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From www.bloodjournal.org by guest on June 18, 2017. For personal use only. Dose-Intensive Melphalan With Blood Stem Cell Support for the Treatment of AL Amyloidosis: One-Year Follow-up in Five Patients By Raymond L. Comenzo, Evan Vosburgh, Robert W. Simms, Peter Bergethon, Diane Sarnacki, Kathleen Finn, Simon Dubrey, Douglas V. Faller, Daniel G. Wright, Rodney H. Falk, and Martha Skinner The morbidity and lethality of AL amyloidosis is caused by the deposition of Ig light chains as fibrillar amyloid protein in vital organs, disrupting their function, and not by the generally low burden of clonal plasma cells that produce the paraproteins. Survival of patients with AL amyloidosis is no more than 1 t o 2 years from the time of diagnosis with current management approaches. Clearly, more effective therapies are needed for this rapidly lethal disease. Five patients were treated with dose-intensive melphalan and blood stem cell support and followed for a period of 1 year. Patients were diagnosed with AL amyloidosis by tissue biopsy and categorized by performance status and organ involvement. Their plasma cell dyscrasias were evaluated with immunofixation electrophoresis of serum and urine specimens, quantitative serum Igs, and immunohistochemical staining of bone marrow biopsy specimens. After treatment with dose-intensive intravenous melphalan followed by infusion of autologous growth-factor-mobilized blood stem cells, clinical evaluations and plasma cell studies were repeated at 3 and 12 months. Three men and 2 women aged 38 t o 53 years were treated. Median performance status (SWOG) was 2 (1 to 3). and clinical presentations included L AMYLOIDOSIS is a plasma cell dyscrasia that results from an excess production of Ig light chains which form insoluble amyloid fibrillar deposits in the kidneys, heart, liver, autonomic and peripheral nerves.'.' Eighty-five percent of patients have evidence of a plasma cell dyscrasia with serum andor urine monoclonal proteins and with lowlevel bone marrow (BM) plasmacytosis showing clonal dominance by either K or A light-chain i ~ o t y p e s . ~ . ~ For patients with AL amyloidosis death usually occurs in 1 to 2 years from diagnosis despite current standard treatment with oral melphalan and prednisone?,6 By comparison, patients with stage I multiple myeloma or monoclonal gammopathies of undetermined significance, whose neoplastic plasma cell burdens are roughly equivalent to those in AL amyloidosis, have median survivals twofold to sevenfold 10nger.~These differences in survival highlight the lethal consequences of systemic amyloid deposition. Elimination of the plasma cell clone producing amyloidogenic proteins is a rational therapeutic goal. The use of myeloablative therapy with allogeneic or autologous BM infusions in patients with multiple myeloma has become an important area of investigation, and complete response rates of 10% to 30% in patients with recurrent or resistant multiple myeloma have been achieved with this approach.8-'' The mortality and morbidity of this form of treatment have been decreased substantially because of the availability of myeloid growth factors and mobilized blood stem ~ e 1 l s . Cognizant l~ of these advances, we used dose-intensive intravenous (IV) melphalan with autologous mobilized blood stem cell support as therapy for AL amyloidosis. We report on the efficacy of this approach in the initial five patients treated, at 12 or more months after treatment. A Blood, Vol 88, No 7 (October l), 1996: pp 2801-2806 nephrotic syndrome (n = I), symptomatic cardiomyopathy (n = 1). gastrointestinal involvement with polyneuropathy (n = 2). and hepatomegaly (n = 1). With a median followup of 13 months (12 t o 17 months), all five patients are well and have shown stable or improved performance status and clinical remission of organ-related dysfunction, including a 50% reduction in daily proteinuria with no change in