Molecular Monitoring of Residual Disease (MRD) during Induction and Intensification Phases in Low Risk Adult B Cell ALL Treated According to the MRC UKALL12 Protocol.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1466-1466 ◽  
Author(s):  
Letizia Foroni ◽  
Wayne Mitchell ◽  
Lena J. Rai ◽  
Anouska Casanova ◽  
Gareth Gerrard ◽  
...  
Keyword(s):  
B Cell ◽  
Residual Disease ◽  
Induction Phase ◽  
Molecular Monitoring ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Significant Parameter ◽  
Standard Risk ◽  
Time Point

Abstract Introduction and aims. Molecular monitoring of minimal residual disease (MRD) using Immunoglobulin (IG) and T cell receptor (TCR) targets has provided an independent and prognostically significant parameter of outcome in adult and childhood acute lymphoblastic leukaemia (ALL). The aim of our study was to evaluate the impact of molecular tests carried out during the first 20 to 24 weeks of chemotherapy for MRD in a standard risk group of adult B cell ALL patients. Patients and Methodology. We evaluated MRD tests in 63 patients with B cell ALL (37M/26F). Median age of our cohort was 24 yrs (range: 15.5–54.6 yrs) while median WBC was 9.9 (range: 1.1–553 × 109l). All were negative for the t(9;22) or t(4;11) translocation and received standard induction chemotherapy or auto stem cell transplant (A-SCT) only. All patients had at least one molecular marker which was tested by quantitative or semi-quantitative PCR with sensitivity ≥1E4 and all tests were carried out at time of morphological remission. End-points were relapse or continuous clinical remission (CCR) with follow up ≥12 months. Time point for molecular evaluation were post induction phase 1, TP1 (up to 1.8 mo), post induction phase 2 (1.8–3.5 mo), post intensification (3.5–5.7 mo). Median follow up was 92 months for patients in CCR (range 12–141 mo) and 15.5 months for patients who relapsed (range: 2.4–49 mo). Results. Thirty-five patients in complete morphological remission were tested at TP1. Relapse free survival (RFS) tests showed a statistically significant correlation (p=0.02) between MRD positive tests and relapse (n=19 pts) and MRD negative tests (n=16 pts) and relapse free survival. In addition, pts with resistant disease at TP1 (n=10; not included above) and MRD positive pts were indistinguishable as far as relapse FS and both faired extremely poorly (Figure A). Thirty patients were analysed at TP2. RFS confirmed the significant association between MRD positivity and poor outcome (n=16 pts) and MRD negativity and CCR (n=14 pts) (p=0.03) (Figure B). MRD data were also available for 43 patients at TP3. Association of MRD positive tests (n=15 pts) and MRD negative tests (n=28 pts) with poor and good outcome, respectively (p=0.0006) (Figure C) was strongest at this time point. Outcome correlated with level of MRD at all time points, with poorer outcome in patients with MRD >1E3. Conclusions. Molecular monitoring during induction and intensification for standard risk B cell ALL patients treated with UKALL12 protocol provides a prognostically significant parameter for the management of adult ALL in otherwise morphological remission and may in the future be used for patients’ stratification. Figure Figure

The Value of Molecular Monitoring for Residual Disease (MRD) in Early Morphological Remitters among Adults Diagnosed with B Cell ALL and Treated According to the MRC UKALL12 Protocol.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1467-1467 ◽  
Author(s):  
Letizia Foroni ◽  
Wayne Mitchell ◽  
Lena J. Rai ◽  
Sue Richards ◽  
Adele Fielding ◽  
...  
Keyword(s):  
B Cell ◽  
Residual Disease ◽  
Phase 1 ◽  
Induction Phase ◽  
Clinical Relapse ◽  
Cell Transplant ◽  
Molecular Monitoring ◽  
Free Survival ◽  
Post Induction ◽  
Time Point

Abstract Molecular monitoring of minimal residual disease (MRD) has become an independent and prognostically significant parameter in assessing outcome in adult and childhood acute lymphoblastic leukaemia (ALL). The aim of our study was to evaluate the impact of MRD in a standard risk group of adult B cell ALL patients who had achieved morphological remission following induction phase 1 therapy as part of the MRC UKALL12 protocol. Patients and Methodology. MRD tests were evaluated in fourty-seven patients with adult B cell ALL. They were negative for the t(9;22) or t(4;11) translocation and had received chemotherapy based treatment or auto stem cell transplant (A-SCT) only. Median age was 23 yrs (range 15.5–54.6 yrs); median WBC was 9.6 (range 1.1–163×109/l) with a predominance of common (28 pts) and pre B ALL (12 pts). All patients had at least one molecular marker which was tested by quantitative or semi-quantitative PCR with sensitivity ≥1E4. End points were either clinical relapse or disease free survival in complete remission with follow up ≥12 months. Time point for molecular evaluation were post induction phase 1, TP1 (median 0.9 mo; range: 0.6–1.8 mo) and post induction phase 2 (median 2.79 mo; range 1.8–3.5 mo). Results. Thirty three pts were tested at TP1 following morphological remission. Relapse free survival (RFS) analysis showed a statistically significant association between MRD positive tests (in 16 pts) and relapse, and MRD negative tests (in 17 pts) and CCR (p=0.03) (Figure 1, left diagram). Twenty five pts were analysed at TP2 following their early morphological remission. At this time point we observed the strongest association between MRD negative tests (in 13 pts) and CCR (in 10 pts) and MRD positive (12 pts) and relapse (in 11 pts) (p=0.01)(Figure 1, right diagram). Conclusions. Molecular monitoring of MRD shows that even among early morphological remitters a group of MRD positive patients can be identified that have poor overall outcome and may benefit from tailored therapies. Molecular assessment of residual disease should be used to stratify treatment in future adult ALL trials. Figure Figure

