Real-life study on the use of response adapted therapy in patients with Hodgkin Lymphoma: Results from a multicenter experience.

Few data are known regarding the use of interim positron emission tomography (iPET) after the first two cycles (iPET2) of chemotherapy in treatment-naïve classical Hodgkin lymphoma (cHL) in routine clinical practice, and about the real-life adoption of intensification strategies for iPET positive patients. We conducted a multicenter retrospective study on cHL to investigate the use of iPET in the real-life setting, its prognostic role and outcomes of patients early shifted to intensification. Six hundreds and forty-one patients were enrolled (62% had advanced stage). iPET2 was positive in 89 patients (14%) including 8.7% and 17% early and advanced stage patients, respectively (p = 0.003). Among iPET 2 positive cases treatment was immediately modified in 19 cases; in 14 cases treatment was modified after an additional positive iPET4. Overall 56 iPET2 positive patients never received intensified therapies. Most frequently used intensified therapy was autologous stem cell transplantation followed by BEACOPP. After a median follow-up of 72 months, the 5-year progression-free survival (PFS) was 82% with iPET2 positive patients showing a worse PFS compared with iPET2 negative cases: 31% versus 85%. Focusing on advanced stage patients with a positive iPET2, the 5-year PFS was 59% for patients shifted to intensified therapy at any time point versus 61% for patients who never received intensified therapy. Our study confirmed the higher curability of naïve cHL patients in a real-world setting, and the prognostic role of iPET2 in this setting. A poor adherence to response-adapted strategy which however did not translate into a difference in patient outcomes.

Successful desensitization in a patient with recurrent anaplastic oligodendroglioma presenting with procarbazine-mediated anaphylaxis.

INTRODUCTION: Procarbazine is an oral chemotherapeutic agent used in the treatment of brain malignancies and is associated with hypersensitivity reactions. In case of grade 4 reactions, rechallenge should be avoided, and the agent should be replaced, unless the treatment is curative, in which case the application of a desensitization protocol should be considered. We present a successful case of desensitization in procarbazine anaphylaxis. CASE REPORT: A 53-year-old male patient was diagnosed with recurrent anaplastic oligodendroglioblastoma. The patient received three cycles of procarbazine, lomustine, and vincristine chemotherapy for malignancy recurrence. In the fourth cycle, on the 12th day of procarbazine treatment, the patient developed anaphylaxis. Procarbazine was given together with premedication as part of the 12-step desensitization process, and the fourth cycle was successfully completed. MANAGEMENT AND OUTCOME: Procarbazine hypersensitivity reactions are observed less frequently than reactions to other chemotherapeutics. We presented a case of procarbazine-associated severe anaphylaxis that was able to continue procarbazine chemotherapy with successful desensitization. This case is important in terms of confirming the procarbazine desensitization protocol. DISCUSSION: In literature there is only one protocol developed was successfully applied in one patient with procarbazine anaphylaxis. In the current case, we took this protocol into consideration in the management of our patient. Following the use of this protocol, the patient was able to continue procarbazine chemotherapy successfully. Procarbazine anaphylaxis is rare, and more cases are needed to be reported to confirm the desensitization protocol and when to continue procarbazine treatment.