creatinine, reversal of symptoms of cardiomyopathy and reductions of posterior wall and septal thickening, reversal of polyneuropathy and gastric atony, and resolution of hepatomegaly by computed tomographic scan. In3 of the 5 patients (60%) at 12 months after treatment, plasma cell dyscrasias could not be detected. Dose-intensive chemotherapy with intravenous melphalan and growth-factor-mobilized blood stem cell support is feasible therapy for patients with AL amyloidosis, even when there is clinical evidence of cardiac involvement. At least some patients with AL amyloidosis achieve complete remission of their plasma cell dyscrasia, improvement in performance status, and clinical remission of organ-specific disease after this form of treatment. 0 1996 by The American Society of Hematology. PATIENTS, MATERIALS, AND METHODS Patients Beginning in January 1994, patients 18 to 61 years old with AL amyloidosis diagnosed by tissue biopsy (defined as the presence of apple-green birefringence on Congo red-stained specimens) were evaluated as previously described, and considered for dose-intensive IV melphalan with blood stem cell support on a clinical trial approved by our institutional review board for human studies, requiring written informed consent.'4.15Melphalan at 200 mg/m' was offered to patients younger than 61 years with adequate cardiac (left ventricular ejection fraction >50%), pulmonary (diffusion capacity >50% predicted), hepatic (bilirubin <2.0 g/dL), and renal function (creatinine < 1.5 mg/dL). At baseline, patients were evaluated clinically and with studies that included blood counts and chemistries, 24-hour urinary protein, From the Transfusion Medicine Service, the Department of Pathology and Laboratory Medicine; the Sections of HematologyOncology, Cardiology, and Rheumatology, the Department of Medicine; the Neurological Unit, Boston City Hospital and the Department of Neurology; the Department of Nursing; the Autologous Stem-Cell Transplant Program in the Cancer Research Center; Boston University Medical Center Hospital, and Boston University School of Medicine, Boston, MA. Submitted February 26, 19%; accepted May 30, 1996. Supported in part by a grant from Amgen. Address reprint requests to Raymond L Comenzo, MD, Director, Transfusion Medicine, H-303, 88 E Newton St, Boston Medical Center, Boston, MA 02118. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact. 0 19% by The American Society of Hematology. OOO6-4971/96/8807-OO41$3.00/0 2801 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. 2802 COMENZO ET AL Table 1. SWOG Patient Performance Status Grading Scale Grade Scale 0 Fully active; able to carry on all predisease activities without restriction. (Karnofsky 90% to 100%) Restricted in physically strenuous activity but ambulatory and able to perform work of a light or sedentary nature, eg, light housework or office work. (Karnofsky 70% to 80%) Ambulatory and capable of all self-care but unable to perform any work activities. Up and about more than 50% of waking hours. (Karnofsky 50% to 60%) Capable of only limited self-care; confined to bed or chair more than 50% of waking hours. (Karnofsky 40% to 50%) Completely disabled. Cannot perform any self-care. Totally confined to bed or chair. (Karnofsky 10% to 20%) Dead 1 2 3 4 5 electrocardiogram, echocardiogram, gastric emptying scan, and computed tomographic scan, as indicated by symptoms and clinical findings. Each patient’s systemic amyloidosis was categorized by extent and predominance of organ-system involvement, and each patient’s performance status was assessed according to Southwestern Oncology Group (SWOG) criteria (Table 1). Presence of a monoclonal plasma cell dyscrasia was assessed by serum and urine immunofixation electrophoresis (IFE-S and IFE-U), and by BM biopsy with standard immunohistochemical staining for light-chain isotypes. Quantitative serum Ig levels, and, after July 1995, quantitative urinary light chains, were measured. Amyloid deposits