Outcome After First Relapse Or Refractory Acute Lymphoblastic Leukemia In Children From 1996 To 2011 – Comparison Of Two Different Treatment Strategies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3381-3381
Author(s):  
Francesco Ceppi ◽  
Michel Duval ◽  
Caroline Laverdiere ◽  
Jean-Marie Leclerc ◽  
Yveline Delvas ◽  
...  
Keyword(s):  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Treatment Strategies ◽  
Late Relapse ◽  
Induction Treatment ◽  
Unrelated Donor ◽  
Refractory Disease ◽  
Early Relapse ◽  
First Relapse ◽  
Risk Of Relapse

Abstract Introduction Newly diagnosed acute lymphoblastic leukemia (ALL) has achieved a cure rate of 80-85% in developed countries. Nevertheless, up to 20% of patients still relapse or have a refractory disease. Approximately 50% of these patients are long term survivors. In our institution, the strategy for relapsed patients had changed from hematopoietic stem cell transplantation (HSCT) after reinduction to all patients to a more tailored approach, offering HSCT to patients at high risk of relapse (e.g. those relapsing early after or during treatment) or for those with late marrow relapse with a related donor after a re-induction treatment. The aims of this study was to analyse the results of treatment for children with ALL in first relapse or refractory disease and to compare the outcome based on the strategy of treatment: re-induction followed by HSCT for all patients versus re-induction followed by HSCT or chemotherapy according the risk of relapse. Patients and Methods This retrospective study analysed treatment and outcome of children (up to 18 years-old) with a first relapse or refractory ALL treated in a single institution from 1996 until 2011. All patients were previously treated according to DFCI protocol 95, 00 or 05. Two treatment strategies have been used for patients refractory or with marrow relapse. Until 2007, they were all treated with a re-induction treatment (usually the same protocol used as first-line induction) followed by an allogeneic HSCT with a related or unrelated donor once complete remission was attained. Starting from 2007, patients with a late marrow relapse were treated with chemotherapy alone (or with HSCT if an HLA sibling donor was available), and patients refractory or with an early relapse received at least 3 cycles of chemotherapy before HSCT (with a related or unrelated donor), to reduce pre-transplant residual disease. Results 64 patients had been diagnosed with a first relapse (n=55) or refractory (n=11) ALL whereas 453 patients were diagnosed with ALL during this fifteen years period. At first diagnosis, median WBC was 20 x109/L, 54 (84.5%) patients were B-ALL, 21 (33%) had a positive CNS and 26 (40.5%) had a favourable or a normal karyotype. According to risk stratification at first diagnosis, 26 (40.5%), 30 (47%) and 8 (12.5%) patients were classified as standard, high- and very high risk, respectively. Median ages at relapse diagnosis were 5.9 (range 1.3-17.1) for relapsed and 8.4 (range 1.4-18.4) years for refractory patients. At relapse, median WBC was 6 x109/L and 39 (61%), 14 (22%) and 11 (17%) presented with an isolated marrow, combined and extramedullary (EM) relapse, respectively. Median interval between diagnosis and relapse was 32.5 (range 0.6-135.1) months and 11 (17 %) were classified as refractory, 25 (39%) were classified as early relapse (<36 months from diagnosis to relapse) and 28 (44%) as late relapse (≥ 36 months from diagnosis to relapse). Until 2007, 29 (85 %) patients with marrow relapse received an allogeneic HSCT. After 2007, 14 (70%) received an allo-HSCT and 6 (30%) were treated with chemotherapy after induction. Estimated 3-year event-free survival (EFS) for the whole population was 53% (28% for early and 84% for late relapse [p>0.001]). Before and after 2007, estimated 3-year EFS was respectively 46% and 65% (p=0.3). Conclusion Introduction of a more intensive re-induction therapy and the treatment of the late relapse with chemotherapy alone had permitted to improve the survival of children with relapse/refractory leukemia, probably due to a better control of minimal residual disease (MRD). MRD-guided reinduction therapy is currently the standard of care for these patients and new therapeutics approaches are still needed for patients with early relapse. Disclosures: No relevant conflicts of interest to declare.

