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High-dose melphalan with autologous stem cell transplantation after VAD induction chemotherapy for treatment of amyloid light chain amyloidosis: a single centre prospective phase II study

Jolanta B. Perz,1 Stefan O. Schonland,1 Michael Hundemer,1 Arnt V. Kristen,2 Thomas J. Dengler,2 Martin Zeier,3 Reinhold P. Linke,4 Anthony D. Ho1 and Hartmut Goldschmidt1 Departments of 1Haematology/Oncology, 2

Cardiology and 3Nephrology, Clinic of Internal

Medicine, University of Heidelberg, Heidelberg, Germany, and 4Max-Planck Institute of Biochemistry, Martinsried/Munich, Germany

Received 25 June 2004; accepted for publication 4 September 2004 Correspondence: Jolanta Perz, MD, Department of Internal Medicine/Haematology, University of Heidelberg, INF 410, 69120 Heidelberg,

Summary Amyloid light chain (AL) amyloidosis is the result of a clonal plasma cell expansion, in which monoclonal light chains transform to amyloid deposit in various tissues and can lead to organ dysfunction and organ failure. The median survival of patients with AL amyloidosis without therapy is 10–14 months. With high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT), haematological and clinical remission rates of up to 50% of treated patients have been reported from phase II studies. HDM followed by ASCT appears to prolong survival in patients, if haematological remission can be reached. In this phase II study, we evaluated vincristine, adriamycin and dexamethasone (VAD) as induction chemotherapy prior to stem cell mobilization and HDM with ASCT. The regimen was, in general, feasible in patients with AL amyloidosis, but VAD chemotherapy had a considerable World Health Organization (WHO) grade III–IV toxicity (25%) and mortality (7%) rate. VAD pretreatment did not interfere with stem cell mobilization and HDM with ASCT was possible in 86% of patients. The overall treatment efficacy was comparable with reported results of HDM and ASCT without preceding chemotherapy. We could not show an additional benefit of VAD induction in terms of increasing haematological response rate; however the 13% mortality rate after HDM and ASCT in our series was lower than the previous report.

Germany. E-mail: [email protected], [email protected]

Keywords: light chain amyloidosis, autologous stem cell transplantation, high-dose melphalan, vincristine, adriamycin and dexamethasone (VAD).

Amyloid light chain (AL) amyloidosis is a result of clonal plasma cell disorder with an incidence rate of 5–13 persons per million per year (Kyle et al, 1992). AL amyloidosis is known to be the most common and the most severe form of systemic amyloidosis. The fibrillar protein deposits derived from monoclonal light chains are produced by the pathological plasma cell clone. After alteration and polymerization these fibrils accumulate as amyloid in tissues such as kidney, heart, gut, liver, peripheral nervous system and lead to organ dysfunction and organ failure (Falk et al, 1997). The median survival of patients with this lethal disease is 10–14 months

from diagnosis without therapy (Kyle et al, 1999). Patients with dominant heart manifestation have even lower survival rates of 12 mm on ECHO in the absence of a history of hypertension or valvular heart disease and/or in the presence of unexplained low voltage (500 mg/d or elevated serum creatinine >170 lmol/l in the absence of other causes of renal disease. Gastrointestinal involvement was indicated by involuntary body weight loss of at least 10%, nausea or diarrhoea unexplained by other gastrointestinal disorders and confirmed by intestinal biopsy. Liver involvement was indicated by hepatomegaly >4 cm below the right costal margin on physical examination or alkaline phosphatase (AP) greater than twice the normal value. Neurological syndromes included symptoms or signs of peripheral sensory neuropathy, motor neuropathy or autonomic neuropathy associated with orthostatic hypotension. Performance status was independently assessed according to WHO criteria by at least two clinicians.

Study design and treatment plan Patients were treated with two to five cycles of VAD chemotherapy in a standard dosing schedule as previously described (Barlogie et al, 1984). Therapy cycles were repeated every 28 d. To avoid the toxic effect of vincristine, adriamycin and dexamethasone chemotherapy (AD) was administered to patients with clinical evidence of neuropathy. The response to therapy was evaluated after the last VAD cycle. For stem cell mobilization, three different regimens: ifosfamide, cyclophosphamide or cyclophosphamide, adriamycin and dexamethasone (CAD) were used starting 4–6 weeks