in BM biopsy specimens stained with Congo red were graded as 0 (none detected), 1 (in vessels only), 2 (moderate interstitial deposits), and 3 (massive interstitial deposits). Using these studies, patients were evaluated at baseline, and again at 3 and 12 months after treatment, and responses to therapy were categorized in terms of (1) changes in performance status, (2) changes in clinical findings and organ-related symptoms of amyloidosis, and (3) persistence or undetectability of a monoclonal plasma cell dyscrasia by serum and urine immunofixation electrophoresis and by marrow biopsy with immunohistochemical staining for light-chain isotypes. Blood Stem Cells Hematopoietic stem and progenitor cells were mobilized with granulocyte colony-stimulating factor (G-CSF, filgrastim; AMGEN, Thousand Oaks, CA) by subcutaneous injection for 4 to 6 days.’’ Daily large-volume leukapheresis was performed between days 4 and 7, and the leukapheresed mononuclear cells were evaluated, cryopreserved, and subsequently infused as previously described.16 Briefly, evaluation of stem cell collections included flow cytometric studies to determine the fraction of cells that were CD34’ and standard progenitor cell assays to calculate the number of colony-forming units granulocyte-macrophage, scored at 14 days of culture. The target dose of CD34+ cells was 5 X 106/kg. Chemotherapy Dose-intensive melphalan was administered 1V over 2 days, 100 mg/m*/d, for a total of 200 mg/m*, and stem cells were infused 72 hours later. Postinfusion cytokine support consisted of G-CSF. Patients received antibiotic prophylaxis with oral ciprofloxacin and intravenous acyclovir beginning on day 3 after stem cell infusion. Hematopoietic recovery was determined by daily blood counts and defined as days from stem cell infusion to recovery of neutrophils >0.5 x 109/Land of platelets >20 sion. X 10y/Lwithout platelet transfu- RESULTS Patients Between January 1, 1994 and December 31, 1994, three men and two women with a median age of 46 years (range, 39 to 53) were treated on this trial. All patients gave written informed consent. We report the 1 year follow-up results in these five consecutive patients who had multiple biopsies from separate sites positive for amyloid (range, 2 to 4) and who were treated at a median of 5 months from diagnosis (range, 2 to 18 months). All of these patients had evidence of amyloid depositions in blood vessels in BM biopsies. All patients tolerated stem cell mobilization and leukaphereses without significant complications. Per kilogram of patient weight, the five patients received a median of 8.3 X lo6 CD34+ cells (3.4 to 12.5) containing 100 X IO4 CFUGM (33 to 133). All patients tolerated dose-intensive melphalan and stem cell infusion (days -4 to 0) without significant complications, and became pancytopenic after dose-intensive melphalan. Hematopoietic reconstitution occurred in all patients by a median of 10 days for neutrophils (range, 9 to 10) and for platelets (9 to 12). At 12 months in these five patients, median complete blood count values were white blood cell count 5.0 x 109/L(4.6 to 5.6), hemoglobin 13.8 gm/dL (13.3 to 15.6) and platelet count 156 X 10y/L (1 18 to 208). All patients had nausea, vomiting, and grade I1 mucositis by the Common Cancer Toxicity Criteria.” One patient became febrile requiring IV antibiotics; blood cultures were negative. Two patients had peripheral and pulmonary edema requiring diuresis. Other toxicities included hypematremia and hyponatremia and increased creatinine. All toxicities resolved within 30 days of therapy. Patient Responses at 12 Months Case one. Patient 1, a 42-year-old man, had gastrointestinal symptoms and peripheral polyneuropathy, and was treated 2 months from diagnosis, having received no prior oral therapy. He had presented with a painful peripheral polyneuropathy, was orthostatic by vital signs with symptoms, and had gastrointestinal symptoms that included dysgeusia, loss of