melphalan and Pneumonia

Drug-induced liver injury (DILI) is a leading cause of liver failure and an important safety issue in drug development. Thalidomide is nowadays used for the treatment of several conditions including multiple myeloma (MM). Several adverse effects have been described but liver toxicity was seldom reported. We describe a case of thalidomide-induced hepatitis in a man treated for MM. The clinical setting and temporal association between the start of the drug and liver injury allowed the assumption of the causative role of thalidomide. As its clinical indications expand we wish to increase awareness of a new potential side effect of thalidomide. A short review on thalidomide-induced liver injury is also presented.

Topics: Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Chemical and Drug Induced Liver Injury; Darbepoetin alfa; Diazepam; Erythropoietin; Fatal Outcome; Humans; Jaundice, Obstructive; Liver Function Tests; Male; Melphalan; Multiple Myeloma; Omeprazole; Pneumonia; Polypharmacy; Prednisolone; Thalidomide

Bleomycin, busulphan, and methotrexate are by far the commonest cytotoxic drugs to cause interstitial pneumonitis. However, many other cytotoxic drugs have been reported to produce similar lung damage. Combined effects of these drugs, and of the drugs with other agents that cause lung damage, such as oxygen and radiation, may result in enhancement of lung damage. Early diagnosis, made possible by awareness of this complication and its correct investigation, may reduce severe morbidity and mortality. In some instances, factors that predispose to lung damage are known, and these have been studied in experimental animals.

Topics: Antineoplastic Agents; Azathioprine; Bleomycin; Busulfan; Carmustine; Chlorambucil; Cyclophosphamide; Drug Therapy, Combination; Humans; Lung; Melphalan; Mercaptopurine; Methotrexate; Mitomycins; Oxygen Inhalation Therapy; Pneumonia; Procarbazine; Radiation Injuries

Bortezomib (Btz) shows robust efficacy in patients with multiple myeloma (MM); however, some patients experience suboptimal responses and show specific toxicities. Therefore, we attempted to identify specific HLA alleles associated with Btz-related toxicities and response to treatment. Eighty-two transplant-ineligible patients with newly diagnosed MM enrolled in a phase II study (JCOG1105) comparing two less intensive melphalan, prednisolone, plus Btz (MPB) regimens were subjected to HLA typing. The frequency of each allele was compared between the groups, categorized based on toxicity grades and responses to MPB therapy. Among 82 patients, the numbers of patients with severe peripheral neuropathy (PN; grade 2 or higher), skin disorders (SD; grade 2 or higher), and pneumonitis were 16 (19.5%), 15 (18.3%), and 6 (7.3%), respectively. Complete response was achieved in 10 (12.2%) patients. Although no significant HLA allele was identified by multiple comparisons, several candidates were identified. HLA-B*40:06 was more prevalent in patients with severe PN than in those with less severe PN (odds ratio [OR] = 6.76). HLA-B*40:06 and HLA-DRB1*12:01 were more prevalent in patients with SD than in those with less severe SD (OR = 7.47 and OR = 5.55, respectively). HLA-DRB1*08:02 clustered in the group of patients with pneumonitis (OR = 11.34). Complete response was achieved in patients carrying HLA-DQB1*03:02, HLA-DQB1*05:01, and HLA-DRB1*01:01 class II alleles. HLA genotyping could help predict Btz-induced toxicity and treatment efficacy in patients with MM, although this needs further validation.

Topics: Aged; Antineoplastic Agents; Bortezomib; Female; Gene Frequency; Genotyping Techniques; HLA Antigens; Humans; Japan; Male; Melphalan; Multiple Myeloma; Peripheral Nervous System Diseases; Pneumonia; Prednisolone; Skin Diseases; Treatment Outcome

The role of more intense conditioning for second transplant was evaluated in myeloma patients achieving at least partial remission (PR) after first transplant with melphalan at 200 mg/m2. Forty-three patients received more intensive conditioning for the second transplant. Nineteen patients received cyclophosphamide 120 mg/kg along with melphalan 200 g/m2 (MEL-CY; group 1) while 24 patients received total body irradiation (1125 cGy) in conjunction with melphalan 140 mg/m2 (MEL-TBI; group 2). Forty-three matched control patients were identified from 450 patients receiving melphalan alone for second transplant (MEL200; group 3). Engraftment and toxicities were comparable among the groups with the exception of increased treatment-related mortality of 8% in group 2 compared to none in groups 1 and 3 (P = 0.07). Despite identical CR rates of 74, 71 and 70%, respectively, in groups 1, 2 and 3 (P = 1.0), event-free survival (median: 27, 15 and 61; P < 0.0001) and overall survival (median: 39, 25 and 76 months; P = 0.003) were significantly decreased in patients receiving more intensive conditioning (groups 1 and 2). Lymphocyte recovery, evaluated as a surrogate for immune recovery, was inferior in more intensively treated patients (groups 1 and 2 compared to group 3). Our findings suggest that more intense conditioning appears to have no benefit in patients responding to their first cycle of high-dose therapy and may even be detrimental in this setting. Bone Marrow Transplantation (2000) 25, 483-487.

