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Evidence of a Graft-Versus-Leukemia Effect in Chronic Lymphocytic Leukemia After Reduced-Intensity Conditioning and Allogeneic Stem-Cell Transplantation: The Cooperative German Transplant Study Group

J. Schetelig, C. Thiede, M. Bornhäuser, R. Schwerdtfeger, M. Kiehl, J. Beyer, H.G. Sayer, N. Kröger, M. Hensel, C. Scheffold, T.K. Held, K. Höffken, A.D. Ho, J. Kienast, A. Neubauer, A.R. Zander, A.A. Fauser, G. Ehninger, W. Siegert

From the Charité Campus Virchow Klinikum and Klinik für Innere Medizin m.S. Hämatologie und Onkologie; Charité Campus Mitte, Humboldt-Universität zu Berlin, Medizinische Klinik II m.S. Onkologie und Hämatologie, Berlin; Universitätsklinikum Carl Gustav Carus, Medizinische Klinik und Poliklinik I, Dresden; Stiftung Deutsche Klinik für Diagnostik GmbH, Zentrum für Blutstammzell-und Knochenmarktransplantation, Wiesbaden; Klinik für Knochenmark-transplantation und Hämatologie/Onkologie GmbH, Idar-Oberstein; Klinikum der Philipps-Universität, Abteilung für Innere Medizin Hämatologie/Onkologie/Immunologie, Marburg; Friedrich Schiller Universität Jena, Klinik für Innere Medizin II; Universitäts-Krankenhaus Eppendorf, Medizinische Klinik Knochenmarktransplantation, Hamburg; Universität Heidelberg, Medizinische Klinik und Poliklinik, Abteilung Innere Medizin V, Hämatologie, Onkologie und Rheumatologie; and Westfälische Wilhelms-Universität, Medizinische Klinik, Innere Medizin A, Münster, Germany.

Address reprint requests to Wolfgang Siegert, MD, Medizinische KIinik II mit Schwerpunkt Onkologie und Hämatologie, Charité Campus Charité Mitte, Schumannstr. 20–21, 10117 Berlin, Germany; email: wolfgang.siegert{at}charite.de.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To study whether hematopoietic stem-cell transplantation (HSCT) after reduced-intensity conditioning is effective and tolerable in patients with advanced chronic lymphocytic leukemia (CLL).

Patients and Methods: Thirty patients with advanced B-cell CLL were included into the study. After reduced-intensity conditioning with fludarabine, busulfan, and antithymocyte globulin, patients received a transplant from related (n = 15) or unrelated donors (n = 15). Minimal residual disease (MRD) was monitored with a clone-specific polymerase chain reaction.

Results: After a median follow-up of 2 years, 23 patients are alive (to date). Neutrophil and platelet engraftment occurred after a median of 17.5 and 15 days, respectively. Acute graft-versus-host disease (GVHD) grade 2 to 4 was observed in 17 patients (56%), and chronic GVHD was observed in 21 patients (75%). Twelve patients (40%) achieved a complete remission (CR), and 16 patients (53%) achieved a partial remission. Late CR occurred up to 2 years after transplantation. MRD was monitored in eight patients with CR. All patients achieved a molecular CR. At last follow-up, six patients were in ongoing molecular CR. Causes of death were treatment-related complications in four patients and progressive disease in three patients. The probability of overall survival, progression-free survival, and nonrelapse mortality at 2 years was 72% (95% confidence interval [CI], 54% to 90%), 67% (95% CI, 49% to 85%), and 15% (95% CI, 1% to 29%), respectively.

