Advertisement
Journal of Clinical Oncology  
Search for:
Limit by:
  Browse by Subject or Issue
Home Search or Browse JCO My JCO Subscriptions Customer Service Site Map

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Seong, C.-M.
Right arrow Articles by Champlin, R. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Seong, C.-M.
Right arrow Articles by Champlin, R. E.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?
Journal of Clinical Oncology, Vol 18, Issue 9 (May), 2000: 1831-1836
© 2000 American Society for Clinical Oncology

Early Detection of Relapse by Hypermetaphase Fluorescence In Situ Hybridization After Allogeneic Bone Marrow Transplantation for Chronic Myeloid Leukemia

By Chy-Myong Seong, Sergio Giralt, Hagop Kantarjian, Jingping Xu, Jolynn Swantkowski, Kimberley Hayes, Armand B. Glassman, Issa Khouri, Martin Korbling, Peter Thall, Michael J. Siciliano, Richard E. Champlin

From the Departments of Blood and Marrow Transplantation, Leukemia, Molecular Genetics, Laboratory Medicine, and Biomathematics, University of Texas M.D. Anderson Cancer Center, Houston, Texas.

Address reprint requests to Richard E. Champlin, MD, Department of Blood and Marrow Transplantation, University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 24, Houston, TX 77030; email rchampli@ mdacc.tmc.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: Standard G-band cytogenetic analysis (CG) provides information on approximately 25 metaphases for monitoring the presence of Philadelphia chromosome positive (Ph+) cells in chronic myelogenous leukemia (CML) patients, making the detection of a low frequency of Ph+ cells problematic. The purpose of this study was to improve the detection of a low frequency of Ph+ cells.

PATIENTS AND METHODS: We combined fluorescence in situ hybridization (FISH) with long-term colcemid exposure, capturing several hundred metaphases in bone marrow cultures (hypermetaphase FISH [HMF]). Using probes that identify Ph+ cells, HMF was compared with CG analysis in the follow-up evaluations of 51 patients with CML at various time points after allogeneic bone marrow transplant (BMT).

RESULTS: Thirty-five patients never showed the presence of Ph+ cells by either method. In four patients, high frequencies of Ph+ cells were detected by both methods. In the remaining 12 patients, Ph+ cells were detected by HMF at time points after BMT when they were not detected by CG. In seven of the 12 patients, low but statistically significant frequencies of Ph+ cells (0.37% to 5.20%) were detected 3 months or later after BMT, and when no intervention was initiated, all seven patients later relapsed. Based on those data, an eighth patient with mixed chimerism and a similar HMF-detected Ph+ frequency (1.8% at 27 months after BMT) was reinfused with donor lymphocytes and achieved remission with 0% Ph+ cells studied by HMF (up to 50 months after BMT). Ph+ cells detected by HMF but not by CG less than 3 months after BMT disappeared on later examination in two of four patients. After detection of Ph+ cells by HMF only, the median time to cytogenetic progression (detection of Ph+ cells by CG) was 101 days.