appetite, nausea, and vomiting. Biopsy specimens of stomach, rectum, BM (1 +), and abdominal fat were positive for amyloid. Sural nerve biopsy was negative. He required total parenteral nutrition (TPN) for profound (25%) weight loss due to gastric atony as documented by a gastric emptying scan showing 0% emptying at 2 hours. Opiates were required for discomfort associated with his peripheral neuropathy. At 12 months he had regained all lost weight, was eating a normal diet without TPN, and had a gastric emptying scan in the supranormal range. A dramatic improvement in performance status was noted, from 3 to 0, and he had returned to full-time employment. He required no medications. As shown in Fig 1, depicting the neurologic exams of this patient across the top, the polyneuropathy had remitted at 3 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. HIGH-DOSE MELPHALAN FOR AL AMYLOIDOSIS 2803 - Baseline 3 Months Y .0) Y L I Baseline n 3 Months Y J1 Legend Temp. Loss Pain Loss Touch LOSS Hyperaesthesia Fig 1. Patient 1 had experienced the transition from pain to numbness in the weeks before treatment. After therapy, the numbness remitted with a brief period of pain in the feet. Currently the patient's only symptom at 12 months is numbness in his toes. Patient 3 had pain, sensory losses, and weakness which largely resolved after therapy. Currently his only symptom at 12 months is mild discomfort of his soles. months, resulting in improved overall function. Resolution of orthostatic and gastrointestinal symptoms occurred 3 to 9 months after dose-intensive melphalan. At baseline, this patient had serum and urine findings of a plasma cell dyscrasia with a monoclonal IgAA in his serum and A light chains in his urine, as well as suppressed noninvolved Ig levels, and a BM biopsy showing 10% plasma cells uniformly staining for A. At 12 months, his BM showed less than 5% plasma cells with staining for both light-chain isotypes, and he had negative IFE-S and IFE-U.IgA and IgM were normal but IgG was 630 mg/dL (normal, 700 to 1,600 mg/dL). Case two. Patient 2, a 46-year-old man with amyloid cardiomyopathy and a myocardial biopsy sample positive for amyloid, was treated 5 months after diagnosis having received a single course of oral melphalan and prednisone containing 32 mg of melphalan. BM (1+) and abdominal fat biopsies were also positive for amyloid. At 12 months of follow-up, performance status over the year improved from 2 to 0, New York Heart Association (NYHA) class improved from III to I, diuretics were no longer needed, and the patient was able to work full-time and exercise strenuously. A comparison of echocardiograms from baseline and 12 months posttherapy showed reductions in the thickness of both the posterior wall and interventricular septum from 1.5 and 1.4 cm to 0.93 and 0.98 cm, respectively, although left ventricular ejection fraction decreased from 56% at baseline to 44% at 12 months. Baseline IF%-S was negative while baseline IFE-U showed A light chains. Baseline BM studies showed 10% plasma cells uniformly staining for A. Although the BM findings at 12 months follow-up had normalized, showing less than 5% plasma cells staining for both lightchain isotypes; although the IFE-S remained negative and the serum IgG level had normalized, increasing from 544 to 960 mg/dL; and, although quantitative urinary A light chains were not detectable, IFE-Ushowed a faint band suggestive of A light chains, a band that had not been detected at 3 months of follow-up. In addition, 24-hour urinary protein increased from 256 mg at baseline to 601 mg at 12 months From www.bloodjournal.org by guest on June 18, 2017. For personal use only. 2804 with unchanged albumin and creatinine, and alkaline phosphatase increased also, from 104 to 277 U/L. The significance of these findings is not clear at this time, in view of the patient’s excellent performance status. (Author’s note: At 2 years posttherapy, IFE-U, IFE-S, and BM were normal and complete