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Relevance of Bone Marrow Cell Dose on Allogeneic Transplantation Outcomes for Patients With Acute Myeloid Leukemia in First Complete Remission: Results of a European Survey

From the Hematopoietic Stem Cell Transplant Unit, Hôpital Saint Louis, and Service d’Hématologie, CHU Saint-Antoine and European Data Management Office (Centre International Greffes de Moelle AP-HP et Centre de Recherche Claude Bernard sur la Thérapie Cellulaire), Institut des Cordeliers, Paris; and Hôpital du Haut Leveque, Pessac, France; Helsinki University Central Hospital, Helsinki, Finland; University "La Sapienza," Rome, and Ospedale San Martino, Genoa, Italy; Hospital Universitario Marqués de Valdecilla, Santander, Spain; and Huddinge University Hospital, Huddinge, Sweden.

Address reprint requests to Vanderson Rocha, MD, Hôpital Saint Louis–Unité de Recherche Clinique, 1, av Claude Vellefaux, 75010 Paris, France; email: vanderson.rocha{at}sls.ap-hop-paris.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Many attempts have been made to improve the results of allogeneic bone marrow transplantation (alloBMT) for patients with acute myeloid leukemia (AML) in first complete remission (CR1). Bone marrow cell dose has been reported to be an important factor in alloBMT; however, its true impact on relapse incidence (RI), leukemia-free survival (LFS), and nonrelapse mortality (NRM) in a large cohort of patients is unknown.

PATIENTS AND METHODS: From January 1992 to December 1999, 572 bone marrow transplantation recipients reported to the European Blood and Marrow Transplantation (EBMT) registry underwent allografting from an HLA-identical sibling donor with an unmanipulated bone marrow for AML in CR1.

RESULTS: The median number of nucleated cells (NCs) infused was 2.6 x 10⁸/kg. Estimated 5-year NRM, LFS, and RI for patients receiving more or less than 2.6 x 10⁸ NCs/kg were, respectively, 18% ± 5% v 30% ± 5% (P = .001), 68% ± 3% v 46% ± 3% (P < .00001), and 14% ± 4% v 24% ± 5% (P = .004). The association of cell dose with the above outcomes was confirmed in multivariate analyses for NRM (relative risk [RR], 0.53; P = .0007), for LFS (RR, 0.53; P = .00008), and for RI (RR, 0.57; P = .02). The cell dose was also an important factor for neutrophil (RR, 0.76; P = .009) and platelet (RR, 0.77; P = .03) recoveries; however, it did not statistically influence the incidence of acute graft-versus-host disease.

CONCLUSION: This study shows that marrow cell dose is one of the most important factors influencing relapse, NRM, and LFS after alloBMT for patients with AML in CR1. Therefore, increasing the marrow cell dose should substantially improve the survival of these patients.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
ALLOGENEIC STEM-CELL transplantation has been used to treat a wide variety of malignant and nonmalignant hematologic diseases. In patients with acute myeloid leukemia (AML) in first complete remission (CR1), several groups have investigated the role of allogeneic bone marrow transplantation (alloBMT) compared with autologous bone marrow transplantation (BMT) and chemotherapy.^1-3 There is no doubt that HLA-identical BMT is still associated with considerable (approximately 30%) transplantation-related mortality, especially in patients older than 35 years of age.^1,3 Nevertheless, it has been reduced over the years.⁴ In most studies, survival after alloBMT was either equivalent or superior to that of conventional chemotherapy or autologous transplantation.^1-3

More favorable outcome after alloBMT requires the prevention of both relapse and nonrelapse mortality. Identification of factors that are predictive for both are of value when attempting to make risk-based recommendations for postremission therapy in AML.

