scholarly journals Next Generation Sequence Minimal Residual Disease (NGS-MRD) Predicts Event Free Survival (EFS) Irrespective of Hematopoietic Cell Transplantation (HCT) Conditioning Regimen, Graft Αβ T and B-Cell Depletion or Patient Weight Category in Children with Acute Lymphoblastic Leukemia (ALL)

2020 ◽  
Vol 26 (3) ◽  
pp. S90-S92
Author(s):  
Hisham Abdel-Azim ◽  
Christopher C. Dvorak ◽  
Nancy Bunin ◽  
Mark C. Walters ◽  
Julie-An M. Talano ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Conditioning Regimen ◽  
B Cell Depletion ◽  
Event Free Survival ◽  
Weight Category ◽  
Free Survival ◽  
Minimal Residual

scholarly journals Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia: A Retrospective Multinational Study

2019 ◽  
Vol 37 (10) ◽  
pp. 770-779 ◽  
Author(s):  
Ching-Hon Pui ◽  
Paola Rebora ◽  
Martin Schrappe ◽  
Andishe Attarbaschi ◽  
Andre Baruchel ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Survival Rate ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Allogeneic Transplantation ◽  
Remission Induction ◽  
Event Free Survival ◽  
Free Survival

PURPOSE We determined the prognostic factors and utility of allogeneic hematopoietic cell transplantation among children with newly diagnosed hypodiploid acute lymphoblastic leukemia (ALL) treated in contemporary clinical trials. PATIENTS AND METHODS This retrospective study collected data on 306 patients with hypodiploid ALL who were enrolled in the protocols of 16 cooperative study groups or institutions between 1997 and 2013. The clinical and biologic characteristics, early therapeutic responses as determined by minimal residual disease (MRD) assessment, treatment with or without MRD-stratified protocols, and allogeneic transplantation were analyzed for their impact on outcome. RESULTS With a median follow-up of 6.6 years, the 5-year event-free survival rate was 55.1% (95% CI, 49.3% to 61.5%), and the 5-year overall survival rate was 61.2% (95% CI, 55.5% to 67.4%) for the 272 evaluable patients. Negative MRD at the end of remission induction, high hypodiploidy with 44 chromosomes, and treatment in MRD-stratified protocols were associated with a favorable prognosis, with a 5-year event-free survival rate of 75% (95% CI, 66.0% to 85.0%), 74% (95% CI, 61.0% to 89.0%), and 62% (95% CI, 55.0% to 69.0%), respectively. After exclusion of patients with high hypodiploidy with 44 chromosomes and adjustment for waiting time to transplantation and for covariables in a Poisson model, disease-free survival did not differ significantly ( P = .16) between the 42 patients who underwent transplantation and the 186 patients who received chemotherapy only, with an estimated 5-year survival rate of 59% (95% CI, 46.5% to 75.0%) versus 51.5% (95% CI, 44.7% to 59.4%), respectively. Transplantation produced no significant impact on outcome compared with chemotherapy alone, especially among the subgroup of patients who achieved a negative MRD status upon completion of remission induction. CONCLUSION MRD-stratified treatments improved the outcome for children with hypodiploid ALL. Allogeneic transplantation did not significantly improve outcome overall and, in particular, for patients who achieved MRD-negative status after induction.

scholarly journals IKZF1plus Defines a New Minimal Residual Disease–Dependent Very-Poor Prognostic Profile in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia

2018 ◽  
Vol 36 (12) ◽  
pp. 1240-1249 ◽  
Author(s):  
Martin Stanulla ◽  
Elif Dagdan ◽  
Marketa Zaliova ◽  
Anja Möricke ◽  
Chiara Palmi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Event Free Survival ◽  
Cell Precursor ◽  
Free Survival ◽  
Prognostic Profile ◽  
Minimal Residual

Purpose Somatic deletions that affect the lymphoid transcription factor–coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica–Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial. Results IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion conferred the worst outcome and, consequently, were grouped as IKZF1plus. The IKZF1plus group comprised 6% of patients with BCP ALL, with a 5-year event-free survival of 53 ± 6% compared with 79 ± 5% in patients with IKZF1 deletion who did not fulfill the IKZF1plus definition and 87 ± 1% in patients who lacked an IKZF1 deletion ( P ≤ .001). Respective 5-year cumulative relapse incidence rates were 44 ± 6%, 11 ± 4%, and 10 ± 1% ( P ≤ .001). Results were confirmed in the replication cohort, and multivariable analyses demonstrated independence of IKZF1plus. The IKZF1plus prognostic effect differed dramatically in analyses stratified by minimal residual disease (MRD) levels after induction treatment: 5-year event-free survival for MRD standard-risk IKZF1plus patients was 94 ± 5% versus 40 ± 10% in MRD intermediate- and 30 ± 14% in high-risk IKZF1plus patients ( P ≤ .001). Corresponding 5-year cumulative incidence of relapse rates were 6 ± 6%, 60 ± 10%, and 60 ± 17% ( P ≤ .001). Conclusion IKZF1plus describes a new MRD-dependent very-poor prognostic profile in BCP ALL. Because current AIEOP-BFM treatment is largely ineffective for MRD-positive IKZF1plus patients, new experimental treatment approaches will be evaluated in our upcoming trial AIEOP-BFM ALL 2017.

