Residual disease at the end of induction therapy as a predictor of relapse during therapy in childhood B-lineage acute lymphoblastic leukemia.

1992 ◽  
Vol 10 (12) ◽  
pp. 1879-1888 ◽  
Author(s):  
R Wasserman ◽  
N Galili ◽  
Y Ito ◽  
J H Silber ◽  
B A Reichard ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Induction Therapy ◽  
Clinical Remission ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Induction Phase ◽  
Increased Risk ◽  
B Lineage ◽  
Wbc Count

PURPOSE More than 95% of children with B-lineage acute lymphoblastic leukemia (ALL) achieve a clinical remission after the induction phase of chemotherapy (first 28 days) as evaluated by morphologic criteria. However, relapse occurs in approximately 30% of these children. The objective of this study was to determine whether the outcome of patients in clinical remission at the end of induction therapy could be predicted using a highly sensitive method to detect residual disease. PATIENTS AND METHODS All children diagnosed with B-lineage ALL at the Children's Hospital of Philadelphia during a 2-year period were eligible. The extent of residual leukemia was quantitated in remission marrow samples obtained at the end of induction therapy in 44 children using a phage clonogenic assay in association with complementarity-determining-region 3 (CDR3)-polymerase chain reaction (PCR). RESULTS Residual disease was a significant predictor of outcome independent of WBC count, age, or sex. The estimated relapse-free survival (RFS) during therapy was 50.4% (+/- 12.6%) for patients with high residual disease (> or = 0.6% leukemia cells among total marrow B cells) versus 91.9% (+/- 5.5%) for those with lower levels (P < .002). There were no significant differences in off-treatment RFS between patients with high or low residual disease who completed therapy in continuous remission (P = .82). The overall estimated RFS was 32.3% (+/- 11.6%) for patients with high residual disease versus 62.6% (+/- 10.7%) for patients with lower levels of residual leukemia cells, with a median follow-up of 5.3 years for patients in continuous remission (P < .008). CONCLUSION PCR detection of high residual disease at the end of induction therapy identifies patients at increased risk for relapse during therapy.

scholarly journals Obesity is associated with residual leukemia following induction therapy for childhood B-precursor acute lymphoblastic leukemia

Blood ◽  
2014 ◽  
Vol 124 (26) ◽  
pp. 3932-3938 ◽  
Author(s):  
Etan Orgel ◽  
Jonathan Tucci ◽  
Waseem Alhushki ◽  
Jemily Malvar ◽  
Richard Sposto ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Induction Therapy ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Increased Risk ◽  
Key Points ◽  
Minimal Residual

Key Points Obesity is associated with increased risk for persistent minimal residual disease after induction therapy for pediatric BP-ALL.

Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2691-2696 ◽  
Author(s):  
Elaine Coustan-Smith ◽  
Jose Sancho ◽  
Michael L. Hancock ◽  
James M. Boyett ◽  
Frederick G. Behm ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Induction Therapy ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Induction Phase ◽  
Continuation Therapy ◽  
Flow Cytometric ◽  
Minimal Residual

Abstract By using rapid flow cytometric techniques capable of detecting one leukemic cell in 104 normal cells, we prospectively studied minimal residual disease (MRD) in 195 children with newly diagnosed acute lymphoblastic leukemia (ALL) in clinical remission. Bone marrow aspirates (n = 629) were collected at the end of remission induction therapy and at 3 intervals thereafter. Detectable MRD (ie, ≥0.01% leukemic mononuclear cells) at each time point was associated with a higher relapse rate (P &lt; .001); patients with high levels of MRD at the end of the induction phase (≥1%) or at week 14 of continuation therapy (≥0.1%) had a particularly poor outcome. The predictive strength of MRD remained significant even after adjusting for adverse presenting features, excluding patients at very high or very low risk of relapse from the analysis, and considering levels of peripheral blood lymphoblasts at day 7 and day 10 of induction therapy. The incidence of relapse among patients with MRD at the end of the induction phase was 68% ± 16% (SE) if they remained with MRD through week 14 of continuation therapy, compared with 7% ± 7% if MRD became undetectable (P = .035). The persistence of MRD until week 32 was highly predictive of relapse (all 4 MRD+patients relapsed vs 2 of the 8 who converted to undetectable MRD status; P = .021). Sequential monitoring of MRD by the method described here provides highly significant, independent prognostic information in children with ALL. Recent improvements in this flow cytometric assay have made it applicable to more than 90% of all new patients.

Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2691-2696 ◽  
Author(s):  
Elaine Coustan-Smith ◽  
Jose Sancho ◽  
Michael L. Hancock ◽  
James M. Boyett ◽  
Frederick G. Behm ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Induction Therapy ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Induction Phase ◽  
Continuation Therapy ◽  
Flow Cytometric ◽  
Minimal Residual

By using rapid flow cytometric techniques capable of detecting one leukemic cell in 104 normal cells, we prospectively studied minimal residual disease (MRD) in 195 children with newly diagnosed acute lymphoblastic leukemia (ALL) in clinical remission. Bone marrow aspirates (n = 629) were collected at the end of remission induction therapy and at 3 intervals thereafter. Detectable MRD (ie, ≥0.01% leukemic mononuclear cells) at each time point was associated with a higher relapse rate (P < .001); patients with high levels of MRD at the end of the induction phase (≥1%) or at week 14 of continuation therapy (≥0.1%) had a particularly poor outcome. The predictive strength of MRD remained significant even after adjusting for adverse presenting features, excluding patients at very high or very low risk of relapse from the analysis, and considering levels of peripheral blood lymphoblasts at day 7 and day 10 of induction therapy. The incidence of relapse among patients with MRD at the end of the induction phase was 68% ± 16% (SE) if they remained with MRD through week 14 of continuation therapy, compared with 7% ± 7% if MRD became undetectable (P = .035). The persistence of MRD until week 32 was highly predictive of relapse (all 4 MRD+patients relapsed vs 2 of the 8 who converted to undetectable MRD status; P = .021). Sequential monitoring of MRD by the method described here provides highly significant, independent prognostic information in children with ALL. Recent improvements in this flow cytometric assay have made it applicable to more than 90% of all new patients.

scholarly journals In vitro and in vivo activity of topotecan against human B-lineage acute lymphoblastic leukemia cells

Blood ◽  
1995 ◽  
Vol 85 (10) ◽  
pp. 2817-2828 ◽  
Author(s):  
FM Uckun ◽  
CF Stewart ◽  
G Reaman ◽  
LM Chelstrom ◽  
J Jin ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Topoisomerase I ◽  
Drug Exposure ◽  
Lymphoblastic Leukemia ◽  
Severe Combined Immunodeficiency ◽  
Water Soluble ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
B Lineage

Topotecan [(S)-9-dimethylaminomethyl-10-hydroxycamptothecin hydrochloride; SK&F 104864-A, NSC 609699], a water soluble semisynthetic analogue of the alkaloid camptothecin, is a potent topoisomerase I inhibitor. Here we show that topotecan stabilizes topoisomerase I/DNA cleavable complexes in radiation-resistant human B-lineage acute lymphoblastic leukemia (ALL) cells, causes rapid apoptotic cell death despite high-level expression of bcl-2 protein, and inhibits ALL cell in vitro clonogenic growth in a dose-dependent fashion. Furthermore, topotecan elicited potent antileukemic activity in three different severe combined immunodeficiency (SCID) mouse models of human poor prognosis ALL and markedly improved event-free survival of SCID mice challenged with otherwise fatal doses of human leukemia cells at systemic drug exposure levels that can be easily achieved in children with leukemia.

scholarly journals Prospective monitoring and quantitation of residual blasts in childhood acute lymphoblastic leukemia by polymerase chain reaction study of delta and gamma T-cell receptor genes

Blood ◽  
1994 ◽  
Vol 83 (7) ◽  
pp. 1892-1902 ◽  
Author(s):  
H Cave ◽  
C Guidal ◽  
P Rohrlich ◽  
MH Delfau ◽  
A Broyart ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell Receptor ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Chain Reaction ◽  
Polymerase Chain ◽  
B Lineage ◽  
Minimal Residual

Abstract We have developed a strategy based on polymerase chain reaction (PCR) for detecting all possible gamma T-cell receptor (gamma TCR) rearrangements and the most common delta TCR rearrangements found in B- lineage and T-acute lymphoblastic leukemia (T-ALL). The segments amplified from blasts are then directly sequenced to derive clonospecific probes. From a series of 45 patients aged 1 to 15 years (42 B-lineage ALL, 3 T-ALL), 35 (83%) could be followed for minimal residual disease with at least one clonospecific probe. Detection of clonal markers using clonospecific probes routinely allowed the detection of 1 to 10 blasts out of 10(5) cells as determined by serial dilutions of the initial samples. Residual disease was quantitated by a competitive PCR assay based on the coamplification of an internal standard. Twenty children were prospectively followed for periods varying from 7 to 30 months. In most children, a progressive decrease of the tumor load was observed, and blasts became undetectable within 6 months after the initiation of treatment. A slower kinetics of decrease in tumor cells was found in three children. These three patients relapsed with blasts that continued to display the initial clonospecific markers. Three other children had a central nervous system relapse despite the absence of detectable medullary residual disease. The use of both delta and gamma TCR genes as clonal markers, as well as simplification in the methods to detect and quantify residual blasts reported here, will allow the study of the large number of patients required to determine the role of the detection of minimal residual disease by PCR in the follow-up of childhood ALL.

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