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Cancer Discovery Apr 2023We present the first comprehensive investigation of clonal hematopoiesis (CH) in 2,860 long-term survivors of pediatric cancer with a median follow-up time of 23.5...
UNLABELLED
We present the first comprehensive investigation of clonal hematopoiesis (CH) in 2,860 long-term survivors of pediatric cancer with a median follow-up time of 23.5 years. Deep sequencing over 39 CH-related genes reveals mutations in 15% of the survivors, significantly higher than the 8.5% in 324 community controls. CH in survivors is associated with exposures to alkylating agents, radiation, and bleomycin. Therapy-related CH shows significant enrichment in STAT3, characterized as a CH gene specific to survivors of Hodgkin lymphoma, and TP53. Single-cell profiling of peripheral blood samples revealed STAT3 mutations predominantly present in T cells and contributed by SBS25, a mutational signature associated with procarbazine exposure. Serial sample tracking reveals that larger clone size is a predictor for future expansion of age-related CH clones, whereas therapy-related CH remains stable decades after treatment. These data depict the distinct dynamics of these CH subtypes and support the need for longitudinal monitoring to determine the potential contribution to late effects.
SIGNIFICANCE
This first comprehensive CH analysis in long-term survivors of pediatric cancer presents the elevated prevalence and therapy exposures/diagnostic spectrum associated with CH. Due to the contrasting dynamics of clonal expansion for age-related versus therapy-related CH, longitudinal monitoring is recommended to ascertain the long-term effects of therapy-induced CH in pediatric cancer survivors. See related commentary by Collord and Behjati, p. 811. This article is highlighted in the In This Issue feature, p. 799.
Topics: Humans; Child; Clonal Hematopoiesis; Hematopoiesis; Mutation; Hodgkin Disease; Survivors
PubMed: 36751942
DOI: 10.1158/2159-8290.CD-22-0956 -
JAMA Oncology Apr 2023Hodgkin lymphoma (HL) survivors have higher rates of colorectal cancer, which may be associated with subdiaphragmatic radiation therapy and/or alkylating chemotherapy....
IMPORTANCE
Hodgkin lymphoma (HL) survivors have higher rates of colorectal cancer, which may be associated with subdiaphragmatic radiation therapy and/or alkylating chemotherapy. Although radiation dose-response associations with breast, lung, stomach, pancreatic, and esophageal cancer after HL have been demonstrated, the association of radiation therapy with colorectal cancer remains unclear.
OBJECTIVE
To quantify the rate of colorectal cancer according to radiation dose to the large bowel and procarbazine dose among HL survivors.
DESIGN, SETTING, AND PARTICIPANTS
A nested case-control study examined 5-year HL survivors at 5 hospital centers in the Netherlands. Participants had been diagnosed with HL in 1964 to 2000, when they were 15 to 50 years of age, and were followed for a median of approximately 26 years. Survivors of HL who developed colorectal cancer and survivors who were selected as controls were individually matched on sex, age at HL diagnosis, and date of HL diagnosis. Data were analyzed from July 2021 to October 2022.
EXPOSURES
Mean radiation doses to the large bowel were estimated by reconstructing individual radiation therapy treatments on representative computed tomography data sets.
MAIN OUTCOMES AND MEASURES
Excess rate ratios (ERRs) were modeled to evaluate the excess risk associated with each 1-gray increase in radiation dose, and potential effect modification by procarbazine was explored.
RESULTS
The study population included 316 participants (mean [SD] age at HL diagnosis, 33.0 [9.8] years; 221 [69.9%] men), 78 of whom were HL survivors who developed colorectal cancer (cases) and 238 who did not (controls). The median (IQR) interval between HL and colorectal cancer was 25.7 (18.2-31.6) years. Increased colorectal cancer rates were seen for patients who received subdiaphragmatic radiation therapy (rate ratio [RR], 2.4; 95% CI, 1.4-4.1) and those who received more than 8.4 g/m2 procarbazine (RR, 2.5; 95% CI, 1.3-5.0). Overall, colorectal cancer rate increased linearly with mean radiation dose to the whole large bowel and dose to the affected bowel segment. The association between radiation dose and colorectal cancer rate became stronger with increasing procarbazine dose: the ERR per gray to the whole bowel was 3.5% (95% CI, 0.4%-12.6%) for patients who did not receive procarbazine, and increased 1.2-fold (95% CI, 1.1-1.3) for each 1-g/m2 increase in procarbazine dose.
