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Allogeneic Hematopoietic Stem-Cell Transplantation After Nonmyeloablative Preparative Regimens: Impact of Pretransplantation and Posttransplantation Factors on Outcome

From the Société Française de Greffe de Moelle Registry, Paris, France.

Address reprint requests to Jean Michel Boiron, MD, PhD, Service des Maladies du Sang, Unité de Greffe, Centre François Magendie, Hôpital Haut-Lévêque, Centre Hospitalo-Universitaire de Bordeaux, Avenue de Magellan, Pessac, 33604 France; email: jean-michel.boiron{at}chu-bordeaux.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To analyze the impact of pre- and posttransplantation factors on the outcome of allogeneic transplantation after nonmyeloablative conditioning regimens.

PATIENTS AND METHODS: Ninety-two allogeneic transplantations after nonmyeloablative preparative regimens were reported to the Société Française de Greffe de Moelle Registry registry. Initial diagnoses were lymphoid diseases (n = 22), myeloma (n = 14), acute leukemia and myelodysplasia (n = 41), chronic myelogenous leukemia (n = 12), and solid tumors (n = 3). Forty-six patients had previously received a transplant, and 49 had progressive disease before transplantation. Three types of conditioning regimens were used with fludarabine or antithymocyte globulins. Eighty-nine patients underwent transplantation, 60 from peripheral-blood progenitor cells. Eighty-six patients received graft-versus-host disease (GHVD) prophylaxis for a median duration of 53 days.

RESULTS: Seventy-nine patients engrafted, with 40 complete and 21 mixed chimerisms. The acute GHVD rate at 3 months was 50% ± 11%. Fifty-two patients achieved complete remission and 12, partial remission. At 18 months after transplantation, the overall survival (OS) and the transplant-related mortality (TRM) were 32% ± 12% and 38% ± 14%, respectively. Initial diagnosis and disease status before transplantation significantly influenced survival. Age and GHVD prophylaxis type significantly influenced TRM. We also showed an impact of GHVD prophylaxis duration on OS and TRM. In multivariate analysis, three factors remained of prognostic value on OS: initial diagnosis, disease status at transplantation, and GHVD prophylaxis duration.

CONCLUSION: This series shows encouraging results from nonmyeloablative conditioning regimens before allotransplantation and demonstrates the impact of some pre- and posttransplantation factors on outcome after transplantation.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
ALLOGENEIC HEMATOPOIETIC stem-cell transplantations (HSCTs) provide effective therapy for a wide range of malignant and nonmalignant disorders, but their advantage over other therapies and their use are limited by high transplant-related mortality (TRM).^1-3 Furthermore, allogeneic HSCT cannot be performed easily in patients older than 55 years or in poor general health because TRM becomes unacceptable. The toxicity of the conditioning regimen administered before transplantation and graft-versus-host disease occurring after transplantation remain the main factors leading to high morbidity and mortality.^4-6 The role of the graft-versus-leukemia or graft-versus-tumor effect, as a positive counterpart of donor alloreactivity, has long been recognized at the experimental and clinical level.^7-12 Furthermore, the efficacy of the graft-versus-malignancy (GVM) effect has been recently demonstrated by using donor lymphocyte infusions (DLI) in order to reinduce remission in patients who have relapsed after allogeneic HSCT.^13-20 A two-step strategy, sometimes called mini- or micro-transplantation, has recently been developed^21,22 to reduce the toxicity of conditioning regimens and to preserve a curative antitumoral effect corresponding to allogeneic HSCT after a nonmyeloablative preparative regimen, whether followed by DLI or not, according to both chimerism and results of minimal residual disease documentation. Different pioneering approaches have been adjusted, taking advantage of the immunosuppressive property of either new purine analogs,^23,24 or a low dose of total-body irradiation (TBI) associated with cyclosporine and mycophenolate mofetil,²⁵ or a regimen containing antithymocyte or antilymphocyte globulins (ATGs/ALGs).^26,27 The feasibility of these nonmyeloablative strategies has been demonstrated, and most patients achieved a donor mixed or complete chimerism with low regimen toxicity.^23-29 We therefore carried out a retrospective analysis of 92 allogeneic HSCT after nonmyeloablative preparative regimens performed in 11 centers of the Société Française de Greffe de Moelle (SFGM) from June 1997 to July 1999 in order to assess the impact of pre- and posttransplantation factors on the outcome.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Between June 1997 and July 1999, 92 allogeneic transplantations after nonmyeloablative preparative regimens were reported to the SFGM registry by 11 SFGM centers. There were 58 males and 34 females, all adults except for two children (10 and 13 years old). The median age of the adult population was 50 years (range, 20 to 62 years). Median time between diagnosis and transplantation was 17 months (range, 2 to 175 months). Pretransplantation characteristics are summarized in Table 1. Initial diagnoses comprised non-Hodgkin’s malignant lymphomas (NHMLs) (16 patients: seven follicular, one mantle-cell, five large cells, two lymphoblastic, one other high grade), multiple myeloma (14 patients), Hodgkin’s disease (three patients), chronic lymphocytic leukemia (three patients), acute leukemias (acute lymphoblastic leukemia in 13 cases, acute myeloid leukemia in 18 cases), myelodysplasia (MDS) (10 patients), chronic myeloid leukemia (CML) (in chronic phase in five cases and in transformation in seven cases), and solid tumors (three patients). Before transplantation, all but two patients (2%) had received prior therapy: 44 (48%) had received conventional chemotherapy while 37 patients (40%) had received an intensive therapy followed either by allotransplantation in 10 patients (11%) or by autotransplantation in 27 patients (29%). Seven patients (8%) had undergone two autotransplantations and two patients (2%) received allotransplantation and autotransplantation before transplantation. Forty-nine patients (53%) were in the progressive stage of the disease (PD) before starting the conditioning regimen and 30 (33%) were in partial response (PR). Only 13 patients (14%) were in complete remission (CR) before transplantation.

