AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANTS ...

[Frontiers in Bioscience 4, e???-???, April 7, 1999]

AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANTS IN COMMUNITY CANCER CENTERS C. D. Buckner, C. H. Weaver, L. S. Schwartzberg, R. Birch, B. Zhen and W. West Response Oncology, Inc., 600 Broadway, Suite 112, , Seattle, Washington TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Mobilization and Harvesting of PBSC 4. Mobilization of PBSC with G-CSF Alone 5. Mobilization of PBSC with Chemotherapy and a Growth Factor 6. Mobilization of PBSC with cyclophosphamide, etoposide (CE) and G-CSF 7. Evaluation of 2 versus 4 g/m2 of Cyclophosphamide in the CE Regimen 8. Comparison of CE to CEP for Mobilization of PBSC 9. Evaluation of Cyclophosphamide, Paclitaxel and G-CSF for Mobilization of PBSC 10. Evaluation of Cyclophosphamide, Docetaxel and G-CSF for Mobilization of PBSC 11. Patients who have Low CD34+ Cell Yields with First Attempts 12. Conclusions Concerning Studies of PBSC Mobilization 13. Current Status of Purging of BM or PBSC 14. Purging of Grafts in Patients with Non-Hodgkin’s Lymphoma 15. Purging of Grafts in Patients with Multiple Myeloma 16. Purging of Grafts in Patients with Breast Cancer 17. Conclusions Concerning Purging of PBSC 18. Neutrophil and Platelet Recovery Following Infusion of PBSC 19. Effects of Infusion of PBSC with a Low CD34+ Cell Dose 21. Treatment Related Morbidity 22. Outcomes of Clinical Trials of Outpatient HDC with PBSC Support 23. Results of HDC in Patients with Breast Cancer 23.1. Patients with Metastatic Breast Cancer 24. Patients with Stage II-III Breast Cancer with ≥10+ Nodes 25. Patients with Stage II-III Breast Cancer with 5-9+Nodes 26. Conclusions Concerning Adjuvant Therapy for Patients with Breast Cancer 27. Results of HDC in Patients with Malignant Lymphoma 27.1. Patients with Hodgkin’s Disease 28. Patients with Low Grade NHL 29. Patients with Intermediate and High-Grade NHL 31. Results of HDC in Patients with Multiple Myeloma 32. Results of HDC in Patients with Ovarian Cancer 33. What is the Future of HDC with PBSC Support 33.1. Use of PBSC will Expand for Indicated Therapy and in the Evaluation of New Therapies 33.2. Immune Therapies will be Evaluated after HDC with PBSC Support 34. References

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ABSTRACT

2. INTRODUCTION

AU: Please provide an abstract

The infusion of autologous hematopoietic stem cells allows the administration of higher than normal doses of marrow toxic chemotherapeutic agents. Further escalation of drug doses with stem cell support is ultimately limited by non-hematopoietic toxicities, primarily to the mucous membranes, lungs and liver. The source of stem cells for support following the administration of high-dose chemotherapy (HDC) was originally from bone marrow (BM) which essentially limited this technology to transplant referral centers. However, the emergence of peripheral blood stem cells (PBSC) over the past decade, as the preferred source of hematopoietic stem cells, has made HDC with stem cell support widely available. Peripheral

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Autologous peripheral blood stem cell transplantation

Table 1. Randomized trials demonstrating superiority of high dose chemotherapy with hematopoietic stem cell support compared to conventional chemotherapy Event-Free Survival Disease Phase Years HDC CC Reference Hodgkin’s Relapse 3 53% 10% 3 NHL First Response 4.5 76% 49% 4 NHL First Relapse 5 46% 12% 6 NHL First Remission 5 59% 39% 5 Myeloma Early Phase 5 28% 10% 9 AML First Remission 5 48% 30% 9 Breast Cancer Metastatic 2 42%* 4%* 7 *= overall survival; Ref. = reference; HDC = high dose chemotherapy; CC = conventional chemotherapy; NHL = non-Hodgkin's lymphoma; AML = acute myeloid leukemia blood stem cells can be collected following the administration of chemotherapy and a growth factor or a growth factor alone in an outpatient or blood bank setting by apheresis(1) and cryopreservation technology is relatively simple and widely available.(2)

ovarian cancer where oncologists participating in these studies believe that HDC with PBSC support is “standard of care”. Data presented here were derived from protocols developed since 1989 by the Clinical Trials Division of Response Oncology Inc.(ROI) involving over 4,000 patients treated with HDC and PBSC support. Approximately 1200 patients/year are evaluated and 650 are treated with HDC and PBSC support in 50 centers by 400 medical oncologists in the ROI network. The list of participating centers is included at the end of this manuscript. This is predominantly an outpatient program with all drugs being administered, PBSC collected and infused in an outpatient department with patients being admitted only for clearly defined complications requiring hospitalization.

