This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mussolin, L. Articles by Rosolen, A. Search for Related Content PubMed PubMed Citation Articles by Mussolin, L. Articles by Rosolen, A. Social Bookmarking                            What's this?

Prognostic Role of Minimal Residual Disease in Mature B-Cell Acute Lymphoblastic Leukemia of Childhood

Lara Mussolin, Marta Pillon, Valentino Conter, Matilde Piglione, Luca Lo Nigro, Paolo Pierani, Concetta Micalizzi, Salvatore Buffardi, Giuseppe Basso, Luigi Zanesco, Angelo Rosolen

From the Clinica di Oncoematologia Pediatrica, Azienda Ospedaliera-Università di Padova, Padova; Clinica Pediatrica, Ospedale S. Gerardo, Monza; Clinica Pediatrica, Ospedale Regina Margherita, Torino; Centro di Riferimento Regionale di Ematologia ed Oncologia Pediatrica, Università di Catania, Catania; Oncoematologia Pediatrica, Politecnico delle Marche, Ancona; Ematologia Pediatrica, Istituto Gaslini, Genova; Ospedale Pausilipon, Napoli; and the Comitato Strategico di Studio Linfoma Non-Hodgkin Associazione Italiana Emato-Oncologia Pediatrica, Italy

Address reprint requests to Angelo Rosolen, MD, Clinica di Oncoematologia Pediatrica, Azienda Ospedaliera-Università di Padova, Via Giustiniani 3, 35128 Padova, Italy; e-mail: angelo.rosolen{at}unipd.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose To study the prevalence of t(8;14) at diagnosis and the response kinetics to treatment of minimal residual disease (MRD) in B-cell acute lymphoblastic leukemia (B-ALL) patients and determine its impact on prognosis.

Patients and Methods A total of 68 children affected by de novo B-ALL enrolled onto the Berlin-Frankfurt-Muenster–based Italian Association of Pediatric Hematology and Oncology LNH-97 clinical protocol were studied. Bone marrow aspirate from each patient was analyzed for the presence of t(8;14)(q24;q32) by long-distance polymerase chain reaction at diagnosis, after the first chemotherapy cycle, and after subsequent cycles until negative for MRD. Morphologic and immunophenotypic analyses were reviewed centrally.

Results A total of 47 patients (69%) were positive for t(8;14)(q24;q32). MRD response kinetics was determined in 39 patients. All of them reached clinical complete remission and most (31 of 39) became MRD negative after the first chemotherapy cycle. The 3-year relapse-free survival (RFS) was 38% (SE = 17%) in patients MRD positive after the first chemotherapy cycle compared with 84% (SE = 7%) in MRD-negative patients (P = .0005), whereas there was no difference in RFS for children who reached a clinical complete remission after the first chemotherapy cycle versus those who did not (RFS = 72% and SE = 9%; RFS = 79% and SE = 11%, respectively; P = .8). In multivariate analysis, MRD was shown to be predictive of higher risk of failure.

Conclusion Our study demonstrated that MRD carries a negative prognostic impact in B-ALL patients and suggests that a better risk-adapted therapy, possibly including the use of anti-CD20 monoclonal antibody, should be considered in selected patients.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
B-cell acute lymphoblastic leukemia (B-ALL) is a rare subtype of ALL, accounting for approximately 1% of childhood leukemias.¹ B-ALL cells are characterized by expression of B-cell–specific surface markers including CD19, CD20, and immunoglobulin (Ig)M, and by L3 morphology according to the French-American-British classification.² The chromosomal translocation t(8;14)(q24;q32) can be identified in most B-ALL.³ In this translocation, the c-myc proto-oncogene, normally located on chromosome 8, is juxtaposed to a transcriptional enhancer of the immunoglobulin heavy-chain locus (IgH) on chromosome 14. The resulting dysregulation of c-myc expression is believed to be responsible for the uncontrolled proliferation of B cells characteristic of this disease.^4,5 The relationship of B-ALL to Burkitt's lymphoma (BL) was recognized early, and it was hypothesized that both represent different manifestations of BL rather than different diseases.⁶ Despite advances in the treatment of these diseases, the event-free survival (EFS) of B-ALL remains approximately 75% to 80% compared with 90% to 95% of BL.⁷ A large polymerase chain reaction (PCR) –based study of minimal residual disease (MRD) in ALL demonstrated unequivocally that monitoring patients serially provides clinically relevant insight into the effectiveness of treatment.⁸ In addition, flow cytometry–based analysis of MRD was also found to predict prognosis in children with ALL.⁹ van Dongen et al¹⁰ showed that a MRD-based risk group classification can be achieved and that this information could be used for the design of childhood ALL protocols with MRD-based stratification of treatment.