remission maintained.) Case three. Patient 3, a 38-year-old man treated 3 months after diagnosis, presented with a painful peripheral polyneuropathy, orthostasis, nausea, abdominal pain, and profound weight loss (55 lb) because of gastric atony. Biopsy specimens of an axillary lymph node, abdominal fat, and BM (2+) were positive for amyloid. He had a performance status of 3 and had received no prior therapy. Opiates were required to treat pain due to his peripheral neuropathy. He had A light chains in both serum and urine and 5% plasma cells in his BM. As was the case for patient 1, the peripheral polyneuropathy, gastrointestinal, and autonomic symptoms resolved over the 12 months after dose-intensive melphalan and no medications were needed or prescribed. The pattern of resolution of his neuropathic symptoms is depicted in the lower panels of Fig 1. Initially the patient required total parenteral nutrition for several months, but by 1 year’s time he was eating a normal diet, had regained 30 lb, and returned to full-time employment. Performance status had improved from 3 to 0. BM biopsy sample was normal and IFE-U and IFE-S were negative. Case four. Patient 4, a 46-year-old woman with hepatomegaly and AL amyloidosis confirmed by liver biopsy specimen, was treated 11 months after diagnosis having received oral therapy including 264 mg of melphalan. At 12 months’ follow-up, performance status improved from 2 to 0 and cranio-caudal liver span by CT scan decreased from 20 cm at baseline to 14.5 cm, demonstrating resolution of hepatomegaly. This patient’s formal abdominal girth measurements over the same period showed a 3-cm decrease without weight change, and alkaline phosphatase decreased from 184 to 136 U L Baseline BM findings showed 12% uniformly K-staining plasma cells, and, although baseline IFE-S was negative, baseline IFE-U showed K light chains. At 12 months’ followup, BM studies were normal, IFE-S remained negtive, and previously noted urinary light chains were not detected by IFE-U. Serum IgG and IgA levels had been suppressed at baseline, whereas, at 12 months, the IgG level had increased to 911 mg/dL but the IgA level remained below normal. With respect to other organ systems, 24-hour urinary protein was reduced from 645 to 90 mg with creatinine unchanged at 1.3 mg/dL, and echocardiogram remained normal. Casefive. Patient 5, a 53-year-old woman with nephrotic syndrome, had had a monoclonal gammopathy of undetermined significance for 15 years before being diagnosed with multiple myeloma and AL amyloidosis. Renal and abdominal fat biopsy specimens were positive for amyloid. At diagnosis, serum IgGA was 3.5 g/dL, IFE-U contained monoclonal IgGA, and BM biopsy had 25% A-staining plasma cells in sheets. After treatment with oral therapy, including 468 mg of melphalan, a reduction in monoclonal paraprotein to 1.3 g/dL was observed. She was treated with dose-inten- COMENZO ET AL sive IV melphalan and stem cell support 18 months after myeloma and amyloidosis were diagnosed. At 1 year posttherapy, her performance status remains a 1 with no evidence of progressive amyloidosis. Of note, the daily urinary protein has decreased from 11,370 mg at the time of stem cell mobilization to 5,040 mg 12 months later, with a creatinine of 1.0 versus a baseline of 1.1 mg/dL. The serum albumin has increased to 3.4 from a baseline of 2.0 g/dL. However, the monoclonal IgGA remained detectable by IFE-S and IFE-U; serum Ig levels were otherwise normal. DISCUSSION AL amyloidosis is a rapidly lethal disease, and therapies currently in use have modified its dismal prognosis only marginally. In a recent trial, 100 patients with AL amyloidosis were prospectively randomized to receive colchicine alone or melphalan, prednisone, and colchicine.l4 Median survival from the time of study entry to end-organ failure in those treated with three drugs was 12.2 months, compared with 6.7 months for those treated with colchicine alone ( P = .087). In an earlier