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VAD Followed by HDM for Treatment of AL Amyloidosis after the last VAD cycle. At the beginning of our study, cyclophosphamide at the dose of 4 g/m2 was considered as the mobilizing regimen of choice for patients without cardiac involvement. In patients with cardiac amyloidosis, ifosfamide (12 g/m2) was given as mobilizing regimen in order to avoid arrhythmias and sudden cardiac death from cyclophosphamide. Because of the severe complications of ifosfamide chemotherapy reported below, the stem cell mobilization procedure was switched to a regimen with cyclophosphamide (1 g/m2), adriamycin and dexamethasone (CAD) for patients with or without cardiac amyloidosis. A protocol amendment concerning the mobilization regimen was approved by the local ethical committee of the University of Heidelberg. Stem cells were mobilized by granulocyte colony-stimulating factor (G-CSF; lenograstim; Chugai Pharma, Frankfurt am Main Germany), at 5 lg/kg, twice a day from day 6 after mobilization chemotherapy until leukaphereses were completed. A minimum collection of 2Æ0 · 106 CD34+ cells/kg body weight (bw) was required to proceed with HDM. Stem cells were stored in dimethyl sulphoxide (DMSO) at )70C. Patients received intravenous HDM at a dose of 200 mg/m2 or at an adjusted dose in case of renal functional impairment depending on creatinine clearance (140 mg/m2, if it was 30– 80 ml/min and 100 mg/m2, if it was below 30 ml/min and in case of haemodialysis) and patients with cardiac functional impairment depending on ejection function, as estimated by ECHO and NYHA classification (140 mg/m2, if it was NYHA II and 100 mg/m2, if it was NYHA III). Autologous stem cells were infused 48 h after the HDM infusion.

Treatment response and outcome evaluation The primary outcome measured was survival after therapy and was assessed for all patients. Patients were assessed for therapy toxicity, for haematological and clinical response after VAD, after stem cell mobilization, 1 month after HDM, at 3, 6 and 12 months after HDM and annually thereafter. At each evaluation, clinical examination, laboratory testing of serum and urine including 24-h urine collection for electrophoresis and immunoelectrophoresis, ECG, ECHO, abdominal ultrasound and bone marrow aspiration were performed.

Haematological and clinical response criteria Complete haematological response (CR) determined at 1 year of follow-up, required that there was no evidence of persistent plasma cell disease in the bone marrow containing 25% reduction of creatinine clearance. Liver involvement response was defined as a >50% reduction of serum AP or reduction of liver size by at least 2 cm in abdominal ultrasound.

Statistical analysis The survival of patients from diagnosis was estimated by Kaplan–Meier analysis and depicted by Kaplan–Meier survival plots. Patient groups were compared by log-rank test and P-values reflected two-sided test results. P < 0Æ05 were defined as statistically significant. Cox regression analysis was performed to assess the impact on survival of age, number of involved organs, type of predominant organ involvement, initial NYHA class, initial renal function, number of VAD cycles, type of stem cell mobilizing chemotherapy, time from diagnosis to HDM and received melphalan dose.

Results Patients characteristics Twenty-eight patients with light chain amyloidosis were treated in this study. The median age at diagnosis was 54 years (range 34–65). There were nine female and 19 male patients in our series. The clonal light chain subtype, classified by immunohistochemical staining, was k in 22 patients and j in six patients. Twenty-five patients had detectable systemic plasma cell disease, whereas in three patients no evidence of plasma cell disease was found in serum and urine, which had consequences for response evaluation. Multiple myeloma stage IA was diagnosed in six patients and multiple myeloma stage IIIA in two patients. Of the remaining 20 patients, monoclonal gammopathy of unknown significance was found in 17, whereas three patients showed no evidence of plasma cell disease in the serum or urine and bone marrow. In each patient, a dominant organ system affected by amyloidosis led to organ dysfunction and caused the clinical disorder. Dominant renal manifestation was the most common in 13 patients (46%) and dominant cardiac manifestation was seen in five patients. Fifteen patients (54%) had more than two organ systems involved, reflecting the extensive disease in the majority of our patients. (For further details, see Table I.)

Treatment preceding HDM and ASCT Three patients received melphalan pretreatment prior to the study therapy: two of them were treated with two cycles (total

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J. B. Perz et al Table I. Patients characteristics and treatment summary.

Number of Dominant Age (years) organs organ

Plasma cell disease

Mobilizing ASCT chemotherapy

48 55 60 56 56 60 64 65 38 39 59 59 58 46 53 58 49 47 60 34 55 45 46 51 64 46 49 58

MG MM IA None None MM IA MM IIIA MM IA MM IA MG MG MM IA MG MG MG MM IIIA MG MM IA MG MG MG MG MG MG MG MG None MG MG

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes No No Yes Yes Yes No Yes

3 2 1 3 1 3 4 2 3 3 5 1 3 4 3 4 2 1 4 2 1 4 2 3 2 1 3 2

Renal Renal Gut/liver Gut/liver Renal Soft tissue Cardiac Renal Cardiac Renal Soft tissue Renal Cardiac Renal Gut/liver Gut/liver Gut/liver Renal Renal Renal Cardiac Renal Renal Soft tissue Renal Gut/liver Cardiac Neuropathy

