Factors influencing hematopoietic recovery (HR) after autologous blood stem cell transplantation (ABSCT) were analyzed in 73 patients with various non-myeloid malignancies (NMM), and in 58 patients with acute myeloblastic leukemia (AML). Peripheral blood stem cells were collected following mobilization with chemotherapy, granulocyte colony-stimulating factor (G-CSF), or chemotherapy plus G-CSF. The conditioning regimen used consisted of either chemotherapy alone (112 cases) or chemotherapy plus total body irradiation (19 cases). The median number of colony-forming units granulocyte–macrophage (CFU-GM) was similar in both groups of patients, with the median number of CD34+ cells infused being higher in the AML group (5.4 vs 4 × 106/kg; P = 0.03). Median time neutrophils >0.5 × 109/l was 13 days in both groups, and median time to a platelet count >20 × 109/l was longer in AML patients (14 vs 12 days; P = 0.01). In multivariate analysis, the only factors affecting neutrophil recovery in the NMM group were the CD34+ cell number (continuous model) and the CFU-GM dose (categorized model) infused, whereas for platelet recovery, previous chemotherapy also remained significant. In the AML group, the only factors significantly affecting the speed of neutrophil recovery were dose of CD34+ cells administered and the patient's age. As for platelet recovery, only the progenitor dose administered remained significant. In the NMM group, the most discriminating cut-off values for a rapid neutrophil and platelet recovery were 1.5 × 106 and 2.5 × 106 CD34+ cells/kg, respectively, and for AML patients these figures were 1.5 × 106 and 4 × 106 CD34+ cells/kg, respectively. Our results confirm the slower HR after ABSCT in AML, and highlight the importance of progenitor cell dose in accelerating HR after ABSCT.
High-dose therapy followed by autologous blood stem cell transplantation (ABSCT) is widely used for the treatment of different malignancies. Several studies have reported data on factors influencing the rate of hematopoietic recovery (HR) after ABSCT, especially in patients with non-myeloid malignancies.1,2 Data about patients with acute myeloblastic leukemia (AML) are, however, very limited, with only a few studies addressing this issue specifically.3–5 Improving knowledge of the different factors affecting HR after ABSCT is important to further enhance the safety of this procedure.
The primary objective of this study was to identify predictive factors affecting HR and the adequate progenitor dose (measured as colony-forming units granulocyte–macrophage, CFU-GM, and CD34+ cells) required for rapid engraftment, in a series of 131 consecutive patients undergoing ABSCT. A secondary objective was to compare the data obtained in 58 patients with AML, with those obtained in 73 patients with different non-myeloid malignancies (NMM).
Patients and methods
Patients included in the ABSCT program at the University Hospital La Fe between November 1989 and October 1996 form the basis of the present study. A total of 145 patients were mobilized during this period, with 131 of them (58 with AML and 73 with NMM) undergoing ABSCT. Patient characteristics at transplantation are listed in Table 1.
Patients with NMM had been pretreated with a variety of chemotherapy regimens, the most common being CHOP and ESHAP in patients with non-Hodgkin's lymphoma (NHL), ABVD and ESHAP in cases with Hodgkin's disease (HD), melphalan plus prednisone and VAD in patients with multiple myeloma (MM) and FEC in patients with breast cancer (BC). The treatment protocols administered to patients with AML varied during the period of study, and have been reported elsewhere.6,7 Most patients had received an induction and a consolidation course including an anthracycline plus Ara-C. Since 1992, an additional intensification course with intermediate dose Ara-C (1 g/m2/12 h, 3 days) was also administered prior to ABSCT. The median number of chemotherapy cycles before transplantation for NMM and AML patients was nine (range 4–32) and two (range 1–15), respectively.