Evaluation of Minimal Residual Disease (MRD) by Quantification of TEL-AML1 Transcripts Is a Powerful Prognostic Tool in Children with T(12;21) Positive Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 322-322
Author(s):  
Jean-Michel Cayuela ◽  
Paola Ballerini ◽  
Marina Romeo ◽  
Vahid Asnafi ◽  
Marie-Francoise Auclerc ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Decision Making ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Induction Treatment ◽  
Prognostic Tool ◽  
Time Points ◽  
Increased Risk ◽  
Level 2 ◽  
Risk Of Relapse

Abstract TEL-AML1 fusion transcripts are found in 25% of children with B-cell precursor ALL (BCP-ALL). From June 1993 to December 1999, 1195 children with BCP-ALL were included in the FRALLE 93 protocol. Out of these, 792 were evaluated for TEL-AML1 transcript expression. There is no difference in terms of initial features, DFS, EFS, survival between evaluated (792) and non evaluated (403) patients. Out of the 792 pts, 191 (24%) expressed TEL-AML1 transcripts at diagnosis. To assess the potential prognostic value of TEL-AML1 transcripts quantification, we have retrospectively analysed follow up marrow samples using Europe Against Cancer procedures for real time quantitative RT-PCR assay, on ABI PRISM 7700 (2 reference labs) and Light Cycler apparatus (1 reference lab). Out of the 191 TEL-AML1+ve pts, 83 were evaluated for MRD at different time points after induction therapy (median = D41 (34–55) (53 evaluable pts), at D111 (62–158) (62 pts), at D216 (159–325) (33 pts) and at D838 (365–1287) (49 pts). According to normalized Ct values, samples were attributed to 4 MRD level ranging from 0 to 3 and defined as follows: 0: Ct>40 ; 1 : 36<Ct≤40 ; 2 : 33<Ct≤36 ; 3 : Ct≤33, corresponding respectively to undetectable MRD ; MRD<10-4 ; 10-4≤MRD<10-3 ; MRD≥ 10-3, with respect to dilution of REH cDNA. Distribution of pts according to MRD level at different time points after induction treatment are summarized in the following table. Seventeen relapses have occurred at a median time of 41 months (17–73)(bone marrow: 7, BM + other: 5, testis: 3, CNS: 2). A level 2 positivity at the end of induction was associated with an increased risk of relapse of 3.31(95%CI:1.02 – 10.76, p =.047) while level 3 positivity was associated with a relative risk of 9.52 (95%CI: 2.91 – 31.08, p =.0002). Positivity at D111 was associated with an increased risk of relapse of 8.6 (2.0 – 38.5, p = 0.0042), whatever the level. Combination of data obtained at D41 and D111 allows to distinguish 3 subsets of pts with decreasing relapse-free survival: from 97.5% (95%CI: 85–100%) in pts with no positivity at D111 whatever the D41 result, to 75% (95%CI: 58–92%) in pts with MRD +ve at D111 with low level at D41 and 42% (95%CI: 14–69%) in pts with MRD +ve at D111 with level 2 or 3 at D41 (p<.0001). No other prognostic factor was found (age, sex, WBC, D8 steroid response, D21 bone marrow response) which renders the MRD profile unique in this matter. Conclusion: RQ-PCR-based MRD detection is a powerful prognostic tool in TEL-AML1+ve leukemia. Combination of two time points allows a relevant stratification of pts according to the risk of relapse, compatible with clinical decision making towards intensification or deescalation in the setting of controlled trials FU time point Number of pts in MRD classes (number of relapses) 0 1 2 3 Not evaluated D41 27 (3) 11 (2) 10 (4) 5 (4) 30 (4) D111 40 (2) 14 (6) 7 (2) 1 (1) 21 (6) D216 29 (2) 2 (1) 1 (0) 1 (1) 50 (13) D838 47 (8) 1 (0) 1 (1) 0 34 (8)

scholarly journals Dissecting the Outcome Difference Between Children and Adolescents and Young Adults (AYAs) with Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1601-1601
Author(s):  
Julie A. Wolfson ◽  
Joshua Richman ◽  
Canlan Sun ◽  
Wendy Landier ◽  
Karen Leung ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Lymphoblastic Leukemia ◽  
Comprehensive Cancer Center ◽  
Late Relapse ◽  
Duration Of Treatment ◽  
Early Relapse ◽  
Relapse Risk ◽  
Race Ethnicity ◽  
Time Varying Covariates ◽  
Risk Of Relapse