Serum Survival CD34+ Melphalan CD34+ creatinine from collection at transplant dose transplanted HDM Adverse (·106/kg bw) (lmol/l) (mg/m2) (106/kg bw) (months) events

Ifosfamide Ifosfamide Cyclophosphamide Ifosfamide Ifosfamide Ifosfamide Ifosfamide Cyclophosphamide Ifosfamide Ifosfamide Ifosfamide Cyclophosphamide

26Æ9 20 28 19Æ1 5Æ3 33Æ2 11 31Æ9 7Æ3 27Æ8 16 23Æ5

70Æ7 99Æ9 79Æ6 91Æ9 111Æ4 106Æ1 59Æ2 81Æ3 144Æ9 113Æ1 78Æ7 537Æ5

100 200 200 200 200 200 200 200 140 200 200 100

10Æ5 4Æ8 14 9Æ55 2Æ7 16Æ6 5Æ5 10Æ6 3Æ2 13Æ9 8 11Æ7

70 68 48 44 45 43 42 0Æ3 8 36 36 33

Cyclophosphamide Ifosfamide Ifosfamide Ifosfamide CAD Ifosfamide CAD CAD

5Æ3 15Æ7 6Æ9 23Æ8 36Æ8 45Æ5 8Æ7 13Æ1

426Æ1 107Æ8 295Æ3 139Æ7 104Æ3 545Æ4 59Æ2 122Æ9

100 200 140 200 200 100 200 140

2Æ7 7Æ85 3Æ45 7Æ93 18Æ4 45Æ5 2Æ9 6Æ55

33 0Æ3 1Æ5 31 31 30 29 27

Dead Dead

Dead Dead Dead

Dead Dead CAD CAD CAD

7Æ5 9Æ3 16Æ7

62Æ8 368Æ6 66Æ3

200 100 200

3Æ75 4Æ65 8Æ35

24 23 18

CAD

17Æ3

80Æ4

100

8Æ65

16

Dead

ASCT, autologous stem cell transplant; HDM, high-dose melphalan; MG, monoclonal gammopathy; MM, multiple myeloma; CAD, cyclophosphamide, adriamycin, dexamethasone.

melphalan dose of 16 mg/m2) and one patient with three cycles (total melphalan dose of 24 mg/m2) of oral melphalan and prednisolone. All other patients did not receive treatment before study inclusion. The median number of VAD cycles administered was 3 (range 1–5). Of the 28 included patients, 24 (86%) were eligible for HDM therapy after VAD induction and received stem cell mobilization regimens as follows: four patients cyclophosphamide, 13 patients ifosfamide and seven patients CAD. The median number of 17Æ0 · 106/kg bw (range 5Æ3–45Æ5 · 106/kg bw) CD34+ cells has been collected in 1–4 leukaphereses. A single leukapheresis procedure was sufficient in 18 patients (75%). (For further details, see Table I.)

HDM and ASCT The median interval from diagnosis to HDM and ASCT was 9 months (range, 4–16 months). Fifteen patients (62%) 546

received 200 mg/m2 melphalan preceding ASCT. The melphalan dose was adjusted to 140 mg/m2 in three patients and to 100 mg/m2 in six patients (three of them on haemodialysis). The median number of 7Æ96 · 106 CD34+ peripheral blood stem cells/kg bw was infused (range 2Æ7–45Æ5 · 106 CD34+ cells/ kg bw). An autologous stem cell back up was harvested in 23 of 24 patients for the eventuality of future relapse therapy. (For further details, see Table I.)

Treatment related mortality and toxicity VAD chemotherapy. Two of 28 patients (7%) succumbed within 10 d after the first VAD cycle. The causes of death were sepsis in severe neutropenia with multi-organ failure and sudden cardiac death after fluid retention. Both patients suffered from extensive light chain amyloidosis with more than two involved organs. WHO grade III–IV gastrointestinal toxicity was seen in two patients: one patient required intravenous nutrition and one patient