Peripheral blood stem cell mobilization
Mobilization characteristics are summarized in Table 1. In patients with NMM, peripheral blood stem cell (PBSC) collections were performed following administration of granulocyte colony-stimulating factor (G-CSF) alone (61%), chemotherapy alone (21%), or chemotherapy plus G-CSF (18%). In patients with AML, most mobilizations (84%) were performed with chemotherapy alone, 11% with chemotherapy followed by G-CSF, and 5% with G-CSF alone. In NMM patients, the chemotherapy regimen used for mobilization varied according to diagnosis. Cyclophosphamide 600 mg/m2 i.v. on day 1, vincristine 1.5 mg/m2 i.v. on day 1, Ara-C 150 mg/m2/12 h s.c. on days 1 to 5, and oral prednisone 100 mg/m2 on days 1 to 5, were administered to patients with MM in all except one case, and ESHAP was administered to patients with HD and NHL in all except two cases. In AML patients, mobilization was performed with the same chemotherapy as that administered for remission induction as has been described elsewhere.6,7 Aphereses were started when the peripheral white blood cell count was >1 × 109/l for patients mobilized with chemotherapy and >10 × 109/l for patients mobilized with chemotherapy plus G-CSF. In patients mobilized with G-CSF alone, PBSC collection was commenced after 4 days with G-CSF.
Methods of PBSC collection and cryopreservation have been previously described elsewhere.8 Harvesting was performed using either of two blood cell separators, the Fenwal CS3000 (Fenwal Laboratories, Deerfield, IL, USA) or Cobe Spectra (Cobe Laboratories, Lakewood, CO, USA). After collection, the cells were placed in 10% (v/v) dimethylsulfoxide (DMSO), frozen to −120°C and stored in liquid nitrogen at −196°C until use.
For enumeration of CFU-GM, cells were grown in a methylcellulose-based clonogenic assay.9 Cultures were incubated at 37°C in a humidified 5% (v/v) CO2 atmosphere. Formation of granulocyte–macrophage colonies was scored on day 10. CD34+ cells were quantitated by flow cytometric analysis.10 Briefly, 100 μl of each sample, containing 5–10 × 105 cells, were incubated for 10 min at room temperature with the phycoerythrin (PE; (HPCA-2))-conjugated anti-CD34 monoclonal antibody (moAb), the fluorescein isothiocyanate (FITC)-conjugated anti-CD33 moAb and PerCP-conjugated anti-CD45 moAb (Becton Dickinson, Mountain View, CA, USA). After incubation, the red cells were lysed, and 65 000 cells were analyzed by fluorescence activated cell sorting (FACScan; Becton Dickinson) for each sample.
Patients with AML received BUCY (54 cases) or BAVC as previously described.11 All lymphoma patients received Ara-C 200 mg/m2 i.v. for 4 days, BCNU 800 mg/m2 i.v. for 4 days, and VP-16 200 mg/m2 i.v. for 4 days. Multiple myeloma patients received total body irradiation 3 Gy/day for 4 days followed by melphalan i.v. (140 mg/m2 for 1 day), with the exception of one patient who was conditioned with chemotherapy alone. Lastly, patients with BC were treated with carboplatin 200 mg/m2 via continuous i.v. for 4 days, cyclophosphamide 1500 mg/m2 via continuous i.v. for 4 days, and thiotepa 125 mg/m2 via continuous i.v. for 4 days.
Patients were transplanted in single-patient, high-efficiency particulate air-filtered rooms. Supportive care included ciprofloxacin, oral fluconazole and prophylactic acyclovir. Mesna was used to prevent hemorrhagic cystitis. Growth factors were not routinely used after transplant. Irradiated and filtered blood products were given to maintain the hemoglobin level above 10 g/dl and the platelet count above 10 × 109/l. In cases of neutropenic fever, empiric broad-spectrum antibiotic therapy was started immediately. Amphotericin B was added for suspected fungal infections.
Patients with NMM and AML were analyzed separately. For patients with NMM, the explanatory variables analyzed included the patient's age, sex, diagnosis, mobilization method, stage of disease, prior chemotherapy, prior radiotherapy, prior exposure to stem cell-toxic chemotherapy, marrow disease, diagnosis-to-ABSCT interval and numbers of CFU-GM and CD34+ cells infused. The variables considered in patients with AML were age, sex, mobilization method, stage of disease, prior chemotherapy, diagnosis-to-ABSCT interval, leukemic relapse and the numbers of CFU-GM and CD34+ cells infused.
