Intravenous Melphalan Research Articles

Whole Blood Stem Cell Reinfusion and Escalated Dose Melphalan in Castration-Resistant Prostate Cancer: A Phase 1 Study

Nontaxane-based chemotherapeutic options in castrate-resistant prostate cancer (CRPC) are limited despite the long natural history of the disease. We carried out a phase 1 dose-escalation study of the alkylating agent melphalan with autologous stem cell transplantation, comparing rapid changes in circulating tumor cells (CTC) and prostate-specific antigen (PSA) as a measure of response. Cohorts of individuals with advanced CRPC received high-dose intravenous melphalan, and autologous blood was returned to patients during treatment. The efficacy endpoints were the PSA reduction rate, CTC response, survival parameters, toxicity and whether reinduction of endocrine sensitivity occurred. Twenty-four patients were recruited. Dose escalation was feasible with the highest dose cohort being reached. Of 23 individuals evaluable for response, 16 had a PSA response of more than 30%; of 11 patients with soft tissue disease, 4 achieved a partial response and 7 had stable disease. Patients with CTC counts that decreased to less than 5 within 2 weeks from the start of therapy had a longer overall survival (30.6 months vs. 15.3 months, P = 0.03) Treatment was associated with myelosuppression and frequent hospitalizations. In 20 patients after the study, hormone therapy was reintroduced when PSA increased again; response rates were high. Autologous transplantation following high-dose alkylating agent chemotherapy induces responses but proved toxic, although dose escalation proved possible. The possibility of using CTCs to identify responders at two weeks may be used to justify such an intensive approach. Many individuals went on to further respond to both docetaxel and hormonal therapy.

A phase II study of risk‐adapted intravenous melphalan in patients with AL amyloidosis

A phase <scp>II</scp> study of risk‐adapted intravenous melphalan in patients with <scp>AL</scp> amyloidosis

Selective pulmonary artery perfusion with melphalan is equal to isolated lung perfusion but superior to intravenous melphalan for the treatment of sarcoma lung metastases in a rodent model

Isolated lung perfusion (ILuP) and selective pulmonary artery perfusion (SPAP) are experimental surgical techniques to deliver high-dose chemotherapy selectively to the lung for the treatment of lung metastases. ILuP with melphalan (MN) has shown to be feasible in clinical studies but can only be used once because it is invasive. SPAP as an endovascular technique can be repeated several times, but no results have been reported so far. Pharmacokinetics and efficacy of SPAP with MN were studied in a rodent lung metastasis model and compared it with ILuP and intravenous (IV) therapy. Pharmacokinetics: forty-five Wag-Rij rats were randomized into three groups: IV 0.5 mg MN, ILuP 0.5 mg MN and SPAP 0.5 mg MN. Every treatment group was again randomized in three groups: 15 min treatment, 30 min treatment and 30 min treatment with 30 min reperfusion. Blood and tissue samples were taken for MN concentrations. twenty-five Wag-Rij rats were randomized into five groups: control, sham thoracotomy, IV 0.5 mg MN, ILuP 0.5 mg MN and SPAP 0.5 mg MN. At day 0, bilateral lung metastases were induced, and treatment followed at day 7. At day 28, rats were sacrificed and pulmonary metastases counted. Survival: thirty Wag-Rij rats were randomized into five groups: control, sham ILuP, IV 0.5 mg MN, ILuP 0.5 mg MN, SPAP 0.5 mg MN. At day 0, left-sided lungmetastases were induced with treatment at day 7. Endpoints were death due to disease or survival up to 90 days. Pharmacokinetics: SPAP and ILuP resulted in significantly higher left lung MN concentrations compared with IV (P = 0.05). SPAP (30 ± 22 nodules) and ILuP (20 ± 9 nodules) resulted in significantly less nodules compared with IV (113 ± 17 nodules; P < 0.01). Survival: median survival of SPAP (74 ± 8 days) was equal to ILuP MN (71 ± 10 days) but significantly longer compared with IV (54 ± 7 days; P < 0.01 both). SPAP with MN for the treatment of sarcoma lung metastases in rats is equally effective to ILuP but resulted in a significantly better survival compared with IV MN. As SPAP can be applied as a minimally invasive endovascular procedure, continued research with this technique is warranted.