Conclusion: Treatment-related mortality after reduced-intensity conditioning followed by allogeneic HSCT was low. The procedure induced molecular remissions in patients with advanced CLL. The observation of late remissions provided evidence of a graft-versus-leukemia effect.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
CHRONIC LYMPHOCYTIC leukemia (CLL) accounts for approximately 25% of all leukemias occurring in Western countries. The course of the disease is remarkably heterogeneous. Patients with progressive CLL have a median survival of 24 to 72 months.¹ However, in patients with fludarabine-refractory disease, the median survival is limited to about 1 year.² Especially for younger patients with aggressive disease, new treatment strategies are warranted. Although molecular remissions can be achieved by high-dose chemotherapy and subsequent autologous transplantation, there is no evidence that the disease can be cured by this approach. In contrast, allogeneic hematopoietic stem-cell transplantation (HSCT) might be advantageous because of a potential graft-versus-leukemia effect (GVL). Evidence of a GVL effect in CLL comes from case reports of remissions after donor lymphocyte infusions (DLI) or withdrawal of immunosuppressive drugs.^3–5 However, allogeneic HSCT is hampered by a treatment-related mortality of up to 50%.⁶ With the development of reduced-intensity conditioning, early transplantation-related mortality could be lowered dramatically. Khouri et al⁷ demonstrated first that successful allogeneic HSCT can be done in patients with indolent lymphoid malignancies without prior myeloablation, but they observed a high rate of transplantation failures. Slavin et al⁸ published data on a fludarabine-based regimen and reported stable hematopoietic engraftment without early procedure-related mortality in 26 patients. Our hypothesis was that patients with CLL might profit from reduced-intensity conditioning because the slow kinetics of tumor-cell growth in CLL generally allow the graft to exert its antileukemic effect. We therefore studied the feasibility and efficacy of allogeneic HSCT after reduced-intensity conditioning in patients with advanced CLL.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility Criteria
Diagnosis of B-cell CLL and staging of the disease were based on criteria recommended in 1996 by the National Cancer Institute (NCI)–sponsored Working Group Guidelines for CLL.⁹ Typing of HLA-A and HLA-B was based on serology or DNA analysis, depending on the local immunogenetic laboratories. HLA-DRB1 was determined by high-resolution molecular typing in all patients and donors. Entry criteria required a diagnosis of CLL, progressive or relapsing disease, age younger than 65 years, a related or unrelated donor fulfilling published criteria on immunogenetic histocompatibility,¹⁰ and sufficient organ function. The treatment protocol was approved by the institutional review board of the Charité Hospital, Humboldt Universität zu Berlin (Berlin, Germany) and the local ethics committees of the participating centers. Written informed consent was obtained from all patients.

Patient Characteristics
Between July 1998 and July 2001, 30 patients with CLL entered the study. In one patient (patient 20), the diagnosis was revised to prolymphocytic leukemia. The patient was not excluded from the analysis. The median age at HSCT was 50 years (range, 12 to 63 years) and the median interval between diagnosis and HSCT was 4 years (range, 1 to 17 years). Pretreatment was heterogeneous with a median of three (range, zero to eight) prior chemotherapy regimens. At HSCT, 14 patients (46%) had chemotherapy-refractory disease; among them, 10 patients (33%) had fludarabine-refractory disease. More details are listed in Table 1. Donors were siblings (n = 13), non–HLA-identical family members (n = 2), and matched unrelated volunteers (n = 15). Two patients with related donors differed unidirectionally from their donors in one class I antigen (one patient in the host-versus-graft direction and one patient in graft-versus-host direction). Of three patients with unrelated donors, two patients with DRB1 mismatches had bidirectional mismatches and one patient had a unidirectional host-versus-graft mismatch. All class II mismatches were at the allele level. Twenty transplantations were performed in which either the donor or the recipient was cytomegalovirus seropositive.

GVHD Prophylaxis
GVHD prophylaxis was initially carried out with cyclosporine (CS) alone (n = 7). After the data indicated severe acute and chronic GVHD, the prophylaxis was intensified after September 1999. Hence, CS was combined with short-course methotrexate (MTX; n = 11) or mycophenolate mofetil (MMF; n = 12) with taper starting at day +30. Targeted CS therapy was prolonged from day +100 to day +180.

Supportive Care
Supportive care was provided according to institutional guidelines for HSCT recipients. For infection prophylaxis patients received oral quinolones and amphotericin B suspension. Empiric antibiotic treatment for neutropenic fever consisted of broad-spectrum antibiotics. Intravenous amphotericin B was added for refractory neutropenic fever or if fungal infection was suspected or documented. RBC transfusions were given to maintain a hemoglobin level of 8 g/dL, and single-donor platelet concentrates were transfused to maintain a platelet count above 10 x 10⁹/L in afebrile patients and above 20 x 10⁹/L in febrile patients.

Assessment of Clinical Outcome
Toxicity was graded according to the NCI common toxicity criteria for BM transplantation. A diagnosis of veno-occlusive disease of the liver was based on the Baltimore criteria.¹¹ GVHD was graded according to consensus criteria.¹² GVHD persisting beyond day +100 or de novo GVHD occurring after day +100 was classified as chronic GVHD. Nonrelapse mortality was defined as death not related to progression of CLL. Remissions were defined according to the NCI criteria.⁹

