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Journal of Clinical Oncology, Vol 26, No 14 (May 10), 2008: pp. 2240-2243 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.7827
High-Dose Melphalan and the Development of Hematopoietic Stem-Cell Transplantation: 25 Years LaterDepartment of Medicine, University Hospitals Case Medical Center, Ireland Cancer Center, Case Western Reserve University
Department of Medicine, University of Rochester Medical Center, Rochester, NY
Department of Blood and Marrow Transplant, University of Louisville, James Graham Brown Cancer Center, Louisville, KY
Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC
Department of Internal Medicine, Meharry Medical College, Nashville, TN
Department of Blood and Marrow Transplant, University of Louisville, James Graham Brown Cancer Center, Louisville, KY In 1983, we reported a novel phase I dose-escalation and pharmacokinetic study of the alkylating agent melphalan in 33 patients with patients with refractory cancer.1 At that time, the therapeutic options of dose-intensity therapy for patients with cancer were much more restricted than they are today. Increasing dose intensity by more frequent administration of marrow-toxic agents was limited by substantial myelosuppression, as the hematopoietic growth factors granulocyte colony-stimulation factor and granulocyte-macrophage colony-stimulation factor were not yet available. To increase dose intensity, predominantly marrow-toxic alkylating agents such as melphalan were chosen for high-dose investigation, as myelosuppression could be overcome via a stem-cell transplantation. By the early 1980s, the techniques of hematopoietic precursor cell collection, processing, and storage were well established and widely available. Our study determined the maximum tolerated dose of intravenous melphalan to be 180 mg/m2 (as 60 mg/m2/d for 3 days) when given in conjunction with autologous bone marrow support, a substantial increase from the maximum dose at that time of approximately 40 mg/m2 orally.1 We demonstrated that damage to the GI tract was the secondary dose-limiting toxicity. Significant responses were noted in refractory malignant melanoma, neuroblastoma, and other tumors. Our conclusion that "high-dose melphalan and autologous bone marrow transplantation was a promising therapy for patients with malignancies for which no effective treatment is known, or for patients whose cancer is refractory to conventional therapeutic agents" has been an accurate prediction. In the 25 years after our report, high-dose melphalan has become a common preparative regimen in combination with hematopoietic stem-cell support. Such studies have facilitated the increasing use of high-dose therapy as a means to improve anticancer therapy. In the decades that followed, there have been many significant advances in stem-cell transplantation (Table 1). Notable is the observation that hematopoietic stem cells can be collected not only from bone marrow, but also from peripheral blood. Usually, chemotherapy with granulocyte colony-stimulation factor is the mobilization stimulus resulting in large numbers of committed hematopoietic progenitor cells collected from the blood; reconstitution is considerably faster than after infusion of conventional bone marrow grafts.2,3 The vast majority of patients now receive stem cells collected from peripheral blood as the graft source for autologous transplants, and this approach is increasingly used in the allogeneic stem-cell transplantation setting as well.4,5 As a result, the more generic term "bone marrow transplant" has been supplanted with the term "hematopoietic stem-cell transplant," though the grafts contain a mixture of immature and mature hematopoietic progenitor cells, including stem cells with self-renewal capacity.6 Since our report in 1983, it is estimated that worldwide approximately 500,000 patients have undergone an autotransplantation procedure and 300,000 patients have received allografts; in 2006, about 36,000 autologous and 19,000 allogeneic stem-cell transplantations were performed worldwide (M Eapen, MM Horowitz, personal communication, October 2007). The diseases for which stem-cell transplantation commonly is used are acute myeloid leukemia, acute lymphoblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, and germ cell tumors, as well as the nonmalignant diseases aplastic anemia, thalassemia major, and inborn errors of metabolism.7
Stem-cell transplantation originally was utilized as the treatment of last resort, but is now utilized extensively by experienced centers earlier in the disease course. Further, use of this therapeutic modality may result in more durable remissions than alternative therapies. Nonetheless, stem-cell transplantation remains plagued by higher morbidity and mortality than other treatment modalities. With a better understanding of drug interactions and dosing, improved tissue typing between patient and donor, better blood component transfusion support and improved antibiotic therapies, and overall supportive care, the treatment-related mortality for autologous and allogeneic stem-cell transplantation are less than 2% and 25%, respectively. High-Dose Melphalan: Toxicity and Supportive Care The most common early and serious problem of stem-cell transplantation is bone marrow suppression. Escalation of the chemotherapy dose results in more tumor cell kill, but correspondingly injures normal marrow cells. Such an effect likely would be fatal if hematopoietic stem-cell rescue is not performed by either autologous or allogeneic stem-cell transplantation. High-dose melphalan in excess of 140 mg/m2 requires hematopoietic stem-cell infusion to restore marrow function.8 Severe neutropenia and the potential for opportunistic infection still complicate stem-cell transplantation, but use of hematopoietic growth factors and potent antibiotics have dramatically lowered morbidity and mortality from infection. Mucositis and injury to the GI tract is one of the most common acute adverse events in stem-cell transplant recipients. Oropharyngeal mucositis usually is quite painful and sometimes may involve the supraglottic area and require intubation. Intestinal injury results in nausea, vomiting, diarrhea, cramping, and occasionally an acute abdomen. One of the major adverse effects of using high-dose melphalan is the development of injury to the entire GI tract. Recipients often require narcotic analgesics and parenteral alimentation; the latter sometimes is associated with the introduction of opportunistic infection in immunocompromised hosts.9 In recent years, recombinant products such as palifermin (keratinocyte growth factor) have been added to the armamentarium and appear to protect the GI tract.10 Subsequently, Phillips et al11 used the cytoprotectant amifostine, a thiol that can act as a scavenger of free radicals generated in tissues, to facilitate the safer use of high-dose melphalan. In fact, pretreatment with this agent enabled melphalan dose escalation to 280 mg/m2 in the course of an autotransplantation (Table 2).