The probability of HR was calculated by the method of incomplete observations.12 Patients were censored at relapse, death or at last control. On univariate analysis, the influence of the various parameters was assessed using the log-rank test. For most numerical variables, two groups were formed using the median as a cut-off value. The progenitor cells infused were categorized in accordance with the most discriminating cut-off values. Categorical data were divided as appropriate into groups. To analyze prior chemotherapy in patients with NMM, two groups were considered, dependent upon whether they had received only one regimen and a maximum of eight cycles of chemotherapy before transplantation, or were more heavily pretreated. In patients with AML, three groups were considered: ⩽2, 3 or >3 previous cycles. To evaluate the influence of myelotoxic drugs (BCNU, melphalan and nitrogen mustard) patients were divided into two groups: (1) low exposure (<7 cycles), and (2) high exposure (⩾7 cycles).
On multivariate analysis, the Cox proportional hazard regression model was used.13 Numerical variables were maintained as such with the exception of the amount of previous chemotherapy, which was coded as described in univariate analysis. Progenitor cells infused were analyzed twice, in the first step as continuous variables, and in the second step as categorical variables.
A significance level of P < 0.05 was chosen. Data were analyzed using SPSS software (9.0.1. version).
Progenitor cells infused
The median (range) for the total number of cells infused in patients with NMM and AML as follows: CD34+ cells, 4 (0.3–86) vs 5.4 (0.2–145.6) × 106/kg, respectively (P = 0.03); CFU-GM 14.8 (0–340) vs 17.3 (0–1228.5) × 104/kg, respectively (P = NS).
Time from transplantation to HR is shown in Table 2. In both diagnostic groups, the median time to reach an absolute neutrophil count of >0.5 × 109/l was 13 days (percentile25%–75%, 11–15). In AML, platelet recovery was slower, and there was also a trend for a slower recovery of the hematocrit to >35% (Table 2).
In order to avoid interference in the study due to early relapse of leukemia, we repeated the analysis after excluding AML patients who relapsed before day 90 post transplant and also after the exclusion of patients who relapsed during the first year after ABSCT. In the former analysis, a trend for a faster recovery of platelets to >20 × 109/l (P = 0.09) and a statistically significant difference for time to reach >150 × 109 platelets/l was observed in patients with NMM (P = 0.001). In the latter analysis, only a trend for a faster recovery of platelets >150 × 109/l favoring patients with NMM (P = 0.08) could be identified.
Three patients with NMM and four with AML did not engraft neutrophils and platelets, and two additional patients with NMM had a partial graft failure affecting only the platelet lineage. These failures were attributed in six patients to the very low number of PBSCs infused and were due to unknown causes in the remaining three cases. We were unable to identify a minimum threshold dose below which HR systematically failed to occur, since some patients transplanted with very low numbers of PBSCs achieved complete and stable engraftment. Finally, seven patients with engraftment failure were given second grafts (back-up bone marrow or apheresis), with successful evolution in two cases.
Factors influencing HR in patients with NMM
The only factors affecting neutrophil recovery in the univariate analysis were the CD34+ cell number and CFU-GM dose infused. The most discriminating cut-off values proved to be 6 × 104 CFU-GM/kg and 1.5 × 106 CD34+ cells/kg (Figure 1a). In the multivariate analysis, the dose of infused CD34+ cells was the only significant factor when considering the progenitors as continuous variables. When considering the progenitors as dichotomized variables, the administration of ⩾6 × 104 CFU-GM/kg was the only significant positive factor (Table 3).
The number of CFU-GM and CD34+ cells transplanted significantly affected platelet recovery on univariate analysis (Figure 2a), with the most discriminating cut-off values being 11.5 × 104 CFU-GM/kg and 2.5 × 106 CD34+ cells/kg. Additional variables, which also significantly affected the speed of platelet reconstitution, included diagnosis, disease stage, previous chemotherapy and diagnosis-to-ABSCT interval (Table 4). However, in a step-wise Cox analysis, only the amount of chemotherapy administered pre-transplant and the dose of CD34+ cells/kg (continuous model) or CFU-GM/kg administered (categorized model) remained as significant factors (Table 4).