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VAD Followed by HDM for Treatment of AL Amyloidosis required abdominal surgery because of acute ileum perforation. WHO grade III infectious complications because of WHO grade III neutropenia were observed in two patients. In one patient with nephrotic syndrome, venous thrombosis and consecutive embolism appeared as a WHO grade IV thrombotic complication. In general, a high rate of WHO grade III–IV toxicity was seen in seven of 28 treated patients (25%). Stem cell mobilizing chemotherapy and leukapheresis. The main complication of stem cell mobilization was the WHO grade III–IV neurotoxicity after ifosfamide chemotherapy seen in eight of 13 patients (61%) and grand malseizures in one patient. The encephalopathy appeared within 3 d after start of ifosfamide infusion in patients who suffered from nephrotic syndrome and had a low serum albumin level and resolved after methylene blue infusion. Thus ifosfamide was not considered as an appropriate chemotherapy for patients with nephrotic syndrome and low serum albumin. However, the neurological symptoms were reversible in each case. Infectious complications WHO grade III–IV were seen in four of 24 patients after stem cell mobilization, independently of the regimen. Renal WHO grade III–IV toxicity appeared in two patients (one after ifosfamide, one after cyclophosphamide) and led to haemodialysis. The toxicity of cyclophosphamide mobilization therapy was low when compared with that of ifosamide. After the CAD regimen, which was administered to five patients, no grade III–IV toxicity was seen. In general, WHO grade III–IV complications were seen in 14 of 24 patients (58%), but no deaths and no further severe adverse events were observed after stem cell mobilizing chemotherapy and during stem cell collection. HDM and ASCT. Three patients died during the first 50 d after HDM and ASCT. Causes of death were cerebral bleeding on day +10, septic shock in neutropenia on day +10 and profound intestinal bleedings on day +48. Gastrointestinal toxicity WHO grade III–IV was observed in 22 patients (92%). Parenteral nutrition was required in 18 patients; five patients were treated this way for more than 10 d. Infectious complications were seen in 19 patients: one patient, WHO grade IV (death in septic shock); eight patients, WHO grade III (37% grade III–IV toxicity); 10 patients, WHO grade II. Granulocyte reconstitution (>0Æ5 · 109/l) was reached after a median of 11 d (range 5–18 d) and the time to platelet reconstitution (>50 · 109/l) was 7 d (range 0–15 d). The median number of transfused packed red cells units was 7 (range 0–9 units) and the median number of transfused platelet concentrate units was 2 (range 0–10 units). In patients with a risk of intestinal bleeding, platelets were transfused to maintain the platelet count above 50 · 109/l. Nephrotoxicity grade I–III was seen in four patients, one of whom became haemodialysis dependent after HDM treatment. Severe complications,

such as arrhythmia or cardiac arrest, which have been previously reported as complications of DMSOcryopreserved stem cell infusion (Zenhausern et al, 2000; Comezo & Gertz, 2002), were not observed.

Treatment response Survival. The median follow-up after HDM and ASCT was 31 months (range 0Æ3–70 months). The 1-year survival from diagnosis was 75% and the 3-year survival was 71% (see Fig 1). We found a trend to worse survival for patients with cardiac involvement and patients with more than two organ systems involved; however these results are not significant in our cohorts (see Figs 2 and 3). Twenty-one of 24 patients (87%) survived at least 3 months after HDM. One patient, in whom the plasma cell disease was refractory to treatment, died 8 months after HDM because of progressive cardiac involvement with recurrent arrhythmia and heart failure. Twenty patients (71% of the patients that were initially included and 83% of HDM-treated patients) are still alive. The

Fig 1. Overall survival time from diagnosis in months: 1-year survival 75%, 3-year survival 71%.

Fig 2. Survival time from diagnosis in months: 1–2 organ versus >2 organs.

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J. B. Perz et al improvement or stabilization of organ function was seen. In three patients (12%), the plasma cell disease was stable 1 year after HDM and ASCT and it had progressed in five (21%). In one patient, the disease progression led to deterioration of organ function and death, 8 months after therapy. Three patients with progressive plasma cell disease had stable organ function 1 year after therapy. Finally, in one patient, who achieved a complete haematological remission HDM, the plasma cell disease recurred 48 months after therapy without evidence of organ dysfunction and a second HDM therapy with stem cell support was performed successfully (see also Table II).

Fig 3. Survival time from diagnosis in months according to the dominantly affected organ.

median follow-up from diagnosis was 39 months (range 1–81 months). The overall therapy-related mortality was 18% (five of 28 patients), whereas the HDM-related mortality was 13% (three of 24 patients). All the five patients who died from treatment complications had a high-mortality risk at the start of therapy: four patients were diagnosed with extensive amyloidosis with more than two organs, one patient with isolated renal amyloidosis was 65 years old. The time from diagnosis to the start of treatment was the only significant predictor for survival in the Cox regression analysis, all other assessed parameters had no impact. Haematological response of plasma cell disease. After VAD chemotherapy of 28 patients, three complete remissions and one partial remission were observed. However, the systemic plasma cell disease was detectable for response assessment in serum or urine only in 25 patients. The haematological remission rate after VAD induction chemotherapy was therefore at least 14% (four of 28 patients) but 16% in the group of 25 patients with detectable plasma cell disease. In 20 patients, stabilization of plasma cell disease could be achieved by VAD induction chemotherapy, whereas two patients were not considered to be eligible for HDM because of plasma cell disease progression and poor clinical status, despite VAD chemotherapy (for further details, see Table II). After HDM with stem cell support, a remission rate of 54% was observed: of 24 patients, 11 complete remissions and two partial remissions. In all patients with a plasma cell response,

