Advances in Hodgkin's lymphoma pharmacotherapy: a focus on histone deacetylase inhibitors.

INTRODUCTION: Classical Hodgkin lymphomas (cHL) usually have excellent cure rates. Yet, for patients with refractory or relapsed cHL, prognosis deteriorates as the disease becomes resistant to subsequent lines of therapies: autologous stem cell transplantation, brentuximab vedotin, and checkpoint inhibitors. Immune escape and drug resistance are hallmarks of Hodgkin Reed Sternberg cell survival, prompting the need for additional therapeutic strategies. Histone modification-based combination is an effective clinical strategy. AREAS COVERED: In this review, we discuss the different histone deacetylase (HDAC) inhibitor molecules that have been developed and studied in cancer therapy with a focus on cHL. We review their preclinical and clinical activities both as single agents and in combination studies. Literature search was conducted in PubMed, Google Scholar, and ClinicalTrials.gov databases, using search terms 'Hodgkin lymphoma,' 'histone deacetylase inhibitor', and variations on such (e.g. 'HDAC' and individual drug names) in combination using operators 'AND,' 'OR,' and 'NOT' according to Boolean logic. EXPERT OPINION: HDAC inhibitors alone will not be sufficient for the treatment of R/RcHL, but given their disease control capacity, synergistic interaction with currently approved drugs, and ability to overcome drug resistance, particularly PD-1 inhibitors, we believe that HDACinhibitors will eventually become incorporated into the treatment armamentarium of cHL.

Outcomes of Cancer Patients with COVID-19: The Virginia Commonwealth University Experience.

PURPOSE: The cancer population is significantly impacted by coronavirus disease 2019 (COVID-19) due to inherent risks of infection imposed by malignancy and therapeutic agents. Evaluating risk factors in this group will lead to improved guidelines for the treatment of malignancy in the setting of a COVID-19 pandemic. PATIENTS AND METHODS: This retrospective study reviewed 295 inpatient cancer patients positive for COVID-19 between February 2020 and December 2021 to determine specific risk factors of mortality and associated complications. Various patient characteristics were collected to evaluate outcomes in patient death, oxygen requirement, ventilatory support, and increased length of stay. RESULTS: 31 (10.5%) of 295 patients died due to COVID-19. Of those that died, the majority had hematologic cancer (48.4%). There was no difference in the odds of death among the cancer groups. Those vaccinated had a reduced risk of death (OR 0.04, CI 0-0.23). Patients with lung cancer (OR 3.69, CI 1.13-12.31), obesity (OR 3.27, CI 1.18-9.27), CHF (OR 2.68, CI 1.07-6.89) were more likely to require ventilation. Those treated with hormonal therapy had higher odds of having a prolonged admission (OR 5.04, CI 1.17-2.53). Otherwise, cancer therapy had no significant difference in any outcome. CONCLUSION: The mortality rate of cancer patients was 10.5%, lower than in other studies. Vaccinations had mortality benefits, but no effect on hypoxia, ventilator use, or LOS. Delaying cancer therapy during peak infection is likely not necessary based on the results of this study. With improved knowledge in the risks of infection and the utility of personalized precautions, both providers and patients can better prepare for another potential wave of COVID-19.

PI3k Inhibitors in NHL and CLL: An Unfulfilled Promise.

Phosphatidylinositol 3-kinases (PI3Ks) are a family of intracellular signal transducer enzymes that can attach a phosphate group to the 3'-hydroxyl of the inositol moiety of membrane-embedded phosphatidylinositol (PI). PI3Ks have been shown to play important roles in cell proliferation, growth, survival, motility, and metabolism. Nonetheless, the PI3K pathway has also shown to be overactivated in several tumors, particularly B-cell malignancies. In recent years, the PI3K signaling pathway has become the major focus of substantial drug discovery and development efforts. Selective (PI3K) inhibitors have been approved for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and indolent non-Hodgkin lymphomas (iNHL), such as follicular lymphoma and marginal-zone lymphoma. Four selective PI3K inhibitors have received accelerated FDA approvals for the treatment of patients with relapsed/refractory (R/R) CLL and/or iNHL based mainly on single-arm Phase II studies: Idelalisib (PI3K-δ inhibitor), copanlisib (dual PI3K-α and PI3K-δ inhibitor), duvelisib (dual PI3K-γ and PI3K-δ inhibitor), and umbralisib (dual PI3Kδ and CK1ε inhibitor). Conversely, recent interim results of randomized control trials (RCTs) involving some of these agents, showed a worrisome trend of decrease in overall survival (OS), and an increase in fatal and severe adverse effects, in comparison with patients in the control arms. Consequently, the class of PI3K inhibitors came under scrutiny, with an FDA expert panel voting on April 21, 2022, recommending that future FDA approvals of PI3K inhibitors be supported by randomized data, rather than single-arm data only, and further discontinuing the use of almost all the PI3K inhibitors in hematologic malignancies. As we believe further research is needed to help potentialize PI3K inhibitors by improving their safety profiles, this mini-review aims at revisiting the clinical successes, the failures, and the promising aspect of this class of drugs, while presenting possible ways that could benefit its successful development.