A Phase II Study of Risk-Adapted Intravenous Melphalan in Patients with AL Amyloidosis,

Abstract 3973 Aims:High-dose IV melphalan is standard autograft (ASCT) conditioning in patients with AL amyloidosis, but careful patient selection is required to avoid high transplant-related mortality rates. In patients ineligible for ASCT, intermediate-dose IV melphalan (IDM) may provide advantages over oral dosing where the already variable intestinal absorption is complicated by gastrointestinal amyloid deposition. We aimed to assess a risk-adapted strategy to IV melphalan dosing in patients with AL amyloidosis. Methods:The MM8 study was a prospective clinical trial conducted by the Australasian Leukaemia and Lymphoma Group. Transplant candidates (minimal cardiac disease including BNP<300ng/L, age <65, ECOG<2, <2 organs involved) received melphalan at 140 or 200mg/m2 IV. All other patients received IDM (melphalan 20mg/m2 IV d1 and dexamethasone 40mg PO d1-4 every 4 weeks for 3–6 cycles). Treatment was continued until 2 cycles beyond free light chain normalisation or maximal response, or to a maximum of 6 cycles. IDM was discontinued if there was no haematologic response after 3 cycles. Results:21 patients enrolled with median age 61yrs. Organ involvement was cardiac 48%, renal 81%, liver 14%, neurologic 43%. 6, 10 and 5 were low, intermediate and high cardiac biomarker risk, respectively. 7 underwent ASCT and 14 IDM.The trial closed early due to excessive myelotoxicity in the IDM arm. In this cohort, grade 3/4 neutropenia and thrombocytopenia during the 1st cycle occurred in 54% and 23%, with 15% having neutropenic fever. Grade 3/4 neutropenia and thrombocytopenia during any cycle occurred in 85% and 54% of patients, with 38% having neutropenic fever. First cycle severe neutropenia was not predicted by age, cardiac or renal function but was significantly more common with lower body surface area (p=0.01). 8 IDM patients died before the 6 month response assessment, 2 achieved a 50% reduction in baseline involved FLC and 4 failed to respond. All 7 patients receiving ASCT are alive at a median of 33 months. Conclusions:IV melphalan at 20mg/m2 is excessively myelotoxic for patients with AL with no evidence of response benefit to offset this toxicity. BNP<300ng/L may identify patients suitable for ASCT.This study was supported by the Leukaemia Foundation of Queensland and Amgen Australia. Disclosures:Mollee:Amgen Australia: Research Funding; Leukaemia Foundation of Queensland: Research Funding. Cannell:Nereus Pharmaceuticals:.

Bortezomib and high-dose melphalan conditioning for stem cell transplantation for AL amyloidosis: a pilot study

Treatment with high-dose intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT) can induce hematologic responses, organ responses and lead to improvement in survival in selected patients with AL (immunoglobulin light chain) amyloidosis.[1][1] The depth of hematologic

High Dose Oral Busulfan and Intravenous Melphalan as Conditioning Therapy for Autologous Hematopoietic Stem Cell Transplant (HSCT) for the Treatment of Pediatric Solid Tumors

High Dose Oral Busulfan and Intravenous Melphalan as Conditioning Therapy for Autologous Hematopoietic Stem Cell Transplant (HSCT) for the Treatment of Pediatric Solid Tumors

Oral Cyclic Melphalan and Dexamethasone for Patients With AL Amyloidosis

Aggressive treatment of amyloid light chain (AL) amyloidosis with high-dose intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT) is effective in inducing hematologic remission and clinical improvement. However, only selected patients with AL amyloidosis are eligible for HDM/SCT because of amyloid-associated organ dysfunction. We report on 70 patients with AL amyloidosis treated with oral cyclic melphalan and dexamethasone. Of 48 evaluable patients who survived and returned for follow-up assessment, 6 patients (13%) achieved a complete hematologic response and 12 patients (25%) a partial hematologic response. Responses were non-inferior for patients receiving weekly "low-dose" dexamethasone compared with those receiving 4 day pulses. Median survival for the 70 patients has not yet been reached with a median follow-up of 17 months. Nineteen patients (27%) received additional treatment leading to improvement in survival. Melphalan/dexamethasone can lead to hematologic responses and improvement in survival, particularly for those who can receive additional treatment for AL amyloidosis.