Long-Term Follow-Up of the Response-Adapted Intergroup EORTC/LYSA/FIL H10 Trial for Localized Hodgkin Lymphoma.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The primary analysis of the Early positron emission tomography (ePET) Response-Adapted Treatment in localized Hodgkin Lymphoma H10 Trial demonstrated that in ePET-negative patients, the risk of relapse increased when involved-node radiotherapy (INRT) was omitted and that in ePET-positive patients, switching from doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) to bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) significantly improved 5-year progression-free survival (PFS). Here, we report the final results of a preplanned analysis at a 10-year follow-up. In the favorable (F) ePET-negative group, the 10-year PFS rates were 98.8% versus 85.4% (hazard ratio [HR], 13.2; 95% CI, 3.1 to 55.8; P value for noninferiority = .9735; difference test P < .0001) in favor of ABVD + INRT; in the unfavorable (U) ePET-negative group, the 10-year PFS rates were 91.4% and 86.5% (HR, 1.52; 95% CI, 0.84 to 2.75; P value for noninferiority = .8577; difference test P = .1628). In ePET-positive patients, the difference in terms of PFS between standard ABVD and intensified BEACOPPesc was no longer statistically significant (HR, 0.67; 95% CI, 0.37 to 1.20; P = .1777). In conclusion, the present long-term analysis confirms that in ePET-negative patients, the omission of INRT is associated with lower 10-year PFS. Instead, in ePET-positive patients, no significant difference between standard and experimental arms emerged although intensification with BEACOPPesc was safe, with no increase in late adverse events, namely, second malignancies.

Pubertal progression in relation to peripubertal exposure to organochlorine chemicals in a cohort of Russian boys.

Background: Peripubertal concentrations of serum dioxins and polychlorinated biphenyls (PCBs) have demonstrated associations with altered age of pubertal onset and sexual maturity in boys, but associations with pubertal progression have received less attention. Methods: The Russian Children's Study is a prospective cohort of 516 boys enrolled in 2003-2005 at age 8 or 9 and followed annually up to 19 years of age. Serum concentrations of dioxin-like toxic equivalents (TEQs), polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and non-dioxin-like PCBs (NDL-PCBs) and whole blood lead levels (BLLs) were quantified from blood samples collected at study entry (age 8-9). Testicular volume (TV) was assessed annually using a Prader orchidometer. Pubertal trajectories were identified by applying Group-Based Trajectory Models (GBTMs) to TV measured from ages 8-19. Associations of peripubertal serum TEQs, PCDDs, PCDFs, and NDL-PCBs with specific progression trajectories were modeled using multinomial logistic regression, adjusting for each boy's birthweight, and for BLL, body mass index and nutritional factors at study entry. Results: Among 489 eligible boys with available exposure measures, we identified three pubertal trajectories using GBTMs: slower (34% of boys), moderate (48%) and faster (18%). Boys with higher peripubertal serum TEQs had higher adjusted odds of being in the moderate versus faster trajectory (adjusted odds ratio (aOR) 1.79, 95% CI 1.01, 3.13) and the slower versus faster trajectory (aOR 1.52, 95% CI 0.82, 2.78) per 1 log unit increase in serum TEQs. Boys with higher peripubertal serum PCDFs had higher adjusted odds of being in the moderate compared to the faster trajectory (aOR 1.92, 95% CI 1.20, 3.03) and of being in the slower versus the faster trajectory (aOR 1.42, 95% CI 0.91, 2.33) per 1 log unit increase. Boys with higher NDL-PCBs had higher adjusted odds of being in the faster trajectory versus the moderate (aOR 2.56, 95% CI 0.91-7.20) or slower (aOR 3.31, 95% CI 1.07, 10.25) trajectory. Boys with higher blood lead levels also had higher adjusted odds of being in the slower trajectory of pubertal progression, compared to either the faster (aOR 1.47, 95% CI 0.89, 2.44) or moderate (aOR 1.20, 95% CI 0.83, 1.75) trajectories, per 1 log unit increase in BLL, although these associations did not attain statistical significance. Conclusion: Boys' peripubertal exposure to dioxins and certain PCBs may alter pubertal progression.

Age-adjusted high-dose chemotherapy followed by autologous stem cell transplantation or conventional chemotherapy with R-MP as first-line treatment in elderly primary CNS lymphoma patients - the randomized phase III PRIMA-CNS trial.

