Intravenous Melphalan Research Articles

The effects of substituting cladribine for fludarabine on outcomes of a reduced intensity conditioning regimen.

e18518 Background: Drug shortages may be encountered especially in times of pandemics and war. The extrapolation of data focusing on different diseases may provide clinical clues for substituting two chemotherapeutic drugs of the same class. The substitution of cladribine for fludarabine in a reduced intensity conditioning (RIC) regimen composed of fludarabine, melphalan and total body irradiation (TBI) may yield similar side effect profile and outcomes. Methods: Consecutive patients undergoing an allogeneic stem cell transplant in our center between November 2019 to December 2022 were included. Within this period cladribine had to be substituted for fludarabine during a drug shortage. All patients received intravenous melphalan 75 mg/m2/day on day -2, and 200 cGy TBI on day -1. The regimen included either subcutaneous cladribine 10 mg/m2/day on days -5 to -2, or intravenous fludarabine 40 mg/m2/day on days -5 to -2. Graft versus host disease (GvHD) prophylaxis included a calcineurin inhibitor (CNI) + mycophenolate mofetil (MMF) for matched related donor transplants; and post-transplant cyclophosphamide + CNI + MMF for matched unrelated (MUD) and haploidentical donors. The distributions and medians of studied parameters in two cohorts were compared with non-parametric methods. Overall survival (OS), progression-free survival (PFS) and transplant-related mortality (TRM) were estimated by the Kaplan-Meier Method. The cut-off for statistical significance was defined as p<0.05. Results: A total of 70 patients (27 in cladribine and 43 in fludarabine cohort) were included. Median age was 59 (22 to 76) and 64.3% constituted males. Median follow-up was 10.2 months (0.1 to 44.7). Acute leukemia diagnosis, intermediate to high disease risk index (DRI) and intermediate to high Charlson comorbidity index (CCI) constituted 45.7%, 60.0% and 58.1% respectively. Haploidentical donors were used in 28.6%. The distribution of gender, diagnosis, DRI and CCI scores, donor type, total CD34 dose given, panel reactive antibody (PRA) positivity were similar. Median days to neutrophil engraftment was shorter with fludarabine (19 vs 16, p=0.01), however, median duration of in-unit stay was similar (27 vs 28 days, p=0.73). TRM, nausea and acute GvHD frequency was lower with cladribine (p=0.35, p=0.001 and p=0.02, respectively). Typhilitis and perianal infections were more common with cladribine (p=0.07 and p=0.04, respectively). OS and PFS were similar (p=0.81 and p=0.66, respectively). When cladribine was compared to fludarabine on day +90, OS was 78,0% (95% CI: 62.3-93.7) vs 65,0% (95% CI: 51.3-78.7); PFS was 70.0% (95% CI: 52.4-87.6) vs 65.0% (95% CI: 51.3-78.7); TRM was 19.0% (95% CI: 3.3-34.7) vs 24.0% (95% CI: 10.3-37.7). Conclusions: Cladribine may be safely constituted for cladribine in a RIC regimen and may yield similar, even some favorable, outcomes when compared to fludarabine.

Increased Exceptional Response and Overall Survival Advantage for Patients with Multiple Myeloma Receiving Melphalan 200mg/m 2 Vs 140 Mg/m 2 Conditioning for Autologous Hematopoietic Stem Cell Transplantation

The standard conditioning regimen for multiple myeloma patients undergoing autologous hematopoietic stem cell transplant (HSCT) is intravenous melphalan dosed at 200mg/m 2 (mel200). Prior retrospective studies indicated that dose reduction to melphalan 140 mg/m 2 (mel140) confers similar progression-free (PFS) and overall survival (OS), leading to increased use of mel140 in patients with comorbidities or advanced age. A recent single-center retrospective study (Sharma et al, Leukemia Lymphoma 2023) identified an OS advantage yet similar PFS for mel200 vs mel140, suggesting that certain patient cohorts may benefit from mel200. These findings require confirmation and better understanding of the risks and benefits to different dosing strategies. We performed a single-center retrospective study of mel dosing and transplant outcomes at the University of Nebraska Medical Center between 2008-2018. Three hundred and sixty-two patients underwent a first autologous HSCT with mel conditioning; 95 received mel140 while 267 received mel200. Nearly all patients received maintenance therapy (n= 357, 99%). Patient demographic and disease factors were largely comparable between mel140 and mel200 cohorts including sex, response prior to HSCT (both 73% for very good partial response or better), and presence of high-risk cytogenetics (t(4;14), t(14;16), t(14;20), del17p; 15% vs 14%). The mel140 group was older (65.1 years vs 59.7 years), had higher hematopoietic cell transplantation-specific comorbidity index (HCT-CI) scores (64% vs 40% at ³3), and International Staging System (ISS) stages (40% vs 22% at stage III) than the mel200 group. Average creatinine clearance at transplant was 71 vs 91 mL/min/m 2 in the mel140 vs mel200 cohorts, respectively. OS favored mel200 with a median survival time of 94.4 vs 69.1 months (mel200 vs mel140, Figure 1, p = 0.002). There was no statistical difference in PFS between mel200 vs mel140 (median PFS 73.0 vs 60.5 months, p = 0.43, respectively). With Cox proportional hazards regression, we performed a multivariate analysis of risk factors on PFS and OS. For OS, age ( p = 0.02) retained statistical significance within the model. Mel dosing and high-risk cytogenetics (both p = 0.09) did not retain significance. HCT-CI may have an effect ( p = 0.04), but due to missing data on n= 125/362 subjects this could not be well evaluated. Response prior to HSCT, creatine clearance at transplant, and ISS stage were not statistically significant. Given the multiple variables assessed and missing data for HCT-CI we separately analyzed mel dosing together with the most significant variable in the model, age. In this subset OS model, mel200 was associated with an improved OS (hazard ratio (HR) 0.64, p = 0.03) while age was associated with an adverse effect (HR 1.11 per 5-year increase, p = 0.06). For the multivariate PFS model, only high-risk cytogenetics (HR 1.82 yes vs no, p = 0.004) retained statistical significance. Median engraftment was faster in mel200 cohort (67% vs 92% engraftment starting at ³D+12, p <0.001). We next examined the impact of mel dosing on the rate of exceptional response (Paquin et al, Blood Cancer Journal 2020), defined as alive and progression-free for 8 or more years. Twenty-nine of 362 patients (8%) met the requirements for exceptional response. Two (7%) received mel140 while 27 (93%) received mel200. Exceptional responders were younger and split evenly between male and female. The majority had at least a very good partial response prior to HSCT (79%). Only 2 exhibited high-risk cytogenetics; one received bortezomib and lenalidomide maintenance, the other only bortezomib. On multivariate analysis, only two factors contributed to exceptional response: mel dose (mel200 odds ratio (OR) 5.22, Table 1, p = 0.01) and HCT-CI (OR 0.66 for increasing score, Table 1, p = 0.02. High-risk cytogenetics was not associated with exceptional responders (OR 0.43 yes vs no, p = 0.38) which may be due to low sample size. We conclude that mel dosing impacts OS but not PFS in our cohort, though this effect is confounded by increasing age and potentially comorbidity. We report for the first time that mel200 dosing increases the rate of exceptional response compared to mel140. Overall, these data support recent conclusions by Sharma et al and challenge the previous reports of similar OS outcomes between mel200 and mel140 dosing.

