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Blood, 15 October 2004, Vol. 104, No. 8, pp. 2600-2602. Prepublished online as a Blood First Edition Paper on June 17, 2004; DOI 10.1182/blood-2003-12-4321. This Article Abstract Full Text (PDF) All Versions of this Article: 2003-12-4321v1 104/8/2600    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ritgen, M. Articles by Dreger, P. Search for Related Content PubMed PubMed Citation Articles by Ritgen, M. Articles by Dreger, P. Related Collections Neoplasia Transplantation Brief Reports Clinical Trials and Observations Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  TRANSPLANTATION Brief report 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 Matthias Ritgen, Stephan Stilgenbauer, Nils von Neuhoff, Andreas Humpe, Monika Brüggemann, Christiane Pott, Thorsten Raff, Alexander Kröber, Donald Bunjes, Richard Schlenk, Norbert Schmitz, Hartmut Döhner, Michael Kneba, and Peter Dreger From the Second Department of Internal Medicine, University of Kiel, Germany; the Third Department of Internal Medicine, University of Ulm, Germany; the Institute of Cellular and Molecular Pathology, University of Hannover, Germany; and the Department of Hematology, AK St Georg, Hamburg, Germany.    Abstract Top Abstract Introduction Study design Results and discussion References   The aim of this study was to investigate if graft-versus-leukemia (GVL) activity conferred by allogeneic stem cell transplantation (allo-SCT) is effective in chronic lymphocytic leukemia (CLL) with unmutated VH gene status. The kinetics of residual disease (MRD) were measured by quantitative allele-specific immunoglobulin heavy chain (IgH) polymerase chain reaction (PCR) in 9 patients after nonmyeloablative allo-SCT for unmutated CLL. Despite an only modest decrease in the early posttransplantation phase, MRD became undetectable in 7 of 9 patients (78%) from day +100 onwards subsequent to chronic graft-versus-host disease or donor lymphocyte infusions. With a median follow-up of 25 months (range, 14-37 months), these 7 patients remain in continuous clinical and molecular remission. In contrast, PCR negativity was achieved in only 6 of 26 control patients (23%) after autologous SCT for unmutated CLL and it was not durable. Taken together, this study shows for the first time that GVL-mediated immunotherapy might be effective in CLL with unmutated VH.    Introduction Top Abstract Introduction Study design Results and discussion References   Recently, the mutational status of the variable region of the immunoglobulin heavy-chain gene (VH) has been established as a crucial prognostic factor in chronic lymphocytic leukemia (CLL). Whereas patients with somatic mutations of the VH gene are characterized by stable disease and long survival, an unmutated germ line VH configuration is associated with a dismal prognosis.1-4 Allogeneic stem cell transplantation (allo-SCT) can result in long-term disease control in a proportion of patients with resistant CLL,5-9 and there is some evidence for graft-versus-leukemia (GVL) activity after allo-SCT.10-12 To date, however, it is unknown whether GVL can be effective in patients with unmutated VH status. Information on this issue is particularly important, as allo-SCT in CLL is increasingly performed using nonmyeloablative conditioning,13-16 implying that the contribution of GVL for disease control becomes even more essential. The purpose of the present study was to investigate whether the therapeutic resistance of unmutated CLL can be overcome by allo-SCT following nonmyeloablative conditioning (NST), and to compare the relative contributions of conditioning regimen and GVL to tumor control.    Study design Top Abstract Introduction Study design Results and discussion References   Patients and treatment protocols Included in this study were consecutive patients from an ongoing prospective trial on NST in CLL17 who had an unmutated VH status and diagnostic material available for longitudinal quantitative molecular monitoring. Minimum follow-up time required was 12 months. Eligibility criteria were as follows: refractoriness or early relapse (within 12 months) after fludarabine-containing treatment or after autologous SCT (auto-SCT); Richter transformation; or high-risk disease as defined by an unfavorable genetic profile (del11 q23 and/or del 17p13 and/or unmutated VH status)18 in the presence of progressive disease. Allogeneic peripheral blood stem cells from granulocyte colony-stimulating factor (G-CSF)–mobilized HLA-identical donors were infused after conditioning by daily fludarabine (30 mg/m2) and cyclophosphamide (500 mg/m2) over 5 days, followed by cyclosporin A (CSA) and short-course methotrexate for graft-versus-host disease (GVHD) prophylaxis. In the case of unrelated donors, antilymphocyte globulin was added. CSA was tapered between day +60 and +100 after transplantation, in the absence of GVHD. Donor lymphocyte infusions (DLIs) were administered from day +120 onwards in the case of incomplete chimerism or residual disease after CSA withdrawal. Patients from a prospective protocol on the value of auto-SCT after myeloablative conditioning in CLL who fulfilled similar criteria served as controls.19 Eligibility and treatment details of auto-SCT have been described elsewhere.4,20 Treatment protocols were approved by the responsible institutional review boards. Molecular