Original Article
Immunologic Purging of Marrow Assessed by PCR before Autologous Bone Marrow Transplantation for B-Cell Lymphoma
N Engl J Med 1991; 325:1525-1533November 28, 1991
- Abstract
- Abstract
Background.
The use of autologous bone marrow transplantation is increasing in the management of advanced cancers. Many investigators have attempted to "purge" autologous marrow of residual tumor cells because of concern that reinfused tumor cells might contribute to relapse. The efficacy of purging remains unproved.
Methods.
We performed clonogenic assays in a tumor cell line in culture to determine the efficiency of immunologic purging. Amplification by the polymerase chain reaction (PCR) was used to detect residual lymphoma cells before and after purging of bone marrow from 114 patients with B-cell non-Hodgkin's lymphoma in whom a translocation (t(14;18)) that could be amplified by PCR was detected at the time of their initial evaluation.
Results.
Immunologic purging in vitro resulted in a 3-to-6-log destruction of cells in the tumor cell line. Residual lymphoma cells were detected by PCR in the bone marrow of all patients before purging. No lymphoma cells could be detected in the marrow of 57 patients after purging. Disease-free survival was increased in these 57 patients as compared with those whose marrow contained detectable residual lymphoma (P<0.00001 ). The ability to purge residual lymphoma cells was not associated with the degree of bone marrow involvement (P = 0.4494) or the previous response to therapy (P = 0.1298).
Conclusions.
The inability to purge residual lymphoma cells was the most important prognostic indicator in predicting relapse. These results provide evidence of the clinical usefulness of ex vivo purging of autologous bone marrow in the treatment of patients with lymphoma and suggest that the reinfusion of malignant cells in autologous marrow contributes to relapse. (N Engl J Med 1991; 325:1525–33.)
Article Activity
- Article
HIGH-dose ablative therapy with rescue of bone marrow function by autologous bone marrow transplantation has become widely used in patients with hematologic and solid tumors.1 2 3 4 5 6 7 8 9 10 Although the infusion of autologous marrow provides sufficient hematopoietic stem cells, there is concern that occult clonogenic tumor cells in the infused marrow may contribute to relapse. In non-Hodgkin's lymphoma, bone marrow infiltration is common at the time of diagnosis and relapse.11 , 12 Attempts have therefore been made to treat the bone marrow in vitro with immunologic and pharmacologic agents to purge it of lymphoma cells before reinfusing it into the patient.2 , 4 , 13 , 14 It has become clear that the bone marrow of patients with lymphoma can be purged in vitro without impairing hematologic engraftment. Controversy persists, however, about whether the removal of residual tumor cells from the bone marrow improves disease-free survival.
One obstacle to determining the effect of bone marrow purging has been the inability to identify accurately occult lymphoma cells in the marrow before and after in vitro purging. Bone marrow judged to be normal on histologic examination may still be infiltrated with lymphoma cells, which may account for up to 5 percent of marrow cells as determined by more sensitive techniques.15 16 17 Cloning of the t(14;18) breakpoints18 19 20 involving the bcl-2 proto-oncogene on chromosome 18 and the immunoglobulin heavy-chain locus on chromosome 14 has made it possible to use amplification by the polymerase chain reaction (PCR) to detect lymphoma cells containing this translocation.21 22 23 This extremely sensitive technique permits the detection of 1 lymphoma cell in 106 normal cells.22 The translocation occurs in approximately 85 percent of patients with follicular non-Hodgkin's lymphoma and 30 percent with diffuse disease.24 25 26 27 28 29
In the present study, we examined the effect of purging the bone marrow of 114 patients with B-cell non-Hodgkin's lymphoma in which bcl-2 translocations were detectable by PCR. We found a strong association between the ability to purge the bone marrow of residual lymphoma cells and disease-free survival after autologous bone marrow transplantation.
