

High Dose ◽

High Dose Methotrexate ◽

Cns Disease ◽

Dose Methotrexate ◽

Significant Difference

Abstract The treatment of pediatric lymphoblastic lymphoma (LL) has developed in parallel with treatment strategies for childhood acute lymphoblastic leukemia using a BFM backbone. The excellent results of the NHL/BFM 90 trial prompted us to design this randomized factorial study to determine whether a regimen without high dose methotrexate (HDMTX) the CCG BFM will result in the same outcome as NHL/BFM-90 and whether intensification with anthracycline and cyclophosphamide would further improve disease free survival. From June 2000 to October 2005, 257 patients with Murphy’s Stage III and IV (excluding CNS disease) LL were randomized to one of the four regimens. All regimens used the BFM/NHL95 backbone. The CCG BFM regimen had intrathecal (IT) methotrexate throughout interim maintenance and maintenance without IV methotrexate. The NHL BFM utilized I.V. Methotrexate 5 Gms/m2 and intrathecal MTX every 2 weeks for four doses during interim maintenance without further intrathecal MTX during maintenance. One of each backbone regimens was further intensified with anthracycline and cyclophosphamide early in induction and delayed intensification. The median age was 10.3 years, 195 (76%) were males; 43 (17%) had >5% bone marrow involvement. Twelve patients with CNS disease were not randomized and received intensification and HD HDMTX with delayed CNS radiation (data not reported here). Major toxicities have been related to bone marrow suppression with 4 toxic deaths, 3 due to sepsis and 1 from cerebral hemorrhage. The frequency of grade III/IV neutropenia (alone, with fever or with infection), anemia, and thrombocytopenia were higher in the intensified arms during induction. Three of the four toxic deaths occurred on the intensified arms. The three years EFS of the HDMTX vs. none is 84.5% ± .3.5% vs. 82.7± 3.8 (ρ= 0.93) and the intensification vs. none is 83.4% ±3.7 vs 83.0% ± 3.6 (ρ= 0.66). Therefore, there was no significant difference between treatment arms. These results suggest that neither HDMTX nor early intensification improves EFS in LL. Future direction should focus on identifying biological factors early in therapy so alternative therapies may be investigated.

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Genomic and clinical characterization of early T-cell precursor lymphoblastic lymphoma

Blood Advances ◽

10.1182/bloodadvances.2021004334 ◽

2021 ◽

Vol 5 (14) ◽

pp. 2890-2900

Author(s):

Xinjie Xu ◽

Christian N. Paxton ◽

Robert J. Hayashi ◽

Kimberly P. Dunsmore ◽

Stuart S. Winter ◽

...

Keyword(s):

T Cell ◽

Single Nucleotide Polymorphism Array ◽

Lymphoblastic Leukemia ◽

Cell Receptor ◽

Genetic Alterations ◽

Lymphoblastic Lymphoma ◽

Cell Precursor ◽

Genomic Features ◽

Frequent Absence ◽

T Lymphoblastic Lymphoma

Abstract Early T-cell precursor phenotype acute lymphoblastic leukemia (ETP-ALL) is a subtype of T-ALL with a unique immunophenotype and genetic abnormalities distinct from conventional T-ALL. A subset of T lymphoblastic lymphoma (T-LLy) also demonstrates the early T-cell precursor immunophenotype and may be a counterpart of ETP-ALL. Unlike ETP-ALL, the incidence, clinical features, and genomic features of ETP-LLy are unknown. We reviewed the immunophenotyping data of 218 T-LLy patients who enrolled in the Children’s Oncology Group AALL0434 clinical trial and identified 9 cases (4%) exhibiting a definitive ETP immunophenotype. We performed single-nucleotide polymorphism array profiling on 9 ETP-LLy and 15 non-ETP T-LLy cases. Compared with non-ETP T-LLy, ETP-LLy showed less frequent deletion of 9p (CKDN2A/B), more frequent deletion of 12p (ETV6) and 1p (RPL22), and more frequent absence of biallelic T-cell receptor γ deletions. Recurrent abnormalities previously described in ETP-ALL such as deletions of 5q and 13q and gain of 6q were not observed in ETP-LLy cases. There were no failures of therapy among the ETP-LLy subtype with a 4-year event-free survival of 100%. Overall, ETP-LLy does not exhibit unifying genetic alterations but shows some distinct genomic features from non-ETP T-LLy suggesting that ETP-LLy may be a distinct entity from non-ETP T-LLy.