study of 101 patients, the progressionfree median survival for those receiving melphalan and prednisone was 16 months whereas for controls receiving colchicine it was 6 months.6 Moreover, evaluation of patient subsets in this study showed differences in response to chemotherapy. Of particular note, none of the 15 patients with polyneuropathy that were studied were found to respond to treatment with oral melphalan and prednisone. Each of these patients experienced progression of their disease without enhanced survival. In contrast, survival for patients with congestive heart failure was significantly longer for those receiving melphalan and prednisone, a median survival of 12 months, versus 5 months for controls. Among patients with nephrotic syndrome there was no survival difference based on regimen. It is against the backdrop of these two prior clinical trials that the significance of this report can be best appreciated, for these trials indicate that oral melphalan, despite its variable bioavailability, is part of a modestly useful treatment regimen and that clinical responses to this oral regimen vary with the type of organ involvement in AL amyloidosis. Although patients with AL amyloidosis usually have minimal burdens of neoplastic plasma cells and limited prior exposure to chemotherapy, they have been excluded from clinical trials of dose-intensive chemotherapy because of treatment-related deaths during autologous marrow transplantation attributed to cardiac The preliminary results we report herein show that the exclusion of patients with AL amyloidosis from such trials may not be warranted; however, the risks should not be minimized, and, therefore, the application of this new therapy must be in the context of appropriately designed clinical trials at centers with extensive experience in the evaluation and treatment of patients with this rare disease and expertise in stem cell transplantation. Eligible patients with AL amyloidosis tolerated stem cell mobilization, leukapheresis, dose-intensive IV melphalan, and its short-term hematologic and gastrointestinal toxicities, From www.bloodjournal.org by guest on June 18, 2017. For personal use only. 2805 HIGH-DOSE MELPHALAN FOR AL AMYLOIDOSIS with minimal morbidity, despite prior evidence of amyloid cardiac disease. In this regard, clinical trials using doseintensive chemotherapy with mobilized blood stem cells for patients with AL amyloidosis should be designed so that the toxicities of the stem cell mobilization regimen do not prevent patients from being treated with dose-intensive melphalan. Our results support the advisability of using growth factor mobilization of stem cells and of dispensing with cyclophosphamide-based mobilization regimens, and their potential infectious and myocardial side effects. In view of prior clinical trials, it is notable that three of five patients experienced durable complete remissions of plasma cell dyscrasias and that all patients experienced improved organ function in the predominant organs of involvement. It is particularly notable that two patients with painful polyneuropathy experienced remissions of neuropathic symptoms after treatment, for the polyneuropathy associated with amyloidosis has been recalcitrant to alternative treatment approaches.2’,22Indeed, a treatment-associated improvement in sensory and motor function has never been reported previously in patients with this disease. The rapid reversal of neuropathic signs and symptoms that we observed questions the commonly held belief that infiltration and compression of vascular and neural elements by amyloid depositions underlie its pathophysiology. Rather, remission of polyneuropathy with a reduction of amyloidogenic plasma cells supports the conclusion that a readily reversible metabolic derangement associated with Ig aggregation into amyloid fibrils may be the pathophysiological mechanism that underlies the polyneuropathy in this disease. Although allogeneic transplantation