Topics: Antigens, CD34; Antineoplastic Agents, Alkylating; beta 2-Microglobulin; Cohort Studies; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Evaluation Studies as Topic; Fever; Graft Survival; Humans; Lymphocyte Count; Melphalan; Multiple Myeloma; Pneumonia; Prognosis; Sepsis; Stomatitis; Survival Rate; Transplantation Conditioning; Transplantation, Autologous; Whole-Body Irradiation

The COVID-19 pandemic has been fueled by SARS-CoV-2 novel variants of concern (VOC) that have increased transmissibility, receptor binding affinity, and other properties that enhance disease. The goal of this study is to characterize unique pathogenesis of the Delta VOC strain in the K18-hACE2-mouse challenge model. Challenge studies suggested that the lethal dose of Delta was higher than Alpha or Beta strains. To characterize the differences in the Delta strain's pathogenesis, a time-course experiment was performed to evaluate the overall host response to Alpha or Delta variant challenge. qRT-PCR analysis of Alpha- or Delta-challenged mice revealed no significant difference between viral RNA burden in the lung, nasal wash or brain. However, histopathological analysis revealed high lung tissue inflammation and cell infiltration following Delta- but not Alpha-challenge at day 6. Additionally, pro-inflammatory cytokines were highest at day 6 in Delta-challenged mice suggesting enhanced pneumonia. Total RNA-sequencing analysis of lungs comparing challenged to no challenge mice revealed that Alpha-challenged mice have more total genes differentially activated. Conversely, Delta-challenged mice have a higher magnitude of differential gene expression. Delta-challenged mice have increased interferon-dependent gene expression and IFN-γ production compared to Alpha. Analysis of TCR clonotypes suggested that Delta challenged mice have increased T-cell infiltration compared to Alpha challenged. Our data suggest that Delta has evolved to engage interferon responses in a manner that may enhance pathogenesis. The in vivo and in silico observations of this study underscore the need to conduct experiments with VOC strains to best model COVID-19 when evaluating therapeutics and vaccines.

Topics: Animals; Antiviral Agents; COVID-19; Disease Models, Animal; gamma-Globulins; Humans; Interferons; Melphalan; Mice; Mice, Transgenic; Pandemics; Pneumonia; SARS-CoV-2

High-dose chemotherapy and autologous stem cell transplantation (ASCT) is the current standard of care for relapsed non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Conditioning regimens with high-dose carmustine have been associated with idiopathic pneumonitis syndrome. We, therefore, created a modified alternative TECAM conditioning regimen, consisting of etoposide, thiotepa, cytarabine, cyclophosphamide, and melphalan.. We retrospectively analyzed our cohort of 212 NHL and HL patients, who had undergone ASCT with the TECAM conditioning regimen from 2000 to 2013. Although toxicity and engraftment were analyzed for all 212 patients, the survival analysis was performed for the 2 largest groups of patients, those with diffuse large B-cell lymphoma (DLBCL) and those with HL (n = 127) to minimize heterogeneity.. The 3-year overall survival among the DLBCL and HL patients was 0.618 (95% confidence interval [CI], 0.490-0.722) and 0.828 (95% CI, 0.701-0.904), respectively. Stage IV disease at transplantation was a statistically significant poor prognostic factor. Higher Eastern Cooperative Oncology Group performance status and progressive disease at transplantation were found to be borderline significant. No idiopathic pneumonitis syndrome cases were reported in our cohort. Six patients died of treatment-related toxicity during the first 100 days. The 3-year progression-free survival was 0.5 (95% CI, 0.37-0.61) for HL patients and 0.49 (95% CI, 0.36-0.60) for DLBCL patients.. Our results are encouraging and justify evaluation of TECAM versus BEAM (carmustine, etoposide, cytarabine, melphalan) in a prospective multicenter study in a large homogenous patient population.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Pneumonia; Retrospective Studies; Thiotepa; Transplantation Conditioning; Transplantation, Autologous; Young Adult