Fluctuating Values of Molecular Residual Disease (MRD) without Molecular Progression After Imatinib Discontinuation in Patients (pts) with Chronic Myeloid Leukemia (CML) Who Have Maintained Complete Molecular Response: Implications for Re-Treatment Criteria and Role of Prior Interferon Therapy. A Pilot Study of the French CML Group (FILMC),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3781-3781 ◽  
Author(s):  
Philippe Rousselot ◽  
Pascale Cony Makhoul ◽  
Delphine Rea ◽  
Philippe Agape ◽  
Franck E Nicolini ◽  
...  
Keyword(s):  
Interferon Therapy ◽  
Residual Disease ◽  
Imatinib Therapy ◽  
Molecular Response ◽  
Relapse Free Survival ◽  
First Line ◽  
Free Survival ◽  
Low Levels ◽  
Sokal Score

Abstract Abstract 3781 Background. We have reported the results of imatinib discontinuation in CML pts in complete molecular response (CMR) for more than 2 years under imatinib therapy (STIM study, Mahon et al. Lancet Oncol. 2010). Among the group of pts without confirmed molecular relapse, a small proportion exhibited low levels of detectable residual disease during a prolonged period of time. Aims. In order to better characterize this phenomenon, we decided to analyse pts who stopped IM following a maintained CMR or an undetectable molecular residual disease (UMRD) and resumed therapy upon loss of major molecular response (MMR). We also aimed to validate the loss of MMR as a robust criterion for the re-introduction of tyrosine kinase inhibitors (TKIs). Patients and methods. CP-CML pts were eligible if they were in CMR (CMR4.5: BCR-ABL/ABL IS ratio <0.0032%) or UMRD (undetectable Bcr-Abl using standardized RTQ-PCR) under imatinib therapy for more than 2 years. Those pts were not enrolled in the STIM study because the study was closed or because they experienced at least one positive value of the BCR-ABL/ABL ratio during the 2 years follow-up. The proposed criterion for resuming imatinib was the loss of MMR (BCR-ABL/ABL IS ratio >0.1%). We calculated relapse free survival (RFS) using three different end-points: First loss CMR/UMRD defined by one occurrence MRD positivity; second loss of CMR/UMRD using the STIM definition (two consecutive increasing values of MRD); third loss of MMR. We also described pts with long lasting fluctuating PCR values. Results. 34 CP-CML pts were included in the analysis. Median follow-up after imatinib discontinuation was 21.3 months (2.2–83.1). Sex ratio (M/F) was 50% with a median age of 54.1 years (27.4–78.2). Sokal score distribution was 34.5%, 37.9% and 27.6% for low, intermediate and high values respectively. 19 out of 34 (55.9%) of the pts received interferon therapy prior to imatinib. Median duration of imatinib therapy and median duration of CMR/UMRD prior to discontinuation was 63.8 months (30.1–120.8) and 33.7 months (7.3–72.8) respectively (only two pts had CMR/UMRD duration less than 2 years). Of note 18 out of 34 pts (52.9%) had a least one MRD positive value after the achievement of CMR/UMRD. After imatinib discontinuation, we identified 11 pts (32.4%) who experienced repeated low levels of detectable MRD without losing their MMR. Median follow-up for these pts with fluctuating values of MRD was 15.4 months (3.5–59.5) and none of them restarted imatinib. We next analysed relapse free survival (RFS) using the loss of MMR criteria (RFS-MMR). Median RFS-MMR was not reached, compared to median RFS using the loss of CMR/UMRD criteria (4.8 months) and median RFS using the STIM criteria (13.8 months) (p=0.003). As a consequence, 62.8% of the pts remain treatment free at 2 years using the loss of MMR criteria for resuming imatinib. Fluctuating values of MRD has already been described after interferon cessation in CML interferon treated pts. We thus asked if prior therapy with interferon before imatinib may influence treatment free survival. Duration of imatinib therapy and Sokal score risk distribution were comparable between pre-treated and non pre-treated pts (p=0.7). However, the median RFS was longer in interferon pre-treated pts as compared to pts who received imatinib first line (not reached versus 7 months, p=0.047). Furthermore, this difference was not significant using the loss of CMR/URMD (p=0.27) to define molecular relapse. Conclusions. We were able to identify a significant number of pts with fluctuating values of MRD after imatinib discontinuation, a proportion underestimated in previous studies. We also validated the loss of MMR as the most accurate and robust criteria for restarting imatinib after imatinib discontinuation. Applying this criterion, we demonstrated that treatment free survival is significantly better in pts previously treated with interferon before imatinib compared to pts who received imatinib as first line therapy. An update of this pilot study on a larger number of patients will be presented. Disclosures: Rousselot: BMS, Novartis: Research Funding. Tulliez:Novartis:. Mahon:Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria; Pfizzer: Honoraria.

