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Arquivos Brasileiros de Oftalmologia 2022The authors report full-field electroretinogram and optical coherence tomography findings of intravitreal melphalan retinal toxicity. An 18-month-old girl with...
The authors report full-field electroretinogram and optical coherence tomography findings of intravitreal melphalan retinal toxicity. An 18-month-old girl with unilateral group D retinoblastoma was evaluated with light-adapted 3 full-field electroretinogram protocol and optical coherence tomography (I-Stand optical coherence tomography, Optovue) after treatment with intravitreal melphalan for active vitreous seeds. After the third injection, the child developed retinal pigment epithelial changes near the injection site. The photopic response of the full-field electroretinogram standard flash cones showed a decrease in amplitude responses of waves a and b in the affected eye compared to the contralateral eye. Optical coherence tomography showed loss of photoreceptors and outer nuclear layers in the affected eye. Melphalan toxicity is dose-dependent, and despite its treatment benefits, it can affect vision. Our case shows an updated, in-depth retinal toxicity assessment of intravitreal melphalan in the human retina with optical coherence tomography and its correlation with electroretinogram changes.
Topics: Child; Female; Humans; Infant; Retinoblastoma; Melphalan; Retinal Neoplasms; Tomography, Optical Coherence; Antineoplastic Agents, Alkylating; Intravitreal Injections; Retina; Electroretinography
PubMed: 35857974
DOI: 10.5935/0004-2749.2021-0037 -
American Journal of Hematology Aug 2023In this phase 1/2 study, carfilzomib was added to high-dose melphalan conditioning prior to autologous stem cell transplantation (ASCT) in patients with multiple myeloma...
In this phase 1/2 study, carfilzomib was added to high-dose melphalan conditioning prior to autologous stem cell transplantation (ASCT) in patients with multiple myeloma that had been treated with ≤2 prior lines of therapy. Carfilzomib was escalated at doses of 27, 36, 45, and 56 mg/m2 on days -6, -5, -2, and -1 before ASCT in the phase 1 component of the study. In addition, all the patients received melphalan 100 mg/m on days -4 and -3. The primary endpoint of the phase 1 component was to identify the maximum tolerated dose, and the primary endpoint of the phase 2 component was the rates of complete response (≥CR) at 1 year after ASCT. The phase 1 dose escalation cohort included 14 patients, and 35 patients were included in the phase 2 cohort. The maximum tested dose was 56 mg/m (MTD). The median time from diagnosis to study enrollment was 5.8 (range 3.4-88.4) months, and 16% of patients had obtained a ≥CR prior to ASCT. The best response within 1 year after ASCT was a ≥ CR rate in 22% for the entire cohort, and 22% for patients treated at the MTD. The ≥VGPR rates improved from 41% before ASCT to 77% by 1 year after ASCT. One patient had a grade 3 renal adverse event, and renal function returned to baseline with supportive care. The rate of grade 3-4 cardiovascular toxicity was 16%. The addition of carfilzomib to melphalan conditioning was safe and resulted in deep responses after ASCT.
Topics: Humans; Melphalan; Multiple Myeloma; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Transplantation Conditioning; Stem Cell Transplantation
PubMed: 37334773
DOI: 10.1002/ajh.26990 -
The Journal of Allergy and Clinical... Mar 2022Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality.
BACKGROUND
Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality.
OBJECTIVE
The effect of conditioning regimen groups of varying intensity on outcomes after transplantation was examined to identify an optimal regimen or regimens for HLH disorders.
METHODS
We studied 261 patients with HLH disorders transplanted between 2005 and 2018. Risk factors for transplantation outcomes by conditioning regimen groups were studied by Cox regression models.