scholarly journals Validation of Minimal Residual Disease as Surrogate Endpoint for Event-Free Survival in Childhood Acute Lymphoblastic Leukemia

2018 ◽  
Vol 2 (4) ◽  
Author(s):  
Stefania Galimberti ◽  
Meenakshi Devidas ◽  
Ausiliatrice Lucenti ◽  
Giovanni Cazzaniga ◽  
Anja Möricke ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Surrogate Endpoint ◽  
Phase Iii ◽  
Event Free Survival ◽  
Free Survival ◽  
The Individual ◽  
Minimal Residual

Abstract Background The aim of this study was to assess whether minimal residual disease (MRD) at the end of induction front-line treatment can serve as a surrogate endpoint for event-free survival (EFS) in childhood B-lineage acute lymphoblastic leukemia. Methods The analysis was based on individual data of 4830 patients from two large phase III trials that asked a randomized question on the effect of different corticosteroids (dexamethasone vs prednisone) during induction chemotherapy on EFS. The association between MRD classified in three ordered categories [negative = 0, low positive = (>0 and <5 × 10−4), and positive = (≥5 × 10-4)] and EFS at the individual and trial levels was evaluated with the meta-analytic approach based on the Plackett copula model. Centers within trial were grouped according to geographical area, and a total of 28 units were identified for the analysis. Results MRD at the end of induction was a poor surrogate for treatment effect on EFS at the trial level, with Rtrial2 = 0.09 (95% confidence interval [CI] = 0.00 to 0.29), whereas at the individual level it was strongly associated with EFS, with an odds ratio of 3.90 (95% CI = 3.35 to 4.44) of failure for patients with higher compared with lower MRD levels. Additional sensitivity and relevant subgroup analyses confirmed these findings at both trial- and patient-level association. Conclusions Although MRD is a robust biomarker highly predictive of outcome for individual patients, clinicians and regulatory bodies should be cautious in using early MRD response in the context of complex multiagent acute lymphoblastic leukemia therapy as an early surrogate endpoint to predict the effect of a randomized treatment intervention on long-term EFS.

scholarly journals Reinduction Platform for Children With First Marrow Relapse of Acute Lymphoblastic Leukemia: A Children's Oncology Group Study

2008 ◽  
Vol 26 (24) ◽  
pp. 3971-3978 ◽  
Author(s):  
Elizabeth A. Raetz ◽  
Michael J. Borowitz ◽  
Meenakshi Devidas ◽  
Stephen B. Linda ◽  
Stephen P. Hunger ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Novel Agents ◽  
Late Relapse ◽  
Oncology Group ◽  
Event Free Survival ◽  
Free Survival ◽  
Significant Challenge ◽  
Minimal Residual

Purpose Treatment of childhood relapsed acute lymphoblastic leukemia (ALL) remains a significant challenge. The goal of the Children's Oncology Group (COG) AALL01P2 study was to develop a safe and active chemotherapy reinduction platform, which could be used to evaluate novel agents in future trials. Patients and Methods One hundred twenty-four patients with ALL and first marrow relapse received three, 35-day blocks of reinduction chemotherapy: 69 with early relapse (ER; < 36 months from initial diagnosis) and 55 with late relapse (LR). Minimal residual disease (MRD) was measured by flow cytometry after each treatment block. Results Second complete remission (CR2) rates at the end of block 1 in 117 assessable patients were 68% ± 6% for ER (n = 63) and 96% ± 3% for LR (n = 54; P < .0001). Five of seven patients with T-cell ALL (T-ALL) failed to achieve CR2. Among patients in CR2, MRD greater than 0.01% was detected at the end of block 1 in 75% ± 7% of ER (n = 36) versus 51% ± 8% of LR (n = 43; P = .0375) and 12-month event-free survival was 80% ± 7% versus 58% ± 7% in MRD-negative versus positive patients (P < .0005). Blocks 2 and 3 of therapy resulted in reduction of MRD burden in 40 of 56 patients who were MRD positive after block 1. Toxicity was acceptable during all three blocks with five deaths (4%) from infections. Conclusion The AALL01P2 regimen is a tolerable and active reinduction platform, suitable for testing in combination with novel agents in B-precursor ALL. Alternative strategies are needed for T-ALL. Serial MRD measurements were feasible and prognostic of outcome.