High-Dose Melphalan: Disease Targets Our phase I study was one of the first to explore systematically the nonhematologic toxicity of a single agent utilizing dose-escalation principles in the context of hematopoietic stem-cell rescue.1 This work set the stage to combine various chemotherapeutic agents used in high dose, provided the nonhematologic toxic effects were not overlapping. High-dose melphalan, alone or in combination, subsequently has been implemented into a variety of preparative regimens for stem-cell transplantation for acute leukemia, other hematologic malignancies, and neuroblastoma.8,12 Melphalan is a component of the highly effective BEAM (carmustine, etoposide, cytarabine, and melphalan) regimen that is one of the most frequently and successfully administered approaches to provide long-term, disease-free survival in relapsed and refractory patients with Hodgkin's and non-Hodgkin's lymphoma.13,14 Further, high-dose melphalan has become a key component of pediatric solid tumor transplant protocols for neuroblastoma,15 Ewing's sarcoma,16 and Wilms’ tumor.17 Melphalan (200 mg/m2) has emerged as the most effective means of safely applying dose-intensive therapy for patients with multiple myeloma.18,19 In fact, high-dose melphalan and autologous stem-cell transplantation is thought to have contributed significantly to improve overall survival as reported when viewed retrospectively in nearly 15,000 patients with multiple myeloma from 1973 to 2003.20 Since transplantation procedures using high-dose melphalan do not result in cumulative toxicity to the GI tract or other organs, this agent is the treatment of choice for performing "tandem" autologous stem-cell transplantation procedures that some groups advocate to improve overall patient outcome in multiple myeloma.19,21 Reduced-Intensity and Nonmyeloablative Allogeneic Stem-Cell Transplantation High-dose chemotherapy and allogeneic stem-cell transplantation (ie, myeloablative therapy) in most instances is used in younger rather than older patients in view of increased risk for treatment-related mortality due to the significant organ injury from the higher doses of chemotherapy given. In addition, the toxic effects of this approach are increased due, in part, to the fact that severe graft-versus-host disease (GVHD) occurs more frequently with advancing age. Reduced-intensity and nonmyeloablative stem-cell transplantations are used increasingly in older patients and in more debilitated patients for a variety of disease indications including multiple myeloma.22 Reduced-intensity or nonmyeloablative transplantation preparative regimens rely less on chemotherapy-induced cell kill; this strategy exploits the graft-versus-tumor effect by using donor cell engraftment (and sometimes donor lymphocyte infusions) to attain mixed and full-donor chimerism.23 Several groups have successfully incorporated high-dose melphalan into reduced-intensity allogeneic stem-cell transplantation regimens for the treatment of multiple myeloma, acute myeloid leukemia, and myelodysplasia.24,25 Also, the strategy of using tandem autografts with a regimen such as single agent high-dose melphalan, followed months later by a reduced-intensity or nonmyeloablative conditioning, is becoming more frequent. For example, for multiple myeloma patients, Center for International Blood and Marrow Transplant Research data show an increase of planned allograft after autograft of approximately 450 transplants in 2000 to 2002 to 800 transplants during the 2003 to 2006 period (M Eapen, MM Horowitz, personal communication, October 2007). Persistent Challenges Many hurdles remain to continue to advance the field of hematopoietic stem-cell transplantation. Using newer approaches, it is uncommon to fail to collect sufficient cells from the patient scheduled to receive an autologous stem-cell transplantation (mobilization failure). On the other hand, only approximately 30% of potential allogeneic transplantation candidates will have a suitable histocompatible sibling donor identified. Use of alternative donors has increased transplantation possibilities for many, but GVHD rates are higher than with matched related donor transplants. Further, GVHD prophylaxis is required after transplantation for all allograft recipients, and use of immunosuppression or the GVHD itself often lead to severe and fatal infections. High-dose conditioning chemotherapy regimens still induce serious and sometimes fatal visceral organ injury, due to the nonspecific nature of these agents. In the autologous stem-cell transplantation setting, occult tumor cells may contaminate the graft and contribute to higher relapse rates. Relapse after transplantation remains the major hurdle in the autologous transplantation setting, in large part due to lack of a graft-versus-tumor effect that is observed in the allogeneic transplantation setting. Relapse rates, though lower with allografts, still represent a meaningful cause of failed transplantation procedures in this modality as well. In both autotransplantation and allotransplantation, immune reconstitution is a slow process and patients remain at risk for delayed infections. Additionally, elderly patients, those with comorbid conditions