Administering higher numbers of CD34+ cells progressively accelerated HR and three dose levels reached statistical significance: <1.5 vs 1.5–15 vs >15 × 106 CD34+ cells/kg (P = 0.003) for neutrophil recovery and <2.5 vs 2.5–16 vs >16 × 106 CD34+ cells/kg (P < 0.0001) for platelet recovery. Regarding CFU-GM dose, although higher numbers also enhanced the speed of engraftment, it was to a lesser extent, and thus no statistically significant categorization of the CFU-GM variable could be identified.
Factors influencing HR in patients with AML
The factors affecting neutrophil recovery in the univariate analysis were the CD34+ cells and CFU-GM dose infused, age, disease stage, prior chemotherapy and relapse before day 90 after transplant. Patients receiving ⩾6 × 104 CFU-GM or >1.5 × 106 CD34+ cells/kg, those ⩾36 years old, those transplanted in the first CR, those who had received ⩽3 cycles of prior chemotherapy and those who did not relapse before day 90 had a significantly shorter duration of neutropenia (Figure 1b). In the multivariate analysis, the dose of infused CD34+ cells and the patient's age were the only factors significantly affecting neutrophil recovery (Table 5).
The dose of CFU-GM/kg and CD34+ cells/kg, stage of the disease and leukemic relapse before day 90 were the factors significantly affecting platelet recovery on univariate analysis. The most discriminating cut-off values were higher than those described for neutrophil recovery, 11.5 × 104 CFU-GM and 4 × 106 CD34+ cells/kg (Figure 2b). In the multivariate analysis, only the progenitor dose administered remained significant (Table 6).
Finally, the administration of higher numbers of PBSCs produced a progressive acceleration in the speed of engraftment, reaching statistical significance at levels of <6 vs 6–30 vs >30 × 104 CFU-GM/kg (P < 0.0001) and <1.5 vs 1.5–15 vs >15 × 106 CD34+ cells/kg (P < 0.0001) for neutrophil recovery, and <4 vs 4–17 vs >17 × 106 CD34+ cells/kg (P = 0.003) for platelet recovery.
Studies comparing HR after ABSCT in patients with NMM or AML have only rarely been reported.3,4,5 In a series of 145 patients, including 31 patients with acute leukemia, Haas et al3 showed that the leukemia group had delayed HR when compared with other diagnoses. However, in that study, there was a remarkable difference between the patient groups with regard to the amount of CFU-GM infused. For instance, the autografts in patients with low-grade NHL contained a median of a 15-fold greater number of CFU-GM per kilogram compared with patients with AML. In a similar study, multivariate analysis showed that HR was adversely associated with the diagnosis of acute leukemia.4 In this report, however, important variables such as the amount of previous chemotherapy or the dose of CFU-GM or CD34+ cells infused were not analyzed. Finally, in a recent study by Lowenthal et al.,5 platelet recovery was slower in patients with acute leukemia than in other diseases. In the multivariate analysis, the conditioning regimen, but not the diagnosis, remained as a significant independent factor influencing HR. In this study, patients were given BU-containing regimens only for acute leukemia, a fact that could explain this finding. In our series, we have also observed a delayed HR in AML patients despite the higher doses of CFU-GM and CD34+ cells administered. Thus, from these studies it can be concluded that time to engraftment is longer in AML patients, and that this protracted HR does not depend on the progenitor cell dose infused (measured as CFU-GM and/or CD34+ cells). The reasons for a slower engraftment in this disease are not very well understood, but it is conceivable that patients with AML, which is considered to be a stem cell-related disorder, may have a reduced or damaged pool of normal stem cells. In this sense, experimental studies have shown a severe clonogenic defect in AML patients,14,15,16 as well as a functional defect in the marrow stroma.17 Moreover, we have observed that when excluding patients who relapse early after ABSCT, the previously observed difference in the rate of HR between both diagnostic groups progressively disappears, suggesting that residual leukemia in the patient may also contribute to delayed engraftment.
