Patterns of Individual Tumor Response Testing (ITRT) and Bone Marrow Minimal Residual Disease (MRD) On Day 15 of Therapy in Childhood Precursor-B-Lineage Acute Lymphoblastic Leukemia (ALL): MRD and Ex Vivo Drug Resistance Have Similar Predictive Value of Relapse.

Abstract Abstract 2448 Introduction: The speed of blast clearance during therapy is a major prognostic factor of outcome in childhood acute lymphoblastic leukemia (ALL). Blast count in the peripheral blood on day 8, or in the bone marrow on day 15 and day 33, have been widely used to deliver risk-directed therapy. Another approach to measure the speed of leukemia clearance is the detection of minimal residual disease during induction therapy, as well as at days 33 and 78 of therapy. In vitro measurements of drug resistance (called recently as ITRT, individual tumor resistance testing) in leukemic cells obtained at diagnosis have been of prognostic significance in the prediction of clinical outcome in selected groups of patients. Objective: The analysis of the prognostic impact of (A) residual disease (MRD) at day 15 of induction therapy; (B) in vitro drug resistance at diagnosis (ITRT), (C) correlation of MRD and ITRT, and (D) multivariate analysis of prognostic role of MRD, ITRT, initial factors and initial therapy response to the risk of relapse. Patients and Methods: A total number of 87 children (aged 1–18 years) diagnosed for pre-B-ALL, treated either with ALL-BMF-90 or ALL-IC-2002 protocol were included into the study. ITRT was tested at diagnosis by the MTT assay. Residual disease at day 15 was measured by flow cytometry and determined for cut-off value BML15<0.5%. The median follow-up was 8.9 yrs (range, 0–11.5). Following drugs were tested: prednisolone, dexamethasone, vincristine, L-asparaginase, daunorubicin, doxorubicin, etoposide and cytarabine. PVA score was determined as combined ITRT profile to prednisolone, vincristine and L-asparaginase. Results: (A) The overall pDFS was 0.721±0.052 and the mean survival 9.1 yrs (95%CI=8.2–9.9). Patients with BML15<0.5% had pDFS=0.816±0.055, while those with BML15>0.5% had pDFS=0.542±0.098 (p=0.009, log-rank). The risk of relapse in BML15-positive patients was 3.0-fold higher (1.3–7.1, p=0.013). (B) pDFS was significantly better for patients with sensitive ITRT profile to: PVA (1.00±0.00 vs 0.61±0.06, p=0.002), prednisolone (0.89±0.05 vs 0.54±0.08, p=00002), vincristine (0.84±0.06 vs 0.61±0.08, p=0.035), daunorubicin (0.094±0.04 vs 0.51±0.08, p=0.00002), and L-asparaginase (0.84±0.06 vs 0.59±0.08, p=0.009). In multivariate analysis in Cox model, the prognostic value was retained only for ITRT for prednisolone (p=0.013, HR=0.08, 95%CI=0.01–0.6) and daunorubicin (p=0.004, HR=0.05, 95%CI=0.01–0.4), while ITRT for PVA score was below of significance (p=0.068, HR=0.03, 95%CI=0.01–1.3). (C) Patients with MRD-positive ALL at day 15 (BML15>0.5%) had higher ITRT for following drugs: doxorubicin (p=0.005, RR=1.8, Mann-Whitney U test), L-asparaginase (p=0.029, RR=3.2), and etoposide (p=0.055, RR=4.1), while no differences were found for other drugs. In multivariate logistic regression, the significance impact to development of BML15>0.5% was found for doxorubicin (p=0.035, OR=0.33) and etoposide (p=0.048, OR=0.14). (D) In multivariate analysis in Cox model for relapse risk, three factors had predictive value: BML15>0.5% (p=0.010, OR=3.3, 95%CI=1.3–8.2), ITRT for prednisolone (p=0.012, OR=4.4, 95%CI=1.4–13) and ITRT for daunorubicin (p=0.018, OR=5.9, 95%CI=1.4–26), while age, prednisolone-poor-response at day 8, BM response at day 15, BM response at day 33, and BCR-ABL rearrangement had no significant value. Conclusions: Patients with residual disease at day 15 had 3-fold higher risk of relapse. Patients with resistant ITRT profile to prednisolone and daunorubicin had respectively 12- and 20-fold higher risk of relapse. Presence of residual blasts at day 15 correlates with ITRT to etoposide and doxorubicin. Finally, persistence of blast in marrow at day 15 (BML15>0.5%) and ex vivo drug resistance (ITRT) to prednisolone and to daunorubicin were the strongest prognostic factors predicting relapse in childhood ALL. Disclosures: No relevant conflicts of interest to declare.