Macroglossia – Not Always AL Amyloidosis

AbstractAbstract 5007 Introduction:Amyloidosis is characterized by extracellular deposition of abnormal insoluble fibrillar proteins. The two most frequent systemic amyloidoses are the light-chain (AL amyloidosis) and familial transthyretin (ATTR) forms. Clinical presentations often vary between the two types. Macroglossia is viewed as pathognomic of AL amyloidosis, and has not previously been described in patients with hereditary TTR amyloidosis. Here, we describe two cases of systemic amyloidosis with macroglossia in which immuno-electron microscopy diagnosed ATTR in one and AL in the other. Case Presentations:A 61 year old woman presented initially to her general internist with weight loss, difficulty swallowing, and tongue numbness. Her clinical exam revealed macroglossia and peripheral neuropathy. Tongue and axillary lymph node biopsies demonstrated amyloid deposits by Congo red staining. There was no evidence of renal, cardiac or other vital organ involvement. She had no evidence of a plasma cell dyscrasia with negative serum and urine immunofixation electrophoresis, normal serum free light chain concentration and ratio as well as polytypic plasma cells in the bone marrow. Immuno-electron microscopy using gold-labeled antibodies was performed on the tongue biopsy. The fibrils were immunoreactive with anti-TTR but not anti-kappa, anti-lambda, or anti-AA antibodies. DNA sequencing identified a known amyloidogenic T60A TTR mutation in exon 3 of chromosome 18, confirming the diagnosis of ATTR with amyloidotic polyneuropathy and macroglossia. The second case involved a 59 year old man with renal insufficiency. He complained of fatigue, weight loss, and tongue swelling. Physical examination was significant for macroglossia and submandibular gland enlargement. Tongue biopsy demonstrated amyloid deposits by Congo red staining. As in the previous case, markers of plasma cell dyscrasia with clonal plasma cells in the bone marrow, blood, and urine were absent. Immuno-electron microscopy of the tongue biopsy documented antibody reactivity to lambda light chain and not TTR, kappa light chain or AA proteins, confirming the diagnosis of AL amyloidosis. He subsequently underwent treatment with high dose intravenous melphalan followed by stem cell transplantation achieving a good clinical response sustained for 2 years to date. Discussion:While macroglossia is thought to be pathognomonic of AL amyloidosis, we report a case of macroglossia with fibrillar ATTR amyloid deposits diagnosed by immuno-electron microscopy. This is contrasted with a clinical presentation consistent with AL in which routine laboratory testing failed to identify evidence of a plasma cell dyscrasia. In both cases, electron microscopy demonstrated immunoreactivity for the fibrils of a single pathogenic protein. The first case was confirmed by DNA sequencing, and the second had a typical response to anti-plasma cell chemotherapy, in spite of the lack of identifiable markers of disease. Disclosures:No relevant conflicts of interest to declare.

Preclinical comparison of intravenous melphalan pharmacokinetics administered in formulations containing either (SBE)7 m‐β‐cyclodextrin or a co‐solvent system

The aim of this work was to evaluate the impact of sulfobutyl ether β-cyclodextrin ((SBE)(7 m)-β-CD; Captisol(®)) on the in vivo pharmacokinetics of melphalan in rats. Melphalan is a chemically unstable antineoplastic drug which in the current commercial formulation (Alkeran(®) for Injection) has some limitations with regard to solubility, stability and biocompatibility. Melphalan formulations containing (SBE)(7 m)-β-CD have previously been evaluated in vitro and shown to significantly reduce the rate of degradation and to simplify the reconstitution procedure for lyophilised melphalan. In this study, melphalan was administered intravenously in rats in formulations that either contain (SBE)(7 m)-β-CD or a co-solvent system (i.e. the commercial formulation). Pharmacokinetic parameters, including half-life, volume of distribution, clearance and extent of renal elimination of melphalan were essentially unchanged between the two formulations. These findings indicate that the pharmacokinetics of melphalan are not altered in the presence of (SBE)(7 m)-β-CD consistent with a rapid shift in the equilibrium to the fully dissociated drug from the fraction associated with the cyclodextrin host molecule upon intravenous administration.