BACKGROUND: Older primary central nervous system lymphoma (PCNSL) patients have an inferior prognosis compared to younger patients because available evidence on best treatment is scarce and treatment delivery is challenging due to comorbidities and reduced performance status. High-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) after high-dose methotrexate (MTX)-based immuno-chemotherapy has become an increasingly used treatment approach in eligible elderly PCNSL patients with promising feasibility and efficacy, but has not been compared with conventional chemotherapy approaches. In addition, eligibility for HCT-ASCT in elderly PCNSL is not well defined. Geriatric assessment (GA) may be helpful in selecting patients for the best individual treatment choice, but no standardized GA exists to date. A randomized controlled trial, incorporating a GA and comparing age-adapted HCT-ASCT treatment with conventional chemotherapy is needed. METHODS: This open-label, multicenter, randomized phase III trial with two parallel arms will recruit 310 patients with newly diagnosed PCNSL > 65 years of age in 40 centers in Germany and Austria. The primary objective is to demonstrate that intensified chemotherapy followed by consolidating HCT-ASCT is superior to conventional chemotherapy with rituximab, MTX, procarbazine (R-MP) followed by maintenance with procarbazine in terms of progression free survival (PFS). Secondary endpoints include overall survival (OS), event free survival (EFS), (neuro-)toxicity and quality of life (QoL). GA will be conducted at specific time points during the course of the study. All patients will be treated with a pre-phase rituximab-MTX (R-MTX) cycle followed by re-assessment of transplant eligibility. Patients judged transplant eligible will be randomized (1:1). Patients in arm A will be treated with 3 cycles of R-MP followed by maintenance therapy with procarbazine for 6 months. Patients in arm B will be treated with 2 cycles of MARTA (R-MTX/AraC) followed by busulfan- and thiotepa-based HCT-ASCT. DISCUSSION: The best treatment strategy for elderly PCNSL patients remains unknown. Treatments range from palliative to curative but more toxic therapies, and there is no standardized measure to select patients for the right treatment. This randomized controlled trial will create evidence for the best treatment strategy with the focus on developing a standardized GA to help define eligibility for an intensive treatment approach. TRIAL REGISTRATION: German clinical trials registry DRKS00024085 registered March 29, 2023.

Duplex sequencing provides detailed characterization of mutation frequencies and spectra in the bone marrow of MutaMouse males exposed to procarbazine hydrochloride.

Mutagenicity testing is an essential component of health safety assessment. Duplex Sequencing (DS), an emerging high-accuracy DNA sequencing technology, may provide substantial advantages over conventional mutagenicity assays. DS could be used to eliminate reliance on standalone reporter assays and provide mechanistic information alongside mutation frequency (MF) data. However, the performance of DS must be thoroughly assessed before it can be routinely implemented for standard testing. We used DS to study spontaneous and procarbazine (PRC)-induced mutations in the bone marrow (BM) of MutaMouse males across a panel of 20 diverse genomic targets. Mice were exposed to 0, 6.25, 12.5, or 25 mg/kg-bw/day for 28 days by oral gavage and BM sampled 42 days post-exposure. Results were compared with those obtained using the conventional lacZ viral plaque assay on the same samples. DS detected significant increases in mutation frequencies and changes to mutation spectra at all PRC doses. Low intra-group variability within DS samples allowed for detection of increases at lower doses than the lacZ assay. While the lacZ assay initially yielded a higher fold-change in mutant frequency than DS, inclusion of clonal mutations in DS mutation frequencies reduced this discrepancy. Power analyses suggested that three animals per dose group and 500 million duplex base pairs per sample is sufficient to detect a 1.5-fold increase in mutations with > 80% power. Overall, we demonstrate several advantages of DS over classical mutagenicity assays and provide data to support efforts to identify optimal study designs for the application of DS as a regulatory test.

'ACOPP' chemotherapy for older and less fit patients with Hodgkin lymphoma-A multicentre, retrospective study.

Management of classical Hodgkin lymphoma in older patients is challenging due to poor tolerance of the chemotherapy regimens used in younger patients. We modified the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone), whereby bleomycin and etoposide were removed and cyclophosphamide dose was reduced, for older patients with co-morbidities. Here we present data from the first 41 patients treated with 'ACOPP' across 3 centres, demonstrating that it can be delivered, with a favourable toxicity profile (TRM 2%) and promising efficacy (2-year PFS and OS, 73% (95% CI: 52-94) and 93% (95% CI: 80-100) respectively).

