Targets and treatments in primary CNS lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare and highly aggressive lymphoma entirely localized in the central nervous system or vitreoretinal space. PCNSL generally initially responds to methotrexate-containing chemotherapy regimens, but progressive or relapsing disease is common, and the prognosis is poor for relapsed or refractory (R/R) patients. PCNSL is often characterized by activation of nuclear factor kappa B (NF-κB) due to mutations in the B-cell receptor (BCR) or toll-like receptor (TLR) pathways, as well as immune evasion. Targeted treatments that inhibit key PCNSL mechanisms and pathways are being evaluated; inhibition of Bruton's tyrosine kinase (BTK) downstream of BCR activation has demonstrated promising results in treating R/R disease. This review will summarize the evidence and potential for targeted therapeutic agents to improve treatment outcomes in PCNSL. This includes immunotherapeutic and immunomodulatory approaches and inhibitors of the key pathways driving PCNSL, such as aberrant BCR and TLR signaling.

Hyperviscosity Syndrome Induced Bilateral Visual and Auditory Impairment in Therapy Resistant Waldenström Macroglobulinemia with MYD88 and CXCR4 Mutations.

Hyperviscosity syndrome (HVS) is an emergent complication of Waldenström macroglobulinemia (WM) characterized by visual, neurologic, and rarely auditory impairment. We report a 69-year-old female with MYD88 and CXCR4-mutant WM who developed HVS resulting in bilateral blindness and deafness associated with neurologic manifestations including confusion, severe generalized weakness, and imbalance. Ophthalmologic evaluation revealed bilateral central retinal vein occlusion (CRVO), diffuse retinal hemorrhages, macular edema, and serous macular detachments (SMD). Magnetic resonance imaging of the brain showed bleeding in the inner ears. Management was challenging as her WM was resistant to systemic therapies including bendamustine + rituximab (BR) and rituximab + bortezomib + dexamethasone (RVD). Bruton's tyrosine kinase inhibitors could not be used initially due to ongoing lower gastrointestinal bleeding. She required five total sessions of plasma exchange and was finally initiated on zanubrutinib, achieving a partial response. She also received intravitreal bevacizumab with rapid resolution of the retinal hemorrhages but with little improvement of the SMD. She had partial restoration of her hearing in the right ear and only slight improvement in her bilateral visual deficits. The management of HVS in frail, elderly patients with therapy-resistant WM can be challenging. In these cases, plasma exchange is required until an effective systemic therapy can be safely instituted. Genomic profiling is important in the management of WM as it can predict treatment resistance and guide therapeutic decisions.

Acquired Factor VII Deficiency Associated With Chronic Myeloid Leukemia Blast Crisis.

Factor VII (FVII) is an important, vitamin K-dependent clotting factor. Acquired FVII deficiency is a rare entity that is associated with serious bleeding complications. We report a case of acquired FVII deficiency in a patient with recurrent chronic myeloid leukemia in blast crisis who developed bilateral retinal hemorrhages. The coagulopathy was corrected with the initiation of chemotherapy and subsequent reduction in peripheral blast count.

IRAK-4 inhibition: emavusertib for the treatment of lymphoid and myeloid malignancies.

Several studies have identified mutations in the MYD88L265P gene as a key driver mutation in several B-cell lymphomas. B-cell lymphomas that harbor the MYD88L265P mutation form a complex with phosphorylated Bruton's tyrosine kinase (BTK) and are responsive to BTK inhibition. However, BTK inhibition in B-cell lymphomas rarely results in a complete response and most patients experience eventual disease relapse. Persistent survival signaling though downstream molecules such as interleukin 1 receptor-associated kinase 4 (IRAK-4), an integral part of the "myddosome" complex, has been shown to be constitutively active in B-cell lymphoma patients treated with BTK inhibitors. Emerging evidence is demonstrating the therapeutic benefit of IRAK-4 inhibition in B-cell lymphomas, along with possibly reversing BTK inhibitor resistance. While MYD88 gene mutations are not present in myeloid malignancies, downstream overexpression of the oncogenic long form of IRAK-4 has been found in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), particularly in AML and MDS that harbor mutations in splicing factors U2AF1 and SF3B1. These data suggest that the anti-leukemic activity of IRAK-4 inhibition can be exploited in relapsed/refractory (R/R) AML/MDS. In this review article, we discuss the currently available pre-clinical and clinical data of emavusertib, a selective, orally bioavailable IRAK-4 inhibitor in the treatment of R/R B-cell lymphomas and myeloid malignancies.