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.

Minimal Residual Disease Status Is the Most Important Preditive Factor in Adults with Acute Lymphoblastic Leukemia. Prospective, Multicenter PALG 4-2002 MRD Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2821-2821 ◽  
Author(s):  
Jerzy Holowiecki ◽  
Malgorzata Krawczyk-Kulis ◽  
Sebastian Giebel ◽  
Krystyna Jagoda ◽  
Beata Stella-Holowiecka ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Disease Status ◽  
High Dose ◽  
Risk Criteria ◽  
Minimal Residual

Abstract Current therapeutic protocols for adult acute lymphoblastic leukemia (ALL) take into account the risk of relapse, in order adjust the treatment intensity to individual patient needs. It is postulated that in addition to “classical” risk criteria the status of minimal residual disease (MRD) should be considered for treatment decisions. The aim of this study was to prospectively evaluate the feasibility and prognostic significance of MRD detected with the use of immunophenotyping for outcome of ALL patients treated according to 4-2002 protocol of the Polish Adult Leukemia Group (PALG). Induction therapy included PDN, Asp and 4x epirubicin+VCR. Consolidation consisted of 2x high-dose AraC+Cy, 2x Mtx+Vep, 6MP, and CNS prophylaxis. Patients stratified to high risk (HR) group according to “classical” criteria based on those formerly developed by GMALL (bcr/abl(+), WBC>30 G/L, prepreB, early or mature T phenotype, age>35y, or prolonged time to achieve CR) were further referred for hematopoietic cell transplantation (HCT), whereas those assigned to standard risk (SR) group were treated with maintenance for 2 years. MRD was tested at the level of 0.1% after completion of induction and consolidation therapy in patients achieving CR, employing multicolor flow-cytometry, including a new “empty spaces” method taking into account an individual pattern of antigen expression on blast cells. 165 ALL pts (B-lineage 79%, T-lineage 21%), aged 29 y (17–60) were included. CR rate equaled 85,5%. 23% of CR pts were assigned to SR, 77%- to HR according to classical criteria. MRD evaluation was possible in all but 8 pts. After induction 37% of CR pts were found MRD(+). Among those who remained in CR, MRD after consolidation was detected in 26% of cases. 64% of patients were MRD(−) at both time-points, whereas in the remaining 36% of cases MRD was detected at least once. MRD status affected both relapse incidence (RI) and leukemia-free survival (LFS). After 3 years the RI was higher for pts with MRD(+) vs. MRD(−) if assessed after induction (82%vs.29%,p=0.00007) and after consolidation (62%vs.41%,p=0.05). For pts with MRD(−) at both study end-points the probability of LFS was 65% whereas for those with MRD(+) after either induction and/or consolidation − 26% (p=0.008). In the respective subgroups RI equaled 28% and 73% (p=0.004). The difference was observed for patients assigned to SR group (20%vs.92%,p=0.01) as well as to HR group (33%vs.70%,p=0.05). In a multivariate analysis including classical risk criteria the MRD status remained the only significant factor predictive for RI (HR: 2.5(1.3–4.8),p=0.006) and LFS (HR: 2.1(1.2–3.9),p=0.01). We conclude that immunophenotyping employing “empty spaces” method is feasible for MRD evaluation in adults with ALL. MRD stzatus after induction and consolidation is the most important predictive factor for RI and LFS. Based on our findings patients with MRD detected after induction and/or consolidation should be offered intensified treatment with the use of HCT irrespective of the absence of other risk factors.

Targeted Therapy With the T-Cell–Engaging Antibody Blinatumomab of Chemotherapy-Refractory Minimal Residual Disease in B-Lineage Acute Lymphoblastic Leukemia Patients Results in High Response Rate and Prolonged Leukemia-Free Survival

2011 ◽  
Vol 29 (18) ◽  
pp. 2493-2498 ◽  
Author(s):  
Max S. Topp ◽  
Peter Kufer ◽  
Nicola Gökbuget ◽  
Mariele Goebeler ◽  
Matthias Klinger ◽  
...  
Keyword(s):  
T Cells ◽  
Adverse Event ◽  
Acute Lymphoblastic Leukemia ◽  
Tumor Cells ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Free Survival ◽  
Grade 3 ◽  
B Lineage ◽  
Minimal Residual