scholarly journals Administration of BPX-501 Cells Following Aβ T and B-Cell-Depleted HLA Haploidentical HSCT (haplo-HSCT) in Children with Acute Leukemias

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 307-307 ◽  
Author(s):  
Franco Locatelli ◽  
Annalisa Ruggeri ◽  
Pietro Merli ◽  
Swati Naik ◽  
Rajni Agarwal ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Pediatric Patients ◽  
Unrelated Donor ◽  
Relapse Free Survival ◽  
Advisory Committees ◽  
Steroid Resistant ◽  
Free Survival ◽  
Equity Ownership

Abstract Background Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established treatment for children with Acute Leukemia (AL). For patients lacking a compatible matched related or unrelated donor, HLA-haploidentical HSCT (haplo-HSCT) from a relative represents a viable alternative. Promising results were reported with a novel method of selective depletion of αβ T and B cells (Locatelli, Blood 2017). This approach is associated with limitations such as suboptimal adaptive immune reconstitution, increased risk of infection and disease relapse. BPX-501 is an allogeneic product consisting of T cells modified to express the inducible caspase-9 (iC9) safety switch and truncated CD19 to allow monitoring and expansion of BPX-501 following transplant. The polyclonal nature of the BPX-501 provides broad virus and tumor-specific immunity, while the safety switch provides the unique ability to promptly and durably resolve graft-versus-host disease (GvHD) symptoms following the administration of rimiducid which induces dimerization and activation of iC9, inducing apoptosis of BPX-501. Aims To evaluate the safety and efficacy of BPX-501 administered after a αβ T and B-cell depleted haplo-HSCT in pediatric patients with AL in morphological complete remission (CR). The objective was to determine whether BPX-501 infusion can increase relapse-free survival (RFS) and overall survival (OS) through an enhanced graft-versus-leukemic (GvL) effect, while maintaining a low risk of GvHD. Methods This multicenter US (NCT03301168) and EU (NCT02065869), prospective trial utilizes αβ-T and B-cell-depleted haplo-HSCT followed by infusion of donor lymphocytes genetically modified with iC9 safety switch (BPX-501) in patients with malignant or non-malignant disorders. A subset of patients had acute high-risk leukemias (AML and ALL). BPX-501 was planned to be infused on day14±4 after the allograft. No post-transplant pharmacological GvHD prophylaxis was employed. Patients who develop GvHD resistant to conventional steroid therapy could receive ≥1 dose of rimiducid to activate iC9. The efficacy-evaluable population (EEP) was defined as any patient with AL who received HSCT, BPX-501 infusion, and at least one follow-up assessment. Results At clinical cut-off (June 30, 2018), 100 patients (EU: 75, US: 25) with AL met the EEP definition. Median follow-up was 14.7 mos (1 - 40.6 mos). Key baseline characteristics are shown in Table 1. The median time for neutrophil and platelet engraftment was 16 (15 - 17) and 12 (11 - 12) days, respectively. Four patients (4.1% [95% CI: 0 - 8%]) experienced primary graft failure. Of 96 evaluable patients, 21 patients developed Grade I-IV aGvHD (21.7% [95% CI: 13.5 - 29.8%]). Five patients developed Grade III-IV aGvHD (3.1% [95% CI: 0 - 6.5%]). Of 82 evaluable patients, 12 patients developed cGvHD (18.1% [95% CI: 8.2 - 22%]), with only three cases being moderate-severe. Rimiducid was administered to 10 patients with steroid-resistant acute GvHD. Best overall clinical response of CR or PR post-rimiducid administration was seen in 8 patients (80%). Among responding patients, 7 patients (87.5%) had a CR. Six patients died after transplantation (6.6% [95% CI: 1.4 - 11.7%]). Relapse Free Survival (RFS) was 82.2% (95% CI: 74.5 - 89.7%). Overall Survival (OS) was 90.1% (95% CI: 83.9 - 96.3%). Efficacy outcomes (TRM, RFS and OS) in AL subsets (AML and ALL) are shown in Table 2. CD3+ and CD3+CD4+ T cells above 500 cells/ml were achieved by 180 and 270 days, respectively. IgA and IgM levels achieved normal values by 180 days. The percentage of circulating and median absolute BPX-501 cells at Day 100 were 9.96% ± 11.6% (0 - 54.9%) and 85.58 ± 165.57 cells/ul (0 - 1001 cells/ml), respectively. Conclusion The adoptive transfer of BPX-501 following αβ-T and B-cell depleted haplo-HSCT represents a novel and highly effective transplantation strategy for pediatric patients with AL. Compared to data from children receiving only αβ T and B-cell depleted haplo-HSCT or matched unrelated donor HSCT (https://bloodcell.transplant.hrsa.gov/research/transplant_data/us_tx_data/survival_data/survival.aspx), this novel approach resulted in a comparable risk of transplant-related mortality and a lower risk of recurrence. Rimiducid was also an effective treatment for patients who developed steroid-resistant GvHD. Disclosures Locatelli: bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Qasim:Orchard: Equity Ownership; Autolus: Equity Ownership; Servier: Research Funding; Bellicum: Research Funding. Nemecek:Novartis Pharmaceuticals Corporation: Other: advisory boards.

