Long-Term Follow-Up of Patients with Non-Hodgkin Lymphoma Following Myeloablativ - 《stemcells》干细胞学杂志干细胞之家



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作者：Mathias Witzens-Hariga, Conny Heilmanna, Manfred Hensela, Martin Kornackera, Axel Bennerb, Rainer Haasa, Stefan Fruehaufa, Anthony D. Hoa作者单位：aDepartment of Hematology and Oncology, University Hospital Heidelberg andbCentral Unit Biostatistics, German Cancer Research Center, Heidelberg, Germany + k+ m4 R: o% C- b$ \' S) F0 j
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      【摘要】
   Graft engineering by CD34  selection of peripheral blood progenitor cells (PBPC) has been used in non-Hodgkin lymphoma (NHL) with the aim to reduce relapse related to tumor cells within the graft. From September 1995 to January 2000, 39 patients with newly diagnosed (n = 31) or relapsed (n = 8) NHL were treated in our institution with myeloablative therapy followed by CD34  selected autologous PBPC transplantation. Thirty-one patients were diagnosed with follicular lymphoma, and eight patients with mantle-cell lymphoma. All patients had advanced disease (26% of patients stage III and 74% stage IV, Ann Arbor classification). Induction therapy resulted in a complete remission in 17 patients and a partial remission in 22 patients. PBPC were mobilized after cytotoxic chemotherapy with granulocyte colony-stimulating factor support. CD34  selection was performed using immunomagnetic beads (Baxter Isolex 300SA or 300i Magnetic Cell Separation System). Most patients (85%) received total body irradiation and high-dose cyclophosphamide as myeloablative regimen. Twelve patients also received rituximab 375 mg/m2 before radiation and before the start of the cyclophosphamide treatment. The mean CD34  cell number for transplantation was 6.5 x 106 CD34  cells/kg of body weight. Platelet recovery (>20,000/&micro;l median on day 13) and leukocyte recovery (>1,000/&micro;l median on day 12) were within expected range. The estimated median follow-up was 47 months. The probabilities of freedom from progression, overall survival, and event-free survival 4 years after transplantation were 96%, 90%, and 87%, respectively, for patients with follicular lymphoma and 42%, 63%, and 33%, respectively, for patients with mantle-cell lymphoma. Risk factors for relapse were age and extranodal manifestation of disease. The rate of lethal infections in the 12-month follow-up period was 8%. We conclude that CD34  selection of autologous transplants following myeloablative therapy is feasible and results in long-term remission in the majority of patients, but the procedure is probably related to a higher rate of lethal infections. , G( y5 }* P2 U' a
      【关键词】 CD -selected PBPC Long-term follow-up Graft engineering Lymphoma High-dose chemotherapy
   INTRODUCTION

Follicular lymphoma (FL) and mantle-cell lymphoma (MCL) are hematologic B-cell malignancies that were considered to be not curable using conventional cytotoxic chemotherapy. Although standard therapy with CHOP (cyclophosphamide 750 mg/m2 per day, doxorubicin 50 mg/m2 per day, vincristine 1.4 mg/m2 per day, and prednisone 100 mg per day) can induce remissions in the majority of patients, median survival is only 8 years in FL and only 2¨C3 years in MCL. Higher doses of chemotherapy followed by autologous transplantation have been attempted to improve therapeutic outcome. The use of peripheral blood progenitor cells (PBPC) as the source of hematopoietic stem cells has been evaluated as an alternative approach to improve upon the efficacy of autologous transplantation in patients with lymphoma, leukemia, and multiple myeloma .
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One concern in the context of autologous transplantation is the risk of reinfusing contaminating NHL cells, which may contribute to relapse .
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In this study, CD34  cells selected by immunomagnetic beads that were consequently detached from the cells were used for autografting of 39 patients with NHL. The primary objective of the study was to evaluate the safety of the transplantation with selected CD34  cells as assessed by the time to hematopoietic reconstitution and the incidence of adverse events. The secondary objectives were to evaluate clinical response rate, disease-free survival, and OS. We found transplantation of CD34 -selected grafts following myeloablative therapy to be feasible and to result in long-term remission in the majority of patients.9 c- S& c4 P; c, V& w9 K, n
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PATIENTS AND METHODS  a2 S& H) \  S" E6 h9 `/ e. q+ I
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Between September 1996 and January 2000, 39 patients with NHL were treated with high-dose therapy (HDT) and autologous transplantation using CD34-selected PBPC. The study was conducted according to the guidelines of the local ethics committee, and informed consent was obtained from all patients. Patient characteristics are shown in Table 1.