RESULTS
Four regimen groups were studied: (1) fludarabine (Flu) and melphalan (Mel) in 123 subjects; (2) Flu, Mel, and thiotepa (TT) in 28 subjects; (3) Flu and busulfan (Bu) in 14 subjects; and (4) Bu and cyclophosphamide (Cy) in 96 subjects. The day 100 incidence of veno-occlusive disease was lower with Flu/Mel (4%) and Flu/Mel/TT (0%) compared to Flu/Bu (14%) and Bu/Cy (22%) (P < .001). The 6-month incidence of viral infections was highest after Flu/Mel (72%) and Flu/Mel/TT (64%) compared to Flu/Bu (39%) and Bu/Cy (38%) (P < .001). Five-year event-free survival (alive and engrafted without additional cell product administration) was lower with Flu/Mel (44%) compared to Flu/Mel/TT (70%), Flu/Bu (79%), and Bu/Cy (61%) (P = .002). The corresponding 5-year overall survival values were 68%, 75%, 86%, and 64%, and did not differ by conditioning regimen (P = .19). Low event-free survival with Flu/Mel is attributed to high graft failure (42%) compared to Flu/Mel/TT (15%), Flu/Bu (7%), and Bu/Cy (18%) (P < .001).
CONCLUSIONS
Given the high rate of graft failure with Flu/Mel and the high rate of veno-occlusive disease with Bu/Cy and Flu/Bu, Flu/Mel/TT may be preferred for HLH disorders. Prospective studies are warranted.
Topics: Busulfan; Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lymphohistiocytosis, Hemophagocytic; Melphalan; Thiotepa; Transplantation Conditioning; Vidarabine
PubMed: 34375618
DOI: 10.1016/j.jaci.2021.07.031 -
Graefe's Archive For Clinical and... Apr 2023To evaluate the efficacy and toxicity of intravitreal carboplatin plus melphalan for the treatment of vitreous seeds in eyes with retinoblastoma (RB).
PURPOSE
To evaluate the efficacy and toxicity of intravitreal carboplatin plus melphalan for the treatment of vitreous seeds in eyes with retinoblastoma (RB).
METHODS
This retrospective series at a tertiary referral center included 22 consecutive RB patients who had received intravitreal carboplatin (16 μg per 0.05 ml) combined with melphalan (30 μg in 0.03 ml) [IVi (Ca-Me)] for treatment of vitreous seeds. Tumor control and drug toxicities were recorded.
RESULTS
There were 22 eyes of 22 patients, divided into primary group (n = 13) without history of previous intravitreal chemotherapy (IViC) and refractory group (n = 9) with history of previous IViC using melphalan and/or topotecan. The demographics and clinical findings of the primary and refractory groups did not differ significantly. The 6-month follow-up revealed complete vitreous seed control (77% vs. 89%, p = 0.47). Vitreous seed recurrence was detected in 1 eye of each group at 6 months. During the next 18-month follow-up period, no recurrence of seed was observed. The response to IVi (Ca-Me) was not significantly influenced by previous IViC (p = 0.70), primary systemic or intra-arterial chemotherapy (p = 0.45), or the type of regression (p = 0.35). The most common tumor treatment complications were retinal detachment (RD) (n = 2), early hypotony (n = 2) and late hypotony (n = 4, unrelated), cataract (n = 2), and severe pigment dispersion (n = 1). Enucleation was performed in 8 eyes, for total RD (n = 1), phthisis bulbi (n = 5), and extensive solid tumor recurrence (n = 2). There was no case of orbital invasion, systemic metastasis, or death.
CONCLUSION
Based on this interventional case series for primary and refractory vitreous RB seeds, carboplatin plus melphalan therapy may be effective with few toxic side effects.