T2-Fluid-attenuated inversion recovery (FLAIR) pseudoprogression in patients with anaplastic oligodendrogliomas treated with procarbazine, lomustine and vincristine (PCV) chemotherapy alone.

BACKGROUND: Pseudoprogression in gliomas has been extensively described after radiotherapy with or without chemotherapy, but not after chemotherapy alone. Here we describe the occurrence of pseudoprogression in patients with anaplastic oligodendrogliomas treated with postoperative procarbazine, lomustine and vincristine (PCV) chemotherapy alone. METHODS: We retrospectively reviewed the medical and radiological files of patients with 1p/19q codeleted, IDH-mutant anaplastic oligodendrogliomas treated with PCV chemotherapy alone who presented magnetic resonance imaging (MRI) modifications suggestive of tumour progression and in whom the final diagnosis was a pseudoprogression. RESULTS: We identified six patients. All patients underwent a surgical resection and were treated with PCV chemotherapy without radiotherapy. After a median of 11 months following the initiation of chemotherapy (range: 3-49 months), the patients developed asymptomatic white matter MRI modifications around the surgical cavity leading to the suspicion of a tumour progression. These modifications appeared as hyperintense on T2-fluid-attenuated inversion recovery (FLAIR) sequence, hypointense on T1 sequence, and lacked mass effect (0/6), contrast enhancement (0/6), restriction on diffusion-weighted imaging (0/4), relative cerebral blood volume (rCBV) increase on perfusion MRI (0/4), and hypermetabolism on 18 F-fluoro-L-dopa positron emission tomography (18 F-DOPA PET) scan (0/3). One patient underwent a surgical resection demonstrating no tumour recurrence; the five other patients were considered as having post-therapeutic modifications based on imaging characteristics. After a median follow-up of 4 years all patients were progression-free. CONCLUSIONS: Anaplastic oligodendroglioma patients treated with postoperative PCV chemotherapy alone occasionally develop T2/FLAIR hyperintensities around the surgical cavity that can wrongly suggest tumour progression. Multimodal imaging and close follow-up should be considered in this situation.

Evaluation of mechlorethamine, vinblastine, procarbazine, and prednisone for the treatment of resistant multicentric canine lymphoma.

Multi-agent chemotherapy successfully induces remission in most naïve, high-grade canine lymphoma patients; however, disease recurrence is common. MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) is an effective rescue protocol used to re-induce remission, but is associated with gastrointestinal toxicity and can be a less desirable option for patients that previously failed vincristine-containing protocols. Therefore, alternative members of the vinca alkaloid family, such as vinblastine, could be potentially advantageous as substitutes for vincristine to reduce gastrointestinal toxicity and chemoresistance. The objective of this study was to report the clinical outcomes and toxicity of 36 dogs with relapsed or refractory multicentric lymphoma treated with a modified MOPP protocol whereby vincristine was replaced with vinblastine (MVPP). The overall response rate to MVPP was 25% with a median progression free survival of 15 days and a median overall survival of 45 days. MVPP at the prescribed doses resulted in modest and transient clinical benefit, but was well tolerated with no treatment delays or hospitalizations secondary to side effects. Given the minimal toxicity, dose intensification could be considered to improve clinical responses.

Risk Factors for Primary Bone Cancer After Childhood Cancer: A PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies Nested Case-Control Study.

PURPOSE: Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation doses below 10 Gy and the dose-response relationship for specific types of chemotherapy. METHODS: Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship. RESULTS: The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation (Ptrend < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m2, the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer. CONCLUSION: To our knowledge, we demonstrate-for the first time-that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m2 increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.

Primary Central Nervous System Lymphoma in an Immunocompetent Young Adult Patient: A Rare Case.