Systemic Relapse in a Young Adult Patient with Primary CNS Diffuse Large B-Cell Lymphoma.

Primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) is a rare form of non-Hodgkin's lymphoma, characterized by an aggressive disease course. While CNS relapse is common, systemic relapse is rare with no consensus on optimal treatment. This paper presents an unusual case of advanced PCNS-DLBCL with systemic relapse, including adrenal gland involvement. A review of the existing literature and a discussion on the management of systemic relapse in PCNS-DLBCL is also provided.

An overview of chemotoxicity and radiation toxicity in cancer therapy.

While immunotherapy and targeted therapies represent major advances against different types of malignancies, the mainstay of cancer therapy continues to be radiation and surgery for localized disease, and chemotherapy for systemic disease, with the preponderance of chemotherapeutic agents (such as anthracyclines, alkylating agents, and antimetabolites) having been developed decades ago. Combination chemotherapy regimens have changed the natural history of once deadly diseases such as breast and prostate cancer and led to curative regimens in advanced hematological malignancies and testicular cancer. However, while oncologists maintain their focus on disease suppression, and where feasible, disease eradication, obstacles to achieving cure remain, such as tumor dormancy and ultimately disease recurrence, as well as both intrinsic and acquired resistance. In this review, complications of current cancer therapies toward major organs (heart, lung, kidney, gastro-intestinal, neuromuscular, brain, and skin) are emphasized, and efforts to mitigate these complications are described. This is particularly relevant for patients treated with curative intent, where adherence to treatment plan, and avoidance of interruptions in treatment schedule are essential for optimal outcome. Consequently, these patients are treated with an "aggressive" approach, with high tolerance for side effects. However, a deeper understanding of normal tissue toxicity resulting from the different cancer therapies remains an area of unmet medical need that will ultimately lead to improved therapeutic index for current and future therapies, planning for treatment adverse effects, and ultimately improvement in patient satisfaction, compliance and outcome.

Role of antibody-based therapy in indolent non-Hodgkin's lymphoma.

Monoclonal antibodies (mAb) for indolent non-Hodgkin's lymphoma (iNHL) including follicular and marginal zone lymphomas was a key therapeutic development that changed the natural history of these diseases. Rituximab, a chimeric anti-CD20 mAb, was the first immunotherapy ever used in cancer, and a current cornerstone of lymphoma therapies. Since, we saw development of humanized antibodies, next generations anti-CD20, mAbs targeting other markers on tumor cells (CD19 and CD22), its microenvironment (PD-1, CD47), antibody drug conjugates and bispecific T cell engagers. Given their activity, safety and specificity, mAbs are well poised to remain an essential therapeutic tool for iNHL and other malignancies.

Phase 1 study of belinostat (PXD-101) and bortezomib (Velcade, PS-341) in patients with relapsed or refractory acute leukemia and myelodysplastic syndrome.

We report the results of a phase 1 dose-escalation study of belinostat and bortezomib in adult patients with acute leukemia or MDS or CML with blast crisis. Thirty-eight patients received IV belinostat days 1-5 and 8-12 with IV bortezomib days 1, 4, 8, and 11 every 21 days. QTc prolongation was the only identified DLT. The RP2Ds were 1.3 mg/m2 bortezomib and 1000 mg/m2 belinostat. One patient with highly refractory MLL-ENL rearranged biphenotypic AML with multiple karyotypic aberrations had a complete pathologic and karyotypic response. One patient with post-MPN AML remained on study with stable disease (SD) for 32 cycles. Whole-exome sequencing revealed no aberrations in the first patient and a hyper-mutator genotype in the second. Eighteen patients had a best response of SD. We conclude that this treatment strategy is feasible but has limited activity in this population. Nevertheless, the factors that predict exceptional responses to this strategy warrant further investigation.

Perspectives on chemotherapy for the management of double-hit lymphoma.