Topics: Humans; Infant; Retinoblastoma; Melphalan; Retinal Neoplasms; Carboplatin; Retrospective Studies; Antineoplastic Agents, Alkylating; Neoplasm Recurrence, Local; Vitreous Body; Neoplasm Seeding; Intravitreal Injections
PubMed: 36401651
DOI: 10.1007/s00417-022-05903-3 -
International Journal of Radiation... Aug 2019
Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Central Nervous System Neoplasms; Chemoradiotherapy; Germinoma; Humans; Magnetic Resonance Imaging; Male; Melphalan; Salvage Therapy; Second-Look Surgery; Tumor Burden; Young Adult
PubMed: 31327425
DOI: 10.1016/j.ijrobp.2018.03.040 -
Eye (London, England) Nov 2022To examine the outcome of salvage intra-arterial chemotherapy (IAC) for patients with recurrent retinoblastoma after the initial course of IAC and determine the factors...
PURPOSE
To examine the outcome of salvage intra-arterial chemotherapy (IAC) for patients with recurrent retinoblastoma after the initial course of IAC and determine the factors influencing clinical outcome.
METHODS
A total of 73 eyes of 71 patients with recurrent retinoblastoma undergoing salvage IAC after initial successfully IAC between May 2014 and May 2019 were retrospectively reviewed for clinical outcomes. Ocular survival and progression-free survival were used to examine the efficacy of salvage IAC. The factors influencing clinical outcomes were determined using univariate and multivariate analyses.
RESULTS
The salvage IAC was delivered at mean 9.4 months (median 7, range 2.1-38.3 months) following the last cycle of initial IAC. 86.5% (64/73) eyes relapsed 16 months after the initial IAC. After the salvage IAC, 57 eyes (78.1%) were salvaged, and no further-line therapies were required for 36 eyes (49.3%). The 2-year Kaplan-Meier ocular survival and progression-free survival estimates after salvage IAC were 66.4% (95% CI, 31.5-42.1%) and 38.2% (95% CI, 17.8-28.8%), respectively. Univariate and multivariate analyses showed that the ocular survival and progression-free survival after salvage IAC were significantly associated with the history of vitreous seeds (p = 0.02 and p = 0.03, respectively).
CONCLUSION
Salvage IAC is effective for the management of recurrent retinoblastoma after the initial successful IAC. Eyes with a history of vitreous seeds in the course of the disease are more likely to relapse and with worse ocular survival. A close follow-up strategy is imperative to treat the recurrent tumour after salvage IAC.
Topics: Humans; Infant; Retinoblastoma; Retinal Neoplasms; Retrospective Studies; Melphalan; Infusions, Intra-Arterial; Neoplasm Recurrence, Local; Treatment Outcome
PubMed: 34654891
DOI: 10.1038/s41433-021-01693-w -
Transplantation and Cellular Therapy Aug 2022Single-agent high-dose melphalan (Mel) followed by autologous stem cell transplantation (ASCT) remains a standard of care in eligible patients with multiple myeloma...
Single-agent high-dose melphalan (Mel) followed by autologous stem cell transplantation (ASCT) remains a standard of care in eligible patients with multiple myeloma (MM), and efforts to improve transplant outcomes by intensifying transplant conditioning have mostly failed. Bendamustine combines both alkylating and antimetabolite properties, can induce responses in MM resistant to other alkylators and represents a promising agent to combine with Mel prior to ASCT. We performed a phase II study to test the safety and efficacy of the high-dose chemotherapy combination of bendamustine, etoposide, cytarabine, and melphalan (BeEAM) in newly diagnosed MM patients up to 70 years of age. The primary study endpoint was the day 100 complete response rate. Sixty-five patients with a median (range) age of 59 (40-69) years underwent transplantation from 2015 to 2020. Other characteristics included Karnofsky performance status <80%, hematopoietic cell transplantation-comorbidity index ≥3, International Staging System III, and high-risk fluorescein in situ hybridization (FISH) in 35%, 46%, 26%, and 44%, respectively. ASCT after BeEAM was well tolerated, and there were no non-relapse deaths through 1 year after transplantation. Although at least 1 nonhematologic grade 3 toxicity was reported in 58 (89%) patients (including grade 3 febrile neutropenia in 48% and stomatitis/esophagitis in 28%), there were no grade ≥3 renal or hepatic toxicity and no grade ≥4 non-hematologic toxicity. The day 100 response rate was ≥CR1 and ≥ very good partial response (VGPR1) in 40% and 89%, respectively. With a median follow-up of 44 (13-70) months, the 3-year overall survival was 92%, 96%, and 90% for all patients and those with standard- and high-risk FISH, respectively. The corresponding values for 3-year progression-free survival was 57%, 72%, and 40%, respectively. When BeEAM-conditioned patients were compared to historical Mel-conditioned cohort, no significant differences were noted in relapse or survival outcomes in univariate or multivariable analysis. In summary, BeEAM was shown to be a safe and effective conditioning regimen before up-front autologous transplant for MM. Although the BeEAM regimen does not appear to offer a significant advantage over single-agent Mel, further studies combining bendamustine and melphalan in the front-line setting may be warranted.