The laboratory techniques used to conduct this kind of study should be simple and rapid so that treatment can be tailored to the adjusted assessment of risk. The t(8;14)(q24;q32) can be detected by long-distance (LD) PCR assay,^11,12 and we have shown previously that it can be used to study minimal bone marrow (BM) infiltration in BL. The assay sensitivity, determined by increasing dilutions of t(8;14) positive cells, was 10^–4.¹³ Bush et al,¹⁴ using the same primer combinations but a two-step amplification protocol in BL patient DNA, observed an interpatient sensitivity variation from 10^–3 to 10^–5, and interpreted this variability as related to the amount of malignant cells within the lymph node samples.

Despite the large number of MRD studies conducted in childhood ALL,^9,15,16 there are no reports about the prognostic relevance of MRD monitoring in childhood B-ALL. To address this question, we investigated prospectively the presence of t(8;14) by LD-PCR in the BM at diagnosis in a series of children affected by B-ALL and treated according to the protocol of the Associazione Italiana di Emato-Oncologia Pediatrica (AIEOP) LNH-97. Clinical characteristics and outcome of this cohort of patients in relationship to MRD kinetics during treatment are reported.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
A total of 68 children (15 females and 53 males) with a median age of 8.9 years (range, 1.2 to 15.1 years) and affected by de novo B-ALL were enrolled onto this study between January 2000 and December 2005. The study was approved by the local ethics committees and informed consent was obtained for all of the patients.

In all of the cases, morphologic and immunophenotypic analyses were centrally reviewed in the AIEOP ALL reference laboratory. Samples were analyzed by applying commercially available fluorochrome-labeled monoclonal antibodies and were classified as B-ALL when expressing pan/mature B-cell antigens (eg, CD19, CD20), surface immunoglobulin, and CD10 antigen (terminal deoxynucleotide transferase and T-cell lineage markers negative). A fraction of BM aspirate in sodium citrate obtained from each patient at diagnosis was used to investigate the presence of t(8;14)(q24;q32) by LD-PCR. High molecular weight genomic DNA was prepared from nucleated cells, isolated by differential lysis, using the QIAamp Tissue Kit (Qiagen, Hilden, Germany), in accordance with the manufacturer's instructions. Detailed information on the assay modified from the original method of Akasaka et al¹¹ was published previously.¹² We used one primer for the c-myc gene (5'-ACAGTCCTGGATGATGATGTTTTTGATGAAGGTCT-3') combined, alternatively, with one of four primers for the IgH locus: 3 primers for the constant regions (Cµ/03: 5'-TGCTGCTGATGTCAGAGTTGTTCTTGTATTTCCAG-3', C/02: 5'-AGGGCACGGTCACCACGCTGCTGAGGGAGTAGAGT-3'; C/01: 5'-TCGTGTAGTGCTTCACGTGGCATGTCACGGACTTG-3') and one for the joining region (JH: 5'- ACCTGAGGAGACGGTGACCAGGGT-3'). All of the primer combinations were used in subsequent PCR assays of the same patient to exclude clonal changes. Quality of genomic DNA was assessed in each case by using a combination of primers of the Human tPA Control Primer Set (Roche Diagnostics, Milan, Italy). Each reaction mixture (50 µL) contained 250 ng of DNA, 60 pmol of each primer, and amounts of deoxynucleotide triphosphates, buffer III, oligonucleotides, and a mix of Taq and Pwo polymerases (Expand Long Template PCR System, Roche Diagnostics), as suggested by the manufacturer. PCR was performed in an ABI Thermal Cycler 9700 (Applied Biosystems, Foster City, CA), using cycle characteristics suggested by the manufacturer and described previously,¹² except for an increase of the total cycle number from 30 to 40 and addition of 1.5 U of Taq polymerase after the first 30 cycles. PCR products were analyzed by agarose gel electrophoresis and visualized under UV illumination after ethidium bromide staining.

If positive for the c-myc/Ig rearrangement, BM aspirate was also requested after the first chemotherapy cycle and after each subsequent cycle until negative. An additional BM aspirate was analyzed after the fifth chemotherapy cycle. For each t(8;14)-positive patient, dilutions of genomic DNA obtained from BM at diagnosis into genomic DNA from the t(8;14)-negative cell line Karpas 299 were performed to establish the patient specific sensitivity level.