Treatment with intravenous melphalan and dexamethasone is not able to overcome the poor prognosis of patients with newly diagnosed systemic light chain amyloidosis and severe cardiac involvement

AbstractTreatment with oral melphalan and dexamethasone (M-Dex) was reported to be effective and feasible in patients with systemic light chain amyloidosis (AL) not eligible for high-dose melphalan. We report on 61 patients with advanced AL who were treated with intravenous M-Dex as first-line therapy. Estimated median overall survival (OS) was 17.5 months. Seventeen patients (28%) died within 3 months, mostly of disease-related complications. In addition, nonhematologic toxicity of Common Terminology Criteria grade 3 or 4 was observed in 20 patients, whereas hematologic toxicity was low. Twenty-seven patients (44%) had hematologic response, including complete in 7 patients (11%) and partial remission in 20 patients (33%). Organ response was observed in 15 patients (25%). The amount of the involved free light chains in serum and Karnofsky Index at diagnosis significantly influenced OS. Plasma levels of the cardiac biomarkers before start of treatment and their increase after the third M-Dex cycle also were strong negative predictors of OS. These parameters might help to identify patients who will not benefit from M-Dex chemotherapy.

TTP disease course is independent of myeloma treatment and response

TTP disease course is independent of myeloma treatment and response

Diagnosis and the treatment of primary amyloidosis

Primary amyloidosis belongs to a group of monoclonal plasma cell disorders, characterized by extracellular deposition of immunoglobulin light chain fibrils in various tissues and subsequent multiorgan dysfunction. We present a 51-year-old female with 2-years history of fatigue on exertion, oedema of face, abdomen and legs, bone pain and obstipation. After diagnostic procedures such as electrophoresis and immunoelectrophoresis of serum and urine proteins, immunohistohemical staining of bone marrow biopsy specimens and Congo red staining of rectal biopsy specimens, the patient received misdiagnosis of multiple myeloma and was referred to our hospital for further treatment. We reevaluated and complemented diagnostic procedures (ehocardiosonography and biopsy of subcutaneaus tissue with Congo red staining), and established diagnosis of primary amyloidosis. The therapy had started with intravenous (i.v.) melphalan and dexamethasone (totally eight cycles) and continued with peroral melphalan and i.v. dexamethasone. Stabilization of the disease was achieved after 35 months of the treatment. The case of this rare and often fatal disease emphasizes significance of early diagnosis and, consequently, initiation of specific therapies which are indispensable to improve the disease prognosis.

Optimization of Fludarabine + Melphalan Conditioning for Marrow Transplantation From Unrelated Donors for Patients with Hematopoietic Malignancies: A Prospective Dose-Finding Trial Using Modified Continual Reassessment Method.