Transplantation. Twenty-nine patients (32%) received bone marrow (BM) and 60 (68%) received peripheral-blood progenitor cells (PBPC). For PBPC transplantation, a median number of 6.64 x 10⁶ CD34+ cells/kg (range, 0.89 to 41) were reinfused. Eighty-eight patients received transplants from HLA-identical sibling donors (28 BM, 60 PBPCs) and one from an HLA-identical unrelated donor (BM).

GVHD prophylaxis. Eighty-six patients (97%) received GVHD prophylaxis. Forty-four patients (51%) were treated with cyclosporine alone, and 42 patients (49%) received cyclosporine combined with corticosteroids (six patients) or methotrexate (36 patients) (Table 1). The median duration of GVHD prophylaxis was 53 days (range, 5 to 775 days). Seventeen patients (19%) received DLI after transplantation: 12 patients received one DLI, three patients received two DLIs, and two patients received three DLIs. Among these patients, seven received DLI according to protocol (they were in CR and in total donor chimerism), two received DLI because of mixed chimerism (they were in CR), and eight received DLI because of persisting disease (seven patients were evaluated for chimerism: two in total donor and five in mixed chimerism).

Statistical Analysis
Categorical data were compared using the ² statistic or the Fisher’s exact test or the Cochran-Mantel-Haenzel statistics. Continuous parameters were compared using the Mann-Whitney or Kruskall-Wallis nonparametric tests. Kaplan-Meier³⁰ product-limit estimates were used to assess the probability of overall survival (OS) for 92 patients. To assess the cumulative incidence of TRM, calculated on 92 patients, and acute GVHD, the competing risk framework was applied.³¹ TRM was defined as death occurring in continuous CR; death from relapse was considered as a competing risk. Competing risks for the occurrence of acute GVHD were deaths without acute GVHD. Variables analyzed in the univariate analysis, which took into account only the 89 allotransplanted patients, were studied for their relation to OS using the log-rank test³² for all variables, except for the duration of the GVHD prophylaxis, which was studied as a time-dependent covariate using an univariate Cox model. Variables significant in univariate analysis with P .2 were examined in multivariate analysis (89 patients) using the Cox proportional hazards model for covariate analysis of censored survival data.³³ Neutropenia was defined as a neutrophil count lower than or equivalent to 0.5 x 10⁹/L, and thrombocytopenia was defined as the number of platelets lower or equivalent to 20 x 10⁹/L.

