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In Reply:

Institute of Hematology and Oncology, Department of Hematology, Institut d'Investigacions Biomèdiques August Pi i Sunyer Hospital Clínic, University of Barcelona, Spain

On the occasion of the publication of our article, "Allogeneic stem cell transplantation may overcome the adverse prognosis of unmutated VH gene in patients with chronic lymphocytic leukemia" Nabhan and Bitran raise a number of questions concerning our article,¹ but they also generally examine the prognosis and management of patients with chronic lymphocytic leukemia (CLL).

Although we appreciate Nabhan and Bitran's comments, we cannot accept their statement that the main conclusion of our article—the fact that allogeneic stem cell transplantation may overcome the adverse prognosis of unmutated VH gene in CLL—is not supported by data. In no part of our article is it claimed that there is a statistically significant difference in terms of event-free or overall survival. On the contrary, throughout the article we cautiously propound the view that the benefit of allogeneic transplantation in patients with unmutated CLL is likely but has not been definitively proved. We close by saying that our results "suggest that the graft-versus-tumor effect may overcome" and also that this should be "confirmed in other series." Nevertheless, even with these caveats, we cannot help considering that the data shown in our article are convincing and that the progression rate is the most important end point for the purpose of our study since event-free and overall survival include events other than progression. Other authors produced similar results, albeit in a shorter series of patients.² On the other hand, as correctly indicated by Nabhan and Bitran, the P value of .06 in event-free-survival is most likely due to the small size of the series. Plausible clinical results should not be dismissed just because, as in this study, the P value is .06 instead of .05.^3,4

The fact that, in the whole series, patients who receive allografts do better than those receiving autografts, independently of the characteristics of the disease, is not surprising, because whereas all autografted patients eventually relapse, there is a plateau in survival curves in allografted patients. This points to a graft-versus-tumor effect, as shown in many reports.^5-7

Regarding other issues, our correspondents ask for the treatment that patients received before transplantation. Since these patients underwent transplantation over many years (a situation that, incidentally, allows us to present long-term results), the salvage regimen varied. In most cases it included fludarabine, fludarabine-based chemotherapy,⁸ and in addition, in some cases, alemtuzumab. Disease status at transplantation is shown in the article.

They also inquire about treatment results based on minimal residual disease (MRD). MRD status before transplant was available in 30 patients, of whom two were MRD negative, thus precluding a meaningful analysis of the outcome based on MRD. As shown in a previous article from our group⁵ and by others,^9-13 the higher the response achieved before autotransplantation the better the outcome; also, whereas MRD detection did herald clinical relapse in autografted patients, this was not necessarily so in those who received an allograft. Moreover, in some allografted patients it took several months to achieve MRD-negative status.

There are other comments such as the prognostic value of ZAP-70 that we certainly appreciate. Although the paper was not intended to discuss this interesting topic, discrepancies between ZAP-70 and VH gene mutational status are much lower when using the technique we first described.¹⁴ Besides technical aspects (eg, monoclonal antibody used), it has recently been suggested that discrepancies might be related to the expression of VH 3.21 genes or poor cytogenetic features in mutated cases with high ZAP-70 expression.¹⁵ In our series, ZAP-70 could be determined in 18 patients and in only one case was there a discrepancy between these two variables (high ZAP-70/mutated VH); moreover, in 110 patients from our database in whom VH gene mutations and ZAP-70 have been studied, discrepant cases account for only 11% of cases. As for cytogenetics, seven of 18 allografted patients had poor cytogenetics, all of them being VH gene unmutated. In the autografted group, five of 15 patients also had unfavorable cytogenetics, all being VH gene unmutated.

Regarding the more general comments, it would be hard to disagree with Nabban and Bitran that CLL is a heterogeneous disease. Concerning the importance of achieving MRD-negative status in this form of leukemia, we provided some of the first evidence in that respect,⁸ so we are quite convinced. However, it could always be argued that patients achieving MRD-negative status may have an intrinsically more indolent form of the disease and hence have a better prognosis.

It is also important, as stressed by our correspondents, to identify patients with poor-risk disease who might benefit from early, intensive therapy. However, despite the progress toward that direction (eg, by identifying prognostic parameters such as cytogenetic abnormalities, VH gene mutational status or ZAP-70 expression that add predictive power to clinical stages),¹⁶ we are still far from this goal. As a result, we continue indicating treatment based on classical criteria of the National Cancer Institute-Working Group¹⁷ but not on biologic features, an important issue currently being addressed in randomized trials and whose benefits have not yet been demonstrated.