Minimal Residual Disease After Allogeneic Stem Cell Transplantation: A Comparison Among Multiparameter Flow Cytometry, Wilms Tumor 1 Expression and Chimerism Status (Complete vs Low-Level Mixed Chimerism) in Patients with Acute Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1971-1971
Author(s):  
Giovanni Rossi ◽  
Angelo Michele Carella ◽  
Maria Marta Minervini ◽  
Lucia Savino ◽  
Andrea Fontana ◽  
...  
Keyword(s):  
Residual Disease ◽  
Leukemic Cells ◽  
Mixed Chimerism ◽  
Multiparameter Flow Cytometry ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Low Level ◽  
Chimerism Analysis ◽  
Minimal Residual

Abstract Abstract 1971 Introduction. Relapse represents the main cause of treatment failure after allogeneic stem cell transplantation (allo-SCT). Thus, monitoring of minimal residual disease (MRD) in allografted patients allows an early detection of recurrence and a subsequent intervention prior to florid relapse. Multiparameter Flow Cytometry (MFC), chimerism, cytogenetics and molecular analysis have been widely used for this purpose, although the gold standard needs to be established yet. The evaluation of fusion transcripts represents the most sensitive method but more than 65% of patients do not demonstrate a molecular target. WT1 mRNA is over expressed in > 90% of patients with acute myeloid leukemia (AML) but it is not so expressed in acute lymphoblastic leukemia (ALL). On the MFC analysis instead, the complexity of maturational patterns and phenotypic shifts after therapy may underestimate residual leukemic cells. Finally, previous papers reported that a state of mixed chimerism (MC) in RT-PCR may identify higher risk of relapse in patients with AML. However, the test has a low sensitivity (from 0,1% to 1%) and recipient cells are not necessarily linked to disease recurrence. Hypothesizing the presence of blast cells in the low-level mixed chimerism (MC, 1%<MC<5% of autologous cells) but not in the complete chimerism (CC, no evidence of autologous cells) status, we used these two ranges as markers of positive and negative MRD, respectively. The aim of our study was twofold. Firstly, to assess the overall agreement among chimerism, MFC and WT1 mRNA methods in monitoring MRD. Secondly, to investigate whether such methods were associated to patient' s relapse-free survival. Methods. Fresh BM samples from 24 patients (17 AML and 7 ALL) in both morphological CR and CC or low-level MC status after allo-SCT were investigated. MRD with MFC, WT1 mRNA expression and chimerism analysis was evaluated at different time points: +1, +3, +6,+12,+18,+24 months after allo-SCT. The immunophenotypic analysis was performed using a six-color combinations and acquiring 250.000 events. RQ- PCR to test WT1 mRNA expression was made according to the standardized and quality-controlled method. Chimerism studies were performed with a multiplex amplification of 16 (STR). The agreement between two methods in monitoring MRD after allo-SCT was assessed by Kappa statistic. Moreover, time-to-event analyses were performed using Cox proportional-hazard models with time-dependent covariates. Risks were reported as hazards ratios (HR) along with their 95% confidence interval (95% CI). Results. Comparisons among results of MFC, RQ-PCR for WT1 mRNA and Chimerism were performed in all 67 serial samples obtained from 24 patients. A significant moderate agreement between MFC and WT1 mRNA evaluations was found (k= 0.463, p<0.001) as well as fair agreement between chimerism and MFC (k= 0.284, p=0.009) and chimerism and WT1 mRNA (k= 0.197, p=0.073). These results suggested a concordance among the three investigated techniques. In particular, the low-level MC would well detect the presence of leukemic cells, since the proportion of positive samples for MFC was not statistically different to the proportion of positive samples for WT1 mRNA within samples with low-level MC. Indeed, among 12 samples with low-level MC, 9 samples (75.0%) were also positive for MFC and 7(58.3%) were also positive for WT1 mRNA. Cut-off of 0.1% and 0.01% for MFC, 83.5 × 104 ABL for WT1 mRNA and 96%-99% of donor cells for chimerism were selected. The median follow-up times for relapse-free was 12.8 mths and the overall estimated relapse-free survival after 36 mths was 66.5%. At the end of follow- up, 5 patients relapsed and 4 patients died. Although not significant, the detection of a positive MRD for all methods were associated to a higher incidence of relapse than the negative MRD. Similar HRs were observed in the analysis of MFC(HR = 6.55, 95%CI= 0.71–60.17, p=0.096) and WT1 mRNA (HR= 7.17, 95% CI=0.77–66.42, p=0.083) whilst a slighter HR was found for the chimerism analysis (HR= 0.40, 95%CI= 0.04–4.44, p=0.456). Conclusions. According to our study MFC, WT1 mRNA and CC or low-level MC displayed an overall agreement in monitoring MRD. In particular, the agreement on the low-level MC may suggest the presence of leukemic cells. The detection of a positive MRD by MFC and WT1 mRNA similarly identified higher risk of relapse in patients with acute leukemia (AL) undergone to allo-SCT. Disclosures: No relevant conflicts of interest to declare.

