Albert Ludwigs University Medical Center Freiburg, Department of Haematology and Oncology, Freiburg, Germany
Received 23 November 2000; revised 2 July 2001; accepted 14 August 2001.
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Abstract |
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Allogeneic hematopoetic stem-cell transplantation (alloHSCT) has curative potential for poor risk lymphoma patients due to the graft-versus-lymphoma effect. High non-relapse mortality with conventional high-dose conditioning indicates the necessity for less toxic transplant strategies.
Patients and methods
Between 1992 and 1999, 25 patients [median age 37 (2060) years] with relapsed or refractory non-Hodgkins lymphoma (NHL, n = 20) or Hodgkins disease (HD, n = 5) received an alloHSCT in our institution. Patients were grafted from HLA matched (17) or mismatched (2) related, or matched unrelated donors (MUD) (6). NHL histological subtypes were lymphoblastic (6), high grade B/T-cell lymphomas (5), follicular (3), mantle cell (2) and CLL, immunocytic, composite lymphoma and panniculitic T-NHL in one patient each. Patients had received a median of four (range three to six) different therapies before alloHSCT, and 10 patients had relapsed after high-dose chemotherapy and autologous (9) or allogeneic (1) HSCT. Remission status prior to allogeneic SCT was CR1 (1), CR2 (1), relapse (11), partial remission (5) or primary refractory induction failure (7). Conventional myeloablative conditioning (cc) regimens contained total body irradiation 12 Gy (5), busulfan 16 mg/kg (7) or BCNU/VP16 (1). Twelve patients received reduced-intensity conditioning (ric) regimens with fludarabine (FLU) plus alkylating agents. Graft-versus-host disease prophylaxis consisted of cyclosporin A ± prednisone or methotrexate. Six patients also received anti-T-lymphocyte globulin.
Results
Twenty-four patients engrafted. Best response after alloHSCT was complete remission in 16 of all patients [64%; 95% confidence interval (CI) 44% to 84%] and in 16 of 22 evaluable patients (73%; 95% CI 53% to 93%), partial remission in three of 25 (12%), and no change in three of 25 (12%) patients. Early death prevented response evaluation in three of 25 patients. Non-relapse mortality was 54% (95% CI 15% to 78%) in patients after cc and 17% (95% CI 0% to 41%) after FLU-based ric (P = 0.03). Six patients died due to progressive disease or relapse. Four patients with HD died, three in complete remission due to non-relapse mortality and one with progressive disease. Eleven of 25 patients are alive with a median follow up of 618 days (range 3832815), with an overall survival of 44% (95% CI 23% to 65%) at 1 year for all patients, while eight of 12 (67%; 95% CI 35% to 98%) patients are alive after ric compared with three of 13 (23%; 95% CI 0% to 50%) after cc (P <0.02).
Conclusions
AlloHSCT induces high rates of complete remission in advanced lymphoma patients, even when the tumor had relapsed after autologous HSCT. It should be considered earlier as part of the therapeutic options in poor risk patients to avoid non-relapse mortality associated with extensive pretreatment. Our novel reduced conditioning regimens show promising results, especially in heavily pretreated patients, and improve survival after allogeneic transplantation.
Key words: allogeneic HSCT, Hodgkins disease, MUD transplantation, non-Hodgkins lymphoma
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Introduction |
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Patients and methods |
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GvHD prophylaxis consisted of cyclosporin A ± methotrexate or prednisone. Anti-T-lymphocyte globulin (ATG-S®; Fesenius Graefeling, Germany) (n = 6) was added in patients with a MUD (n = 5) or mismatched related donor (n = 1).
Supportive care
Supportive care was carried out as published previously [9]. All patients received G-CSF starting on day 1 (n = 5) or day 7 (n = 20).
Statistical analysis
The KaplanMeier method was used to calculate event-free survival, overall survival, the probability of non-relapse mortality and the CI, using GraphPad Prism software (San Diego, CA, USA).
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Results |
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Graft-versus-host disease
Acute GvHD °0/I developed in 76% (95% CI 58% to 94%), °IIIV in 24% (95% CI 6% to 42%), and °IIIIV in 16% (95% CI 1% to 31%) of all patients. In 16 patients surviving beyond day 100, chronic GvHD is absent (n = 8), limited (n = 5) or extensive (n = 3).