CONCLUSION: The results demonstrate the ability of HMF to detect low but clinically relevant levels of leukemic cells not detected by CG in transplant patients. The data indicate that HMF can detect low levels of Ph+ cells before standard cytogenetics at a time that may be useful in monitoring disease status and planning clinical interventions.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
CHRONIC MYELOID leukemia (CML) is a hematologic malignancy characterized by excessive clonal proliferation of myeloid cells and their progenitors.1 It is typically associated with a reciprocal translocation between chromosome 9 and 22, t(9;22)(q34;q11), resulting in fusion of a central portion of the BCR gene to the second exon of the ABL gene.2-5 Although CML may have a prolonged course, it is generally a fatal disease with conventional therapy. Patients with CML undergoing allogeneic bone marrow transplant (BMT) from an HLA-identical sibling during the chronic phase have a 50% to 80% chance of long-term disease-free survival.6-8 Much of the benefit of allogeneic BMT is mediated by an immune graft-versus-leukemia effect.8 The most direct evidence for this effect is the finding that donor lymphocyte infusions (DLI) can reinduce complete remission in approximately 70% of patients relapsing after BMT. Results of DLI are best when given early in the course of relapse.9-15 Therefore, it becomes important to have a means of quantitative analysis for the low frequency of Philadelphia chromosome positive (Ph+) cells in the marrow of such patients. Standard G-band cytogenetic analysis (CG) provides information on only a relatively small number of cells (< 25 metaphases) in such preparations, making the detection of a low frequency of Ph+ cells problematic. Polymerase chain reaction (PCR)– based molecular assays for BCR/ABL rearrangement are highly sensitive for the detection of Ph+ cells, and with quantitative methods, they may prove predictive for relapse, particularly in T-cell–depleted recipients. Some patients, however, may remain in durable complete remission despite persistently positive PCR results.16,17 We have combined fluorescence in situ hybridization (FISH) with long-term colcemid exposure of bone marrow cultures (called hypermetaphase FISH [HMF]) and have shown it be effective in monitoring for the presence of specific chromosomal entities present in low frequency in leukemia patients undergoing treatment.18 This approach is both sensitive and specific; up to 1,000 metaphases can routinely be studied, and the rate of false-positive readings is less than 2 x 10-4.

In this report, we applied the HMF technique to improve detection of early relapse after allogeneic BMT. HMF allowed the detection of low levels of Ph+ cells in 12 marrow transplant recipients who had not been found to have Ph+ disease by CG analysis performed simultaneously. The clinical significance of the HMF findings in those 12 patients was evaluated in an attempt to identify conditions when therapeutic intervention with DLI might be most effective in reestablishing complete remission.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Fifty-one patients who received allogeneic BMT for CML at the University of Texas M.D. Anderson Cancer Center between January 1990 and September 1995 were the subject of this analysis. The transplantation protocols were approved by the M.D. Anderson Institutional Review Board. Samples were analyzed by HMF and separately by standard CG analyses.19 The HMF assays were performed without knowledge of the patients’ cytogenetic results or clinical status.

Transplant Regimen
Patients received either thiotepa (5 to 10 mg/kg), cyclophosphamide (120 mg/kg), and total-body irradiation (10.2 to 12 Gy) with CD8 or T-cell–depleted transplants19-21 or thiotepa (750 mg/m2), busulfan (12 mg/kg), and cyclophosphamide (120 mg/kg) and unmodified marrow transplantations.20

CG
CG analysis was performed on freshly aspirated bone marrow samples. Metaphases were analyzed for G-bands using trypsin-Giemsa techniques, as previously described. Twenty to 25 metaphases were analyzed.19

HMF
After a 24-hour culture of bone marrow aspirates followed by the addition of colcemid 1 µg/mL and culture for an additional 24 hours for HMF preparation,18 cells were fixed in acid-alcohol and dropped on slides by procedures standard in this laboratory. The E6B probe, from 5 million base pairs of human DNA spanning the breakpoint on chromosome 9q34 involved in the Ph translocation, was labeled with biotin for visualization with fluorescein for FISH detection of the Ph chromosome.22 Digoxigenin-labeled alpha satellite DNA probe (Oncor, Gaithersberg, MD) for chromosome X, locus DXZ 1, was used for FISH identification (visualization with rhodamine) of donor cell versus recipient cells.23 Two-color detection for each of the probes, fluorescent microscopy, and photography were carried out, as previously reported.22 Criteria for evaluating Ph+ and Ph- cells were as published18; two chromosome regions of equal green fluorescence indicate Ph- cells, and three chromosome regions (one clearly less robust than the other two) indicate Ph+ cells. Donor cells (male) were identified as having only one red fluorescent chromosomal region, whereas female recipient cells had two such regions. A host-derived, Ph+ cell is shown as an example in Fig 1.



View larger version (170K):
[in this window]
[in a new window]
  		Fig 1. Two-color FISH on an HMF preparation of a recipient (female) Ph+ cell. The E6B probe (detected by fluorescein) identifies (in green) the 9q34 region, a small portion of which can be shown to be translocated and is interpreted as being the Ph chromosome. The X chromosome probe, which hybridizes to the centromeric region of that chromosome (detected by rhodamine), identifies the cell as female (host origin in this case).