	RESULTS

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Engraftment
Among 92 patients, six patients were not assessable for engraftment (three patients died during the conditioning regimen before transplantation and three patients died soon after transplantation). Seventy-nine patients (92%) of 86 assessable patients engrafted. Twenty-one (35%) out of 60 patients who received PBPC and 14 (48%) out of 29 who received BM had previously received allo- or autotransplants. We studied in a multivariate analysis the impact on engraftment of the source of stem cells, previous treatment (transplant v no transplant), and conditioning regimens (FBT + ATG/ALG v IFA). A significant difference was observed between BM and PBPCs (P = .04) and between patients who had previously received transplants and those who had not (P = .04), and we found no significant influence from conditioning regimens. The median duration of neutropenia ( < 0.5 x 10⁹/L) was 18 days (range, 1 to 50 days) and the median duration of thrombocytopenia (< 20 x 10⁹/L) was 19 days (range, 1 to 76 days). There was no significant difference regarding the duration of neutropenia (median, 16 days [range, 1 to 45 days] and 20 days [range, 9 to 50 days], respectively) and the duration of thrombocytopenia (median 19 days [range, 1 to 76 days] and 19 days [range, 1 to 50 days], respectively). However, the type of conditioning regimen, after adjusting for source of cells, significantly influenced the duration of thrombocytopenia (FBT, 14 days; IFA, 21 days; ATG/ALG, 26 days; P = .001) and the duration of neutropenia (FBT, 13.5 days; ATG/ALG, 24 days; IFA, 24.5 days; P = .0001).

GVHD
The incidence of acute GVHD at 3 months was 50% (± 11%). We studied separately the incidence of acute GVHD and chronic GVHD for patients who never received DLI (n = 62 assessable patients) and for patients who received DLI (n = 17 assessable patients). Of the first 62 patients, 10 developed grade 1 acute GVHD; eight, grade 2; four, grade 3; and five, grade 4. In patients receiving a BM transplant, of the 20 assessable patients, we observed three grade 1, four grade 2, and one grade 4, whereas in patients receiving PBPCs, out of 42 assessable patients, we observed seven grade 1, four grade 2, four grade 3, and four grade 4. Regarding conditioning with (n = 46) or without (n = 16) ATG/ALG, we noted seven grade 1 acute GVHD, eight grade 2, two grade 3, three grade 4, and three grade 1, two grade 3, two grade 4, respectively. Of 36 patients assessable for chronic GVHD after 3 months, 13 developed a limited form and three developed an extensive form. In the PBPC group, of 23 assessable patients, 11 developed chronic GVHD (nine limited and two extensive) and in the BM group, five out of 13 assessable patients developed chronic GVHD (four limited and one extensive). Out of the 17 patients who received DLI, 10 patients received DLI within 3 months after transplantation, four patients developed acute GVHD (one grade 1, one grade 2, one grade 3, and one grade 4), and two developed chronic GVHD. Of the other seven who received DLI 3 months after transplantation, three patients developed acute GVHD (two grade 1 and one grade 4). After one DLI, six of the 12 patients developed acute GVHD (three grade 1, one grade 2, one grade 3, one grade 4); after 2 DLIs, one of the three patients developed acute grade 4 GVHD. No acute GVHD was detected after three DLIs (two patients). Chronic GVHD was observed in two patients after one and two DLIs. Details on GVHD according to initial diagnosis are given in Table 2.

In addition, 24 patients (21 CR, three PR) showed a disease response with no expression of acute GVHD after transplantation. Twenty-six patients presented a response after transplantation while developing acute GVHD (22 CRs: nine grade 1, eight grade 2, three grade 3, two grade 4; four PRs: one grade 1, one grade 3, two grade 4). Seventeen patients received DLIs: of eight who achieved a CR before DLI, five remained in CR, one progressed in PR, and two progressed to PD after DLI; of six who achieved a PR before DLI, three remained in PR, and three progressed after DLI; and of three who were in PD before DLI, all three remained in PD after DLI.

In addition, three patients (one CR, two PRs) showed a disease response after DLI with no expression of acute GVHD, and six patients presented a response after DLI while developing acute GVHD (four CRs: two grade 1, one grade 3, one grade 4; two PRs: one grade 2, one grade 4). We found that the pretransplantation diagnosis had a significant influence on the response at the last follow-up (acute leukemias/CML(T)/MDS v NHML/multiple myeloma/Other: P = .006). We observed no significant influence from the conditioning (FBT v IFA v ATG/ALG), the regimen containing ATG/ALG (FBT + ATG/ALG v IFA), or the duration of ATG. Table 2 illustrates the results as a function of pretransplantation diagnosis.

