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Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus, 01307 Dresden, Germany
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental Design: Recipient conditioning consisted of fludarabine 30 mg/m2 on days -6 to -2 and i.v. busulfan 3.3 mg/kg on days -6 to -5. Antithymocyte globuline was added at 2.5 mg/kg i.v. on days -5 to -2. The patients were grafted with bone marrow (n = 13) or peripheral blood stem cells either unmanipulated (n = 20) or CD34+ selected (n = 9). Graft-versus-host disease prophylaxis was performed with cyclosporine A (CsA, n = 12), CsA/methotrexate (n = 12), or CsA/mycophenolate mofetil (n = 18).
Results: With a median follow-up of 13 months (range, 5–26 months), the actuarial disease-free survival is 64% and 38% for patients with lymphoid malignancies and standard-risk leukemia compared with only 14% for patients with high-risk disease. The main cause of treatment failure was relapse of disease in high-risk patients (n = 14). An increased incidence of primary (n = 1) or secondary graft-failure (n = 8) was observed (21%). Chimerism analysis of CD56+/CD3--sorted natural killer (NK) cells, available in 10 patients, showed an impaired increase of donor NK cell chimerism between day 10 and 30 after transplantation in three of four patients with graft failure, whereas the percentage of donor NK cells surpassed 75% in all of the six patients with stable engraftment.
Conclusions: Unrelated transplants after dose-reduced conditioning are associated with a higher risk of graft-failure. Pretransplant host immunosuppression has to be optimized to overcome resistance to grafts from unrelated donors after nonmyeloablative conditioning therapy.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Significant graft-versus-leukemia effects have been demonstrated in patients with recurrent leukemia after allogeneic BM transplantation. Prolonged remission can be achieved by donor lymphocyte infusions in 70 to 80% of patients with relapsing chronic myeloid leukemia (1 , 2) . Investigators in several centers have now started to explore dose-reduced conditioning using either purine analogue or low-dose TBI-based regimens to establish a mixed lympho-hematopoietic chimerism, which is the prerequisite for subsequent adoptive transfer of donor lymphocytes and their antileukemic effects.
Stable mixed donor chimerism has been demonstrated in a canine model after nonmyeloablative conditioning therapy (3) . Encouraging clinical results have been achieved by using reduced doses of alkylating agents together with purine analogues for conditioning therapy (4 , 5) . Only recently (6) , stable engraftment was described in patients after 200-rad TBI combined with immunosuppressive drugs. Other investigators (7) reached the same goal by combining cyclophosphamide at 150–200 mg/kg with thymic irradiation and antithymocyte globuline (ATG).
In most of these studies, hematopoietic stem cell grafts from HLA-identical sibling donors have been used. Taking into account the limited number of patients for whom an HLA-identical sibling donor can be identified, the use of alternative donors being either matched unrelated volunteers or mismatched family members has to be explored.
In this report, we summarize the clinical results of 42 patients receiving grafts from unrelated donors. We could show the feasibility of unrelated transplants after dose-reduced conditioning with stable remissions in standard-risk patients. A high rate of graft failure (21%) was observed. CML patients and recipients of HLA-mismatched grafts had the highest risk for this complication.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patient Characteristics.
The patient characteristics are summarized in Table 1
. Forty-two patients were enrolled in the study. Twenty-seven were male, and 15 were female. The age range at the time of transplantation was 16 to 65 years (median, 47 years). Twenty-two patients had AML or MDS, eight had CML, five had ALL, six had CLL or indolent NHL, and one had MM. The cohort of high-risk patients had failed up to four lines of chemotherapy (median, 2). The median time interval from diagnosis to the transplant was 18 months (range, 4–85). The median Karnofsky performance score at the time of transplantation was 70% (range, 50–90%).
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Conditioning Regimen.
Conditioning therapy was performed as described before (9)
. Busulfan (Sigma-Aldrich, Deisenhofen, Germany) at 3.3 mg/kg/day was infused over 3 h on days -6 and -5. The area under the curve achieved after a single-dose infusion of 3.3 mg/kg busulfan had been shown to be equivalent to 4 x 1 mg/kg of the oral formulation (10)
. Fludarabine (Medak, Munich, Germany) was given at 30 mg/m2/day over 30 min from day -6 to day -2. Antithymocyte globuline (Rabbit; Pasteur Mérieux, Lyon, France) was administered at a daily dose of 2.5 mg/kg over 4 h from day -5 to day -2. In four patients, ATG Fresenius (Bad Homburg, Germany) was used at a daily dose of 10 mg/kg.