Abstract BACKGROUND: AYAs (15-39y) with ALL have poor survival compared to children (1-14y). Placement on pediatric vs. adult clinical trials has been implicated in these differences, but a more comprehensive approach (sociodemographics, clinical prognostic factors, treatment provider/ intensity) is lacking and needs to be examined in the real world environment. We address this gap by evaluating factors contributing to the inferior outcome in AYA at a granular level. METHODS: The study included242 patients diagnosed with ALL between 1990 and 2010 at age 1-39y and treated at a comprehensive cancer center (irrespective of enrollment on clinical trial). Medical record abstraction yielded the following: Sociodemographics: payor, race/ethnicity, socioeconomic status (SES); Clinical Prognosticators: WBC at diagnosis (<100k vs. ≥100k), time between diagnosis and first clinical remission (1st CR: <5% blasts in marrow); wide temporal span precluded use of contemporary prognosticators across entire cohort; Treatment Approach: combinations of pediatric/adult oncologist and pediatric/adult therapeutic protocol (pediatric MD + pediatric protocol vs. adult MD + adult protocol vs. other); duration of treatment phases (induction, post-induction, maintenance); gaps between phases (>15d); early cessation of therapy. Using Cox regression analyses, time to relapse was evaluated from achievement of 1st CR, and censored at relapse, death, and hematopoietic cell transplantation in 1st CR or date of last contact. Five patients did not enter remission and were excluded from the analysis. We analyzed patients for two patterns of relapse: [1] Early Relapse: From 1st CR (n=237) through planned completion of therapy, with phases of therapy as time-varying covariates; [2] Late Relapse: Patients who completed treatment (n=121) were evaluated from date of last treatment until event/ follow-up. RESULTS: Clinical and demographic characteristics were similar between AYAs (n=142) and children (n=95) [non-white race/ethnicity: 67% vs. 66%, p=0.9; public insurance: 39% vs. 34%, p=0.4; WBC>100K 27% vs. 20%, p=0.2; median time to remission: 31d vs. 31d, p=0.91). However, AYAs received fewer months of maintenance therapy than children (median=14.9m vs 24.8m, p<0.001). AYAs experienced poorer relapse-free survival (5y RFS: 46%, 95%CI 38-55%) vs. children (72%, 95%CI 63-80%; p<0.001) (Figure) Early Relapse: Compared with children, AYAs had a 6-fold higher risk of relapse (HR=6.0, 95%CI 3.2-11.3, p<0.001). In a multivariable model (adjusting for gender, race/ ethnicity, payor, WBC, time to 1st CR, gaps in treatment, early cessation of therapy and physician/ therapy), the risk of relapse was partially mitigated, (HR=3.8, 95%CI 1.6-9.4, p=0.003). Other variables independently associated with relapse included months to 1st CR (HR=2.1, 95%CI 1.4-3.0, p<0.001); treatment gap (HR=5.8, 95%CI 2.4-14.3, p<0.001); early cessation of therapy (HR=3.6, 95%CI 1.2-11.4, p=0.03); and high WBC (HR=2.0, 95%CI 1.2-3.5, p=0.01). Late Relapse: In patients who completed therapy (n=121), multivariable analysis revealed a higher risk of relapse (HR=2.9, 95%CI 0.9-9.1, p=0.07) for AYAs, adjusting for gender, race/ ethnicity, payor, SES, duration of treatment phases, high WBC, time to achieve remission and physician/ therapy. The only other variable associated with relapse risk was duration of maintenance in months; longer duration of maintenance was protective (HR=0.9, 95%CI 0.8-0.95, p<0.001). CONCLUSIONS: Several factors explain, in part, the poor early outcome among AYAs, including longer time to remission, longer gaps between phases and early cessation of therapy. Among those who complete all phases of therapy, AYAs continue to have inferior outcomes, but the magnitude of difference is reduced, and duration of maintenance therapy remains the critical independent predictor of relapse risk. These findings highlight the need to elucidate the remaining factors that could explain the difference in outcome between AYAs and children, such as host and disease biology, and adherence to prescribed therapy; these are currently under investigation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Long-term Outcome of Children with Acute Lymphoblastic Leukemia Treated with IC-BFM2002 Regimen

2021 ◽  
pp. 87-95
Author(s):  
Gholamreza Bahoush
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Recurrence Rate ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Late Relapse ◽  
Long Term Outcome ◽  
Early Relapse ◽  
Group A ◽  
Group B