Survival outcomes following autologous stem cell transplant with melphalan 140mg/m2 versus 200mg/m2 preparative regimens in patients with multiple myeloma

The standard preparative regimen for autologous stem cell transplant (ASCT) in multiple myeloma (MM) is 200 mg/m2 of intravenous melphalan; however, a dose of 140 mg/m2 is often used when concerns exist related to patient age, performance status, organ function, and other factors. It is unclear whether a lower dose of melphalan impacts post-transplant survival outcomes. We performed a retrospective review of 930 patients with MM who underwent ASCT with 200 mg/m2 versus 140 mg/m2 melphalan. On univariable analysis, no difference in progression-free survival (PFS) was observed, however, an overall survival (OS) benefit was observed in patients receiving 200 mg/m2 melphalan (p = 0.04). Multivariable analyses showed patients receiving 140 mg/m2 faired no worse than those receiving 200 mg/m2. While a subset of younger patients with normal renal function may achieve superior OS with a standard dose of 200 mg/m2 melphalan, these findings suggest an opportunity to individualize the ASCT preparative regimen to optimize outcomes.

Reduced-Intensity Conditioning with Fludarabine/Busulfan Versus Fludarabine/Low-Dose Melphalan in Patients with Non-Hodgkin Lymphoma Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Background Allogeneic hematopoietic stem cell transplantation (HCT) is a curative treatment for patients with relapsed and refractory non-Hodgkin lymphoma (NHL). Although reduced-intensity conditioning (RIC) regimens are the standard treatment, the optimal regimen remains unknown. Fludarabine plus a reduced dose of busulfan (Flu/Bu2) and intermediate-dose melphalan (140 mg/m2; Flu/Mel140) are commonly used in RIC regimens for patients with NHL. In contrast, fludarabine plus low-dose melphalan (80-100 mg/m2; Flu/Mel80-100) is expected to reduce non-relapse mortality (NRM), and the Flu/Mel100 regimen appears to be at least as effective as the Flu/Mel140 regimen in a single-center cohort. Several studies have compared the use of Flu/Bu2 and Flu/Mel140 in patients with NHL and reported that Flu/Bu2 was associated with a lower NRM and higher overall survival (OS) compared to Flu/Mel140. However, no studies have compared Flu/Bu2 and Flu/Mel80-100 in patients with NHL. Therefore, this study aimed to compare Flu/Bu2 and Flu/Mel80-100 in patients with NHL undergoing allogeneic HCT. Methods This study included 523 adult patients with NHL who underwent allogeneic HCT following Flu/Bu2 (269 patients) or Flu/Mel80-100 (254 patients) for the first time between January 2009 and December 2020. We excluded patients whose donor source was cord blood or whose graft versus host disease prophylaxis was posttransplant cyclophosphamide. Flu/Bu2 consisted of fludarabine (125-180 mg/m2) and intravenous busulfan (6.4 mg/kg), while Flu/Mel80-100 consisted of fludarabine (125-180 mg/m2) and intravenous melphalan (80-100 mg/m2). Administration of total body irradiation at a low dose (≤ 4 Gy) and anti-thymocyte globulin were permitted. Missing data were imputed using a single-imputation method. The primary endpoint was 5-year OS, and the secondary endpoints were 5-year progression-free survival (PFS), 5-year cumulative incidence of relapse, and 5-year cumulative incidence of NRM. OS and PFS were evaluated using the log-rank test. The other endpoints were evaluated using Gray's method. Multivariable analyses were performed to estimate the treatment effects of Flu/Bu2 compared with those of Flu/Mel80-100 using the Cox proportional hazards model, to adjust for potential confounding factors between Flu/Bu2 and Flu/Mel80-100 that could influence the outcomes. In addition, an inverse probability of treatment weighting (IPTW) approach that was based on a propensity score was used for OS. The endpoints are shown as hazard ratios (HRs) and 95% confidence intervals (CIs). Results The median age was 56 years (interquartile range, 49-62 years), and 307 patients (59%) were male. There were 313 (60%) patients with B-cell NHL and 210 (40%) patients with natural killer/T-cell NHL. Regarding disease status at transplant, 297 patients (57%) had complete or partial response, and 226 (43%) patients had no response. Significantly more patients in the Flu/Mel80-100 group had Eastern Cooperative Oncology Group Performance Status > 2, total body irradiation administration, and > 3 chemotherapy lines before allogeneic HCT. Regarding the primary endpoint, the 5-year OS were 55.5% (95% CI, 49.1-61.4) and 43.2% (95% CI, 36.2-50.0) in the Flu/Bu2 and Flu/Mel80-100 groups, respectively (p = 0.011). In the multivariable analysis, the HR of 5-year OS was 1.38 (95% CI, 1.06-1.81) compared to the Flu/Bu2 and Flu/Mel80-100 groups (p = 0.018). After applying IPTW, the 5-year OS were 55.2% (95% CI, 48.7-61.7) and 43.5% (95% CI, 36.3-50.6) in the Flu/Bu2 and Flu/Mel80-100 groups, respectively (p = 0.031) (Figure). The adjusted HR of 5-year OS was 1.46 (95% CI, 1.13-1.90) compared to that of the Flu/Bu2 and Flu/Mel80-100 groups (p = 0.004). Regarding the secondary endpoint, the Flu/Bu2 group had a similar 5-year PFS, with an adjusted HR of 1.12 (95% CI, 0.88-1.43, p = 0.34), similar 5-year cumulative risk of relapse, with an adjusted HR of 0.82 (95% CI, 0.63-1.06, p = 0.13), and lower cumulative risk of NRM, with an adjusted HR of 1.58 (95% CI, 1.05-2.38, p = 0.027). Conclusion In this population, the 5-year OS was better in patients who received Flu/Bu2 than in those who received Flu/Mel80-100. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Gastrointestinal Bleeding Secondary to High-Dose Melphalan Pretreatment in Patients with Multiple Myeloma Was Associated with the Mode of Melphalan Administration.