studies Immunoglobulin heavy chain (IgH) sequencing, mutational status assessment,3,4 interphase cytogenetics,18 and chimerism studies21 were done as described previously. IgH real-time polymerase chain reaction (RQ-PCR) for MRD quantification was performed with an ABI PRISM 7700 thermal cycler (Applied Biosystems, Weiterstadt, Germany).22 DNA from samples with known CLL cell content as assessed by standard flow cytometry (CD19/CD5/CD23/CD20 coexpression) were serially diluted in pooled polyclonal DNA to generate at least 5 standards. Specificity and sensitivity was defined as the last dilution with target DNA detectable or, in case of nonspecific amplification, the dilution with cycle threshold (CT) values at least one cycle lower than the lowest CT value found in polyclonal DNA. Each PCR showed a standard curve correlation coefficient of at least 0.95 with a slope of 3.0 to 3.9, minimum sensitivity was 10–4, and MRD level calculation was based on comparative CT analysis between follow-up samples and standards. Normalization by parallel amplification of the albumin gene22 allowed calculating of sensitivity levels for negative samples.    Results and discussion Top Abstract Introduction Study design Results and discussion References   Altogether, 9 patients with unmutated high-risk CLL who had undergone NST and 26 control patients who had undergone auto-SCT for unmutated CLL met the inclusion criteria for this study. NST patients had pretransplantation characteristics similar to the auto-SCT group in terms of sex, age, VH homology, unfavorable fluorescence in situ hybridization (FISH) karyotype, lymphocyte doubling time (LDT), and stage, but were more heavily pretreated and had a longer time from diagnosis to transplantation (Table 1). View this table: [in this window] [in a new window]   Table 1.. Patient characteristics   Peripheral blood MRD kinetics in the NST patients were characterized basically by a biphasic pattern with an only modest decrease in the early posttransplantation phase (median MRD level: 1.9 x 10–1 [range, 2.9 x 10–3-1.9 x 100] before NST versus 1.1 x 10–2 [range, 1.8 x 10–4-2.3 x 10–2] at day +100; P = .002), followed by a marked reduction of more than 2 logs in the MRD levels between day +100 and day +200 (8.4 x 10–5 [range, 1.0 x 10–5-1.1 x 10–2]; P =.005). During follow-up, MRD levels stayed low and became durably undetectable in 7 of 9 patients (78%; Figure 1). In 5 of the 9 NST patients, disappearance of RQ-PCR–measurable MRD occurred subsequent to development of extensive chronic GVHD. Three patients remained free of GVHD. Two of these patients converted to sustained MRD negativity after DLI without any GVHD, one without conversion to complete chimerism (Figure 1), whereas one patient failed to eliminate MRD despite DLI. The remaining patient, who was the only carrier of a 17p13 deletion in this series, showed evidence of early clinical relapse with progressive bulky lymphadenopathy prior to the onset of extensive chronic GVHD 4 months after allo-NST. Although GVHD was associated with declining but positive MRD levels, the patient died in progressive disease at month +19.All other 8 patients are in ongoing complete clinical remission with a median follow-up of 29 months (range, 14-41 months) after transplantation. View larger version (34K): [in this window] [in a new window]   Figure 1.. MRD kinetics after autologous SCT and nonmyeloablative allogeneic SCT. MRD levels (number of CLL-specific DNA copies per total DNA copies in the sample compared with the reference [pretherapeutic] sample) of patients after myeloablative conditioning and auto-SCT (A) and after nonmyeloablative allo-SCT (B). () denotes MRD-positive samples; () denotes the sensitivity of PCR-negative samples (calculated minimum MRD level, which would have been detected in this particular sample); and () denotes percentage of donor chimerism. (C-F) Individual MRD kinetics in correlation to cyclosporine withdrawal (C), DLI (D), and chronic GVHD (E). (F) Case with discordant MRD and chimerism data, implying that GVL can induce CLL clearance without achieving full donor chimerism.   Auto-SCT resulted in an immediate reduction of MRD levels (6.4 x 10–3 [range, 4.0 x 10–4-3.9 x 10–1] before SCT versus 2.3 x 10–4 [range, 5 x 10–6-2.5 x 10–1]atday +100; P = .0002) without further decrease during longer follow-up (median clone-specific DNA copy number at 2 years after transplantation was 5.0 x 10–4 [range, 1 x 10–5-6 x 10–1]; P = .43 if compared to day +100). Although 6 of 26 patients (23%) eventually became PCR negative, there were only 2 patients whose MRD levels remained below the threshold of detection until their most recent follow-up at 28 and 29 months after transplantation, respectively (Figure 1). Clinical relapse, progression, or death was observed in 11 patients after auto-SCT, translating into a median progression-free survival of 48 months. Occurrence of clinical relapse was not predictable by day +100 MRD levels, day +360 MRD levels, or by achievement of MRD negativity at any time after transplantation. There is circumstantial evidence that GVL mechanisms contribute to disease control after allo-SCT in CLL.6,8-12,16,17 However, using sensitive longitudinal MRD quantification, the present study is the first to demonstrate a clear correlation between CLL load kinetics and immune modulating maneuvers after NST. Our results show that