Stem Cell and BM Collection.
The sources of hematopoietic stem cells are provided in Table 1
. BM was harvested on day 0 after informed consent of the donor in general anesthesia using conventional techniques. Mobilization of PBSCs was performed using 7.5 µg/kg lenograstim or 10 µg/kg filgrastim for 5 days and one or two aphereses on days 5 and 6. The product was cryopreserved when indicated. During the initial study period, CD34-positive selection of PBSCs from nine unrelated donors, of whom five had a HLA mismatch, was performed using an immunomagnetic device (CliniMACS; Milteny Biotec, Bergisch Gladbach, Germany) according to the manufacturer instructions (11)
. All of the patients who had received CD34-selected PBSCs were infused with unselected donor MNCs adjusted to contain 1 x 105/kg CD3-positive T cells on day 14 and 1 x 106/kg on day 21 when no signs of GvHD were detectable. Those T cells had been collected and frozen before granulocyte colony-stimulating factor stimulation. When <4 x 106 CD34-positive cells/kg were obtained with the first apheresis, unmanipulated PBSCs were infused. BM was infused without prior manipulation.
Supportive Care.
The patient rooms occupied by either one or two persons at the same time from the start of conditioning until neutrophil engraftment were supplied with filtered air. All of the patients received antibacterial and antifungal prophylaxis with ciprofloxacine at 500 mg twice daily and fluconazole at 200 mg/day. In addition, acyclovir was given at 1200 mg daily. All of the patients received prophylaxis with cotrimoxazole or pentamidine against Pneumocystis carinii infection. Patients with negative CMV IgG titers received blood products from CMV seronegative donors. Bacterial and fungal surveillance cultures were performed every second week. Broad-spectrum antibiotics were given whenever body temperature increased beyond 38.5°C, when C-reactive protein increased significantly, or when a positive finding was made on chest X-ray. PCR for CMV DNA and pp65 antigen testing in peripheral blood were performed once weekly. Patients received filgrastim at 5 µg/kg/day from day + 6 until the neutrophil count reached 1.0 x 109/liter. Hemoglobin was maintained at a level of >5 mmol/liter, and the platelet count was maintained at >20 x 109/liter with in-line filtered and irradiated (30 Gy) blood products.
GvHD Prophylaxis.
GvHD prophylaxis was performed with 5 mg/kg CsA i.v. starting 1 day before infusion of the graft. Further i.v. or oral dosage was adapted according to CsA trough blood levels. High-risk AML patients with >30% blasts in the BM (n = 3) and the patients transplanted with CD34+-selected PBSCs received only CsA (n = 9). Additional MTX (5 mg/m2) was administered in the first 12 recipients receiving unmanipulated grafts on days +1, +3, and +6. MMF was given p.o. at 2 g from day +1 to day +40 instead of MTX to the subsequent patients (n = 18) because the rate of acute GvHD 
grade II with MTX still seemed to be quite high (6 of 12; 50%), and animal data supposed MMF also to be useful as graft rejection prophylaxis (3)
. Patients developing acute GvHD were maintained at CsA and MMF and received 2 mg/kg/day prednisolone in addition, which was tapered upon clinical response.
Analysis of Chimerism.
Samples for chimerism analysis in peripheral blood were drawn twice weekly during hospital stay and weekly in the out-patient department. Chimerism analysis was performed as described recently (12)
. In brief, DNA was extracted from peripheral blood samples using a silica-based procedure (QiaAmp DNA blood kit; Qiagen, Hilden, Germany). Multiplex PCR was then performed using the AmpFlSTR Profiler kit (Applied Biosystems, Weiterstadt, Germany). High-resolution polyacrylamide-gel electrophoresis and four-color fluorescence detection were performed on an ABI 377 automated DNA sequencer. For each STR allele, the area under the curve for the corresponding signal was automatically processed by the GeneScan 3.1 software (PE Biosystems). The percentage of the donor chimerism was obtained by the following calculation: 
. Finally, a mean value was calculated for all of the informative (different between donor and recipient) alleles. The values are given as percentage donor signal.
Cell Sorting for Subset Analysis.
