Hepatic response after high-dose melphalan and stem cell transplantation in patients with AL amyloidosis associated liver disease

High-dose melphalan chemotherapy and autologous peripheral blood stem cell transplantation has been shown to result in durable hematologic response and prolonged overall survival in systemic AL amyloidosis. In this retrospective study, we evaluated clinical and hematologic responses in 69 patients with predominant liver involvement who were treated with high-dose intravenous melphalan and autologous stem cell transplantation from 1998 to 2006. Nine patients (13%) died from treatment-related mortality, similar to patients without hepatic involvement. The overall survival was 81% at one year and 61% at five years, by Kaplan-Meier estimates. A hematologic complete response was achieved by 53% (31/58) of patients at one year. A hepatic response occurred in 57% (33/58) at one year after high-dose intravenous melphalan and autologous stem cell transplantation and 63% (19/30) at two years after high-dose intravenous melphalan and autologous stem cell transplantation. In conclusion, hepatic disease improves in almost 2/3 patients treated with high-dose intravenous melphalan and autologous stem cell transplantation who have a complete or partial hematologic response to treatment.     

Treatment of AL-amyloidosis and some other types of amyloidosis

Patients with AL-amyloidosis are treated at present by conventional or large-dose chemotherapy with autologous transplantation of haematopoietic stem cells, similarly as patients with multiple myeloma. Only the timing of treatment is different. In myeloma treatment is usually indicated only in clinical stage II or III, in clinical stage I only in case of adverse prognostic factors. In AL-amyloidosis treatment is indicated immediatelyafter establishment of the diagnosis. It was found that high-dose chemotherapy with autologous transpantation of haematopoietic cells is at present the most effective treatment for selected patients with not advanced forms of primary systemic AL-amyloidosis. Allogenic transplantation of the liver is treatment of choice in ATTR amyloidosis. In AA-amyloidosis the basis of treatment is removal or suppression of the chronic inflammatory process, possibly colchicin administration.     

Dramatic improvement of POEMS syndrome following autologous haematopoietic cell transplantation

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, serum monoclonal protein and skin changes) is a rare plasma cell disorder of unknown pathogenesis and is diagnosed by the demonstration of a plasma cell proliferation at the biopsy of an osteoesclerotic lesion. When the lesions are in a limited area, radiation therapy is usually highly effective. Patients with disseminated disease require systemic chemotherapy, which is not effective in most cases. A patient with severe widespread POEMS syndrome resistant to melphalan who experienced a dramatic improvement after high-dose melphalan followed by autologous haematopoietic cell transplantation (AHCT) is reported. We believe that this is the first reported case of POEMS syndrome treated with AHCT, a procedure that could be considered in similarly affected patients.     

Multiple myeloma: the number of reinfused plasma cells does not influence outcome of patients treated with intensified chemotherapy and PBPC support

Multiple myeloma (MM) is characterized by the expansion of tumor plasma cells in bone marrow (BM), but neoplastic cells have been consistently detected in peripheral blood (PB). Peripheral blood progenitor cell (PBPC) collections have been widely used to support high-dose therapy for MM patients. A flow cytometric technique has been used to detect plasma cells in PB and PBPC harvests. High CD38 expression identified these cells, and their nature was confirmed by the coexpression of specific antigens, such as CD138 and cytoplasmic immunoglobulins. Malignant plasma cell reinfusion could negatively affect response rate and survival, as demonstrated in other hematological malignancies. To address this issue, the relationship between the number of reinfused plasma cells, response to chemotherapy and event-free survival (EFS) have been analyzed. Sixty-four MM patients were treated with intensified chemotherapy at diagnosis. They were mobilized with cyclophosphamide and G-CSF, and then treated with melphalan 100 mg/m2 (MEL100) followed by PBPC support. A second course was given after 2 months, and a third to patients not in complete remission. There was no correlation between the number of reinfused plasma cells and response rate after this intensified chemotherapy: patients attaining complete remission received 3.6 x 106/kg CD38+ cells, while those with a partial or no response received 5.6 and 2.9 x 106/kg CD38+ cells. Similarly, there was no correlation between the number of reinfused plasma cells and EFS. Patients receiving less than 4.85 x 106/kg CD38+ cells experienced a median EFS of 34.2 months as opposed to 36.4 months for those receiving more than 4.85 x 106/kg CD38+ cells (P = 0.7). Recurrence of the disease is consistently observed in MM: our data suggest that in vivo residual tumor cells, rather than reinfused plasma cells are more likely to be responsible for relapse. Bone Marrow Transplantation (2000) 25, 25-29.     