in select patients with AL amyloidosis may be the organ compromise of patients with AL,amyloidosis may increase the risk of this approach. However, allogeneic BM would be free of contaminating clonal cells whereas mobilized autologous blood stem cell preparations may contain clonal plasma cell Ex vivo treatment of autologous stem cell preparations to remove contaminating neoplastic cells may prove important for maximizing efficacy of this treatment approach.2sHence, ex vivo purging procedures, combined with polymerase chain reaction assays for molecular markers of clonal cells, may be useful in the development of future clinical trial^.^^.^' In conclusion, AL amyloidosis, often a rapidly lethal plasma cell dyscrasia, is amenable to treatment with doseintensive IV melphalan, followed by growth-factor-mobilized blood stem cell support for hematopoietic rescue, Remissions of both the plasma cell dyscrasia and clinical symptoms and signs of amyloidosis occur with this treatment approach; furthermore, objective amelioration of amyloidrelated organ dysfunction may occur despite persistence of the plasma cell dyscrasia. The durability of the clinical remissions achieved by this treatment approach remains to be determined, as does the impact of this approach on resorption of amyloid deposits and patient survival. Nevertheless, our results indicate that this therapy can be conducted safely in patients with AL amyloidosis and that dramatic clinical improvements can be achieved. ACKNOWLEDGMENT We are grateful for the efforts of Rebecca Brown, Rita Galvin, and the oncology nurses in the F3 Hematology-Oncology Clinic (Boston, MA) and on Atrium 7 East; and for those of Kate Murphy and the apheresis staff in the BUMCH Blood Bank (Boston, MA). We also thank Ceit McCaleb, Sharon Olsen, Virginia Banis, and Charles Breen for patient coordination. REFERENCES 1. Isobe T, Osserman E F Patterns of amyloidosis and their association with plasma-cell dyscrasia, monoclonal immunoglobulins and Bence-Jones proteins. N Engl J Med 290:473, 1974 2. Glenner GG: Amyloid deposits and amyloidosis: The betafibrilloses. N Engl J Med 302:1283, 1980 3. Skinner M, Benson MD, Cohen AS: Amyloid fibril protein related to immunoglobulin light chains. J Immunol 114:1433, 1975 4. Buxbaum J: Mechanisms of disease: Monoclonal immunoglobulin deposition. Hematol Oncol Clin North Am 6:323, 1992 5. Kyle RA, Greipp PR: Amyloidosis (AL): Clinical and laboratory features in 229 cases. Mayo Clin h o c 58:665, 1983 6. Kyle RA, Greipp PR, Garton JP, Gertz MA: Primary systemic amyloidosis: Comparison of melphaladprednisone versus colchicine. Am J Med 79:708, 1985 7. Kyle RA: “Benign” monoclonal gammopathy-After 20 to 35 years of follow-up. Mayo Clin Proc 63:26, 1993 8. McElwain TJ, Powles RL: High-dose intravenous melphalan for plasma-cell leukemia and myeloma. Lancet 12322, 1983 9. Barlogie B, Hall R, Zander A, Dicke A, Alexanian R: Highdose melphalan with autologous bone marrow transplantation for multiple myeloma. Blood 67: 1298, 1986 10. Barlogie B, Alexanian R, Dicke KA, Zagars G, Spitzer G, Jagganath S, Horwitz L: High-dose chemotherapy and autologous bone marrow transplantation for resistant multiple myeloma. Blood 70:869, 1987 11. Jagganath S, Barlogie B, Dicke K, Alexanian R, Zagars G, Cheson B, Lemaistre FC, Smallwood L, m i t t K, Dixon DO: Autologous bone marrow transplantation in multiple myeloma: Identification of prognostic factors. Blood 76:1860, 1990 12. Jagganath S, Vesole DH, Barlogie B, Tricot G: Peripheral blood stem cell transplantation in multiple myeloma. Ann HematoV Oncol 2:53, 1994 13. Comenzo RL, Berkman EM: Hematopoietic stem and progenitor cells from blood: Emerging uses for new components for transfusion. Transfusion 35:335, 1995 14. Skinner M, Anderson JJ, Simms R, Falk R, Wang M, Libbey CA, Jones LA, Cohen AS: Treatment of 100 patients with primary amyloidosis: A randomized trial of melphalan, prednisone, and colchicine versus colchicine only. Am