CONCLUSIONS AND RELEVANCE
This nested case-control study of 5-year HL survivors found a dose-response association between radiation therapy and colorectal cancer risk, and modification of this association by procarbazine. These findings may enable individualized colorectal cancer risk estimations, identification of high-risk survivors for subsequent screening, and optimization of treatment strategies.
Topics: Male; Humans; Child; Female; Hodgkin Disease; Procarbazine; Case-Control Studies; Survivors; Colorectal Neoplasms
PubMed: 36729438
DOI: 10.1001/jamaoncol.2022.7153 -
Cancer Medicine Mar 2023Rituximab, high-dose methotrexate (HD-MTX), procarbazine and vincristine (R-MPV), has significantly prolonged the survival of patients with primary central nervous...
BACKGROUND
Rituximab, high-dose methotrexate (HD-MTX), procarbazine and vincristine (R-MPV), has significantly prolonged the survival of patients with primary central nervous system lymphoma (PCNSL), but predictive factors for response to R-MPV have not yet been investigated. Herein, we investigated the correlation of MYD88 L265P and CD79B Y196 mutations, which are the most frequently found molecular alterations in PCNSL, with prognosis of patients with PCNSL treated with R-MPV.
METHODS
We investigated the long-term clinical course and status of MYD88 and CD79B genes in 85 patients with PCNSL treated with R-MPV or HD-MTX treatment, and the correlation of these genetic mutations with prognosis.
RESULTS
R-MPV achieved an excellent tumor control rate (61.6% and 69.9% of 5-year progression-free and overall survival rates, respectively). While MYD88 L265P mutation had no significant effect on survival, patients with CD79B Y196 mutations exhibited prolonged survival (p < 0.05). However, the association of CD79B Y196 mutation with a better prognosis was not observed in the HD-MTX cohort, which indicated that CD79B Y196 mutation was a predictive marker for a favorable response to R-MPV. Furthermore, we established an all-in-one rapid genotyping system for these genetic mutations.
CONCLUSIONS
In conclusion, CD79B Y196 mutation is a potent predictive marker for favorable response to R-MPV in PCNSL. The rapid identification of MYD88 L265P and CD79B Y196 mutations can be helpful not only for the accurate molecular diagnosis of PCNSL but also for the prediction of response to R-MPV.
Topics: Humans; Lymphoma, Large B-Cell, Diffuse; Myeloid Differentiation Factor 88; Mutation; Rituximab; Central Nervous System; Central Nervous System Neoplasms; Methotrexate; CD79 Antigens
PubMed: 36478416
DOI: 10.1002/cam4.5512 -
EJHaem Nov 2022PEP-C (prednisolone, etoposide, procarbazine and cyclophosphamide) is an orally administered daily chemotherapy regimen used with palliative intent in relapsed...
PEP-C (prednisolone, etoposide, procarbazine and cyclophosphamide) is an orally administered daily chemotherapy regimen used with palliative intent in relapsed refractory lymphoma. To our knowledge, no data on PEP-C have been reported since the original group described the regimen. Here we present a multicentre retrospective cohort reporting our use of PEP-C in 92 patients over an 8-year period. We find that even heavily pretreated lymphoma can respond to PEP-C, particularly low-grade lymphoma (including mantle cell) and lymphoma that was sensitive to the previous line of systemic therapy (chemosensitive). These characteristics may help in the selection of patients likely to derive benefit. The median overall survival of patients with chemosensitive lymphoma treated with PEP-C is 217 days. Within the limitations of a retrospective cohort, we find that PEP-C is well tolerated: the most common toxicity leading to discontinuation is marrow suppression. We suggest that PEP-C should be considered for patients with relapsed refractory lymphoma in two settings: first, where there is no licensed alternative; and second, where the licensed alternative is an intravenous drug and the patient would prefer to choose an oral chemotherapy option.