Methods
Patients and Bone Marrow Samples
One hundred fourteen patients with B-cell non-Hodgkin's lymphoma were studied. At the time that bone marrow was obtained, all the patients had chemosensitive disease, as reflected by the presence of minimal disease after aggressive induction or salvage chemotherapy. Minimal disease was defined as either a complete remission or a partial remission, as indicated by the reduction of the tumor masses to 2 cm or less and the degree of marrow infiltration by lymphoma cells to 5 percent or less according to the initial protocol, but to less than 20 percent of the intertrabecular space according to subsequent protocols. Bone marrow samples were obtained only after the human-protection committees of our institutions gave appropriate validation and the patients gave informed consent. Bone marrow biopsy and aspiration were performed at the time of evaluation and before marrow sampling, to assess the lymphomatous infiltration. Immunophenotyping documented the expression of B1 (CD20) antigen in all tumors.
Bone marrow was reinfused after it was purged with the use of anti—B-cell monoclonal antibodies and rabbit complement. Marrow samples were cryopreserved in vials before and after purging. Genomic DNA was isolated by cell lysis with nonionic detergents and proteinase K (Sigma, St. Louis).30 After lysis, the purged samples were washed in medium containing 2.5 mg of deoxyribonuclease per milliliter (Sigma) to prevent cell clumping. This ensured that genomic DNA from purged cells was not copurified during the DNA-extraction process. DNA was also extracted according to established procedures in 50 patients. In 38 patients it was also extracted before and after purging from samples that were not cryopreserved; in 10 of these patients, it was extracted from samples obtained after each of three treatment cycles. In the majority of patients, cells isolated from diagnostic lymph nodes were cryopreserved. Normal bone marrow was obtained from healthy volunteer donors.
Monoclonal Antibodies
Anti-B1 is an IgG2a murine monoclonal antibody with specificity for CD20, a 35-kd cell-surface glycoprotein present on normal and malignant B cells.31 , 32 Anti-B5 is an IgM murine monoclonal antibody with specificity for activated B cells and the majority of B-cell lymphomas.33 Anti-J5 is an IgG2a murine monoclonal antibody with specificity for the common acute lymphoblastic leukemia antigen CD10.34 , 35 All three antibodies induce cell lysis when used with rabbit complement.
Marrow Purging
Between 1982 and 1986, patients with marrow infiltration of up to 5 percent were eligible for the study, and purging was performed with anti-B1 alone.36 In 1986 and thereafter, patients with up to 20 percent residual marrow infiltration after induction or salvage therapy were eligible, and purging was performed with anti-B1, anti-B5, and anti-J5. Bone marrow was obtained as previously described.14 The mononuclear-cell fraction was incubated with saturating concentrations of monoclonal antibodies for 15 minutes at 4°C. Rabbit complement (extracted from the serum of three-to-four-week-old rabbits; Pel Freez, Brown Deer, Wis.) was added at predetermined dilutions for each lot and incubated with target cells for 30 minutes at 37°C in the presence of deoxyribonuclease (2.5 mg per milliliter) to prevent cell clumping. The cells were pelleted by centrifugation, and the procedure was repeated twice, for a total of three treatment cycles. The cells were washed three times, resuspended in autologous serum and 10 percent dimethyl sulfoxide (Sigma), and cryopreserved.
Lymphoma Cell Lines
Raji cells are a human Burkitt's lymphoma B-cell line expressing CD20, CD10, and B5. The human lymphoma B-cell line DHL-6, which contains a bcl-2 translocation, was a gift from Dr. A. Epstein (University of Southern California, Los Angeles).