VAD with or without subsequent high-dose melphalan followed by autologous stem cell support in AL amyloidosis: Japanese experience and criteria for patient selection

Patients with AL amyloidosis were treated with VAD (vincristine, doxorubicin and dexamethasone) with or without high-dose melphalan followed by auto-PBSCT according to eligibility criteria based on disease severity, and prospectively investigated the therapeutic benefits and complications. Thirty-one patients were enrolled in this study. VAD and subsequent high-dose melphalan with auto-PBSCT were performed only in patients who met all of the eligibility criteria. Among patients ineligible for this treatment, VAD alone was performed in those with satisfactory general status. Eleven patients met the eligibility criteria, and of these, 7 were treated with VAD and subsequent high-dose melphalan with auto-PBSCT. Seven patients received VAD alone, and the remaining 17 were treated with the supportive therapy. Among the 14 patients treated with chemotherapy, 9 (5 of the 7 treated with VAD and high-dose melphalan, and 4 of the 7 treated with VAD alone) showed complete hematological response with apparent improvement of amyloidosis-related clinical symptoms. Serious complications of chemotherapy were cytomegalovirus infection and pneumocystis carinii pneumonia seen in 1 and 2 patients, respectively. These chemotherapies may be effective for reduction of M-protein and are also useful in improving of amyloidosis-induced organ dysfunction. In patients who cannot tolerate high-dose melphalan, VAD alone is a potent therapeutic option, although there are possible harmful effects on the heart and peripheral nerve.     

Reduced intensity allogeneic stem cell transplantation for systemic primary amyloidosis refractory to high-dose melphalan

Complete elimination of the plasma cell dyscrasia is a rational therapeutic goal, as intercepting supply of precursor protein is a necessary condition for a major regression of amyloid deposits. High-dose melphalan with autologous stem cell transplantation has shown the ability to induce complete hematological response (HR) along with recovery of organ dysfunction. However, the rate of HR with this treatment rarely exceeds 40%. We describe here the first known case of successful reduced intensity allogeneic stem cell transplantation (RIST) for a patient with primary amyloidosis complicated with nephrotic syndrome but without cardiac disease, who had obtained only partial HR by high-dose melphalan with autologous stem cell transplantation. RIST may be feasible and be capable of achieving complete HR along with recovery from nephrotic syndrome with acceptable toxicity.     

VAD with or without subsequent high-dose melphalan followed by autologous stem cell support in AL amyloidosis: Japanese experience and criteria for patient selection.

Patients with AL amyloidosis were treated with VAD (vincristine, doxorubicin and dexamethasone) with or without high-dose melphalan followed by auto-PBSCT according to eligibility criteria based on disease severity, and prospectively investigated the therapeutic benefits and complications. Thirty-one patients were enrolled in this study. VAD and subsequent high-dose melphalan with auto-PBSCT were performed only in patients who met all of the eligibility criteria. Among patients ineligible for this treatment, VAD alone was performed in those with satisfactory general status. Eleven patients met the eligibility criteria, and of these, 7 were treated with VAD and subsequent high-dose melphalan with auto-PBSCT. Seven patients received VAD alone, and the remaining 17 were treated with the supportive therapy. Among the 14 patients treated with chemotherapy, 9 (5 of the 7 treated with VAD and high-dose melphalan, and 4 of the 7 treated with VAD alone) showed complete hematological response with apparent improvement of amyloidosis-related clinical symptoms. Serious complications of chemotherapy were cytomegalovirus infection and pneumocystis carinii pneumonia seen in 1 and 2 patients, respectively. These chemotherapies may be effective for reduction of M-protein and are also useful in improving of amyloidosis-induced organ dysfunction. In patients who cannot tolerate high-dose melphalan, VAD alone is a potent therapeutic option, although there are possible harmful effects on the heart and peripheral nerve.     