n

Clinical response of renal function in the subgroup of patients with nephrotic syndrome. More than 50% of the included patients (16 of 28) suffered from nephrotic syndrome with a urine protein excretion of more than 3000 mg/d at the time of diagnosis. Of these 16 patients with nephrotic syndrome, nine had a normal renal function with serum creatinine lower than 130 lmol/l and seven had a serum creatinine higher than 130 lmol/l. Two patients were initially on haemodialysis. In the subgroup of patients with nephrotic syndrome, a remission rate of 50% was achieved after ASCT: six complete remissions and two partial remissions. In five of six patients with complete haematological remission (31% of the whole group of patients with nephrotic syndrome), a clinical remission of nephrotic syndrome with a decline of urine protein excretion to lower than 3000 mg/d was observed. All patients with haematological and clinical remissions initially had serum creatinine lower than 130 lmol/l. In the group of patients with serum creatinine higher than 130 lmol/l at the start of treatment, three became haemodialysis dependent and three died as a result of treatment complications or disease progression. Patients with an initially impaired renal function are therefore at high risk of severe treatment complications after VAD and HDM with stem cell transplantation. On the contrary, one patient on haemodialysis at the start of treatment achieved stable disease and benefitted from treatment in terms of performance status 1 year after therapy.

Discussion Untreated systemic AL amyloidosis is, in almost all cases, a progressive and fatal disease (Kyle et al, 1992). Long-term survival has only rarely been observed after conventional chemotherapy. HDM combined with stem cell support is used

Death because Complete Partial Stable Progression of progressive Treatment disease deaths remission remission disease and alive

VAD 28 3/28 HDM 24 11/24

1/28 2/24

20/28 3/24

4/24

2/28 1/24

Table II. Response evaluation of plasma cell disease after VAD and at 1 year after HDM.

2/28 3/24

VAD, vincristine, adriamycin and dexamethasone; HDM, high-dose melphalan.

548

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VAD Followed by HDM for Treatment of AL Amyloidosis widely after it was reported to be feasible in the treatment of patients with light chain amyloidosis (Comenzo et al, 1998; Gillmore et al, 1999). HDM chemotherapy is able to suppress the underlying monoclonal plasma cell disease. Several reports (Sanchorawala et al, 2004) have suggested the superiority of HDM to cyclic oral standard-dose melphalan and prednisone for the therapy of AL amyloidosis. The procedure-related mortality is high, 15–40% (Gertz et al, 2000; Skinner et al, 2004), and the symptomatic improvement and functional recovery of organ functions are usually slow. Nevertheless, nearly 50% of patients achieve haematological remission from their disease (Comenzo et al, 1998; Comezo & Gertz, 2002). Until now, HDM chemotherapy has not been compared with conventional regimens in a randomized controlled clinical trial. Dispenzieri et al (2004) performed a retrospective matched-pair analysis of patients treated with low-dose cyclic melphalan/prednisone chemotherapy and patients treated with HDM. They demonstrated a significantly better survival rate for the group of patients treated with HDM chemotherapy (Dispenzieri et al, 2004). The use of additional induction chemotherapy prior to HDM has been evaluated in a few studies to date (Sezer et al, 1999; van Gameren et al, 2002; Gono et al, 2003). New regimens, including induction chemotherapy prior to HDM need to be tested in order to assess whether the results of this regimen can be improved in terms of toxicity and efficacy. But results on toxicity and efficacy of sequential therapy procedures containing induction chemotherapy and HDM are limited. The impact of two cycles of melphalan and prednisolone chemotherapy prior to HDM has been investigated in a recent prospective randomized study (Sanchorawala et al, 2004). The result indicate that previously untreated patients with AL amyloidosis have no additional benefit from the treatment with oral chemotherapy prior to HDM with respect to survival, haematological response and likelihood of clinical improvement. The authors suggest that patients with cardiac involvement even suffer a survival disadvantage if HDM is delayed by initial treatment with oral chemotherapy. Thirteen per cent of the reported patients, treated with an initial oral chemotherapy, could not proceed to HDM because of clinical deterioration that led to death. On the contrary, Dispenzieri et al (2001) argued that the eligibility for HDM with ASCT per se was a prognostic parameter for survival. Vincristine, adriamycin and dexamethasone is well known to be effective in multiple myeloma (Barlogie et al, 1984) and has been reported to be feasible and effective in patients with AL amyloidosis (Sezer et al, 1999; van Gameren et al, 2002; Gono et al, 2003). High-dose dexamethasone, which is probably the most effective part of this combination chemotherapy has been evaluated in combination with low-dose melphalan (Palladini et al, 2001, 2004). With conventional melphalan and high-dose dexamethasone, more than 63% of patients not eligible for high-dose chemotherapy showed a response in plasma cell disease compared with a 30% remission rate after conventional melphalan and prednisolone therapy. The therapy