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Identification Of Low Risk Group In Infants With Acute Lymphoblastic Leukemia By Flow Cytometric Minimal Residual Disease Measurement At Day 15 Of Interfant-99 and Interfant-06 Protocols Treatment

Blood ◽

10.1182/blood.v122.21.1333.1333 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1333-1333

Author(s):

Alexander Popov ◽

Barbara Buldini ◽

Paola de Lorenzo ◽

Emanuella Giarin ◽

Annamaria Di Meglio ◽

...

Keyword(s):

Residual Disease ◽

Risk Group ◽

Cox Model ◽

Lymphoblastic Leukemia ◽

Low Risk ◽

Older Children ◽

Flow Cytometric ◽

Minimal Residual ◽

Risk Of Relapse

Abstract Background Acute lymphoblastic leukemia (ALL) in infants is a relatively rare disease with peculiar biological features and worse outcome in comparison to ALL in older children. Infant ALL is characterized by a high frequency of MLL gene rearrangements, mainly CD10-negative B-cell precursor ALL (BCP-ALL) immunophenotype and high tumor burden at diagnosis. Even with new therapeutic approaches event-free survival (EFS) in this subgroup of patients does not exceed 50%. Although flow cytometric (FCM) minimal residual disease (MRD) detection at day 15 of remission induction is well established for patients' stratification in older children treated with the AIEOP-BFM-2009 protocol, the prognostic value of FCM MRD in infant ALL is not fully known yet. Aim of the present study was to evaluate the prognostic significance of FCM MRD measurement in infants with ALL treated with Interfant-99 and Interfant-06 protocols in AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) centers in Italy. Patients and methods Between May 1999 and December 2011, 120 consecutive infants aged 0 to 365 days with newly diagnosed ALL were treated in AIEOP centers with the Interfant99 and the on-going Interfant-06 protocols. Among these patients, 51 (42.5%) with available day 15 follow-up bone marrow samples were included in this study on FCM MRD. In 39 (76.5%) cases, different types of MLL gene rearrangements were identified by fluorescence in situ hybridization (FISH), while 12 (23.5%) patients had germline MLL. MRD detection was performed by 4-6-color FCM. Median follow-up time was 3.5 years (range: 1 month – 7.5 years). Outcome was estimated by evaluating the probability of EFS and the cumulative incidence of relapse (CIR). Analysis of prognostic relevance of FCM MRD in combination with other criteria used for stratifying patients enrolled in the Interfant-06 protocol was performed with the Cox model on the cause-specific hazard of relapse. Results and discussion We classified infants according to the AIEOP-BFM day 15 stratification into three risk groups: 14 patients (27.5%) were considered at standard risk (SR: MRD less than 0.1%), 9 patients (15.7%) at high risk (HR: MRD 10% or more), and the majority of infants (29, 56.9%) at intermediate risk (IR: MRD 0.1% to 10%). As the 14 SR patients had 3-year EFS and CIR significantly better than other patients, we considered two major groups of patients with different outcome: SR group (MRD<0.1%) with 3-year EFS 77.9% (standard error, SE, 11.3) and CIR 14.9% (SE 10.2), and non-SR group with 3-year EFS 32.0% (SE 8.5) and CIR 58.0% (SE 8.8, p=0.0104 and p=0.0085, respectively). Half of SR group (7 of 14 cases) had germline MLL. 4 out of 7 MLL-positive SR-patients were in continuous complete remission (CCR) In contrast, the majority of infants in the non-SR group carried various types of MLL rearrangements. Only 5 cases in the non-SR group were MLL germline and only two of them are still in CCR. We evaluated the prognostic impact of day 15 MRD in MLL-positive cases (n=39). In this cohort of patients, we also observed a difference, although not statistically significant, between SR and non-SR groups both in 3-year EFS (57.1%, SE 18.7 and 30.9%, SE 9.2, respectively; p=0.3630) and in 3-year CIR (28.6%, SE 18.9 and 60.9%, SE 9.5, respectively; p=0.1733). We evaluated the suitability of MLL negativity and of day 15 FCM MRD <0.1% as single criterion for the identification of low-risk patients. Each factor, when separately analyzed in a Cox model, was significantly correlated with a reduction in the risk of relapse, as shown in Table 1, left panel. Nevertheless, as day 15 FCM MRD levels are strictly related to MLL status, the Cox model which analyzes jointly the two factors, is unable to identify the one independently impacting on the risk of relapse (Table 1, right panel). Thus, although being a strong prognostic factor by itself, day 15 FCM MRD stratification did not confer an advantage in relapse prediction when considered in combination with MLL status, which is the only low-risk group criterion in the Interfant-06 stratification. Conclusion Day 15 FCM MRD proved to be a suitable variable predicting treatment failure and can be used as an alternative or in combination with Interfant-06 stratification criteria to identify SR patients. Disclosures: Popov: Alexion: Research Funding.