Objective To analyze the characteristics of gastrointestinal bleeding secondary to high-dose melphalan pretreatment in patients with multiple myeloma. Methods Between 1 January 2016 and 31 October 2021, 26 patients with multiple myeloma after autologous peripheral blood hematopoietic stem cell transplantation with high-dose melphalan pretreatment were recruited. They were assigned to either the oral administration group or the intravenous administration group according to the administration modes, or to either the gastrointestinal bleeding group or the nongastrointestinal bleeding group. Analyses were performed based on the differences in general gastrointestinal symptoms and hemorrhage between different administration modes and on the differences in the general gastrointestinal symptoms, platelet alterations, and the intestinal microecology before pretreatment between patients with and without gastrointestinal bleeding. Results Of the 26 included patients, heavy secondary gastrointestinal bleeding was found in 6 patients with intravenous pretreatment. In patients given intravenous melphalan, those with gastrointestinal bleeding showed more pronounced general symptoms such as nausea and vomiting versus those without. There was no significant difference in platelet alterations between the two groups. Gastrointestinal bleeding was associated with more significant microecological disturbances than no bleeding. Conclusion Gastrointestinal bleeding secondary to high-dose melphalan pretreatment in patients with multiple myeloma was associated with the mode of melphalan administration, adverse symptoms at pretreatment, and the intestinal microecology prior to pretreatment. Thus, improvement of the intestinal microecology prior to pretreatment and mitigation of adverse gastrointestinal symptoms during pretreatment may contribute to a lower incidence of secondary gastrointestinal bleeding and enhanced transplantation safety.

To transplant or not to transplant in multiple myeloma

Multiple myeloma (MM) is the second most common hematologic cancer resulting from proliferation and accumulation of abnormal plasma cells (myeloma cells) with a preferential homing in the bone marrow. It causes significant morbidity including lytic bone lesions, renal insufficiency, anemia, and infections, to name just a few. Although MM remains largely incurable, it is a chemo-sensitive disease. The use of high-dose intravenous melphalan (100-140 mg/m2) in the treatment of MM was first studied almost 4 decades ago.Subsequently, the dose of melphalan was increased and was followed by autologous hematopoietic stem cell to decrease the aplasia-associated toxicity. Results from phase 3 studies comparing chemotherapy alone to chemotherapy followed by high-dose melphalan and autologous stem cell transplantation appeared in the mid-90s with the publication of the IFM-90 study demonstrating significant clinical benefits on response rate, event-free survival and even overall survival in a cohort of two hundred previously untreated patients under the age of 65 years. This landmark study was followed by confirmatory studies in the early 2000’s. Within the last 2 decades, although improvement in the treatment of transplant-eligible patients is mostly the result of better induction regimens and due to the addition of maintenance therapies, autologous stem cell transplantation remains a cornerstone treatment for MM patients. Indeed, despite novel and more effective treatments for MM, autologous stem cell transplantation continues to demonstrate clinical benefits (Table 1). Moreover, tandem autologous transplantation has demonstrated progression-free survival and overall survival benefits for some patients with poor risk cytogenetics.
 In 2022, with better knowledge of MM, awareness of potential consequences of high-dose melphalan and with novel and more effective treatment modalities, the role of autologous stem cell transplantation is certainly becoming a question for debate. The purpose of this article is to present the pros and cons of autologous stem cell transplantation in our Canadian reality (Figure 1). This article aims to better assess its role as a therapeutic option considering our health system’s limited resources in which many novel drugs will not be available/accessible in Canada for several more years to come.

Guidelines for high dose chemotherapy and stem cell transplantation for systemic AL amyloidosis: EHA-ISA working group guidelines

AL amyloidosis is a systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. High dose intravenous melphalan and autologous stem cell transplantation was developed for the treatment of AL amyloidosis in the early 1990s and was prompted by its success in multiple myeloma. This application has evolved significantly over the past three decades. These guidelines provide a comprehensive assessment of eligibility criteria, stem cell collection and mobilisation strategies and regimens, risk-adapted melphalan dosing, role for induction and consolidation therapies, specific supportive care management, long-term outcome with respect to survival, haematologic response and relapse and organ responses following stem cell transplantation. These guidelines are developed by the experts in the field on behalf of the stem cell transplant working group of the International Society of Amyloidosis (ISA) and European Haematology Association (EHA).