Outcome
Response is evaluable in 22 of 25 patients. Sixteen patients (73%) achieved complete remission and complete donor chimerism in the bone marrow. One patient with composite lymphoma, after previous autoHSCT, relapsed on day 43. A secondary sustained complete remission was achieved after cessation of immunosuppression in conjunction with local radiation therapy. As of 1 November, 2000, 11 of 25 are alive at a median follow-up of 618 days (range 3832815), with an overall survival at 1 year of 44% (95% CI 23% to 65%) (Figure 1). Four patients achieving only short-term partial remission died of progressive disease on days 31, 35, 82 and 162, respectively. None of these four patients had ever achieved a remission after any standard chemotherapy. Two patients, also after autoHSCT, relapsed on days 75 and 123, and died due to progressive disease on days 159 and 267, respectively. ARDS with respiratory failure was the cause of death in three patients with previous TBI (12 Gy) or mediastinal bulk irradiation. Other causes of death were interstitial pneumonia (two patients), aspergillosis (2) and hemolytic uremic syndrome/microangiopathic hemolytic anemia (HUS/MAHA) (1). Four of five patients with HD died because of ARDS (two patients), HUS/MAHA (1) in complete recovery, or persistent disease (1). Overall non-relapse mortality in all patients was 32% (95% CI 12% to 52%). Event-free survival, is 36% (95% CI 16% to 50%) for all patients at 1 year.
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Chemoresistent versus chemosensitive lymphomas
Twenty-three patients, not transplanted in complete remission, were divided into the subgroups chemoresistent (13) and chemosensitive (10) lymphomas. Three of 13 in the first group (23%; 95% CI 0% to 50%) are alive and six of 13 (46%) achieved complete recovery compared with six of 10 (60%; 95% CI 23% to 97%) and nine of 10 (90%) in the chemosensitive group. Non-relapse mortality is 31% (95% CI 2% to 60%) and 40% (95% CI 6% to 77%), and event-free survival 23% (95% CI 0% to 50%) versus 40% (95% CI 6% to 77%); differences are not statistically significant. Overall survival shows an advantage for the chemosensitive group (23% versus 60%; not statistically significant).
Patients with and without previous autoHSCT
Seven of nine patients with previous autoHSCT achieved complete remission (78%) and four of nine (44%; 95% CI 4% to 85%) are alive compared with seven of 15 (47%; 95% CI 18% to 60%) without previous transplantation. Overall survival (44% versus 47%), event-free survival (22% versus 47%) and non-relapse mortality (33% versus 27%) showed no statistically significant differences.
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Discussion |
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The very poor risk of our patient population must be taken into account when the efficacy of alloHSCT for NHL is being considered. Only 8% were transplanted in complete recovery, but 64% of all patients and 73% of the evaluable patients achieved complete remission with alloHSCT. Twelve patients have not relapsed and seven patients with hitherto chemoresistant relapsed lymphoma or primary induction failure achieved complete recovery. Seven of eight evaluable patients who had received previous autoHSCT achieved complete remission (87%) and only two of seven have relapsed. Therefore, failure of previous autoHSCT does not appear to adversely affect the treatment results or non-relapse mortality after alloHSCT.
Our results are certainly encouraging, but the outcome of the patients with HD after cc is disappointing. Three patients died in complete remission due to non-relapse mortality, mainly ARDS, and one failed to achieve a response. Only one patient is alive in partial remission as of day 383. This poor outcome has been observed previously by Milpied et al. [6], who reported a non-relapse mortality of 65%. The most likely explanation may be found in the extensive pretreatment including radiotherapy. We agree with Anderson [4] that only selected patients with HD should receive alloHSCT and reduced intensity conditioning regimens should be introduced earlier in high-risk patients.
In conclusion, our results appear to support the assumption that alloHSCT has curative potential in patients with poor risk lymphomas, most likely due to the lack of lymphoma involvement of the graft and the proven graft-versus-lymphoma effect. Significantly reduced non-relapse mortality can be expected from the use of FLU-based ric regimens without loss of efficacy. Reduced non-relapse mortality may also permit incorporation of alloHSCT earlier into the therapy course in patients with unfavorable entities such as mantle cell lymphomas [13].
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Acknowledgements |
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Note added in proof |
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Footnotes |
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References |
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2.
Ratanatharathorn V, Uberti J, Karanes C et al. Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkins lymphoma. Blood 1994; 84: 10501055.
3.
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7. Bearman SI, Appelbaum FR, Back A et al. Regimen-related toxicity and early posttransplant survival in patients undergoing marrow transplantation for lymphoma. J Clin Oncol 1989; 7: 12881294.[Abstract]
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13. Khouri IF, Lee M, Romaguera J et al. Allogeneic hematopoetic transplantation for mantle-cell lymphoma: Molecular remissions and evidence of graft-versus-malignancy. Ann Oncol 1999; 10: 12931299.[Abstract]