Patients, materials, and methods

Patient population

Only patients who received autologous peripheral blood stem cell transplants for non-Hodgkin's lymphoma (NHL) were included in the study. Patients who received bone marrow (BM) harvests or the combination of APHSCT and BM harvests were excluded. Between 1987 and 2001, a total of 303 autologous transplants were performed in the Mayo Clinic for patients with NHL. In all, 47 transplanted before 1993 were excluded because they received only BM harvest as their stem cell source. Of the 256 patients transplanted from 1993 to 2001, 190 patients (74%) received only APHSCT and were included in this study. The rest of the patients received either BM harvest or a combination of autologous peripheral blood stem cells and BM stem cells. Data from our previous publication⁶ of 53 patients who received only autologous peripheral blood stem cells were also included in the analysis of this study.

This is a retrospective study where data have been prospectively collected over time and entered into a computerized database. Response to therapy, relapse, and survival data are updated continuously. No patients were lost to follow-up. All patients gave written, informed consent allowing the use of their medical records for medical research. Approval of the study was obtained from the Mayo Clinic Institutional Review Board and was in accordance with US federal regulations and the Declaration of Helsinki.

End points

The primary end point of the study was the correlation between the A-ALC and ALC-15. Secondary end points included overall survival (OS) and progression-free survival (PFS) based on the dose of infused A-ALC, as well as assessment of factors impacting on A-ALC. The ALC-15 was calculated from the standard complete blood cell count, and the infused A-ALC for each apheresed unit collection was calculated as follows: (% collection lymphocytes) (absolute WBC)/kg.

Prognostic factors

The international age-adjusted prognostic index^11,12 (age (60 vs <60), lactate dehydrogenase (LDH) >normal for age/sex, performance status (PS) (2 vs <2), extranodal sites(2 vs <2), and stage (I/II vs III/IV)) at the time of transplantation, in addition to the number of pre-transplant treatments, chemosensitive disease status, and complete response (CR) status before transplantation, were used in the study.

Peripheral blood stem cell (lymphocyte autograft) collection

Patients received granulocyte-colony stimulating-factor (G-CSF) (10 g/kg) daily for 5–7 consecutive days by subcutaneous injection. Apheresis collections were performed with a Fenwal CS3000-plus blood-cell collector (Baxter, Deerfiel, IL, USA). In all, 10–12 l of blood were processed daily, at flow rates of 50–60 ml/min, using a Hickman catheter or antecubital veins. Patients underwent daily apheresis collections until a target of 2.0 10⁶ CD34 cells/kg or greater was achieved. Pre-stem cell mobilization ALC was obtained from a complete blood cell count prior to G-CSF administration. Peripheral blood ALC at the time of collection (PC-ALC) were obtained from complete blood cell counts.

Conditioning regimens

In total, 96 patients received BEAM (BCNU (300 mg/m²), etoposide (100 mg/m²), ARA-C (100 mg/m²), and melphalan (140 mg/m²)), 82 patients received BEAC (BCNU (300 mg/m²), etoposide (100 mg/m²), ARA-C (100 mg/m²), and cyclophosphamide (35 mg/kg)), and 12 patients received cyclophosphamide (60 mg/m²) and total body irradiation (12 Gy).

Response and survival

Response criteria were based on the guidelines from the NHL International Workshop.¹³ CR was defined as complete regression of all measurable or evaluable disease including radiologically demonstrable disease, BM involvement, or peripheral blood involvement. Partial response (PR) was defined as a reduction in the sum of the products of measurable lesions' longest diameter and perpendicular diameters of 75% or greater, with a 50% or greater decrease in hepatomegaly or splenomegaly (measured from the costal margin), if there was previous known liver or spleen involvement. Stable disease was defined as less than PR, but was not progressive disease. Disease progression was defined as a 50% or more increase in the sum of the products of the longest diameter and the perpendicular diameter of measurable lesion(s) from the prestudy measurement, the appearance of new lesions, or a 2-cm increase in spleen or liver size due to lymphoma. Relapsed disease was defined as the appearance of any new lesion or increase by 50% or more in the size of previously involved sites.

OS was measured from the date of transplantation to the date of death or last follow-up. PFS was defined as time from transplantation to disease progression, relapse, death, or last follow-up.