FACS was performed on a FACS Vantages cell sorter (Becton Dickinson, San Jose, California). MNCs were enriched by density gradient centrifugation (Lymphoprep; Pharmacia, Freiburg, Germany) from 30 to 60 ml of peripheral blood, depending on the actual cell counts. Erythrocytes were removed by hypotonic lysis. MNCs were then incubated with the following monoclonal fluorophore-conjugated antibodies: anti-CD3 PECy5, anti-CD3 PE, and anti-CD15 PE (Coulter Immunotech Diagnostics, Hamburg, Germany), anti-CD4 PE (PharMingen, Hamburg, Germany), anti-CD8 FITC and anti-CD56 FITC (DAKO Diagnostika, Hamburg, Germany). After washing in PBS solution, cells were sorted into the following populations: CD3+/CD4+ and CD3+/CD8+, CD3-/CD56+. The sample containing the granulocytes was incubated with anti-CD15 PE (Coulter Immunotech) and sorted as described above. Whenever possible, between 1,500–10,000 cells were sorted for each population. Samples were also collected to assess the purity of the sort for at least three populations whenever possible. The median purity, as measured by repeated FACS analysis, was 98% (range, 92–100%).
Study End Points.
Engraftment defined as >0.5 x 109/liter neutrophils for 3 days, >50 x 109/liter platelets without transfusion and treatment-related mortality in this patient cohort were the primary end points. Primary graft failure was defined as no hematological recovery until day +21. Secondary graft failure occurred when patients who had recovered in the early post-transplant period experienced cytopenia and decreasing chimerism not associated with relapsing disease. Secondary end points were the rate of acute GvHD observed and disease-free survival. Organ toxicity was documented according to the toxicity scales developed by the cancer therapy evaluation program of the National Cancer Institute. Acute and chronic GvHD were graded according to consensus criteria (13
, 14)
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Statistical Methods.
Most quantitative parameters are provided as median or mean with range or SD. The estimated overall and disease-free survival was calculated as of November 1st, 2000 from the day of transplantation and depicted according to the methods of Kaplan and Meier (15)
. The probability of survival of different groups were compared using the method of Kaplan-Meier with a log-rank test (Mantel-Haenszel). Univariate analysis was performed with the Fisher’s exact test. Cox’s regression model was used for multivariate analysis. All of the analyses were performed with the SPSS soft ware package 6.0 (SPSS Software, Munich, Germany).
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Extramedullary toxicity with a toxicity score of greater than 2 was observed in four patients only. One patient experienced a hemorrhagic cystitis requiring local therapy. Reversible jaundice with bilirubine levels elevated more than 10-fold was observed in two patients. One patient had a pneumonitis on day 21 that was attributed to a CMV reactivation. Fever of unknown origin (>38.5°C) occurred in 15 patients and lasted between 1 and 6 days. The median time with less than 0.5 x 109/liter neutrophils was 8 days (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29)
. Therefore, we did not observe early infectious complications. The overall day-100 treatment-related mortality was 12%. Nevertheless, seven patients died from opportunistic infections after a longer time of immunosuppressive treatment and one patient from heart failure 1 year after transplantation. CMV antigenemia was treated with ganciclovir in 16 patients (37%).
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. The median time to recover an absolute neutrophil count of 0.5 x 109/liter was 13 days (range, 10–24 days) and of platelets above 50 x 109/liter, it was 16.5 days (range, 11–39 days). The median transfusion requirements were six packed RBCs (range, 0–20 units) and four thrombapheresis products (range, 0–23 units). Platelet engraftment was not different in patients with ABO-matched grafts compared to those with mismatched grafts. One patient with CML did not recover with his blood counts, and no donor signals could be detected until day 28 when autologous PBSCs were reinfused to rescue the patient. Eight patients (three CMLs, two MDSs, 1 secondary-AML, 1 ALL, and 1 CLL) experienced late loss of graft function and decreasing donor chimerism. In six of those eight cases, an autologous PBSC graft could be reinfused to reconstitute hemopoiesis. The two other patients (UPN 169 and 181) remained aplastic and died from infectious complications.
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. Cox regression analysis with the mentioned risk factors for graft failure confirmed HLA-mismatch to be of borderline significance (P = 0.065).
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. The analysis could be performed for 10 patients between day 10 and 30 after transplantation. In this subgroup, all of the six recipients with stable engraftment obtained more than 75% donor NK cell chimerism, whereas three of four patients with graft failure did not surpass the 75% level (P = 0.03; Fisher’s exact test). The median absolute number of NK cells between day 10 and 30 was similar for patients with durable engraftment (9.8 x 106/liter; range 1.3–31) or with graft failure (6.8 x 106/liter; range 3.1–19). Because subset chimerism was available only for a limited number of patients, no multivariate statistical analysis was performed. The CD15+ myeloid compartment showed early complete donor chimerism in most patients. As expected, a low percentage of donor T cells was observed, especially in recipients of CD34+-selected PBSCs. Given the low number of patients with complete data for the CD4+ and CD8+ subsets and the low absolute lymphocyte counts early after transplantation (range, 0.06. to 0.46 x 109/liter), the graphs for CD4+ and CD8+ are not provided.