Clonogenic Assay
The mononuclear-cell fraction of normal bone marrow from healthy donors was isolated by density-gradient centrifugation and irradiated at a rate of 11.1 Gy per minute, for a total dose of 40 Gy. Raji cells were added to irradiated mononuclear cells of normal marrow in a 1:20 ratio and suspended at a concentration of 2×107 cells per milliliter. The cell suspensions were treated with monoclonal antibodies and complement three times, according to the protocol for marrow from the patients. The cells were washed and plated in limiting dilution assays.37 Each treatment sample was serially diluted from 5×105 cells to 0.5 cell per 100 μl; 48 to 96 aliquots of each dilution were plated. The cells were incubated for 14 to 18 days, and growth at each serial dilution was assessed under an inverted-phase microscope as present or absent. The plot of the number of negative wells at each dilution against the total number of cells at each point followed a Poisson probability distribution. The frequency of clonogenic cells within the test population was estimated by chi-square minimization.38
PCR Amplification
Nested oligonucleotide amplification was performed at both the major breakpoint18 19 20 and the minor cluster region39 of the bcl-2/IgH hybrid gene in each sample as previously described.40 In brief, samples containing 1 μg of genomic DNA in a final volume of 50 μl (50 mM potassium chloride; 10 mM TRIS hydrochloride; 2.25 mM magnesium chloride; 0.01 percent gelatin; 200 nmol of oligonucleotide primers; 200 μmol each of deoxyadenosine triphosphate, deoxycytidine triphosphate, deoxyguanosine triphosphate, and deoxythymidine triphosphate; and 1.5 U of Taq polymerase [Cetus, Emeryville, Calif.]) were initially amplified for 25 cycles in a thermal cycler (Cetus). Reamplification of a 5-μl aliquot of this amplified mixture was performed for 30 cycles in a final volume of 50 μl, with oligonucleotide primers internal to the original primers. Aliquots of the final reaction product were analyzed by electrophoresis in 4 percent agarose gel (NuSieve, FMC, Rockland, Me.) containing ethidium bromide and visualized under ultraviolet light. DNA was blotted onto zeta-probe blotting membranes (Bio-Rad, Richmond, Calif.), and bcl-2—specific DNA was detected by hybridization for eight hours with 32P-labeled oligonucleotide probes. Oligonucleotides were Radio-labeled with [γ32P]ATP and T4 polynucleotide kinase (New England Biolabs, Beverly, Mass.). Standard precautions were taken against cross-contamination of amplified material,41 which was never taken to areas where DNA extraction was performed. For each amplification, DNA from a 10—5 dilution of the cell line DHL-6 in normal bone marrow cells served as a weak positive control, and PCR buffer containing heat-inactivated proteinase K as a negative control. Each sample was analyzed at least four times at each breakpoint site. In addition, in samples with no detectable PCR product, PCR amplification was repeated with oligonucleotide primers specific to the gene encoding the human B-cell activation antigen B7, to ensure that DNA could be amplified in all samples.
Statistical Analysis
The relations between the patients' characteristics at base line, the results of PCR analysis of the marrow samples after purging, and the time to relapse were assessed with the log-rank test.42 Relations between base-line characteristics and the presence or absence of residual lymphoma cells detectable by PCR after purging were assessed with Fisher's exact test43 and, for ordered categories, the Wilcoxon test for ordered categorical variables.44 Stratified log-rank tests that made use of study variables thought to be prognostic of a longer time to relapse were also performed. Cox proportional-hazards regression45 was used in an attempt to estimate the effect of covariates on the risk of relapse. The curves for disease-free survival were estimated according to the method of Kaplan and Meier46 and compared by the log-rank test.
Results
Outcome of Purging
Clonogenic and PCR-Detectable Lymphoma Cells
The ability to purge tumor cells from normal bone marrow with monoclonal antibodies and complement was tested with an in vitro tumor-cell-line model. The lymphoma cell line Raji was added to mononuclear cells of bone marrow from normal donors in a 1:20 ratio. This suspension was treated with each monoclonal antibody alone, with the antibodies in combination, and in the presence of complement for a total of three treatment cycles, to deplete the marrow of clonogenic Raji cells. As shown in Figure 1Figure 1