Flow Cytometric and Molecular Analyses
Immunophenotypic and chimerism analyses were carried out every other week during the first 2 months, monthly during the next 4 months, and thereafter every 6 to 12 months. DNA from these samples was extracted and preserved for additional molecular analyses. Complete clearance of CD5/CD19-coexpressing cells from peripheral blood was defined in the presence of normal lymphocyte counts if the percentage of CD5/CD19-coexpressing cells per total CD19-positive cells was less than 25% or the kappa/lambda ratio was not shifted to more than 2:1 in agreement with the initial phenotype.¹³ Overall donor chimerism was analyzed using a multiplex polymerase chain reaction (PCR) as previously described.¹⁴

Before HSCT, DNA extracted from peripheral-blood mononuclear cells, BM, or lymph nodes was preserved for the generation of a clone-specific primer for PCR monitoring of minimal residual disease (MRD). The protocols used for PCR amplification, cloning, and sequencing were described previously.¹⁵ Briefly, DNA extraction, PCR setup, and post-PCR manipulations were strictly separated and aerosol-resistant pipet tips were used for all steps to avoid cross-contamination. A seminested PCR strategy was used for amplification of rearranged variable, diversity, and joining sequences. PCR products were separated on 3% agarose gels and stained with ethidium bromide (0.5 µg/mL). PCR bands were subcloned into a pCR II vector (TA-Cloning Kit; Invitrogen, Leek, the Netherlands). After transformation of competent Escherichia coli (One Shot INV F'; Invitrogen) and plating on selective agar (50 µg/mL ampicillin, 40 µg/mL X-Gal [BioVectra, Prince Edward Island, Canada]), between eight and 20 white colonies were picked per sample and minipreps were prepared from 5-mL overnight liquid cultures using the Mini Plasmid Spin Kit (Qiagen, Hilden, Germany). DNA sequencing of plasmids was performed on the model 377 automatic DNA sequencer (Applied Biosystems [ABI], Foster City, CA) using Dye Terminator Cycle sequencing kits (ABI) as recommended by the manufacturer. T7 and M13 reverse primers were used for forward and backward sequencing. Clone-specific PCR was performed using a dual clone-specific assay using forward and backward primers on the basis of the individual immunoglobulin heavy-chain variable region sequence. Specificity was controlled by amplification of the donor pretransplantation sample whenever available. PCR conditions were as reported recently,¹⁵ but the annealing temperature ranged from 55 to 60°C according to the melting temperature of the individual primer set. A hot-start polymerase (AmpliTaq Gold; Perkin-Elmer, Norwalk, CT) was used in all experiments to prevent unspecific amplification, and a total of 35 cycles were performed. Sensitivity, as determined by dilution experiments, was between 10^-4 and 10^-5.

Statistical Analysis
Feasibility was defined as a statistical end point in terms of 1-year treatment-related mortality. The sample size was determined to detect a 30% reduction of treatment-related mortality with a significance level of .05 and a power of 0.8 compared with historical data of 46% treatment-related mortality in 54 patients with CLL and a matched related-donor transplantation.⁶ Efficacy was defined as the rate of maximal responses after HSCT in terms of complete remission (CR) and partial remission (PR) according to NCI criteria.

Data were analyzed as of February 28, 2002. Comparisons of categorical variables were done by means of the ² test. Incidences of time-dependent variables and survival estimates were calculated by the method of Kaplan and Meier. Survival intervals were measured from the day of transplantation until death from any cause. Patients who were alive at the time of the analysis were censored at the date of last follow-up. Progression-free survival was measured from the day of transplantation until the date of confirmed progression, relapse, or death from any cause. Comparisons of progression-free survival and nonrelapse mortality were based on the log-rank test.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Engraftment
All patients were assessable for engraftment. Neutrophil counts more than 0.5 x 10⁹/L were reached after a median of 17.5 days (range, 6 to 37 days), and platelet counts more than 20 x 10⁹/L were reached after a median of 15 days (range, 9 to 62 days). Complete donor chimerism developed rapidly, with a median of 95% donor cells (range, 9% to 100%) in peripheral blood 4 weeks after transplantation. Late secondary graft failure occurred in one patient (patient 11) on day +210 in the presence of progressive disease (PD). In another patient (patient 8) with PR, lymphocyte counts remained high, and despite donor neutrophil and platelet engraftment, the overall donor chimerism never surpassed 20%.

Toxicities
Chemotherapy induced mild, short-term nausea. In one patient the application of ATG caused grade 3 allergic toxicity. Seven patients (23%) developed grade 3 mucositis and needed short-term nutritional support. Within the first 30 days, an increase of bilirubin 2 mg/dL was documented in 13 patients (43%). Two patients had a transient increase in creatinine BORDER="0"> 2 mg/dL. Fever lasted for a median of 2 days (range, 0 to 24 days). Six patients (20%) did not develop fever at all. According to Baltimore criteria, one patient (patient 21) had veno-occlusive disease. One patient (patient 28) had a nonfatal ischemic stroke on day +1. He recovered with mild residual cerebral dysfunction.