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for grade II-IV GvHD, several patients had a late occurrence of GvHD symptoms. The probability of acute GvHD grade II-IV was 32% with one patient dying from acute GvHD grade IV after immunosuppressive prophylaxis had been stopped early. Regression analysis showed no significant impact of disease, donor-recipient sex, graft-source, GvHD prophylaxis, and number of CD34+ and CD3+ cells in the graft on the risk of acute GvHD. The organ involvement, as well as the grade of acute and chronic GvHD, is summarized in Table 2
. Chronic GvHD beyond day 100 was documented in 16 patients (9 limited, 7 extensive).
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. The actuarial disease-free survival was significantly better in patients with SR (38%) and lymphoid malignancies (64%) compared with the HR group (14%; P = 0.04 for SR versus HR and 0.0025 for lymphoid versus HR). There was no significant difference for overall and disease-free survival between patients who received completely HLA-matched grafts compared with recipients of mismatched grafts. Fourteen patients died because of relapsing disease, 7 from opportunistic infections, 3 from early toxicity (sepsis, GvHD, and pneumonitis), and 1 from heart failure 1 year after transplantation.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The effectiveness of allogeneic cell therapy after dose-reduced conditioning relies mainly on graft-versus-leukemia effects of alloreactive and minor-histocompatibility antigen-specific T cells (20)
. The experience in CML patients suggests that these effects are even more pronounced after allogeneic transplantation from unrelated donors (21)
. Therefore, we decided to incorporate the use of unrelated matched donors in this protocol evaluating a dose-reduced preparative regimen. Given the increased risk of GvHD and graft failure after transplantation from unrelated donors, we used antithymocyte globuline to achieve suppression of host-versus-graft and graft-versus-host reactions. Because the rate of acute GvHD grade II-III was still 50% with the use of CsA and MTX, the GvHD prophylaxis was adapted to a combination of CsA and MMF for patients with unselected grafts during the study period. The latter compound has shown to decrease the rate of acute GvHD in a dog leukocyte antigen (DLA)-mismatched dog model and has shown to be effective to support engraftment after conditioning with 200-cGy total body irradiation (22
, 3) . Although the rate of acute GvHD grade II appeared to be lower (22%) with the combination of CsA and MMF, matched-pair comparison was not possible because of the heterogeneous patient population.
In a previous study (9) we had shown that ATG is not necessary for stable engraftment in the related setting after conditioning therapy with 150 mg/m2 fludarabine and 50% of the usual busulfan dose. Nevertheless, the dose of ATG used could have been too low. On the other hand, the long half-life time of ATG might have led to an in vivo depletion of donor T cells that are important mediators of engraftment, especially after low-dose conditioning. We have omitted ATG from the preparative regimen in a second cohort of seven patients with unrelated donors and have not seen any graft failure since then (data not shown). Other forms of in vivo T-cell depletion might be advantageous to decrease the risk of acute GvHD without hampering engraftment. Encouraging results with a very low rate of acute GvHD and no graft failure have been achieved with the use of CAMPATH-1H by a study group from the United Kingdom (17) . Because the eight recipients of unrelated transplants in their series received BM grafts after a regimen containing melphalan and fludarabine, the data cannot be compared directly with ours. Nevertheless, the use of in vivo CAMPATH-1H should be studied prospectively in nonmyeloablative transplants from unrelated donors.
The higher rate of graft failure in patients with CML can be seen in relation with the less intensive pretreatment or prior IFN application (23) . Higher rates of graft failure in CML patients have also been published for conventional transplants from unrelated donors in a retrospective registry analysis (24) .
The HLA match grade is an accepted risk factor for graft failure after allogeneic stem cell transplantation (25) . Especially HLA-C mismatching has been shown to be highly predictive for this complication after transplants from unrelated donors (26) . The patient cohort in our study is too small and heterogeneous to perform multivariate analysis for these and other risk factors like CD34+ cell dose and source of donor cells, and many patients had early treatment failure because of disease relapse.