Topics: Bendamustine Hydrochloride; Cytarabine; Drug Therapy, Combination; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Neoplasm Recurrence, Local; Transplantation, Autologous
PubMed: 35598842
DOI: 10.1016/j.jtct.2022.05.022 -
Clinical Cancer Research : An Official... Jul 2019Carfilzomib is a novel generation proteasome inhibitor. The Carmysap trial demonstrated that twice-weekly KMP (carfilzomib, melphalan, prednisone) might challenge the...
PURPOSE
Carfilzomib is a novel generation proteasome inhibitor. The Carmysap trial demonstrated that twice-weekly KMP (carfilzomib, melphalan, prednisone) might challenge the MPV (melphalan, prednisone, bortezomib) standard. We sought to study KMP weekly, allowing to increase carfilzomib's dose with maintained efficacy and improved safety profile.
PATIENTS AND METHODS
IFM2012-03, a phase I multicenter study of KMP weekly in elderly patients with newly diagnosed multiple myeloma (eNDMM), aimed to determine the MTD of carfilzomib. Carfilzomib was given intravenously at 36, 45, 56, and 70 mg/m/day on days 1, 8, 15, and 22 with melphalan and prednisone, for nine 35-day induction cycles, followed by carfilzomib maintenance for 1 year. Three dose-limiting toxicities (DLT) determined MTD at the lower dose.
RESULTS
Thirty eNDMMs were treated, 6 per cohort at 36, 45, and 56 mg/m and 12 at 70 mg/m². There was one DLT at 36 mg/m (lymphopenia), one at 45 mg/m (lysis syndrome), two at 56 mg/m (cardiac insufficiency and febrile neutropenia), and two at 70 mg/m (vomiting and elevated liver enzymes). The safety profile was acceptable; however, specific attention must be paid to the risk of cardiovascular events, especially for elderly patients. The overall response rate was 93.3%, with 46.6% complete response.
CONCLUSIONS
The MTD dose of carfilzomib was 70 mg/m in this KMP weekly study in eNDMM. Response rates, and especially CR rate, were remarkable in this population, and would benefit from being assessed in a larger-scale study. The IFM2012-03 study demonstrated that the MTD of carfilzomib weekly is 70 mg/m in eNDMM, and 56 mg/m for patients older than 75 years. Carfilzomib used weekly in combination has a good efficacy and safety profile in eNDMM.
Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Maximum Tolerated Dose; Melphalan; Multiple Myeloma; Oligopeptides; Patient Safety; Prednisone; Response Evaluation Criteria in Solid Tumors; Survival Rate; Treatment Outcome
PubMed: 31053600
DOI: 10.1158/1078-0432.CCR-18-3642 -
American Journal of Hematology Feb 2024Fludarabine/busulfan and fludarabine/melphalan are viable options as conditioning regimens. However, the optimal fludarabine-based conditioning in cord blood...