Primary CNS Lymphoma (PCNSL) is a rare form aggressive extra nodal     non-Hodgkin Lymphoma (NHL) that comprising 1-2% of the primary brain tumors that develops in the brain, spinal cord, eye or leptomeningeal area without evidence of systemic involvement. The overall incidence of PCNSL with immunocompetent patients is only 0,47/100.000 year in PCNSL. Approximately 10-20% of patients have ocular involvement and around one third have multifocal neurological disease. Overall long-term survival rate only 20-40%, this is because the management of PCNSL is limited to ability of the drug due to cross the blood brain barrier (BBB). We present a B-cell central nervous system lymphoma in an immunocompetent patient who treat responses with chemotherapy.          A 35-year-old man presented to our hospital with suddenly unconscious 4 hours before admission. He was experiencing headache and blurred of vision withing 3 months and have episode seizure. On Examination, GCS E2 M3 Aphasia, Hemiparesis dextra, papil edema, VOD/VOS: NLP. The other physical exam was normal. Laboratory tests  Hb 10,7 g/dl, LDH 446 U/L, and D-dimer 3,21ug/ml.  Rubella IgG 76,9, CMV Ig G 245,6 and, HSV IgG and IgM negative, HIV test non-reactive, Toxoplasma IgG and Toxoplasma IgM negative, HbsAg and HCV test negative. Brain MRI and MRI Spectroscopy: Lobulated mass size 7,08 cm x 4,75 cm at caudates nucleus sinistra-periventricular lateralis sinistra, Cholin/NAA ratio: 5-9, Cholin/Creatin ration 6-11 suspect malignancy dd/Lymphoma. MRI whole spine: Bulging discus intervertebral C4-C5. Chest and Abdomen CT-Scan are normal. Bone Survey normal, EEG: Epileproform left temporal. Cerebrospinal Fluid: Gliosis reaction sup malignancy.The patient underwent craniotomy and biopsy Pathology Anatomy and IHC Basal Ganglia revealed a Diffuse Large B Cell Lymphoma (NHL) Non-Germinal Center, CD 20 +, Ki 67 95% (High Grade), CD 45 +, CD 3 -, BCL6 +, Mum 1+. The patient we give induction therapy with RMP Regimens (Rituximab 375 mg/m2, day 1, 15 and 29, High Dose Methotrexate (HDMTX) 3000mg/m2 day 2, 16 and 30, and Procarbazine 60mg/m2 day 3-12) because Procarbazine in not available in Palembang we change to Dacarbazine 375mg/m2 days 3,17 and 31), Dexamethasone 5mg/6 hours, and has finished  Low Dose Whole Brain Radiotherapy for consolation therapy. PCNSL is rare form aggressive extra nodal NHL, especially in Immunocompetent patient. In this particular case of patients High Dose Methotrexate Chemotherapy has achieved high respond especially for this patient that showed GCS E4M5V6 and recovery neurological deficit after 2 cycle chemotherapy.

Association of Radiation and Procarbazine Dose With Risk of Colorectal Cancer Among Survivors of Hodgkin Lymphoma.

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.

[Molecular pathogenesis and therapeutic development of primary central nervous system lymphoma: update and future perspectives].

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.

Treatment Options for Recurrent Primary CNS Lymphoma.

OPINION STATEMENT: 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/m2) 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.

Successful treatment with tirabrutinib for relapsed Bing-Neel syndrome following high-dose methotrexate and craniospinal irradiation.

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.

Cost-Effectiveness of Colorectal Cancer Surveillance in Hodgkin Lymphoma Survivors Treated with Procarbazine and/or Infradiaphragmatic Radiotherapy.