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Role Of Day-15 Peripheral Blood MRD Assessment In Pediatric B-ALL Patients

Blood ◽

10.1182/blood.v122.21.1384.1384 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1384-1384

Author(s):

Karthik B.K Bommannan ◽

Man Updesh Singh Sachdeva ◽

Parveen Bose ◽

Deepak Bansal ◽

Ram Kumar Marwaha ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Acute Lymphoblastic Leukemia ◽

Minimal Residual Disease ◽

Peripheral Blood ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Childhood Acute Lymphoblastic Leukemia ◽

Minimal Residual ◽

Risk Of Relapse

Abstract Introduction Minimal residual disease (MRD) has emerged as an independent prognostic factor for patients of acute lymphoblastic leukemia (ALL). There is a strong correlation between MRD levels in bone marrow and the risk of relapse in childhood & adult leukemias 1, 2. Bone marrow MRD (BM-MRD) level of ≥ 0.01% is considered as positive and a mid-induction MRD of ≥ 1% is associated with high risk of relapse 3. Recently, the concept of peripheral blood MRD (PB-MRD), as a replacement for BM-MRD, has hit the lime light. In pediatric B-ALL, presence of PB-MRD is associated with a high relapse rate in comparison to cases which are PB-MRD negative 4, 5. This study was aimed to compare the levels of mid-induction (day 15) MRD levels in bone marrow and peripheral blood of pediatric B-ALL patients with a hypothesis that PB-MRD levels correlate with BM-MRD levels, and thus can predict BM-MRD levels for further management of the patient. Methods Forty newly diagnosed CD19+CD10+CD34+/- pediatric B-ALL patients under Vincristine, L-Asparaginase and Dexamethasone, were assessed for MRD levels on their paired day 15 PB & BM samples using six colour flow cytometry. With informed consent, both the samples were collected in EDTA vacutainers and lyse-stain-wash technique was used to prepare a single six colour tube comprising of SYTO 13/ CD34PE/ CD20PerCP/ CD19 PECy7/ CD10APC/ CD45APCH7 for each sample. The processed samples were run on BD FACS Canto II with acquisition of 1 million events or till the tubes were empty. Analysis was done using BD FACS Diva software and MRD of ≥ 0.01% was considered positive. Results Among 40 pairs of day 15 PB and BM samples, 25 (62.5%) were BM-MRD positive. Sixteen pairs (40%) had PB-MRD and BM-MRD co-positivity, 9 pairs (22.5%) had isolated BM-MRD positivity and 15 pairs (37.5%) were MRD negative in both PB and BM samples. In other words, among the 25 BM-MRD positive cases, simultaneous PB-MRD was positive in 16 patients (64%) and none of the samples had isolated PB-MRD positivity. Overall analysis of MRD positive cases showed a direct correlation between PB-MRD and BM-MRD (ρ = +0.684, p < 0.000) and BM-MRD levels were 7 times higher than the PB-MRD. In addition, ROC analysis with PB-MRD of ≥ 0.01% as a cut-off, revealed that, the most likelihood of PB-MRD being positive was when BM-MRD was ≥ 0.31%. Conclusions In contrast to the sparsely available literature, our study shows a significant correlation between PB & BM-MRD levels in day 15 paired samples of B-ALL cases. The MRD levels were 7 times higher in BM as compared to PB and PB-MRD was mostly positive with BM-MRD of ≥0.31%. In other words, day 15 PB-MRD positivity indirectly indicates that there is a minimum BM-MRD of 0.31%. Since literature reports prognostic significance of mid-induction BM-MRD at levels ≥1%, on day 15, an assessment of peripheral blood MRD alone, might yield clinically relevant prognostic