Molecular Remission After Allogeneic or Autologous Transplantation of Hematopoietic Stem Cells for Multiple Myeloma

2000 ◽  
Vol 18 (11) ◽  
pp. 2273-2281 ◽  
Author(s):  
Giovanni Martinelli ◽  
Carolina Terragna ◽  
Elena Zamagni ◽  
Sonia Ronconi ◽  
Patrizia Tosi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Remission ◽  
Molecular Basis ◽  
Residual Disease ◽  
Autologous Transplantation ◽  
Molecular Monitoring ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Exact Test

PURPOSE: To assess the clinical relevance of minimal residual disease (MRD) in patients with multiple myeloma (MM), 50 patients were monitored while they were in complete clinical remission (CCR) after autologous or allogeneic stem-cell transplantation. PATIENTS AND METHODS: Stringent molecular monitoring using clonal markers based on rearranged immunoglobulin heavy-chain genes was performed in 44 of 50 MM patients in CCR. Molecular clinical remission (MCR) was defined as more than one consecutive negative polymerase chain reaction (PCR) test result. RESULTS: Twelve (27%) of 44 molecularly monitored patients achieved MCR; four of the 12 became PCR-positive, and one of these four relapsed. In comparison with patients who did not achieve MCR, patients who achieved MCR had a significantly lower relapse rate (41% v 16%; P < .05) and longer relapse-free survival (35 v 110 months; P < .005). Fourteen of 26 patients in CCR who had received allografts were evaluated on a molecular basis: seven (50%) of the 14 achieved MCR and did not relapse; one of the seven remaining patients relapsed. Thirty of 47 patients in CCR who received autografts were evaluated on a molecular basis: five (16%) of the 30 achieved MCR; two of these five became PCR-negative, and one of these two relapsed. Ten of the 25 remaining patients later relapsed. For these nonrandomized groups, the higher MCR rate after allograft procedures was statistically significant (P < .01; Fisher’s exact test). CONCLUSION: MCR can be obtained in a relatively high proportion of MM patients who have achieved CCR after undergoing allograft procedures and in a smaller fraction of patients after undergoing autograft procedures. In approximately one fourth of MM patients who achieve CCR after transplantation, it may be possible to keep the disease burden constantly below the PCR threshold. Because MCR was associated with prolonged relapse-free survival, these patients could have a relatively favorable clinical outcome.

Value of Molecular Monitoring for Minimal Residual Disease Preceding Autologous SCT Following Diagnosis of B Cell Acute Lymphoblastic Leukemia in Patients Treated with the MRC UKALL12 Protocol.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1468-1468
Author(s):  
Letizia Foroni ◽  
Wayne Mitchell ◽  
Lena J. Rai ◽  
Anouska Casanova ◽  
Bella Patel ◽  
...  
Keyword(s):  
B Cell ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Clinical Relapse ◽  
Cell Transplant ◽  
Molecular Monitoring ◽  
Median Period ◽  
Time Of Harvest ◽  
Minimal Residual

Abstract Introduction and aims. Molecular monitoring of minimal residual disease has provided an independent and prognostically significant parameter in evaluating outcome in adult and childhood acute lymphoblastic leukaemia (ALL). The aim of our study was to assess the impact of MRD measured in bone marrow samples collected at time of harvest or prior to harvest in adult B cell receiving autologous stem cell transplant and correlate MRD with overall clinical outcome. Patients and Methodology. Patients were selected as de novo adult ALL of B cells. All patients were negative for the t(9;22) or (4;11) and had received chemotherapy followed by an autologous SCT (A-SCT). All patients had at least one molecular marker which was tested by quantitative or semi-quantitative PCR with sensitivity ≥1E4. End points were either clinical relapse or CCR with follow up ≥12 months except for two patients who died in CR following transplant, due to infections. Time point for molecular evaluation was a test preceding A-SCT or harvested BM. Nineteen patients were evaluable prior to/or at time of harvest. Nine were females and nine were males. Median age was 25.2 yrs (range: 15.2–52 yrs), total WCC was 7.1 (range: 2.3–68.9×109/l) at time of diagnosis with common ALL (14 pts) as the predominant phenotype. Patients received an A-SCT at a median period of 6 months from diagnosis (range: 5–18 months). Eight patients relapsed (median period to relapse: 22 mo; range: 8–35 mo) and 8 were in continuous clinical remission (CCR) (median follow up 33 mo; range: 8–139 mo). Median interval between Auto-SCT and relapse was 13.7 mo (range: 3–29 mo). Results. In seven patients residual disease was demonstrated in the BM prior to A-SCT and 6 of them relapsed. In 12 patients no residual disease was detected at time of harvest or prior to transplant and 10 are at present in CCR. The association between MRD positivity and relapse and MRD negativity and CCR was statistically significant in this cohort of patients (p=0.002)(Figure 1). Conclusions. Molecular monitoring of MRD can provide a useful tool for the monitoring of residual disease in BM harvest prior to SCT and correlates with outcome. It is therefore important that all BM harvests are tested for residual disease in future clinical trial that may use MRD for patients’ stratification. MRD tests prior to Auto-SCT and relapse FS MRD tests prior to Auto-SCT and relapse FS