INTRODUCTION: Double-hit (DHL) and triple-hit lymphomas (THL) have long been among the most clinically aggressive molecular subtypes of diffuse large B-cell lymphomas. In the 2016 revised WHO classification, they represent a new entity called high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6. Unlike most B-cell lymphomas, they have poor response to standard R-CHOP therapy, tend to quickly develop resistance to cytotoxic chemotherapies, and are associated with higher central nervous system (CNS) infiltration. This can lead to increased risk of relapse and worse prognosis. DHL/THL represent a subset of lymphomas with unmet medical need. AREA COVERED: The authors present the available data for the current treatment regimens including intensive chemotherapy regimens, hematopoietic stem-cell transplantation (HSCT), and CNS prophylaxis. They also discuss treatment for relapsed disease including targeted therapies. EXPERT OPINION: There is currently no accepted standard of care for DHL/THL. For frontline therapy, we recommend enrollment in a well-designed clinical trial if possible, otherwise DA-EPOCH-R with CNS prophylaxis is a commonly used first-line therapy. The authors recommend close surveillance for patients achieving complete response, but for those who fail to achieve a complete response, then clinical trials, more aggressive salvage chemotherapy regimens, or cellular therapies are usually considered.

Marginal Zone Lymphoma: State-of-the-Art Treatment.

OPINION STATEMENT: Despite being the second most common indolent non-Hodgkin's lymphoma (iNHL), marginal zone lymphoma (MZL) remains largely understudied, and given its underlying disease heterogeneity, it is challenging to define a single treatment approach for these patients. For localized disease, local therapy is recommended such as triple therapy for H. pylori in gastric extranodal MZL, splenectomy for splenic MZL, and radiotherapy for nodal MZL. For disseminated disease with low tumor burden, a watch and wait or single-agent rituximab can be used. However, for symptomatic disease, a similar approach to follicular lymphoma (FL) can be used with chemoimmunotherapy approaches such as bendamustine and rituximab. High FDG uptake is not common in MZL and is not diagnostic by itself of transformation to high-grade lymphoma but informs the choice of the site to be biopsied. Transformation into a large B cell lymphoma is treated with R-CHOP-like regimens. Patients with relapsing disease after at least one CD20-based therapy have several recently approved chemotherapy-free options including B cell receptor inhibitors such ibrutinib (approved specifically in MZL) and immunomodulatory agents such as lenalidomide and rituximab (FDA approved in MZL and FL). Phosphoinositide 3-kinase (PI3K) inhibitors have shown excellent activity in iNHL, specifically in MZL, with breakthrough designation status for copanlisib and umbralisib, allowing off label use of this class of agents in clinical practice. With the availability of prospective clinical trials using chemo-free approaches, specifically those targeting abnormal signaling pathways activated in MZL tumors and its microenvironment, treating physicians are encouraged to enroll patients on these clinical trials in order to better understand the underlying biology, mechanisms of response, and resistance to current therapies and help design future rationale combination strategies.

Correction: Synergistic interactions between PLK1 and HDAC inhibitors in non-Hodgkin's lymphoma cells occur in vitro and in vivo and proceed through multiple mechanisms.

[This corrects the article DOI: 10.18632/oncotarget.15649.].

Case of a CD3 Negative Hepatosplenic T-Cell Lymphoma: Diagnostic and Therapeutic Challenges.

Hepatosplenic T-cell lymphomas (TCLs) are a rare, aggressive subset of TCLs, accounting for less than 5% of all peripheral T-cell and natural killer (NK) cell lymphomas. We report the case of a CD3 negative hepatosplenic T-cell lymphoma in a 42-year-old female, who presented with left-sided abdominal pain. She underwent a liver biopsy that showed marked abnormal sinusoidal lymphoid infiltration. PET scan revealed increased splenic and pharyngeal lymph node uptake. Immunophenotype was remarkable for negative CD3, gamma delta T-cell receptor, and alpha beta-T-cell receptor expression. She received 6 cycles of DA-EPOCH, had primary refractory disease and then underwent palliative splenectomy secondary to painful necrosis. Then, she was started on pralatrexate as a single agent and then in combination with romidepsin as a potential bridge to an allogeneic stem cell transplantation from her sibling.

Treatment of Primary Central Nervous System Posttransplant Lymphoproliferative Disorder in an Adult Kidney Transplant Recipient: A Case Report.