90Yttrium Ibritumomab Tiuxetan (Zevalin) for the Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Report of 5 Cases.

Radioimmunotherapy (RIT) with radio-labeled monoclonal antibodies to CD20 produces a high response rate in patients with low-grade B-cell lymphomas. The use of this modality in patients with chronic lymphocytic leukemia (CLL) has been sporadic in clinical trials and was hampered by the extensive marrow involvement seen commonly in patients with CLL, which would produce a high risk for marrow aplasia after treatment with RIT. Herein, we report our experience with RIT in 5 patients with CLL or SLL showing short-lived responses and significant myelosuppression. After 90Y-ibritumomab tiuxetan treatment, the median time to relapse was 65 days, and no cases of MDS or AML were observed during follow-up. All patients experienced grade ≥3 thrombocytopenia and neutropenia, with median durations of 39.5 days and 107 days, respectively.

Successful Anatomy Adapted Therapeutic Management and Genetic Profiling of Primary Pituitary Diffuse Large B-Cell Lymphoma.

Primary pituitary diffuse large B-cell lymphoma (PPL) has been regarded as a subtype of primary central nervous system lymphoma (PCNSL); however, the pituitary gland is located outside the blood brain barrier (BBB) with neural and vascular connections to the brain. Given its unique anatomic location, a combination of non-central nervous system (CNS)-penetrating and CNS-penetrating therapeutic agents can be employed to treat PPL. We report a female patient with PPL who was successfully managed with anatomy-adapted therapy incorporating non-CNS penetrating chemoimmunotherapy [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)] alternating with CNS-penetrating chemoimmunotherapy [rituximab, high-dose methotrexate, and high-dose cytarabine (RMA)]. She received a total of eight cycles of treatment with four cycles of each regimen following partial transsphenoidal resection. She achieved a complete response after two cycles and has remained in complete remission for the last eight years. To our knowledge, this is the longest documented survival in a patient with PPL. Targeted genomic profiling with Next-Generation Sequencing (NGS) was recently performed on the lymphoma tissue. The genomic profile of PPL in this patient is quite different from the findings typically associated with PCNSL. We suggest that PPL may be biologically distinct from PCNSL and should be treated with an anatomy adapted approach. Additional research is necessary to confirm our findings.

Multiply Relapsed Secondary CNS Non-Germinal Center Diffuse Large B-Cell Lymphoma Successfully Treated with CNS-Centric Therapy.

Secondary central nervous system involvement by systemic diffuse large B-cell lymphoma (DLBCL) carries a very poor prognosis. We present a female patient who had two episodes of intracerebral central nervous system (CNS)-only relapse of systemic non-germinal center diffuse large B-cell lymphoma (NGC-DLBCL). Her treatment at initial diagnosis consisted of induction with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and intrathecal (IT) - methotrexate (MTX) followed by consolidation with autologous stem cell transplant (ASCT) after high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy. She had the first CNS-only relapse 1.5 years post-ASCT and received whole brain radiation therapy (WBRT). She developed the second intracerebral CNS-only relapse 2 years post-WBRT. A CNS-centric therapeutic approach with salvage chemoimmunotherapy incorporating rituximab, high-dose methotrexate (HD-MTX), high-dose cytarabine (HiDAC), and ibrutinib was utilized for her second CNS-only relapse. She underwent consolidation with a second ASCT following high-dose carmustine (BCNU) and thiotepa chemotherapy. Given her high risk of CNS recurrence, she was started on maintenance ibrutinib. To date, she has remained in complete remission for 3 years. In our experience, multiply relapsed secondary CNS lymphoma (SCNSL) with this response is very rare. We suggest one CNS-centric therapeutic approach that can potentially salvage patients with SCNSL who have not had prior exposure to adequate CNS-directed therapies but acknowledge that additional research is necessary to validate our findings.