The rationale to use mobilized PBSCs whenever possible in our study was to overcome the risk of graft failure after less intensive conditioning by a higher dose of CD34+ cells and the knowledge that higher BM cell doses have been related to a better outcome for patients with high-risk leukemia (27) . After having seen graft failure in two patients who had received CD34-positive-selected PBSCs, we decided to use unmodified PBSCs thereafter. Nevertheless, this policy did not prevent graft failure in three cases receiving unselected PBSCs where the number of CD34+ cells infused was adequate. The course of the hematological parameters in the patients with graft failure strongly suggests that 50% busulfan cannot be called "nonmyeloablative" in the context of allogeneic stem cell transplantation because all of the patients experienced aplasia and had to be rescued with autologous stem cells.
The observation of a decreased donor NK cell chimerism in three patients with graft failure is interesting. Donor NK cells that normally come up early after allogeneic stem cell transplantation could hardly be detected, suggesting that the residual fraction of host NK cells mediated graft failure. The importance of donor NK cells for engraftment after conventional conditioning therapy has been shown previously (28 , 29) . Targeting NK cell function using antibodies against CD44 can facilitate engraftment in mismatched transplants after nonmyeloablative conditioning in a large animal model (30) . Because comparable antibodies are currently developed in the human system, this approach might become an attractive strategy for future clinical trials.
The prolonged aplasia after graft failure might result from the additive effects of busulfan administration and temporary competition between recipient and donor hematopoiesis (31) . In contrast to low-dose TBI-based regimen (3) , mixed chimerism could only be detected in the T-cell compartment for a limited time period.
Although the early extramedullary toxicity of the preparative regimen was moderate with only 12% toxic deaths until day 100, the nonrelapse mortality associated with chronic GvHD and opportunistic infections is considerable. This has to be kept in mind when the age limits for studies including allogeneic cell therapy after modified conditioning therapy are set up. The use of a dose-reduced conditioning regimen was not helpful in patients with acute leukemia or MDS who had elevated blast counts by the time of inclusion. Early relapse was the cause of treatment failure in one-third of all of the patients. This reflects the progressed disease status of most patients included. Many years of allogeneic BM transplantation and studies on the use of adoptive immunotherapy with donor lymphocytes have shown that immunotherapy is not sufficient to control rapidly proliferating acute leukemia (2 , 32) .
Despite the inclusion of older patients and patients with intensive pretreatment, this study shows encouraging results in patients with standard risk diseases, indolent lymphoma, and CLL. In these diseases, the competition between antigen-dependent cellular toxicity and tumor proliferation seems to favor effective graft-versus-tumor effects (5) .
In summary, our results show the feasibility of allogeneic transplantation of BM and PBSCs from unrelated donors after a preparative regimen containing a purine analogue and 50% of the common busulfan dose. The rate of graft failure is significantly higher than after transplants from matched sibling donors. Prolonged remission can only be achieved in patients with a limited burden of disease by the time of the transplant, and GvHD and opportunistic infections still remain unsolved problems.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by the Deutsche Krebshilfe, Grant No. 70-2755. 
2 To whom requests for reprints should be addressed, at Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus, Fetscherstraße 74, 01307 Dresden, Germany; Phone: 49-351-458-4704; Fax: 49-351-458-5362; E-mail: bornhaeuser{at}oncocenter.de
3 The abbreviations used are: TBI, total body irradiation; CML, chronic myeloid leukemia; CLL, chronic lymphocytic leukemia; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; NHL, non-Hodgkin’s lymphoma; ALL, acute lymphoblastic leukemia; MM, multiple myeloma; BM, bone marrow; PBSC, peripheral blood stem cell; GvHD, graft-versus-host disease; CMV, cytomegalovirus; CsA, cyclosporine A; MTX, methotrexate; MMF, mycophenolate mofetil; FACS, fluorescence-activated cell sorting; MNC, mononuclear cell; CR, complete remission; CP, chronic phase; SR, standard risk; HR, high risk.
Received 1/25/01; revised 4/26/01; accepted 5/ 9/01.
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REFERENCES |
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in patients with chronic-phase Philadelphia chromosome-positive chronic myelogenous leukemia before allogeneic bone marrow transplantation may adversely affect transplant outcome. Blood, 85: 2981-2990, 1995.This article has been cited by other articles:
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M. L. Sorror, M. B. Maris, B. Storer, B. M. Sandmaier, R. Diaconescu, C. Flowers, D. G. Maloney, and R. Storb Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of pretransplantation comorbidities Blood, August 15, 2004; 104(4): 961 - 968. [Abstract] [Full Text] [PDF]
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