Background: Changes in pediatric chemotherapy regimens over the last three decades have introduced a variety of protocols to increase the survival of patients with acute lymphoblastic leukemia (ALL). Intercontinental Berlin-Frankfort-Munich (IC-BFM) 2002 is one of the protocols widely used in countries that could not perform minimal residual disease by polymerase chain reaction (MRD PCR) method. Evaluation the results of these regimens is very effective in improving their quality. Materials and Methods: Children with newly diagnosed ALL in Ali Asghar Children's Hospital were randomly divided into two groups. Patients in both groups underwent chemotherapy according to IC-BFM 2002 protocol. Patients were divided into two groups based on the type of reinduction regimen, so that patients in-group A received protocol II and patients in-group B received protocol III as a reinduction regimen. Then demographic information and patient outcome were statistically analyzed with SPSS 23. Results: Sixty-three patients were included in the study. There were 32 patients in-group A (18 boys and 14 girls) and 31 patients in-group B (11 boys and 20 girls). The number of high-risk patients was higher in-group A, but this difference was not statistically significant. The recurrence rate in-group B patients was about seven times higher than the recurrence rate in group A patients, and this difference was statistically significant. In-group A, no patients had an early relapse, while about half of the recurrences in-group B occurred as early relapse and the rest as late relapse. CNS recurrence occurred in only two patients. 5-yr EFS of all enrolled patients was 88.90 ± 8.00% (95% CI). This rate for group A and B was 96.90 ± 6.20% (95% CI) and 80.60 ± 14.20% (95% CI), respectively (P=0.022). Conclusion: It seems that IC-BFM 2002 protocol is an appropriate treatment regimen with acceptable results for children with ALL in developing countries, a workable protocol with significant consequences. Protocol II seems to be suitable for reinduction and increasing the Methotrexate dose may not be necessary for non-high-risk groups.

scholarly journals Minimal Residual Disease and IKZF1 As Predictors of Relapse, and Increased Treatment Related Mortality in Down Syndrome Acute Lymphoblastic Leukemia: A Unique and Large International Matched Case-Control Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 827-827
Author(s):  
Naomi Michels ◽  
Judith M. Boer ◽  
Marta Lopez-Yurda ◽  
Hester A. De Groot-Kruseman ◽  
Vincent van der Velden ◽  
...  
Keyword(s):  
Research Funding ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Induction Treatment ◽  
Free Survival ◽  
Minimal Residual ◽  
Risk Of Relapse ◽  
Treatment Related Mortality ◽  
Related Mortality