Posttransplant lymphoproliferative disorder is a serious complication of solid-organ transplant. Extranodal involvement is common; however, isolated involvement of the central nervous system is extremely rare and represents a particularly difficult therapeutic challenge with no current consensus on optimal treatment. Here, we describe a 70-year-old woman who developed Epstein-Barr virus-related primary central nervous system lymphoma 19 months after kidney transplant. Immunosuppression was reduced, and the patient was started on high-dose methotrexate, which was complicated by acute kidney injury and discontinued. She then received a rituximab and temozolomide chemotherapeutic regimen and achieved complete clinical response. Seventeen months after diagnosis, she is alive and has not developed any other posttransplant lymphoproliferative disorder. We review the current literature and discuss treatment options for patients with primary central nervous system posttransplant lymphoproliferative disorder following kidney transplant.

A Phase II Trial of Bortezomib and Vorinostat in Mantle Cell Lymphoma and Diffuse Large B-cell Lymphoma.

BACKGROUND: The proteasome inhibitor bortezomib has demonstrated marked preclinical activity when combined with the histone deacetylase inhibitor vorinostat in leukemia, multiple myeloma, and mantle cell lymphoma (MCL) cells. The present study evaluated the efficacy and safety of the combination in patients with relapsed or refractory MCL and diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: The present multicenter, nonrandomized phase II trial used a Simon 2-stage design with 3 cohorts: cohort A, MCL with no previous bortezomib (including untreated MCL); cohort B, MCL with previous bortezomib; and cohort C, relapsed or refractory DLBCL with no previous bortezomib. Vorinostat (400 mg) was administered orally on days 1 to 5 and 8 to 12 before bortezomib (1.3 mg/m2), which was administered intravenously on days 1, 4, 8, and 11 of each 21-day cycle. RESULTS: For the 65 treated patients (22 in cohort A, 4 in cohort B, and 39 in cohort C), the overall response rate was 31.8%, 0%, and 7.7%, respectively. The median progression-free survival was 7.6 months for cohort A and 1.8 months for cohort C. In cohort A, 7 patients had a partial response (PRs), 5 had stable disease (SD), 7 had progressive disease (PD), 1 was not assessed, and 2 were not evaluable. In cohort B, 2 had SD and 2 had PD. In cohort C, 3 had a PR, 8 had SD, 23 had PD, and 5 were not assessed. Baseline NF-κB activation, measured as nuclear RelA by immunohistochemistry, did not correlate with clinical response. CONCLUSION: The combination of bortezomib and vorinostat is safe and has modest activity in MCL and limited activity in DLBCL.

Synergistic interactions between PLK1 and HDAC inhibitors in non-Hodgkin's lymphoma cells occur in vitro and in vivo and proceed through multiple mechanisms.

Interactions between the polo-like kinase 1 (PLK1) inhibitor volasertib and the histone deacetylase inhibitor (HDACI) belinostat were examined in diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells in vitro and in vivo. Exposure of DLBCL cells to very low concentrations of volasertib in combination with belinostat synergistically increased cell death (apoptosis). Similar interactions occurred in GC-, ABC-, double-hit DLBCL cells, MCL cells, bortezomib-resistant cells and primary lymphoma cells. Co-exposure to volasertib/belinostat induced a marked increase in M-phase arrest, phospho-histone H3, mitotic errors, cell death in M-phase, and DNA damage. Belinostat diminished c-Myc mRNA and protein expression, an effect significantly enhanced by volasertib co-exposure. c-Myc knock-down increased DNA damage and cell death in response to volasertib, arguing that c-Myc down-regulation plays a functional role in the lethality of this regimen. Notably, PLK1 knock-down in DLBCL cells significantly increased belinostat-induced M-phase accumulation, phospho-histone H3, γH2AX, and cell death. Co-administration of volasertib and belinostat dramatically reduced tumor growth in an ABC-DLBCL flank model (U2932) and a systemic double-hit lymphoma model (OCI-Ly18), accompanied by a pronounced increase in survival without significant weight loss or other toxicities. Together, these findings indicate that PLK1/HDAC inhibition warrants attention as a therapeutic strategy in NHL.

A phase 1 study of bortezomib and romidepsin in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, indolent B-cell lymphoma, peripheral T-cell lymphoma, or cutaneous T-cell lymphoma.