information. A paired analysis at different time points might also establish a similar correlation as seen in the present study, eliminating the need of BM-MRD during further follow ups of the patient. This will help in avoiding an invasive procedure and improve patient compliance. References 1. Irving J, Jesson J, Virgo P, Case M, Minto L, Eyre L, et al. Establishment and validation of a standard protocol for the detection of minimal residual disease in B lineage childhood acute lymphoblastic leukemia by flow cytometry in a multi-center setting. haematologica. 2009;94(6):870-4. 2. Coustan-Smith E, Sancho J, Behm FG, Hancock ML, Razzouk BI, Ribeiro RC, et al. Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood. 2002;100(1):52-8. 3. Basso G, Veltroni M, Valsecchi MG, Dworzak MN, Ratei R, Silvestri D, et al. Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow. Journal of Clinical Oncology. 2009;27(31):5168-74. 4. Elain CS, Sancho J, Michael LH, Bassem. Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia. Blood. 2002;100 (7):2399-402. 5. Brisco MJ, Sykes PJ, Hughes E, Dolman G, Neoh SH, Peng LM, et al. Monitoring minimal residual disease in peripheral blood in B lineage acute lymphoblastic leukaemia. British journal of haematology. 1997;99(2):314-9. Disclosures: No relevant conflicts of interest to declare.

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Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent outcome

Blood ◽

10.1182/blood.v99.4.1253 ◽

2002 ◽

Vol 99 (4) ◽

pp. 1253-1258 ◽

Cited By ~ 121

Author(s):

Charlotte Nyvold ◽

Hans O. Madsen ◽

Lars P. Ryder ◽

Jeanette Seyfarth ◽

Arne Svejgaard ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Minimal Residual Disease ◽

Residual Disease ◽

Cox Model ◽

Lymphoblastic Leukemia ◽

Cell Disease ◽

Excellent Outcome ◽

Minimal Residual ◽

Risk Of Relapse

The postinduction level of minimal residual disease (MRD) was quantified with a competitive polymerase chain reaction (PCR) technique in 104 children with acute lymphoblastic leukemia (ALL) diagnosed between June 1993 and January 1998 and followed for a median of 4.2 years. A significant correlation was found between the MRD level on day 15 (D15) and day 29 (D29) after the start of induction therapy (rs = 0.70, P < .0001). The 15 patients with T-cell disease had higher D29 MRD than those with B-lineage ALL (P = .01). Age was positively related to D29 MRD (rs = 0.32, P = .001). The 16 patients who had a relapse had higher D15 and D29 MRD levels than the patients who stayed in remission (median levels D15, 1% versus 0.1%,P = .03; D29, 0.4% versus 0.01%,P = .0001). No patients with a MRD level less than 0.01% on D29 have so far had a relapse, whereas the 7-year probability of event-free survival for patients with higher MRD levels was 0.52 (P = .0007). The group of patients with a D29 MRD less than 0.01% included patients with T-cell disease, white blood cell count more than 50 × 109/L at diagnosis, or age 10 years or older, and could not be identified by up-front criteria. The best-fit Cox model to predict the risk of relapse included D29 MRD (P = .004) and age (P = .009). These findings indicate that with the present treatment protocol MRD quantification at an early stage of therapy identifies patients with a very low risk of relapse. Further trials are needed to reveal whether such patients with D29 MRD less than 0.01% can be cured with less intensive chemotherapy, which would reduce the risk of serious late effects as well as the costs of therapy.