Patients were treated according to the protocol AIEOP LNH-97 for the diagnosis and therapy of B-cell non-Hodgkin's Lymphoma and B-ALL, based on a slightly modified Berlin-Frankfurt-Muenster 95 strategy.⁷ Treatment consisted of 5-day treatment with corticosteroids and low-dose cyclophosphamide (prephase) followed by five or six 5-day cycles of high dose-intensity chemotherapy using, in different combinations, dexamethasone, cyclophosphamide, ifosfamide, methotrexate, cytarabine, doxorubicin, etoposide, and intrathecal therapy (Appendix Fig A1 and Table A1, online only).

Definition of Disease Extent and Response
In addition to BM infiltration, patients with B-ALL may have localized disease. In the analysis of this aspect, tumor mass was defined as presence of abdominal mass or significant lymphomatous tumor in the head and neck or other sites, whereas focal involvement of liver, spleen, and kidney, or hepatosplenomegaly exceeding 4 cm from costal margin, were considered organ involvement, as in previous studies.¹ Bone involvement was defined by x-ray and/or magnetic resonance imaging.

Clinical complete remission (CR) was defined as absence of morphologic involvement of BM and central spinal fluid, no evidence of tumor mass as determined by imaging studies, and absence of organ involvement (including reduction of bone lesions in the absence of new bone localizations).

Statistical Analysis
All patients included in the study had at least 12 months follow-up from diagnosis. Survival analyses were performed according to the Kaplan-Meier method¹⁷ with differences compared by the log-rank test. Overall survival was calculated from the date of diagnosis to the date of death as a result of any reason or to the date of last follow-up; EFS was calculated from the date of diagnosis to the date of an event (tumor failure, death as a result of any reason, second malignancy) or to the date of last follow-up. Progression-free survival was calculated from the date of diagnosis to the date of the first event (nonresponse and relapse) or to the date of last follow-up, and relapse-free survival (RFS) was calculated from the date of clinical CR to the date of relapse or last follow-up.

To take into account prognostic factors when comparing RFS of patient subgroups, Cox regression analysis¹⁸ was used, including variables with P < .1 in univariate analysis.

The difference between the levels of lactate dehydrogenase (LDH) at diagnosis in the group with positive or negative MRD at the end of the first chemotherapy cycle was analyzed by the Mann-Whitney U test. All P values are two sided, with a type I error rate fixed at 0.05. Statistical analysis was performed using the SAS Statistical Program, version 8.2 (SAS Institute Inc, Cary, NC).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The main clinical characteristics and treatment results of the B-ALL patient population studied are listed in Table 1. Bone marrow specimens from 68 consecutive children with B-ALL were studied for the presence of the t(8;14)(q24;q32) by LD-PCR. DNAs extracted from all of the samples were suitable for LD-PCR analysis because amplification of 4.8- to 15-kb fragments of the control tPA gene was achieved in each case. Overall, 47 patients (69%) were positive for t(8;14)(q24;q32), with a PCR product ranging in size between 2.0 and 9.5 kb, thus confirming the variability of the breakpoints on both chromosomes. Dilution assays performed to determine the patient-specific sensitivities revealed a sensitivity of 10^–4 in most patients (39 of 47) and 10^–3 or 10^–4 in the remaining eight children (Appendix Table A2; Fig A2, online only).

The 3-year overall survival and EFS of the entire cohort of 68 patients was 74% (SE = 6%) and 67% (SE = 6%), respectively. The progression-free survival for the 47 patients with t(8;14)(q24;q32)-positive B-ALL was 69% (SE = 7%), whereas for the remaining 21 t(8;14)(q24;q32)-negative patients progression-free survival was 71% (SE = 10%; P = .96). Of these negative patients, five experienced relapse and one was a nonresponder; four of these patients died as a result of disease progression.

MRD and response kinetics to treatment were investigated in 39 of the 47 t(8;14)-positive patients. The other eight children could not be studied because of insufficient sampling. They had a median LDH value of 2,906 IU/L, two of eight had tumor mass, and one was CNS positive. Six of eight patients reached a CR and two of them experienced relapse. Four of eight died: one as a result of sepsis in CR and three as a result of progressive disease. Details on patients who experienced relapse are summarized in Table 2.

