Hodgkin lymphoma: Focus on evolving treatment paradigms.

Hodgkin lymphoma (HL) is a highly curable B-cell malignancy of germinal center origin. Biologically it is a hematologic malignancy that is highly dependent on the immune microenvironment and utilizes immune escape through upregulation of the programmed-death ligands on the neoplastic cells. Despite being highly curable, consensus is lacking nationally and internationally about the optimal approach to management, particularly in limited-stage disease. The addition of brentuximab vedotin and checkpoint inhibitors for the management of HL has led to a rapidly changing treatment landscape. Further studies should be done to include these novel agents at all stages of disease to determine improvements in frontline cure rates and long-term toxicity.

Severe Lenalidomide-Associated Hyperbilirubinemia.

Immunomodulatory drugs (IMids), such as thalidomide and lenalidomide, are used to treat plasma cell neoplasms and B-cell malignancies. We present a case of severe direct hyperbilirubinemia in a patient taking lenalidomide-based therapy for plasmacytoma. Imaging was unrevealing, and liver biopsy showed only mild sinusoidal dilation. Roussel Uclaf Causality Assessment (RUCAM) score was 6, indicating lenalidomide was a probable cause of the injury. To our knowledge, this is the highest reported direct bilirubin regarding lenalidomide drug-induced liver injury (DILI), with a peak bilirubin of 41mg/dL. While a clear pathophysiology was not identified, this case provides important considerations regarding lenalidomide safety.

Carfilzomib, Lenalidomide, and Dexamethasone Followed by Lenalidomide Maintenance for Prevention of Symptomatic Multiple Myeloma in Patients With High-risk Smoldering Myeloma: A Phase 2 Nonrandomized Controlled Trial.

IMPORTANCE: High-risk smoldering myeloma has a 5-year risk of progression to symptomatic multiple myeloma of approximately 75%. Treatment with lenalidomide decreases the risk of progression; however, novel triplet regimens are superior, and earlier disease may be more treatment sensitive. OBJECTIVE: To evaluate the use of carfilzomib, lenalidomide, and dexamethasone (KRd) with lenalidomide maintenance therapy as early intervention in high-risk smoldering myeloma and to determine the rates of minimal residual disease (MRD)-negative complete response (CR). DESIGN, SETTING, AND PARTICIPANTS: In this single-arm, single-center, phase 2 nonrandomized controlled trial, responses were evaluated at every cycle during KRd treatment and every 3 cycles subsequently. Bone marrow biopsies and imaging were performed by cycle 8 and then annually. The study enrolled patients from May 29, 2012, to July 23, 2020, at the National Institutes of Health Clinical Center, a highly specialized tertiary cancer center. Patient key eligibility criteria included a diagnosis of high-risk smoldering myeloma based on the Mayo Clinic, Spanish, and/or Rajkumar, Mateos, and Landgren criteria. INTERVENTIONS: Patients received eight 4-week cycles of intravenous carfilzomib 36 mg/m2 (first 2 doses, 20 mg/m2), dexamethasone (20 mg, cycles 1-4; 10 mg, cycles 5-8 twice weekly), and lenalidomide 25 mg (days 1-21) followed by twenty-four 28-day cycles of maintenance lenalidomide 10 mg (days 1-21). Stem cell harvest and storage were optional. MAIN OUTCOMES AND MEASURES: The primary outcome was the MRD-negative CR rate. Key secondary outcomes included duration of MRD-negative CR and progression to multiple myeloma. RESULTS: A total of 54 patients (median age, 59 years [range, 40-79 years]; 30 men [55.6%]; and 2 Asian [3.7%], 15 Black [27.8%], 1 Hispanic [1.9%], and 36 White [66.7%] patients) were enrolled, with a median potential follow-up time of 31.9 months (range, 6.7-102.9 months). The MRD-negative CR rate was 70.4% (95% CI, 56.4%-82.0%), with a median sustained duration of 5.5 years (95% CI, 3.7 years to not estimable). The 8-year probability of being free from progression to multiple myeloma was 91.2% (95% CI, 67.4%-97.9%), and no deaths occurred. Nonhematologic grade 3 adverse events occurred in 21 patients (38.9%) and included thromboembolism, rash, and lung infection, with no grade 4 events. CONCLUSIONS AND RELEVANCE: Results of this phase 2 nonrandomized controlled trial suggest that treatment of high-risk smoldering myeloma with novel triplet regimens, such as KRd and lenalidomide maintenance therapy, may alter the natural history of smoldering myeloma by significantly delaying development of end-organ disease. Randomized clinical trials are needed to confirm this favorable benefit-to-risk profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01572480.