and patients with advanced, refractory disease, are not deemed acceptable candidates for the procedure. Finally, late consequences of stem-cell transplantation are becoming increasingly well recognized and include a high incidence of second malignancies, endocrine abnormalities, iron overload, osteoporosis, and other maladies. CONCLUSION Many advances have been realized since our 1983 phase I/II study report in the Journal of Clinical Oncology using high-dose melphalan.1 Despite the plethora of data to support the curative potential of stem-cell transplantation in hematologic malignancies and immunologic and genetic disorders, this approach still is underutilized. The failure of stem-cell transplantation in breast cancer may have contributed to this perception.26-28 More patients with a relapse still responsive to chemotherapy should be considered for an autologous stem-cell transplantation procedure.29 While issues such as socioeconomic considerations and stem-cell graft availability contribute to the inability to perform the transplantation, in other situations use of transplantation often is considered too late or not at all.30,31 Clearly, the decision to proceed with this life-saving treatment must be weighed against the risks, but scientific progress continues to be made. Our early work, where we modified definitions of dose-limiting toxic effects and helped establish new adverse event criteria, has contributed to furthering the field of stem-cell transplantation. We look forward to the next generation of rationally designed combination protocols that will exploit new biologic concepts in stem-cell transplantation. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Hillard M. Lazarus, Gordon L. Phillips, Roger H. Herzig, David D. Hurd, Steven N. Wolff, Geoffrey P. Herzig Provision of study materials or patients: Hillard M. Lazarus, Roger H. Herzig, David D. Hurd, Steven N. Wolff, Geoffrey P. Herzig Collection and assembly of data: Hillard M. Lazarus, Gordon L. Phillips, Roger H. Herzig, David D. Hurd, Steven N. Wolff, Geoffrey P. Herzig Data analysis and interpretation: Hillard M. Lazarus, Gordon L. Phillips, Roger H. Herzig, David D. Hurd, Steven N. Wolff, Geoffrey P. Herzig Manuscript writing: Hillard M. Lazarus, Gordon L. Phillips, Roger H. Herzig, David D. Hurd, Steven N. Wolff, Geoffrey P. Herzig Final approval of manuscript: Hillard M. Lazarus, Gordon L. Phillips, Roger H. Herzig, David D. Hurd, Steven N. Wolff, Geoffrey P. Herzig
ACKNOWLEDGMENTS We thank Alvin Schmaier, MD, and Edward Stadtmauer, MD, for careful review and thoughtful comments. REFERENCES 1. Lazarus HM, Herzig RH, Graham-Pole J, et al: Intensive melphalan chemotherapy and cryopreserved autologous bone marrow transplantation for the treatment of refractory cancer. J Clin Oncol 1:359-367, 1983[Abstract] 2. Schmitz N, Dreger P, Linch DC, et al: Randomised trial of filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients. Lancet 347:353-357, 1996[CrossRef][Medline] 3. Beyer J, Schwella N, Zingsem J, et al: Hematopoietic rescue after high-dose chemotherapy using autologous peripheral-blood progenitor cells or bone marrow: A randomized comparison. J Clin Oncol 13:1328-1335, 1995[Abstract] 4. Gratwohl A, Baldomero H, Frauendorfer K, et al: EBMT activity survey 2004 and changes in disease indication over the past 15 years. 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Tallman MS, Gray R, Robert NJ, et al: Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med 349:17-26, 2003 28. Hagmann M: Scientific misconduct: Cancer researcher sacked for alleged fraud. Science 287:1901-1902, 2000[Medline] 29. Guglielmi C, Martelli M, Federico M, et al: Risk-assessment in diffuse large cell lymphoma at first relapse: A study by the Italian Intergroup for Lymphomas. Haematologica 86:941-950, 2001 30. Mitchell JM, Meehan KR, Kong J, et al: Access to bone marrow transplantation for leukemia and lymphoma: The role of sociodemographic factors. J Clin Oncol 15:2644-2651, 1997 31. Gratwohl A, Passweg J, Baldomero H, et al: Economics, health care systems and utilization of haematopoietic stem cell transplants in Europe. Br J Haematol 117:451-468, 2002[CrossRef][Medline] 32. 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Vose JM, Bierman PJ, Enke C, et al: Phase I trial of iodine-131 tositumomab with high-dose chemotherapy and autologous stem-cell transplantation for relapsed non-Hodgkin's lymphoma. J Clin Oncol 23:461-467, 2005 40. Nademanee A, Forman S, Molina A, et al: A phase 1/2 trial of high-dose yttrium-90-ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma. Blood 106:2896-2902, 2005 41. Ullmann AJ, Lipton JH, Vesole DH, et al: Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 356:335-347, 2007 42. Attal M, Harousseau JL, Leyvraz S, et al: Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 108:3289-3294, 2006 43. Moreau P, Facon T, Attal M, et al: Comparison of 200 mg/m2 melphalan and 8 Gy total body irradiation plus 140 mg/m2 melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: Final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial. Blood 99:731-735, 2002
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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