Biology of Blood and Marrow Transplantation
Volume 15, Issue 5 , Pages 632-638, May 2009

Platelet Engraftment in Patients with Hematologic Malignancies following Unmanipulated Haploidentical Blood and Marrow Transplantation: Effects of CD34+ Cell Dose and Disease Status

Peking University Institute of Hematology, Peking University People's Hospital, Beijing, China

Received 15 December 2008; accepted 3 February 2009.

Article Outline

Abstract 

Unmanipulated haploidentical blood and marrow transplantation has been developed as an alternative transplantation strategy for patients without an HLA-matched related or unrelated donor. In this transplantation setting, factors associated with hematopoietic recovery have not been defined completely. The aim of this study was to investigate the effects of donor and recipient characteristics on neutrophil and platelet engraftment after unmanipulated HSCT. The study group comprised 348 patients who underwent unmanipulated haploidentical blood and marrow transplantation to treat hematologic malignancy at a single institution between 2002 and 2007. Factors correlating with neutrophil and platelet engraftment posttransplantation were analyzed retrospectively. All patients achieved an absolute neutrophil count ANC of 500/μL in a median of 13 days (range, 9 to 49 days). Of the 348 patients, 331 (95.11%) achieved an untransfused platelet count of > 20,000/μL in a median of 16 days (range, 7 to 356 days). Multivariate analysis showed that the amount of CD34+ cells infused (CD34+ cells ≥ 2.19 × 106/kg recipient weight vs < 2.19 ×106/kg recipient weight; hazard ratio [HR] = 1.695; 95% confidence interval [CI] = 1.361 to 2.112; P < .0001), and disease stage (advanced vs early; HR = 0.724; 95% CI = 0.577 to 0.907; P = .005) were independently associated with increased risk of platelet engraftment. Our results suggest that low numbers of CD34+ cells in allografts and advanced-stage disease may be critical factors associated with delayed platelet engraftment after unmanipulated haploidentical transplantation.

Key Words: Engraftment, CD34+ cell, Disease stage, Unmanipulated blood and marrow transplantation

 

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Introduction 

Haploidentical stem cell transplantation (HSCT) is an alternative transplantation strategy for patients without a HLA-matched related or unrelated donor 1, 2, 3, 4, 5. One major issue that must be overcome for successful HSCT is graft rejection 1, 3. Current and potential strategies to overcome graft failure include megadoses of CD34+ donor cells, immunosuppressive and selective myeloablative conditioning regimens, and cotransplantation of mesenchymal stem cells 1, 3, 5. Recently, we developed a new method for HSCT that does not require in vitro T cell depletion. This strategy, which we call the GIAC protocol, applies sequential in vivo modulation of the recipient, the donor T cell function, and the dose of donor hematopoeitic stem cells. The GIAC protocol entails the following: donor treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF) to induce donor immunologic tolerance; intensified immunologic suppression to promote engraftment and prevent graft-versus-host disease (GVHD); antithymocyte immunoglobin (ATG) for GVHD and graft rejection prophylaxis; and a combination of rhG-CSF–primed bone marrow (G-BM) harvest and rhG-CSF–mobilized peripheral blood stem cell (PBSC) (G-PB) harvest to provide stem cell grafts. Under this GIAC protocol, all patients achieved full engraftment; the incidence of acute and chronic GVHD was comparable in the matched and mismatched cohorts 2, 4, 5, 6.

In HLA-matched allogeneic and autologous HSCT settings, multiple factors are associated with hematopoietic reconstitution, including donor–recipient sex matching, conditioning regimen, number of CD34+ cells infused, ABO mismatch, and numbers of CD3+ cells, CD8+ cells, and subsets of CD34+ cells in the allograft 7, 8, 9, 10, 11, 12, 13, 14, 15. The source of stem cells (bone marrow or peripheral blood) also affects engraftment kinetics, with PBSCs clearly associated with more rapid recovery of both neutrophils and platelets. Few published studies have investigated the effects of HLA match, CD34+ cell dose, and other patient and donor characteristics on engraftment kinetics in recipients of unmanipulated haploidentical blood and marrow grafts, however. We retrospectively analyzed data from 348 recipients of unmanipulated haploidentical blood and marrow allografts for patient, donor, and graft factors that might affect engraftment kinetics. We used factors identified from univariate analysis to construct multivariate statistical models to identify the variables that independently affected neutrophil and platelet recovery in this HSCT protocol 2, 4, 5, 16.