A phase 1 study was conducted to determine the dose-limiting toxicities and maximum-tolerated dose (MTD) for bortezomib followed by romidepsin on days 1, 8, and 15 in patients with relapsed/refractory CLL/SLL or B- or T-cell lymphoma. Eighteen treated patients were evaluable for response. The MTD was 1.3 mg/m2 bortezomib and 10 mg/m2 romidepsin; median treatment duration was 3 cycles at this dose. The dose-limiting toxicities were grade 3 fatigue, vomiting, and chills. Two patients had partial responses, one lasting >2 years, 8 had stable disease, and 8 had progressive disease. The median duration of stable disease was 3.5 cycles. Correlative studies examining expression of NF-кB, XIAP, Bcl-xL, and Bim yielded variable results. The safety profile was consistent with that reported for single-agent bortezomib and romidepsin. This regimen has modest activity in heavily pretreated patients with relapsed/refractory CLL or B- or T-cell lymphoma. NCT00963274.

Phase 1 trial of carfilzomib (PR-171) in combination with vorinostat (SAHA) in patients with relapsed or refractory B-cell lymphomas.

A phase 1 study with carfilzomib and vorinostat was conducted in 20 B-cell lymphoma patients. Vorinostat was given orally twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib (given as a 30-min infusion) on days 1, 2, 8, 9, 15, and 16. A treatment cycle was 28 days. Dose escalation initially followed a standard 3 + 3 design, but adapted a more conservative accrual rule following dose de-escalation. The maximum tolerated dose was 20 mg/m2 carfilzomib and 100 mg vorinostat (twice daily). The dose-limiting toxicities were grade 3 pneumonitis, hyponatremia, and febrile neutropenia. One patient had a partial response and two patients had stable disease. Correlative studies showed a decrease in NF-κB activation and an increase in Bim levels in some patients, but these changes did not correlate with clinical response.

Romidepsin for the treatment of non-Hodgkin's lymphoma.

INTRODUCTION: Patients with relapsed or refractory lymphoma remain a population with unmet medical needs. Histone deacetylase inhibitors (HDACIs) represent a novel class of anticancer drugs currently in development in several malignancies. Inhibition of HDACs leads to acetylation of histone and non-histone proteins, which in turn results in epigenetic modification of gene expression that leads to a plethora of effects, such as cell cycle arrest, apoptosis and inhibition of angiogenesis. Romidepsin is a novel HDACI that has demonstrated preclinical and clinical activity. AREAS COVERED: This review discusses the different HDACs and epigenetic regulation with a particular focus on the preclinical and clinical development of romidepsin in lymphoma. The review of romidepsin includes: the mechanism of action, its synergistic interaction with novel agents, pivotal clinical trials that lead to its US FDA approval in cutaneous T-cell lymphoma and peripheral T-cell lymphoma as well as active combinations currently in clinical trials. EXPERT OPINION: Romidepsin is a potent HDACI with clinical activity in T-cell lymphoma where novel agents and combinations are desperately needed. A deeper understanding of the molecular characteristics of this class of agents will allow the design of more potent drugs with improved toxicity profiles and future rational combinations that will expand the indication and benefit from these novel agents.

Single-agent obatoclax (GX15-070) potently induces apoptosis and pro-survival autophagy in head and neck squamous cell carcinoma cells.

OBJECTIVES: More than half of head and neck squamous cell carcinoma (HNSCC) patients are initially treated with curative intent, but will relapse over the course of their disease and have poor prognosis with a median survival of approximately 6months. Novel therapeutic approaches are in desperate need for this patient population. The anti-apoptotic BCL-2 family proteins such as BCL-2, BCL-XL, and MCL-1 are involved in oncogenesis and chemoresistance and are overexpressed in HNSCC. Obatoclax is a small-molecule antagonist of the BH3-binding groove of anti-apoptotic BCL-2 family. We evaluated the activity of obatoclax against 4 HNSCC cell lines (UMSCC-1, Cal33, 1483, UMSCC-22A). METHODS: Cell viability was determined by MTT assay, cell cycle status by propidium iodide staining, and apoptosis by Annexin-V staining and immunoblotting. Autophagy was assessed by immunofluorescence and immunoblotting. RESULTS: All four HNSCC cell lines were highly sensitive to single-agent obatoclax with IC50's ranging from 46 to 177nM. Obatoclax induced apoptosis in all four HNSCC cell lines as evidenced by increases in sub-G1 DNA content, Annexin-V staining, and PARP cleavage. In addition, obatoclax induced autophagy in all 4 cell lines, and the addition of the autophagy inhibitor chloroquine enhanced obatoclax cytotoxicity. CONCLUSION: Our findings demonstrate potent monotherapeutic activity of obatoclax against HNSCC cells, and enhancement of this activity in the presence of chloroquine. This preclinical study suggests that obatoclax might have therapeutic value in the treatment of HNSCC, either alone or in combination with inhibitors of autophagy.