Statistical analysis

OS and PFS were analyzed using the method described by Kaplan and Meier.¹⁴ The differences between survival curves were tested for statistical significance using the two-tailed log-rank test. The Cox proportional hazards model¹⁵ was used to assess A-ALC, as a prognostic factor for post transplant OS and PFS times as well as to adjust for other known prognostic factors. Risk ratios reported are for risks associated with patients having high (equal or greater than 0.5 10⁹ lymphocytes/kg) vs low (less than 0.5 10⁹ lymphocytes/kg) A-ALC values. The prognostic factors tested included age (60 years or older), LDH (greater than normal for age/sex), stage (III/IV), extranodal sites (two or more), PS (ECOG, 2 or greater), number of pre-transplant treatment regimens, chemosensitive disease defined as CR or PR, and CR status alone before transplantation. Factors tested to identify association with ALC-15 (as a continuous variable) included A-ALC, age (60 or greater), conditioning regimens, CR status pre-transplantation, disease status prior to transplantation (relapse, progression, PR, or CR), extranodal sites (two or more), histology, LDH (greater than normal for age/sex), number of pre-transplant treatment regimens, PS (two or more), post transplant cytokines (G-CSF vs GM-CSF), pre-mobilization ALC, sex, and stage III/IV. Factors tested to identify association with A-ALC (as a continuous variable) included age (60 or more), CR status pre-transplantation, disease status pre-transplantation (relapse, progression, PR, or CR), extranodal sites (two or more), histology, LDH (greater than normal for age/sex), number of pre-transplant treatment regimens, PS (two or more), PC-ALC, pre-mobilization ALC, sex, and stage III/IV. The cutoff of an ALC of 500 cells/l or more at day 15 after APHSCT was used based on our previous publications.^1,2,3,4 The cutoff of an infused A-ALC of 0.50 10⁹ lymphocytes/kg was based on the median of the infused A-ALC for the cohort group. This choice of threshold yielded the greatest differential in survival at 0.5 10⁹ lymphocytes/kg based on ² values analyzed at different cut-points (0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, and 0.9 10⁹ lymphocytes/kg) from log-rank tests. The ² analysis and Fisher Exact tests were used to determine relations between categorical variables; the Wilcoxon rank-sum test and Spearman correlation coefficient were used for continuous variables. All P-values represented were two-sided, and statistical significance was declared at P<0.05.

RESULTS

Patient characteristics

A total of 190 patients were identified for the study; the median age for the cohort group was 54 years (range, 23–73 years) at the time of transplantation. The median infused A-ALC was 0.5 10⁹ lymphocytes/kg (range, 0.008–2.34 10⁹ lymphocytes/kg). Base-line patient characteristics are listed in Table 1 according to patients that received an A-ALC less than 0.5 10⁹ lymphocytes/kg vs patients that received equal or greater than 0.5 10⁹ lymphocytes/kg. No differences between the groups were identified for patient characteristics or prognostic factors, except for ALC at day 15 post-APHSCT. None of the patients received purged or CD34-selected stem cells.

Table 1 - Base-line characteristics of patients according to infused autograft absolute lymphocyte count (A-ALC).

Full table

Role of infused A-ALC on ALC-15

In an attempt to identify factors that influence early post APHSCT lymphocyte ALC-15 recovery, we identified no correlation between ALC-15 and patient base line characteristics and prognostic factors listed in Table 2, except for A-ALC. We discovered a strong correlation between the infused A-ALC and ALC-15 (Spearman's rho, r=0.71, P<0.0001) (Figure 1). Stratifying patients with ALC-15 of 500 cells/l or more compared with those with ALC-15 fewer than 500 cells/l, a higher median number of lymphocytes (Figure 2) were infused into patients achieving an ALC-15 of 500 cells/l or more compared with those with ALC-15 fewer than 500 cells/l (median number of 0.68 10⁹ lymphocytes/kg (range 0.04–2.21 10⁹ lymphocytes/kg) vs 0.34 10⁹ lymphocytes/kg (range 0.04–1.42 10⁹ lymphocytes/kg), P<0.0001]. The mean number of A-ALC infused to patients with ALC-15 500 cells/l was 0.75 10⁹ lymphocytes/kg (95% CI: 0.69–0.81 10⁹ lymphocytes/kg) compared with ALC-15 <500 cells/l of 0.36 10⁹ lymphocytes/kg (95% CI: 0.30–0.42 10⁹ lymphocytes/kg). We also analyzed the role of A-ALC in long-term immune engraftment and studied the correlation of A-ALC and ALC recovery at 6 months post-APHSCT. We identified no correlation between A-ALC and ALC recovery at 6 months post-APHSCT (r=0.08, P=0.25).

Figure 1.