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Materials and Methods 

Patient Population 

Patients with hematologic malignancies suitable for allogeneic HSCT without an HLA-identical related or unrelated donor were candidates for this study. A total of 348 patients with malignant hematologic disease who underwent unmanipulated HLA-mismatched HSCT between October 2002 and December 2007 were enrolled. Written informed consent was obtained from all patients and donors. The study design was approved by the Institutional Review Board of Peking University Institute of Hematology and the Ethics Committee of Peking University People's Hospital. Table 1 summarizes characteristics of the 348 study patients [17].

Table 1. Patient, Donor, and Graft Characteristics
Number of patients348
Recipient age at HSCT, years, median (range)24 (2-54)
Recipient sex, n (%)
Male224 (64.4%)
Female124 (35.6%)
Recipient weight, kg, median (range)64 (12-110)
Underlying disease, n (%)
Acute myelogenous leukemia100 (28.7%)
Acute lymphoblastic leukemia117 (33.6%)
Chronic myelogenous leukemia105 (30.2%)
Myelodysplastic syndrome17 (4.9%)
Others9 (2.6%)
Disease status at transplantation, n (%)∗
Early-stage disease215 (61.8%)
Advanced-stage disease133 (38.2%)
Time to transplantation after diagnosis, days, median (range)210 (58-7000)
Donor age at HSCT, years, median (range)40 (14-67)
Sex match, n (%)
D male–R male110 (31.6%)
D male–R female57 (16.4%)
D female–R male114 (32.8%)
D female–R female67 (19.3%)
Donor type, n (%)
One locus mismatch47 (13.5%)
Two loci mismatch138 (39.7%)
Three loci mismatch163 (46.8%)
ABO compatibility, n (%)
Matched188 (54%)
Major mismatched69 (19.8%)
Minor mismatched69 (19.8%)
Bidirectional mismatched22 (6.3%)
Donor–recipient relationship, n (%)
Patient–child194 (55.7%)
Sibling–sibling108 (31.0%)
Child–patient36 (10.3%)
Others10 (2.9%)
Graft source, n (%)
G-PB + G-BM348 (100%)
Infused CD3+ cells ×108/kg recipient weight, median (range)1.64 (0.35-6.34)
Infused CD4+ cells ×108/kg recipient weight, median (range)0.85 (0.19-3.81)
Infused CD8+ cells ×108/kg recipient weight, median (range)0.63 (0.13-2.99)
Infused CD34+ cells ×106/kg recipient weight, median (range)2.19 (0.83-9.69)
Conditioning regimen, n (%)
Modified busulfan/cyclophosphamide + ATG348
GVHD prophylaxis, n (%)
CsA + ATG + MMF348

∗Disease status at transplantation was defined as described previously 4, 17.

Transplantation Procedure 

All patients received a myeloablative conditioning regimen comprising a combination of cytosine arabinoside 4 g/m2/day on days -10 and -9, busulfan 12 mg/kg given orally in 12 doses over 3 days (days -8, -7, and -6), cyclophosphamide 1.8 g/m2/day on days -5 and -4, simustine (Me-CCNU) 250 mg/m2 orally on day -3, and rabbit ATG (Thymoglobulin; Sangstat, Fremont, CA) 2.5 mg/kg per day i.v. on days -5 through -2 4, 5, 18.

Donors received rhG-CSF (filgrastim) 5 μg/kg s.c. once daily for 5 to 6 days. On the fourth day, bone marrow cells were harvested. The target total nucleated cell count of 3.0 × 108 cells/kg recipient weight was achieved (median, 3.51 × 108; range, 1.06 to 9.52 × 108). On days 5 and 6, peripheral blood progenitor cells (PBPCs) were collected using Fenwal CS3000 (Fenwal Laboratories, Deerfield, IL) and Cobe Spectra (Cobe Laboratories, Lakewood, CO) blood cell separators. Anticoagulant citrate dextrose solution (ACD-A) was used as the anticoagulant. The whole blood:anticoagulant ratio was 11:1. The target mononuclear cell count of 3.0 × 108 cells/kg recipient weight was achieved (median, 3.49 × 108; range, 0.83 to 12.10 × 108) . The median volume pheresed was 12 L (range, 4.5 to 15 L). The fresh and unmanipulated bone marrow and PBPCs collected on day 5 were infused into the recipients. In those with advanced-stage disease, a second apheresis was performed, and PBSCs were cryopreserved for prophylaxis and treatment of relapse 16, 19.