INTRODUCTION Down syndrome patients with acute lymphoblastic leukemia (DS ALL) are less likely to have a favorable (cyto)genetic subtype and are at higher risk of relapse and treatment-related mortality (TRM) than non-DS ALL (Buitenkamp et al., Blood 2014). At present, the independent predictive value of minimal residual disease (MRD) is unclear and may be biased by an unequal distribution of (cyto)genetic risk groups among DS ALL and non-DS ALL patients. This study was aimed to decipher the prognostic implications of MRD and IKZF1 deletions and the frequency of TRM in a matched cohort of DS ALL cases and non-DS ALL controls. METHODS Each DS ALL patient was matched to 3 non-DS ALL patients based on treatment protocol, induction treatment, cytogenetic subtype, IKZF1 status, age (cutoff at 10 years), and white blood cell count (cutoff at 50,000 cells/µl). For MRD analysis, matching was only on induction treatment and excluded the MRD-guided treatment arm; for survival analyses, matching included the MRD-guided treatment arm, thus resulting in two separately matched cohorts. Patients who died during induction were excluded from matching. Absolute MRD levels were measured with RQ-PCR, log-transformed and analyzed with a multilevel mixed-effects linear regression model. Matched Cox proportional hazard regression models were used to analyze event-free survival (EFS), overall-survival (OS), relapse-free survival (RFS) and mortality in remission as surrogate for TRM. RESULTS Patients treated between 2002 and 2018 on Dutch DCOG-ALL10/11 trials, Australian ANZCHOG-ALL8 and AIEOP-BFM-ALL2009 trials, and UKALL2003 trial were included, resulting in 160 DS ALL and 5313 non-DS ALL patients. Out of these 160 DS ALL patients, 13 died during induction versus 42/5313 non-DS ALL patients (8.1% versus 0.8%, p&lt;0.0001). Exclusion of induction deaths and patients with missing IKZF1 or MRD data, resulted in 110 DS ALL matched to study MRD differences (1 DS ALL could not be matched and was excluded), and 93 DS ALL matched to analyze survival (ALL11 was excluded due to short follow-up; 3 DS ALL could not be matched and were excluded). In the matched cohort, 22% (24/110) had favorable cytogenetics, 19% (21/110) had an IKZF1 deletion, 26% (29/110) were ≥10 years, and 17% (19/110) had a WBC ≥50,000 cells/µl. Only 3 cases (2 DS, 1 non-DS) did not achieve complete remission (excluding induction deaths). Median follow-up time of survivors was 7.1 years. The MRD levels did not differ between DS ALL and matched non-DS ALL patients at end of induction (p=0.96) nor when analyzed over time (p=0.43). In accordance, the 5-yr RFS did not differ between DS ALL and matched non-DS ALL patients (85 ± 4% versus 89 ± 2%, p=0.09). The 5-yr TRM of patients in remission was higher in DS ALL compared to non-DS ALL (11 ± 3% versus 3 ± 1%, p=0.001). In line, 5-yr EFS was lower in DS ALL compared to non-DS ALL patients (74 ± 5% versus 86 ± 2%, p=0.0007), as was 5-yr OS (77 ± 5% versus 93 ± 2%, p=0.0001). Multivariable analysis revealed that IKZF1 deletion can discriminate DS ALL patients at high risk of relapse (RFS: HR&gt;3, 95% CI=1-12, p=0.05). The effect of IKZF1 deletion was stronger in DS ALL patients than in the non-DS ALL patients in our cohort. CONCLUSION The MRD levels did not differ between DS ALL and non-DS ALL patients when matched for (cyto)genetics and other risk factors. In accordance, the overall relapse rate of DS ALL patients did not differ from that of matched non-DS ALL patients. Similar to non-DS ALL, IKZF1 deletion is an adverse risk factor for DS-ALL, indicating the need for treatment aimed at reducing the high relapse risk. DS ALL patients suffer more frequently from death in induction and from treatment while in remission, which jeopardizes treatment intensification. Therefore, the efficacy of targeted, less toxic therapies such as immunotherapies should be assessed in DS ALL. Disclosures van der Velden: Jansen: Research Funding; BD Biosciences: Research Funding; Amgen: Honoraria, Research Funding. Pieters:jazz farmaceuticals: Consultancy; medac: Consultancy. Zwaan:Celgene: Consultancy, Research Funding; Pfizer: Research Funding; BMS: Research Funding; Janssen: Consultancy; Servier: Consultancy; Roche: Consultancy; Incyte: Consultancy; Sanofi: Consultancy; Jazz Pharmaceuticals: Other: Travel support; Daiichi Sankyo: Consultancy.

scholarly journals Advances in the Diagnosis and Treatment of Pediatric Acute Lymphoblastic Leukemia

2021 ◽  
Vol 10 (9) ◽  
pp. 1926
Author(s):  
Hiroto Inaba ◽  
Ching-Hon Pui
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Detailed Analysis ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Treatment Strategies ◽  
Chemotherapeutic Agents ◽  
Response To Treatment ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Therapeutic Implications

The outcomes of pediatric acute lymphoblastic leukemia (ALL) have improved remarkably during the last five decades. Such improvements were made possible by the incorporation of new diagnostic technologies, the effective administration of conventional chemotherapeutic agents, and the provision of better supportive care. With the 5-year survival rates now exceeding 90% in high-income countries, the goal for the next decade is to improve survival further toward 100% and to minimize treatment-related adverse effects. Based on genome-wide analyses, especially RNA-sequencing analyses, ALL can be classified into more than 20 B-lineage subtypes and more than 10 T-lineage subtypes with prognostic and therapeutic implications. Response to treatment is another critical prognostic factor, and detailed analysis of minimal residual disease can detect levels as low as one ALL cell among 1 million total cells. Such detailed analysis can facilitate the rational use of molecular targeted therapy and immunotherapy, which have emerged as new treatment strategies that can replace or reduce the use of conventional chemotherapy.

scholarly journals Marrow Transplants From Unrelated Donors for Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1410-1414 ◽  
Author(s):  
Jorge Sierra ◽  
Jerry Radich ◽  
John A. Hansen ◽  
Paul J. Martin ◽  
Effie W. Petersdorf ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Early Stage ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Unrelated Donor ◽  
Effective Treatment Option ◽  
Patients At Risk ◽  
Unrelated Donors ◽  
First Relapse ◽  
Philadelphia Chromosome Positive