Cardiovascular outcomes in breast cancer survivors: a systematic review and meta-analysis.

AIMS: It is unclear whether the future risk of cardiovascular events in breast cancer (Bc) survivors is greater than in the general population. This meta-analysis quantifies the risk of cardiovascular disease development in Bc patients, compared to the risk in a general matched cancer-free population, and reports the incidence of cardiovascular events in patients with Bc. METHODS AND RESULTS: We searched PubMed, Scopus, and Web of Science databases (up to 23 March 2022) for observational studies and post hoc analyses of randomized controlled trials. Cardiovascular death, heart failure (HF), atrial fibrillation (AF), coronary artery disease (CAD), myocardial infarction (MI), and stroke were the individual endpoints for our meta-analysis. We pooled incidence rates (IRs) and risk in hazard ratios (HRs), using random-effects meta-analyses. Heterogeneity was reported through the I2 statistic, and publication bias was examined using funnel plots and Egger's test in the meta-analysis of risk. One hundred and forty-two studies were identified in total, 26 (836 301 patients) relevant to the relative risk and 116 (2 111 882 patients) relevant to IRs. Compared to matched cancer-free controls, Bc patients had higher risk for cardiovascular death within 5 years of cancer diagnosis [HR = 1.09; 95% confidence interval (CI): 1.07, 1.11], HF within 10 years (HR = 1.21; 95% CI: 1.1, 1.33), and AF within 3 years (HR = 1.13; 95% CI: 1.05, 1.21). The pooled IR for cardiovascular death was 1.73 (95% CI 1.18, 2.53), 4.44 (95% CI 3.33, 5.92) for HF, 4.29 (95% CI 3.09, 5.94) for CAD, 1.98 (95% CI 1.24, 3.16) for MI, 4.33 (95% CI 2.97, 6.30) for stroke of any type, and 2.64 (95% CI 2.97, 6.30) for ischaemic stroke. CONCLUSION: Breast cancer exposure was associated with the increased risk for cardiovascular death, HF, and AF. The pooled incidence for cardiovascular endpoints varied depending on population characteristics and endpoint studied. REGISTRATION: CRD42022298741.

This work investigated the absolute and relative risk of cardiovascular outcomes in breast cancer survivors. Breast cancer was associated with a higher risk of cardiovascular death, heart failure (HF), and atrial fibrillation when compared to the general population.The incidence for cardiovascular death, HF, and coronary artery disease were 1.73, 4.44, and 4.29 per 1000 person-years, respectively.Clinicians should carefully assess breast cancer survivors for their cardiovascular risk factor profile and monitor their cardiovascular function.

Outcomes of Patients With Classic Hodgkin Lymphoma Who Relapsed After Autologous Stem Cell Transplant.