Although there is controversy about the relative merits of HDC with PBSC support compared to lower-dose chemotherapy treatments with or without the administration of growth factors most published randomized trials have shown superiority for HDC. Selected randomized prospective clinical trials, summarized in table 1, have demonstrated better event-free (EFS) or overall survival (OS) following HDC with stem cell support compared to conventional dose therapy for patients with: Hodgkin’s disease who have relapsed with or without resistant disease(3), aggressive non-Hodgkin’s lymphoma (NHL) as initial therapy(4), aggressive NHL as consolidation in first complete remission (CR)(5), NHL with responding disease who have relapsed after achieving a remission(6), newly diagnosed metastatic breast cancer (7), newly diagnosed multiple myeloma(8) acute myeloid leukemia (AML) in first remission.(9) No randomized trial has shown HDC with stem cell support to be inferior to conventional dose chemotherapy but some studies have shown equivalency or differences in favor of HDC that were not statistically significant, possibly due to small numbers of patients evaluated.(10,11)

3. MOBILIZATION AND HARVESTING OF PBSC Initially, PBSC were harvested after chemotherapy alone, usually high doses of cyclophosphamide (Cy) and infused after HDC.(15,16) Following the availability of recombinant growth factors, granulocyte-colony stimulating factor (G-CSF) or granulocyte macrophage-colony stimulating factor (GMCSF) were added to high doses of Cy with or without other drugs such as etoposide and cisplatin.(15) With the use of chemotherapy and G-CSF or GM-CSF adequate quantities of PBSC, as measured by the number of CD34+ cells, can be collected in 1-3 aphereses in the majority of patients.(17-19) The administration of G-CSF or GM-CSF alone, without chemotherapy, for mobilization of PBSC is associated with lower, but generally adequate, CD34+ cell yields, has lower morbidity, no hospitalization and apheresis can be scheduled for weekday performance making this the method of choice for blood banks.(1,20,21)

Over the past two decades numerous phase II studies have evaluated HDC supported by autologous hematopoietic stem cells in a variety of chemosensitive malignant diseases including malignant lymphoma, AML, chronic myeloid leukemia, multiple myeloma, breast cancer, ovarian cancer, neuroblastoma, Ewing’s sarcoma, germ cell tumors, brain tumors and lung cancer. Review of results of autologous transplants for all these diseases is beyond the scope of this review but have been reviewed elsewhere.(12-14)

Several studies, summarized in table 2, have been carried out to define yields of PBSC following different regimens. In all these studies CD34+ cell number was used as a measure of hematopoietic PBSC content of the apheresis product.(22) In these studies the minimum CD34+ cell dose necessary for proceeding to HDC was assumed to be ≥2.5 x 106/kg and the optimal dose was ≥5.0 x 106 CD34+ cells/kg.(23,24,20,25,1,22) For comparisons between regimens, effectiveness of a mobilization regimen

The purpose of this manuscript is to present the results of clinical trials of HDC with PBSC support performed in community cancer centers under the supervision of practicing oncologists. Diseases treated are breast cancer, malignant lymphoma, multiple myeloma and

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Table 2. Evaluation of regimens for mobilization of PBSC Number of Regimen Diagnosis CD34+ Cells/kg/ Apheresis Reference Patients (range) 31 Breast Cancer 0.70 (0.1-4.4) 21 G-CSF 10 µg/kg 32 Breast Cancer 1.20 (0.1-6.8) 21 G-CSF 30 µg/kg 497 CE/G-CSF Varied 5.84 (0.002-56.31) 17 Breast Cancer (II-III) 9.90 (0.4-100.3) 26 162 C (2 g/m2) E/G-CSF 156 C (4 g/m2) E/G-CSF Breast Cancer (II-III) 11.10 (0.01-158.1) 26 41 CE/G-CSF Lymphoma 8.16 (0.02-42.16) 19 40 CEP/G-CSF Lymphoma 4.62 (0.01-21.02) 19 44 CE/G-CSF Multiple Myeloma 18.72 (0.64-65.91) 52 141 C paclitaxel/G-CSF Breast Cancer (IV) 3.66 (0.06-25.8) 18 66 C docetaxel/G-CSF Breast Cancer (IV) 7.12 (0.01-47.07) 27 G-CSF = granulocyte-colony stimulating factor; C = cyclophosphamide, E = etoposide, P = cisplatin, II, III, IV = clinical stage of breast cancer was evaluated by determining the number of CD34+ cells harvested/kg/apheresis.(20)

5. MOBILIZATION OF PBSC WITH CHEMOTHERAPY AND A GROWTH FACTOR

4. MOBILIZATION OF PBSC WITH G-CSF ALONE

A variety of chemotherapy and growth factor regimens for mobilization of PBSC have been evaluated and results of studies carried out in an outpatient setting by physicians affiliated with the Clinical Trials Division of ROI are reviewed below and in table 2.