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Proposal of a Genetic Classifier for Risk Group Stratification in Pediatric T-Cell Lymphoblastic Lymphoma Reveals Significant Differences to T-Cell Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v124.21.2398.2398 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2398-2398 ◽

Cited By ~ 1

Author(s):

Bettina R. Bonn ◽

Martin Zimmermann ◽

Sebastian Balbach ◽

Marius Rohde ◽

Ilske Oschlies ◽

...

Keyword(s):

T Cell ◽

Cumulative Incidence ◽

Risk Group ◽

Lymphoblastic Leukemia ◽

Genetic Alterations ◽

Lymphoblastic Lymphoma ◽

Treatment Intensity ◽

Mutational Hotspots ◽

Group Stratification ◽

Notch1 Mutations

Abstract Introduction T-cell lymphoblastic lymphoma (T-LBL) represent the second most common subtype of Non-Hodgkin lymphoma (NHL) in children and adolescents. In contrast to other pediatric NHL-subtypes and acute lymphoblastic leukemia (ALL) criteria for the stratification of treatment intensity are lacking in T-LBL. Consequently all patients receive identical treatment intensity resulting in over- and under-treatment of a relevant but not yet characterized subgroup of patients. Recently a genetic classifier for adult T-ALL patients was reported. Whether T-ALL and T-LBL represent one or two diseases remains an ongoing discussion. Whole exome sequencing data of pediatric T-LBL cases now support the hypothesis that T-ALL and T-LBL, despite pathogenic similarities are biologically different. Here we used our large dataset of well defined and uniformly treated pediatric patients with T-LBL to define molecular risk factors of the disease. Methods All pediatric T-LBL patients of the NHL-BFM group with sufficient material available were sequenced for abnormalities in the genes: NOTCH1, FBXW7, NRAS, KRAS, PTEN, PIK3R1, PIK3CA using Sanger sequencing of known mutational hotspots and loss of heterozygosity of chromosome 6q using fragment length analyses. Patients were treated uniformly according to NHL-BFM protocols for T-LBL. Clinical data were available from the data base of the NHL-BFM study center. Accompanying molecular research for the trials NHL-BFM 95 and EURO-LB 02, in which these patients were recruited, has been approved by the ethical committees of the Hannover Medical School and Justus-Liebig University Giessen, Germany. Results The observed frequencies of somatic mutations with 95% confidence intervals were: NOTCH1 61% (51-70%), FBXW7 18% (12-27%), PTEN 15% (9-23%) in 114 analyzed patients, N-RAS + K-RAS 10% (5-18%) in 99 analyzed patients, PIK3R1+PIK3CA in 8% (4-15%) in 107 analyzed patients, and LOH6q 12% (8-17%) in 217 analyzed patients. Detailed evaluation of potential associations of distinct mutation status and clinical characteristics revealed a statistically significant association of NOTCH1 mutations (p=0.006) and FBXW7 mutations (p=0.034) with age below 10 years compared to patients with germline status. All other analyses evaluated for each gene separately taking into account age, gender, stage of disease, CNS disease, bone marrow involvement, mediastinal tumor, and general condition at diagnosis did not identify any statistically significant association. Concerning the concurrence or exclusion of the analyzed alterations, NOTCH1 mutations were significantly associated with FBXW7 mutations (p=0.03). LOH6q positive patients presented significantly more often in cases with NOTCH1 wildtype status (p=0.03) and PTEN mutations and FBXW7 mutations turned out to present mutually exclusive (p=0.03). The analyses concerning patients outcome allowed the proposal of an new genetic classifier defining three risk groups: 1) Good risk group (GR) comprising 39% (35/91) of patients defined by NOTCH1 mutation and no RAS or PIK3 mutation with a cumulative incidence of relapse of 11+5%. 2) Intermediate risk group (IR) with all non-GR and non-HR patients including 46% (42/91) of patients with a cumulative incidence of relapse of 20+6%. 3) High-risk group (HR) of 15% (14/91) of patients defined by NOTCH1 wildtype in combination with PTEN mutation and/or LOH6q positivity associated with a cumulative incidence of relapse of 64+14%. Except for an overrepresentation of patients 10 to 15 years of age in the HR arm, none of tested patients’ characteristic parameters of was associated with risk group. Conclusion Detailed analyses of genetic alterations in pediatric T-LBL revealed relevant somatic mutation frequencies for gene loci of the PTEN/PI3K pathway and the RAS pathway. Together with earlier published results on the prognostic relevance of NOTCH1 mutations and chromosome 6q alterations the analyzed cohort of about 100 uniformly treated pediatric T-LBL patients allowed the definition of a genetic classifier for risk group stratification. This proposed classifier requires prospective validation. The here proposed genetic classifier for T-LBL might be worth to be analyzed in pediatric T-ALL. Interestingly our proposed T-LBL classifier includes some aspects in parallel, but overall differed significantly from the earlier published classifier for adult T-ALL. Disclosures No relevant conflicts of interest to declare.