profound and sustained complete molecular responses occur only after establishing chronic GVHD or DLI, whereas the influence of the conditioning regimen on the tumor cell load is limited. Of note, all patients studied had an unmutated VH gene status, showing for the first time that unmutated CLL is sensitive to GVL. Since the GVL-mediated antileukemic activity observed here is clearly superior to that of the intensified fludarabine-cyclophosphamide regimen used for conditioning as well as to the fully myeloablative treatment administered for auto-SCT, allo-SCT appears to be the most effective and yet only potentially curative modality available for treatment of unmutated CLL. This conclusion is confirmed by a recent preliminary report of clinical observations.23 In contrast, auto-SCT can reduce but not eradicate PCR-measurable tumor load in the majority of patients with unmutated CLL. This observation is in line with previous studies showing that complete responses documented by clinical criteria and by less-sensitive CDR3 consensus primer PCR assays are not durable after auto-SCT.4,12,20,23 In summary, this study demonstrates that allo-SCT can provide sustained disease control in unmutated CLL. Complete elimination of measurable MRD after allo-SCT is largely dependent on GVL, whereas the contribution of the conditioning regimen to treatment success appears to be limited. These results may help to define the future role of allo-SCT within the growing therapeutic arsenal for high-risk CLL.    Acknowledgements   The authors are grateful to the German CLL Study Group (DCLLSG; chairman Michael Hallek) and all the contributing centers taking care of patients being enrolled in this study. As in all studies of the DCLLSG, the cytogenetic studies were performed by S. Stilgenbauer, A. Kröber, and H. Döhner at the University of Ulm, the MRD and chimerism analyses were performed by M. Ritgen,A. Humpe, and M. Kneba at the University of Schleswig-Holstein in Kiel.    Footnotes   Submitted December 22, 2003; accepted April 12, 2004. Prepublished online as Blood First Edition Paper, June 17, 2004; DOI 10.1182/blood-2003-12-4321. Supported by the "Deutsche José Carreras Leukämie-Stiftung e.V." (LR02/18), München, Germany; Wilhelm-Sander Stiftung (2001.004.1); and Fresenius AG, Germany. An Inside Blood analysis of this article appears in the front of this issue. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Matthias Ritgen, Second Department of Internal Medicine, Chemnitzstr 33, D-24116 Kiel, Germany; e-mail: m.ritgen{at}med2.uni-kiel.de.    References Top Abstract Introduction Study design Results and discussion References   Damle RN, Wasil T, Fais F, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94: 1840-1847.[Abstract/Free Full Text] Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94: 1848-1854.[Abstract/Free Full Text] Kröber A, Seiler T, Benner A, et al. VH mutational status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood. 2002;100: 1410-1416.[Abstract/Free Full Text] Ritgen M, Lange A, Stilgenbauer S, et al. 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Dreger P, Stilgenbauer S, Benner A, et al. The prognostic impact of autologous stem cell transplantation in patients with chronic lymphocytic leukemia: a risk-matched analysis based on the VH gene mutational status. Blood. 2004;103: 2850-2858.[Abstract/Free Full Text] Thiede C, Bornhauser M, Oelschlagel U, et al. Sequential monitoring of chimerism and detection of minimal residual disease after allogeneic blood stem cell transplantation (BSCT) using multiplex PCR amplification of short tandem repeat-markers. Leukemia. 2001;15: 293-302.[CrossRef][Medline] [Order article via Infotrieve] Bruggemann M, Droese J, Bolz I, et al. Improved assessment of minimal residual disease in B cell malignancies using fluorogenic consensus probes for real-time quantitative PCR. Leukemia. 2000;14: 1419-1425.[CrossRef][Medline] [Order article via Infotrieve] Moreno C, Colomer D, Villamor N, Esteve J, Bosch F, Montserrat E. Allogeneic, but not autologous, stem-cell transplantation overcomes the negative impact of unmutated VH genes in patients with CLL [abstract]. Blood. 2003;102: 11a. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: CLL: to mend it or be rid of it Terry Hamblin Blood 2004 104: 2210. [Full Text] [PDF] This article has been cited by other articles: T. Nishida, M. Hudecek, A. Kostic, M. Bleakley, E. H. Warren, D. Maloney, R. Storb, and S. R. Riddell Development of Tumor-Reactive T Cells After Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplant for Chronic Lymphocytic Leukemia Clin. Cancer Res., July 15, 2009; 15(14): 4759 - 4768. [Abstract] [Full Text] [PDF] L. Farina, C. Carniti, A. Dodero, A. Vendramin, A. Raganato, F. Spina, F. Patriarca, F. Narni, F. Benedetti, A. Olivieri, et al. 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[Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) All Versions of this Article: 2003-12-4321v1 104/8/2600    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ritgen, M. Articles by Dreger, P. Search for Related Content PubMed PubMed Citation Articles by Ritgen, M. Articles by Dreger, P. Related Collections Neoplasia Transplantation Brief Reports Clinical Trials and Observations Related Article in Blood Online Social Bookmarking                   What's this?

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