J Med 100:290, 1996 15. Cohen AS, Skinner M: The diagnosis of amyloidosis, in Cohen AS (ed): Laboratory Diagnostic Procedures in the Rheumatic Diseases (ed 3). Orlando, FL, Grune and Stratton, 1985, p 377 16. Comenzo RL, Vosburgh E, Weintraub LW, Tansan S, Arkin CF, Wright DG: Mobilized peripheral blood stem and progenitor cells for hematopoietic rescue collected by large-volume leukapheresis. Transfusion 35:493, 1995 17. Investigator’s Handbook: A Manual for Participants in Clinical Trials of Investigational Agents Sponsored by the Division of Cancer Treatment, National Cancer Institute, Revised Edition. Washington, DC, Government Printing Office, 1993 (NIH publication no. 93-2770) 18. Mehta J, Nagler A, Slavin S: Marrow transplantation in multiple myeloma (letter). N Engl J Med 326:1087, 1992 19. Gharton G: Marrow transplantation in multiple myeloma (letter). N Engl J Med 326:1087, 1992 20. Barlogie B: Marrow transplantation in multiple myeloma (letter). N Engl J Med 326:1088, 1992 21. KeIly JJ, Kyle RA, O’Brien PC,Dyck PJ: The natural history From www.bloodjournal.org by guest on June 18, 2017. For personal use only. 2806 of peripheral neuropathy in primary systemic amyloidosis. Ann New rol 6:1, 1979 22. Dustin MA, Skinner M, Anderson J, Cohen AS: Peripheral neuropathy as an early marker of AL amyloidosis. Arch Intern Med 149:358, 1989 23. Gahrton G , Tura S, Ljungman P, Belanger C, Brandt L, Cavo M, Facon T, Granena A, Gore M, Gratwohl A, Lowenberg B, Nikoskelainen J, Reiffers JJ, Samson D, Verdonck L, Volin L: Allogeneic bone marrow transplantation in multiple myeloma. N Engl J Med 325:1267, 1991 24. van Buren M, Hene RJ, Verdonck LF, Verzijlbergen FJ, Lokhorst HM: Clinical remission after syngeneic bone marrow transplantation in a patient with AL amyloidosis. Ann Intern Med 122508, 1995 2.5. Brugger W, Bross KJ, Glatt M, Weber F, Mertelsman R, Kanz L: Mobilization of tumor cells and hematopoietic progenitor cells into peripheral blood of patients with solid tumors. Blood 83:636, 1994 26. Ross AA, Cooper BW, Lazarus HM, Mackay W, Moss TJ, Ciobanu N, Tallman MS, Kennedy MJ, Davidson NE, Sweet D, Winter C, Akard L, Jansen J, Copelan E, Meagher RC, Herzig RH, Klump TR, Kahn DG, Warner NE: Detection and viability of tumor cells in peripheral blood stem cell collections from breast cancer COMENZO ET AL patients using immunocytochemical and clonogenic assay techniques. Blood 82:2605, 1993 27. Moss TJ, Ross AA: The risk of tumor cell contamination in peripheral blood stem cell collections. J Hematotherapy 1 :22.5. I992 28. Gazitt Y, Reading CC, Hoffman R, Wickrema A, Vesole DH, Jagganath S, Condino J, Lee B, Barlogie B, Tricot G : Purified CD34+ Lin-Thy+ stem cells do not contain clonal myeloma cells. Blood 86:381, 199.5 29. Gribben JG, Freedman AS, Neuberg D, Roy DC, Blake KW. Woo SD, Grossbard ML, Rabinowe SN, Coral F, Freeman GJ, Ritz J, Nadler LM: lmmunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma. N Engl J Med 325:1525, 1991 30. Negrin RS, Pesando J: Detection of tumor cells in purged bone marrow and peripheral-blood mononuclear cells by polymerase chain reaction amplification of hcl-2 translocations. J Clin Oncol 12:1021, 1994 3 I . Schiller G, Vescio R, Freytes C, Spitzer G, Sahebi F, Lee M, Wu CH, Cao J, Lee JC, Hong CH, Lichtenstein A, Lill M, Hall J , Berenson R, Berenson J: Transplantation of CD34+ peripheral blood progenitor cells after high-dose chemotherapy for patients with advanced multiple myeloma. Blood 86:390, 1995 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. 1996 88: 2801-2806 Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients RL Comenzo, E Vosburgh, RW Simms, P Bergethon, D Sarnacki, K Finn, S Dubrey, DV Faller, DG Wright, RH Falk and M Skinner Updated information and services can be found at: http://www.bloodjournal.org/content/88/7/2801.full.html Articles on similar topics can be found in the following Blood collections Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.