Droxidopa for Treatment of Refractory Orthostatic Hypotension in Patients with AL Amyloidosis: A Case Series

BackgroundOrthostatic hypotension due to autonomic dysfunction is a well-known complication of light chain (AL) amyloidosis, which can become progressively debilitating and difficult to manage. Treatment of the underlying plasma cell dyscrasia will eventually decrease further amyloid deposition. Management of orthostatic hypotension secondary to AL amyloidosis improves quality of life and facilitates delivery of plasma cell therapy. Pharmacologic interventions include fludrocortisone, sympathomimetic agents such as midodrine, droxidopa, the acetylcholinesterase inhibitor pyridostigmine or the norepinephrine transporter (NET) inhibitor atomoxetine. Fludrocortisone is often poorly tolerated in amyloid patients because it may exacerbate edema. Droxidopa is a synthetic amino acid analog that is directly metabolized to norepinephrine by dopa-decarboxylase, which increases blood pressure (BP) by inducing peripheral arterial and venous vasoconstriction.AimsTo assess the effectiveness of droxidopa in patients with AL amyloidosis with severe orthostatic hypotension refractory to midodrine. Also, to describe effective dose of droxidopa, duration of therapy, adverse effects and reasons for discontinuation.MethodsA regional retrospective study was done in patients with AL amyloidosis with severe, refractory orthostatic hypotension who received droxidopa. Retrospective data was reviewed from 2018 to 2021 at a single academic center in the United States.ResultsFive patients with AL amyloidosis were included in the study; three patients had lambda-restricted plasma cell dyscrasia and two had multiple myeloma (MM) associated AL amyloidosis (both kappa light chain restricted). Of the five patients, all had cardiac, renal, autonomic nervous system and peripheral nervous system involvement and two of the five had gastrointestinal involvement as well. Given their poor performance status and advanced organ involvement, none of the patients were eligible for high-dose intravenous melphalan with autologous peripheral blood stem cell transplantation (HDM/SCT), and thus were treated with cyclophosphamide, bortezomib and dexamethasone (CyBorD). All patients achieved very good partial response to complete hematologic response. The main findings are summarized in table 1.All patients had severe, symptomatic orthostatic hypotension that was objectively defined as a decrease in systolic blood pressure by 20 millimeters of mercury (mmHg) or a decrease in diastolic blood pressure of 10 mmHg from supine to either sitting or standing in the clinic or at home (Freeman R consensus statement on the definition of orthostatic hypotension, 2011). Initial treatment for all patients included midodrine, ranging from 5 to 30mg TID based on individual tolerance. Three of the patients also were initially treated with fludrocortisone 0.05 to 0.2mg daily (use limited by fluid retention). Only one patient was on pyridostigmine 30mg TID (case 5). Given persistence of symptoms despite therapy, droxidopa was started at 100mg TID in all patients, and the dose was titrated as tolerated. None required the maximal approved dose of 600mg TID.The indication to start droxidopa was based on refractory, symptomatic orthostatic hypotension in all five patients. After initiation of droxidopa, all except for one patient reported improvement both in symptoms of lightheadedness as well as measurements of orthostatic blood pressure values. By the end of this study, three patients continued treatment with droxidopa (cases 1-3); one was weaned-off after resolution of symptoms (case 5) and one was discontinued due to supine hypertension (case 4).ConclusionData shows that droxidopa is an effective treatment of orthostatic hypotension refractory to midodrine in patients with AL amyloidosis. Slow titration may be important to minimize rapid changes in blood pressure. Further studies are warranted to assess droxidopa's safety and compare with other treatments for orthostatic hypotension. [Display omitted] DisclosuresHughes: Amgen: Speakers Bureau; Rigel: Other: Advisory Board, Research Funding; Abbvie: Speakers Bureau; Karyopharm: Other: Advisory Board, Speakers Bureau. Sanchorawala: Celgene: Research Funding; Takeda: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Oncopeptide: Research Funding; Karyopharm: Research Funding; Sorrento: Research Funding; Pfizer: Honoraria. Sloan: Nuvectis: Consultancy; Abbvie: Consultancy; Stemline: Consultancy; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Pharmacosmos: Membership on an entity's Board of Directors or advisory committees.

Lentivirus-mediated gene therapy for Fabry disease

Enzyme and chaperone therapies are used to treat Fabry disease. Such treatments are expensive and require intrusive biweekly infusions; they are also not particularly efficacious. In this pilot, single-arm study (NCT02800070), five adult males with Type 1 (classical) phenotype Fabry disease were infused with autologous lentivirus-transduced, CD34+-selected, hematopoietic stem/progenitor cells engineered to express alpha-galactosidase A (α-gal A). Safety and toxicity are the primary endpoints. The non-myeloablative preparative regimen consisted of intravenous melphalan. No serious adverse events (AEs) are attributable to the investigational product. All patients produced α-gal A to near normal levels within one week. Vector is detected in peripheral blood and bone marrow cells, plasma and leukocytes demonstrate α-gal A activity within or above the reference range, and reductions in plasma and urine globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) are seen. While the study and evaluations are still ongoing, the first patient is nearly three years post-infusion. Three patients have elected to discontinue enzyme therapy.

Transplant Outcomes with Fludarabine and Melphalan in High Risk AML Patients By Donor Types