 

   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Standard CG and HMF were carried out on all 51 patients at various time points after BMT. Four patients had high frequencies of Ph+ cells detected by both HMF and CG at all time points tested. Two subsequently died from their disease, and two have responded to DLI and have remained in complete remission for more than 2 years. Twelve patients were HMF-positive on initial determination without evidence of Ph+ cells by CG. The cytogenetic data (HMF and CG), intervention procedures carried out, and outcomes for the 12 patients are listed in Table 1. The median time to cytogenetic progression (HMF Ph+, CG Ph- to HMF Ph+, CG Ph+) was 101 days. Low, but statistically significant, levels of Ph+ cells seen at first sampling in patients no. 9 and 10 did not necessarily have clinical significance; they have had negative HMF and CG studies. That these frequencies of Ph+ cells were detected seems to have been a likely consequence of the early time point after BMT (< 3 months). Detection of Ph+ cells by sensitive techniques within a few months after BMT has not had clinical significance in other studies as well, possibly because of the graft-versus-leukemia effect that is postulated to eradicate minimal residual disease after transplant.16 Two of the patients (no. 5 and no. 6) died of therapy-related complications after being scored for less than 5% Ph+ cells less than 3 months after BMT and were not assessable for later relapse.


View this table:
[in this window]
[in a new window]
  		Table 1. CG and HMF Results and Southern Blot Detection of Recipient Cells and Cells With BCR/ABL Chimeric Gene in Allogeneic BMT CML Patients Sampled at Different Time Points After BMT
 
Clearly, HMF detects low frequencies of Ph+ cells not detected by CG. It is expected that, when the frequency of Ph+ cells is low, they might not be detected when only a small number of cells can be scored (typically < 30 cells in CG) but might be detected when more than 200 cells can be scored (as by HMF). Based on data18 indicating that the false-positive readings in this procedure are less than 2 x 10-4, the frequencies of Ph+ cells detected, with the exception of the positive readings in patient no. 11, are statistically significantly different from 0%.

Low percentages of Ph+ cells detected for the first time later than 3 months after BMT occurred in six patients (nos. 1, 2, 3, 4, 8, and 12) before they were detected by CG. These preceded clinical relapse as indicated by the subsequent readings and/or course of the disease in those patients. Acting on the information that low but significant levels of Ph+ cells present beyond 3 months after BMT may predict relapse, DLI was carried out on patient no. 7.24 In that patient, low frequencies of Ph+ cells were detected by HMF 28 and 30 months after BMT. Also, over that same 2-month period, 274 to 328 recipient-derived female cells out of a sample of 400 cells (68% to 82%) were detected (Fig 1).

Low frequencies of Ph+ cells were seen in patient no. 11 at two sample points 26 and 44 months after BMT. Patients may harbor Ph+ cells for years before relapse and continued monitoring is needed. Residual Ph+ cells may also be suppressed by the immune graft-versus-leukemia effect related to allogeneic transplantation, which may prevent overt relapse in these patients.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
HMF Detection of Low but Statistically Significant Frequencies of Cancer Cells
Cytogenetic studies after allogeneic BMT for patients with Ph+ CML are of fundamental importance for documenting and monitoring the presence of residual malignant cells. Although some patients have only transient recurrence of Ph+ cells, Offit et al25 reported on 16 CML patients in whom Ph+ cells were detected after transplant by standard cytogenetics; 12 of the patients experienced relapse (usually within 6 months in T-cell–depleted BMT recipients). Alimena et al26 reported that the detection of Ph+ marrow cells at various intervals after BMT, even at low frequency (< 10%), was generally followed by a progressive increase of Ph+ cells and/or a hematologic relapse. Although cytogenetic analysis with G-banding is specific and reliable for detecting Ph+ cells, its sensitivity is limited by the relatively small number of cells analyzed in typical preparations (generally <= 25 metaphases); hence, the statistical confidence in the measurement is low.