Results of alloBMT, such as hematopoietic recovery, nonrelapse mortality, relapse, and disease-free survival, are influenced by patient-, disease-, donor-, and transplantation-related factors. Among those factors, a high bone marrow cell dose is associated with the improvement of hematopoietic recovery and survival more specifically in BMT for severe aplastic anemia.^5-7 Bone marrow cell dose has also been described as an important favorable factor in unrelated and syngeneic BMT for patients with leukemia.^8,9

Bone marrow cell dose is a variable that can be controlled by clinicians because it is a product of cells harvested according to the recipient’s body weight. Recommendations have been made to harvest 2 x 10⁸ nucleated cells (NCs) per kilogram of the recipient’s body weight. In order to study the impact of cell dose on transplantation outcome in a homogeneous cohort of patients, we analyzed 572 patients with AML in CR1 who underwent transplantation from an HLA-identical sibling bone marrow donor that were reported to the European Blood and Marrow Transplantation (EBMT) group between 1992 and 1999.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Data Collection and Patient Selection
The EBMT registry is a voluntary working group of more than 450 transplantation centers. Participants are required once a year to report all consecutive transplantations and follow-up. The Acute Leukemia Working Party of the EBMT is in charge of validating and checking submitted data to ensure data quality. This study included 572 patients receiving alloBMT from HLA-identical siblings who were older than 16 years of age at the time of transplantation, had AML in CR1, and had received a non–T-cell–depleted transplantation between January 1, 1992, and January 1999.

Definition of Outcomes
The primary outcomes were (1) nonrelapse mortality (NRM), defined as the cause of all nonleukemic deaths; (2) relapse incidence (RI); defined on the basis of morphologic evidence of leukemia in bone marrow, or other extramedullary organs; and (3) leukemia-free survival (LFS), defined as the time interval from transplantation to the first event (either relapse or death in complete remission). Other outcomes were (4) hematopoietic recovery (neutrophil and platelet recoveries were analyzed separately, and defined by a neutrophil count of 0.5 x 10⁹/L for 3 consecutive days and an untransfused platelet count of 50 x 10⁹/L for 7 consecutive days; the median time of recovery was calculated by the product limit method) and (5) graft-versus-host disease (GVHD) (acute GVHD [aGVHD] was diagnosed and graded at each transplantation center according to Seattle criteria¹⁰). Only patients with grade II or superior were considered as having GHVD. Chronic GVHD (cGVHD) was defined according to standard criteria.¹¹ Patients surviving without relapse for more than 100 days after transplantation with sustained donor engraftment were considered as assessable for cGVHD.

Statistical Analysis
The median and range were the values reported for quantitative variables. The following patient or graft characteristics were analyzed for their potential prognostic value on each of the outcomes: patient and donor characteristics (age and sex matching, cytomegalovirus serology, ABO compatibility), disease factors (WBC count at diagnosis, French-American-British [FAB] classification, cytogenetics, interval from diagnosis to CR1, interval from CR1 to BMT), and transplantation-related factors (NCs infused per kilogram, conditioning regimen, GVHD prevention, center). For these prognostic analyses, continuous variables were categorized as follows: each variable was first divided into five categories at approximately the 20th, 40th, 60th, and 80th percentiles. If the relative event rates (ratio of the observed number of events to the expected number of events in a category, assuming no variation across categories) in two or more adjacent categories (and the mean times to event) were not substantially different, these categories were then grouped. If no clear pattern was observed for the primary outcomes, the median was taken as a cutoff point.¹² To compare both groups of patients receiving more or less than the median number of NCs infused, we used the ² test for categorical variables and nonparametric Mann-Whitney U test for continuous variables.

Patients were censored at the time of relapse or at the last follow-up.¹³ Probability of hematopoietic recovery, aGVHD, and LFS were estimated by the product-limit method.¹⁴ The significance of differences between curves was estimated by the log-rank test (Mantel-Cox). All variables associated with outcome with a value of P < .10 in univariate analysis and those statistically different (P < .05) between both groups of patients (Table 1) were included in the Cox proportional hazards model. Then, a backward stepwise procedure was used to select covariates (P < .05) included in the final Cox proportional hazards model.¹⁵ In a previous EBMT study, because center effect was observed on outcomes in patients receiving a BMT for AML in CR1,¹⁶ all further multivariate analyses were stratified by the transplantation centers.