PubMed: 36467809
DOI: 10.1002/jha2.537 -
Asian Journal of Surgery May 2023
Topics: Humans; Prednisone; Rituximab; Etoposide; Thalidomide; Procarbazine; Neoplasm Recurrence, Local; Lymphoma, B-Cell; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome
PubMed: 36424265
DOI: 10.1016/j.asjsur.2022.11.012 -
Journal of Clinical Oncology : Official... Feb 2023Patients with bulky stage I/II classic Hodgkin lymphoma (cHL) are typically treated with chemotherapy followed by radiation. Late effects associated with radiotherapy...
PURPOSE
Patients with bulky stage I/II classic Hodgkin lymphoma (cHL) are typically treated with chemotherapy followed by radiation. Late effects associated with radiotherapy include increased risk of second cancer and cardiovascular disease. We tested a positron emission tomography (PET)-adapted approach in patients with bulky, early-stage cHL, omitting radiotherapy in patients with interim PET-negative (PET-) disease and intensifying treatment in patients with PET-positive (PET+) disease.
METHODS
Eligible patients with bulky disease (mass > 10 cm or 1/3 the maximum intrathoracic diameter on chest x-ray) received two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by interim fluorodeoxyglucose PET (PET2). Patients with PET2-, defined as 1-3 on the 5-point scale, received four additional cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine. Patients with PET2+ received four cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone followed by 30.6 Gy involved-field radiation.
RESULTS
Of 94 evaluable patients, 53% were female with median age 30 years (range, 18-58 years). Eight-five (90%) had stage II disease, including 48 (51%) with stage IIB/IIBE. Seventy-eight (78%) were PET2- and 21 (22%) were PET2+. The predominant toxicity was neutropenia, with 9% of patients developing febrile neutropenia and one developing sepsis. The primary end point of 3-year progression-free survival (PFS) was 93.1% in PET2- and 89.7% in PET2+ patients. Three-year overall survival was 98.6% and 94.4%, respectively. The estimated hazard ratio comparing PFS of patients with PET2+ and patients with PET2- was 1.03 (85% upper bound 2.38) and was significantly less than the null hypothesis of 4.1 (one-sided = .04).
CONCLUSION
Our study of PET-adapted therapy in bulky stage I/II cHL met its primary goal and was associated with an excellent 3-year PFS rate of 92.3% in all patients, with the majority being spared radiotherapy and exposure to intensified chemotherapy.
Topics: Humans; Female; Adult; Male; Hodgkin Disease; Vinblastine; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Bleomycin; Dacarbazine; Neoplasm Staging; Positron-Emission Tomography; Vincristine; Prednisone
PubMed: 36269899
DOI: 10.1200/JCO.22.00947 -
Journal of Clinical Medicine Sep 2022Primary central nervous system lymphomas (PCNSLs) are sensitive to chemotherapy. The standard treatment is high-dose methotrexate (MTX)-based chemotherapy. There are no...
Successful Treatment of Acute Uric Acid Nephropathy with Rasburicase in a Primary Central Nervous System Lymphoma Patient Showing a Dramatic Response to Methotrexate-Case Report.
BACKGROUND
Primary central nervous system lymphomas (PCNSLs) are sensitive to chemotherapy. The standard treatment is high-dose methotrexate (MTX)-based chemotherapy. There are no reports of successful treatment of acute uric acid nephropathy with rasburicase after MTX administration in PCNSLs.