Avelumab, a PD-L1 Inhibitor, in Combination with Hypofractionated Radiotherapy and the Abscopal Effect in Relapsed Refractory Multiple Myeloma.

LESSONS LEARNED: Despite the initial optimism for using immune checkpoint inhibition in the treatment of multiple myeloma, subsequent clinical studies have been disappointing. Preclinical studies have suggested that priming the immune system with various modalities in addition to checkpoint inhibition may overcome the relative T-cell exhaustion or senescence; however, in this small data set, radiotherapy with checkpoint inhibition did not appear to activate the antitumor immune response. BACKGROUND: Extramedullary disease (EMD) is recognized as an aggressive subentity of multiple myeloma (MM) with a need for novel therapeutic approaches. We therefore designed a proof-of-principle pilot study to evaluate the synergy between the combination of the anti-PD-L1, avelumab, and concomitant hypofractionated radiotherapy. METHODS: This was a single-arm phase II Simon two-stage single center study that was prematurely terminated because of the COVID-19 pandemic after enrolling four patients. Key eligibility included patients with relapsed/refractory multiple myeloma (RRMM) who had exhausted or were not candidates for standard therapy and had at least one lesion amenable to radiotherapy. Patients received avelumab until progression or intolerable toxicity and hypofractionated radiotherapy to a focal lesion in cycle 2. Radiotherapy was delayed until cycle 2 to allow the avelumab to reach a study state, given the important observation from previous studies that concomitant therapy is needed for the abscopal effect. RESULTS: At a median potential follow-up of 10.5 months, there were no objective responses, one minimal response, and two stable disease as best response. The median progression-free survival (PFS) was 5.3 months (95% confidence interval [CI]: 2.5-7.1 months), and no deaths occurred. There were no grade ≥3 and five grade 1-2 treatment-related adverse events. CONCLUSION: Avelumab in combination with radiotherapy for patients with RRMM and EMD was associated with very modest systemic clinical benefit; however, patients did benefit as usual from local radiotherapy. Furthermore, the combination was very well tolerated compared with historical RRMM treatment regimens.

Inhibition of Bruton tyrosine kinase in patients with severe COVID-19.

Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off-label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10-14 day treatment course, acalabrutinib improved oxygenation in a majority of patients, often within 1-3 days, and had no discernable toxicity. Measures of inflammation - C-reactive protein and IL-6 - normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4/8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2/8 (25%) discharged on room air. Ex vivo analysis revealed significantly elevated BTK activity, as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. These results suggest that targeting excessive host inflammation with a BTK inhibitor is a therapeutic strategy in severe COVID-19 and has led to a confirmatory international prospective randomized controlled clinical trial.

Phase 1/2 study of alemtuzumab with dose-adjusted EPOCH in untreated aggressive T and NK cell lymphomas.