	RESULTS

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Patient, Disease, and Transplantation Characteristics
A total of 572 adults with AML in CR1 who underwent transplantation in 87 centers met the eligibility criteria. Patient, donor, and transplantation characteristics are listed in Table 1. Most frequently, patients reached the CR1 with one (73%) or two (20%) courses of chemotherapy. Data on cytogenetics were available in 54% (n = 307) and an abnormal karyotype was detected in 135 patients.

Preparative regimens varied between centers; however, 330 patients (57%) received an association of total-body irradiation (TBI) plus cyclophosphamide with or without another drug, 221 patients (39%) received an association of busulfan plus cyclophosphamide, and 21 patients (4%) received other types of chemotherapy (Table 1). As GVHD prophylaxis, most of the patients received cyclosporine associated with short-course methotrexate (n = 500 [87.3%]).

Bone Marrow Cell Dose
Bone marrow NC dose ranged from 0.18 to 9.8 x 10⁸/kg recipient body weight. We found that a cutoff point at the median dose of 2.6 x 10⁸/kg gave the greatest discrimination for all end points studied between high (> 2.6 x 10⁸/kg; n = 285) and low cell doses ( 2.6 x 10⁸/kg; n = 287). We also analyzed the influence of cell dose on LFS according to percentiles as shown in Fig 1.

View larger version (14K): [in this window] [in a new window]   Fig 1. Kaplan-Meier estimate of LFS after BMT for adults with AML, according to bone marrow cell dose infused in five categories (percentiles).

Outcomes
Neutrophil and platelet recovery. Five hundred fifty (96%) patients achieved neutrophil recovery. Engraftment was not achieved in only two patients. The median time to achieve a neutrophil count greater than 500 x 10⁹/L was 19 days (range, 4 to 79 days). Patients receiving a higher cell dose (> 2.6 10⁸/kg) had an earlier neutrophil recovery (18 days) compared with 20 days for patients receiving a lower cell dose (P < .0001). In a multivariate analysis, cell dose was an important prognostic factor (relative risk [RR], 0.76; 95% confidence interval [CI], 0.61 to 0.93; P = .009) among other factors favorably influencing recovery, namely, the absence of TBI (RR, 0.61; 95% CI, 0.48 to 0.78; P < .0001) and GVHD prophylaxis with the cyclosporine alone without methotrexate (RR, 0.35; 95% CI, 0.24 to 0.51; P < .0001).

Median time to achieve a platelet count greater than 50,000 was 25 days (range, 12 to 522 days). Patients receiving a higher number of NCs had earlier platelet recovery at day 24, whereas it took 28 days for patients receiving fewer cells (P < .0001). In a multivariate analysis, the following factors increased the speed of platelet recovery: (1) cell dose (> 2.6 x 10⁸/kg) (RR, 0.77; 95% CI, 0.60 to 0.97; P = .03), (2) sex matching other than female donor to male recipient (RR, 0.76; 95% CI, 0.58 to 0.99; P = .05), and (3) WBC count 70 x 10⁹/L at diagnosis (RR, 0.70; 95% CI, 0.50 to 0.97; P = .03).

Acute and chronic GVHD. Acute GVHD ( grade II) was observed in 173 patients (grade II, 113 [22%]; grade III, 36 [7%]; and grade IV, 24 [5%]). Estimated probability of developing aGVHD ( grade II) at day 100 was 36% ± 3% for patients receiving a lower cell dose compared with 32% ± 3% in patients receiving a higher cell dose (P = .34). In a multivariate analysis, the only factor increasing the risk of aGVHD was FAB classification (M5 and M6) (RR, 0.56; 95% CI, 0.38 to 0.76; P = .002). Data on observed cGVHD were available in 397 patients. Eighty-two (44%) of 187 patients receiving a lower cell dose had cGVHD compared with 99 (47%) of 210 patients receiving a higher cell dose (P = .51).