Scattered plot comparing the infused A-ALC and the absolute lymphocyte count (ALC) recovery at day 15 after APHSCT. Strong correlation was identified between the infused A-ALC and the ALC recovery at day 15 after APHSCT (Spearman correlation rho factor, r=0.71, P<0.0001).

Full figure and legend (62K)

Figure 2.

Box plot of infused A-ALC in patients with an absolute lymphocyte count (ALC) recovery 500 cells/l at day 15 and patients with an ALC recovery <500 cells/l at day 15 after APHSCT. The horizontal line within each box represents the median, the lower and upper borders of each box represent the 25th and the 75th percentiles, respectively. Outliers, values that exceed these boundaries are depicted as single points. By the Wilcoxon rank-sum test, a statistically significant difference was identified when comparing the median value of A-ALC (0.68 10⁹ lymphocytes/kg) received by patients with an ALC recovery 500 cells/l at day 15 and the median value of A-ALC (0.34 10⁹ lymphocytes/kg) received by patients with an ALC recovery <500 cells/l at day 15 after APHSCT (P<0.0001).

Full figure and legend (49K)

Table 2 - Correlation between ALC-15 and patients characteristics/prognostic factors.

Full table

Survival based on the infused A-ALC

By December 2001, 95 (50%) of 190 patients in the study had died. Recurrent or progression of disease was the cause of death in 86 patients. The transplant-related mortality for the cohort group was only 4.7% (9/190). Three patients died of complications of myelodysplastic syndrome, two patients of acute respiratory distress syndrome, one patient of leukemia, one patient of pneumonia, one patient of renal failure, and one patient of septic shock. None of the patients developed clinically evident autologous graft-versus-host disease. The median follow-up time for all patients was 36 months, with a maximum of 111 months. Of the 86 deaths due to disease relapse or progression, 31 (36%) patients had an infused A-ALC of 0.5 10⁹ lymphocytes/kg or more and 55 (64%) patients had an infused A-ALC less than 0.5 10⁹ lymphocytes/kg. Of the nine deaths due to transplant-related mortality, five (56%) patients received an infused A-ALC of 0.5 10⁹ lymphocytes/kg or more and four (44%) patients had an infused A-ALC fewer than 0.5 10⁹ lymphocytes/kg. Using the cutoff point of 0.5 10⁹ lymphocytes/kg, the median OS (Figure 3a) and PFS (Figure 3b) times were significantly better for patients infused with an A-ALC of 0.50 10⁹ lymphocytes/kg or more compared with patients infused with A-ALC fewer than 0.50 10⁹ lymphocytes/kg (76 vs 17 months, P<0.0001; 49 vs 10 months, P<0.0001, respectively). Owing to the multiple histological diagnoses, we assessed the effect of the lymphocyte dose on the OS and PFS in the two largest histological groups in this study: diffuse large cell and follicular lymphoma. Using the cutoff point of 0.50 10⁹ lymphocytes/kg, the median OS and PFS were significantly better for patients infused with A-ALC 0.50 10⁹ lymphocytes/kg compared with patients infused with A-ALC <0.50 10⁹ lymphocytes/kg in the diffuse large cell group (55 vs 16 months, P<0.0063; 49 vs 9 months, P<0.0067, respectively) and in the follicular group (not reached vs 9 months, P<0.0001; 108 months vs 7 months, P<0.0001, respectively).

Figure 3.

(a) Kaplan–Meier estimates of OS of patients infused with an autograft absolute lymphocyte count (A-ALC) 0.50 10⁹ lymphocytes/kg vs patients with an infused A-ALC <0.50 10⁹ lymphocytes/kg. The median OS was 76 months in the group of patients with an A-ALC 0.50 10⁹ lymphocytes/kg and 17 months in the group of patients with an A-ALC <0.50 10⁹ lymphocytes/kg. The OS rates at 5 years were 57 and 20%, respectively (P<0.0001). (b) Kaplan–Meier estimates of PFS of patients infused with an A-ALC 0.50 10⁹ lymphocytes/kg vs patients with an infused A-ALC <0.50 10⁹ lymphocytes/kg. The median PFS was 49 months in the group of patients with an A-ALC 0.50 10⁹ lymphocytes/kg and 10 months in the group of patients with an A-ALC <0.50 10⁹ lymphocytes/kg. The PFS rates at 5 years were 50 and 13%, respectively (P<0.0001).