Fludarabine/busulfan and fludarabine/melphalan are viable options as conditioning regimens. However, the optimal fludarabine-based conditioning in cord blood transplantation (CBT) remains unclear. Therefore, this retrospective, registry-based study aimed to analyze the impact of five fludarabine-containing conditioning regimens on 1395 adult patients (median age, 61 years) with acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia who underwent their first CBT. Treatment outcomes of fludarabine combined with melphalan (100-140 mg/m ) and low-dose total body irradiation (TBI; FM140T); melphalan (80-99 mg/m ) and TBI (FM80T); busulfan (12.8 mg/kg) and melphalan (FB4M); busulfan (12.8 mg/kg) and TBI (FB4T); and busulfan (6.4 mg/kg) and TBI (FB2T) were compared. The 3-year survival rate was 67%, 53%, 44%, 36%, and 39%, respectively (p < .0001). The FM140T survival rate was the most favorable after adjusting for confounders, and the hazard ratios (vs. FM140T) for overall mortality were as follows: FM80T, 1.6 (95% confidence interval [CI], 1.2-2.2); FB4M, 2.1 (95% CI, 1.6-2.8); FB4T, 2.7 (95% CI, 2.0-3.7); and FB2T, 2.2 (95% CI, 1.6-3.1). The better survival observed with FM140T, regardless of the disease, disease risk, age, or transplant year, was attributed to the lower relapse rate and lower non-relapse mortality (NRM) associated with fewer infectious deaths. Conversely, FB4T was associated with a higher relapse rate and higher NRM. The findings indicate that the outcomes of CBT in myeloid malignancies were highly dependent on both the alkylating agent and its dose in combination with fludarabine. Therefore, compared with fludarabine/busulfan-based conditioning, FM140T may be the preferred regimen.
Topics: Adult; Humans; Middle Aged; Busulfan; Melphalan; Retrospective Studies; Cord Blood Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation; Vidarabine; Leukemia, Myeloid, Acute; Myeloproliferative Disorders; Recurrence; Graft vs Host Disease; Transplantation Conditioning
PubMed: 38165068
DOI: 10.1002/ajh.27172 -
Journal of Chromatography. B,... May 2023As a hydrolysis mediated drug in vivo, the pharmacokinetics of melphalan are highly variable in patients. Few methodologies could simultaneously measure the...
As a hydrolysis mediated drug in vivo, the pharmacokinetics of melphalan are highly variable in patients. Few methodologies could simultaneously measure the concentrations of melphalan and its hydrolyzed metabolites in plasma. The aim of this study was to develop a simple, rapid and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of melphalan and its hydrolyzed metabolites, monohydroxy melphalan (MOH melphalan) and dihydroxy melphalan (DOH melphalan). A simple protein precipitation was employed for sample preparation and melphalan-d8 was used as internal standard. Baseline separation of target analytes was achieved using an XSelect HSS T3 column (2.1 × 50 mm, 5 µm) with a gradient elution at a flow rate of 0.5 mL/min in 5 min. The monitored transitions were m/z 305.1 → 287.7 for melphalan, m/z 287.1 → 228.0 for MOH melphalan, m/z 269.3 → 251.8 for DOH melphalan, and m/z 313.1 → 295.7 for melphalan-d8. The method was fully validated in accordance with the FDA guideline. The calibration curves were established over the range of 5.22-5220 ng/mL for melphalan, 7.94-1588 ng/mL for MOH-melphalan, and 15.0-3000 ng/mL for DOH-melphalan with the regression coefficients greater than 0.99. The intra- and inter-day coefficients of variation for the analytes were ≤11.0% and all the biases were less than 8.3%. The method has been successfully applied to the quantification of melphalan and its metabolites in clinical plasma samples obtained from hematopoietic stem cell transplantation patients who received a dose of melphalan for pre-transplant conditioning.
Topics: Humans; Chromatography, Liquid; Tandem Mass Spectrometry; Melphalan; Hydrolysis; Reproducibility of Results; Chromatography, High Pressure Liquid
PubMed: 37060813
DOI: 10.1016/j.jchromb.2023.123698