NRM
A total of 129 patients died from nonleukemic causes. At 5 years, NRM was 24% ± 4%. In univariate and in multivariate analysis (Table 2), bone marrow cell dose was an important factor among other known factors influencing the risk of dying from a nonleukemic cause. In fact, 5-year cumulative incidence of NRM was 30% ± 5% in patients wh underwent transplantation with a lower bone marrow cell dose (2.6 x 10⁸/kg) and 18% ± 5% in patients receiving a higher cell dose (P = .001) (Fig 2A). Other factors (P < .05) associated with a lower NRM were patient age 35 years (17% ± 4% v 30% ± 5%, P = .002), shorter interval from CR1 to BMT (17% ± 5% v 29% ± 6%, P = .003), M1/M2/M3/M4 versus M5/M6 (21% ± 3% v 38% ± 3%, P = .0003), normal cytogenetics (22% ± 4% v 30% ± 8%, P = .03), and donor age 35 years (17% ± 4% v 30% ± 6%, P = .002). In a multivariate analysis, a higher bone marrow cell dose was associated with a decreased NRM (RR, 0.53; 95% CI, 0.44 to 0.64; P = .0007). In addition to cell dose, other factors decreasing the risk of NRM are listed in Table 2.

View larger version (13K): [in this window] [in a new window]   Fig 2. Cumulative incidences of (A) NRM and (B) RI and Kaplan-Meier estimate of (C) LFS after BMT for adults with AML, according to bone marrow cell dose infused.

One hundred thirty-one of 287 recipients receiving a lower cell dose and 78 of 285 patients receiving a higher cell dose died. Recurrent leukemia was the most frequent primary cause of death in both groups (accounting for 40% [n = 52] of deaths in the group of 2.6 x 10⁸/kg and 36% [n = 28] in the group of > 2.6 x 10⁸/kg). Causes of death according to cell dose are listed in Table 3. Deaths related to infection from any cause or graft failure were more common in the group of patients receiving a lower bone marrow cell dose (P = .008).

Five-year cumulative incidence of LFS was 57% ± 2%. Figure 1 shows 5-year LFS according to five categories of cell dose. Patients receiving a lower cell dose had 5-year LFS of 46% ± 3%, whereas it was 68% ± 3% in patients receiving a higher cell dose (P < .0001) (Fig 2C). Other factors associated with a better LFS were age younger than 35 years (64% ± 3% v 50% ± 3%, P = .004), WBC count 70 x 10⁹/L (60% ± 3% v 45% ± 6%, P = .008), FAB classification (M1/M2/M3/M4) (60% ± 2% v 45 ± 6%, P = .001), normal cytogenetics (59% ± 2% v 50% ± 4%, P = .02), donor age 35 years (64% ± 3% v 50% ± 3%, P = .002), ABO compatibility (61% ± 3% v 52% ± 5%, P = .04), and cyclosporine plus methotrexate as GVHD prophylaxis (59% ± 2% v 44% ± 6%, P = .01). In a multivariate analysis, bone marrow cell dose was an important factor among other risk factors such as patient age, FAB classification, and cytogenetics abnormality (Table 2).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This study shows that the marrow cell dose is an important factor influencing hematopoietic recovery and NRM, and, for the first time to our knowledge, we report a clear influence of cell dose on relapse. Consequently, cell dose has an important impact on LFS after alloBMT for AML in CR1.

We have found that higher cell dose reduces NRM from 30% to 18%. The effect of marrow cell dose was also reported to affect NRM after unrelated BMT.^8,9 In our study, the causes of death related to infections were more frequent in the group of patients receiving fewer cells, probably because of delayed engraftment and immune recovery.¹⁸

It is believed that the antileukemic activity of alloBMT is provided both by the high dose-intensity of the conditioning regimen and by an immune-mediated graft-versus-leukemia effect.¹⁹ Undoubtedly, higher doses of TBI were associated with lower recurrence of leukemia,^20,21 but in many studies the benefit of better control of leukemia was offset by higher NRM.^19-21 In the present study, we show that a high bone marrow cell dose can decrease relapse from 24% to 14%. Intriguingly, this effect seems to be distinct from the so-called graft-versus-host and the graft-versus-leukemia effect. In fact, a higher cell dose was not associated with an increased incidence of aGVHD. Although in univariate analysis we observed that there was a trend of more relapses in patients without clinical signs of GVHD (data not shown), in the multivariate analysis, only a higher tumor burden at diagnosis (WBC count > 70 x 10⁹/L) and a lower cell dose ( 2.6 x 10⁸/kg) were predictive for an increased incidence of relapse. We can speculate that the reason why a higher cell dose decreased relapse without increasing GVHD relies on the fact that there are cell subtypes other than T cells that could influence relapse.²² Further prospective studies quantifying bone marrow cell subsets in the graft and their association with relapse will need to verify this hypothesis.