CASE PRESENTATION
A 54-year-old man with a history of gout presented with a change in character and cognitive dysfunction. MRI showed a large enhancing mass spanning the bilateral frontal lobes and the right temporal lobe. After endoscopic biopsy, an MTX, procarbazine, and vincristine (MPV) regimen was initiated for the treatment of the PCNSL. After the initiation of chemotherapy, the patient experienced a gout attack, and blood examination revealed acute renal failure (ARF) and hyperuricemia. The considered causes of ARF included MTX toxicity and acute uric acid nephropathy. As the dramatic effect of MTX was observed, treatment was continued despite ARF, most probably due to acute hyperuricemia due to tumor lysis, which was treated in parallel. After an improvement in renal function, MTX was resumed, and rasburicase was initiated to control hyperuricemia. A complete response was obtained after induction chemotherapy. Hyperuricemia was controlled with rasburicase, and renal function was preserved.
CONCLUSIONS
Acute uric acid nephropathy should be considered when ARF occurs after the initiation of MTX in PCNSLs, especially in newly diagnosed PCNSL patients with large tumors or hyperuricemia.
PubMed: 36233415
DOI: 10.3390/jcm11195548 -
Current Treatment Options in Oncology Nov 2022Primary CNS lymphoma (PCNSL) constitutes a rare extranodal variant of non-Hodgkin lymphoma (NHL) with an annual incidence of 0.45/100,000. Given the paucity of large... (Review)
Review
Primary CNS lymphoma (PCNSL) constitutes a rare extranodal variant of non-Hodgkin lymphoma (NHL) with an annual incidence of 0.45/100,000. Given the paucity of large prospective clinical trials, there is no consensus treatment for refractory or relapsed (r/r) PCNSL, and available strategies are largely based on retrospective analyses. Patient age, performance status, previously administered treatment, duration of response, and molecular characteristics guide selection of salvage therapy. Patients with a good performance status (KPS >70), particularly ≤65 years, and adequate organ function should be considered for salvage polychemotherapy. Based on its high overall response rate even in the relapsed setting, we choose high-dose (≥ 3.5g/m) methotrexate (HD-MTX) based regimens, e.g., R-MPV (rituximab, HD-MTX, procarbazine, and vincristine), for remission re-induction as long as patients were sensitive to first line HD-MTX-based regimens, especially when duration of previous response was ≥ 1 year. Following successful remission induction, we choose myeloablative chemotherapy (e.g., thiotepa, busulfan, cyclophosphamide) and subsequent autologous stem cell transplant in curative intent whenever feasible. Alternatively, conventional chemotherapy regimens (for example, monthly HD-MTX) or low-dose whole-brain radiation therapy (WBRT) are selected for consolidation in non-transplant candidates in complete remission. In cases of HD-MTX refractory disease or contraindications, we use pemetrexed; temozolomide/rituximab; high-dose cytarabine; or whole brain radiation for remission induction. Clinical trial participation is considered as well. Emerging therapies for upfront or salvage therapy under ongoing investigation include bruton tyrosine kinase inhibition (e.g., ibrutinib), immunomodulatory drugs (e.g., lenalidomide), immune checkpoint inhibitors (ICI, e.g., nivolumab), and chimeric antigen receptor T (CAR-T) cell therapy.
Topics: Humans; Thiotepa; Busulfan; Rituximab; Central Nervous System Neoplasms; Agammaglobulinaemia Tyrosine Kinase; Receptors, Chimeric Antigen; Methotrexate; Vincristine; Brain Neoplasms; Retrospective Studies; Lenalidomide; Pemetrexed; Nivolumab; Temozolomide; Immune Checkpoint Inhibitors; Procarbazine; Prospective Studies; Antineoplastic Combined Chemotherapy Protocols; Cranial Irradiation; Lymphoma, Non-Hodgkin; Cytarabine; Cyclophosphamide
PubMed: 36205806
DOI: 10.1007/s11864-022-01016-5 -
[Rinsho Ketsueki] the Japanese Journal... 2022Primary central nervous system lymphoma (PCNSL) is a rare extra-nodal non-Hodgkin's lymphoma confined to the central nervous system with a diffuse large B-cell lymphoma...