Immune checkpoint inhibitors (ICIs) and brentuximab vedotin (BV) are novel agents for classic Hodgkin lymphoma, including relapse after autologous stem cell transplant (ASCT). However, their impact on survival post-ASCT relapse, in comparison with conventional therapy, is less known due to the lack of randomized controlled trials. Clinical characteristics and outcomes of 115 patients with relapse (or progression) after ASCT are studied. After a median follow-up of 8.59 years from post-ASCT relapse, the median progression-free survival (PFS) and overall survival (OS) were 0.91 and 5.07 years, respectively. Median lines of therapy after post-ASCT relapse was 2 (range, 1-12). The median PFS was not reached (NR) versus 1.11 versus 0.50 versus 0.85 versus 0.78 years (P = 0.006) and OS was NR versus 7.60 versus 3.08 versus 3.51 versus 3.17 years (P = 0.28) in patients first treated with ICIs versus BV versus investigational agents versus chemotherapy versus radiation therapy (RT). First-line treatment with novel agents (ie, ICIs and BV) was associated with superior outcomes compared with investigational agents and chemotherapy/RT with a median PFS of 1.65 versus 0.50 versus 0.79 years (P = 0.003) and a median OS of 7.60 versus 3.08 versus 3.32 years (P = 0.08). Regardless of lines of therapy, the treatment with ICIs had the most favorable outcome with a median PFS and OS of 3.98 and NR years, respectively. Allogeneic stem cell transplant (allo-SCT) was done in 23 patients (20%), and the median post-allo-SCT PFS and OS were 1.31 and 2.35 years, respectively. In conclusion, survival following post-ASCT relapse improves significantly when patients receive novel agents.

Yttrium-90 Ibritumomab Tiuxetan is Cost-Effective Compared to Bendamustine + Rituximab in Low-grade Lymphomas.

BACKGROUND: Yttrium-90 ibritumomab tiuxetan [(90)Y-IT] is a CD20-targeted radio-immunotherapeutic agent. It has shown an excellent therapeutic activity with high tolerability against previously untreated follicular lymphoma (FL) and marginal zone B cell lymphoma (MZL). It is an attractive therapeutic option as the treatment schedule is short and convenient. The aim of our study is to determine the cost-effectiveness of (90)Y-IT in comparison to the standard-of-care bendamustine + rituximab (BR) in the first-line treatment of low-grade FL (LG-FL) and MZL in the real world. PATIENTS AND METHODS: We included all patients who were treated with standard-dose (90)Y-IT for previously untreated LG-FL and MZL at the Mayo Clinic Cancer Center (N = 51). A comparator arm with a historical cohort of previously untreated LG-FL and MZL patients who received BR was used (N = 92). RESULTS: Inverse propensity weighting was utilized to balance the 2 study arms. There were no differences in terms of overall response rate (100% vs. 98%, P = .18), complete response rate (94% vs. 95%, P = .91), or 5 years progression-free survival (76% vs. 75%, P = .63) between patients who received (90)Y-IT and BR, respectively. Within the first year, patients who received (90)Y-IT required an average of 4.5 fewer oncology clinic visits (P < .001), an average of 10 fewer days of therapeutic use (P < .001), and 40% less use of growth factors (P < .001) as compared to the BR group. The direct therapeutic cost of (90)Y-IT treatment was 54% less than that of 6 cycles of BR. CONCLUSION: The findings suggest that (90) Y-IT is more cost-effective than BR and is a viable alternative in up-front management of LG-FL and MZL.

DTRMWXHS-12, a novel Bruton tyrosine kinase inhibitor, in combination with everolimus and pomalidomide in patients with relapsed/refractory lymphomas: An open-label, multicenter, phase 1a/1b study.

Preclinical studies have shown augmented activity when combining Bruton tyrosine kinase inhibitors (BTKi) with inhibitors of mammalian target of rapamycin (mTOR) and immunomodulatory agents (IMiD). We conducted a phase 1, open-label study at five centers in USA to evaluate the safety of triplet BTKi/mTOR/IMiD therapy. Eligible patients were adults aged 18 years or older with relapsed/refractory CLL, B cell NHL, or Hodgkin lymphoma. Our dose escalation study used an accelerated titration design and moved sequentially from single agent BTKi (DTRMWXHS-12), doublet (DTRMWXHS-12 + everolimus), and then to triplet therapy (DTRMWXHS-12 + everolimus + pomalidomide). All drugs were dosed once daily on days 1-21 of each 28-day cycle. The primary goal was to establish the recommended phase 2 dose of the triplet combination. Between September 27, 2016, and July 24, 2019, a total of 32 patients with a median age of 70 years (range 46 to 94 years) were enrolled. No MTD was identified for monotherapy and the doublet combination. The MTD for the triplet combination was determined to be DTRMWXHS-12 200 mg + everolimus 5 mg + pomalidomide 2 mg. Responses across all studied cohorts were seen in 13 of 32 (41.9%). Combining DTRMWXHS-12 with everolimus and pomalidomide is tolerable and shows clinical activity. Additional trials could confirm benefit of this all-oral combination therapy for relapsed/refractory lymphomas.

Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases.

PURPOSE: An ongoing challenge in cancer is the management of primary and metastatic brain malignancies. This is partly due to restrictions of the blood-brain barrier and their unique microenvironment. These challenges are most evident in cancers such as lymphoma and melanoma, which are typically responsive to treatment in systemic locations but resistant when established in the brain. We propose interleukin-1 receptor-associated kinase-4 (IRAK-4) as a potential target across these diseases and describe the activity and mechanism of oral IRAK-4 inhibitor CA-4948. EXPERIMENTAL DESIGN: Human primary central nervous system lymphoma (PCNSL) and melanoma brain metastases (MBM) samples were analyzed for expression of IRAK-4 and downstream transcription pathways. We next determined the central nervous system (CNS) applicability of CA-4948 in naïve and tumor-bearing mice using models of PCNSL and MBM. The mechanistic effect on tumors and the tumor microenvironment was then analyzed. RESULTS: Human PCNSL and MBM have high expression of IRAK-4, IRAK-1, and nuclear factor kappa B (NF-κB). This increase in inflammation results in reflexive inhibitory signaling. Similar profiles are observed in immunocompetent murine models. Treatment of tumor-bearing animals with CA-4948 results in the downregulation of mitogen-activated protein kinase (MAPK) signaling in addition to decreased NF-κB. These intracellular changes are associated with a survival advantage. CONCLUSIONS: IRAK-4 is an attractive target in PCNSL and MBM. The inhibition of IRAK-4 with CA-4948 downregulates the expression of important transcription factors involved in tumor growth and proliferation. CA-4948 is currently being investigated in clinical trials for relapsed and refractory lymphoma and warrants further translation into PCNSL and MBM.

Successful CNS-Centric Therapeutic Management and Genomic Profiling of Primary Cranial Vault Diffuse Large B-Cell Lymphoma.

Primary cranial vault lymphoma (PCVL) is a rare lymphoma involving the skull with or without extra- and intracranial extension. Most cases of PCVL are diffuse large B-cell lymphoma (DLBCL). We report a case of primary cranial vault diffuse large B-cell lymphoma (PCV-DLBCL) that was successfully treated with anthracycline-based chemoimmunotherapy (CIT) alternating with central nervous system (CNS)-directed CIT with high-dose methotrexate and high-dose cytarabine. CNS-centric therapy was given for suspected cerebral cortical involvement and presumed elevated risk of CNS recurrence. The patient has remained in complete remission for 4.25 years following treatment. We suggest that PCV-DLBCL is potentially curable with CNS-directed therapy. Additionally, we provide genomic profiling results indicating an indeterminate cell of origin and multiple genetic mutations which are not frequently seen in DLBCL.

Poly-lymphomatous Syndrome With Concurrent or Sequential Hodgkin and Non-Hodgkin lymphoma.

INTRODUCTION: The development of Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) concurrently or sequentially in the same patient is a rare clinical scenario and can be labeled as a poly-lymphomatous syndrome (PLS). METHODS: We report clinico-pathologic characteristics and survival outcomes of 7 such cases from our institution. In concurrent PLS, HL is present with NHL in the same location (composite PLS) or in separate locations (discordant PLS). Sequential presentations were seen with HL following NHL or vice versa (sequential PLS). CONCLUSIONS: It is essential to perform adequate biopsies in supposedly relapsed or refractory settings to diagnose PLS. We suggest that the incidence of PLS is likely underestimated due to the under-utilization of repeat biopsies. In patients with concurrent PLS, the treatment should ideally cover both types of lymphoma with an emphasis on tailoring the treatment towards the more aggressive lymphoma. In patients with sequential PLS, the treatment should target the new lymphoma. Consolidation treatments such as autologous hematopoietic cell transplant should be considered when there is a component of relapsed cHL or aggressive NHL. Based on our experience, PLS does not appear to be associated with a poor prognosis. Further research is necessary for better understanding of the biology and management of PLS.