Bone marrow cell dose is a product of cells harvested and the recipient’s body weight. We found that patients receiving lower cell dose weighed more than those receiving a higher cell dose. One could argue that a recipient’s obesity is an adverse factor for outcomes after alloBMT.²³ Surprisingly, studies that reported obesity as an independent risk factor of poorer outcomes after BMT did not include cell dose as a prognostic variable. Moreover, other studies have not shown the impact of obesity on transplantation outcomes,²⁴ thus showing the weakness of this variable and its dependence on other factors.

In our study, we have also found that female donors gave fewer cells to male recipients, probably reflecting a weight disproportion. In addition, we have also observed that in the lower cell dose group, transplantations with major ABO incompatibilities were more frequent. In consequence, weight disproportion should also be considered in the choice of donor and a higher cell dose harvested in cases of major ABO incompatibilities because of nonspecific cell loss associated with plasma or RBC removal.

To which limit can we improve outcomes of alloBMT by increasing the cell dose? We found that cell doses higher than 3.8 x 10⁸/kg of the recipient’s body weight did not substantially improve LFS after BMT (Fig 1). Despite few complications after marrow donation, the duration of anesthesia and the volume of marrow collected were associated with a higher incidence of donor discomfort and delayed recovery time after the donation.²⁵ On the basis of the present study, we recommend that during the marrow collection transplantation centers should monitor the number of cells collected, with a target between 3 and 4 x 10⁸ NCs/kg of recipient’s body weight, instead of 2 x 10⁸ NCs/kg as previously recommended. This target of marrow collection should not increase risks for the donor.

Of course, one immediately would think that the simplest way to increase the cell dose is with the use of granulocyte colony-stimulating factor–mobilized allogeneic peripheral blood stem cells (PBSCs). With PBSC transplantationss, NC dose is increased six-fold and the T-cell dose 10-fold.²⁶ Randomized studies comparing PBSC transplantations with BMTs have shown that hematopoietic recovery is faster without increase of aGVHD^26-29; however, the incidence of cGVHD is probably higher.^27-29 For the moment, there is no evidence that PBSCs are superior in terms of outcome (LFS or survival) when compared to bone marrow in patients who undergo transplantation in the early phase of malignant diseases, such as AML in CR1.^27-29 Moreover, it is difficult to compare both sources of stem cells because of the differences of composition of the graft in different cell subsets including lymphocytes or mesenchymal cells and other cellular components possibly influencing the final outcome. In contrast, PBSCs are stimulated by hematopoietic growth factors and, in consequence, all cell subsets (including those bearing the same phenotype as those of bone marrow) may be functionally different.³⁰ For all these reasons, it may be possible that the cell dose effect, as seen in the BMTs, could not be observed when a different stem-cell source (ie, PBSCs) is considered.

Another approach recently described to increase the cell dose has been to prime the bone marrow donor with granulocyte colony-stimulating factor. In comparison with PBSC transplantations, allogeneic primed BMTs have shown a similar engraftment rate and have shown a reduced severity of aGVHD and cGVHD.³¹

In conclusion, bone marrow cell dose is primarily under the control of the clinician, which differs from other variables known to strongly affect transplantation outcomes that depend on patient characteristics. Therefore, it seems mandatory, on the basis of these findings, to harvest more than 3 x 10⁸ cells/kg during the collection procedure. This simple measure should result in a better survival for patients undergoing BMT for AML in CR1. These data should not be generalized, and they may not apply to transplantations for hematopoietic malignancies other than AML in CR1.

	NOTES

 
Presented in part at the Forty-Second Annual Meeting of the American Society of Hematology, San Francisco, CA, December 1-5, 2000.

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Submitted November 14, 2001; accepted July 18, 2002.

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