Prophylaxis for GVHD included cyclosporine A (CSA) and short-term methotrexate (MTX) with mycophenolate mofetil (MMF). CSA was started on day -9 at a dosage of 2.5 mg/kg i.v., with the switch made to an oral formulation as soon as the patient was able to take medication orally after engraftment. A trough concentration of 150 to 300 ng/mL was used to adjust the CSA dosage. MMF was administered orally, 0.5 g every 12 hours, from day -9 to day 30 posttransplantation, then 0.25 g twice daily for 1 to 2 months. The MTX dosage was 15 mg/m2 i.v. on day 1 and 10 mg/m2 on days 3, 6, and 11 posttransplantation. The diagnosis and grading of GVHD were done according to published criteria 20, 21, 22. Filgrastim 5 μg/kg/day s.c. was given to all recipients from day 6 posttransplantation until the neutrophil count reached 0.5 × 109 cells/L for 3 consecutive days. Bone marrow aspiration and cytogenetic studies were performed at 1, 2, and 3 months after transplantation to assess engraftment. HLA DNA typing and polymerase chain reaction DNA fingerprinting (short tandem repeat) were used for donor chimerism detection. For each patient, at least 2 tests were performed to confirm donor chimerism 4, 5, 18.

Evaluation and Definitions 

Engraftment was demonstrated by increasing neutrophil and platelet counts unsupported by transfusions. Neutrophil engraftment after transplantation was defined as an absolute neutrophil count (ANC) exceeding 500/μL for 3 consecutive days. The first of these 3 consecutive days was considered the day of engraftment. Platelet recovery was defined as the time after transplantation needed to achieve a blood platelet count exceeding 20,000/μL without transfusion support for 7 consecutive days. Graft failure was defined as persistently decreasing peripheral blood cell counts and progressive bone marrow hypoplasia (< 25% cellularity) occurring after documented engraftment and in the absence of leukemic relapse, drug toxicity, or infection and persisting for at least 14 days. The day of graft failure was assigned to the day on which the ANC declined to < 500/μL.

Statistical Analysis 

Summary statistics, including proportions, means, standard deviations, 95% confidence intervals (CIs), medians, and ranges, were used to describe the patient characteristics, pretransplantation variables, and posttransplantation outcomes. The associations between donor and recipient characteristics and hematopoietic engraftment were analyzed using the Kaplan-Meier method or calculated using the “cmprsk” library in the R statistical package (University of Auckland; http://www.r-project.org). The log-rank test was used in survival analysis, and the Grey test was used in cumulative incidence analyses. To confirm outcomes and adjust for potential confounding factors, multivariate Cox proportional hazards models were assessed for the proportional hazards assumption and for testing interaction terms with covariates. Variables included in the models were age (continuous; < vs ≥ the median), sex, donor–patient sex match (female to male vs others), ABO match (identical and minor vs major and bidirectional), HLA match (1 locus vs 2 loci vs 3 loci), disease risk (high risk vs standard risk), CD34 dose (continuous; < vs ≥ the median), and CD3 cell dose (continuous; < vs ≥ the median). The χ2 test and Mann-Whitney U test were used for categorical variables and continuous variables, respectively. Calculations were carried out using SPSS 13.0 statistical software (SPSS Inc, Chicago, IL). R software was used to calculate the cumulative incidence considering the presence of competing risk.

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Results 

Neutrophil and Platelet Engraftment 

All 348 patients achieved an ANC of 500/μL. The median time to achieve an ANC > 500/μL was 13 days (range, 9 to 49 days), comparable to the times reported previously in HLA-matched settings [23]. A total of 331 patients achieved an untransfused platelet count of > 20,000/μL, in a median time of 16 days (range, 7 to 356 days). Seventeen patients failed to reach a sustained platelet count of > 20,000/μL by the end of follow-up; all of these patients received a transfusion with irradiated whole blood-derived pooled platelets (1 ×1011/unit). Eleven of these 17 patients died without achieving platelet engraftment, at a median of 78 days (range, 33 to 260 days) posttransplantation.