Abstract 2273Poster Board II-250 BackgroundDevelopment of reduced intensity conditioning (RIC) regimen has enabled older patients, who are not expected to tolerate the toxicity of myeloablative conditioning, to be treated with allogeneic HSCT. Because the risk of rejection after BMT is substantially higher than that of PBSCT in RIC transplantation, PBSC is commonly used for RIC transplantation. However, PBSCT from unrelated donors is not currently available in Japan. Therefore, a better dosage of conditioning to ensure engraftment in RIC with BM is needed. Here, we selected the fludarabine plus melphalan regimen which has sufficient potential to induce marrow engraftment if melphalan at 180mg/m2 is used, and planned further optimization of melphalan dosage. The rationale for modulating the dose of melphalan resulted from accumulated observations that melphalan is associated with toxicities, while fludarabine is not. Because the optimal dose of melphalan to minimize regimen-related toxicities and to enable sustained engraftment remains unknown to date, we investigated the recommended dose of melphalan in a phase I study. Patients and MethodsTo adjust the melphalan dose, we adopted a modified continual reassessment method (CRM) which has been hypothesized to allow a faster and more accurate dose reduction/escalation in patients needed to reach the recommended dose compared with classical algorithmic dose modification design. The conditioning regimen consisted of 125 mg/m2 intravenous fludarabine (day-6∼-2) in combination with the examination dose of intravenous melphalan (day-3, -2). Because the use of fludarabine at 125mg/m2 and melphalan at 180mg/m2 was known to induce reliable engraftment, we set the first dose level to receive 160mg/m2 of melphalan. The primary endpoint was an achievement of donor-type T-cell chimerism at day 28 with successful engraftment defined as 90% or more donor cells. Five patients were planned to be accrued for each dose level and chimerism data was used to determine the next dose. A maximum dose reduction of melphalan for the next level was limited to 30mg/m2 to avoid the potential risk of graft-failure. GVHD prophylaxis consisted of short term methotrexate and tacrolimus. The eligibility criteria were 1) patients with hematological malignancies, who have had more than 3 course of chemotherapy, 2) age, 55 to 65 years, or 40 to 54 years with substantial comorbidity (HCT-CI of 1 or more), 3) no prior stem cell transplantation. The protocol was approved by the Institutional Review Board of each institution. All patients and donors provided written informed consent. ResultsSeventeen patients were enrolled at doses between 130mg/m2 and 160mg/m2, including one protocol violation and one early death (brain hemorrhage). Both were unavailable for assessment according to the study definition in advance. Of the 15 evaluable patients (9 male, 6 female), the median age was 58 years old (range: 45-63), and their diagnosis were 10 AML, 2 NHL, 1 CML 1 ALL and 1 plasmacytoma. The dose was reduced from 160mg/m2 (level-1) to 130mg/m2 (level-2) after 5 consecutive full donor chimerism (all were 100% at day 28) were observed in level-1. In the level-2, we observed four patients with 100% chimera, and one with 0% chimera at day 28, which eventually resulted in graft-failure. Following the calculation by CRM from level-2, the examination dose was increased to 135mg/m2 (level-3). In the level-3, 5 consecutive full donor chimerism (four 100% and one 90.4%) were observed again. Because the next examination dose was calculated as within 5mg/m2 from the level-3 (135mg/m2), the study was complete as projected. We could not detect any significant difference among the dose levels in terms of toxicity, relapse rate or survival. DiscussionSuccessful dose finding using modified CRM was accomplished. The strategy using engraftment as a primary endpoint instead of toxicity promotes a better chance to determine the optimal dosage compared with the classical phase I trial design with modified Fibonacci method. Our findings demonstrated the melphalan dose of 135mg/m2 in combination with fludarabine is able to induce initial full donor chimerism after unrelated donor BMT and is recommended for further phase II evaluation. Disclosures:No relevant conflicts of interest to declare.

Characterization of Early Natural Killer Cell Reconstitution Following Autologous Transplantation in Multiple Myeloma.