Purpose Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL. Patients and Methods Patients with MRD persistence or relapse after induction and consolidation therapy were included. MRD was assessed by quantitative reverse transcriptase polymerase chain reaction for either rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic aberrations. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dose of 15 μg/m2/24 hours. Results Twenty-one patients were treated, of whom 16 patients became MRD negative. One patient was not evaluable due to a grade 3 adverse event leading to treatment discontinuation. Among the 16 responders, 12 patients had been molecularly refractory to previous chemotherapy. Probability for relapse-free survival is 78% at a median follow-up of 405 days. The most frequent grade 3 and 4 adverse event was lymphopenia, which was completely reversible like most other adverse events. Conclusion Blinatumomab is an efficacious and well-tolerated treatment in patients with MRD-positive B-lineage ALL after intensive chemotherapy. T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse.

scholarly journals Augmented Consolidation Therapy Based on Minimal Residual Disease (MRD) and Analysis of the Measurement of Sequential MRD in Childhood Acute Lymphoblastic Leukemia : Children's Cancer and Leukemia Study Group of JAPAN (CCLSG), Cclsg ALL 2004 Protocol Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3724-3724
Author(s):  
Arata Watanabe ◽  
Toshinori Hori ◽  
Yasuto Shimomura ◽  
Chihaya Imai ◽  
Atsushi Ogawa ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Prognostic Factor ◽  
Standard Therapy ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Consolidation Therapy ◽  
Free Survival ◽  
Time Points ◽  
Group 5 ◽  
Minimal Residual

Abstract BACKGROUND: Minimal residual disease (MRD) level after induction (Time Point1:TP1) and before consolidation therapy (Time Point2:TP2) has a strong impact in prediction of outcome for childhood acute lymphoblastic leukemia and it has clinical utility of a prognostic factor to stratify the risk groups in many current studies. We measured MRD levels on various time points to evaluate their prognostic significance in MRD-based augmented therapy. PATIENTS & METHODS: From June 2004 to September 2009, we prospectively assigned 333 consecutive children with ALL, 1〜19 years of age, to receive one of three treatment protocols on the stratification based on National Cancer Institute (NCI) risk criteria. NCI standard risk:SR, NCI high risk:HR and those with a white blood cell count≧1000x109 per L was defined as high-high risk:HHR. Patients were stratified again at TP2, patients with MRD level over 10-3 were assigned to salvage arm, treated in augmented therapy. Among 333 patients, 326 were eligible and 245 were MRD quantifiable. Then, we re-evaluated those samples by RQ-PCR according to the guideline of Euro MRD. Finally 167 cases were analyzed at 7 time points of MRD quantification in the CCLSG ALL2004 study. RESULTS: The overall 5-year event free survival (5-EFS) rate for ALL2004 was 82.5±2.1% (n=326), and 5-EFS of SR group (n=267), HR group (n=86) and HHR group (n=33) were 84.8±2.5%, 80.1±4.3% and 74.7±7.8%, respectively. In the SR group, 5-EFS of standard therapy group (n=124) with TP2 MRD<10-3 was 87.5±3.0% and augmented therapy group's 5-EFS was 80.0±10.3% (n=15, p=0.6124). In the HR group, 5-EFS of standard therapy was 83.1±5.1% (n=54) and augmented therapy group's was 57.1±18.7% (n=7, p=0.870). In the HHR group, 5-EFS of standard therapy was 87.5±8.3% (n=16) and augmented therapy group's was 51.4±20.4% (n=7, p=0.054). TP1, at week 7, at the end of induction, 5-year relapse free survival (5-RFS) was 87.4.% in MRD negative cases (n=115) and 58.3% in MRD positive cases (n=36), and the differences were significant. TP2,week13, during consolidation, and TP3, at week 19 or 22, and at TP4, at week 26 to 28, had significant difference on 5-RFS with cut off of both 10-3 and 10-4. TP7, at the end of therapy, 2 patients were MRD positive and were thought molecular relapse. Additionally, we investigated changes in MRD levels of relapsed cases (n=35). MRD remained cases (n=4), MRD late disappeared cases (n=4), and MRD converted to positivity cases (n=4) were observed. CONCLUSIONS: The impact of predictive power of PCR MRD at TP1 and TP2 was validated, still more TP3 and TP4 were also statistically significant in CCLSG ALL2004 study. Even the patients whose final MRD level was negative could relapse, it is needed to investigate other prognostic factor except MRD. Disclosures Imai: Juno Therapeutics: Patents & Royalties.