Table 1. Clinical characteristics. T3 A# U- E2 H0 J& Z! K
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Twenty patients were men, and 19 patients were women. The median age was 48 years (range, 32¨C63 years). Before transplantation, 31 patients were in first remission, and 8 patients were in second remission. FL was present in 31 patients, and MCL in 8. All patients were in advanced stage of disease, with 10 patients with stage III and 29 in stage IV (modified Ann Arbor classification). The prognostic parameter lactate dehydrogenase (LDH) was elevated in five patients. The Follicular Lymphoma International Prognostic Index (FLIPI) was determined for the 31 patients with FL. Thirty-two percent had a score of 1 (low), 48% a score of 2 (intermediate), and 19% a score of 3 or 4 (high). In 29 patients, there was an extranodal disease manifestation, with bone marrow as the most frequent site (Table 2).

Table 2. Graft characteristics

Thirty-one patients received first-line treatment, and eight patients were treated in relapse. The median duration of the first remission in these patients was 19 months (range, 5¨C77 months). Treatment history of the patients in relapse is shown in Table 3.

Table 3. Extranodal disease

Study Treatment
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Thirty-four patients received induction therapy followed by mobilization therapy and leukapheresis. Five patients in relapse received mobilization therapy without previous induction therapy. The results of the induction therapy are shown in Tables 4 and 5( w& n$ }8 l8 d

Table 4. Previous therapies in patients who experienced relapse

Table 5. Results of induction chemotherapy4 {5 k  K& D" A' c) g8 K

PBPC mobilization was performed by using the HAM (cytosinarabinoside 2 g/m2 every 12 hours days 1 and 2 and mitoxantrone 10 mg/m2 days 2 and 3)  or D-BEAM (dexamethasone 24 mg per day, days 1¨C7, melphalan 30 mg/m2 day 2, carmustine 60 mg/m2 day 3, etoposide 75 mg/m2 per day, and cytosinarabinoside 200 mg/m2 per day days 4¨C7) protocol, followed by administration of granulocyte colony-stimulating factor (G-CSF). Sixteen patients who received HAM were additionally treated with rituximab as in vivo purging. Stem cell harvest was performed between 10 and 17 days after the last day of mobilization therapy.+ f1 ^0 h: H# ]& V6 S" e9 Z' g

Leukapheresis/ ]/ S' X) B: F& p$ N9 j  z
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Autologous PBPC were obtained by continuous-flow leukapheresis using a Fenwal CS 3000 (Baxter, Munich, Germany, http://www.baxter.de) or, since 1998, also by a Spectra device (Cobe Laboratories, Lakewood, CA, http://www.cobe.com). Blood volume processed per run was 10¨C20 l. Flow rate was 50¨C70 ml/minute (Fenwal CS 3000) or 70¨C150 ml/minute (Spectra device).9 ?( X. r( r3 P! @

The collection goal was to obtain a transplantation with a minimum of 2.5 x 106 CD34  cells/kg of body weight. Thirteen patients required one leukapheresis, 24 patients two leukaphereses, 1 patient four leukaphereses, and 1 patient six leukaphereses to reach the collection goal. CD34  selection was performed in all patients; 15 patients obtained an additional nonselected transplant as back-up. Back-up leukapheresis products were cryopreserved in 10% dimethyl sulfoxide by controlled-rate freezing and were stored in the vapor phase of liquid nitrogen.
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CD34 Selection9 z, V( t/ B2 u% l6 g& _0 U