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Significance of Mediastinal Mass in Acute Lymphoblastic Leukemia

PEDIATRICS ◽

10.1542/peds.55.6.889 ◽

1975 ◽

Vol 55 (6) ◽

pp. 889-893

Author(s):

Yaddanapudi Ravindranath ◽

Joseph Kaplan ◽

W. W. Zuelzer

Keyword(s):

Bone Marrow ◽

Retrospective Study ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Clinical Characteristics ◽

Mediastinal Mass ◽

Lymphoblastic Leukemia ◽

Bone Marrow Involvement ◽

Cell Tumor ◽

Lymphoblastic Lymphoma

A mediastinal mass (MM) is found at the time of diagnosis in 10% to 15% of children with acute lymphoblastic leukemia (ALL).1 In view of the frequent progression of childhood mediastinal lymphoblastic lymphoma (MLL) to leukemia,2,3 ALL + MM may be MLL with early bone marrow involvement. We have found that MLL is a T cell tumor, while ALL is a tumor of cells with neither T nor B cell characteristics.4 Therefore, if ALL + MM is a leukemic stage of MLL, patients with ALL + MM and ALL may differ in their clinical characteristics and responses to therapy. To test this hypothesis, we conducted a retrospective study to compare children with ALL + MM and ALL followed in this clinic over the last seven years.

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Impact of Course of Therapy on Response Rate and Duration with the Bexxar® Therapeutic Regimen (Tositumomab and Iodine I 131 Tositumomab) and with Chemotherapy.

Blood ◽

10.1182/blood.v104.11.132.132 ◽

2004 ◽

Vol 104 (11) ◽

pp. 132-132 ◽

Cited By ~ 1

Author(s):

John P. Leonard ◽

Andrew D. Zelentz ◽

Julie M. Vose ◽

Mark S. Kaminski

Keyword(s):