Detailed information on molecular disease response kinetics and follow-up of each patient is listed in Table 3. Of note, 38 of 39 patients had a morphologically negative BM aspirate after the first chemotherapy cycle, whereas only one (patient 37) had 1% immature lymphoid cells without L3 morphology. Most of the patients became molecularly negative after the first chemotherapy cycle (79%). Median LDH values at diagnosis were 5,525 IU/L (range, 3,150 to 24,240 IU/L) and 3,200 IU/L (range, 863 to 32,402 IU/L) in patients MRD positive or negative, respectively, after the first chemotherapy cycle (P = .044).

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Survival analysis. (A) Relapse-free survival (RFS) analysis in B-cell acute lymphoblastic leukemia patients according to complete remission (CR) achievement defined by morphologic and clinical findings; (B) RFS according to minimal residual disease (MRD) status in BM after the first chemotherapy cycle.

The univariate analysis taking into account the variables sex, age, CNS involvement, WBC count, tumor mass, organ involvement, LDH, and MRD is listed in Table 5. In the Cox regression analysis MRD positivity after the first chemotherapy cycle was the only significant negative prognostic factor on RFS (P = .0025), with a hazard ratio of 6.95.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

Given that the t(8;14) can be detected successfully by LD-PCR with a sensitivity of 10^–3 to 10^–4, we conducted a prospective study of MRD kinetics in B-ALL patients enrolled onto the AIEOP LNH-97 protocol, which yielded a slightly lower outcome compared with both a series of B-ALL patients treated by the Berlin-Frankfurt-Muenster group⁷ and with a more recent CNS-negative series of B-ALL treated on the French-American-British/LMB96 study,¹⁹ although the cohorts of patients are not fully comparable in terms of clinical characteristics. The measurement of MRD at critical intervals during the disease course is an important tool to evaluate the effectiveness of therapy in children with ALL. At any point during clinical remission, the detection of MRD was associated with a higher risk of subsequent relapse,^8,9 so the extent of residual disease was of critical importance in predicting treatment outcome. With this study, we aimed to establish whether in B-ALL, similar to other ALL types, the measurement of MRD may be relevant for clinical decisions, making use of a fast and relatively inexpensive method, LD-PCR. To date, to our knowledge, there are no data in the literature regarding this specific issue, possibly because B-ALL is a rare malignancy compared with the more frequent ALL, and the prospective analysis of a sufficient number of samples for MRD studies is difficult.

Interestingly, most of the patients became LD-PCR negative in the BM after the first chemotherapy cycle. These data show the high efficacy of the current high dose-intensive chemotherapy in clearing the tumor cells from BM, despite its massive blast infiltration at diagnosis.

We observed that molecular remission before the second chemotherapy cycle had a prognostic impact. In fact, only five of 31 MRD-negative children experienced relapse, whereas five of eight patients who remained MRD positive after the first cycle experienced a relapse. Notably, all five of these MRD-positive patients had a microscopically negative BM; two (patients 34 and 37) were also positive at a subsequent time point before a relapse could be diagnosed. In addition, two patients who were MRD negative after the first cycle became molecularly positive before the last cycle and later experienced relapse. Interestingly, when evaluated based on standard clinical and morphologic criteria, the time of achievement of CR did not significantly affect the RFS (Fig 1A), whereas the timing of achievement of molecular remission identified patients with significantly different prognosis (Fig 1B).

It is well established that level of serum LDH is an independent prognostic factor in BL; in fact, higher levels are associated with advanced-stage disease and a less favorable outcome.^20,21 In B-ALL the median LDH level is usually higher than in BL. Burmeister et al²² showed a median LDH level of 2,880 U/L in a cohort of B-ALL adult patients. In our B-ALL series, a statistically significant difference of LDH levels between MRD-positive and -negative patients after the first chemotherapy cycle was observed; overall levels were also higher than reported for BL patients.¹³ Although MRD may have a different impact in the context of different trials, taken together our data suggest that MRD is of prognostic relevance in pediatric B-ALL, in that persistence of molecular disease (but also molecular relapse while receiving therapy) seems to predict subsequent clinical relapse.

If we consider that among children with molecularly positive BM after the first chemotherapy cycle, all patients who experienced a relapse, except one, died as a result of disease progression, the availability of a molecular assay that can predict clinical relapse represents a critical tool to suggest adoption of additional therapeutic intervention for patients at risk. Among other treatment options, we would suggest that children with MRD positivity before the second cycle of chemotherapy or those who experience a molecular relapse be considered candidates for additional treatment, including anti-CD20 monoclonal antibody. Our study gives a rationale for the use of anti-CD20 in a specific clinical entity where the limited population of pediatric patients would not allow us to conduct randomized trials to assess the impact of anti-CD20 in the context of the current high dose-intensity chemotherapy regimens.

