- Deferred autologous stem cell transplantation in systemic AL amyloidosis. [Journal Article]
- BCBlood Cancer J 2018 Nov 05; 8(11):101
- High-dose melphalan with autologous stem cell transplantation (ASCT) can induce durable haematological and organ responses in systemic AL amyloidosis (AL). Stringent selection criteria have improved ...
High-dose melphalan with autologous stem cell transplantation (ASCT) can induce durable haematological and organ responses in systemic AL amyloidosis (AL). Stringent selection criteria have improved safety of ASCT in AL but most patients are transplant-ineligible. We report our experience of deferred ASCT in AL patients who were transplant-ineligible at presentation but had improvements in organ function after induction chemotherapy, enabling them to undergo ASCT. Twenty-two AL patients underwent deferred ASCT from 2011 to 2017. All had serial organ function and clonal response assessment. Organ involvement and responses were defined by amyloidosis consensus criteria. All patients were transplant-ineligible at presentation, predominantly due to advanced cardiac involvement. All received bortezomib-based therapy, with 100% haematologic response (86% complete response (CR)/very good partial response (VGPR)), enabling reversal of ASCT exclusion criteria. Patients underwent deferred ASCT for haematologic progression (45%) or consolidation (55%). There was no transplant-related mortality. Haematologic responses post-ASCT: CR 50%, VGPR 27%, PR 18%, non-response 5%. In all, 85.7% achieved cardiac responses. Median overall survival (OS) was not reached. Median progression-free survival (PFS) was 54 months. This selected cohort achieved excellent haematologic responses, organ responses, PFS and OS with deferred ASCT. If larger studies confirm these findings, this may widen the applicability of ASCT in AL.
- Melphalan dose in myeloma patients ≥65 years of age undergoing high-dose therapy and autologous stem cell transplantation: a multicentric observational registry study. [Journal Article]
- BMBone Marrow Transplant 2018 Nov 02
- The optimal melphalan dose prior to autologous stem cell transplantation (ASCT) is not known for elderly multiple myeloma (MM) patients. We analyzed data of all MM patients ≥65 years (n = 388) enroll...
The optimal melphalan dose prior to autologous stem cell transplantation (ASCT) is not known for elderly multiple myeloma (MM) patients. We analyzed data of all MM patients ≥65 years (n = 388) enrolled in the observational Swiss Blood Stem Cell Transplantation Registry. The median age was 67 years (65-77). Single ASCT was performed in 344 (88.7%) patients, with 259 patients (75.3%) receiving a melphalan dose of 200 mg/m2 (MEL200), and 85 patients (24.7%) receiving lower doses (MELlow) (median 140 mg/m2, range 70-180 mg/m2). MEL200 patients were slightly younger, and had a better renal function, but did not differ with regards to ISS stage, cytogenetic risk, remission status, and KPS. Overall mortality at day 100 was 1.5% without differences between the MEL groups (p = 0.621). Median progression-free survival (PFS) in the MEL200 and the MELlow group was 27.7 and 22.1 months, respectively (p = 0.294). Median overall survival (OS) in the MEL200 and in MELlow group was 91.2 and 61.2 months (p = 0.015). However, multivariate analysis showed no significant association of the melphalan dose and OS (HR 0.734; CI95% 0.264-2.038; p = 0.553). In conclusion, our data reveal no significant differences in safety and PFS for elderly myeloma patients treated with MEL200 or with lower MEL doses.
- Safety and efficacy of propylene glycol-free melphalan as conditioning in patients with AL amyloidosis undergoing stem cell transplantation. [Journal Article]
- BMBone Marrow Transplant 2018 Nov 02
- High-dose melphalan is the standard conditioning regimen for patients with AL amyloidosis receiving autologous stem cell transplantation. Conventional formulations require propylene glycol (PG) as a ...
High-dose melphalan is the standard conditioning regimen for patients with AL amyloidosis receiving autologous stem cell transplantation. Conventional formulations require propylene glycol (PG) as a co-solvent and melphalan has limited solubility and chemical stability after reconstitution, with potential risks for propylene glycol-related complications. Captisol-stabilized propylene glycol-free (PG-free) melphalan has been developed with improved solubility and chemical stability. We compared a cohort of patients with AL amyloidosis receiving PG melphalan (n = 96) to those receiving PG-free melphalan (n = 48) as conditioning for autologous stem cell transplantation. Median time to neutrophil and platelet engraftment was the same; 14 days PG melphalan vs 14 days PG-free melphalan, p = 0.73 and 16 days PG melphalan vs 16 days PG-free melphalan, p = 0.52, respectively. Hospitalization rate was similar in both cohorts, 68% PG melphalan vs 58% PG-free melphalan, p = 0.27. All-cause mortality at 100 days was not statistically significant, 3% PG melphalan vs 2% PG-free melphalan, p > 0.99. Overall response rate (ORR) and rates of complete response (CR) were similar (ORR 93% PG melphalan vs 94% PG-free melphalan, p > 0.99 and CR 39% PG melphalan vs 32% PG-free melphalan, p = 0.46). PG-free melphalan showed a comparable safety and efficacy profile to PG melphalan in patients with AL amyloidosis receiving stem cell transplantation.