Immunomagnetic CD34 selection was performed with the Baxter Isolex 300 SA or the 300i Magnetic Cell Separation System (Baxter Immunotherapy, Irvine, CA) according to the manufacturer's protocol. The CD34-selected PBPC were then cryopreserved in 10% dimethyl sulfoxide by controlled-rate freezing and were stored in the vapor phase of liquid nitrogen.
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CD34  content was controlled by flow cytometry. In three patients, an additional CD19 depletion was performed.
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HDT
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Thirty-three patients were conditioned with a combination of 14.4 Gy of fractionated total body irradiation (TBI; over 4 days) and cyclophosphamide 200 mg/kg (50 mg/kg per day over 4 days). Twelve patients also received rituximab (375 mg/m2) before radiation and before the start of the cyclophosphamide treatment. Six patients were conditioned with the BEAM (carmustin 300 mg/m2 per day on day 1, cytosinarabinoside 200 mg/m2 2x per day on days 2¨C5, etoposide 100 mg/m2 2x per day on days 2¨C5, and melphalan 140 mg/m2 per day on day 6) protocol. All patients received a transplant with CD34 -selected PBPC. Hematologic restitution was defined as platelets above 20 cells per nanoliter and leukocytes above 1 cell per nanoliter. In our center, differential blood counts were not available on public holidays and weekends on a routine basis. To monitor reconstitution more closely, we therefore chose the absolute leukocyte count as lead parameter. Patients with fever (38.5¡ãC) were treated with ceftazidim. If the fever persisted for more than 72 hours, vancomycin and amphotericin B were added. Red cells were transfused at a hemoglobin level below 8 g/dl and according to clinical requirement. Platelets were given if the platelet count was below 20 cells per nanoliter. Only three patients required G-CSF for leukocyte recovery.. _" ~( _7 [" ]. `3 Y
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Treatment After HDT8 A$ R; B% E) }; N. g9 ]! J: @

Thirteen patients had bulky disease and were irradiated at a median of 3 months (range, 1¨C8 months) after HDT with a median dose of 30 Gy (range, 24¨C40 Gy). Three patients received interferon maintenance therapy; however, in two of these patients the treatment had to be stopped because of pancytopenia.

Statistical Analysis
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EFS, PFS, and OS were calculated with the SAS software (SAS Institute, Cary, NC, http://www.sas.com). Univariate analysis was calculated with Cox regression analysis with Firth's correction.) u+ s7 X- {( m. d  L$ B% g8 I

RESULTS. T. L% }- q: o" T9 `: ]9 z& u0 B

PBPC Transplantation and Hematologic Reconstitution0 i+ d4 f; u9 M3 L4 `7 `. R
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After mobilization therapy with HAM or D-BEAM, all patients were in remission (complete, n = 17; partial, n = 22). In 26 (67%) of 39 patients additional leukaphereses were performed because of the cell selection process. Of the 39 patients, all CD34  cells (100%) recovered in 6 patients, whereas CD34 cell losses of up to 81% were observed in 32 patients (Table 2). The purity of CD34 -selected products was a median of 98.35% (range, 59.2%¨C102.16%; Table 2). The purity of the CD34 -selected products was excellent with the Baxter device and, thus, comparable with recently used devices .& X$ n* t9 K4 V2 T/ Z# T/ ~) [
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Following high-dose conditioning therapy, the patients received a CD34 -selected transplant that contained a median of 6.5 x 106 CD34  cells per kg of body weight (range, 2.5 x 106¨C17.6 x 106 cells per kg of body weight) and a median of 7.1 x 106 mononuclear cells (MNC)/kg of body weight (range, 2.6¨C29.68 MNC/kg of body weight).' P( ~- f+ [) Q& k$ x

Platelets were reconstituted at a median of 13 days after transplantation; leukocyte recovery occurred a median of 12 days after transplantation, and two patients experienced graft failure. One of these patients received a nonselected back-up transplant 14 days after the first transplantation. The other patient died 57 days after transplantation as a consequence of multiple organ failure. The patients experienced a median of 3 days with fever (range, 0¨C11 days). Patients with fever were treated with intravenous antibiotics for a median of 12 days. There were a median of six platelet transfusions and four erythrocyte transfusions in each patient. Parenteral nutrition was required by most patients and lasted a median of 10 days. Median duration of hospital stay was 16 days (range, 11¨C28 days; Table 6).