scholarly journals Reducing minimal residual disease with blinatumomab prior to HCT for pediatric patients with acute lymphoblastic leukemia

2019 ◽  
Vol 3 (13) ◽  
pp. 1926-1929 ◽  
Author(s):  
Amy K. Keating ◽  
Nathan Gossai ◽  
Christine L. Phillips ◽  
Kelly Maloney ◽  
Kristen Campbell ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Pediatric Patients ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Free Survival ◽  
Key Points ◽  
Minimal Residual

Key Points Children treated with blinatumomab for B-ALL with MRD had few side effects and proceeded to hematopoietic cell transplant without delay. Blinatumomab given prior to transplant reduces MRD and results in favorable leukemia-free survival, toxicity, and overall survival.

scholarly journals Fludarabine and Busulfan Plus Low Dose TBI Versus Cyclophosphamide Plus TBI in Allogeneic Hematopoietic Cell Transplantation for Adult Acute Lymphoblastic Leukemia: Equivalent Outcomes in a Recent, Large Canadian Multicenter Cohort

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 663-663 ◽  
Author(s):  
Craig Speziali ◽  
Andrew Daly ◽  
Mohamed Abuhaleeqa ◽  
Janet Nitta ◽  
Yasser Abou Mourad ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Instrumental Variable ◽  
Low Dose ◽  
Hematopoietic Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Conditioning Regimen ◽  
Progression Free Survival ◽  
Point Estimate ◽  
Free Survival ◽  
Transplant Center

Abstract Background: Allogeneic hematopoietic cell transplantation (HCT) is an important treatment for adults with acute lymphoblastic leukemia (ALL). The combination of cyclophosphamide with total body irradiation (TBI) at doses of 1200 to 1500 cGy (Cy/TBI1200) has been used in most prospective trials of HCT in ALL. However, TBI is associated with significant short and long term toxicities. Although Cy/TBI/1200 is the standard of care at most Canadian transplant centers one center instead prefers a conditioning regimen including fludarabine, busulfan, and low dose TBI (400 cGy) (Flu/Bu/TBI400) (Daly et al. BBMT 2012). We sought to compare the outcomes of HCT for adults with ALL who routinely received either Cy/TBI1200 or Flu/Bu/TBI400 as their conditioning regimen with the hypothesis that the regimens will result in similar outcomes. Conditioning regimen was highly correlated with transplant center, minimizing any selection bias in which clinicians might choose a regimen perceived to be of lower toxicity for selected patients. Methods: We included patients aged 18 or above who underwent a first myeloablative HCT for ALL in complete remission at one of three Canadian transplant centers from 2004-2014. Two of the centers use Cy/TBI1200 as a preferred conditioning regimen and the third center preferred Flu/Bu/TBI400. As the choice of conditioning regimen is strongly linked to transplant center we have performed an instrumental variable analysis in which the instrumental variable was the transplant center preference. Other transplant practices, including indications for transplant and supportive care, were similar between the centers. Overall survival (OS), progression-free survival (PFS), relapse rate (RR), and non-relapse mortality (NRM) were compared between groups. Results: A total of 146 patients were included, with 74 treated at centers that prefer Cy/TBI1200, of whom 72 received Cy/TBI1200 as conditioning, and 72 were treated at a Flu/Bu/TBI400 center, of whom 71 received Flu/Bu/TBI400. Importantly, no significant difference in transplant year, cytogenetic risk group, disease status at time of transplant, stem cell source, or graft versus host disease prophylaxis regimen was seen (Table 1). There were more patients with poor performance status in the Flu/Bu/TBI400 center (p = 0.004), and more ATG use in that centre (p < 0.001). In univariate analysis, there was no difference between centers in terms of OS and PFS (Figure 1). Similarly, in multivariable regression models there was no difference in either OS or PFS (Table 2). Cumulative incidence of non-relapse mortality was similar between groups (2 year point estimate of 12% in Cy/TBI1200 centers and 16.7% in the Flu/Bu/TBI400 centre, p=0.62). Cumulative incidence of relapse was lower in the Flu/Bu/TBI400 center (p = 0.05, 2 year point estimate of 31% in Cy/TBI centers and 18.5% in Flu/Bu/TBI 400 centers). Discussion: In this recently treated cohort of adults ALL with minimal selection bias, we demonstrate that similar rates of overall and progression free survival can be achieved with conditioning regimens that contain low doses of TBI. Table 1 Baseline Details: Table 1. Baseline Details: Disclosures Daly: Sanofi-Genzyme: Other: Advisory Board. Seftel:Otsuka: Research Funding.

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