Background: Fludarabine and melphalan (FM) reduced intensity conditioning regimen has been widely used for allogeneic stem cell transplantation (allo-SCT) in AML patients not eligible for more ablative regimens. In this study, we looked into a contemporary group of high risk AML patients treated with FM and updated their outcome expectation by donor type. Methods: We included 292 AML patients who had first allo-SCT between January 2010 and December 2019 if their donors were haploidential (haplo, n=142) or matched related sibling (MSD, n=49) or matched unrelated donor (MUD, n=101) and their conditioning regimen was intravenous melphalan given as 100 mg/m2 or 140 mg/m2 in addition to fludarabine. Graft versus host disease (GvHD) prophylaxis was either tacrolimus and methotrexate (n=91) or tacrolimus with post-transplant cyclophosphamide (PTCy) +/- Mycophenolate mofetil (n=201). The primary outcome was relapse-free survival (RFS) defined as time to relapse or death whichever happened first. Secondary outcomes was overall survival (OS). Results: The median age was younger in haplo transplants compared with MDS or MUDs (50 vs. 63)(Table 1). There were more patients in first or second complete remission with count recovery (CR1/2) in haplo group compared with MSD (29%) and MUD (37%) but that did not reach significance (p=0.22). High risk disease risk by European Leukemia Net (ELN), advance group, was also distributed similarly between donor groups (21% in MSD, 32% in MUD and 24% in haplo, p=0.5). Hematopoietic comorbidity index (HCT-CI) >2 was frequent in all donor groups (43% in MSD, 46% MUD and 36% haplo, p=0.4). Hematopoietic stem cell source and GvHD prophylaxis differed by donor as expected; all haplo patients but 15 had bone marrow (BM, 89%) while 2% of MSD and 26% of MUD had BM. GvHD prophylaxis was PTCy in all haplo patients but half of the MUD patients (49%) and some of the MSD also received PTCy (20%). The median follow-up of 143 survivors was 24 months (range, 1 to 102 months). RFS at 2 years was 41.6% (95% confidence interval (CI) 35.5%- 47.6%) and OS was 48.6% (95% CI=42.1%-54.7%). Outcome estimates by donor types are presented in table 2. Considering the haplo patients were younger, we also analyzed RFS for older patients aged >50 and >60 separately (Figure). Causes of death was mostly relapse in all donor types; 54.2% in MSD, 40.4% in MUD and 44.7% in haplo. Cox regression model for RFS revealed that CR1/2 or CR without count recovery (CRi/p) were favorable prognostic variables compared with advanced disease (hazard ratio (HR)=0.35, 95%CI=0.25-0.51, p<0.001 and HR=0.65, 95%CI=0.44-0.96, p=0.03) but ELN adverse risk (HR=1.91, 95%CI=1.37-2.65, p<0.001) and HCT-CI>2 (HR=1.62, 95%CI=1.17-2.23, p=0.003) were poor prognostic markers. Age >50 was not a prognostic factor for RFS. Conclusion: FM remains to be an effective conditioning regimen that is leading to similar RFS after transplant with different donor types. Despite smaller sample size, even older haploidentical patients had RFS that was not significantly different compared with older MSD and MUD patients. However, relapse remains to be the major reason of failure in patients with high risk features including disease status not in CR with count recovery at allo-SCT and/or adverse ELN risk. Innovative strategies either with more ablative regimens or post-transplant maintenance or integration of cellular therapy options are needed to improve outcomes for those AML patients. Disclosures Oran: Celgene: Consultancy; ASTEX: Research Funding; Arog Pharmaceuticals: Research Funding. Ciurea:Kiadis Pharma: Current equity holder in publicly-traded company, Research Funding. Mehta:Incyte: Research Funding; Kadmon: Research Funding; CSL Behring: Research Funding. Alousi:Incyte: Honoraria, Research Funding; Therakos: Research Funding; Alexion: Honoraria. Popat:Bayer: Research Funding; Novartis: Research Funding. Kebriaei:Pfizer: Other: Served on advisory board; Amgen: Other: Research Support; Ziopharm: Other: Research Support; Novartis: Other: Served on advisory board; Jazz: Consultancy; Kite: Other: Served on advisory board. Champlin:Actinium: Consultancy; Cytonus: Consultancy; Omeros: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Takeda: Patents & Royalties; Genzyme: Speakers Bureau; Johnson and Johnson: Consultancy.

Palliative cytoreduction with low dose intravenous melphalan in patients with acute myeloid leukemia refractory to prior treatment

ABSTRACT Background Hyperproliferative crises with hyperleukocytosis occur frequently in the disease course of refractory or relapsed acute myeloid leukemia (AML). Palliative cytoreduction aims to control blast count in order to avoid life-threatening complications and preserve quality of life in patients unfit for intensive treatment. In our center, low-dose intravenous melphalan is sometimes used with this intent. Methods We performed a retrospective analysis of patients with AML who were treated with low-dose intravenous melphalan (15–30 mg/m2) in a palliative setting. Results Thirty patients with AML who received low-dose melphalan (15–25 mg/m2) were identified. In total, 63 administrations of low-dose melphalan were counted. A clear cytoreductive effect (>50%) was seen within a few days in 78% of melphalan administrations. The median duration of response after an individual dose was 17 days (interquartile range [IQR] 10–26). The median overall survival was 29 days (IQR 16–73). Most common side effects were worsening pancytopenia with neutropenic fever and an increase in transfusion dependency and tumor lysis syndrome. Conclusion Intravenous low-dose melphalan is effective, quick and safe as palliative cytoreductive therapy in patients with hyperproliferative AML. It can be considered in palliative care of patients refractory to prior treatment with preserving acceptable quality of life. Our small retrospective cohort is the first to report the use of low-dose intravenous melphalan as palliative cytoreductive treatment in this population.

Intravenous busulfan and melphalan versus high-dose melphalan as a conditioning regimen for early autologous stem cell transplantation in patients with multiple myeloma: a propensity score-matched analysis

We compared the efficacy and toxicity of busulfan and melphalan (BUMEL) and those of high-dose melphalan (HDMEL) as conditioning regimens for autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM) through a propensity score-matched analysis. No significant difference in the complete response and overall response rate after ASCT was observed between BUMEL and HDMEL. After a median follow-up of 37.3 months in the BUMEL group and 50.8 months in the HDMEL group, the median progression-free survival was calculated to be 32.9 months and 25.2 months (p = 0.995). With respect to non-hematologic toxicities, infections were more frequently reported in the BUMEL group (p < 0.001). Three patients who received BUMEL developed veno-occlusive disease (VOD), and all of them recovered without administration of defibrotide. In conclusion, BUMEL is an effective alternative conditioning regimen in terms of efficacy, but attention should be paid to toxicities.

Parietal skull extramedullary relapse in multiple myeloma

A 59-year-old man was diagnosed with kappa light chain multiple myeloma (MM), CS IIIA (DS), I (ISS), carrying del(17 p), 80% of plasma cell bone marrow infiltration and lytic bone...

