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Toxicities of high-dose chemotherapy and autologous hematopoietic cell transplantation in older patients with lymphoma.

ABSTRACT: High-dose chemotherapy and autologous hematopoietic cell transplantation is an effective consolidation therapy in lymphoma; however, its use in elderly patients has been limited because of concerns for greater toxicity in this group. We investigated the toxicities of carmustine, etoposide, cytarabine, and melphalan (BEAM) and autologous hematopoietic cell transplantation (AHCT) in 346 patients in 2 age groups: 279 patients aged 60 to 69 years and 67 patients aged ≥70 years. The majority developed severe toxicities; the most common were febrile neutropenia, gastrointestinal, infections, and cardiovascular. Older patients were at higher risk for grade ≥3 cardiovascular toxicities (hazard ratio [HR], 3.36; 95% confidence interval [CI], 2.25-5.00; P < .001) and skin toxicities (HR, 2.45; 95% CI, 1.08-5.54, P = .032). In the older group, nonrelapse mortality at 100 days and at 2 years was 2.99% (95% CI, 0.55-9.32) and 6.2% (95% CI, 1.97-13.95), respectively, vs 1.79% (95% CI, 0.68-3.92) and 2.91% (95% CI, 1.37-5.42), respectively, in the younger group. When adjusting for the number of grade ≥3 toxicities within the first 100 days, older patients had a 1.71-fold (95% CI, 1.08-2.71) increased risk for progression or death relative to younger patients. Although BEAM followed by AHCT is effective, it is associated with significant organ toxicities, especially in patients aged ≥70 years. Interventions to mitigate toxicities while maintaining efficacy are much needed.

SUBMITTER: Dahi PB

PROVIDER: S-EPMC8270665 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Lymphoma patients treated with autologous transplantation (ASCT) live an increasingly long life with the recent advancement in therapeutic modalities. This has resulted in an increase in the incidence of therapy-related myeloid neoplasms (t-MN), which is one of the leading causes of non-relapse mortality. Several observational studies have linked the development of t-MN after ASCT with the intensity and frequency of chemotherapy, particularly alkylating agents, use of total body irradiation (TBI), and peripheral blood progenitor cells. In addition, role of genetic factors is increasingly being identified. It is postulated that the use of chemotherapy prior to ASCT results in DNA damage of progenitor cells, mitochondrial dysfunction, and altered gene expression related to DNA repair, metabolism as well as hematopoietic regulation. Cytogenetic studies have shown the presence of abnormalities in the peripheral blood progenitor cells prior to ASCT. It is, therefore, likely that the reinfusion of peripheral blood progenitor cells, proliferative stress on infused progenitor cells during hematopoietic regeneration and associated telomere shortening ultimately result in clonal hematopoiesis and blastic transformation. Cytopenias, myelodysplasia, or cytogenetic abnormalities are common and can be transient after ASCT; therefore, only when present together, they do confirm the diagnosis of t-MN. Attempts to reduce the occurrence of t-MN should be directed toward minimizing the exposure to the identified risk factors. Although the median survival is few months to less than a year, studies have shown the promising role of allogeneic transplantation in select young t-MN patients without high-risk cytogenetics. In this review we will explain the recent findings in the field of t-MN in lymphoma patients that have implications for identifying the molecular and genetic mechanisms of leukemogenesis and discuss potential strategies to reduce the risk of t-MN in this patient population.

Project description:A prospective study of 312 patients [194 with multiple myeloma (MM) and 118 with lymphomas (LYMPH)] receiving high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT) was conducted. Ficolins are innate immune defense factors, able to distinguish between "self" "abnormal self," and "non-self" and contribute to the elimination of the last two by direct opsonization and/or initiation of complement activation via the lectin pathway. Concentrations of ficolin-1, ficolin-2, and ficolin-3 in serially taken serum samples were determined as were the polymorphisms of the corresponding (FCN1, FCN2, and FCN3) genes. Serum samples were collected before conditioning chemotherapy, before HSCT, and once weekly post-HSCT (four to five samples in total); some patients were also sampled at 1 and/or 3 months post-transplantation. The control group (C) consisted of 267 healthy unrelated individuals. Median ficolin-1 and ficolin-2 (but not ficolin-3) levels in MM patients' sera taken before chemotherapy were lower (and correspondingly frequencies of the lowest concentrations were higher) compared with controls. That appeared to be associated with the malignant disease itself rather than with post-HSCT complications (febrile neutropenia, infections accompanied, or not with bacteremia). Higher frequencies of the FCN1 genotype G/A-C/C-G/G (corresponding to polymorphisms at positions -542, -144, and +6658, respectively) and FCN2 gene heterozygosity for the -857 C>A polymorphism were found among patients diagnosed with MM compared with the C group. Furthermore, FCN2 G/G homozygosity (-557 A>G) was found more frequently and heterozygosity G/T at +6424 less frequently among LYMPH patients than among the healthy subjects. Heterozygosity for +1637delC mutation of the FCN3 gene was more common among patients diagnosed with lymphomas who experienced hospital infections. Although no evidence for an association of low ficolin-1 or ficolin-2 with infections during neutropenia following chemotherapy before HSCT was found, we observed a possible protective effect of ficolins during follow-up.

Project description:BackgroundPrimary central nervous system lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL) confined to the central nervous system (CNS) with rising incidence among patients > 65 years. Although elderly patients are able to tolerate aggressive systemic chemotherapy, previous studies have demonstrated inferior outcomes for patients who present with a poor performance status (PS) and older age. Usually, intensive treatment approaches including high-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) are only offered to patients younger than 65-70 years of age.MethodsThis is an open-label, multicentric, non-randomized, single arm phase II trial. We will recruit 51 immuno-competent patients with newly diagnosed PCNSL from 12 German centers. The objective is to investigate the efficacy of age-adapted induction treatment followed by HDT-ASCT. All enrolled patients will undergo induction chemotherapy consisting of 2 cycles of rituximab 375 mg/m2/d (days 0 & 4), methotrexate 3.5 g/m2 (d1), and cytarabine 2 × 2 g/m2/d (d2-3) every 21 days. After 2 cycles of induction chemotherapy, patients achieving at least stable disease will undergo HDT-ASCT with busulfan 3.2 mg/kg/d (days - 7-(- 6)) and thiotepa 5 mg/kg/d (days - 5-(- 4)) followed by autologous stem cell transplantation. The primary endpoint of this study is 1-year progression-free survival (PFS). Secondary endpoints include PFS, overall survival, treatment response and treatment-related morbidities. Minimal follow-up after treatment completion is 12 months.DiscussionCurrent treatment options for PCNSL have improved over the last years, resulting in the potential to achieve durable remission or cure in patients < 70 years. Age alone may not be the only criterion to select patients for this effective treatment approach and probably many elderly patients are undertreated just because of advanced age. There have been no multicentre trials investigating this curative treatment concept in elderly and fit PCNSL patients so far. We aim to answer whether HDT-ASCT is feasible and effective in fit patients > 65 years with newly-diagnosed PCNSL.Trial registrationGerman clinical trials registry DRKS00011932 registered 18 August 2017.

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Toxicities of high-dose chemotherapy and autologous hematopoietic cell transplantation in older patients with lymphoma.

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