Peripheral blood stem cells can be mobilized with growth factors alone without chemotherapy.(20) The optimal growth factor or combination of growth factors for mobilization of PBSC has yet to be defined. However, the most commonly used growth factor for mobilization of PBSC is G-CSF administered in doses of 5-10 µg/kg with initiation of collections on day 5.(20) In order to optimize usage different doses and schedules of G-CSF are still being evaluated.(21)

6. MOBILIZATION OF PBSC WITH CYCLOPHOSPHAMIDE, ETOPOSIDE (CE) AND GCSF Four hundred ninety seven patients with a variety of malignant diseases received Cy (4 g/m2), etoposide (600 mg/m2) and G-CSF (6 µg/kg/day) for mobilization and collection of a target CD34+ cell harvest ≥2.5 x 106/kg.(17) Results of this study are summarized in table 2. A median of 14.71 x 106 CD34+ cells/kg (range, 0.08137.55) was harvested with a median of 2 (range, 1-11) aphereses. Ninety-one percent of patients yielded ≥2.5 x 106 CD34+ cells/kg. Patients with stage II-III breast cancer, with pre-treatment platelet counts ≥150 x 109/L and patients who had received ≤1 prior chemotherapy regimen had improved CD34+ cell yields. However, the majority of patients with adverse risk factors yielded ≥2.5 x 106 CD34+ cells/kg. These observations confirm previous reports that the intensity of prior therapy adversely affects the quantity of CD34+ cells harvested. Pre- and posttreatment variables did not predict with any certainty the small fraction of patients who failed to yield ≥2.5 x 106 CD34+ cells/kg with multiple aphereses.

The effects of escalating doses of G-CSF on yields of CD34+ stem cells were evaluated in 90 patients with metastatic breast cancer and the results are summarized in table 2.(21) Fifty-five patients were randomized to receive G-CSF 10, 20, 30 or 40 µg/kg/day with more CD34+ cells/kg/apheresis being harvested after the 3 highest dose levels. Thirty-five additional patients were randomized to receive 10 or 30 µg/kg of G-CSF. The median number of CD34+ cells collected after 10 µg/kg (n=31) was 0.7 x 106/kg/apheresis (range 0.1-4.4) compared to 1.2 (range 0.1-6.8) after 30 µg/kg (n=32) (p=0.04). Among patients randomized to 10 versus 30 µg/kg, more achieved ≥5.0 x 106 CD34+ cells/kg and less aphereses were required to achieve ≥2.5 x 106 CD34+ cells/kg after the higher dose (p=0.04). In multivariate analyses patients receiving 10 µg/kg (n=31) had lower yields of CD34+ cells (p=0.026) and had a 3.3 fold increase in the probability of not achieving ≥5.0 x 106 CD34+ cells/kg as compared to patients receiving 20-40 µg/kg (n=59). Patients who had received radiation had a 2.9 fold probability of not achieving ≥2.5 x 106 CD34+ cells/kg. These data suggested that, in patients with good marrow reserves, doses of G-CSF above 10 µg/kg/day mobilized more CD34+ cells with fewer aphereses and may be useful when high numbers of CD34+ cells are desired. However, as a generality, increasing the dose of G-CSF did not improve CD34+ yields in heavily pretreated patients. As shown in table 2 the highest dose of G-CSF mobilized fewer CD34+cells/kg/apheresis than any of the chemotherapy regimens evaluated.

7. EVALUATION OF 2 VERSUS 4 G/M2 OF CYCLOPHOSPHAMIDE IN THE CE REGIMEN The purpose of this study was to develop a less toxic outpatient chemotherapy regimen for mobilizing PBSC in patients with non-metastatic breast cancer and the results of this study are summarized in table 2(26). Three hundred and eighteen patients with newly diagnosed stage II-III breast cancer who had received conventional-dose adjuvant chemotherapy were randomized to receive intermediate-dose Cy (2 g/m2), etoposide (600 mg/m2) and G-CSF 6 µg/kg/day (ID-Cy, N=162) or high-dose Cy (4

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g/m2) and the same doses of etoposide and G-CSF (HDCy, N=156) followed by the collection of PBSC. Patients who received the highest dose of Cy also received mesna for prevention of hemorrhagic cystitis. Three hundred seventeen of 318 patients had apheresis performed. The median numbers of CD34+ cells collected in a median of 2 aphereses following ID-Cy and HD-Cy were 19.9 and 22.2 x 106/kg, respectively (p=0.04). The fractions of patients achieving CD34+ cell harvests ≥2.5 or ≥5.0 x 106/kg were not different between the two regimens. More patients receiving HD-Cy had grade 3-4 nausea (p=0.001), vomiting (p=0.03) and mucositis (p=0.04). The fractions of patients having a neutrophil nadir