Full figure and legend (116K)

Univariate analysis

Age, chemosensitive disease, CR status before transplantation, number of pre-transplantation chemotherapy regimens, and stage were not predictive of OS and PFS. A-ALC, extranodal sites, LDH, and PS were significant predictors of OS in the univariate analysis. Only A-ALC and LDH were significant predictors in the univariate analysis for PFS (Table 3).

Table 3 - Univariate analysis for OS and PFS.

Full table

Multivariate analysis

A-ALC was an independent predictor for OS (RR=0.60; P<0.0001) and PFS (RR=0.64; P<0.0001) when compared to the significant predictors identified in the univariate analysis, including extranodal sites, LDH, and PS (Table 4).

Table 4 - Multivariate analysis for OS and PFS.

Full table

Autograft peripheral blood ALC

The identification of A-ALC as an independent prognostic factor for survival and its strong correlation with ALC-15 led us to investigate what factors may influence A-ALC collection. No association between A-ALC and patient base line characteristics and prognostic factors listed in Table 5 were identified, except for PC-ALC. We found a strong correlation between PC-ALC and A-ALC (r=0.76, P<0.0001). Clinical characteristics and disease status did not show any impact on PC-ALC (Table 6). As all patients received the same stem cell mobilization regimen (G-CSF), this important factor was not included in the analysis.

Table 5 - Correlation between A-ALC and patients characteristics/prognostic factors.

Full table

Table 6 - Correlation between PC-ALC and patients characteristics/prognostic factors.

Full table

Discussion

Patients with NHL achieving an ALC-15 500 cells/l after APHSCT have a superior survival compared with patients achieving an ALC-15 <500 cells/l.⁴ Our previous reports did not address factors affecting ALC-15 recovery.^1,2,3,4 Therefore, we set out to identify factors affecting ALC recovery at day 15 after APHSCT with the hope of improving clinical outcomes of patients treated with APHSCT. Our findings show no correlation between the CD34 cell counts and ALC-15. Rutella et al¹⁶ and Herr et al⁸ have reported no correlation between the CD34 cell dose and lymphocyte recovery post-APHSCT. Likewise, no correlation was identified between ALC-15 and base line characteristics and prognostic factors with the exception of A-ALC in our cohort of NHL patients. Here, we present data supporting the observation that ALC-15 post-APHSCT is directly dependent on the dose of infused A-ALC with direct impact on clinical end points.

Our study shows a strong correlation between the infused A-ALC and the ALC-15 after AHPSCT. We found that patients achieving an ALC-15 500 cells/l received a higher number of infused autograft lymphocytes. Our data corroborate previous publications describing the impact of the reinfused graft lymphocytes with lymphocyte recovery post transplantation. In the allogeneic setting, recipients of peripheral blood progenitor cells (PBPC) have higher numbers of T and B cells compared with recipients of bone marrow transplantation (BMT) at 1 and 11 months post transplantation.¹⁷ In a randomized study, day 28 ALCs and CD4+ CD25+ cells were higher after PBPC compared with BMT.¹⁸ It is well established that the allo-PBPC harvest contains at least 1 log more T cells than a BM graft.¹⁹ Thus, the authors argued that early recovery of lymphoid cells after allo-PBPC is more likely a consequence of the high T cells in the graft, rather than the faster maturation of lymphoid precursors in the recipient.²⁰ In the autologous setting, patients receiving auto-PBPC resulted in faster total lymphocyte counts and T-cell subsets recovery compared to patients receiving auto-BMT, which was explained by the higher number of lymphocytes within the peripheral blood stem cell product.^21,22,23 Several studies have demonstrated a faster lymphocyte recovery for patients receiving autologous unmanipulated PBPC compared with patients receiving CD34+-selected autologous peripheral blood stem cells.^16,24,25 Rutella et al¹⁶ identified a higher number of lymphocyte recovery in the unselected PBPC group vs the CD34+-selected group (P<.0035) at 2 months after APHSCT. At week 4 post-APHSCT, the repopulation of CD3+ T cells occurred more rapidly in the unselected PBPC group than in the CD34+-selected group (P<0.034). The absolute count of CD4+ T cells in the unselected PBPC group was significantly higher than in the CD34+-selected group (P<0.034 and P<0.021 on weeks 4 and 8, respectively). Moreover, Rutella et al¹⁶ reported that the amount of passively transferred lymphocytes correlated inversely with time to achieve a lymphocyte count >0.5 10⁹/l (r=-0.63, P<0.01). These findings suggest an important role for infused A-ALC in improving lymphocyte recovery after APHSCT. The studies of autologous unmanipulated PBPC vs CD34+-selected stem cell transplantations have only addressed the potential for life-threatening opportunistic infections based on the immune reconstitution from these two sources of apheresis collection. No consideration was given to the impact of immune reconstitution on the underlying malignancy. To our knowledge, our current study demonstrates the first evidence that infused A-ALC have a direct impact on survival after APHSCT. We determined that patients receiving higher numbers of infused A-ALC (0.50 10⁹ lymphocytes/kg) experienced improved survival after APHSCT. A-ALC was identified as an independent prognostic factor for OS and PFS in NHL patients undergoing APHSCT. This supports our contention that infused A-ALC play an important role in the clinical outcomes of patients undergoing APHSCT. No correlation was identified between A-ALC and patient base line characteristics and prognostic factors with the exception of PC-ALC. Therefore, elevated levels of peripheral blood lymphocytes allowed greater lymphocyte collection in the autograft, which directly impacts upon survival post-APHSCT. Stem cell mobilization regimen contribution to the collection of A-ALC was not analyzed in this study because all patients received the same mobilization regimen (G-CSF). Preliminary data comparing NHL patients in this study with a cohort of patients with multiple myeloma (data not shown) mobilized with cyclophosphamide plus growth factor (G-CSF or GM-CSF) as their stem cell mobilization regimen demonstrated that multiple myeloma patients obtained less A-ALC compared to the NHL patients mobilized with G-CSF alone (0.310 10⁹ lymphocytes/kg vs 0.537 10⁹ lymphocytes/kg, respectively, P <0.0001). Also, multiple myeloma patients had lower PC-ALC compared to NHL patients (2.99 10⁹/l vs 4.985 10⁹/l, respectively, P<0.0001). Even though these data suggest that stem cell mobilization regimens may influence A-ALC by affecting the numbers of PC-ALC at the time of apheresis collection, an unbiased analysis to understand how different mobilization regimens affect A-ALC and PC-ALC should be performed in patients with the same histological diagnosis.