Graft-Versus-Host Disease (GVHD)
Acute GVHD grade 2 to 4 was observed in 17 patients (56%) and acute GVHD grade 3 to 4 was observed in six patients (20%). The incidence of acute GVHD grade 2 to 4 in patients with related donors was 27% compared with 87% in unrelated donors (P = .003). The median onset of acute GVHD was on day +20 (range, day +10 to +58) after transplantation. Limited chronic GVHD was seen in 15 (54%) of 28 assessable patients, whereas six patients (21%) had extensive GVHD. For patients with related versus unrelated donors, the incidence of extensive chronic GVHD was 13% versus 31% (P = .372), respectively. The addition of MTX or MMF to CS-based GVHD prophylaxis resulted in a nonsignificant reduction (52% v 71%; P = .427) of acute GVHD grade 2 to 4 compared with CS monotherapy.

GVHD-Related Complications
Two patients with acute GVHD grade 4 died because of invasive aspergillosis (patient 21) and sepsis (patient 1) on days 62 and 86, respectively. Viral encephalitis occurred in two patients after treatment of acute GVHD grade 2, caused by an unknown infectious agent on day +35 (patient 10) and by herpes simplex virus on day +60 (patient 14). Both patients recovered and are alive and well. One patient (patient 12) with extensive chronic GVHD died from cytomegalovirus pneumonia. Two more patients had pneumonia requiring mechanical ventilation on days +158 (patient 5, Chlamydia pneumoniae) and +226 (patient 10, infectious agent unknown), but recovered without sequelae. One patient (patient 16) who was taking high-dose prednisolone treatment for extensive chronic GVHD developed a psychosis and attempted suicide on day +295. After reduction of prednisolone, she recovered without sequelae.

Response
All patients were assessable for disease response. So far, 12 patients (40%) achieved a CR and 16 patients (53%) achieved a PR. Two patients (7%) had no response. Remissions often occurred late. In 12 patients with a follow-up of more than 2 years, the CR rate increased from 25% at 1 year to 66% at 2 years after transplantation. Flow cytometric monitoring of residual disease revealed slow kinetics of tumor-cell clearance. Clearance of CD5/CD19-coexpressing lymphocytes from peripheral blood was achieved at a median of 4 months (range, 1 to 14 months), with an overall probability of 85% (Fig 1). The clinical course of a 58-year-old woman (patient 13) with CLL refractory to chemotherapy highlights the cytoreductive power of this procedure. At the time of HSCT, she had a lymphocyte count of 89 x 10⁹/L and enormous abdominal lymph node enlargements (Fig 2). After HSCT, her blood count normalized and the abdominal tumor masses resolved. On day +581 she was in PR with residual BM infiltration. In total, six of 12 patients who achieved a CR had been refractory to fludarabine before HSCT. At last follow-up of 23 living patients, 12 patients (52%) were in CR and eight patients (35%) were in good PR, with no direct evidence of residual disease with the exception of persisting thrombocytopenia (n = 3) or BM infiltration as the single residual manifestation (n = 5; Table 2).

View larger version (9K): [in this window] [in a new window]   Fig 1. Clearance of CD5/CD19-coexpressing cells from peripheral blood in 23 patients with a well-defined cell population before hematopoietic stem-cell transplantation (HSCT). Time intervals were measured from the day of HSCT until the first negative result.

View larger version (127K): [in this window] [in a new window]   Fig 2. Response of abdominal masses. Computed tomography scans on (A) day 14 and (B) day +370 of patient 13 with chronic lymphocytic leukemia refractory to chemotherapy.

View larger version (11K): [in this window] [in a new window]   Fig 3. Molecular monitoring. (•) Detection of clone-specific DNA; () a negative polymerase chain reaction result.