Abstract 4641 BackgroundDespite the advent of novel therapies, multiple myeloma (MM) remains incurable and high-dose chemotherapy (HDC) with autologous stem cell transplantation (SCT) remains an important therapy for this incurable malignancy. Prior research has suggested that early lymphocyte immune reconstitution following HDC/SCT may be associated with improved outcomes; however, little is known regarding the biologic mechanisms underlying this phenomenon. A potent natural killer (NK) cell versus MM effect has also been demonstrated by our group and others previously, and NK cells are the first lymphocyte subset to recover following HDC/SCT. Herein, we characterize the nature of this recovery to suggest that the early post-transplant period may be an especially favorable environment in which to augment the NK cell versus MM effect to improve outcomes for patients with MM undergoing HDC/SCT. MethodsWith informed consent and under institutional review board approval, peripheral blood samples from patients with multiple myeloma undergoing HDC/SCT were collected on the day of first peripheral white cell count > 1500/uL post- HDC/SCT. All patients received intravenous melphalan (200mg/m2) as the preparative regimen. Mononuclear cells were isolated and, by flow cytometry, CD56(+),CD3(-) NK cells were comprehensively immunophenotyped for expression of inhibitory and activating ligands. NK cell activation and cytotoxicity were assessed by ELISPOT and chromium release assays. Clinical outcome was assessed as a function of early NK cell recovery. Results11 patients (median age 57, 8 male, 3 female) with a median of 1 prior regimen to transplant (range 1-9) have been assessed to date. 1 patient was mobilized with AMD-3100, 3 had cyclophosphamide mobilizations and 7 were mobilized with neupogen alone. The average CD34(+) cell dose received was 5.22 (+/- SD 2.39). The median day of peripheral white cell recovery was day +12 (range 11-18). The median absolute lymphocyte count on sample procurement day was 410 (range 340 – 820), of which an average of 37% (range 13 – 70) were NK cells. Although total white count on procurement day correlated with CD34(+) cell dose (p = 0.02), neither absolute lymphocyte count or NK cell count correlated significantly with CD34(+) cell dose and mobilization strategy did not affect NK cell count. NK cell reconstitution correlated with best response to HDC/SCT (p=0.02), the average NK cell count for patients ultimately achieving CR was 389 (+/- 131) as compared to those achieving PR or less (171 +/- 101). Interestingly, nearly half of reconstituting NK cells (46% +/- SD 20) expressed CD117 (c-kit receptor), a marker shown previously to be associated with earlier stages of NK cell development. Inhibitory KIR (CD158a on 36% +/-17 and CD158b on 36% +/- 24) and NKG2A (76% +/- 10) expression also seemed restricted to the CD117(+) NK cells. This population of NK cells also displayed NKG2D (25% +/- 22) and CD16 (73% +/-8). Reconstituting NK cells were capable of interferon gamma production against MM tumor targets similar to NK cells isolated from healthy donors (E:T = 20:1, 956 +/- 98 spots/well versus 896 +/-85, p = n/s). Granzyme B production against MM tumor targets also compared to normal controls (E:T = 20:1, 547 +/- 66 versus 573 +/- 50, p= n/s). Moreover, reconstituting NK cells showed enhanced cytotoxicity against MM tumor targets when pre-treated with an inhibitory KIR blocking antibody (IPH2101/1-7F9) similar to healthy donor NK cells. DiscussionTaken together, we provide quantitative and qualitative data to suggest that early NK cell recovery post-SCT may contribute to outcome in patients with MM. This may be an optimal period to implement immunomodulatory strategies to augment NK cell function to improve outcomes for patients with MM undergoing HDC/SCT. Reconstituting NK cells, although exhibiting a relatively unique immunophenotype compared to mature NK cells in healthy, normal donors, appear to retain properties of activation and cytotoxicity. Given the favorable effector:target ratio in vivo following SCT, these results support further research into immunotherapeutic manipulation of the reconstituting NK cell clone to improve efficacy of HDC/SCT in patients with MM. Disclosures:Andre:Innate Pharma: Employment. Squiban:Innate Pharma: Employment. Romagne:Innate Pharma: Employment.

Oral Cyclic Melphalan and Dexamethasone in the Treatment of Patients with AL Amyloidosis; Ineligible for High-Dose Melphalan and Stem Cell Transplantation.

Abstract 1883Poster Board I-906AL amyloidosis is caused by a clonal plasma cell dyscrasia and is characterized by widespread, progressive amyloid deposition leading to multisystem organ failure and death. In this disease, amyloid protein deposits are derived from monoclonal immunoglobulin light chains. Aggressive treatment of AL amyloidosis with high dose intravenous melphalan followed by autologous stem cell transplant (HDM/SCT) is effective in inducing hematologic remission and clinical improvement. However, only selected patients with AL amyloidosis are eligible for HDM/SCT due to amyloid-associated organ dysfunction. Recently, several investigators have demonstrated the efficacy of treatment with oral cyclic melphalan and dexamethasone (Mel/Dex) in inducing hematologic responses and improving survival for patients with AL amyloidosis. We report on 70 patients with AL amyloidosis who were treated with oral Mel/Dex. Oral melphalan was administered at 0.22 mg/kg/day for D1-4 and dexamethasone at 20-40 mg one day per week and repeated every month. The median age was 65 years (range, 46-84) and the median number of organ system involvement was 3 (range, 1–6). Majority of the patients (n=31) had predominant cardiac involvement. The reasons to select this regimen of Mel/Dex rather than HDM/SCT included severe cardiac involvement (n=23), age > 75 years (n=6), patient choice (n=6), severe autonomic neuropathy (n=6), poor functional status (n=5), treatment started by local physicians (n=9), complications of stem cell mobilization and collection precluding HDM (n=5) and others (n=11). Patients received a median of 4 cycles of Mel/Dex, (range 1-13). Hematologic responses were not evaluable in 22 patients due to early death, toxicity or patients failing to return for follow-up. Of 48 evaluable patients, 7 patients (15%) achieved a complete hematologic response. Median survival for these 70 patients has not yet been reached with a median follow-up of 17 months. Overall survival is 60% at 3 years. Thirteen of these patients received additional treatment for their disease. In conclusion, oral cyclic melphalan and dexamethasone can lead to hematologic complete responses in 15% of patients and to improvement in survival for patients with AL amyloidosis, who are not eligible for HDM/SCT. Disclosures:relevant conflicts of interest to declare.

