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Hematology/oncology and Stem Cell... Dec 2022Lymphoma is seen as a highly treatable and curable malignancy with aggressive treatment methods. Efficacy is often limited by toxicity and many patients need alternative...
OBJECTIVE/BACKGROUND
Lymphoma is seen as a highly treatable and curable malignancy with aggressive treatment methods. Efficacy is often limited by toxicity and many patients need alternative treatment strategies as they cannot tolerate existing high cytotoxic approaches. Our aim is to compare BEAM [carmustine (BCNU), etoposide, cytarabine (ARA-C, cytosine arabinoside), and melphalan] and mitoxantrone-melphalan (Mx-Mel) regimens utilized in our patients with a diagnosis of lymphoma who underwent autologous stem cell transplantation (ASCT), and to demonstrate that the Mx-Mel regimen has similar but less toxic results than the BEAM regimen we have been using frequently as standard conditioning regimen.
METHODS
A total of 101 patients with lymphoma who underwent ASCT were included in our study. The BEAM regimen included BCNU, etoposide, ARA-C, and melphalan. The Mx-Mel regimen included mitoxantrone and melphalan.
RESULTS
Of 101 patients included in the study, 60 (59.4%) received BEAM and 41 (40.6%) received Mx-Mel (40.6%) conditioning regimen. The median time to neutrophil engraftment was 10 (range: 9-20) days and 12 (range: 9-12) days in the BEAM and Mx-Mel arms, respectively; it was statistically significantly shorter in the BEAM arm (p = .001).
CONCLUSION
This study demonstrates that the Mx-Mel regimen has similar efficacy and toxicity compared with the BEAM regimen. Although time to neutrophil engraftment was shorter in the BEAM arm, it did not result as significant transplant-related complications between the two regimens. The Mx-Mel regimen is seen as a good alternative with low toxicity and high efficacy.
Topics: Humans; Carmustine; Melphalan; Etoposide; Mitoxantrone; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Lymphoma; Cytarabine; Antineoplastic Combined Chemotherapy Protocols; Transplantation Conditioning
PubMed: 33933474
DOI: 10.1016/j.hemonc.2021.03.005 -
Transplantation and Cellular Therapy Dec 2022For eligible patients with multiple myeloma (MM) and amyloid light chain (AL) amyloidosis, high-dose chemotherapy and autologous hematopoietic cell transplantation (HCT)...
For eligible patients with multiple myeloma (MM) and amyloid light chain (AL) amyloidosis, high-dose chemotherapy and autologous hematopoietic cell transplantation (HCT) is a standard and widely used consolidation therapy. Autologous HCT requires specialized care at a transplantation center and investment from patients and caregivers. We studied the safety and feasibility of delivering transplantation care in a homebound setting to decrease the burden of therapy and increase access to autologous HCT. Patients with MM and AL amyloidosis undergoing autologous HCT were eligible if they resided in designated ZIP codes and had a full-time caregiver, Wi-Fi connection, HCT Comorbidity Index ≤3, and Karnofsky Performance Status score ≥80. High-dose melphalan (on day -2) and hematopoietic cell reinfusion (day 0) were administered in the outpatient clinic. Protocol-specific home care was provided from day +1 through engraftment. Patients were assessed and blood was drawn daily by advanced practice providers. Interventions were delivered by registered nurses. Attending physicians communicated daily through telemedicine. Quality of life, patient and caregiver satisfaction, and fecal microbiota profiling data were collected. Fifteen patients were enrolled and received transplantation care at home starting on day +1 following hematopoietic cell infusion. Patients remained in the program for an average of 12 days and required an average of 2 outpatient visits while receiving home care. Seven of 15 patients were admitted for a median of 4 days (range, 3 to 10 days); admission occurred on day +7 in 5 patients, on day +8 in 1 patient, and on day +12 in 1 patient for neutropenic fever in 2 patients, fever attributed to engraftment syndrome in 2 patients, diarrhea in 2 patients, and dehydration in 1 patient. Only 1 patient had a documented infection (Clostridioides difficile). One patient admitted with neutropenic fever required intensive care unit admission for a gastrointestinal bleed. Forty-seven percent of the patients experienced a grade ≥3 nonhematologic toxicity. There were no deaths on the study. Patients and caregivers reported high satisfaction with care. Microbiota diversity patterns were similar to those of autologous HCT recipients who did not receive post-HCT care at home, although a subset of the cohort maintained microbiota diversity throughout. Homebound HCT in an urban setting is safe and feasible, with less than one-half of patients requiring inpatient admission. Despite increased patient and caregiver responsibility in the homebound setting compared with an inpatient setting, patient and caregiver satisfaction was high. These results support expansion of homebound transplantation care programs.