Finally, we did not find any correlation between CNS involvement and MRD. This may be due to the small number (15%) of CNS-positive children in our series of patients. Only the study of large cohorts of patients would allow us to determine whether possible relationships between MRD and CNS disease exist.

In summary, for the first time to our knowledge, we have reported the response kinetics of MRD in a relatively large cohort of patients with B-ALL, and have described its prognostic implications. Similarly to that demonstrated for the most frequent B-cell precursor and T-cell lineage acute lymphoblastic leukemias of childhood,^8,23,24 our study suggests that also in children with mature B-ALL an early molecular remission obtained with current treatment strategies is an index of better prognosis. Future larger prospective studies that can determine the MRD also in the t(8;14)-negative patients (eg, by Ig gene rearrangement analyses) will allow us to determine the role of MRD in B-ALL and set the basis for additional improvement of the current high cure rate for B-ALL patients.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Lara Mussolin, Angelo Rosolen

Provision of study materials or patients: Valentino Conter, Matilde Piglione, Luca Lo Nigro, Paolo Pierani, Concetta Micalizzi, Salvatore Buffardi

Data analysis and interpretation: Lara Mussolin, Marta Pillon, Giuseppe Basso, Angelo Rosolen

Manuscript writing: Lara Mussolin, Marta Pillon, Valentino Conter, Luca Lo Nigro, Angelo Rosolen

Final approval of manuscript: Luigi Zanesco, Angelo Rosolen

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Associazione Italiana di Emato-Oncologia Pediatrica (AIEOP) LNH-97 treatment plan for B-cell non-Hodgkin's lymphoma/B-cell acute lymphoblastic leukemia. NOTE. Letters in boxes on right indicate different chemotherapy cycle designations used in Table A1. LDH, lactate dehydrogenase; P, prephase.

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A2. Long-distance polymerase chain reaction sensitivity assay. Lanes 2 to 7: serial dilutions of a t(8;14)-positive patient's DNA from bone marrow at diagnosis (lane 2): 10–1 (lane 3), 10–2 (lane 4), 10–3 (lane 5), 10–4 (lane 6), and 10–5 (lane 7). Size of MYC-immunoglobulin heavy-chain amplification product: 8.0 kb. Lane 1: molecular weight marker (MWM).

	ACKNOWLEDGMENTS

 
We thank Gloria Tridello, PhD, for the statistical analysis; Ilaria Zecchini for the support in data collection and management; and the colleagues from various Associazione Italiana di Emato-Oncologia Pediatrica (AIEOP) Centers for contributing biologic samples and patient clinical information.

	NOTES

 
Supported by Fondazione Città della Speranza, Associazione Italiana contro le Leucemie and by Camera di Commercio di Venezia.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
1. Reiter A, Schrappe M, Ludwig WD: Favorable outcome of B-cell acute lymphoblastic leukemia in childhood: A report of three consecutive studies of the BFM Group. Blood 80:2471-2478, 1992[Abstract/Free Full Text]

2. Bennett TJ, Catovsky D, Daniel M, et al: Proposal for the classification of the acute leukaemias: French-American-British (FAB) cooperative group. Br J Haematol 33:451-458, 1976[Medline]

3. Berger R, Bernheim A, Brouet JC, et al: T(8;14) translocation in a Burkitt's type of lymphoblastic leukemia (L3). Br J Haematol 43:87-90, 1979[Medline]

4. Bornkamm GW, Polack A, Eick D: c-Myc Deregulation by Chromosomal Translocation in Burkitt's Lymphoma. New York, NY, Marcel Dekker Inc, 1988

5. Boxer LM, Dang CV: Translocations involving c-myc and c-myc function. Oncogene 20:5595-5610, 2001[CrossRef][Medline]

6. Magrath IT, Ziegler JL: Bone marrow involvement in Burkitt's lymphoma and its relationship to acute B cell leukaemia. Leuk Res 4:33-59, 1980[CrossRef][Medline]

7. Woessmann W, Seideman K, Mann G, et al: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasm: A report of the BFM Group Study NHL-BFM 95. Blood 105:948-958, 2005[Abstract/Free Full Text]

8. Cavé H, van der Werff ten Bosch J, Suciu S, et al: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukaemia: European Organization for Research and treatment of Cancer-Childhood Leukemia Cooperative Group. N Engl J Med 339:591-598, 1998[Abstract/Free Full Text]