schedule with conventional melphalan and high-dose dexamethasone seems to be very promising for patients with light chain amyloidosis. Mehta (2004) recently pointed out that, until now, the role of pretreatment induction and, especially the role of high-dose dexamethasone has not been determined in the setting of HDM and ASCT. In this study we investigated the impact of VAD pretreatment induction on outcome of HDM followed by ASCT in, to our knowledge, the biggest collective of AL amyloidosis patients to date. In general, we found that HDM with autologous stem cell support after VAD induction was feasible in patients with light chain amyloidosis; however VAD had a significant toxicity and mortality in our cohort (7%). Of the VAD-treated patients, 86% proceeded to HDM. The mortality after HDM was 14% in our cohort, which was comparable with the mortality rates of 15% previously reported (Comezo & Gertz, 2002; Skinner et al, 2004). In our view, the 7% mortality rate after VAD was acceptable if one takes into account the bad prognosis of AL amyloidosis patients, especially those patients with more than two affected organs (54% of our series). The reported toxicity and mortality rates underline the bad prognosis of patients with multiple organ involvement, who are not only a high-risk group for complications after HDM with stem cell transplantation but even after VAD chemotherapy. The therapy should be performed only in centres with comprehensive experience in the treatment of patients with amyloidosis and experience of ASCT. As a result of the infectious complications, the prophylactic use of antibiotics seems to be essential for the treatment of patients with AL amyloidosis either with cyclic VAD chemotherapy or HDM. Vincristine, adriamycin and dexamethasone chemotherapy did not seem to interfere with stem cell mobilization and stem cell collection. In all 24 patients, a sufficient number of CD34+ stem cells for two autologous transplantations could be collected. Thus, patients with AL amyloidosis who have received VAD chemotherapy can undergo stem cell mobilization and collection if they meet the eligibility criteria. On the contrary, the plasma cell clearance before stem cell apheresis may play a role on the outcome of HDM and ASCT (Perfetti et al, 1998). Our cohort achieved a CR rate of 10% (12% of 25 patients with detectable plasma cell disease) after VAD chemotherapy. While the outcome rates after HDM are promising, future studies should focus on limiting treatment-related toxicity and improving the haematological remission rate and survival after therapy. Strategies including the use of induction chemotherapy prior to stem cell mobilization may contribute this field. There are indications that high-dose dexamethasone-based regimens can increase the haematological response rate and survival in patients with AL amyloidosis (Palladini et al, 2001, 2004). Among 28 patients, an overall haematological remission rate of 54% was reached after the combination regimen of VAD and HDM with stem cell support. After VAD alone, 14% (16% of patients with detectable plasma cell disease) of

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J. B. Perz et al patients obtained a haematological remission. In our view, the overall survival of 72% after a median follow-up of 39 months and the haematological remission rate indicate a therapy benefit of the sequential treatment regimen. Fifty per cent of the patients in the nephrotic syndrome subgroup achieved haematological remission and 31% of them showed clinical remission of the nephrotic syndrome. Clinical remission of organ manifestation is possible in patients with AL amyloidosis. In the case of two patients with nephrotic syndrome, amyloid deposits still persisted in histological tissue reexamination (Zeier et al, 2003), even when organ disease remission was evident. The only parameter with prognostic impact on survival was the longer time from diagnosis to the start of treatment. None of the other assessed parameters had a prognostic impact on survival. The longer time between diagnosis and the start of treatment probably indicates the impact of eligibility for HDM. Dispenzieri et al (2001) argued that the eligibility for HDM with ASCT per se was a prognostic parameter for survival. On the contrary, the results from other groups indicate that the delay in HDM with ASCT has a negative impact on survival (Moreau et al, 1998). The question of the optimal timing for HDM therapy, especially the question of induction therapy integration to the treatment regimen remains unclear and needs to be addressed further. In conclusion, our study demonstrates the utility of the regimen combining VAD and HDM with stem cell transplantation in patients with AL amyloidosis. In this phase II study, additional VAD chemotherapy did not increase the haematological and clinical remission rate compared with the results of treatment studies with HDM and ASCT without induction chemotherapy. Mortality and response rates reported here seem to be comparable with previously reported data on HDM and ASCT without induction chemotherapy. Thus, a randomized phase III study could possibly elucidate the role of induction therapy prior to HDM. New treatment strategies have to be sought to improve the results of HDM therapy (Mehta, 2004). Because of the high-toxicity rate, regimens combining high-dose dexamethasone-based induction therapy with HDM and ASCT should only be used in clinical trials. Randomized phase III studies are necessary to elucidate the role of the induction chemotherapy prior to HDM and new treatment strategies have to be sought to improve the results of treatment in AL amyloidosis.