Topics: Humans; Quality of Life; Pilot Projects; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Melphalan; Multiple Myeloma; Immunoglobulin Light-chain Amyloidosis
PubMed: 36182105
DOI: 10.1016/j.jtct.2022.09.014 -
International Journal of Molecular... Dec 2022Histone deacetylase inhibitors show synergy with several genotoxic drugs. Herein, we investigated the biological impact of the combined treatment of panobinostat and...
Histone deacetylase inhibitors show synergy with several genotoxic drugs. Herein, we investigated the biological impact of the combined treatment of panobinostat and melphalan in multiple myeloma (MM). DNA damage response (DDR) parameters and the expression of DDR-associated genes were analyzed in bone marrow plasma cells (BMPCs) and peripheral blood mononuclear cells (PBMCs) from 26 newly diagnosed MM patients. PBMCs from 25 healthy controls (HC) were examined in parallel. Compared with the ex vivo melphalan-only treatment, combined treatment with panobinostat and melphalan significantly reduced the efficiency of nucleotide excision repair (NER) and double-strand-break repair (DSB/R), enhanced the accumulation of DNA lesions (monoadducts and DSBs), and increased the apoptosis rate only in patients’ BMPCs (all p < 0.001); marginal changes were observed in PBMCs from the same patients or HC. Accordingly, panobinostat pre-treatment decreased the expression levels of critical NER (DDB2, XPC) and DSB/R (MRE11A, PRKDC/DNAPKc, RAD50, XRCC6/Ku70) genes only in patients’ BMPCs; no significant changes were observed in PBMCs from patients or HC. Together, our findings demonstrate that panobinostat significantly increased the melphalan sensitivity of malignant BMPCs without increasing the melphalan sensitivity of PBMCs from the same patients, thus paving the way for combination therapies in MM with improved anti-myeloma efficacy and lower side effects.
Topics: Humans; Melphalan; Multiple Myeloma; Panobinostat; Leukocytes, Mononuclear; DNA Repair
PubMed: 36555311
DOI: 10.3390/ijms232415671 -
Blood Advances Jun 2023The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based...
The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P < .001 and HR 5.01, P < .001, respectively) and OS (HR 3.85, P < .001 and HR 8.13, P < .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post-auto-HSCT.
Topics: Adult; Humans; United States; Multiple Myeloma; Melphalan; Neoplasms, Second Primary; Transplantation, Autologous; Lenalidomide; Hematologic Neoplasms
PubMed: 36827681
DOI: 10.1182/bloodadvances.2022009138 -
Update on the Contemporary Treatment of Light Chain Amyloidosis Including Stem Cell Transplantation.The American Journal of Medicine Apr 2022The management of immunoglobulin light chain (AL) amyloidosis is complex. Emerging data have shown promising results for several novel agents. We review the management... (Review)
Review
The management of immunoglobulin light chain (AL) amyloidosis is complex. Emerging data have shown promising results for several novel agents. We review the management of AL amyloidosis, including factors that determine transplant eligibility, treatment options for transplant-ineligible patients, and treatment options for relapsed/refractory AL amyloidosis. For carefully selected patients, high-dose melphalan and stem cell transplantation is recommended. Transplant eligibility criteria generally include biopsy-proven amyloidosis, evidence of a plasma cell dyscrasia, involvement of at least one major organ, and adequate performance status. For transplant-ineligible patients, bortezomib-based regimens are recommended, including: 1) bortezomib, oral melphalan, and dexamethasone (BMDex); 2) bortezomib, cyclophosphamide, and dexamethasone (CyBorD or VCd); and 3) subcutaneous daratumumab (DARA SC) and VCd. The latter option is based on a landmark trial that led to the first US Food and Drug Administration-approved therapy for AL amyloidosis. For relapsed/refractory disease, novel therapeutics including proteosome inhibitors, immunomodulatory agents, and monoclonal antibodies have shown promising results. In this review, we summarize data for various therapeutics in different clinical scenarios of AL amyloidosis.
