Extended follow up of high-dose melphalan and autologous stem cell transplantation after vincristine, doxorubicin, dexamethasone induction in amyloid light chain amyloidosis of the prospective phase II HOVON-41 study by the Dutch-Belgian Co-operative Trial Group for Hematology Oncology

Abstract Abstract 3401 Poster Board III-289 Introduction: Systemic amyloid light chain amyloidosis (AL) is a fatal monoclonal plasma cell disorder which leads to depositions of insoluble fibrils in different organs. Treatment with conventional chemotherapy results in low numbers of complete remission (CR). High-dose melphalan (HDM) with autologous haematopoietic stem cell transplantation (SCT) induces the highest rates of CR (up to 40%) which is a prerequisite for longterm survival. An attempt to further increase CR rate might be the administration of induction therapy (Perz et al., BJH 2004). Patients and treatment: From 2003 until 2008, a prospective phase II trial has been performed in our institution. The patients were treated with sequential therapy of 1-3 courses of pulsed dexamethasone (dexa, 40 mg), mobilization chemotherapy with cyclophosphamide 1g/m2, adriamycin 60mg/m2 and dexa followed by HDM and auto-SCT. Exclusion criteria were age > 70 years, symptomatic heart involvement > NYHA stage II and WHO performance status >2. The primary objective of the study was efficacy (CR rate) and tolerability of the treatment. It was planned to include 46 patients in a three step design (Chen 1997). Until October 2008 thirty patients with newly diagnosed AL (median age 55 years; median number of involved organs 2; involved free light chains in serum median 117 mg/l; cardiac Mayo staging system (Dispenzieri et al., JCO 2004) median stage 1) were included. Because patient recruitment was too slow the study was stopped. Results: The median follow-up for survival according to Korn (1986) of all pts is 41 months after study inclusion. The follow up of the last patient is 4 months after HDM. In the first 5 pts 3 toxic deaths occurred during dexa. After amendment of antibiotic prophylaxis no further treatment-related deaths were observed. Other serious adverse events were arterial thromboses in 2 pts with nephrotic syndrome and sepsis with renal failure in 1 pt. Five pts stopped dexa due to toxicity before completing the planned 3 cycles. Four pts could not be transplanted due to AL progression. Overall, 23 patients have been transplanted. Hematological response was induced in 13 out of 25 (52%) evaluable pts (CR n=4) following induction treatment. After HDM CR was obtained in 12 / 23 (52%) and partial remission in 10 / 23 (43%). This led to organ response (OR) in 13 out of 23 (57%) evaluable patients. No patient died of transplant-related mortality. Overall, 6 pts died due to AL progression. Hematological relapse occurred in 2 pts with CR and progression in 5 pts with PR. Median overall survival (OS) for the whole group is not reached. The last death occurred at 25 months after inclusion with a resulting estimated survival probability of 68% at that time point (figure 1). OS was significantly improved after HDM in those patients who achieved CR compared to patients without CR (p=0.05, figure 2). Summary: Induction therapy with pulsed dexa prior HDM is feasible and effective, but has remarkable toxicity. CR and OR rates after HDM can be increased with this intensive therapy approach compared to historical controls. Furthermore, pts with CR have a low risk of relapse and have an excellent survival. Further improvement regarding toxicity and CR rates might be achieved using lower dosage of steroids and incorporation of the new drugs in the induction therapy prior HDM. Disclosures: No relevant conflicts of interest to declare.

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Bortezomib, Doxorubicin and Dexamethasone (PAD) Prior to High-Dose Melphalan / Autologous Stem Cell Transplantation for Newly Diagnosed Plasma Cell Dycrasias.

Blood ◽

10.1182/blood.v114.22.4960.4960 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4960-4960

Author(s):

Delphine Lebon ◽

Berengere Gruson ◽

Reda Garidi ◽

Jean Luc Dutel ◽

Corinne Thevenot ◽

...

Keyword(s):

Stem Cell ◽

Renal Insufficiency ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Autologous Stem Cell Transplantation ◽

Plasma Cell ◽

Response Rates ◽

High Dose ◽

High Dose Melphalan

Abstract Abstract 4960 High-dose melphalan (HDM) with autologous stem cell transplantation (ASCT) is the standard of care for myeloma (MM) patients aged < 70 years. Achievement of complete/very good partial response (CR/VGPR) is prognostic for improvement overall survival (OS) and use of more effective induction regimens prior to HDT-ASCT may result in improvement post-transplant responses. We performed a retrospective analysis of newly MM pts treated with bortezomib-doxorubicin-dexamethasone (PAD) prior HDM-ASCT. From October 2005 and July 2008, 20 previously untreated MM pts were enrolled: median age was 56 years (range 44-68), 50% male. Of them, 3 had primary plasma cell leukemia (pPCL), 5 were on dialysis for MM-related renal impairment. Cytogenetic was available for 9: 2 (1 pPCL and 1 MM) had t(4;14). PAD included Bortezomib (1.3 mg/m2 on D1, 4, 8, 11), doxorubicin (9mg/m2 D1-D4), dexametasone (40mg D1-D4): 4 cycles (13 pts), 3 (6 pts), and 2 (1). Response rates after PAD were CR 10%, VGPR 50%, PR 20%, SD 10%. 1 pt died of pulmonary hypertension related to MM after 2 cycles of PAD. Neurologic toxicity ' grade 2 was observed in 3 pts and DVT in 1. Following induction, 17 pts underwent PBSC harvesting: cyclopsphamide + G-CSF (8), G-CSF only (10). Median yields were 7.9 106 CD34/kg (6-10.5). 17 pts underwent HDM: 200 mg/m2 (12 pts) and 140 mg/m2 (5 pts with renal insufficiency, including 3 on dialysis), followed with ASCT. 1 pt benefited a double HDM/ASCT and 1 (pPCL) a mini-allotransplant 3 monts after. There was no treatment related mortality. Response rates 3 months post ASCT (17 pts) were: CR 18%, VGPR 70%, PR 6%, SD 6%. 1 SD post PAD obtained VGPR after Thal-Dex had double HDM/ASCT with CR. With a median follow-up of 23 months (7-34), median OS has not been reached and 1-year survival was 95%. At the reference date of July 2009 85% are alive, 5 pts relapsed: median 12 months (6-14), EFS was 31 months and 2 pts with t(4;14) are alive in CR/VGPR at 23 and 31 months Concerning the 3 pPCL pts: 1 remained alive in CR 12 months post allo-transplant (follow-up 23 months), 1 was in CR post PAD and relapsed 11 months post HDM/ASCT (survival = 20 months) and 1 is alive at 12 months from diagnosis with a refractory disease. Dialysis could be interrupted for 3 pts in CR/VGPR: 1 after PAD, 2 after ASCT.. In conclusion, according to previously published results (Popat R, British Journal of Haematology 2008), PAD regimen in preparation of HDM/ASCT is safe and highly active in MM patients. Moreover, prolonged remissions and survivals could be obtained in pPCL patients and reversal of severe renal insufficiency observed. Disclosures No relevant conflicts of interest to declare.

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