Tumor like presentation of primitive amyloidosis: amyloidoma

INTRODUCTION: AL-amyloidosis is a rare disease due to monoclonal immunoglobulin deposits, secondary to lymphoproliferative disorder or primitive. The deposits of amyloidosis have usually a systemic repartition. We report a tumor like presentation of amyloidosis, so-called amyloidoma. EXEGESIS: A 72-year old woman lost 10 kg within 6 months, associated with epigastric and mediastinal bulks. The biopsy of the abdominal mass showed AL-amyloidosis with kappa light chains. Since no secondary etiology could be found, the final diagnosis of primary AL-amyloidosis in a tumour like presentation, or amyloidoma, was performed. Investigations showed cardiac involvement with MRI findings, as well as kidney and bone marrow involvement. Oral melphalan as monotherapy was administered. The prognosis and the treatment of this unusual disease are discussed. CONCLUSION: Amyloidoma is a rare presentation of amyloidosis which should be evocated in front of a soft tissue mass with no clear etiology.     

A combination of anti-interleukin 6 murine monoclonal antibody with dexamethasone and high-dose melphalan induces high complete response rates in advanced multiple myeloma

To improve the complete response (CR) rate in advanced multiple myeloma (MM) without increasing the toxicity of high-dose therapy, we have used a new conditioning regimen. A combination of BE-8 [an anti-interleukin 6 (IL-6) murine monoclonal antibody] and dexamethasone followed by high-dose melphalan (220 mg/m2) and autologous stem cell transplantation was used to treat a series of 16 patients with advanced multiple myeloma. A strong inhibition of IL-6 activity evaluated by quantification of C-reactive protein was observed in all patients and was correlated with the high CR rate achieved with this combination therapy.     

IgM AL amyloidosis due to B cell lymphoproliferative disorder: efficacy of high-dose melphalan followed by autologous stem cell transplantation.

This report concerns a patient with IgM AL amyloidosis due to a B cell lymphoproliferative disorder who was successfully treated with VAD and subsequent high-dose melphalan followed by autologous stem cell support. After this chemotherapeutic regimen, the patient showed complete hematological remission and improvement in nephrotic syndrome. These findings suggest that high-dose melphalan may also be effective for lymphoplasmacytoid cells producing monoclonal IgM which are phenotypically distinct from plasma cells. Myeloablative therapies, such as high-dose melphalan, should definitely be considered as a treatment option for AL amyloidosis, irrespective of the type of precursor immunoglobulin.     

What is the role of giant cells in AL-amyloidosis?

AL-amyloidosis is one of the most common amyloidoses and can be found in a localized and a systemic form. The precursor protein is an immunoglobulin light chain which as AL-protein in both localized and systemic AL-amyloidosis shows the same pattern of fragmentation and changes of primary structure. In this work it is shown that that there is a difference between localized and systemic amyloidosis in respect to accompanying giant cells which constantly are found associated with amyloid deposits in localized AL-amyloidosis. In addition, giant cells were found together with amyloid deposits in lymph nodes of some cases of systemic AL-amyloidosis. Based on these findings and electron microscopic studies, it is discussed whether the giant cells actively participate in amyloid fibril formation by uptake and modification of the precursor protein or the giant cells are part of a foreign body reaction. Included in this work are two new cases of localized lung (lambda I) and ureteric (kappa I) AL-amyloidosis.     

IgM AL amyloidosis due to B cell lymphoproliferative disorder: efficacy of high-dose melphalan followed by autologous stem cell transplantation

This report concerns a patient with IgM AL amyloidosis due to a B cell lymphoproliferative disorder who was successfully treated with VAD and subsequent high-dose melphalan followed by autologous stem cell support. After this chemotherapeutic regimen, the patient showed complete hematological remission and improvement in nephrotic syndrome. These findings suggest that high-dose melphalan may also be effective for lymphoplasmacytoid cells producing monoclonal IgM which are phenotypically distinct from plasma cells. Myeloablative therapies, such as high-dose melphalan, should definitely be considered as a treatment option for AL amyloidosis, irrespective of the type of precursor immunoglobulin.     