The acute pulmonary responses after exposure to sulfur and nitrogen mustards are well documented whereas the late pulmonary effects are not. With a novel focus on the immune system this paper investigate whether late phase pulmonary effects developed in rats exposed to the nitrogen mustard melphalan are linked to the acute responses and whether the reactions are genetically regulated. The DA rat strain was used to establish a lung exposure model. Five other inbred rat strains (PVG, PVG.1AV1, LEW, WF and F344) were compared within the model at selected time points. All rat strains displayed a biphasic pattern of leukocyte infiltration in the lungs, dominated by neutrophils 2 days after exposure and a second peak dominated by macrophages 29 days after exposure. The number of macrophages was higher in the DA rat compared with the other strains. The infiltration of lymphocytes in the lungs varied in both time of appearance and magnitude between strains. The quantity of collagen deposition in the lungs varied between strains at day 90; LEW and WF displayed high collagen content which coincided with an increased level of cytotoxic T cells. LEW further displayed an increased number of T helper cells and natural killer (NK) T cells in the lungs. The results in this study suggest there is a link between the development of lung fibrosis and high cytotoxic cell responses and that there is a genetic influence, as there are variations in acute and late adverse reactions between rat strains in both timing and magnitude.

Topics: Acute Disease; Animals; Chemical Warfare Agents; Disease Models, Animal; Female; Genetic Predisposition to Disease; Instillation, Drug; Intubation, Intratracheal; Killer Cells, Natural; Lymphocyte Count; Melphalan; Neutrophil Infiltration; Pneumonia; Pulmonary Fibrosis; Rats; Rats, Inbred Strains; Severity of Illness Index; Species Specificity; T-Lymphocytes, Helper-Inducer; Time Factors

To assess factors associated with severe pulmonary toxicity after myeloablative conditioning using total body irradiation (TBI) followed by allogeneic stem cell transplantation.. A total of 101 adult patients who underwent TBI-based myeloablative conditioning for hematologic malignancies at Duke University between 1998 and 2008 were reviewed. TBI was combined with high-dose cyclophosphamide, melphalan, fludarabine, or etoposide, depending on the underlying disease. Acute pulmonary toxicity, occurring within 90 days of transplantation, was scored using Common Terminology Criteria for Adverse Events version 3.0. Actuarial overall survival and the cumulative incidence of acute pulmonary toxicity were calculated via the Kaplan-Meier method and compared using a log-rank test. A binary logistic regression analysis was performed to assess factors independently associated with acute severe pulmonary toxicity.. The 90-day actuarial risk of developing severe (Grade 3-5) pulmonary toxicity was 33%. Actuarial survival at 90 days was 49% in patients with severe pulmonary toxicity vs. 94% in patients without (p < 0.001). On multivariate analysis, the number of prior chemotherapy regimens was the only factor independently associated with development of severe pulmonary toxicity (odds ratio, 2.7 per regimen).. Severe acute pulmonary toxicity is prevalent after TBI-based myeloablative conditioning regimens, occurring in approximately 33% of patients. The number of prior chemotherapy regimens appears to be an important risk factor.

Topics: Acute Disease; Adult; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Etoposide; Female; Graft vs Host Disease; Hematologic Neoplasms; Humans; Lung; Male; Melphalan; Middle Aged; Pneumonia; Retrospective Studies; Risk Factors; Stem Cell Transplantation; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation; Young Adult

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Fatal Outcome; Humans; Leukemia, Myeloid, Acute; Melphalan; Pneumonia; Recurrence; Siblings; Treatment Outcome; Trichoderma

The case of a 74-year-old female with an IgD kappa plasma cell leukemia is presented. In contrast to the majority of the cases in the literature, this patient responded rather well to melphalan and prednisolone and survived for 20 months after starting treatment. Another remarkable feature was the simultaneous occurrence of a double uterine neoplasm, a malignant mixed Müllerian tumor of the homologous variety (also called carcinosarcoma).

Topics: Adnexa Uteri; Aged; Allopurinol; Ampicillin; Carcinosarcoma; Female; Gentamicins; Humans; Hysterectomy; Immunoglobulin D; Immunoglobulin kappa-Chains; Leukemia, Plasma Cell; Melphalan; Pneumonia; Prednisolone; Uterine Neoplasms