Primary Bone Marrow Lymphoma: De Novo and Transformed Subtypes.

Diffuse large B-cell lymphoma (DLBCL) is well known for selectively involving certain extranodal locations such as the central nervous system (CNS), testes, and skin. DLBCL or high-grade B-cell lymphoma selectively involving the bone marrow is rare and has been sparsely reported in the medical literature. We report two cases of lymphoma presenting with primary bone marrow involvement without evidence of involvement of any other sites. The first case represents de novo DLBCL. The patient achieved complete remission with initial treatment, had a bone marrow-only relapse three years later, and achieved a second complete remission following non-transplant salvage therapy. The second case had findings consistent with "double hit" Richter's transformation of chronic lymphocytic leukemia with translocation of c-MYC and BCL-2. This patient had an aggressive clinical course characterized by rapid progression with CNS involvement within three months resulting in the demise of the patient. These two cases represent two distinct subtypes of primary bone marrow lymphoma: de novo and transformed. Further research is necessary to gain a better understanding of this rare lymphoma entity and develop novel therapies.

Impact of Rituximab and Corticosteroids on Late Cytopenias Post-Chimeric Antigen Receptor T Cell Therapy.

Chimeric antigen receptor (CAR) T cell therapy represents a significant advancement in the treatment of patients with relapsed/refractory B cell lymphoid malignancies. Cytokine release syndrome and immune effector cell-associated neurotoxicity represent the most acute serious adverse events post CAR T cell therapy but the occurrence and persistence of cytopenias post CAR T cell therapy represent a significant adverse event and a management challenge. While most patients typically recover blood counts by 30 days, a significant subset of patients have persistent or late cytopenias beyond 30 days. Patients receiving CAR T cell are heavily pre-treated and the impact of prior therapies on late cytopenias is not well understood. In this study, we found an association between increased number of rituximab infusions and/or cumulative rituximab dose received prior to CAR T cell infusion and persistent anemia and thrombocytopenia at 90 and 180 days afterwards. An overall increased number of prior lines of therapy was also associated with persistent lymphopenia and anemia at 90 days while receiving a prior autologous hematopoietic cell transplant was associated with a greater risk of neutropenia and lymphopenia.

Intravascular Large B Cell Lymphoma with CNS Involvement Successfully Treated with High-Dose Methotrexate and High-Dose Ara-C Based CNS-Directed Chemoimmunotherapy Alternating with Anthracycline Based Chemoimmunotherapy.

Intravascular large B cell lymphoma (IVL) is a rare subtype of diffuse large B cell lymphoma confined to small blood vessels with a predilection for CNS involvement. The prognosis of IVL with CNS involvement (CNS-IVL) is extremely poor. The optimal treatment for CNS-IVL is not well defined. Thus, we report three patients with CNS-IVL successfully treated with a CNS-centric approach consisting of high-dose methotrexate (HDMTX) and high-dose Ara-C (HiDAC) based CNS-directed chemoimmunotherapy (CIT) alternating with anthracycline-based CIT. Our rationale for intensifying the CNS-directed therapy is the presence of intracerebral bleeding in two of our patients which would result in extravasation of lymphoma cells into the cerebral parenchyma with the development of CNS lymphoma. All three patients have achieved excellent therapeutic outcomes. Two patients with intracerebral bleeding have been in complete remission (CR) for about 11 years and 4 years. One patient was successfully induced into CR about 10 months ago and currently is in CR. This unique therapeutic approach should be further explored for CNS-IVL.