Acquired factor X deficiency in patients with amyloid light-chain amyloidosis: incidence, bleeding manifestations, and response to high-dose chemotherapy

Acquired deficiency of factor X occurs in patients with systemic amyloid light-chain (AL) amyloidosis, presumably due to adsorption of factor X to amyloid fibrils. Of 368 consecutive patients with systemic AL amyloidosis evaluated at Boston Medical Center, 32 patients (8.7%) had factor X levels below 50% of normal. Eighteen of these patients (56%) had bleeding complications, which were more frequent and severe in the 12 patients below 25% of normal; 2 episodes were fatal. Ten factor X-deficient patients received high-dose melphalan chemotherapy followed by autologous stem cell transplantation. Of 7 patients alive 1 year after treatment, 4 had a complete hematologic response, and all 4 experienced improvement in their factor X levels. One of 2 additional patients with partial hematologic responses had improvement in factor X. Thus, aggressive treatment of the underlying plasma cell dyscrasia in AL amyloidosis can lead to the amelioration of amyloid-related factor X deficiency.     

52-j?hriger Patient mit schwerer Herzinsuffizienz bei multiplem Myelom

Cardiac amyloidosis represents a prognostically relevant comorbidity in multiple myeloma. We report the case of a patient in whom severe heart failure symptoms as a consequence of cardiac AL-amyloidosis resolved after tandem high-dose melphalan therapy followed by autologous blood-stem cell transplantation. Partial regression of cardiac amyloid deposits and improvement of cardiac function were objectified.     

Scleromyxedema: role of high-dose melphalan with autologous stem cell transplantation

Scleromyxedema, the most severe manifestation of the spectrum of lichen myxedematosus, is characterized by cutaneous mucinosis, extracutaneous manifestations, and a monoclonal gammopathy. Seven of 8 patients evaluated at our center were treated with high-dose melphalan (180 mg/m(2) intravenously) and autologous peripheral blood stem cell transplantation, with marked improvement of gastrointestinal, central nervous system, pulmonary manifestations, and Karnofsky performance status. Five patients obtained a cutaneous complete remission and 2 patients had partial remissions. Three patients with slight progression in the skin at 12, 8, and 4 months after treatment received a second cycle of high-dose melphalan and had further symptomatic improvement. The lichen myxedematosus-scleromyxedema spectrum appears to be a continuum that requires the presence of a serum paraprotein and differs in severity of skin lesions, extracutaneous manifestations, and performance status. High-dose melphalan followed by autologous transplantation appears effective for improving the symptoms and systemic manifestations of scleromyxedema.     

Primary systemic amyloidosis presenting as polymyalgia rheumatica and giant cell arteritis

Primary systemic amyloidosis or AL-amyloidosis is an uncommon disease characterized by the accumulation in vital organs of a fibrillar protein consisting of monoclonal light chains. It is a plasma-cell dyscrasia related to multiple myeloma where clonal plasma cells in the bone marrow produce immunoglobulins that are amyloidogenic. A monoclonal component is present in the serum or urine of 90% of patients. The presentation of most patients with AL amyloidosis is usually related to congestive heart failure, nephrotic syndrome o peripheral neuropathy, but there are unusual features suggesting giant cell arteritis (GCA) and polymyalgia rheumatic (PMR). Although in the majority of AL cases the plasma cells clone is small, the assumption is that the outcome of the disease is uniformly fatal (median survival 12-15 months) and treatment is analogous to those used in malignant proliferative disease. We describe a patient with AL amyloidosis who presented with manifestations of GCA and PMR, and we review the main characteristics of primary amyloidosis.     