- Strategies to improve outcomes of autologous hematopoietic cell transplant in lymphoma. [Review]
- BMBone Marrow Transplant 2018 Nov 02
- High-dose chemotherapy and autologous hematopoietic cell transplantation (HDT-AHCT) remains an effective therapy in lymphoma. Over the past several decades, HDT with BEAM (carmustine, etoposide, cyta...
High-dose chemotherapy and autologous hematopoietic cell transplantation (HDT-AHCT) remains an effective therapy in lymphoma. Over the past several decades, HDT with BEAM (carmustine, etoposide, cytarabine, and melphalan) and CBV (cyclophosphamide, carmustine, and etoposide) have been the most frequently used preparatory regimens for AHCT in Hodgkin (HL) and non-Hodgkin lymphoma (NHL). This article reviews alternative combination conditioning regimens, as well as novel transplant strategies that have been developed, to reduce transplant-related toxicity while maintaining or improving efficacy. These data demonstrate that incorporation of maintenance therapy posttransplant might be the best way to improve outcomes.
- Pharmacokinetics and Exposure-Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma. [Journal Article]
- ATAdv Ther 2018; 35(11):1859-1872
- CONCLUSIONS: These data support the recommended 16 mg/kg dose of daratumumab and the respective dosing schedules in the POLLUX and CASTOR pivotal studies.
- Real-life data on safety and efficacy of autologous stem cell transplantation in elderly patients with multiple myeloma. [Journal Article]
- AHAnn Hematol 2018 Oct 27
- Autologous stem cell transplantation (ASCT) is still debatable in treatment of patients over 65 years with multiple myeloma (MM). We performed a retrospective analysis of newly diagnosed MM patients ...
Autologous stem cell transplantation (ASCT) is still debatable in treatment of patients over 65 years with multiple myeloma (MM). We performed a retrospective analysis of newly diagnosed MM patients who underwent ASCT between January 2010 and July 2016. A non-transplanted group with similar clinical characteristics, aged 65-70 years old, diagnosed and treated in the same timeline was used for comparison. We analyzed a total of 155 patients, 132 of which underwent ASCT (≤ 65 years, n = 103, median 56 years; > 65 years, n = 29, median 67 years) and 23 non-transplanted (median 68 years). Conditioning consisted of melphalan 200 mg/m2 (MEL200) in younger patients and melphalan 140 mg/m2 (MEL140) in half of elderly patients. Stratifying by age, there were no statistically significant differences concerning transplant-related myelotoxicity and non-hematopoietic toxicity; however, elderly patients conditioned with MEL200 had higher needs of transfusional support and more days of intravenous antibiotics. Those patients also had higher needs of transfusional support, higher grade of mucositis (p = 0.028), and more days of intravenous antibiotics (p = 0.019) than the elderly transplanted with MEL140. Global transplant-related mortality was 3.8%. Survival was not influenced by age. Non-transplanted elderly patients had comparable disease features, and induction response was similar in both groups (before ASCT in the transplanted cohort). Survival of transplanted elderly patients was superior to non-transplanted (OS, 59 months vs 30 months, p = 0.037; EFS, 45 months vs 27 months, p = 0.014). Selected elderly patients when transplanted have similar disease response and survival as younger patients. A higher dose of melphalan has more toxicity, but it is globally a well-tolerated procedure.
- Modified dose of melphalan-prednisone in multiple myeloma patients receiving bortezomib plus melphalan-prednisone treatment. [Journal Article]
- KJKorean J Intern Med 2018 Oct 26
- CONCLUSIONS: Modifying the dose of MP might be a feasible and effective therapeutic approach for multiple myeloma patients receiving VMP treatment.
- Overexpression of HIF-1α contributes to melphalan resistance in multiple myeloma cells by activation of ERK1/2, Akt, and NF-κB. [Journal Article]
- LILab Invest 2018 Oct 23
- Multiple myeloma (MM) commonly displays multidrug resistance and is associated with poor prognosis. Therefore, it is important to identify the mechanisms by which MM cells develop multidrug resistanc...