Minimal Residual Disease (MRD) Monitoring in CBFB-MYH11 Acute Myeloid Leukemia (AML) Is of Prognostic Relevance for Relapse-Free Survival.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2298-2298
Author(s):  
Andrea Corbacioglu ◽  
Claudia Scholl ◽  
Karina Eiwen ◽  
Lars Bullinger ◽  
Stefan Frohling ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Residual Disease ◽  
Fusion Transcript ◽  
Prognostic Impact ◽  
Consolidation Therapy ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Transcript Levels ◽  
Minimal Residual

Abstract Detection of minimal residual disease (MRD) in acute myeloid leukemia (AML) associated with specific gene fusions is an important tool for the assessment of response to treatment and the individual risk of relapse. The real-time quantitative RT-PCR (RQ-PCR) method allows the quantification of fusion transcript levels at distinct time points during treatment. While in acute promyelocytic leukemia (APL) MRD monitoring has been clearly shown to be predictive for clinical outcome, the prognostic value of MRD in CBFB-MYH11 AML could not consistently been demonstrated yet. Small patient populations and the availability of bone marrow (BM)/peripheral blood (PB) samples at defined time points mainly hamper most studies. We evaluated the prognostic impact of MRD in a large cohort of CBFB-MYH11 AML by RQ-PCR. A total of 44 patients (16–60 years) were treated within one of the AMLSG treatment trials (AMLHD93 n=4, AMLHD98A n=27, AMLSG07-04 n=13). Patient samples (BM and/or PB) were collected at study entry (n=75), during treatment (n=199), and during follow up (n=140). Following high-dose cytarabine (HiDAC) consolidation therapy, patients received a second course of HiDAC (n=25); autologous stem cell transplantation (SCT) (n=13) or allogeneic SCT from a matched related family donor (n=6) depending on the treatment protocol. Median follow up was 22.5 months. Quantitative CBFB-MYH11 fusion transcript expression was measured by RQ-PCR using TaqMan technology. Primers and probes were chosen according to Europe Against Cancer (EAC) standard protocols. Sensitivities ranged from 10−3 to 10−4.Transcript levels at diagnosis ranged from 6208 to 312987 (median 34293.5). There was no prognostic impact of pretreatment transcript levels on relapse free survival (RFS). The ratio of transcript levels after 2 induction cycles and pretreatment levels ranged from 0 to 0.0049; again, this ratio had no impact on RFS. In contrast, during consolidation therapy 63% of the patients became RQ-PCR negative and RFS was significantly superior (RFS after 2 years 75%) compared to RQ-PCR positive patients (RFS after 2 years 32%) (p=0.03). After consolidation, seven of the RQ-PCR negative patients became positive at least in one BM-sample during follow up. Four patients developed transcript levels above 10 and all relapsed, whereas the three patients with transcript levels remaining below 10 are in continuous remission (p=0.0001). In our study, transcript levels during and after consolidation therapy are significantly associated with clinical outcome in CBFB-MYH11 AML. Risk-adapted therapy may be considered for those patients remaining positive during consolidation therapy. The identification of transcript levels above 10 after consolidation therapy might allow early treatment decisions.

scholarly journals Outcome in Children With Standard-Risk B-Cell Acute Lymphoblastic Leukemia: Results of Children’s Oncology Group Trial AALL0331

2020 ◽  
Vol 38 (6) ◽  
pp. 602-612 ◽  
Author(s):  
Kelly W. Maloney ◽  
Meenakshi Devidas ◽  
Cindy Wang ◽  
Leonard A. Mattano ◽  
Alison M. Friedmann ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Oncology Group ◽  
Free Survival ◽  
Drug Induction ◽  
Cell Acute Lymphoblastic Leukemia ◽  
To Receive ◽  
Standard Risk

PURPOSE Children’s Oncology Group (COG) AALL0331 tested whether intensified postinduction therapy that improves survival in children with high-risk B-cell acute lymphoblastic leukemia (ALL) would also improve outcomes for those with standard-risk (SR) ALL. PATIENTS AND METHODS AALL0331 enrolled 5,377 patients between 2005 and 2010. All patients received a 3-drug induction with dexamethasone, vincristine, and pegaspargase (PEG) and were then classified as SR low, SR average, or SR high. Patients with SR-average disease were randomly assigned to receive either standard 4-week consolidation (SC) or 8-week intensified augmented Berlin-Frankfurt-Münster (BFM) consolidation (IC). Those with SR-high disease were nonrandomly assigned to the full COG-augmented BFM regimen, including 2 interim maintenance and delayed intensification phases. RESULTS The 6-year event-free survival (EFS) rate for all patients enrolled in AALL0331 was 88.96% ± 0.46%, and overall survival (OS) was 95.54% ± 0.31%. For patients with SR-average disease, the 6-year continuous complete remission (CCR) and OS rates for SC versus IC were 87.8% ± 1.3% versus 89.1% ± 1.2% ( P = .52) and 95.8% ± 0.8% versus 95.2% ± 0.8% ( P = 1.0), respectively. Those with SR-average disease with end-induction minimal residual disease (MRD) of 0.01% to < 0.1% had an inferior outcome compared with those with lower MRD and no improvement with IC (6-year CCR: SC, 77.5% ± 4.8%; IC, 77.1% ± 4.8%; P = .71). At 6 years, the CCR and OS rates among 635 nonrandomly treated patients with SR-high disease were 85.55% ± 1.49% and 92.97% ± 1.08%, respectively. CONCLUSION The 6-year OS rate for > 5,000 children with SR ALL enrolled in AALL0331 exceeded 95%. The addition of IC to treatment for patients with SR-average disease did not improve CCR or OS, even in patients with higher MRD, in whom it might have been predicted to provide more value. The EFS and OS rates are excellent for this group of patients with SR ALL, with particularly good outcomes for those with SR-high disease.