Monoclonal antibody-purged autologous bone marrow transplantation therapy for multiple myeloma

Eleven patients with plasma cell dyscrasias underwent high-dose chemoradiotherapy and anti-B-cell monoclonal antibody (MoAb)-treated autologous bone marrow transplantation (ABMT). The majority of patients had advanced Durie-Salmon stage myeloma at diagnosis, all were pretreated with chemotherapy, and six had received prior radiotherapy. At the time of ABMT, all patients demonstrated good performance status with Karnofsky score of 80% or greater and had less than 10% marrow tumor cells. Eight patients had residual monoclonal marrow plasma cells and 10 patients had paraprotein. Following high-dose melphalan and total body irradiation (TBI) there were seven complete responses, three partial responses, and one toxic death. Granulocytes greater than 500/mm3 were noted at a median of 21 (range 12 to 46) days posttransplant (PT) and untransfused platelets greater than 20,000/mm3 were noted at a median of 23 (12 to 53) days PT in 10 of the 11 patients. Natural killer cells and cytotoxic/suppressor T cells predominated early PT, with return of B cells at 3 months PT and normalization of T4:T8 ratio at 1 year PT. Less than 5% polyclonal marrow plasma cells were noted in all patients after transplant. Three of the seven complete responders have had return of paraprotein, two with myeloma, and have subsequently responded to alpha 2 interferon therapy. Eight patients are alive at 18.9 (8.9 to 43.1) months PT and four remain disease-free at 12.3, 17.5, 18.9, and 29 months PT. This preliminary study confirms that high-dose melphalan and TBI can achieve high response rates without unexpected toxicity in patients who have sensitive disease, and that MoAb-based purging techniques do not inhibit engraftment. Although the follow-up is short- and long-term outcome to be determined, relapses post-ABMT in these heavily pretreated patients suggest that ABMT or alternative treatment strategies should be evaluated earlier in the disease course.     

AL amyloidosis manifesting as systemic lymphadenopathy

We report three patients with AL amyloidosis manifesting as systemic lymphadenopathy, mainly in the cervical and supraclavicular regions. Histopathology of lymph nodes showed massive deposition of AL amyloid with no abnormal findings suggestive of lymphoproliferative disorders. Two of the patients were considered to be classifiable as primary systemic AL amyloidosis based on the presence of M-protein in serum and abnormal plasma cells or lymphoplasmacytoid cells in the bone marrow probably producing the precursor immunoglobulin, although no visceral organs were affected. The size of the involved lymph nodes in these two patients increased gradually, and one was treated with rituximab and VAD (vincristine, doxorubicin and dexamethasone) followed by high-dose melphalan with autologous peripheral blood stem cell transplantation (auto-PBSCT). The remaining patient showed no obvious change in the size of lymph nodes or detectable M-protein in serum. The prognosis of AL amyloidosis manifesting as lymphadenopathy is usually good as long as there are no hematological malignancies or rapid increases in the size of lymph nodes, but in cases of the systemic type, intensive chemotherapy, such as high-dose melphalan with auto-PBSCT, should be actively considered in order to avoid possible involvement of visceral organs.     

The Arkansas approach to therapy of patients with multiple myeloma

This chapter gives an account of the experience of the Arkansas myeloma program since 1989 with transplant-supported high-dose melphalan, novel agents, and prognostic factors as they relate to standard laboratory features, gene expression profiling, and magnetic resonance imaging (MRI). Incorporation of novel agents and new concepts, such as post-tandem transplant consolidation therapy, has improved the rate and duration of complete response and prolonged event-free and overall survival rates. With Total Therapy 2, median survival exceeds 8 years, while Total Therapy 3 with added bortezomib has sustained complete remissions in more than 90% of patients at 2 years which, when used as a survival surrogate in Total Therapy 2, assured a high 6-year survival rate of 75%. Gene expression profiling identified 15% of patients with very short survival. MRI-defined focal lesions are associated with poor outcome, while their resolution - although slower than the time course of attaining clinical complete remission - conferred superior survival. Representing a frequent source of recurrence, with genetic profiles (in both plasma and stromal cells) distinct from those in random bone-marrow samples, therapeutic efforts are directed at hastening onset and increasing frequency of focal lesion resolution.