The median numbers of cells infused wee as follows: total nuclear cells, 7.33 × 108/kg (range, 2.40 to 17.85 × 108/kg); CD34+ cells, 2.19 × 106/kg (range, 0.83 to 9.69 × 106/kg); CD3+ cells, 1.64 × 108/kg (range, 0.35 to 6.34 × 108/kg); CD4+ cells, 0.85 × 108/kg (range, 0.19 to 3.81 × 108/kg); CD8+ cells, 0.63 × 108/kg (range, 0.13 to 2.99 × 108/kg). The CD34+ cell counts were 0.75 × 106/kg (range, 0.04 to 8.20 × 106/kg) in the bone marrow and 1.26 × 106/kg (range, 0.70-6.46 × 106/kg) in the peripheral blood components.

Recipient and Donor Characteristics Associated with Engraftment 

In this analysis (Table 2), the most prominent finding was the association between the number of CD34+ cells in the allograft and the degree of platelet engraftment. Platelet engraftment was achieved by 161 of the 174 patients who received a CD34+ cell dose < 2.19 × 106/kg (92.5%) and by 170 of the 174 patients who received a dose ≥ 2.19 × 106/kg (97.7%), for respective actuarial probabilities of 92.27% ± 2.13% and 97.13% ± 1.36% (P < .001). The median time to achieve an untransfused platelet count > 20,000/μL was significantly shorter in the patients receiving a CD34+ cell dose ≥ 2.19 ×106/kg (14 days [range, 7 to 258 days] vs 18.5 days [range, 9 to 356 days]; P < .001).

Table 2. Univariate Analysis of the Factors Affecting Neutrophil and Platelet Engraftment in Patients with Hematologic Malignancies after Unmanipulated HLA-Mismatched/Haploidentical Blood and Marrow Transplantation
Neutrophil EngraftmentPlatelet Engraftment
VariablesHR95% CIPHR95% CIP
Recipient age0.9140.740–1.129.4050.7770.625–0.965.022
Sex0.6220.658–1.027.0840.9270.739–1.162.510
Weight1.0980.889–1.355.3860.9310.750–1.156.520
Disease status0.8240.660–1.030.0890.7460.596–0.935.011
Time to transplantation after diagnosis0.8130.657–1.005.0560.8690.700–1.079.202
HLA match0.9310.800–1.084.3560.8380.720–0.975.022
Patient–donor sex match1.0450.835–1.308.7021.0080.802–1.268.944
Donor age0.9270.749–1.146.4810.8880.715–1.104.285
Patient–donor ABO compatibility1.0190.801–1.296.8770.9020.705–1.155.414
Infused nuclear cells/kg recipient weight1.0180.950–1.092.6081.2491.005–1.552.045
Infused CD3+ cells/kg recipient weight1.1260.912–1.391.2701.1400.918–1.415.236
Infused CD4+ cells/kg recipient weight1.0840.877–1.339.4541.0470.843–1.301.675
Infused CD8+ cells/kg recipient weight,1.0370.839–1.281.7371.2701.022–1.578.031
Infused CD34+ cells/kg recipient weight1.1160.903–1.378.3091.6321.312–2.031< .0001
CMV antigenemia1.2220.987–1.513.0651.1430.919–1.423.230
HC1.1520.924–1.437.2081.0170.813–1.272.883
VOD0.8730.465–1.639.6730.8390.432–1.628.604

HR = hazard ratio; CI = confidence interval; HLA = human leukocyte antigen; CMV = cytomegalovirus; HC = hemorrhagic cystitis; VOD = hepatic veno-occlusive disease.

Our findings also demonstrate the negative effects of advanced disease on platelet recovery. Platelet engraftment was achieved by 122 of 133 patients with advanced-stage disease (91.7%), compared with 209 of 215 those with early-stage disease (97.2%), with respective actuarial probabilities of 91.28% ± 2.58%, and 96.86% ± 1.28% (P = .007). The median time to achieve an untransfused platelet count > 20,000/μL was significantly shorter in patients with early disease than those with advanced disease (15 days [range, 7 to 356 days] vs 18 days [range, 8 to 258 days]; P = .016).