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Levels of Minimal Residual Disease Prior to Transplant Influence Outcome of Adult Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v126.23.4374.4374 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4374-4374

Author(s):

Federico Lussana ◽

Tamara Intermesoli ◽

Francesca Gianni ◽

Cristina Boschini ◽

Arianna Masciulli ◽

...

Keyword(s):

Bone Marrow ◽

Peripheral Blood ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Conditioning Regimen ◽

Philadelphia Chromosome ◽

Molecular Response ◽

Minimal Residual ◽

Reduced Intensity ◽

Risk Of Relapse

Abstract Background With the advent of imatinib and the other tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1, the outcomes of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) improved substantially. Nonetheless, allogeneic stem cell transplantation (alloSCT) in first complete remission (CR1) remains the consolidation therapy of choice in Ph+ ALL. Evidence is emerging that post-transplant relapse is influenced by the persistence of minimal residual disease (MRD), with an inferior outcome of patients undergoing transplantation with measurable level of MRD (Sramkova L et al, Pediatr Blood Cancer 2007; Bar M et al. Leuk Res Treatment 2014). Considering that a deeper molecular response can probably be achieved with innovative targeted therapies, such as second and third-generation TKIs or immunotherapy, an accurate evaluation of MRD values before alloSCT may be very relevant. Aim of the study. To evaluate the predictive relevance of MRD levels before transplant in Ph+ALL patients in CR1 on the probabilities of (i) overall survival (OS), (ii) relapse incidence (CIR) and (iii) leukemia free survival (LFS) Patients and methods. One hundred and six adult patients (median age 41.2, range 19-62) with newly diagnosed Ph+ ALL (as determined by cytogenetic or molecular analysis) were enrolled into 2 prospective NILG protocols (09/00 ClinicalTrial.gov Identifier: NCT00358072 and 10/07 ClinicalTrial.gov Identifier: NCT00358072) and were treated with chemotherapy and imatinib. One hundred (94%) achieved CR1, of whom 72 patients underwent an alloSCT in CR1 and are the subject of this report. MRD was determined by quantitative polymerase chain reaction (RQ-PCR) according to validated methods. Results. Among the 72 patients undergoing alloSCT, MRD status before transplant was available for 65 patients (90%). Twenty-four patients (37%) achieved a complete molecular response (BCR-ABL/ABL<1x10-5) at time of conditioning (MRD- group), while 41 (63%) remained carriers of any positive MRD level in the bone marrow or peripheral blood (MRD+ group), ranging from 1.2x10-4 to 2x10-1. Patients' characteristics were similar between MRD+ and MRD- groups, except for a higher hemoglobin levels and a predominance of male gender in MRD- group, as summarized in Table 1. Thirty-five patients received alloSCT from a sibling and 37 from unrelated donor. The conditioning regimen to alloSCT was myeloablative in 85% and reduced intensity in 15% of patients. The stem cell source was the bone marrow in 19%, the peripheral blood in 78% and cord blood in the remaining 3% of patients. For the whole patient cohort (n=106), the median follow-up was 2.8 years (range 0.06-11.8), with a 5 years OS of 41%. The OS of patients receiving alloSCT was 50%. The MRD negativity at time of conditioning was associated with a significant benefit in terms of risk of relapse with a CIR of 8% compared to 39% of patients with MRD positivity (p=0.007) (Figure 1A). Nonetheless, the LFS and OS probability were not significant different in MRD- compared to MRD+ patients (58% vs 41%, p=0.17 and 58% vs 49%, p=0.55, respectively) (Figure1B), likely due to the effective post-relapse treatment with TKIs and/or DLI. The cumulative incidence of non relapse mortality was similar in MRD- compared to that of MRD+ group (33% vs 20%, p=0.22). Conclusions. Our results confirm that patients undergoing alloSCT with measurable levels of MRD show a significant increase risk of relapse after transplant. These results highlight the importance of achieving a complete molecular remission before transplant that should be considered an essential prerequisite for successful alloSCT. Table 1. Patients' characteristics according to MRD group Characteristics MRD negative (N=24) MRD positive (N=41) P Age years , median (range) 45.0 (21.4-58.2) 42.7 (18.5-62.4) 0.95 Male sex (%) 16 (67) 15 (37) 0.01 WBC, X 109/L, median (range) 27.7 (0.9-350.0) 12.0 (1.1-680.0) 0.12 Hemoglobin, g/dL, median (range) 11.4 (5.4-14.6) 9.0 (3.7-16.5) 0.02 Platelets, X 109/L, median (range) 41.0 (4.0-336.0) 34.0 (3.0-325.0) 0.44 LDH, U/L median (range) 1231 (353-8104) 715 (65-6194) 0.12 Conditioning regimen (%)Reduced intensity Myeloablative 4 (17)20 (83) 7 (17)34 (83) 1.00 Donor type (%)SiblingUnrelated 13 (54)11 (46) 18 (44)23 (56) 0.73 Graft type (%)Bone marrow Peripheral blood Cord blood 3 (12)20 (83)1 (4) 9 (22)31 (76)1 (2) 0.91 Figure 1. CIR and LFS according to MRD group Figure 1. CIR and LFS according to MRD group Disclosures No relevant conflicts of interest to declare.