Median Duration ◽

Response Rate ◽

Bone Marrow Involvement ◽

Initial Response ◽

Response Rates ◽

Patient Specific ◽

Low Grade ◽

Bulky Disease ◽

Continuous Response ◽

Duration Of Response

Abstract Low grade NHL with or without transformation is characterized by recurrence. Initial response rates with chemotx are high, but all patients ultimately relapse, and the response rates and durations of response typically decline with each subsequent course of chemotx. In the pivotal trial of Bexxar (JCO 19:3918 2001) there were significantly more patients with longer durations of response than after their last qualifying chemotx. The aim of the current retrospective study was to evaluate the efficacy of Bexxar and prior chemotx by course of treatment in a larger group of patients. Response rates (RR) and duration of response data were available from the treatment histories of the 230 patients from five clinical studies. Demographics: median age, 56 years; age > 60, 34%; median number of prior regimens, 3 (range 1–13); bone marrow involvement, 48%; bulky disease, 32%; transformed histology 28%; IPI score ≥ 2, 81%; and refractory to their preceding regimen, 80%. The patient-specific dosing regimen for Bexxar was previously described (JCO 19:3918). RR and durations for chemotx used as the 2nd, 3rd, 4th, 5th, 6th and >6th treatment were compared to Bexxar for the same numerical treatment. At each successive treatment course, there was a consistently higher RR and duration of response after Bexxar than after chemotx (Table). The actual differences in RR may be greater, as the data for Bexxar are based on responses observed on at least 2 evaluations >4 weeks apart, as assessed by an independent, blinded Masked Independent Randomized Radiology and Oncology (MIRROR) panel. The reported RR for chemotx are based on Investigator-assessed unconfirmed responses. Of note, the % responding pts in continuous response at ≥ five year after receiving Bexxar for the 2nd, 3rd, 4th, 5th, 6th and >6th relapse were 41%, 21%, 25%, 35%, 36 and 9%, respectively. While RR decreased with number of prior therapies, the durations of response and percent in continuous response after Bexxar were substantial and consistent across the range of the number of prior therapies. Treatment/Regimen Number Chemotx Bexxar n Response Rate (Unconfirmed) Median Duration of Response (months) n Response Rate (Confirmed) Median Duration of Response (months) 2 183 51% 8.0 27 74% 14.4 3 145 52% 5.0 44 64% 47.2 4 98 45% 5.0 54 52% 10.8 5 45 40% 4.0 48 54% 11.0 6 33 36% 4.0 21 52% 27.0 7 or more 48 19% 3.5 36 42% 9.6

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Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801

Blood ◽

10.1182/blood-2006-11-056754 ◽

2007 ◽

Vol 109 (12) ◽

pp. 5136-5142 ◽

Cited By ~ 168

Author(s):

Daniel J. DeAngelo ◽

Daohai Yu ◽

Jeffrey L. Johnson ◽

Steven E. Coutre ◽

Richard M. Stone ◽

...

Keyword(s):

Overall Survival ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Complete Remission ◽

Lymphoblastic Leukemia ◽

Disease Free Survival ◽

Lymphoblastic Lymphoma ◽

Level Of Consciousness ◽

Grade 3 ◽

Group B

AbstractNelarabine (506U78) is a soluble pro-drug of 9-β-d-arabinofuranosylguanine (ara-G), a deoxyguanosine derivative. We treated 26 patients with T-cell acute lymphoblastic leukemia (T-ALL) and 13 with T-cell lymphoblastic lymphoma (T-LBL) with nelarabine. All patients were refractory to at least one multiagent regimen or had relapsed after achieving a complete remission. Nelarabine was administered on an alternate day schedule (days 1, 3, and 5) at 1.5 g/m2/day. Cycles were repeated every 22 days. The median age was 34 years (range, 16-66 years); 32 (82%) patients were male. The rate of complete remission was 31% (95% confidence interval [CI], 17%, 48%) and the overall response rate was 41% (95% CI, 26%, 58%). The principal toxicity was grade 3 or 4 neutropenia and thrombocytopenia, occurring in 37% and 26% of patients, respectively. There was only one grade 4 adverse event of the nervous system, which was a reversible depressed level of consciousness. The median disease-free survival (DFS) was 20 weeks (95% CI, 11, 56), and the median overall survival was 20 weeks (95% CI, 13, 36). The 1-year overall survival was 28% (95% CI, 15%, 43%). Nelarabine is well tolerated and has significant antitumor activity in relapsed or refractory T-ALL and T-LBL.

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Analysis of FDG PET Diffuse Bone Marrow Uptake in Staging of Hodgkin’s Disease: A Reflect of Disease Infiltration or Just Inflammation?.

Blood ◽

10.1182/blood.v112.11.1456.1456 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1456-1456

Author(s):

Pierre Y Salaun ◽

Thomas Gastine ◽

Loic Campion ◽

Pierre Cambefort ◽

Caroline Bodet-Milin ◽

...