Results of Immunologic Purging as Assessed by Clonogenic Cell Growth in a Tumor-Cell-Line Model., the growth of the clonogenic tumor cell line was reduced after in vitro immunologic purging with the and—B-cell monoclonal antibody anti-B1, anti-B5, or anti-J5 and complement, as compared with purging with antibody or complement alone (P = 0.014). In this assay, antibody and complement lysis was capable of an approximately 3-log killing of the tumor cell line. Two or three antibodies in combination reduced the growth of clonogenic tumor cells more than did a single antibody alone (P = 0.0066).To determine whether immunologic purging could eradicate lymphoma cells from the patients' bone marrow, reducing their number to a level below the limit of detection by PCR, we analyzed samples from 10 patients whose marrow contained cells with the bcl-2 translocation. Each sample was treated with anti-B1, anti-B5, and anti-J5 monoclonal antibodies and complement and washed in medium containing deoxyribonuclease to ensure that purged tumor-cell DNA was not copurified during the extraction process. DNA was extracted from samples obtained before and after each of the three purging cycles, and 1 μg of DNA from each sample was analyzed by PCR amplification. After the third treatment cycle, no lymphoma cells could be detected by PCR in six bone marrow samples. In each case, three cycles of treatment were required to eradicate all cells detectable by PCR. The results obtained by PCR amplification of samples obtained before and after each of the three treatment cycles from three representative patients are shown in Figure 2Figure 2
Detection by Southern Blot Analysis of bcl-2 Translocation—Specific Sequences Amplified by PCR.A. After the third treatment, no lymphoma cells were detected in the samples from Patients 1 and 2, but residual lymphoma-specific DNA was found in the sample from Patient 3. These results in our patients' samples confirmed the results of other studies of lymphoma cell lines.47 Residual Lymphoma Cells
As of December 28, 1990, 205 patients with B-cell non-Hodgkin's lymphoma had been treated at our center with an identical protocol, which included high-dose chemotherapy, total-body irradiation, and purging of autologous bone marrow before transplantation. Patients were included in the present study if they had a documented breakpoint for the bcl-2 translocation that could be amplified by PCR and if marrow samples were available for analysis before and after lysis. The bcl-2 translocation was identified by PCR in the diagnostic tissue of 125 patients, and marrow samples obtained before and after purging were available for 114 patients. In addition, samples were available before and after purging for 47 patients who had B-cell non-Hodgkin's lymphoma with no translocation involving bcl-2 that could be amplified by PCR. These samples were analyzed as controls.
DNA was extracted from samples before and after purging and PCR was performed at both major and minor breakpoint regions of the bcl-2 translocation to assess whether lymphoma cells were present. Each of the samples obtained before and after purging was analyzed four times, and the investigators were blinded with regard to the clinical outcome in the patient and whether a bcl-2 translocation had been previously identified in that patient. In bone marrow obtained before purging, lymphomatous infiltration was detected by PCR in all 114 patients in whom a bcl-2 translocation was detected in the diagnostic tissue. Immunologic purging resulted in the depletion of lymphoma cells detectable by PCR in the purged samples from 57 patients; residual lymphoma cells were detected by PCR in the samples from the other 57 patients. The findings in representative samples from nine patients before and after purging are shown in Figure 2B. The lanes for Patients 1, 2, 3, and 4 represent samples in which no lymphoma cells with the bcl-2 translocation could be detected in the purged sample by PCR, and the lanes for Patients 5, 6, 7, 8, and 9 represent samples in which lymphoma cells remained detectable by PCR after purging. Although equal amounts of DNA were analyzed in each PCR reaction, there did not appear to be any correlation between the intensity of the PCR signal in the sample before purging and the detection of residual lymphoma cells afterward. PCR was performed with serial dilutions of the prelysis and postlysis samples to determine the titer at which the PCR product could no longer be detected, to provide a semiquantitative estimate of DNA with the translocation in each sample. There was no correlation between the titer of DNA with the translocation in the prelysis sample and the ability to purge detectable lymphoma cells (P = 0.138 by Wilcoxon test for ordered categorical variables). Since no quantitative differences were found to account for the difference in the response to purging, there may be intrinsic differences in the susceptibility of lymphoma cells from different patients to the purging regimen.
In 38 cases in which DNA was extracted from both fresh and cryopreserved samples after purging, cryopreservation had no effect on the detection of residual lymphoma cells by PCR. Similarly, identical results were obtained in 50 cases in which the DNA was extracted by both conventional techniques and cell lysis with nonionic detergents and proteinase K digestion. There were no false positive results, since no PCR product was detected in any of the samples from patients whose diagnostic tissue did not contain a breakpoint for the bcl-2 translocation that could be amplified by PCR. PCR was performed with primers for the V (variable) region of the gene for the B-cell activation antigen (B7) on all samples without detectable bcl-2 translocation, to confirm that genomic DNA could be amplified by PCR in all samples (data not shown).