With respect to variables that influence the rate of engraftment, our analysis confirmed the importance of the progenitor cell dose. In patients with NMM, the CD34+ cell cut-off values providing the best discrimination were in the range of previous reports,3,18,19 although other authors have proposed that optimal numbers might be greater.2,20,21 Threshold values of CFU-GM for rapid engraftment were somewhat higher than those observed in other studies.3,18,19,20,22 Finally, and in line with other studies, the progenitor cell dose for rapid platelet engraftment was higher than that necessary for a rapid neutrophil engraftment.1
In studies of patients with AML, very few reports have evaluated the influence of the infused progenitor cell dose on engraftment, and those published included only a low number of patients.5,23,24,25,26,27 Thus, the minimum or optimal dose to be infused in this disease has not yet been defined. As regards CFU-GM, threshold values have ranged between >5–10 × 104/kg25 and >50 CFU-GM × 104/kg23 whereas other authors have failed to find an influence of this variable on the rate of engraftment.27 In respect to the CD34+ cell dose, Demirer et al24 and Martin et al26 reported that patients transplanted with >2.5 × CD34+ 106/kg had a faster recovery of platelet counts, and in a co-operative study, patients transplanted with >12 × 106/kg CD34+ cells had a more rapid neutrophil and platelet recovery as compared with those receiving <3 × 106/kg.27 Lastly, in a recently published report by the Bordeaux group, the number of CD34+ cells, but not the number of CFU-GM infused, showed a significant influence on the speed of engraftment.5 In that study, the cut-off values established were the medians of the whole series and it is possible that the results could have been different if other cut-off levels, adjusted to the distribution of values in patients with AML, had been analyzed. In our study, the largest so far reported analyzing factors that influence engraftment in AML patients, the progenitor cell dose infused also remained the most important variable influencing engraftment kinetics in this diagnosis. It is noteworthy that patients with AML required a higher CD34+ cell dose for a rapid platelet recovery than patients with NMM, with a pronounced delay observed in those patients receiving <4 × 106/kg. This may reflect the above-mentioned stem cell or microenvironment defect,14,15,16,17 and supports the early observation of Juttner et al28 suggesting that the progenitor cell dose to be infused might need to be higher in AML than in other diseases. Finally, in these patients, the progenitor cell dose for a rapid platelet engraftment was also higher than that necessary for a rapid neutrophil engraftment, the thresholds proposed in our study not necessarily being applicable to other centers because of inter-laboratory variability.
We also confirmed in both diagnostic groups the previously reported dose–response relationship between the quantity of infused CD34+ cells and the kinetics of engraftment.2,29 However, the need to infuse large numbers of progenitors is in question, since this could be associated with an increased risk of reinfusing large numbers of clonogenic tumor cells without obtaining significant reductions in transplant-related toxicity.30
Lastly, it should be mentioned that because of the high correlation between CD34+ cells and CFU-GM values, the Cox model selected either one or another depending on minimal statistical differences. In our study, there was a clear tendency for the CD34+ cell dose to remain in the model when PBSCs were considered as continuous variables, and it is well known that the prognostic value of a continuous variable is better assessed when it is maintained as such than when it is categorized.31 Thus, we believe that the predictive power of the CD34+ cell dose might be somewhat higher than that of the CFU-GM number. In our opinion, this greater predictive power together with its better standardization and rapidity for obtaining results makes CD34+ cell enumeration the most reliable measure for predicting the kinetics of HR.
With regard to other variables, in patients with NMM, prior chemotherapy also maintained an independent predictive value on the speed of platelet reconstitution. This is consistent with other studies32,33,34 and may reflect the fact that chemotherapy not only induces quantitative damage, but that it also affects the marrow microenvironment or produces qualitative damage on PBSCs not detectable through the enumeration of CD34+ cells or CFU-GM assays.
In AML patients, greater age was significantly associated with a faster neutrophil recovery. Although difficult to explain, this finding could be due to the association by chance of older age with some favorable categories of other variables.
In summary, our study shows that the progenitor cell dose administered (measured as CD34+ cells or CFU-GM) is the most important variable influencing engraftment in patients undergoing ABSCT. Likewise, our report shows that patients with AML may have a delayed HR, particularly of platelets, as compared with patients with NMM. Finally, CFU-GM and CD34+ cell threshold numbers classically used in patients with NMM may not be appropriate for AML patients, and this point should be further investigated.
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About this article
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