Bortezomib and High Dose Melphalan Followed by Autologous Stem Cell Transplantation (BortHDM/SCT) for the Treatment of AL Amyloidosis: Results of a Feasibility Study.

Abstract 4353AL amyloidosis is caused by a clonal plasma cell dyscrasia and is characterized by widespread, progressive amyloid deposition leading to multisystem organ failure and death. In this disease, amyloid protein deposits are derived from monoclonal immunoglobulin light chains. Aggressive treatment of AL amyloidosis with high dose intravenous melphalan followed by autologous stem cell transplant (HDM/SCT) is effective in inducing hematologic remission and clinical improvement. Furthermore, we have observed in ∼ 500 patients treated with HDM/SCT that achievement of a hematologic complete response (CR), i.e. disappearance of monoclonal gammopathy, normalization of serum free light chain ratio and clonal plasma cell dyscrasia, is a critical determinant of clinical improvement and prolonged survival. Bortezomib (Bor) has been reported to have activity in patients with AL amyloidosis. Furthermore, a synergistic effect between bortezomib and melphalan has been demonstrated in vitro and in vivo. Thus, the combination of bortezomib and HDM is a logical approach to study. Because of the importance of hematologic CR in treatment outcome, we conducted a feasibility study to determine whether addition of bort to HDM/SCT would be tolerable and would increase hematologic CR rates. Additional objectives of the study were to determine overall survival. Eligibility for entry into the trial required diagnosis of AL amyloidosis, age > 18 years, and adequate performance status (SWOG ≤ 2) and cardiopulmonary function (LVEF > 45%, DLCO > 50%). Peripheral blood stem cells were collected by leukapheresis following G-CSF mobilization, with minimum yields of 2.5 × 106 CD34+ cells/kg required for participation in the trial. Bortezomib was administered at 1 mg/m2 on D -6, D -3, D +1, and D +4 and HDM at 140-200 mg/ m2 in two divided doses on D -2 and D -1. From 10/2008 to 7/2009, 8 patients were enrolled (median age 57, range 46-68; median number of involved organs 2, range 1-4). Of the 8 patients enrolled, 1 patient was removed from the protocol because of cardiac arrhythmia during stem cell mobilization and collection phase that precluded treatment with HDM/SCT. Of the 7 patients who received BorHDM/SCT, there was no treatment-related mortality within 100 days of SCT and there were no unexpected hematologic or non-hematologic toxicities associated with addition of bortezomib to HDM/SCT. The median times to neutrophil and platelet engraftment was D +10 and D +14 after SCT, respectively. Of 6 patients evaluable for early responses, normalization of serum free light chain levels and ratio occurred in 5 of 6 (83%) by D +14 and one patient achieved a 45% reduction in serum free light chain concentration at D +14. Of the initial 2 patients with longer follow-up, both have achieved a hematologic CR at 6 months following BorHDM/SCT. Follow-up is ongoing and hematologic responses appear to be well-maintained. Thus, this pilot study demonstrates that bortHDM/SCT is tolerable for selected patients with AL amyloidosis and leads to a high rate of hematologic responses. Disclosures:Off Label Use: Bortezomib in the treatment of AL amyloidosis.

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.