We next examined whether the ability to purge the marrow of detectable lymphoma cells correlated with the patients' clinical characteristics. The group with residual lymphoma or detectable lymphoma cells after purging and the group without detectable disease were balanced with respect to sex, tumor histology, and previous extranodal disease (Table 1Table 1
Characteristics of Patients with B-Cell Non-Hodgkin's Lymphoma and bcl-2 Translocation, According to the Result of PCR Analysis after Purging.). The ability to deplete cells that were detectable by PCR was not associated with disease status (a complete or partial response) (P = 0.1298) or the absence or presence of bone marrow involvement at the time of bone marrow transplantation (P = 0.4494). In contrast, more patients with a history of histologically documented bone marrow infiltration had residual detectable lymphoma after purging (P = 0.0305). The two groups of patients did not differ significantly in their tumor stage at diagnosis (P = 0.0952), but 92 of the 114 patients had stage IV disease. Logistic-regression analysis of study characteristics was used to attempt to predict which patients would be purged of detectable residual lymphoma. The best model for such prediction is based only on the presence or absence of a history of histologic bone marrow involvement. Of the 29 patients with no history of marrow involvement, 20 (69 percent) had no detectable lymphoma cells after purging, whereas of the 85 patients with a history of such involvement, 37 (44 percent) had no detectable lymphoma cells after purging (P = 0.0169). No other base-line variable significantly improved the ability of this model.Loss of Lymphoma Cells Detectable by PCR and Disease-free Survival after Transplantation
We analyzed the effect of the ability to purge residual lymphoma cells from bone marrow on the outcome of high-dose therapy. As shown in Figure 3Figure 3
Actuarial Probability of Disease-free Survival after Autologous Bone Marrow Transplantation in 114 Patients with B-Cell Non-Hodgkin's Lymphoma., disease-free survival after autologous bone marrow transplantation was strongly associated with the absence of detectable residual lymphoma cells after purging (P<0.00001). Of the 57 patients with no detectable lymphoma cells after purging, only 4 (7 percent) have relapsed. Data on two other patients among these 57 were censored 24 and 28 months after transplantation. Both died of causes unrelated to transplantation or lymphoma and were found to have no lymphoma on gross and microscopical examination at autopsy. In contrast, of the 57 patients who had residual lymphoma detectable by PCR after purging, 26 (46 percent) have relapsed. After the median period of follow-up of all 114 patients (23 months), 22 (39 percent) of the 57 with residual detectable lymphoma after purging had relapsed, in contrast to 3 (5 percent) of the 57 with no residual lymphoma cells after purging.We also examined whether the increase in disease-free survival among patients with no detectable residual lymphoma after purging was associated with their disease status or degree of marrow involvement before purging. Patients in complete remission had increased disease-free survival, as compared with patients in partial remission (P = 0.0021) (Fig. 4Figure 4
Disease-free Survival after Transplantation, According to Disease Status at Transplantation.A). However, of the 49 patients in complete remission, disease-free survival among the 29 who had no residual detectable lymphoma in the bone marrow after purging was increased as compared with survival in the 20 with detectable lymphoma cells after purging (P = 0.0012) (Fig. 4B). Similarly, disease-free survival among the 65 patients in partial remission was improved in the 28 who had no residual lymphoma cells after purging as compared with the 37 who did (P = 0.0011) (Fig. 4C).As shown in Figure 5Figure 5
Disease-free Survival after Transplantation, According to Degree of Bone Marrow Involvement at Transplantation.A, the degree of histologic bone marrow involvement in samples obtained before purging was also associated with increased disease-free survival after high-dose therapy (P = 0.0054). However, as shown in Figure 5B, among the 65 patients with no morphologic evidence of bone marrow infiltration before purging, disease-free survival in the 35 whose purged samples contained no detectable lymphoma was better than that in the 30 who had detectable lymphoma cells after purging (P = 0.0001). Similarly, as shown in Figure 5C, among the 38 patients who had minimal bone marrow involvement on morphologic assessment at the time of initial marrow sampling (≤5 percent of the intertrabecular space), disease-free survival among the 20 who had no residual lymphoma after purging was better than that of the 18 who did (P = 0.005). Eleven patients had overt histologic bone marrow involvement (10 to 20 percent of the intertrabecular space) in samples obtained before purging; in only 2 of these 11 patients did purging result in the depletion of detectable lymphoma cells. Disease-free survival after high-dose therapy in this group is shown in Figure 5D. The histologic subtype of lymphoma was not associated with disease-free survival after high-dose therapy (P = 0.249). However, when the patients were grouped according to subtype, disease-free survival was improved among those whose samples contained no detectable lymphoma cells after purging, as compared with those whose samples contained residual detectable disease, whether the disease was low grade (P = 0.0001), had progressed from low grade to intermediate grade (P = 0.0571), or was intermediate grade (P = 0.0184) (data not shown).Attempts were made to estimate the multiplicative effect of covariates on the risk of relapse by constructing a model with use of Cox proportional-hazards regression. Patients with residual detectable lymphoma cells had an instantaneous risk of relapse 9.9 times that of patients with no detectable lymphoma cells after purging (95 percent confidence interval, 3.4 to 28.3). The addition of other base-line covariates did not significantly improve this model.