BMT CTN 1803: Haploidentical Natural Killer Cells (CSTD002) to Prevent Post-Transplant Relapse in AML and MDS (NK-REALM)

Background and Rationale: Relapse remains the leading cause of treatment failure for patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic blood or marrow transplantation (BMT). Although relapse rates vary based on patient population, age, and conditioning intensity, relapse is experienced in at least 30-50% after conventional BMT in high-risk AML/MDS. Initial safety and post-BMT relapse risk reduction results are reported by investigators at MD Anderson Cancer Center in a phase I study of ex vivo-expanded, donor-derived, haploidentical natural killer (NK)-cell infusion in conjunction with haploBMT. Of 13 patients with high-risk myeloid malignancies treated with NK cells, no infusion reactions or dose-limiting toxicities occurred and only 1 patient, treated at the lowest dose of 1×105 cells/kg, relapsed (Ciurea, Blood 2017). This experience supports investigation of CSTD002, a product derived from haploidentical donor NK cells and expanded ex vivo using plasma membrane (PM21) nanoparticles bearing membrane-bound IL-21 and 4-1BBL. This study represents a public-private partnership between the sponsor (Kiadis Pharma) and the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), leveraging existing National Institutes of Health-supported clinical trials infrastructure to conduct a complex cellular immunotherapy trial. We used contemporary, unpublished data from the Center for International Blood and Marrow Transplant Research registry to determine baseline relapse rates that informed the statistical design. Doses of NK cells expanded by a novel method and exceeding those previously achieved in most published studies will be given in the peri-transplant period to test the hypothesis that haploidentical NK cells can mediate an effective anti-leukemia response. Trial Design and Methods: BMT CTN 1803 is a phase II, single-arm, open-label, multicenter trial designed to investigate the safety and efficacy of CSTD002 for the treatment of patients with high-risk AML or MDS undergoing haploBMT. An initial safety run-in phase will precede enrollment into the full study of approximately 60 patients. Major inclusion criteria of patients and donors are listed in the Table. Peripheral blood will be drawn from the donor to start the NK-cell expansion approximately 5 weeks before the planned haploBMT. Patients will receive intravenous (IV) melphalan 140 mg/m2 (100 mg/m2 for patients ≥60 years old) on Day -7; fludarabine 40 mg/m2 IV on Days -7, -6, -5, and -4; and 2 Gy of total body irradiation on Day -3. Donor bone marrow will be harvested and given on Day 0. Three doses of CSTD002 will be administered IV on Days -2, +7, and +28, relative to the haploBMT. The recommended dose of CSTD002 for administration will be formulated at 1×108 NK cells/kg of recipient body weight. Graft-versus-host disease (GVHD) prophylaxis is post-transplantation cyclophosphamide with tacrolimus and mycophenolate mofetil. The primary endpoint is cumulative incidence of relapse at 1 year post haploBMT in patients receiving at least 1 infusion of CSTD002. Secondary endpoints are safety and tolerability of CSTD002; overall survival; non-relapse mortality; relapse-free survival; GVHD-free survival; cumulative incidence of acute GVHD and chronic GVHD; hematologic recovery; donor-cell engraftment; primary and secondary graft failure; overall incidence of toxicity; and cumulative incidence of infections including cytomegalovirus re-activation and symptomatic BK virus hemorrhagic cystitis. Exploratory endpoints are systemic immunosuppression-free survival; immune reconstitution at Days 28, 100, and 365 post haploBMT; proportion of patients with detectable minimal residual disease at Days 28 and 100 post haploBMT; feasibility of administering the planned CSTD002 doses; and impact of NK-cell alloreactivity on relapse and survival. Disclosures Vasu: Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: Clinical trial support. Bejanyan:Kiadis Pharma: Other: advisory board. Devine:Kiadis Pharma: Other: Protocol development (via institution); Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta; Bristol Myers: Other: Grant for monitoring support &amp; travel support. Krakow:Bellicum Pharmaceuticals: Research Funding; Highpass Bio: Research Funding; Magnolia Innovations: Other: Personal fees. Logan:Eisai: Other: Personal fees; Astellas: Other: Grant; Kiadis (formerly Cytosen): Other: Grant; Novartis: Other: Personal fees; Kite: Other: Grant. Luznik:Merck: Research Funding, Speakers Bureau; Genentech: Research Funding; AbbVie: Consultancy; WindMiL Therapeutics: Patents &amp; Royalties: Patent holder. Barrett:Kiadis Pharma (formerly Cytosen): Other: Personal fees; Biologics Consulting Company: Other: Personal fees. Shan:Kiadis Pharma (formerly Cytosen): Employment. Champlin:Actinium: Consultancy; Johnson and Johnson: Consultancy; Sanofi-Genzyme: Research Funding.

L-type amino-acid transporter 1 (LAT1) expression is predictive of response to autologous stem cell transplantation for multiple myeloma

L-type amino acid transporter 1 (LAT1) plays a key role in cell growth and survival. Overexpression is a common feature of many malignancies to support increased protein synthesis demand. Among patients with multiple myeloma, high LAT1 expression has been shown to be associated higher risk disease but also a higher response rate following treatment with oral melphalan in clinical and pre-clinical models (Isoda, et al, Cancer Sci, 2014; Hathi, et al, J Nucl Med, 2018). Oral melphalan is infrequently used in today's clinical practice; however, high-dose intravenous melphalan is the standard of care for conditioning prior to autologous stem cell transplantation (ASCT).

Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial

High-dose chemotherapy with haemopoietic stem-cell rescue improves event-free survival in patients with high-risk neuroblastoma; however, which regimen has the greatest patient benefit has not been established. We aimed to assess event-free survival after high-dose chemotherapy with busulfan and melphalan compared with carboplatin, etoposide, and melphalan. We did an international, randomised, multi-arm, open-label, phase 3 cooperative group clinical trial of patients with high-risk neuroblastoma at 128 institutions in 18 countries that included an open-label randomised arm in which high-dose chemotherapy regimens were compared. Patients (age 1-20 years) with neuroblastoma were eligible to be randomly assigned if they had completed a multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide with or without topotecan, vincristine, and doxorubicin) and achieved an adequate disease response. Patients were randomly assigned (1:1) to busulfan and melphalan or to carboplatin, etoposide, and melphalan by minimisation, balancing age at diagnosis, stage, MYCN amplification, and national cooperative clinical group between groups. The busulfan and melphalan regimen comprised oral busulfan (150 mg/m2 given on 4 days consecutively in four equal doses); after Nov 8, 2007, intravenous busulfan was given (0·8-1·2 mg/kg per dose for 16 doses according to patient weight). After 24 h, an intravenous melphalan dose (140 mg/m2) was given. Doses of busulfan and melphalan were modified according to bodyweight. The carboplatin, etoposide, and melphalan regimen consisted of carboplatin continuous infusion of area under the plasma concentration-time curve 4·1 mg/mL per min per day for 4 days, etoposide continuous infusion of 338 mg/m2 per day for 4 days, and melphalan 70 mg/m2 per day for 3 days, with doses for all three drugs modified according to bodyweight and glomerular filtration rate. Stem-cell rescue was given after the last dose of high-dose chemotherapy, at least 24 h after melphalan in patients who received busulfan and melphalan and at least 72 h after carboplatin etoposide, and melphalan. All patients received subsequent local radiotherapy to the primary tumour site followed by maintenance therapy. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17. Between June 24, 2002, and Oct 8, 2010, 1347 patients were enrolled and 676 were eligible for random allocation, 598 (88%) of whom were randomly assigned: 296 to busulfan and melphalan and 302 to carboplatin, etoposide, and melphalan. Median follow-up was 7·2 years (IQR 5·3-9·2). At 3 years, 146 of 296 patients in the busulfan and melphalan group and 188 of 302 in the carboplatin, etoposide, and melphalan group had an event; 3-year event-free survival was 50% (95% CI 45-56) versus 38% (32-43; p=0·0005). Nine patients in the busulfan and melphalan group and 11 in the carboplatin, etoposide, and melphalan group had died without relapse by 5 years. Severe life-threatening toxicities occurred in 13 (4%) patients who received busulfan and melphalan and 29 (10%) who received carboplatin, etoposide, and melphalan. The most frequent grade 3-4 adverse events were general condition (74 [26%] of 281 in the busulfan and melphalan group vs 103 [38%] of 270 in the carboplatin, etoposide, and melphalan group), infection (55 [19%] of 283 vs 74 [27%] of 271), and stomatitis (138 [49%] of 284 vs 162 [59%] of 273); 60 (22%) of 267 patients in the busulfan and melphalan group had Bearman grades 1-3 veno-occlusive disease versus 21 (9%) of 239 in the carboplatin, etoposide, and melphalan group. Busulfan and melphalan improved event-free survival in children with high-risk neuroblastoma with an adequate response to induction treatment and caused fewer severe adverse events than did carboplatin, etoposide, and melphalan. Busulfan and melphalan should thus be considered standard high-dose chemotherapy and ongoing randomised studies will continue to aim to optimise treatment for high-risk neuroblastoma. European Commission 5th Framework Grant and the St Anna Kinderkrebsforschung.

Phase 2 study using intravenous busulfan and melphalan conditioning regimen for autologous stem cell transplantation in patients with multiple myeloma: interim analysis (KMM150)

Phase 2 study using intravenous busulfan and melphalan conditioning regimen for autologous stem cell transplantation in patients with multiple myeloma: interim analysis (KMM150)

Effect of Severe Hypoalbuminemia on Myelosuppression and Other Toxicities of High Dose Melphalan and Autologous Stem Cell Transplantation in AL Amyloidosis Patients

Background: Treatment of AL amyloidosis with high dose intravenous melphalan followed by autologous stem cell transplant (HDM/SCT) is effective in inducing hematologic and clinical remissions associated with prolonged survival. The major toxicities are myelosuppression and GI side effects. Studies have shown that ~75% of melphalan in the blood is bound to plasma proteins, with ~25% free. We hypothesized that AL patients with severe nephrotic syndrome and profound hypoalbuminemia might have a higher fraction of free melphalan, a higher effective dose, and greater toxicity of treatment.Methods: Patients with AL amyloidosis and severe hypoalbuminemia, defined as serum albumin level of < 2 g/dL, treated from 2011 to 2013, were studied retrospectively. The stem cell transplant database was queried for dose of HDM, treatment-related complications, and days of neutrophil and platelet engraftment after SCT.Results: Of 71 patients with AL amyloidosis who underwent HDM/SCT between Jan 2011 and Dec 2013, 12 patients had severe hypoalbuminemia. Of these, 5 received full HDM at 200 mg/m2 and 7 received modified HDM at 140 mg/m2. All patients received GCSF mobilized peripheral blood stem cells following HDM, with a median stem cell dose of CD34+ cells 8.1 x 106/kg (range, 4.0 to 12.2). The median time to engraftment of neutrophils was 11 days, and not statistically different based upon melphalan dose. The median time to platelet engraftment was 13 days, and also did not differ significantly by dose. These times were similar to controls without severe hypoalbuminemia. Grade 4 toxicities were observed in 2 of 7 patients with modified HDM/SCT and 1 of 5 patients with full HDM/SCT.Conclusions: These data suggest that patients with severe hypoalbuminemia do not have more prolonged myelosuppression or increased non-hematologic toxicities compared to other patients. In this retrospective study, we did not measure free melphalan concentrations in the blood. However, these data suggest that patients with severe hypoalbuminemia do not require adjustment of melphalan dosing. DisclosuresNo relevant conflicts of interest to declare.