BACKGROUND: Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy (IRT) and/or procarbazine have an increased risk of developing colorectal cancer. We investigated the cost-effectiveness of colorectal cancer surveillance in Dutch Hodgkin lymphoma survivors to determine the optimal surveillance strategy for different Hodgkin lymphoma subgroups. METHODS: The Microsimulation Screening Analysis-Colon model was adjusted to reflect colorectal cancer and other-cause mortality risk in Hodgkin lymphoma survivors. Ninety colorectal cancer surveillance strategies were evaluated varying in starting and stopping age, interval, and modality [colonoscopy, fecal immunochemical test (FIT, OC-Sensor; cutoffs: 10/20/47 µg Hb/g feces), and multi-target stool DNA test (Cologuard)]. Analyses were also stratified per primary treatment (IRT and procarbazine or procarbazine without IRT). Colorectal cancer deaths averted (compared with no surveillance) and incremental cost-effectiveness ratios (ICER) were primary outcomes. The optimal surveillance strategy was identified assuming a willingness-to-pay threshold of €20,000 per life-years gained (LYG). RESULTS: Overall, the optimal surveillance strategy was annual FIT (47 µg) from age 45 to 70 years, which might avert 70% of colorectal cancer deaths in Hodgkin lymphoma survivors (compared with no surveillance; ICER:€18,000/LYG). The optimal surveillance strategy in Hodgkin lymphoma survivors treated with procarbazine without IRT was biennial FIT (47 µg) from age 45 to 70 years (colorectal cancer mortality averted 56%; ICER:€15,000/LYG), and when treated with IRT and procarbazine, annual FIT (47 µg) surveillance from age 40 to 70 was most cost-effective (colorectal cancer mortality averted 75%; ICER:€13,000/LYG). CONCLUSIONS: Colorectal cancer surveillance in Hodgkin lymphoma survivors is cost-effective and should commence earlier than screening occurs in population screening programs. For all subgroups, FIT surveillance was the most cost-effective strategy. IMPACT: Colorectal cancer surveillance should be implemented in Hodgkin lymphoma survivors.

Hodgkin Lymphoma on Hemodialysis: A Review of Treatment and Recommendations.

Chemotherapy for classic Hodgkin lymphoma (cHL) patients on hemodialysis (HD) is an extremely challenging situation because pharmacokinetic and pharmacodynamic studies of most chemotherapeutics are lacking for the HD patient, and the small amount of evidence available comes mostly from case reports and small case series. In this review, we provide recommendations based on treatment experience of cHL patients on HD in the literature. HD patients undergoing chemotherapy are at risk of overdose and toxicities because many drugs are significantly eliminated by the kidneys, and at the same time, are at risk of undertreatment because many drugs are removed by HD. Therefore, dose modifications and timing of drug administration in relation to HD sessions must be carefully planned according to the distinct traits of each chemotherapeutic. We carried out an exhaustive literature review of reports of actual administrations of chemotherapeutics to cHL on HD, and also extrapolated data from reports of the same chemotherapeutics that were administered to HD patients with malignancies other than cHL. We summarized the information found in the literature, and provide practical and balanced recommendations concerning dose modifications and optimal timing of drug administration in relation to HD sessions for each chemotherapeutic. Chemotherapy regimens and individual chemotherapeutics studied in this review include ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine), BEACOPP (bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisolone), MOPP (mechlorethamine + vincristine + procarbazine + prednisolone), gemcitabine, vinorelbine, brentuximab vedotin, and PD-1 inhibitors (nivolumab and pembrolizumab).

Early Postoperative Treatment versus Initial Observation in CNS WHO Grade 2 and 3 Oligodendroglioma: Clinical Outcomes and DNA Methylation Patterns.