Finally, regarding the role of transplants in the management of CLL, these should be conducted within trials. Since patients with mutated VH genes or low ZAP-70 expression tend to have good prognosis they should not undergo transplantation at all unless they show unequivocal unfavorable prognostic features. We have virtually abandoned autografts in patients with CLL since all patients autografted eventually relapse and a survival benefit has not been convincingly demonstrated. However, patients with poor risk features having achieved complete response and lacking an HLA-matched sibling donor may still be reasonable candidates. Regarding allogeneic transplants, we offer this treatment to patients refractory to purine analogs-based therapy because of their extremely poor prognosis; older or unfit patients and those patients with chemotherapy sensitive disease are offered nonmyeloablative transplants. However, in no case we do advocate allogeneic transplantation as upfront therapy.¹⁸

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Moreno C, Villamor N, Colomer D, et al: Allogeneic stem-cell transplantation may overcome the adverse prognosis of unmutated VH gene in patients with chronic lymphocytic leukemia. J Clin Oncol 23:3433-3438, 2005[Abstract/Free Full Text]

2. Ritgen M, Stilgenbauer S, von Neuhoff N, et al: Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy chain gene status: Implications of minimal residual disease measurement with quantitative PCR. Blood 104:2600-2602, 2004[Abstract/Free Full Text]

3. Goodman SN: Toward evidence-based medical statistics. 1: The P value fallacy. Ann Intern Med 130:995-1004, 1999[Medline]

4. Browner WS: The reliability of P values. Science 301:167-168, 2003

5. Esteve J, Villamor N, Colomer D, et al: Stem cell transplantation for chronic lymphocytic leukemia: Different outcome after autologous and allogeneic transplantation and correlation with minimal residual disease status. Leukemia 15:445-451, 2001[CrossRef][Medline]

6. Mattsson J, Uzunel M, Remberger M, et al: Minimal residual disease is common after allogeneic stem cell transplantation in patients with B-cell chronic lymphocytic leukemia and may be controlled by graft-versus-host disease. Leukemia 14:247-254, 2000[CrossRef][Medline]

7. Dreger P, Brand R, Hansz J, et al: Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning. Leukemia 17:841-848, 2003[CrossRef][Medline]

8. Bosch F, Ferrer A, Lopez-Guillermo A, et al: Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia. Br J Haematol 119:976-984, 2002[CrossRef][Medline]

9. Dreger P, Van Biezen A, Brand R, et al: Prognostic factors for survival after autologous stem cell transplantation for chronic lymphocytic leukemia (CLL): The EBMT experience. Blood 96:482a, 2000 (abstr 2071)

10. Dreger P, Montserrat E: Autologous and allogeneic stem cell transplantation for chronic lymphocytic leukemia. Leukemia 16:985-992, 2002[CrossRef][Medline]

11. Esteve J, Montserrat E, Dreger P, et al: Stem cell transplantation (SCT) for chronic lymphocytic leukemia (CLL): Outcome and prognostic factors after autologous and allogeneic transplants. Blood 98:482a, 2001 (abstr 397)

12. Jabbour E, Keating MJ, Champlin RE, et al: Stem cell transplantation for chronic lymphocytic leukemia: Should not more patients get a transplant? Bone Marrow Transplant 34:289-297, 2004[CrossRef][Medline]

13. Paneesha S, Milligan DW: Stem cell transplantation for chronic lymphocytic leukaemia. Br J Haematol 128:145-152, 2005[CrossRef][Medline]

14. Crespo M, Bosch F, Villamor N, et al: ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 348:1764-1775, 2003[Abstract/Free Full Text]

15. Kienle D, Krober A, Winkler D, et al: High ZAP-70 and differential expression of B-cell receptor related genes in chronic lymphocytic leukemia with V3-21 gene usage. Blood 104:221a, 2004 (abstr 773)

16. Montserrat E: Assessing prognosis in patients with chronic lymphocytic leukemia a quarter of a century after Rai and Binet staging systems. Ann Oncol 15:1450-1451, 2004[Free Full Text]

17. Cheson BD, Bennett JM, Grever M, et al: National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: Revised guidelines for diagnosis and treatment. Blood 87:4990-4997, 1996[Free Full Text]

18. Montserrat E, Moreno C, Esteve J, et al: How we treat refractory CLL. Blood (in press)

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Related Correspondence

• Chronic Lymphocytic Leukemia: To Transplant or Not to Transplant... That Is the Question?
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