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Co-culture model of B-cell acute lymphoblastic leukemia recapitulates a transcription signature of chemotherapy-refractory minimal residual disease

Scientific Reports ◽

10.1038/s41598-021-95039-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Stephanie L. Rellick ◽

Gangqing Hu ◽

Debra Piktel ◽

Karen H. Martin ◽

Werner J. Geldenhuys ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Tumor Cells ◽

Minimal Residual Disease ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Adherent Cells ◽

Cell Acute Lymphoblastic Leukemia ◽

Minimal Residual

AbstractB-cell acute lymphoblastic leukemia (ALL) is characterized by accumulation of immature hematopoietic cells in the bone marrow, a well-established sanctuary site for leukemic cell survival during treatment. While standard of care treatment results in remission in most patients, a small population of patients will relapse, due to the presence of minimal residual disease (MRD) consisting of dormant, chemotherapy-resistant tumor cells. To interrogate this clinically relevant population of treatment refractory cells, we developed an in vitro cell model in which human ALL cells are grown in co-culture with human derived bone marrow stromal cells or osteoblasts. Within this co-culture, tumor cells are found in suspension, lightly attached to the top of the adherent cells, or buried under the adherent cells in a population that is phase dim (PD) by light microscopy. PD cells are dormant and chemotherapy-resistant, consistent with the population of cells that underlies MRD. In the current study, we characterized the transcriptional signature of PD cells by RNA-Seq, and these data were compared to a published expression data set derived from human MRD B-cell ALL patients. Our comparative analyses revealed that the PD cell population is markedly similar to the MRD expression patterns from the primary cells isolated from patients. We further identified genes and key signaling pathways that are common between the PD tumor cells from co-culture and patient derived MRD cells as potential therapeutic targets for future studies.

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Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia

Blood ◽

10.1182/blood.2019001417 ◽

2020 ◽

Vol 136 (2) ◽

pp. 210-223 ◽

Cited By ~ 2

Author(s):

Eun Ji Gang ◽

Hye Na Kim ◽

Yao-Te Hsieh ◽

Yongsheng Ruan ◽

Heather A. Ogana ◽

...