Detection of the bcl-2 Translocation after Transplantation
In 25 patients, we prospectively analyzed whether there were detectable lymphoma cells in the peripheral blood at the time of transplantation and afterward. Multiple blood samples were obtained from each patient during hospitalization for transplantation and six months after transplantation. The results of PCR analysis of bone marrow and multiple blood samples obtained six months after transplantation from two representative patients (Patients 1 and 8 as represented in Fig. 2B) are shown in Figure 6.Figure 6
Detection by Southern Blot Analysis of bcl-2 Translocation-Specific Sequences Amplified by PCR. There was no association between the presence or absence of circulating lymphoma cells with the bcl-2 translocation in the peripheral blood before high-dose therapy and their presence or absence after such therapy (data not shown). However, peripheral-blood cells containing the bcl-2 translocation were detected by PCR in 13 of 14 patients who had residual lymphoma cells after purging. In contrast, no cells with the translocation could be detected in any of the peripheral-blood samples from the 11 patients who had no residual lymphoma cells after purging.Discussion
A major concern about the use of autologous bone marrow transplantation has been the possibility that clonogenic tumor cells reinfused with autologous marrow may contribute to relapse. In previous studies we showed that patients with advanced non-Hodgkin's lymphoma with a bcl-2 translocation that can be detected by PCR invariably have bone marrow infiltration after conventional-dose induction or salvage therapy.40 We therefore performed immunologic purging in an attempt to remove lymphoma cells from the marrow of all patients with B-cell non-Hodgkin's lymphoma before they underwent autologous bone marrow transplantation. In the present report, we show that immunologic purging induced a 3-to-6-log destruction of cells according to clonogenic assays with an in vitro tumor cell line. In addition, purging eliminated lymphoma cells detectable by PCR in 57 of 114 patients who had a breakpoint involving the bcl-2 translocation that could be amplified by PCR in bone marrow obtained before purging. More important, patients given infusions of autologous marrow depleted of residual lymphoma cells had a statistically significant increase in disease-free survival as compared with those given autologous marrow containing residual lymphoma cells.
The results of the present study do not definitively demonstrate whether residual lymphoma cells in autologous marrow contribute to relapse. However, the inability to purge marrow of lymphoma cells detectable by PCR is the most accurate prognostic indicator of relapse. These results may be interpreted in three ways. First, marrow that contained residual lymphoma cells after purging may have contained increased numbers of lymphoma cells before purging. If true, this might reflect greater tumor bulk in the patient, which would contribute to the higher rates of relapse. Second, the failure to purge all detectable lymphoma cells might allow the clinician to identify patients who have unique subtypes of lymphoma more resistant to an ablative regimen and who are therefore at higher risk of relapse. Third, purging is clinically important since residual lymphoma cells detected in the marrow after the procedure may represent clonogenic tumor cells capable of contributing to relapse. If correct, these findings would be compelling evidence of the efficacy of purging. All three mechanisms may possibly explain the results of the PCR analysis or contribute to relapse after autologous bone marrow transplantation.
In the small group of patients with overt (10 to 20 percent) marrow infiltration, tumor bulk appears to correlate with the inability to purge detectable lymphoma cells. The bone marrow could be purged in only 2 of 11 such patients, and 7 patients relapsed. However, a number of observations dissociate tumor burden from the ability to purge detectable lymphoma cells. Before purging, no association was found between the amount of PCR-amplified DNA in the marrow sample and the elimination of cells detectable by PCR. At that time, there was no association between the achievement of a complete or partial remission with conventional therapy and the ability to purge detectable lymphoma cells. These findings argue that the failure to purge detectable lymphoma cells cannot be explained entirely by a greater tumor burden in the marrow. Moreover, the data support the conclusion that the higher incidence of relapse observed among patients whose purged marrow retained detectable lymphoma cells was not due simply to greater tumor burden in these patients.