HMF identifies low frequencies of Ph+ cells not detected by CG because HMF allows evaluation of a much larger number of cells in each sample. For example, consider a hypothetical patient with a true level of 3% Ph+ cells. If we assume conservatively, based on the empirical evidence of zero Ph+ cells per 5,000 cells in samples from a known normal subject,18 that the false-positive and false-negative rates each are less than 2 x 10-4, then the probability of observing a given cell to be Ph+ in this patient is .0302. To decide whether this patient is Ph+, formally, one tests the null hypothesis that the patient is normal, ie, has no Ph+ cells, versus the alternative that the patient has some Ph+ cells. Ideally, the overall false-positive and false-negative rates of the test should be controlled. For samples of n = 25, n = 400, or n = 500 cells, rules that control the overall false-positive probability to be less than .0001 are to declare the patient Ph+ if (s)he has more than two Ph+ cells, more than two Ph+ cells, or more than three Ph+ cells, respectively. However, the false-negative probabilities of these rules, ie, the probabilities that a patient with 3% Ph+ cells is declared normal, are less than 0.01% for the n = 400 and n = 500 rules but 82.6% for the n = 25 rule. That is, a sample of size n = 25 cells, which is typical with CG, has a high risk of declaring a Ph+ patient normal. Changing the rule to more than one Ph+ cell out of 25 cells doesn’t fix this problem because the false-positive rate becomes 0.5%, but the false-negative rate is 46.5%, still an unacceptably high risk of missing a true Ph+ level of 3%. If this type of rule is applied to patient no. 7 in Table 1, (s)he would be declared Ph+ based on each of the first two samples (two Ph+ cells out of 400 cells and seven Ph+ cells out of 400 cells) but Ph- based on each of the subsequent four samples, with a false-positive risk of 3.0% and a false-negative risk of less than 0.0064%. A sample size of 25 cannot achieve anywhere near these levels of reliability.

Clinical Significance of Ph+ Cells Detected Early (3 months) After BMT
Disappearance of the Ph+ clone may occur in patients who had detectable cells early after transplant, presumably related to the graft-versus-leukemia effect. Consistent with this premise, detection of Ph+ metaphases generally predicts relapse after a T-cell–depleted or syngeneic transplant, presumably because of a lack of effective graft-versus-leukemia activity. As in patients no. 9 and no. 10, it is not unusual to see a low frequency of Ph+ cells within 3 months after BMT that are not detected subsequently. Similar results using HMF were reported by El-Rifai et al21 on two patients.

Clinical Significance of Ph+ Cells Detected 3 Months or Later After BMT
In all seven cases where we found low but statistically significant levels of Ph+ cells by HMF that were not detectable by CG, the next cytogenetic readings (all within 6.5 months) indicated a higher percentage of Ph+ cells. These data are also supported in the study by El-Rifai et al,21 in which two patients with significantly low levels (0.15%) of Ph+ cells, which were detected 4 months after BMT, relapsed. The level of Ph positivity that warrants therapeutic intervention is uncertain. In our study, patient no. 11 may be an example of a patient having less than a clinically significant level of Ph+ cells. In this patient, at 26 months after BMT, one cell in 500 was recorded as Ph+. Although below our level of statistical significance, it is interesting to note that a second positive cell (out of 400 assayed) was recorded 18 months later (after two Ph- readings in between), and close follow-up of this patient is warranted. Significantly low levels of Ph+ cells (< 0.30%) that have not resulted in relapse Ph+ readings 4 months later have also been reported for four patients by El-Rifai et al.21 These data suggest that patients with less than 0.30% Ph+ cells detected by HMF (which would also be readily detected by PCR) may continue to sustain remission and may not require immediate intervention; however, close monitoring is still warranted.

When to Intervene?
Early recognition of CML relapse after BMT is becoming increasingly important with the recent documentation that DLI can reinduce complete remission via a graft-versus-leukemia effect. This approach is most effective when applied early in the course of relapse. Kolb et al13 reported that, among 84 patients, 14 patients (82%), 39 patients (78%), and one patient (12.5%) achieved complete remission after DLI for cytogenetic relapse, hematologic relapse, and transformed phase relapse, respectively. Similar data was reported by Collins et al.15 Van Rhee et al11 reported a higher remission rate and a lower risk of marrow aplasia and other complications in patients transplanted early in cytogenetic relapse rather than in overt hematologic relapse. Early intervention at a time in which donor-derived hematopoietic cells are dominant might prevent the complications associated with pancytopenia.