Multiple myeloma (MM) commonly displays multidrug resistance and is associated with poor prognosis. Therefore, it is important to identify the mechanisms by which MM cells develop multidrug resistance. Our previous study showed that multidrug resistance is correlated with overexpression of multidrug resistance protein 1 (MDR1) and Survivin, and downregulation of Bim expression in melphalan-resistant RPMI8226/L-PAM cells; however, the underlying mechanism of multidrug resistance remains unclear. In the present study, we investigated the mechanism of multidrug resistance in melphalan-resistant cells. We found that RPMI8226/L-PAM and ARH-77/L-PAM cells showed increased phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and Akt, and nuclear localization of nuclear factor κB (NF-κB). The combination of ERK1/2, Akt, and NF-κB inhibitors with melphalan reversed melphalan resistance via suppression of Survivin expression and enhanced Bim expression in melphalan-resistant cells. In addition, RPMI8226/L-PAM and ARH-77/L-PAM cells overexpressed hypoxia-inducible factor 1α (HIF-1α) via activation of ERK1/2, Akt, and NF-κB. Moreover, suppression of HIF-1α by echinomycin or HIF-1α siRNA resensitized RPMI8226/L-PAM cells to melphalan through downregulation of Survivin expression and upregulation of Bim expression. These results indicate that enhanced Survivin expression and decreased Bim expression by HIF-1α via activation of ERK1/2, Akt, and NF-κB play a critical role in melphalan resistance. Our findings suggest that HIF-1α, ERK1/2, Akt, and NF-κB inhibitors are potentially useful as anti-MDR agents for the treatment of melphalan-resistant MM.
- A three-dimensional organoid model recapitulates tumorigenic aspects and drug responses of advanced human retinoblastoma. [Journal Article]
- SRSci Rep 2018 Oct 23; 8(1):15664
- Persistent or recurrent retinoblastoma (RB) is associated with the presence of vitreous or/and subretinal seeds in advanced RB and represents a major cause of therapeutic failure. This necessitates t...
Persistent or recurrent retinoblastoma (RB) is associated with the presence of vitreous or/and subretinal seeds in advanced RB and represents a major cause of therapeutic failure. This necessitates the development of novel therapies and thus requires a model of advanced RB for testing candidate therapeutics. To this aim, we established and characterized a three-dimensional, self-organizing organoid model derived from chemotherapy-naïve tumors. The responses of organoids to drugs were determined and compared to relate organoid model to advanced RB, in terms of drug sensitivities. We found that organoids had histological features resembling retinal tumors and seeds and retained DNA copy-number alterations as well as gene and protein expression of the parental tissue. Cone signal circuitry (M/L+ cells) and glial tumor microenvironment (GFAP+ cells) were primarily present in organoids. Topotecan alone or the combined drug regimen of topotecan and melphalan effectively targeted proliferative tumor cones (RXRγ+ Ki67+) in organoids after 24-h drug exposure, blocking mitotic entry. In contrast, methotrexate showed the least efficacy against tumor cells. The drug responses of organoids were consistent with those of tumor cells in advanced disease. Patient-derived organoids enable the creation of a faithful model to use in examining novel therapeutics for RB.
New Search Next
- Pharmacokinetic-Pharmacodynamic Model of Neutropenia in Patients With Myeloma Receiving High-Dose Melphalan for Autologous Stem Cell Transplant. [Journal Article]
- CPCPT Pharmacometrics Syst Pharmacol 2018 Oct 20
- High-dose melphalan (HDM) is part of the conditioning regimen in patients with multiple myeloma (MM) receiving autologous stem cell transplantation (ASCT). However, individual sensitivity to melphala...
High-dose melphalan (HDM) is part of the conditioning regimen in patients with multiple myeloma (MM) receiving autologous stem cell transplantation (ASCT). However, individual sensitivity to melphalan varies, and many patients experience severe toxicities. Prolonged severe neutropenia is one of the most severe toxicities and contributes to potentially life-threatening infections and failure of ASCT. Granulocyte-colony stimulating factor (G-CSF) is given to stimulate neutrophil proliferation after melphalan administration. The aim of this study was to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model capable of predicting neutrophil kinetics in individual patients with MM undergoing ASCT with high-dose melphalan and G-CSF administration. The extended PK/PD model incorporated several covariates, including G-CSF regimen, stem cell dose, hematocrit, sex, creatinine clearance, p53 fold change, and race. The resulting model explained portions of interindividual variability in melphalan exposure, therapeutic effect, and feedback regulation of G-CSF on neutrophils, thus enabling simulation of various doses and prediction of neutropenia duration.