In the univariate analysis (Table 2), 5 other factors were found to be associated with platelet engraftment: recipient age (P = .022), HLA match (P = .022), disease stage (P = .011), number of infused nuclear cells/kg recipient weight (P = .045), and number infused CD8+ cells/kg recipient weight (P = .031). Among those patients who achieved a sustained platelet count > 20,000/μL, an increased CD34 cell dose was suggestively associated with a shorter time to platelet recovery, although the strength of this association was relatively weak (R = -0.237; P < .001). In addition, trends toward associations between sex (female vs male; P = .084), time to transplantation after diagnosis (≤ 210 days vs > 210 days; P = .056), and disease stage (advanced stage vs early stage; P = .089) with neutrophil engraftment were demonstrated (Table 2).

As reported previously [5], in this cohort of 348 patients, 198 developed cytomegalovirus (CMV) antigenemia, 126 developed hemorrhagic cystitis (HC), and 10 developed hepatic veno-occlusive disease (VOD). The cumulative incidences of these 3 complications were 56.90% ± 2.70%, 36.20% ± 2.60%, and 2.90% ± 0.90%, respectively. The median time to onset was 35.5 days (range, 10 to 132 days) for CMV antigenemia, 33 days (range, 13 to 189 days) for HC, and 10.5 days (range, 6 to 15 days) for VOD. Univariate analysis revealed a trend toward an association between CMV antigenemia and neutrophil engraftment (P = .065). No association between CMV antigenemia, HC, or VOD and platelet engraftment was observed (Table 2).

Multivariate Analysis 

Multivariate analysis demonstrated no effects of age, sex, HLA mismatch, ABO mismatch, CD3+ and CD34+ cell dose, CMV antigenemia, HC, or VOD on the incidence of neutrophil engraftment. Considering the factors affecting platelet engraftment, we attempted to enter all variables with a P value < .1 (ie, recipient age, HLA mismatch, number of infused CD8+ cells/kg recipient weight, and number of infused CD34+ cells/kg recipient weight) into the regression. In multivariate analysis, number of infused CD34+ cells (hazard ratio [HR] = 1.695; 95% CI = 1.361 to 2.112; P < .0001) (Figure 1) and disease stage (advanced vs early; HR = 0.724; 95% CI = 0.577 to 0.907; P = .005) (Figure 2) were independently associated with an increased risk of platelet engraftment.

  • View full-size image.
  • Figure 1 

    Effect of CD34+ cell dose on the kinetics of platelet engraftment in patients with hematologic malignancies receiving T cell–replete blood and marrow transplantation from HLA-mismatched/haploidentical related donors.

  • View full-size image.
  • Figure 2 

    Effect of disease stage at transplantation on the kinetics of platelet engraftment in patients with hematologic malignancies receiving T cell–replete blood and marrow transplantation from HLA-mismatched/haploidentical related donors.

To explore whether the CD34+ cell dose, as one of the most important factors identified, is independent of disease status, the patients were classified into 2 groups according to disease status. Multivariate Cox regression analysis also demonstrated that higher CD34+ cell dose (≥ 2.19 × 106/kg) in the allografts was associated with faster platelet engraftment in patients with early disease (HR = 1.573; 95% CI = 1.192 to 2.077; P = .001) and those with advanced disease (HR = 1.876; 95% CI = 1.294 to 2.720; P < .0001).

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Discussion 

In this study, all patients achieved neutrophil engraftment within 14 days of transplantation. A few patients still experienced delays in platelet recovery, however, necessitating more transfusion support and putting them at increased risk for bleeding. Our findings indicate that the CD34+ cell dose is critical to successful platelet engraftment. Several previous studies have demonstrated a strong inverse correlation between CD34+ cell dose and platelet engraftment kinetics, with an estimated threshold minimum of no less than 5 × 106cells/kg recipient weight for rapid platelet recovery 24, 25, 26, 27. Our findings are consistent with those of some previous studies 25, 26 but suggest that a threshold CD34+ cell dose of 2.19 × 106/kg is sufficient for rapid platelet engraftment. Our lower threshold CD34+ cell dose than those reported by other researchers may result from our strict gating for the CD34+ cell assay [28]. Another potential explanation may be linked to our use of a significantly lower rhG-CSF dose (5 μg/kg/day vs 10 to 15 μg/kg/day) 29, 30.