To evaluate the feasibility and clinical efficacy of the combination of alemtuzumab with dose-adjusted etoposide/cyclophosphamide/doxorubicin/vincristine/prednisone (DA-EPOCH) as upfront therapy for untreated aggressive T and NK cell lymphomas, a phase 1/2 trial was conducted. Thirty patients were treated with the study regimen, consisting of alemtuzumab on day 1 of a 21 day cycle with standard dosing of DA-EPOCH for 6-8 cycles. Alemtuzumab 30 mg IV was used for the phase 2 component. Of 30 treated patients, 17 had a complete response (CR) and eight had a partial response (83.3% overall response rate). The median overall survival and progression-free survival were 20.2 and 6.6 months, respectively. There were five treatment-related deaths on study mainly due to infectious complications, including one case each of disseminated toxoplasmosis and pneumonia and two cases of sepsis. Alemtuzumab with DA-EPOCH is of limited clinical utility due to unacceptable toxicity, despite the high rate of CR.

Azacitidine-associated pleuropericardial effusion in myelodysplastic syndrome: A case report.

Azacitidine, a deoxyribonucleic acid hypomethylating agent, is used in the treatment of myelodysplastic syndrome. Common adverse effects of azacitidine include bone marrow suppression, injection site reactions, nausea, vomiting, diarrhea, and fatigue. This report focuses on pleuropericardial effusions, an infrequently reported and potentially reversible adverse effect of azacitidine. In this case report, pleuropericardial effusion manifested as the sole radiographic finding in the evaluation of cough occurring during the eighth cycle of treatment with azacitidine. Symptoms and radiographic abnormalities resolved with corticosteroids and diuretics, and the patient could continue with therapy.

First-line ibrutinib for Bing-Neel syndrome.

The authors present a case of an elderly man with a history of Waldenstrom macroglobulinaemia in remission who presented with progressively worsening gait abnormalities and falls for several months. His examination was notable for bilateral lower extremity weakness and an unsteady gait. Brain and spinal MRI showed focal leptomeningeal enhancement in the brain and spinal column. Lumbar puncture was performed and cerebrospinal fluid flow cytometry demonstrated a monoclonal CD5/CD10-negative, CD20-positive B-cell lymphocyte population consistent with a diagnosis of Bing-Neel syndrome. He was started on ibrutinib, an oral Bruton's tyrosine kinase inhibitor, and had marked improvement in his weakness and gait. Repeat imaging 2 months after starting ibrutinib showed improvement in his leptomeningeal enhancement. During subsequent follow-up, he continued to tolerate ibrutinib and had a sustained clinical response.

No patient left behind: The promise of immune priming with epigenetic agents.

Checkpoint inhibitors, monoclonal antibodies that inhibit PD-1 or CTLA-4, have revolutionized the treatment of multiple cancers. Despite the enthusiasm for the clinical successes of checkpoint inhibitors, and immunotherapy, in general, only a minority of patients with specific tumor types actually benefit from treatment. Emerging evidence implicates epigenetic alterations as a mechanism of clinical resistance to immunotherapy. This review presents evidence for that association, summarizes the epi-based mechanisms by which tumors evade immunogenic cell death, discusses epigenetic modulation as a component of an integrated strategy to boost anticancer T cell effector function in relation to a tumor immunosuppression cycle and, finally, makes the case that the success of this no-patient-left-behind strategy critically depends on the toxicity profile of the epigenetic agent(s).

RRx-001 in Refractory Small-Cell Lung Carcinoma: A Case Report of a Partial Response after a Third Reintroduction of Platinum Doublets.

RRx-001 is a pan-active, systemically nontoxic epigenetic inhibitor under investigation in advanced non-small cell lung cancer, small-cell lung cancer and high-grade neuroendocrine tumors in a Phase II clinical trial entitled TRIPLE THREAT (NCT02489903), which reexposes patients to previously effective but refractory platinum doublets after treatment with RRx-001. The purpose of this case study is first to report a partial response to carboplatin and etoposide in a patient with small-cell lung cancer pretreated with RRx-001, indicating episensitization or resensitization by epigenetic mechanisms, and second to discuss the literature related to small-cell lung cancer and episensitization.