We assessed the role of A-ALC in long-term immune reconstitution and found no correlation between A-ALC and ALC recovery at 6 months post-APHSCT. This suggest that A-ALC is important in early immune recovery as other factors may influence long-term immunologic reconstitution such as lymphoid cells in the host that survive the conditioning regimen, hematopoietic stem cells in the graft that differentiate into immune competent cells after transplantation and residual host stem cells. The specific lymphocyte subsets in the infused A-ALC and ALC recovery at day 15 after APHSCT associated with survival remain unknown due to the retrospective nature of the study. A few studies have reported that infusion of autologous lymphocytes in addition to stem cells resulted in rapid reconstitution of CD4 and CD8T cells, but failed to demonstrate any association with survival.²⁶ T cells and natural killer (NK) cells have been reported to be the main lymphocyte subsets collected during stem cell mobilization.²⁷ Studies of immunoreconstitution after APHSCT have shown delayed recovery of T and B cells following stem cell transplantation.^28,29 However, normal NK cell numbers and function recovery have been documented as early as 2 weeks after APHSCT.³⁰ We have recently reported that the dose of infused autograft peripheral blood NK cells directly correlates with ALC-15.³¹ This argues in favor of the clinical significance of early NK cell engraftment as a manifestation of early reconstitution of antitumor immunosurveillance and its direct impact on ALC-15 and survival post-APHSCT. The elucidation of how NK cells selectively recognize and lyse tumor is expanding with the understanding of inhibitory and activating NK cell receptors. Information is now available on the killer immunoglobulin-like receptors (KIR) following allogenic BMT, suggesting that differences in NK cell repertoire can impact upon the outcome of transplant for hematological malignancies in the allogeneic setting.^32,33,34 It is reasonable to hypothesize that a similar mechanism of antitumor activity based on the NK cell receptor repertoire in the allogeneic setting may apply to autologous stem cell transplantation.

In summary, our study demonstrates a strong correlation between the infused peripheral blood autograft lymphocyte count and ALC recovery at day 15 post-APHSCT, directly influencing survival after APHSCT. This is the first study showing that infused peripheral blood A-ALC are critically important for survival after APHSCT. The correlation of the infused peripheral blood A-ALC with ALC recovery and survival after APHSCT suggest that stem cell mobilization and collection should not be viewed only as means of achieving hematopoietic engraftment (white blood cells and platelets recovery), but also as means of achieving immunologic engraftment with direct consequences on clinical outcome. We hope that these data will support further investigations directed at maximizing post-APHSCT immunologic recovery, potentially leading to improve clinical outcomes and change in practice.

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