Acknowledgements We thank Marc Raab, Iris Breitkreuz, Mathias Witzens, Frauke Bellos, Eike Buss and Gerlinde Egerer from the Department of Haematology at the University in Heidelberg for the care of patients and R. Oos, J. Lindermeyer and M. Bandmann from Max-Planck Institute for Biochemistry in Martinsried/Munich for technical assistance. Cytonet A.G. Heidelberg undertook stem cell leukapheresis, stem cell preparation and storage. 550

The work was supported by a grant from Chugai Pharma Germany and the Deutsche Forschungsgemeinschaft Bonn/ Germany (Li 247, 12-3). Preliminary results of this study were presented at the Annual Meeting of the American Society of Hematology ASH 2002, at the Annual Meeting of the European Group for Blood and Marrow Transplantation EBMT 2004 and at the Xth International Symposium on Amyloid and Amyloidosis ISAA 2004.

References Barlogie, B., Smith, L. & Alexanian, R. (1984) Effective treatment of advanced multiple myeloma refractory to alkylating agents. The New England Journal of Medicine, 310, 1353–1356. Blade, J., Samson, D., Reece, D., Apperley, J., Bjorkstrand, B., Gahrton, G., Gertz, M., Giralt, S., Jagannath, S. & Vesole, D. (1998) Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. British Journal of Haematology, 102, 1115–1123. Comenzo, R.L., Vosburgh, E., Falk, R.H., Sanchorawala, V., Reisinger, J., Dubrey, S., Dember, L.M., Berk, J.L., Akpek, G., LaValley, M., O’Hara, C., Arkin, C.F., Wright, D.G. & Skinner, M. (1998) Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: survival and responses in 25 patients. Blood, 91, 3662–3670. Comezo, R.L. & Gertz, M.A. (2002) Autologous stem cell transplantation for primary systemic amyloidosis. Blood, 99, 4276–4282. Dispenzieri, A., Lacy, M.Q., Kyle, R.A., Therneau, T.M., Larson, D.R., Rajkumar, S.V., Fonseca, R., Greipp, P.R., Witzig, T.E., Lust, J.A. & Gertz, M.A. (2001) Eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival. Journal of Clinical Oncology, 19, 3350– 3356. Dispenzieri, A., Kyle, R.A., Lacy, M.Q., Therneau, T.M., Larson, D.R., Plevak, M.F., Rajkumar, S.V., Fonseca, R., Greipp, P.R., Witzig, T.E., Lust, J.A., Zeldenrust, S.R., Snow, D.S., Hayman, S.R., Litzow, M.R., Gastineau, D.A., Tefferi, A., Inwards, D.J., Micallef, I.N., Ansell, S.M., Porrata, L.F., Elliott, M.A. & Gertz, M.A. (2004) Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplant: a case control study. Blood, 103, 3960–3963. Falk, R.H., Comenzo, R.L. & Skinner, M. (1997) The systemic amyloidosis. The New England Journal of Medicine, 337, 898–909. van Gameren, I.I., Hazenberg, B.P., Jager, P.L., Smit, J.W., Vellenga, E., Gertz, M.A., Kyle, R.A. & Greipp, P.R. (2002) AL amyloidosis treated with induction chemotherapy with VAD followed by high dose melphalan and autologous stem cell transplantation. Amyloidosis, 9, 165–174. Gertz, M., Lacy, M., Gastineau, D.A., Inwards, D.J., Chen, M.G., Teffei, A., Kyle, R.A. & Litzow, M.R. (2000) Blood stem cell transplantation as therapy for primary systemic amyloidosis. Bone Marrow Transplantation, 26, 963–969. Gertz, M.A., Lacy, M.Q., Dispenzieri, A., Gastineau, D.A., Chen, M.G., Ansell, S.M., Inwards, D.J., Micallef, I.N., Tefferi, A. & Litzow, M.R. (2002) Stem cell transplantation for the management of primary systemic amyloidosis. The American Journal of Medicine, 113, 549– 555.

ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 127, 543–551

VAD Followed by HDM for Treatment of AL Amyloidosis Gillmore, J.D., Apperley, J.F. & Craddock, C. (1999) High-dose melphalan and stem cell recue for AL amyloidosis. In: Amyloid and Amyloidosis (ed. by R.A. Kyle & M.A. Gertz), CRC Press, Parthenon Publishers. Gono, T., Matsuda, M., Dohi, N., Hoshi, K., Tada, T., Sakashita, K., Koike, K., Aizawa, M. & Ikeda, S. (2003) Nephrotic syndrome due to primary AL amyloidosis, successfully treated with VAD and subsequent high-dose melphalan followed by autologous peripheral blood stem cell transplantation. Internal Medicine, 42, 72–77. Kyle, R.A., Linos, A., Mary Beard, C., Linke, R.P., Gertz, M.A., O’Fallon, M. & Kurland, L.T. (1992) Incidence and natural history of primary systemic amyloidosis (AL) in Olmsted Country, Minnesota: 1950–1989. Blood, 79, 1817–1822. Kyle, R.A., Gertz, M.A., Greipp, P.R., Witzig, T.E., Lust, J.A., Lacy, M.Q. & Therneau, T.M. (1997) A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. The New England Journal of Medicine, 336, 1202–1207. Kyle, R.A., Gertz, M.A., Greipp, P.R., Witzig, T.E., Lust, J.A., Lacy, M.Q. & Therneau, T.M. (1999) Long-term survival (10 years or more) in 30 patients with primary amyloidosis. Blood, 93, 1062– 1066. Linke, R.P. (2000) Highly sensitive diagnosis of amyloid and variuos amyloid syndromes using congo red fluorescence. Virchows Archiv, 436, 439–448. Mehta, J. (2004) High-dose therapy for amyloidosis: the end of the beginning. Blood, 103, 3612–3613. Moreau, P., Leblond, V. & Baurquelot, P. (1998) Prognostic factors of survival and response after high-dose therapy and autologous stem cell transplantation in systemic AL amyloidosis: a report on 21 patients. British Journal of Haematology, 101, 766. Palladini, G., Anesi, E., Perfetti, V., Obici, L., Invernizzi, R., Balduini, C., Ascari, E. & Merlini, G. (2001) A modified high-dose dexamethasone regimen for primary systemic (AL) amyloidosis. British Journal of Haematology, 113, 1044–1046. Palladini, G., Perfetti, V., Obici, L., Caccialanza, R., Semino, A., Adami, F., Cavallero, G., Rustichelli, R., Virga, G. & Merlini, G. (2004) Association of melphalan and high-dose dexamethasone is effective

and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood, 103, 2936–2938. Perfetti, V., Ubbiali, P., Magni, M., Colli Vignarelli, M., Casarini, S., Matteucci, P., Gianni, A.M. & Merlini, G. (1998) Cells with clonal light chains are present in peripheral blood at diagnosis and in apheretic stem cell harvests of primary amyloidosis. Bone Marrow Transplantation, 23, 323–327. Sanchorawala, V., Wright, D.G., Seldin, D.C., Falk, R.H., Finn, K.T., Dember, L.M., Berk, J.L., Quillen, K., Anderson, J.J., Comenzo, R.L. & Skinner, M. (2004) High-dose intravenous melphalan and autologous stem cell transplantation as initial therapy or following two cycles of oral chemotherapy for the treatment of AL amyloidosis: results of a prospective randomized trial. Bone Marrow Transplantation, 33, 381–388. Sezer, O., Schmid, P., Schweigert, M., Heider, U., Eucker, J., Harder, H., Sinha, P., Radtke, H. & Possinger, K. (1999) Rapid reversal of nephrotic syndrome due to primary sytemic AL amyloidosis after VAD and subsequent high-dose chemotherapy with autologous stem cell support. Bone Marrow Transplantation, 23, 967–969. Skinner, M., Anderson, J.J. & Simms, R. (1996) Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only. The American Journal of Medicine, 100, 290–298. Skinner, M., Sanchorawala, V., Seldin, D.C., Dember, L.M., Falk, R.H., Berk, J.L., Anderson, J.J., O’Hara, C., Finn, K.T., Libbey, C.A., Wiesman, J., Quillen, K., Swan, N. & Wright, D.G. (2004) High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Annals of Internal Medicine, 140, 85–93. Zeier, M., Perz, J., Linke, R.P., Donini, U., Waldherr, R., Andrassy, K., Ho, A.D. & Goldschmidt, H. (2003) No regression of renal AL amyloid in monoclonal gammopathy after successful autologous blood stem cell transplantation and significant clinical improvement. Nephrology, Dialysis, Transplantation, 18, 2644–2647. Zenhausern, R., Tobler, A., Leoncini, L., Hess, O.M. & Ferrari, P. (2000) Fatal cardiac arrhythmia after infusion of dimethyl sulfoxidecryopreserved hematopoietic stem cells in a patient with severe primary cardiac amyloidosis and end-stage renal failure. Annals of Hematology, 79, 523–526.

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