Table 6. Transplantation and supportive therapy

Platelet and leukocyte recovery were dependent on the number of CD34  cells transplanted (p = .0001 and .0006, respectively; Fig. 1A, 1B). Patients who received a transplant containing more than 5.6 x 106 CD34  cells per kg of body weight had a faster platelet and leukocyte reconstitution than patients who received transplants with less than 5.6 x 106 CD34  cells per kg of body weight.
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Figure 1. Leukocyte and platelet reconstitution, transplanted CD34  cell number, and extranodal disease. (A): Leukocyte reconstitution and transplanted CD34  cell number. The red line represents patients (pts) who received transplants with more than 5.6 x 106 cells per kg of body weight; the blue line represents pts who received transplants with less than 5.6 x 106 cells per kg of body weight (p = .0006) (B): Platelet reconstitution and transplanted CD34  cell number. The red line represents pts with transplants with more than 5.6 x 106 cells per kg of body weight; the blue line represents pts with transplants with less than 5.6 x 106 cells/kg body weight (p = .0001). Pts who received transplants in second remission had a slower platelet reconstitution than did pts in first remission (p = .01; data not shown). Pts with extranodal disease had a slower platelet reconstitution than did pts without extranodal disease (p = .008). This is probably attributable to the fact that nearly all pts with extranodal disease in our cohort had bone marrow infiltration. The number of pts was too low for multivariate analysis. (C): Pts with extranodal disease had a slower platelet reconstitution than did pts without extranodal disease (p = .008).

Antibiotic Treatment
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The median duration of antibiotic treatment after transplantation was 12 days (range, 0¨C53 days). Age was a significant risk factor for long antibiotic treatment (p = .04). The number of transfused stem cells also influenced the duration of the antibiotic treatment (p = .07). The more PBSC the patients received, the less antibiotic treatment was required (p = .07; not shown). Extranodal disease, elevated LDH, elevated sCD25 (> 900 U/ml) , number of chemotherapy cycles, first-line versus second-line therapy, and rituximab therapy (yes vs. no) were not significant risk factors.4 B! B0 n& c2 G
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Survival7 Q9 K, d/ @0 T/ w

The probabilities of freedom from progression (FFP), OS, and EFS 4 years after transplantation were 96%, 90%, and 87%, respectively, for patients with FL and 42%, 63%, and 33%, respectively for patients with MCL. (Figs. 2A and 2B and 3 A and 3B). The median follow-up time was 47 months. Risk factors for unfavorable EFS were age (p = .07) and extranodal disease (p = .07). Number of transplanted CD34  cells, elevated LDH, elevated sCD25, number of chemotherapy cycles, first-line versus second-line therapy, and rituximab therapy (yes vs. no) were not significant risk factors. In the total group of 39 patients, there were seven deaths during the follow-up period (Table 7). In the small group of patients who were treated during relapse (n = 8), there were three deaths. In the group of patients receiving first-line treatment (n = 31), there were four deaths. Two deaths occurred within 100 days after transplantation, both due to septic multiple organ failure. One of these patients had experienced graft failure before. Taken together, the rate of death due to infection within the first year in this patient cohort is approximately 8%. Two additional patients died in the first year after transplantation, one because of cerebral mass hemorrhage and one because of respiratory failure. In years 2, 3, and 6 of follow-up there were three deaths (one infection, one respiratory failure, one relapse). All deaths occurred in patients with extranodal disease.; _5 N) ]5 L* {0 y- T0 f5 j+ ?# A- J
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Figure 2. EFS. (A): Probability for EFS 4 years after transplantation was 87.1% in the group of patients with FL. (B): Probability for EFS 4 years after transplantation was 33.3% in the group of patients with MCL. Abbreviations: EFS, event-free survival; FL, follicular lymphoma; MCL, mantle-cell lymphoma.
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Figure 3. Overall survival (OS) (A): Probability for OS 4 years after transplantation was 90.3% in the group of patients with FL. (B): Probability for overall survival 4 years after transplantation was 62.5% in the group of patients with MCL. Abbreviations: FL, follicular lymphoma; MCL, mantle-cell lymphoma.