PURPOSE: The treatment of oligodendroglioma consists of tumor resection and radiochemotherapy. The timing of radiochemotherapy remains unclear, and predictive biomarkers are limited. EXPERIMENTAL DESIGN: Adult patients diagnosed with isocitrate dehydrogenase (IDH)-mutated, 1p/19q-codeleted CNS WHO grade 2 and 3 oligodendroglioma at the Medical University of Vienna and the Kepler University Hospital Linz (Austria) in 1992 to 2019 were included. Progression-free (PFS) and overall survival (OS) between early postoperative treatment and initial observation were compared using propensity score-weighted Cox regression models. DNA methylation analysis of tumor tissue was performed using Illumina MethylationEPIC 850k microarrays. RESULTS: One hundred thirty-one out of 201 (65.2%) patients with CNS WHO grade 2 and 70 of 201 (34.8%) with grade 3 oligodendroglioma were identified. Eighty-three of 201 (41.3%) patients underwent early postoperative treatment, of whom 56 of 83 (67.5%) received radiochemotherapy, 15 of 84 (18.1%) radiotherapy (RT) only and 12 of 83 (14.5%) chemotherapy only. Temozolomide-based treatment was administered to 64 of 68 (94.1%) patients, whereas RT + procarbazine, lomustine (CCNU), and vincristine (PCV) were applied in 2 of 69 (3.5%) patients. Early treatment was not associated with PFS [adjusted hazard ratio (HR) 0.74; 95% CI, 0.33-1.65, P = 0.459] or OS (adjusted HR: 2.07; 95% CI, 0.52-8.21, P = 0.302) improvement. Unsupervised clustering analysis of DNA methylation profiles from patients receiving early treatment revealed two methylation clusters correlating with PFS, whereas no association of clustering with O6-methylguanine methyltransferase (MGMT) promoter methylation, CNS WHO grade, extent of resection, and treating center could be observed. CONCLUSIONS: In this retrospective study, early postoperative treatment was not associated with improved PFS/OS in oligodendroglioma. The potentially predictive value of whole-genome methylation profiling should be validated in prospective trials.

Improvement of functional outcome for patients with newly diagnosed grade 2 or 3 gliomas with co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 trial.

BACKGROUND: Given the young age of patients with CNS WHO grade 2 and 3 oligodendrogliomas and the relevant risk of neurocognitive, functional, and quality-of-life impairment with the current aggressive standard of care treatment, chemoradiation with PCV, of the tumour located in the brain optimizing care is the major challenge. METHODS: NOA-18 aims at improving qualified overall survival (qOS) for adult patients with CNS WHO grade 2 and 3 oligodendrogliomas by randomizing between standard chemoradiation with up to six six-weekly cycles with PCV and six six-weekly cycles with lomustine and temozolomide (CETEG) (n = 182 patients per group accrued over 4 years) thereby delaying radiotherapy and adding the chemoradiotherapy concept at progression after initial radiation-free chemotherapy, allowing for effective salvage treatment and delaying potentially deleterious side effects. QOS represents a new concept and is defined as OS without functional and/or cognitive and/or quality of life deterioration regardless of whether tumour progression or toxicity is the main cause. The primary objective is to show superiority of an initial CETEG treatment followed by partial brain radiotherapy (RT) plus PCV (RT-PCV) at progression over partial brain radiotherapy (RT) followed by procarbazine, lomustine, and vincristine (PCV) chemotherapy (RT-PCV) and best investigators choice (BIC) at progression for sustained qOS. An event concerning a sustained qOS is then defined as a functional and/or cognitive and/or quality of life deterioration after completion of primary therapy on two consecutive study visits with an interval of 3 months, tolerating a deviation of at most 1 month. Assessments are done with a 3-monthly MRI, assessment of the NANO scale, HRQoL, and KPS, and annual cognitive testing. Secondary objectives are evaluation and comparison of the two groups regarding secondary endpoints (short-term qOS, PFS, OS, complete and partial response rate). The trial is planned to be conducted at a minimum of 18 NOA study sites in Germany. DISCUSSION: qOS represents a new concept. The present NOA trial aims at showing the superiority of CETEG plus RT-PCV over RT-PCV plus BIC as determined at the level of OS without sustained functional deterioration for all patients with oligodendroglioma diagnosed according to the most recent WHO classification. TRIAL REGISTRATION: Clinicaltrials.gov NCT05331521 . EudraCT 2018-005027-16.