Topics: Amyloidosis; Bortezomib; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Stem Cell Transplantation
PubMed: 35081382
DOI: 10.1016/j.amjmed.2022.01.011 -
Gan To Kagaku Ryoho. Cancer &... Jun 2023This study aimed to identify the risk factors of febrile neutropenia(FN)onset associated with melphalan(L-PAM)therapy. Thirty-nine patients(21 men, 18 women)were...
This study aimed to identify the risk factors of febrile neutropenia(FN)onset associated with melphalan(L-PAM)therapy. Thirty-nine patients(21 men, 18 women)were administered L-PAM intravenously for multiple myeloma(MM)from April 2011 to February 2022 at the Department of Hematology of Gifu Municipal Hospital. Patients were classified into those with and without FN(Grade 3 or higher), complete blood count and liver function tests were performed immediately before starting therapy. Univariate analysis with Fisher's exact probability test was performed. Factors with p<0.2 were considered as independent variables for multivariate analysis in the multiple logistic regression analysis. A multivariate analysis with 2 independent variables, lactate dehydrogenase(LD)level>222 U/L(upper limit of the facility reference value)and white <3.3×103/μL(lower limit of the facility reference value)from the univariate analysis, and FN onset(Grade 3 or higher)as the dependent variable showed that LD level>222 U/L(odds ratio: 6.33, 95% confidence interval: 1.12-35.8, p=0.037)was a significant factor. In conclusion, patients with LD levels >222 U/L immediately before starting therapy require adequate monitoring for FN onset following L-PAM administration.
Topics: Male; Humans; Female; Melphalan; Multiple Myeloma; Hospitals, Municipal; Risk Factors; Febrile Neutropenia
PubMed: 37317605
DOI: No ID Found -
Blood Advances Jul 2023Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is...
Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peritransplantation alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from the Bone Marrow Transplant Clinical Trials Network 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism <5% after initial engraftment and/or requirement of cellular intervention). Thirty-three patients with hemophagocytic lymphohistiocytosis (n = 25) and other IEIs (n = 8) who underwent HCTs with T-cell-replete grafts were included. Patients with day 0 alemtuzumab levels ≤0.32 μg/mL had a markedly lower incidence of MC, 14.3%, vs 90.9% in patients with levels >0.32 μg/mL (P = .008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels >0.32 μg/mL (P = .08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day 14+ CXCL9 level ≤2394 pg/mL (day 14+ median) was 73.6% vs 0% in patients with a level >2394 pg/mL (P = .002). CXCL9 levels inversely correlated with alemtuzumab levels. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely affect sustained engraftment in the nonmyeloablative HCT setting. This trial was registered at www.clinicaltrials.gov as #NCT01998633.
Topics: Humans; Alemtuzumab; Antibodies, Monoclonal, Humanized; Melphalan; Hematopoietic Stem Cell Transplantation; Tissue Donors; Chemokine CXCL9
PubMed: 37042921
DOI: 10.1182/bloodadvances.2022009478 -
Clinical Lymphoma, Myeloma & Leukemia Nov 2021In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved...
Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma: Frailty Subgroup Analysis of ALCYONE.