Primary central nervous system lymphoma (PCNSL) is a rare extra-nodal non-Hodgkin's lymphoma confined to the central nervous system with a diffuse large B-cell lymphoma (DLBCL) histology and is highly prevelant in elderly patients. Whole brain radiotherapy (WBRT) does not provide considerable remission; rather it is highly involved in the development of leukoencephalopathy with delayed neurotoxicity, notably in elderly patients. Standard care for newly diagnosed patients with PCNSL comprised induction with high-dose methotrexate (HD-MTX)-based multi-agent immunochemotherapy, such as R-MPV (rituximab, MTX, procarbazine, vincristine) yielding 70-75% complete response rate, followed by HD-cytarabine consolidation. Consolidation high-dose chemotherapy with the key drug thiotepa supported by autologous stem cell transplant has recently been investigated to replace WBRT in multiple randomized trials, demonstrating non-inferiority to WBRT with less neurotoxicity. Comprehensive genetic analyses have revealed high rates of oncogenic mutations in CD79B and MYD88 genes, the hallmarks for MCD/C5 subtype of DLBCL, leading to constitutive activation of NF-κB signaling pathways in PCNSL. Bruton's tyrosine kinase (BTK), an intermediate kinase downstream to CD79B/MYD88, has emerged as a promising therapeutic target. Furthermore, tirabrutinib, a second-generation BTK inhibitor, has shown substantial activity against relapsed/refractory PCNSL, resulting in its approval in 2020 in Japan. Additionally, other new agents against PI3-kinase and immunotherapies including immunomodulatory agents, immune checkpoint blockade, and CAR-T have been actively tested in clinical trials.
Topics: Agammaglobulinaemia Tyrosine Kinase; Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System; Central Nervous System Neoplasms; Combined Modality Therapy; Cytarabine; Humans; Immune Checkpoint Inhibitors; Lymphoma, Non-Hodgkin; Methotrexate; Myeloid Differentiation Factor 88; NF-kappa B; Phosphatidylinositol 3-Kinases; Procarbazine; Receptors, Chimeric Antigen; Rituximab; Thiotepa; Vincristine
PubMed: 36198540
DOI: 10.11406/rinketsu.63.1145 -
Journal of Clinical and Experimental... 2022A 63-year-old man was diagnosed with Waldenström's macroglobulinemia (WM). Six courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and...
A 63-year-old man was diagnosed with Waldenström's macroglobulinemia (WM). Six courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) resulted in complete remission, but WM relapsed three years after R-CHOP. After six courses of BR (bendamustine, rituximab), the serum IgM level and CRP normalized. Four years after BR, the patient presented with muscle weakness, sensory disturbance, and myoclonus of lower limbs. T2-weighted magnetic resonance imaging (MRI) showed areas of signal hyperintensity with contrast enhancement in the right temporal and parietal lobes in brain parenchyma, medulla, bilateral basal ganglia, white matter of occipital lobe, and thoracic spinal cord at the Th2-11 levels. Open brain biopsy revealed diffuse proliferation of small lymphocytes and plasmacytoid lymphocytes on the brain surface and around cerebral blood vessels, resulting in a diagnosis of Bing-Neel syndrome (BNS). Two courses of R-MPV (rituximab, methotrexate, procarbazine, and vincristine) resulted in progressive disease, but the neurological symptoms and MRI findings improved following craniospinal irradiation of 30.6 Gy. Three years after craniospinal irradiation, T2-weighted MRI showed recurrence of BNS with progression of myoclonus of lower limbs and IgM elevation. Tirabrutinib was started for the second recurrence of WM and progression of BNS. Two months after the initiation of treatment with tirabrutinib, the myoclonus of lower limbs disappeared and the MRI findings showed improvement. Serum IgM levels decreased and no adverse events were observed. Tirabrutinib shows promise as a therapeutic option for relapsed BNS.
Topics: Humans; Male; Middle Aged; Bendamustine Hydrochloride; Craniospinal Irradiation; Cyclophosphamide; Doxorubicin; Imidazoles; Immunoglobulin M; Methotrexate; Myoclonus; Prednisolone; Procarbazine; Pyrimidines; Rituximab; Vincristine; Waldenstrom Macroglobulinemia
PubMed: 36171098
DOI: 10.3960/jslrt.22018