9. Coustan-Smith E, Sancho J, Hancock ML, et al: Clinical importance of minimal residual disease in childhood acute lymphoblastic leukaemia. Blood 96:2691-2696, 2000[Abstract/Free Full Text]

10. van Dongen JJM, Seriu T, Panzer-Grmayer ER, et al: Prognostic value of minimal residual disease in acute lymphoblastic leukemia in childhood. Lancet 352:1731-1738, 1998[CrossRef][Medline]

11. Akasaka T, Muramatsu M, Ohno H, et al: Application of long-distance polymerase chain reaction to detection of junctional sequences created by chromosomal translocation in mature B-cell neoplasms. Blood 88:985-994, 1996[Abstract/Free Full Text]

12. Basso K, Frascella E, Zanesco L, et al: Improved long-distance polymerase chain reaction for the detection of t(8;14)(q24;q32) in Burkitt's lymphomas. Am J Pathol 155:1479-1485, 1999[Abstract/Free Full Text]

13. Mussolin L, Basso K, Pillon M, et al: Prospective analysis of minimal bone marrow infiltration in pediatric Burkitt's lymphomas by long-distance polymerase chain reaction for t(8;14)(q24;q32). Leukemia 17:585-589, 2003[CrossRef][Medline]

14. Bush K, Borkhardt A, Wössmann W, et al: Combined polymerase chain reaction methods to detect c-myc/IgH rearrangement in childhood Bukitt's lymphoma for minimal residual disease analysis. Haematologica 89:818-825, 2004[Abstract/Free Full Text]

15. Cazzaniga G, d'Aniello E, Corral L, et al: Results of minimal residual disease (MRD) evaluation and MRD-based treatment stratification in childhood ALL. Best Pract Res Clin Haemat 15:623-638, 2002[CrossRef]

16. Cazzaniga G, Biondi A: Molecular monitoring of childhood acute lymphoblastic leukemia using antigen receptor gene rearrangements and quantitative polymerase chain reaction technology. Haematologica 90:382-390, 2005[Abstract/Free Full Text]

17. Kaplan EL, Meier P: Non parametric estimation from incomplete observation. J Am Stat Assoc 53:457-481, 1958[CrossRef]

18. Cox DR: Regression models and life tables. J R Stat Soc 34:187-220, 1972

19. Goldman S, Gerrard M, Sposto R, et al: Excellent results in children and adolescents with isolated mature B-acute lymphoblastic leukemia (B-ALL) (Burkitt): Report from the French-American-British (FAB) International LMB study FAB/LMB96. Blood 106:234, 2005 (abstr)

20. Cairo MS, Krailo MD, Morse M, et al: Long-term follow-up of short intensive multiagent chemotherapy without high-dose methotrexate (Orange) in children with advanced non-lymphoblastic non-Hodgkin's lymphoma: A children's cancer study group report. Leukemia 16:594-600, 2002[CrossRef][Medline]

21. Csako G, Ian T, Magrath MD, et al: Serum total and isoenzyme lactate dehydrogenase activity in American Burkitt's lymphoma patients. Am J Clin Pathol 78:712-717, 1982[Medline]

22. Burmeister T, Schwartz S, Horst HA, et al: Molecular heterogeneity of sporadic adult Burkitt-type leukemia/lymphoma as revealed by PCR and cytogenetics: Correlation with morphology, immunology and clinical features. Leukemia 19:1391-1398, 2005[CrossRef][Medline]

23. Pui CH, Campana D: New definition of remission in childhood acute lymphoblastic leukaemia. Leukemia 14:783-785, 2000[CrossRef][Medline]

24. Gruhn B, Hongeng S, Yi H, et al: Minimal residual disease after intensive induction therapy in childhood acute lymphoblastic leukaemia predicts outcome. Leukemia 12:675-681, 1998[CrossRef][Medline]

Submitted February 16, 2007; accepted August 20, 2007.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				E. Coustan-Smith, J. T. Sandlund, S. L. Perkins, H. Chen, M. Chang, M. Abromowitch, and D. Campana Minimal Disseminated Disease in Childhood T-Cell Lymphoblastic Lymphoma: A Report From the Children's Oncology Group J. Clin. Oncol., July 20, 2009; 27(21): 3533 - 3539. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mussolin, L. Articles by Rosolen, A. Search for Related Content PubMed PubMed Citation Articles by Mussolin, L. Articles by Rosolen, A. Social Bookmarking                            What's this?