Keyword(s):

Bone Marrow ◽

Fdg Pet ◽

Univariate Analysis ◽

Bone Marrow Involvement ◽

Tumor Burden ◽

Rank Test ◽

Liver Uptake ◽

Bulky Disease ◽

Inflammatory Parameters ◽

Bone Marrow Uptake

Abstract FDG-PET has been successfully evaluated in the management of Hodgkin’s lymphoma (HL) and the most recent international guidelines recommended FDG-PET for initial staging and final therapeutic assessment. However, FDG PET diffuse bone marrow uptake (BMU) is frequently observed and remains difficult to analyse. The aim of this study was to evaluate the correlation between bone marrow involvement and BMU in HD. Methods: 106 HD patients (median age was 31 years range from 9 to 81; male gender in 23 cases) who underwent FDG PET/CT were retrospectively analysis. BMU level was graduated according to liver uptake. In addition, as semi-quantitative reference SUVmax was assessed upon sacral promontory. These data were compared with patient characteristics including age, Ann Arbor staging, bulky disease (Tumor burden > 10 cm), presence of B symptoms, bone foci on PET (n=106), bone marrow biopsy (n=75), leukocyte count (n=74), LDH (n=87) and inflammatory parameters measured in the serum (C-Reactive Protein (CRP) (n=83) and fibrinogen (n=60)). Univariate and multivariate analysis were performed. A Fisher’s exact test and a Kruskal-Wallis equality of population rank test were used to analyse qualitative and quantitative parameters, respectively. Results: No statistical link was found between BMU and stage, bulky disease, bone marrow involvement (BMI), bone foci on PET or LDH. In contrast, univariate analysis showed correlation between BMU and age (p =0.0001), B symptoms (p =0.028 for clinical), CRP (p=0.0001), fibrinogen (p=0.0111) and leukocyte (p=0.0024). Multivariate parameters analysis found independent correlation between BMU and CRP level (p<0.0001). Sacrum SUV was correlated with inflammatory parameters as BMU and with disease extension parameters like stage (p=0.0001), BMI on biopsy (p=0.0127) and bone foci on PET (p=0.0498). No BMI was found in patients presented with SUVmax below 3.5. Conclusion: This study demonstrates that the intensity of FDG-PET bone marrow uptake in HD is not correlated to BMI but related to inflammatory parameters probably reflecting the cellular activation within the BM. Semi-quantitative analysis of SUV could be useful to improve bone uptake interpretation because no infiltration is found under a SUV level.

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Second Allogeneic Transplants for Relapsed Acute Lymphoblastic Leukemia Result in High Response Rates of Short Duration: Further Intervention Is Required to Maintain Response.

Blood ◽

10.1182/blood.v114.22.4293.4293 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4293-4293

Author(s):

Partow Kebriaei ◽

Rima Saliba ◽

Gabriela Rondon ◽

Laura Worth ◽

Laurence J.N. Cooper ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Univariate Analysis ◽