HMF can quantitatively assess early cytogenetic relapse. In our observations, seven of seven patients relapsed who had low levels of Ph+ cells (0.37% to 5.2%) detected by HMF and not by CG more than 3 months after BMT. Consistent with the concept that intervention is most efficacious given at a time of low burden of malignant cells, remission was induced by DLI in patient no. 7 who had 1.8% Ph+ cells 29 months after BMT. Firm conclusions on the indications for donor lymphocyte induction require further study in larger numbers of patients. This requires consideration of clinical factors as well as stage of disease at transplant, T-cell depletion, and histocompatibility relationships. However, the data presented suggests that the presence of 1% to 2% Ph+ cells by HMF at any single time point at least 3 months after BMT or progressively higher readings at least 3 months after BMT with at least 0.37% Ph+ cells may warrant intervention.

In conclusion, HMF provided a quantitative method to detect and observe the frequency of Ph+ cells after allogeneic BMT. The ability to score large numbers of cells provides statistical confidence regarding the frequency of malignant cells and may allow institution of DLI or other therapy early in the course of leukemia relapse at a time when intervention may be most effective. In future studies, it will be useful to apply the newer quantitative approaches to reverse transcriptase PCR27 on the same samples analyzed by HMF to evaluate these different approaches for measuring clinically significant minimal residual disease.


   ACKNOWLEDGMENTS
 
Supported in part by grant nos. CA43936, CA49639, and CA55164 from the National Institutes of Health, Bethesda, MD.

We thank Kenneth D. Muller for his support.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Champlin RE, Golde DW: Chronic myelogenous leukemia: Recent advances. Blood 65:1039-1047, 1985[Free Full Text]

2. Rowley JD: The Philadelphia chromosome translocation: A paradigm for understanding leukemia. Cancer 65:2178-2184, 1990[Medline]

3. Lifshitz B, Fainstein M, Marcelle C, et al: bcr genes and transcripts. Oncogene 2:113-117, 1987

4. Shtivelman E, Lifshitz B, Gale RP, et al: Alternative splicing of RNAs transcribed from the human ABL gene and from the BCR-ABL fused gene. Cell 47:277-284, 1986[Medline]

5. Maxwell S, Kurzrock R, Talpaz M, et al: Analysis of P210bcr-abl tyrosine protein kinase activity in various subtypes of Philadelphia chromosome-positive cells from chronic myelogenous leukemia patients. Cancer Res 47:1731-1739, 1987[Abstract/Free Full Text]

6. Thomas ED, Clift RA: Indications for marrow transplantation in chronic myelogenous leukemia. Blood 73:861-864, 1989[Free Full Text]

7. Champlin RE, Goldman JM, Gale RP: Bone marrow transplantation in chronic myelogenous leukemia. Semin Hematol 25:74-80, 1988[Medline]

8. Snyder DS, McGlave PB: Treatment of chronic myelogenous leukemia with bone marrow transplantation. Hematol Oncol Clin North Am 4:535-557, 1990[Medline]

9. Kolb H, Mittermuller J, Clemm C, et al: Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76:2462-2465, 1990[Abstract/Free Full Text]

10. Szer J, Grigg A, Phillips G, et al: Donor leukocyte infusions after chemotherapy for patients relapsing with acute leukemia following allogeneic BMT. Bone Marrow Transplant 11:109-111, 1993[Medline]

11. van Rhee F, Lin F, Cullis J, et al: Relapse of chronic myeloid leukemia after allogeneic bone marrow transplant: The case for giving donor leukocyte transfusions before the onset of hematologic relapse. Blood 83:3377-3383, 1994[Abstract/Free Full Text]

12. Hertenstein B, Wiesneth M, Novotny J, et al: Interferon-a and donor buffy coat transfusions for treatment of relapsed chronic myeloid leukemia after allogeneic bone marrow transplantation. Transplantation 56:1114-1118, 1993[Medline]