Chimerism after transplantation. Sixty-eight patients were evaluated for chimerism after transplantation. Fifty-one patients did not receive DLI, and 17 patients received DLI during progression. Before any DLI, 40 patients (59%) achieved total donor chimerism, 21 (31%) achieved mixed chimerism, and seven (10%) showed no chimerism (Table 4). No significant difference was noted among BM and PBPC transplant recipients. The type of conditioning, the regimen containing ATG/ALG, and the duration of ATG did not influence results in terms of chimerism. In the case of PBPC transplantation, a significant impact of the number of CD34+ cells was observed on early posttransplantation chimerism (P = .03). At the time of the last follow-up, 48 patients who did not receive DLI and 16 patients who received DLI were evaluated for chimerism. Of the patients who did not receive DLI (n = 48), 29 were in total donor chimerism after transplantation and, at the last follow-up, 21 patients remained in total donor chimerism, six showed a mixed chimerism, and two showed a recipient profile. Of the 12 patients in mixed chimerism after transplantation, four remained in mixed chimerism, six improved to a total donor chimerism, and two showed a recipient profile at the last follow-up. Of the seven patients who had no chimerism after transplantation, one improved to mixed chimerism and six remained stable. No significant impact was found on long-term chimerism results regarding the hematopoietic stem cell source, the number of CD34+ cells, the type of conditioning, or the regimen containing ATG/ALG. Among patients who received DLI after transplantation, 16 patients were evaluated for chimerism at the time of the posttransplantation follow-up. Eight of the nine patients in total donor chimerism remained in total donor chimerism and one showed a mixed chimerism at the last follow-up. Of the seven patients in mixed chimerism, one improved to total donor chimerism, five remained in mixed chimerism, and one showed a recipient profile at the last follow-up. Results according to the initial diagnosis are given in Table 2.

View larger version (10K): [in this window] [in a new window]   Fig 1. OS and TRM for all patients. Solid line, OS; dotted line, TRM.

Univariate analysis showed that the interval duration between diagnosis and transplantation, the conditioning regimen, and previous pretransplantation therapy did not significantly influence OS and TRM (Table 5). However, diagnosis (P = .01) (Fig 2) and disease status at the time of transplantation (P = .03) significantly influenced OS. In addition, TRM was significantly influenced by age (P = .03) and GVHD prophylaxis type (P = .04). The duration of GVHD prophylaxis, considered as a time-dependent variable, also significantly influenced either OS (P = .006) or TRM (P = .01). Finally, TRM tended to be higher with PBPC than with BM (P = .07) transplants. Multivariate analysis (Table 6) retained only three factors significantly influencing OS: pretransplantation diagnosis (P = .01), disease status at transplantation time (P = .02), and GVHD prophylaxis duration (P = .04). Of the 47 deaths after transplantation, 29 were transplant-related, an insufficient number to study TRM in a multivariate analysis.

View larger version (10K): [in this window] [in a new window]   Fig 2. OS according to diagnosis. Solid line, NHML, multiple myeloma, and others (CML in chronic phase, chronic lymphocytic leukemia, Hodgkin’s disease, and solid tumor); dotted line, acute leukemias, CML t, and MDS.

	DISCUSSION

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Different pioneering approaches have been adjusted to reduce the intensity of the conditioning regimen. Two groups of investigators have developed probably the least radical regimen: they took advantage of the immunosuppressive property of new purine analogs such as fludarabine and cladribine^23,24 in combination with other antileukemic agents. In myeloid malignancies, new purine analogs were combined with cytarabine and idarubicin ("FLAG-ida") or with melphalan.²³ In lymphoid malignancies, it was combined with cyclophosphamide or with a platinum/cytarabine regimen.²⁴ At the opposite end of the spectrum of new nonintensity conditioning regimens, Storb et al²⁵ have developed a nearly nonmyeloablative therapy with low-dose TBI (2 Gy) and an intensive immunosuppression regimen combining mycophenolate mofetil and cyclosporine, adjusted in an experimental model, and recently introduced in clinical use. Between both approaches, two other preparative regimens have been used, based on the combination of rabbit ATGs and fludarabine²⁶ or horse ALGs and cyclophosphamide,²⁷ similar to the conditioning used for aplastic anemia.⁴² The Boston group performed thymic irradiation (7 Gy),^27,43 in line with data gathered in an experimental model of mixed chimerism induction.⁴⁴ The benefits of immunosuppressant agents such as ATG or CAMPATH (Millenium and Ilex U.K., Surrey, United Kingdom) before transplantation have not been defined nor have the optimum time and duration of GVHD prophylaxis. T-cell depletion has been shown to be feasible, but its overall impact on outcome of nonablative therapies has not been assessed.⁴⁵ In our study, we observed that the type of GVHD prophylaxis significantly influenced TRM, and we demonstrated how long GVHD prophylaxis improved the survival rate and lowered TRM. This result should be interpreted with caution. Indeed, considering two groups of GVHD prophylaxis patients, we observed a 91% response rate after transplantation in the group with a long duration (> 53 days) of prophylaxis versus 70% in the group with a short duration ( 53 days). The impact of GVHD prophylaxis duration on survival and TRM may be related to the response after transplantation.