Response Rates ◽

Disease Stage ◽

Disease Relapse ◽

Hematopoietic Stem ◽

Preparative Regimen ◽

Cytogenetic Profile

Abstract Abstract 4293 The major cause of failure after allogeneic hematopoietic stem cell transplantation (SCT) for acute lymphoblastic leukemia (ALL) is disease relapse. Patients and Methods We analyzed the outcome of second SCT for treatment of disease relapse occurring within 6 months (n=10) or after 6 months (n=18) following first SCT in 28 ALL patients (12F/16M) with median age 23.5 years (range 3-50) transplanted between 1993 and 2009 at our institution. At time of SCT 43% of patients had advanced remission beyond CR1 (n=12) and 57% had active disease (n=16). High risk cytogenetic profile defined by the presence of t(9;22) or t(4;11) translocation, or hypodiploid clone was noted in 43% of patients (n=12) at time of diagnosis. A myeloablative busulfan- or TBI-based transplant preparative regimen (n=8) or reduced-intensity fludarabine-based regimen (n=20) was used followed by matched sibling (n=17), matched unrelated (n=9), or mismatched cord blood (n=2) infusion. A different donor was used in 54% of cases. GVHD prophylaxis was either tacrolimus-based (n=20) or cyclosporine-based (n=8). Only one patient in this analysis received consolidation following second SCT in the form of prophylactic donor lymphocyte infusion (DLI). Results 26 patients were evaluable for response with 2 early deaths within 30 days of SCT. Overall response rate was 88% with 38% sustained (n=10) and 50% complete (n=13) response rates. Acute grades II-IV and III-IV GVHD rates were 27% (n=7) and 12% (n=3), respectively; chronic extensive GVHD was noted in 1 patient. Progression-free (PFS) and overall survival (OS) were 27% and 42%, respectively, at 1 year. However, there is only one long-term survivor at 5 years, with a median follow-up time of 6 months among 5 survivors. The primary cause of death was disease relapse (n=14), with remaining causes GVHD (n=4), infection (n=2), multi-organ failure (n=2). Disease characteristics, including WBC count and cytogenetic profile at diagnosis, time to first remission, time to progression after first SCT, time between first and second SCT, age at SCT, intensity of SCT preparative regimen, disease stage at SCT, donor relation, use of same or different donor, and development of GVHD were evaluated in a univariate analysis for PFS following second SCT without any statistically significant factors identified. There was a trend for longer PFS in patients who had a late relapse following first SCT (p=.06). At 1 year, PFS was 29% for patients whose disease progressed after 6 months following first SCT versus only 12% for those who had very early relapse (p=.06, Figure 1). Conclusions In summary, a second allogeneic SCT remains an effective method for achieving response in a highly refractory patient population. However, post-SCT interventions are needed to achieve sustained response, as demonstrated by the long-term remission of the only patient who received post SCT prophylactic DLI. A significant proportion of patients remain disease-free up to one year following second SCT, thereby providing a window of time to administer consolidation in the form of immunotherapy or low-dose chemotherapy maintenance. Disclosures: No relevant conflicts of interest to declare.

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Allogeneic stem cell transplantation (allo-SCT) in adult acute lymphoblastic leukemia (ALL)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.17513 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 17513-17513

Author(s):

S. J. Wu ◽

M. Yao ◽

J. L. Tang ◽

Y. C. Chen ◽

A. L. Cheng ◽

...

Keyword(s):

Overall Survival ◽

Survival Benefit ◽

Proportional Hazards Model ◽

Lymphoblastic Leukemia ◽

Univariate Analysis ◽

Early Period ◽

Population Based ◽

Cox Proportional Hazards Model ◽

Time Dependent ◽

Immortal Time Bias

17513 Background: Although viewed as a potentially curable disease, the outcome of adult ALL is extremely poor. The role of allo-SCT, a possible curative modality, is of debate. Although the solid evidence is lacking, allo-SCT is viewed as a standard treatment in some institutions and some trials. The objective of the study is to clarify the effect of allo-SCT in the treatment of adult ALL patietns. Methods: From Jan. 1999 to Jun. 2006, we included 103 adult ALL patients whose age were between 15 and 55, the upper limit of age for allo-SCT in this institution. Their data, including clinical characteristics, cytogenetic results, treatment response and outcomes, were collected. To avoid the “immortal-time bias” in assessing the effect of transplant, the results from a time-independent and time-dependent Cox proportional hazards model were compared. We also conducted a population-based study to compare the outcomes of these patients with those diagnosed between Jan. 1986 and Dec.1993 in our institution. Results: There were 46 females and 57 males. The median age was 25.8, with 63 patients (61.2%) younger than 30. The median survival was 21.9 months and the 3-year overall survival was 34.2%. 48 patients(46.6%) received allo-SCT. The transplant conferred to marginally better survival in univariate analysis (p=0.049), but by time-dependent regression method, there was, after adjusting for other risk factors, no survival benefit for patients receiving transplant (HR 1.452, 95% CI 0.766∼2,751, p=0.253). The outcomes of these 103 patients were compared with another group of 69 patients diagnosed in the early period, among whom 13 patients(18.8%) received transplant. Although with higher proportion of patients undergoing allo- SCT, there was no advance in overall survival (p=0.157). Conclusions: In adult ALL, the outcome is still poor. Although there are new treatment protocols and modalities in chemotherapy and transplantation, these advances do not reflect to survival improvement. Transplantation provides limited survival benefit in population-based viewpoint. The candidates of allo-SCT should thus be carefully selected and allo-SCT should not be viewed as a standard in the treatment of adult ALL patients. No significant financial relationships to disclose.

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