We also found significantly delayed platelet recovery in the recipients with advanced-stage disease compared with those with early-stage disease (actuarial probability: 91.28% ± 2.58% vs 96.86% ± 1.28%; P = .005), suggesting that disease stage is important to successful platelet engraftment in this unmanipulated HSCT setting 4, 5. To the best of our knowledge, the patients with advanced-stage disease typically received more cycles of chemotherapy than those with early-stage disease, and some may have undergone transplantation while in relapse; these patients could have more minimal residual disease that survived the conditioning regimen [31]. Stromal damage from high-dose chemotherapy and leukemic cells surviving after conditioning may contribute to delayed platelet engraftment in these patients 32, 33.

We failed to demonstrate an association between CD34+ cell dose and neutrophil engraftment. Numerous studies in various transplantation settings have investigated the relationships between clinical outcomes and total graft cell dose, as well as doses of individual cell subsets 34, 35. Regardless of cell source, an almost consistent finding has been an association between higher CD34+ cell dose and more rapid neutrophil engraftment 9, 11, 24, 36. Results from these studies suggest that a relatively low CD34+ cell dose (ie, 2 to 4 × 106 cells/kg recipient weight) is the minimum required for rapid engraftment [36]. These considerations, along with our institutional target of ≥ 2 × 106 CD34+ cells/kg, likely explain much of the poor correlation between engraftment and CD34+ cell dose in the present study. Moreover, the effects of CD3+ cells on engraftment have been demonstrated previously 37, 38, 39. Urbano-Ispizua et al. [39] studied 257 patients in T cell–depleted transplantation settings and found that the number of CD3+ cells in the inoculum (with a threshold of 0.2 × 106 cells/kg) is the most critical factor in maintaining sustained engraftment. Our significantly higher CD3+ cell counts (median, 1.64 × 108cells/kg) in the allografts may be sufficient to maintain engraftment even in haploidentical settings. In addition, the differences in engraftment kinetics between platelets and neutrophils may account, at least in part, for our finding of an association between CD34+ cell dose and platelet engraftment, but not neutrophil engraftment.

Megadoses of CD34+ cells have been used to overcome graft rejection in HSCT with ex vivo T cell depletion 40, 41. In our protocol, CD34+ cell dose in the mixture grafts of G-PB and G-BM is an important factor affecting neutrophil and platelet engraftment, although other factors, including ATG, and CD3+ cell dose in the mixture grafts of G-PB and G-BM, also may contribute to hematopoietic reconstitution. Taken together, our findings and those of others 7, 9, 11, 14, 36 suggest almost universally that CD34+ cell dose is a key factor in hematopoietic engraftment not only in HLA-matched/haploidentical HSCT protocols 14, 36, 40, 42, but also in autologous HSCT settings 7, 9.

In summary, our results demonstrate that a CD34+ cell dose in the inoculum < 2.19 × 106cells/kg is a critical factor associated with delayed platelet engraftment after unmanipulated HSCT. A higher CD34+ cell dose is desirable to ensure rapid platelet engraftment, especially in patients with advanced-stage disease, because this is also associated with delayed platelet recovery in our transplantation setting.

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Acknowledgments 

Financial disclosure: This work was supported by grants from the National Outstanding Young Scientist's Foundation of China (30725038), Scientific Research Fund for Capital Medicine Development (2005-1010), and Program for Innovative Research Team in University (IRT0702). We have no potential conflicts of interest to report. We thank San Francisco Edit (http://www.sfedit.net) for their assistance in editing this manuscript.

Author contributions: Y.-J.C. performed research, analyzed and interpreted data, drafted the manuscript, and approved the final version. L.-P.X. performed research, analyzed and interpreted data, drafted the manuscript, and approved the final version. X.-J.H. was involved in study conception and design, revised the manuscript in response to reviews, and approved the final version.All of the remaining authors were involved in study design and patient treatment.

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 Financial disclosure: See Acknowledgments on page 637.

PII: S1083-8791(09)00077-9

doi:10.1016/j.bbmt.2009.02.001

Biology of Blood and Marrow Transplantation
Volume 15, Issue 5 , Pages 632-638, May 2009

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