Clinical characteristics, prognostic indicators, and survival outcomes in intravascular lymphoma: Mayo Clinic experience (2003-2018).

Intravascular lymphoma (IVL) is a rare extranodal non-Hodgkin lymphoma. We performed a retrospective analysis of 55 IVL patients who were treated at our institution 2003-2018. Median age at diagnosis was 68 years, and 64% were males. The most frequent presenting symptoms were skin rash 43% and weight loss 30%. MRI brain on IVL patients with CNS involvement (CNS-IVL) showed multifocal involvement in 76% (13/17). 89% (17/19) of non-CNS-IVL patients with abnormal FDG-PET had biopsy of an avid lesion resulting in definitive diagnosis. The top diagnostic biopsy site was the bone marrow (45%). 56% had multiorgan involvement. Based on CNS involvement, 36.5% (20/55) had CNS-IVL and 63.5% (35/55) had non-CNS-IVL. CNS-IVL group consists of clinically isolated CNS involvement (CNS-only IVL) (22%;12/55) and mixed clinical CNS and peripheral site involvement (M-IVL) (14.5%; 8/55). Non-CNS-IVL group consists of clinically isolated skin involvement (skin-only IVL) (9%; 5/55) and peripheral IVL with or without skin involvement (P-IVL); (54.5%; 30/55). Skin involvement was predominantly in the lower extremities. Pathologically, 89% (48/54) were B-cell IVL. Rituximab + high-dose methotrexate-based regimen were used in 75% (12/16) of CNS-IVL patients and RCHOP in 60% (17/28) of non-CNS-IVL patients. Estimated 5-year progression free survival (PFS) and overall survival (OS) for the entire cohort were 38.6% and 52%, respectively. Skin-only IVL was associated with excellent survival. Platelet count <150x109 /L, age > 60Y, and treatment without Rituximab were poor prognostic factors. Further research is necessary to identify novel therapies.

A real-world study of combined modality therapy for early-stage Hodgkin lymphoma: too little treatment impacts outcome.

Multiple clinical trials have assessed de-escalation strategies from combined modality therapy (CMT) to chemotherapy-alone for the treatment of early-stage classical Hodgkin lymphoma (cHL), confirming similar outcomes. The application of these data to the real-world is limited, however. We conducted a retrospective, multicenter cohort study comparing CMT vs chemotherapy-alone in patients with early-stage cHL (stage IA-IIB) treated between January 2010 and December 2020. Positron emission tomography (PET) scans after chemotherapy cycle 2 (PET2) were independently reviewed by a nuclear radiologist (Deauville score ≥4, positive; ≤3, negative). Patient outcomes were compared by using an intention-to-treat analysis. Among 125 patients (CMT, n = 63; chemotherapy-alone, n = 62) with a median follow-up of 59.8 months (95% CI, 48.6-71.0), no differences in overall survival were observed (5-year overall survival, CMT 98.0% vs chemotherapy-alone 95.1%; log-rank test, P = .38). However, there was reduced progression-free survival (PFS) with chemotherapy-alone among all patients (2-year PFS, CMT 95.1% vs chemotherapy-alone 75.3%; log-rank test, P = .005) and in those with bulky (n = 43; log-rank test, P < .001), unfavorable (n = 81; log-rank test, P = .002), or PET2-positive (n = 15; log-rank test, P = .02) disease. No significant differences in PFS were seen for patients with non-bulky (log-rank test, P = .35), favorable (log-rank test, P = .62), or PET2-negative (log-rank test, P = .19) disease. Based on our real-world experience, CMT seems beneficial for patients with early-stage cHL, especially those with PET2-positive and unfavorable disease. Chemotherapy-alone regimens can lead to comparable outcomes for patients with favorable, non-bulky, or PET2-negative disease. We conclude that although results seen in clinical trials are replicated in certain patient subgroups, other subgroups not fitting trial criteria do poorly when radiotherapy is excluded.