Long-Term Outcome Of Patients With AL Amyloidosis Treated With High-Dose Melphalan and Stem Cell Transplantation: 19 Year Experience At a Single Center

Aggressive treatment of AL amyloidosis with high dose intravenous melphalan followed by autologous stem cell transplant (HDM/SCT) is effective in inducing hematologic and clinical remissions associated with prolonged survival. We have performed 593 transplants from July 1994 to December 2012 in the Amyloidosis Center at Boston Medical Center/Boston University School of Medicine. Patients were enrolled in several sequential institutional review board–approved protocols during the 19-year study period. Eligibility criteria for all protocols required biopsy proof of amyloid disease; evidence of a plasma cell dyscrasia and exclusion of other types as appropriate; at least one major affected organ; and adequate measures of cardiac and pulmonary function, and performance status. Functional measures included cardiac ejection fraction 40% or greater, absence of symptomatic pleural effusions, absence of heart failure or arrhythmias resistant to medical management, oxygen saturation of 95% or greater on room air, lung diffusion capacity of 50% or more of predicted, supine systolic blood pressure of 90 mm Hg or greater, and Southwest Oncology Group performance status score of 2 or less unless limited by peripheral neuropathy. Age, renal function, time from diagnosis, prior therapy, and details of the conditioning regimen varied among the trials.Overall, the median age of patients treated with HDM/SCT was 57 years (range, 28-80). Treatment-related mortality (TRM) defined as death occurring within 100 days after SCT occurred in 51 patients, leading to overall TRM of 9% (n=51/593). Additionally, there were 11 deaths during stem cell mobilization and collection phase. No death has occurred since 2005 during stem cell mobilization and collection and TRM has improved to 5% (n=11/235). Total of 324 patients (55%) received full dose melphalan at 200 mg/m2 and 269 (45%) received modified dose melphalan at 100-140 mg/m2 per protocol, based upon age and organ function. Hematologic CR, as defined by international consensus criteria, occurred in 40% (n=202/508) of evaluable patients measured at 6-12 months post SCT; by intention-to-treat the CR rate was 34%. Hematologic CR occurred in 44% (n=129/291) patients who received 200 mg/m2 of HDM compared to 34% (n=73/217) patients who received 100-140 mg/m2 of HDM (chi square p=0.015). Hematologic relapse occurred in 40 patients (20%) with CR at a median of 3.9 years (range, 1.6-12.4). The median overall survival (OS) is 6.7 years with a median follow-up of 4.5 years. The median OS has not been reached for patients achieving a hematologic CR but exceeds 12.4 years, compared to 5.9 years for those not achieving CR (log-rank p<0.001). The median OS for patients following hematologic relapse is 3.5 years. Twenty-five % of patients are alive, up to 19 years after undergoing HDM/SCT.These data highlight the remarkable long-term survival results that can be obtained in patients with AL amyloidosis treated with HDM/SCT. While survival is strongly dependent upon achieving a hematologic CR, the survival of patients who do not achieve a CR and of those who relapse after CR also is notable, suggesting a benefit of treatment. Strategies to improve risk-stratification of patients and reduce TRM, as well as using sequential or combination therapies to increase the CR rate, will likely improve outcomes in the future for patients who just a few years ago were considered to have a rapidly fatal diagnosis. Disclosures:No relevant conflicts of interest to declare.

A Phase 1/2, Open-Label, Prospective, Multicenter Study to Evaluate the Efficacy and Safety of the Lower Dose of Bortezomib Plus Busulfan and Melphalan As a Conditioning Regimen in Patients with Multiple Myeloma Undergoing Autologous Peripheral Blood Stem Cell Transplantation: Result of Phase 1 Trial

AbstractAbstract 1937 Background:Despite the advantages of autologous stem cell transplantation (ASCT) over conventional chemotherapy, the results of ASCT in multiple myeloma (MM) are still unsatisfactory. Intravenous (iv) melphalan at a dose of 200 mg/m2 is the most commonly used conditioning regimen for ASCT. However, better conditioning regimens are still needed, and more intensive conditioning regimens have been investigated. We evaluated the role of bortezomib-containing regimen (escalated dose of bortezomib + iv busulfan and iv melphalan) in the MM patients who had a sensitive response to bortezomib during the induction chemotherapy. In the phase 1 trial, we assessed the MTD (maximum tolerated dose) of bortezomib. The trial is registered on National Cancer Institute website, number NCT01255527. Methods:Nine MM patients who were candidate for ASCT enrolled in this study. M:F=5:4 and median age were 59 (34–62). They were treated with escalating doses of bortezomib as a conditioning regimen (N=3/group; 0.7, 1.0, and 1.3 mg/m2 on D-6, D-3 & D+1) and a fixed dose of busulfan (3.2 mg/kg from D-5 to D-3) and melphalan (140 mg/m2 on D-2). Dose limiting toxicities (DLT) were defined as any toxicity of grade 3 or greater, with the following exceptions: vomiting, fatigue, alopecia, libido, amenorrhea, nausea, febrile neutropenia, infection, anorexia, depression, anxiety, and cytopenias. Grade 3/4 hematological toxicity was acceptable. Grade 4 of mucositis, °Ã Grade 3 diarrhea and °Ã Grade 3 cardiac toxicity were regarded as DLT. Only one patients had grade 3 oral mucositis and there were no other non hematologic toxicities of grade 3 or greater. DLT refers only to toxic events (symptomatic grade °Ã 3 toxicity) that occur until day +28 after ASCT and are attributed as possibly, probably, or definitely due to treatment. Results:Four patients had grade 3 oral mucositis (2 in 0.7 mg/m2 group, 1 in 1.0 mg/m2 group and 1 in 1.3 mg/m2 group), but no grade 4 (considered as DLT) oral mucositis. No other non hematologic toxicities of grade 3 or greater. Therefore, there were no dose limiting toxicities in this phase 1 trial and MTD of bortezomib was 1.3 mg/m2. Median times to ANC > 0.5 · 106/L and platelet > 20 · 106/L were 12 and 10 days, respectively, with no graft failures. All patients achieved at least very good partial response. Six patients (67%) achieved complete remission(CR) after ASCT. Conclusion:In the phase 1 trial, MTD of bortezomib was 1.3 mg/m2. Addition of bortezomib to busulfan and melphalan conditioning regimen shows to be safe, well-tolerated and worthy of phase 2 trial. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.