Patients with detectable lymphoma cells in the marrow sample after purging may be a subgroup with disease more resistant to therapy. Although all lymphomas in this study expressed CD20, and most lymphomas with the bcl-2 translocation express CD 10 and B5,48 , 49 we do not know the phenotype of the clonogenic lymphoma cell. Bone marrow that retains detectable lymphoma cells may contain clonogenic lymphoma cells that lack or weakly express the targeted antigens or that are more resistant to complement-mediated lysis. These cells may also be intrinsically more resistant to an ablative regimen. However, we observed no difference in response to induction or salvage therapy between the group of patients with residual lymphoma cells after purging and the group without such cells.
Finally, it is possible that PCR-positive lymphoma cells in the purged marrow are residual clonogenic tumor cells that contribute to relapse. If this is true, patients might be expected to have relapses at both old and new sites of disease. However, most patients have relapses at sites of previous bulk disease.1 2 3 This provides strong evidence that relapse is due to endogenous lymphoma that is resistant to therapy. Of the 57 patients given reinfusions of bone marrow containing no detectable lymphoma cells, all have had negative results in peripheral-blood samples and only 4 patients have relapsed. In contrast, six months after high-dose therapy, PCR analysis detected tumor cells in the peripheral blood of 13 of 14 patients given reinfused marrow containing residual detectable lymphoma. Although reinfused lymphoma cells may home to all lymphoid sites, not all sites may have the microenvironment necessary for clonogenic tumor-cell growth. Since previous sites of disease are likely to provide a microenvironment conducive to lymphoma-cell growth, reinfused clonogenic lymphoma cells may be expected to proliferate at sites of bulk disease. This can be likened to the homing of hematopoietic progenitors after the reinfusion of marrow. Although hematopoietic progenitors are found in the circulation after bone marrow is reinfused, hematopoiesis eventually occurs only in the marrow. Therefore, the reappearance of disease at a site of previous bulk disease may not always represent failure to eradicate endogenous disease; it may also represent seeding by reinfused clonogenic lymphoma cells.
Although our results do not prove conclusively that purging is essential, they are compelling evidence that reinfused lymphoma cells contribute to relapse. It must be stressed that these findings may apply only to patients whose lymphomas contain a bcl-2 translocation. Whether these data are generalizable to patients with other lymphoid or hematologic neoplasms or even solid tumors must still be addressed. However, they suggest that one should be cautious about assuming that relapse is wholly due to tumor cells remaining in the patient rather than to neoplastic cells reinfused in autologous bone marrow.
Supported by grants (CA-40216 and CA-34183) from the National Cancer Institute, a Fogarty International Center grant (TWO4496 [to Dr. Gribben]), a grant (CA-06516–28 [to Dr. Neuberg]) from the National Institutes of Health, and a grant (5–KO8-CA-0115 [to Dr. Freedman]) from the U.S. Public Health Service. Dr. Roy is a scholar of the Fonds de la Recherche en Santé du Québec.
We are indebted to Drs. Stuart F. Schlossman and Baruj Benacerraf for their guidance, encouragement, and support throughout this study; to Dr. Jeffrey Sklar for his advice and generous assistance when needed; to Mary Whelan for data collection and Kirsten Hildebrandt for assistance in the preparation of the manuscript; and to Drs. Stephen Cannistra and Margaret Shipp for their critical review of the paper.
Source Information
From the Divisions of Tumor Immunology and Biostatistics, Dana–Farber Cancer Institute (D.N.), and the Department of Medicine, Harvard Medical School (J.G.G., A.S.F., D.C.R., K.W.B., S.D.W., M.L.G., S.N.R., F.C., G.J.F., J.R., L.M.N.), both in Boston. Address reprint requests to Dr. Gribben at the Division of Tumor Immunology. Dana–Farber Cancer Institute, 44 Binney St., Boston, MA 02115.
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