Table 7. Deaths after transplantation

Relapse
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After transplantation, there were relapses in 8 of 39 patients. Median time between transplantation and relapse was 21 months (range, 39 days to 59 months). The relapsed patients were treated heterogeneously. Two patients received RTE chemotherapy (rituximab 375 mg/m2 day 1, endoxan 700 mg/m2 days 2¨C4, and docetaxel 75 mg/m2 day 2), one patient received rituximab monotherapy, two patients received an allogeneic transplantation, and one patient received a second autologous transplantation.

DISCUSSION
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Here we report the results of a clinical trial in which CD34-selected PBPC were transplanted following HDT in 39 patients with NHL. The probabilities of FFP, OS, and EFS 4 years after transplantation were 96%, 90%, and 87%, respectively, for patients with FL and 42%, 63%, and 33%, respectively, for patients with MCL. Therefore, we conclude that transplantation of CD34 -selected PBPC is feasible and results in long-term clinical remission in the majority of patients. A matched-pair analysis of the patients with FL in this study with a patient group that was treated with HDT and unselected transplantation showed no difference in OS (M. Kornacker et al., submitted for publication).
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Previously, Horning et al. treated patients with relapsed FL with a related protocol . In that study, 37 patients were treated with CVP (cyclophosphamide, vincristine, and prednisone); HDT with TBI, etoposide, and cyclophosphamide; and a bone marrow transplantation with purged bone marrow. B-cell depletion was performed with negative selection with anti-CD9, -CD10, -CD19 and -CD20 antibodies. OS and FFP were 92% and 76%, respectively, after 5 years and 86% and 70%, respectively, after 10 years. Patients in the Horning et al. study were younger (median age, 37 years) than in our study (median age, 48 years), and all patients in the Horning et al. study were treated in first remission.

Hematologic reconstitution in our study was within expected range. After 12 days, there was a leukocyte recovery (>1 cell per nanoliter); after 13 days, platelets reconstituted (>20 cells per nanoliter). Earlier studies have shown that 2.5 x 106 CD34  cells per kg of body weight is required for a rapid and sustained hematologic recovery . These observations are in accordance with this data set where transfusion of more than 5.6 x 106 CD34  cells per kg of body weight resulted in a significantly accelerated platelet and leukocyte reconstitution. Risk factors for a prolonged platelet recovery in our study were a low CD34  cell number, extranodal manifestation of disease (p = .008), and treatment in relapse (p = .01).
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For OS, age and extranodal manifestation of disease were the most important risk factors. Due to the low number of patients in this study, this risk factor did not reach statistical significance (p = .12 and .21, respectively). Interestingly, the risk factors we have identified are in accordance with the results of a large international cooperative analysis including 1,795 patients .
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As mentioned earlier, this study was initiated at a time when the anti-CD20 antibody rituximab was not available. Following the addition of rituximab to cytotoxic chemotherapy, it became apparent that this combination is highly effective in depleting B cells from the peripheral blood during G-CSF-enhanced leukocyte recovery. This in vivo purging capacity is best reflected by the polymerase chain reaction negativity that can be achieved in patients originally harboring t(14;18)-positive lymphoma cells. A first study was published by Gianni et al. showing that in patients with low-grade lymphoma, the addition of two cycles of rituximab to the mobilization therapy resulted in a reduced tumor cell contamination of the transplant . However in vitro purging techniques, as applied in this study, are time-consuming and expensive. The cost of CD34 cell selection is approximately 8,500 Euros. The majority of our patients (67%) needed at least one additional leukapheresis because of the cell selection process. The cost per leukapheresis adds 1,500 Euros. These leukaphereses are also considered an additional patient strain.0 ]3 e  A* H; F# ~0 l
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Another problem of these techniques seems to be the relatively high rate of lethal infections occurring in our study, a rate of 8%. Treatment with the anti-CD20 antibody rituximab before stem cell collection can be easily performed and serves both as an anti-lymphoma treatment and an in vivo purging and can now be considered the purging method of choice.
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DISCLOSURES  \* R  P; D* q/ ^  C3 J  Q# W. n

The author indicates no potential conflicts of interest.
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ACKNOWLEDGMENTS

M.W.-H. and C.H. contributed equally to this work. R.H. is currently affiliated with the Department of Hematology and Oncology and Clinical Immunology, University Hospital D¨¹sseldorf, D¨¹sseldorf, Germany.
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