BACKGROUND
In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status.
PATIENTS AND METHODS
Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients.
RESULTS
Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median follow-up, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P < .0001), frail (32.9 vs. 19.5 months; HR, 0.51; P < .0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10)-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%).
CONCLUSION
Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status.
Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Female; Humans; Male; Melphalan; Multiple Myeloma; Prednisone
PubMed: 34344638
DOI: 10.1016/j.clml.2021.06.005 -
Transplantation and Cellular Therapy Aug 2022High-dose melphalan is one of the main cytotoxic DNA alkylating agents and is used in many transplantation conditioning regimens. Studies have shown a wide range of drug...
High-dose melphalan is one of the main cytotoxic DNA alkylating agents and is used in many transplantation conditioning regimens. Studies have shown a wide range of drug exposure when a traditional weight-based dose of melphalan is used. The optimal melphalan dose in BEAM (carmustine, etoposide, cytarabine, and melphalan), which results in maximum efficacy with acceptable toxicity, is unknown. In this pharmacokinetic (PK) analysis of 105 patients with lymphoma undergoing treatment with BEAM and autologous hematopoietic cell transplantation, we initially estimated melphalan exposure as area under the curve (AUC) by a noncompartmental analysis and subsequently compared it with a newly developed 2-compartment population-PK model. The 2 models correlated closely with each other. We found that the traditional fixed weight-based dosing of propylene glycol-free (captisol-enabled) melphalan in BEAM results in a wide variation in exposure as estimated by both models. Higher melphalan exposure was significantly associated with increased metabolic toxicities but did not seem to impact progression-free survival. Although our study suggests a melphalan AUC of 8 mg·h/L as a potential target in BEAM, larger prospective studies using personalized PK-directed melphalan dosing are needed to determine the optimal melphalan exposure in lymphomas.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Melphalan; Prospective Studies; Transplantation, Autologous
PubMed: 35545213
DOI: 10.1016/j.jtct.2022.05.003 -
Drug Design, Development and Therapy 2021Despite recent therapeutic advances, multiple myeloma (MM) patients experience relapses as they become resistant to various classes and combinations of treatment.... (Review)
Review
Despite recent therapeutic advances, multiple myeloma (MM) patients experience relapses as they become resistant to various classes and combinations of treatment. Melphalan (L-PAM) is an ageless drug. However, its use in the autologous stem cell transplantation (ASCT) setting and the innovative quadruplet regimen as well as daratumumab, bortezomib, and prednisone make this old drug current yet. Melflufen is a peptide-conjugated alkylator belonging to a novel class of compounds, representing an overcoming of L-PAM in terms of mechanism of action and effectiveness. The improved melflufen cytotoxicity is related to aminopeptidase activity, notably present in normal and neoplastic cells and remarkably heavily overexpressed in MM cells. Upon entering a cell, melflufen is cleaved by aminopeptidases, ultimately releasing the L-PAM payload and eliciting further the inflow and cleavage of the conjugated peptide. This virtuous loop persists until all extracellular melflufen has been utilized. The aminopeptidase-driven accumulation results in a 50-fold increase in L-PAM cell enrichment as compared with free alkylator. This condition produces selective cytotoxicity, increased on-target cell potency, and decreased off-target cell toxicity, ultimately overcoming resistance pathways triggered by previous treatments, including alkylators. Due to its distinct mechanism of action, melflufen plus dexamethasone as a doublet, and in combination with other novel drugs, has the potential to be beneficial for a broad range of patients with relapsed/refractory (RR) MM in third- or even in second-line therapy. The safety profile of melflufen has been consistent across studies, and no new safety concerns have been identified when melflufen was administered in doublet and triplet combinations. Based on growing clinical evidence, melflufen could be not only a good addition in the fight against RRMM but also a drug with a very favorable tolerability profile.
Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Humans; Melphalan; Multiple Myeloma; Phenylalanine
PubMed: 34262262
DOI: 10.2147/DDDT.S295215