scholarly journals Role of Systemic High-Dose Methotrexate and Combined Approaches in the Management of Vitreoretinal Diffuse Large B-Cell Lymphoma: A Single Center Experience 1990-2018

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 574-574
Author(s):  
Alessia Castellino ◽  
Jose Pulido ◽  
Patrick Johnston ◽  
Kay M. Ristow ◽  
Nabila Nora Bennani ◽  
...  
Keyword(s):  
B Cell ◽  
Clinical Characteristics ◽  
Rank Test ◽  
High Dose ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Cns Relapse ◽  
Large B Cell

Abstract Introduction. Vitreoretinal lymphoma (VRL) is a rare ocular malignancy. Diagnosis and optimal treatment remain a challenge for clinicians. We present clinical characteristics and outcome of a cohort of 69 patients affected by vitreoretinal diffuse large B-cell (DLBCL) lymphoma treated at Mayo Clinic over a 28-year period. Methods. We accessed the Mayo Clinic Lymphoma Data Base to identify all patients > 18 years old with VRL diagnosed between 01/01/1990 and 01/31/2018. Only patients with DLBCL, confirmed at pathological review, were included. Clinical characteristics, therapies, response, relapse patterns and follow up status were collected and analyzed in the cohort and in the different subgroups: primary (PVRL, localized only in eye at diagnosis) vs concurrent (CVRL) vs secondary VRL (SVRL). Chi-squared test, Fisher's exact test and Wilcoxon's signed-rank test were used for analysis. Failure-free survival (FFS), overall survival (OS), central nervous system (CNS) and eye relapse-free survival were analyzed according to Kaplan Meier method. Differences between subgroups were compared with log-rank test. Since the group of SVRL can be affected by a survivorship selection bias, it was investigated separately for the outcome analysis. Results. A total of 69 patients with vitreoretinal DLBCL were included. At diagnosis, 33 (48%) were PVRL, 18 (26%) CVRL (eye plus CNS (N=17) or systemic (N=1) disease) and 18 (26%) had SVRL (9 primary CNS lymphomas, 9 systemic at diagnosis, among which 4 were primary testicular lymphomas). Unilateral intraocular involvement was observed in 16 (23%) cases. Clinical characteristics are reported in Table I. At diagnosis, patients received a systemic treatment in 35 (50%, including high-dose systemic MTX (HD-MTX, N 14, 20%), MTR (HD-MTX, Temozolomide and Rituximab) (N 7, 10%) and CHOP (Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) with or without Rituximab (N 10, 15%)), combined systemic plus intraocular treatment in 15 (22%), local radiotherapy in 10 (14%) and intraocular therapy (intraocular injections of rituximab or MTX or steroids or a combination of these) in 9 (13%) cases. Systemic Rituximab, autologous stem cell transplantation (ASCT) and therapeutic vitrectomy/enucleation were performed in 36 (53%), 20 (29%) and 5 (7%) patients, respectively. The median number of treatments was 2 (range 0-10). Among PVRL and CVRL (N=51), median FFS, CNS relapse-free survival, eye relapse-free survival and OS were: 1.8 y, 4.9 y, 3.8 y and 4.1 y, respectively (Fig 1). Among PVRL they were: 2.6 y, not reached (NR), 5.2 y and 9.3 y, respectively. No CNS relapse occurred beyond 4 years in the PVRL subgroup. The median OS for patients diagnosed between 1990 and 1999, in contrast to 2000 and 2018 was 1.5 y vs 9.4 y respectively (p= 0.0002). OS was significantly higher in PVRL, as compared to CVRL (p= 0.04). Previous immunosuppression and poor performance status were predictive of worse outcome (p=0.04), while ASCT correlated with higher OS (p= 0.009). In PVRL, a combined systemic + intraocular therapy was associated with higher FFS (p=0.002) and CNS-relapse free survival (p= 0.003), but no difference in OS was observed. Among 18 SVRL, at a median follow-up of 1.1 y after vitreoretinal relapse, median FFS and OS were 0.3 y and 1.3 y, respectively. Systemic toxicities included 8 (11.6%) acute renal failures, 8 (11.6%) infections, and 3 (4.3%) hemorrhages. Intraocular toxicities included cataract in 11, vitreal detachment in 3 , ocular hypertension in 5, retinal vessel occlusion in 3 and keratitis in 2 cases. Of 69 patients, 39 (56.5%) died secondary to lymphoma (N=21, 53.8%), infectious toxicity (N=2, 5.2%), unrelated (N=3, 7.7%) or unknown (N=13, 33.3%) causes. Conclusions. VR DLBCL is a rare disease, which can occur as primary, concurrent with systemic, or in relapsed disease. OS over the decades has significantly improved. In PVRL, no late CNS relapses were observed, while late intraocular relapses can occur. A combined approach with intraocular + systemic HD-MTX based treatment at diagnosis was associated with a higher FFS and CNS-relapse free survival in PVRL and is recommended in bilateral involvement, even though no differences in OS were observed. Treatment consolidation with ASCT can be considered in cases with concurrent systemic disease. Further studies are needed to confirm these results and to better define the role of new drugs in treatment of this uncommon malignancy. Disclosures Witzig: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals High Level of Successful TKI Discontinuation in Chronic Myeloid Leukemia (CML) Patients: Preliminary Results of AST-Argentina Stop Trial