Bortezomib, low‐dose intravenous melphalan, and dexamethasone for patients with relapsed multiple myeloma

This multicenter phase I/II study investigated the maximum tolerated dose (MTD), safety, and efficacy of low dose intravenous (IV) melphalan in combination with bortezomib for patients with relapsed multiple myeloma (MM). Patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 and escalating doses of IV melphalan (2.5-10.0 mg/m(2)) on day 2 of a 28-day cycle for a maximum of eight cycles. Dexamethasone 20 mg was added for progressive or stable disease. Fifty-three patients were enrolled. The MTD was defined at melphalan 7.5 mg/m(2) and bortezomib 1.3 mg/m(2). The overall response rate (ORR) was 68% (23% complete or near-complete responses [CR/nCR]) whilst at the MTD (n = 33) the ORR was 76% (34% CR/nCR). After median follow-up of 17 months, the median progression free survival was 10 months, rising to 12 months at the MTD (P < 0.05 vs. non-MTD regimens). The median overall survival was 28 months, but was not yet reached at the MTD. Grade 3/4 adverse events included thrombocytopenia (62%), neutropenia (57%), infection (21%), and neuropathy (15%). Bortezomib and low-dose IV melphalan combination therapy is a safe and highly effective regimen for patients with relapsed MM. These data suggest further investigation of this combination is warranted.

Treatment-Related Mortality in Patients with AL Amyloidosis Undergoing High-Dose Melphalan and Stem Cell Transplantation: Trend Over The Past 14 Years at a Single Institution

Abstract AL amyloidosis is caused by a clonal plasma cell dyscrasia and characterized by widespread, progressive amyloid deposition leading to multisystem organ failure and death. Aggressive treatment of AL amyloidosis with high dose intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT) is effective in inducing hematologic and clinical remissions and in extending survival. However, HDM/SCT is a challenging treatment for patients with AL amyloidosis, given their multisystem disease. Morbidity and mortality are associated with all phases of HDM/SCT: during stem cell mobilization and collection, during post-treatment myelosuppression, and following hematopoietic engraftment. Between 7/1994 and 7/2008, 496 HDM/SCT were performed for patients with AL amyloidosis, (median age = 56, range 28–80), at Boston University Medical Center. Treatment-related mortality is defined as deaths during stem cell mobilization and collection phase as well as within 100 days after SCT. Overall treatment-related mortality was 12% (58/496). Of the 58 deaths, 11 (2%) occurred during the stem cell mobilization and collection phase of treatment, while 47 (9%) occurred within 100 days after SCT. Deaths during stem cell mobilization and collection were associated with cardiac arrhythmia (n=1), irreversible congestive heart failure (n=2), refractory hypotension (n=3), myocardial infarction due to small vessel amyloid disease (n=1), massive GI bleeding (n=3) and pulmonary embolism (n=1). There were 5 cardiac arrests leading to death during the stem cell infusion procedure. There were additional 42 deaths from D + 1 to D + 100 after SCT. Deaths during this period were associated with sepsis (33%), cardiac arrhythmia (26%) and hemorrhagic complications (10%). Overall treatment-related mortality was 14% (52/371) during the period from 7/1994 to 7/2004, the first decade of HDM/SCT for patients with AL amyloidosis at Boston University Medical Center. However, overall treatment-related mortality has considerably improved to 5% (6/125) during the period from 8/2004 to 7/2008. Improvement in treatment-related mortality rate over the past 14 years at this institution may be due to improved patient selection, to improvement in supportive care and to the cumulative experience of the treating multidisciplinary team physicians. In summary, HDM/SCT in AL amyloidosis presents unique clinical challenges, particularly because of the cardiovascular instability of patients and the risks of both thrombosis and bleeding. Both clinicians and patients who proceed with this aggressive form of therapy must be prepared for both the usual and unusual toxicities that may occur. Treatment-related mortality can be expected to be substantially greater at centers with limited experience with HDM/SCT for AL amyloidosis, compared with centers with much experience that focus on this complex disease.

Febrile Reactions Occurring With Second Cycle of High Dose Melphalan and Stem Cell Transplantation in Patients With AL Amyloidosis: A “Melphalan Recall” Reaction

Systemic AL amyloidosis is a clonal plasma cell disease characterized by the wide spread deposition of amyloid fibrils into tissues and organs. Treatment for this disease is directed towards reducing the production of amyloidogenic monoclonal light chains by attacking the underlying plasma cell dyscrasia. Aggressive treatment with high dose intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT) is effective in inducing hematologic and clinical remissions and in extending survival.