Transplantation of marrow from unrelated donors was investigated in patients with Philadelphia chromosome-positive (Ph1+) acute lymphoblastic leukemia (ALL) who lacked a suitable family donor. Eighteen patients underwent transplantation at our center between 1988 and 1995. The median patient age was 25 years (range, 1.7 to 51 years). Seven patients were in first complete remission, 1 in second remission, 3 in first relapse, and the remaining 7 had more advanced or chemotherapy refractory leukemia at transplant. All patients were conditioned with cyclophosphamide and total body irradiation followed by marrow transplants from closely HLA-matched, unrelated volunteers. Posttransplant graft-versus-host disease (GVHD) prophylaxis included methotrexate with either cyclosporine or FK506. Graft failure was not observed. Severe (grades III-IV) GVHD appeared in 6 of 17 evaluable patients and chronic extensive GVHD in 7 of 13 patients at risk. Five patients had recurrent ALL after transplantation and another 4 died from causes other than leukemia. Six patients transplanted in first remission, 2 in first relapse, and 1 in second remission remain alive and leukemia-free at a median follow-up of 17 months (range, 9 to 73 months). The probability of leukemia-free survival at 2 years is 49% ± 12%. These data indicate that unrelated donor marrow transplantation is an effective treatment option for patients with early stage Ph1+ ALL without a family match and suggest that in such patients an unrelated donor search should be initiated as soon as possible after diagnosis.

scholarly journals PROGNOSTIC SIGNIFICANCE AND TREATMENT IMPLICATIONS OF MINIMAL RESIDUAL DISEASE STUDIES IN PHILADELPHIA-NEGATIVE ADULT ACUTE LYMPHOBLASTIC LEUKEMIA

2014 ◽  
Vol 6 (1) ◽  
pp. e2014062 ◽  
Author(s):  
Orietta Spinelli ◽  
Manuela Tosi ◽  
Barbara Peruta ◽  
Marie Lorena Guinea Montalvo ◽  
Elena Maino ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Adult Acute Lymphoblastic Leukemia ◽  
Cure Rates ◽  
Sensitive Individual ◽  
Minimal Residual ◽  
Risk Of Relapse

Acute lymphoblastic leukemia (ALL) is curable in about 40-50% of adult patients, however this is subject to ample variations owing to several host- and disease-related prognostic characteristics. Currently, the study of minimal residual disease (MRD) following induction and early consolidation therapy stands out as the most sensitive individual prognostic marker to define the risk of relapse following the achievement of remission, and ultimately that of treatment failure or success. Because substantial therapeutic advancement is now being achieved using intensified pediatric-type regimens, MRD analysis is especially useful to orientate stem cell transplantation choices. These strategic innovations are progressively leading to greater than 50% cure rates. 

scholarly journals Comparing transplant outcomes in ALL patients after haploidentical with PTCy or matched unrelated donor transplantation

2020 ◽  
Vol 4 (9) ◽  
pp. 2073-2083 ◽  
Author(s):  
Monzr M. Al Malki ◽  
Dongyun Yang ◽  
Myriam Labopin ◽  
Boris Afanasyev ◽  
Emanuele Angelucci ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Philadelphia Chromosome ◽  
Disease Stage ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Gvhd Prophylaxis ◽  
Conditioning Intensity

Abstract We compared outcomes of 1461 adult patients with acute lymphoblastic leukemia (ALL) receiving hematopoietic cell transplantation (HCT) from a haploidentical (n = 487) or matched unrelated donor (MUD; n = 974) between January 2005 and June 2018. Graft-versus-host disease (GVHD) prophylaxis was posttransplant cyclophosphamide (PTCy), calcineurin inhibitor (CNI), and mycophenolate mofetil (MMF) for haploidentical, and CNI with MMF or methotrexate with/without antithymoglobulin for MUDs. Haploidentical recipients were matched (1:2 ratio) with MUD controls for sex, conditioning intensity, disease stage, Philadelphia-chromosome status, and cytogenetic risk. In the myeloablative setting, day +28 neutrophil recovery was similar between haploidentical (87%) and MUD (88%) (P = .11). Corresponding rates after reduced-intensity conditioning (RIC) were 84% and 88% (P = .47). The 3-month incidence of grade II-IV acute GVHD (aGVHD) and 3-year chronic GVHD (cGVHD) was similar after haploidentical compared with MUD: myeloablative conditioning, 33% vs 34% (P = .46) for aGVHD and 29% vs 31% for cGVHD (P = .58); RIC, 31% vs 30% (P = .06) for aGVHD and 24% vs 29% for cGVHD (P = .86). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 44% and 51% with haploidentical and MUD (P = .56). Corresponding rates after RIC were 43% and 42% (P = .6). In this large multicenter case-matched retrospective analysis, despite the limitations of a registry-based study (ie, unavailability of key elements such as minimal residual disease testing), our analysis indicated that outcomes of patients with ALL undergoing HCT from a haploidentical donor were comparable with 8 of 8 MUD transplantations.