Keyword(s):

Drug Resistance ◽

Tyrosine Kinase ◽

B Cell ◽

Kinase Inhibitor ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Underlying Mechanism ◽

Conditional Knockout

Abstract Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin α6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human α6-blocking Ab P5G10 induces apoptosis in primary ALL cells in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo. We further analyzed the underlying mechanism of α6-associated apoptosis using a conditional knockout model of α6 in murine BCR-ABL1+ B-cell ALL cells and showed that α6-deficient ALL cells underwent apoptosis. In vivo deletion of α6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that α6 deletion in murine ALL was associated with changes in Src signaling, including the upregulation of phosphorylated Lyn (pTyr507) and Fyn (pTyr530). Thus, our data support α6 as a novel therapeutic target for ALL.

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Pharmacogenetics of minimal residual disease response in children with B-precursor acute lymphoblastic leukemia: a report from the Children's Oncology Group

Blood ◽

10.1182/blood-2007-09-114082 ◽

2008 ◽

Vol 111 (6) ◽

pp. 2984-2990 ◽

Cited By ~ 33

Author(s):

Stella M. Davies ◽

Michael J. Borowitz ◽

Gary L. Rosner ◽

Kristin Ritz ◽

Meenakshi Devidas ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Minimal Residual Disease ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Response To Therapy ◽

Oncology Group ◽

Risk Status ◽

Prognostic Features ◽

Minimal Residual

Abstract Minimal residual disease (MRD) as a marker of antileukemic drug efficacy is being used to assess risk status and, in some cases, to adjust the intensity of therapy. Within known prognostic categories, the determinants of MRD are not known. We measured MRD by flow cytometry at day 8 (in blood) and at day 28 (in bone marrow) of induction therapy in more than 1000 children enrolled in Pediatric Oncology Group therapy protocols 9904, 9905, and 9906. We classified patients as “best risk” if they had cleared MRD by day 8 of therapy and as “worst risk” if they had MRD remaining in bone marrow at day 28, and tested whether MRD was related to polymorphisms in 16 loci in genes hypothesized to influence response to therapy in acute lymphoblastic leukemia (ALL). After adjusting for known prognostic features such as presence of the TEL-AML1 rearrangement, National Cancer Institute (NCI) risk status, ploidy, and race, the G allele of a common polymorphism in chemokine receptor 5 (CCR5) was associated with more favorable MRD status than the A allele (P = .009, logistic regression), when comparing “best” and “worst” risk groups. These data are consistent with growing evidence that both acquired and host genetics influence response to cancer therapy.

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

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2014.062 ◽

2014 ◽

Vol 6 (1) ◽

pp. e2014062 ◽

Cited By ~ 5

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.

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Minimal residual disease in acute lymphoblastic leukemia detected by immune selection and gene rearrangement analysis.

Journal of Clinical Oncology ◽

10.1200/jco.1989.7.3.338 ◽

1989 ◽

Vol 7 (3) ◽

pp. 338-343 ◽

Cited By ~ 32

Author(s):

M Bregni ◽

S Siena ◽

A Neri ◽

R Bassan ◽

T Barbui ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Minimal Residual Disease ◽

Gene Rearrangement ◽

Bone Marrow Cells ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Immune Selection ◽

Gene Rearrangement Analysis ◽

Minimal Residual

We have developed an assay for the detection of malignant residual cells in the bone marrow from patients with B- or T-lineage acute lymphoblastic leukemia (ALL) in clinical remission. This assay involves an immune selection step followed by immunoglobulin or T-cell receptor gene rearrangement analysis and allows the detection of one contaminating tumor cell out of 1,000 normal bone marrow cells. We have examined the bone marrow of 11 patients with adult ALL in remission over a 24-month period. Five patients relapsed in the bone marrow and one in the CNS. The assay allowed the detection of minimal residual disease in four of five patients that subsequently relapsed in the bone marrow, 1.5 to 9 months before the relapse became morphologically and clinically manifest. Residual disease was not found in the bone marrow from patients in continuous remission and from the single patient who relapsed in the CNS. We conclude that the ability of the assay described here to detect minimal residual disease with high specificity can provide information for further understanding of the biology of ALL and hopefully for the clinical management of patients with this disease.

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