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-5
Author(s):  
Carolina Pavlovsky ◽  
Ana Ines Varela ◽  
Isolda I. Fernandez ◽  
Maria Belen Sanchez ◽  
Maria Del Rosario Custidiano ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Rank Test ◽  
Molecular Response ◽  
Molecular Monitoring ◽  
Relapse Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Stop Trial ◽  
Tki Treatment

Introduction: Treatment-free remission (TFR) is an emerging treatment goal for chronic myeloid leukemia (CML) patients in deep molecular response (DMR). Current evidence shows that 40%-60% of patients relapse while in TFR; and nearly all regain response once tyrosine kinase inhibitors (TKIs) treatment are reinitiated. However a robust predictor of prolonged TFR has not been reported yet. Considering real-life setting, 2 key factors may affect TFR outcome if not properly done: Access to serial molecular monitoring at optimal timepoints and quality laboratory terms as accuracy, sensitivity and rapid results. This motivated the creation of the AST study in our region to guarantee adequate molecular monitoring for TFR in Argentina and characterize new prognostic biomarkers helpful to identify more accurately patients who will be able to sustain TFR. We aimed to assess the proportion of patients with sustained major molecular response (MMR) after TKIs discontinuation and define precise conditions for stopping treatment. Methods: This prospective, multicentre Argentina Stop Trial (AST) trial is recruiting chronic phase CML patients under TKI treatment for at least ≥ 4 years, in DMR (≥MR4.0) sustained for ≥ 2 years in standardized laboratory, confirmed typical BCR-ABL1 transcripts b3a2 and/or b2a2 and aged &gt; 18 years. Molecular tests are centralized in 2 harmonized laboratories and performed monthly for the first 6 months, every 2 months until the first year, and every 3 months during the second year. If patients lost MMR, TKI was restarted immediately. Molecular relapse Free Survival was estimated by Kaplan-Meier method. Difference between survival variables was evaluated through log-rank test. Multivariate analysis was performed through Cox proportional hazards model. The cutoffs of the numerical variables were considered according to the log-rank test. Results: Between February 2019 and July 2020, we evaluated 50 CML patients of whom 46 were enrolled from 7 centers in Argentina and 4 were screening failures. Recruitment was interrupted due to COVID-19 pandemic. Patient median age was 57.5 years (range 24-85). Before discontinuation, TKI treatment was as follows: Imatinib 37/46 (80%), Nilotinib 5/46 (11%) and Dasatinib 4/46 (9%), 2G-TKI as 1st line, 11% of the patients received non-branded treatment. Sokal risk score showed to be low in 22 patients (48%), intermediate in 14 (30%) and high in 10 (22%). Median follow-up was 10 months (range 4-17) and the estimated molecular relapse-free survival was 80.2% (95%CI 69-93) at 6 months Fig 1. Longer DMR durations before discontinuation were associated with increased probability of maintaining response at 6 and 12 months: 83.2% for patients who had &gt;54 months in DMR vs 70% with &lt;54 months and 72% vs 23.3% respectively (p=0.0453) Fig 2. Cox multivariate analysis was performed including different variables as age at diagnosis, time in DMR, time in TKI previous to discontinuation and Sokal risk. The only significant variable associated to improved prognosis was time in DMR (HR 2.8 95%CI 1.002-8.07 p=0.0495). Our cohort had a long time on TKI treatment previous to discontinuation, median 10.5 years (4.16-17.5) probably considering it a favorable factor for the high TFR rates described at 6 months. Among the 46 patients included, 15 (33%) lost MMR, all restarted treatment with the same TKI used before discontinuation, 12/15 (80%) regained MMR with a median time of 3 months (range1-8) and 9/15(60%) obtained MR 4.0 with a median time of 3 months (range1-5). Conclusion: This is the first multicenter study of TKI discontinuation in CML patients in Argentina showing that TKI can be safely discontinued in those who achieve and maintain a DMR before discontinuation. We observed high rates of molecular relapse free survival, although longer follow-up is needed. We must continue with this approach for patients participating in TFR trials or TFR programs in order to decrease the risk of relapse and make this goal a fact in our region. This discontinuation study will allow in a near future significant saving of economic resources and might improve patients quality of life specially in those who are currently experiencing treatment adverse events. Disclosures Pavlovsky: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Pfizer: Speakers Bureau; Pint Pharma: Speakers Bureau. Varela:Novartis: Consultancy, Speakers Bureau. Pavlovsky:Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Varifarma: Speakers Bureau. Moiraghi:BMS: Speakers Bureau; Novartis: Speakers Bureau.

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