scholarly journals Flow cytometric evaluation of CD38 expression levels in the newly diagnosed T-cell acute lymphoblastic leukemia and the effect of chemotherapy on its expression in measurable residual disease, refractory disease and relapsed disease: an implication for anti-CD38 immunotherapy

2020 ◽  
Vol 8 (1) ◽  
pp. e000630
Author(s):  
Prashant Ramesh Tembhare ◽  
Harshini Sriram ◽  
Twinkle Khanka ◽  
Gaurav Chatterjee ◽  
Devasis Panda ◽  
...  
Keyword(s):  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cytotoxic Chemotherapy ◽  
Refractory Disease ◽  
Cd38 Expression ◽  
Flow Cytometric ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Relapsed Disease ◽  
Flow Cytometric Evaluation ◽  
Measurable Residual Disease

BackgroundRecently, anti-CD38 monoclonal antibody (Mab) therapy has become a focus of attention as an additional/alternative option for many hematological neoplasms including T-cell acute lymphoblastic leukemia (T-ALL). It has been shown that antitumor efficacy of anti-CD38-Mab depends on the level of CD38 expression on tumor cells. Reports on CD38 expression in T-ALL are scarce, and data on the effect of cytotoxic chemotherapy on CD38 expression are limited to very few samples. Moreover, it lacks entirely in refractory disease and in adult T-ALL. We report the flow cytometric evaluation of CD38 expression in T-ALL blasts at diagnosis and the effect of cytotoxic chemotherapy on its expression in measurable residual disease (MRD), refractory disease (MRD≥5%), and relapsed disease in a large cohort of T-ALL.MethodsThe study included 347 samples (188 diagnostic, 100 MRD, 24 refractory and 35 relapse samples) from 196 (children: 85; adolescents/adults: 111) patients with T-ALL. CD38-positive blasts percentages (CD38-PBPs) and expression-intensity (mean fluorescent intensity, CD38-MFI) were studied using multicolor flow cytometry (MFC). MFC-based MRD was performed at the end-of-induction (EOI-MRD, day 30–35) and end-of-consolidation (EOC-MRD, day 78–85) subsequent follow-up (SFU-MRD) points.ResultsPatients were classified into early thymic precursor subtype of T-ALL (ETPALL, 54/188, 28.7%), and non-ETPALL (134/188, 71.3%). Of 188, EOI-MRD assessment was available in 152, EOC-MRD was available in 96 and SFU-MRD was available in 14 patients. CD38 was found positive in 97.9% (184/188) of diagnostic, 88.7% (110/124) MRD (including 24-refractory) and 82.9% (29/35) relapsed samples. Median (95% CI) of CD38-PBPs/MFI in diagnostic, MRD, refractory, and relapsed T-ALL samples were, respectively, 85.9% (82.10%–89.91%)/4.2 (3.88–4.47), 74.0% (58.87%–83.88%)/4.6 (3.67–6.81), 79.6% (65.25%–96.11%)/4.6 (3.33–8.47) and 85.2% (74.48%–93.01%)/5.6 (4.14–8.99). No significant difference was noted in CD38 expression between pediatric versus adult and patients with ETPALL versus non-ETPALL. No change was observed in CD38-MFI between diagnostic versus MRD and diagnostic versus relapsed paired samples. However, we noticed a mild drop in the CD38-PBPs in MRD samples compared with the diagnostic samples (p=0.016).ConclusionWe report an in-depth analysis of CD38 expression in a large cohort of T-ALL at diagnosis, during chemotherapy, and at relapse. Our data demonstrated that CD38 is robustly expressed in T-ALL blasts with a little effect of cytotoxic chemotherapy making it a potentially effective target for antiCD38-Mab therapy.

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