13. Kolb H, Schatternberg A, Goldman J, et al: Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients: European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 86:2041-2050, 1995[Abstract/Free Full Text]

14. Antin J: Graft-versus-leukemia: No longer an epiphenomenon. Blood 82:2273-2277, 1993[Free Full Text]

15. Collins RH Jr, Shpilberg O, Drobyski WR, et al: Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. Clin Oncol 15:433-444, 1997

16. Radich J, Gehly G, Gooley T, et al: Polymerase chain reaction detection of the BCR-ABL after allogeneic BMT for CML: Results and implications in 346 patients. Blood 85:2632-2638, 1995[Abstract/Free Full Text]

17. Miyamura K, Tahara T, Tanimoto M, et al: Long persistent bcr-abl positive transcript detected by PCR after marrow transplant for CML without clinical relapse: A study of 64 patients. Blood 81:1089-1093, 1993[Abstract/Free Full Text]

18. Seong DC, Kantarjian H, Ro J, et al: Hypermetaphase FISH for quantitative monitoring of Ph-positive cells in patients with CML during treatment. Blood 86:2343-2349, 1995[Abstract/Free Full Text]

19. Trujillo J, Cork A, Ahearn M, et al: Hematologic and cytologic characterization of 8;21 translocation in AML. Blood 53:695-706, 1979 [Abstract/Free Full Text]

20. Schafer R, Zischler H, Brisner U, et al: Optimized oligonucleotide for DNA fingerprinting. Electrophoresis 369-374, 1988

21. El-Rifai W, Ruutu T, Vettenranta K, et al: Minimal residual disease after allogeneic bone marrow transplantation for chronic myeloid leukemia: A metaphase-FISH study. Br J Haematol 92:365-369, 1996[Medline]

22. Seong DC, Song MY, Henske E, et al: Analysis of interphase cells for the Philadelphia translocation using painting probe made by inter-alu PCR from a radiation hybrid. Blood 83:2268-2273, 1994[Abstract/Free Full Text]

23. Durnam DM, Anders KR, Fisher L, et al: Analysis of the origin of marrow cells in bone marrow transplant recipients using a Y-chromosome-specific in situ hybridization assay. Blood 74:2220-2226, 1989[Abstract/Free Full Text]

24. Seong D, Giralt S, Fischer H, et al: Usefulness of detection of minimal residual disease by ’hypermetaphase’ fluorescent in situ hybridization after allogeneic BMT for chronic myelogenous leukemia. Bone Marrow Transplant 19:565-570, 1997[Medline]

25. Offit K, Burns JP, Cunningham I, et al: Cytogenetic analysis of chimerism and leukemia relapse in chronic myelogenous leukemia patients after T-cell-depleted bone marrow transplantation. Blood 75:1346-1355, 1990[Abstract/Free Full Text]

26. Alimena G, Luia MR, Mecucci C, et al: Cytogenetic follow-up after BMT for Ph1-positive CML. Bone Marrow Transplant 5:119-127, 1990[Medline]

27. Cross N, Feng L, Chase A, et al: Competitive PCR to estimate the number of BCR-ABL transcripts in CML after BMT. Blood 82:1929-1936, 1993[Abstract/Free Full Text]

Submitted February 18, 1997; accepted January 5, 2000.


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


This article has been cited by other articles:


Home page
 Mayo Clin Proc.Home page
A. Tefferi, G. W. Dewald, M. L. Litzow, J. Cortes, M. J. Mauro, M. Talpaz, and H. M. Kantarjian
Chronic Myeloid Leukemia: Current Application of Cytogenetics and Molecular Testing for Diagnosis and Treatment
Mayo Clin. Proc., March 1, 2005; 80(3): 390 - 402.
[Abstract] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Seong, C.-M.
Right arrow Articles by Champlin, R. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Seong, C.-M.
Right arrow Articles by Champlin, R. E.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

About
JCO		 Editorial
Roster		 Advertising
Information		 Librarians &
Institutions		 Rights &
Permissions		 PDA Services

Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
Terms and Conditions of Use
  HighWire Press HighWire Press™ assists in the publication of JCO Online