The feasibility of all these nonmyeloablative strategies has been demonstrated, a majority of the patients achieving a donor mixed or complete chimerism with low regimen-related toxicity.^23-29 Nevertheless, the populations studied were heterogeneous. Patients with malignancies undergoing transplantations in Slavin’s series²⁶ generally had less advanced disease and were younger than the patients in Giralt and Khouri’s^23,24 or in Syke’s studies.²⁷ In our series, the population studied was also heterogeneous, but the majority of them presented PD and had received substantial treatment before transplantation. We demonstrated the importance of the pretransplantation disease status with significantly longer survival if patients underwent transplantation in CR or PR, as after standard allogeneic transplantation. In addition, we observed a significant impact of pretransplantation diagnosis on OS with longer survival if patients presented lymphoid or Hodgkin’s disease, CML in chronic phase, myeloma, or solid tumor than if patients had acute leukemia, CML in transformation, or myelodysplasia. We used the same types of conditioning as described in the literature,^23,24,26 and we observed no influence due to the type of conditioning, the regimen containing ATG or ATG duration on engraftment, chimerism, response of the disease, OS, and TRM. However, this study showed a significant influence from the conditioning regimen and the number of CD34+ cells on chimerism after transplantation.

With this in mind, after a nonintensity cytotoxic regimen, the engraftment conditions are limited and a large dose of unmanipulated CD34+ cells has to be transplanted in the patients. PBPCs are usually preferred to BM cells.^23-26 The present study showed no graft failure after using BM cells. We observed a significant effect on engraftment of hematopoietic stem-cell source and of previous auto- or allotransplantations, and we could speculate on the role of microenvironmental defects for the graft failures observed in the PBPC group. We observed no influence on chimerism, the response of the disease, and OS from the hematopoietic stem-cell source. Furthermore, we noted a trend for higher TRM when using PBPCs. The results of influence of conditioning regimens on engraftment, response of disease, and chimerism should be considered cautiously because of the small number of subjects.

Apart from Storb’s experiment,²⁵ which involved treatment on an outpatient basis, these nonmyeloablative regimens have not eliminated regimen-related toxicity. Most patients experienced transient but severe neutropenia.^23,24,26,27 In our series, the cumulative incidence of TRM was 38%. We found that the type of conditioning significantly influenced the duration of aplasia, with a shorter duration after fludarabine, busulphan, and the ATG combination. Furthermore, acute GVHD, which occurred spontaneously or after DLI, remains an unresolved issue, considering its incidence and its severity. Our study showed a 50% incidence of acute GVHD at 3 months, and we observed after PBPC transplantation more severe acute GVHD and more chronic GVHD than after BM transplantation. Interestingly, we observed that a high number of patients achieved a response after transplantation without developing acute GVHD. This complication was the first cause of death in Slavin’s preliminary experiment.²⁶ In our series the first cause of death was progressive disease (38%) followed by infection (25%). Yet the majority of the published experiments were limited to matched related-donor HSCT. Mismatched related and matched and mismatched unrelated donor HSCT experiments are only beginning to be reported in this field.^46-48

Finally, even in our series, the posttransplantation follow-up remains generally short, calling for caution in the assessment of the long-term antitumor efficacy of these procedures. Determining whether the incidence and severity of complications related to the transplantation are lower than those observed after ablative therapies will require clinical trials in comparable groups of patients. Comparisons between nonmyeloablative and myeloablative regimens will also be needed before this therapy can be considered for younger patients eligible for a conventional myeloablative transplant. Given our observations, the strategy of allogeneic transplantation after nonmyeloablative conditioning could be proposed preferentially to patients who meet the following conditions: (1) have either lymphomas, CML, or myeloma; (2) are in response after conventional therapy; (3) receive a large number of CD34+ (selected) cells; (4) are treated after a regimen containing fludarabine and a long GVHD prophylaxis followed by prophylactic and preemptive DLI; (5) have documented chimerism and minimal residual disease.

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Submitted August 11, 2000; accepted March 21, 2001.

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