View larger version (14K): [in this window] [in a new window]   Fig 4. The 2-year probability of overall and progression-free survival was 72% (95% confidence interval [CI], 54% to 90%) and 67% (95% CI, 49% to 85%), respectively. Estimates of nonrelapse and relapse mortality were 15% (95% CI, 1% to 29%) and 16% (95% CI, 0% to 32%), respectively.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Our hypothesis was that reduced-intensity conditioning and HSCT might be a promising approach for patients with advanced CLL because the kinetics of tumor-cell growth in CLL provides enough time for the graft to exert a GVL effect. In fact, 28 of 30 patients achieved a remission. Time to maximal response varied from 1 month to 2 years after transplantation. Long persistence of residual disease was documented by flow cytometry and clone-specific PCR. At the most recent follow-up, 12 of 23 living patients were in CR and eight patients were in good PR, with either persisting thrombocytopenia or residual BM infiltration as the single manifestation. Six patients who achieved CR were refractory to fludarabine before HSCT. Evidence of a GVL effect stems from two observations: the occurrence of CRs in patients with chemotherapy-refractory disease and the delayed clearance of CD5/CD19-coexpressing cells and clone-specific DNA. Preliminary evidence of the existence of a GVL effect in CLL came from several case reports of patients who reached CR after withdrawal of immunosuppression, the occurrence of GVHD, or DLI.^3–5,16 Most of these observations were made after standard conditioning protocols and the extent of the GVL effect in relation to the cytoreductive power of the conditioning regimen could not be estimated. However, the GVL effect is still poorly understood. Donor lymphocyte infusions were of limited efficacy in our trial, and the fact that late remissions were often observed in the presence of extensive chronic GVHD raises doubt about the specificity of the antileukemic effect.

With the use of a clone-specific PCR identifying the rearranged complementarity-determining region 3 of the clonal B cells, we applied the most specific and sensitive tool for the detection of MRD. Our data show that eight of eight patients with CR achieved a PCR-negative status at some time after HSCT, but only six of eight patients were in ongoing molecular remission at last follow-up. However, the predictive value of a PCR-negative status has not been validated in large trials, and the short follow-up of our study restricts conclusions about long-term disease-free survival. Provan et al¹⁷ published data on the monitoring of MRD with a clone-specific PCR after allogeneic HSCT. Eight of 10 patients became PCR-negative and none of these patients relapsed. However, two patients died from treatment-related toxicity and the follow-up of the remaining six patients was only 1 to 4 years.

Another aim was to reduce the toxicity of the conditioning regimen and thereby to lower treatment-related mortality after allogeneic HSCT in CLL. The combination of fludarabine, busulfan, and ATG has moderate chemotherapy-related toxicity that is reflected by a low nonrelapse mortality at day +100.^8,18 However, of greater concern than the acute chemotherapy-related toxicity after HSCT is the morbidity and mortality caused by acute and chronic GVHD. Despite intensification of GVHD prophylaxis by the combination of CS with short-course MTX or MMF, GVHD still remained the major problem. This was particularly true for patients with unrelated donors. In our study, the 2-year probability of nonrelapse mortality was 28% in unrelated transplants and zero in related transplants, resulting in an overall nonrelapse mortality of 15%. These results are promising compared with the up to 50% treatment-related mortality after standard related allogeneic transplants in CLL.^6,16,19 Thus, there is hope that the obstacle of high treatment-related mortality after allogeneic HSCT in patients with CLL can be overcome with the use of reduced-intensity conditioning.

In a preliminary analysis, donor type, chemosensitivity, prior fludarabine-exposure and sensitivity, and the number of prior chemotherapy regimens did not show a significant influence on 2-year progression-free survival. However, the meaning of this analysis is limited because of the small number of patients and the large number of potential risk factors. Therefore, the most important task for the near future is to identify groups of patients who might benefit most from allogeneic HSCT. In particular, the significance of biologic risk factors of CLL, such as the 17p and 11q aberration or the mutational status of the variable heavy-chain gene on the outcome after HSCT, have to be evaluated.^20,21

In conclusion, with the use of reduced-intensity conditioning, allogeneic HSCT in patients with CLL can be carried out safely. There is evidence of a powerful GVL effect in CLL. HSCT after dose-reduced conditioning might therefore become a promising treatment option for advanced CLL. Larger trials with a longer follow-up are warranted to determine the optimal timing of this procedure in the course of the disease, and to evaluate the impact of biologic and clinical risk factors on the outcome after allogeneic transplantation.

	ACKNOWLEDGMENTS

 
We thank H.J. Deeg (Fred Hutchinson Cancer Research Center, Seattle, WA) for critically reading the manuscript; the staff for providing excellent care; T. Braun, C. Theuser, K. Davis, and L. Kraut for data management; and U. Löwel, M. Hartwig, and P. Grassmel for excellent technical assistance in molecular analyses.

	NOTES

 
Supported by the Deutsche Krebshilfe (70-2755; C.T.,M.B.).

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted December 2, 2002; accepted April 17, 2003.

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