SOHO State of the Art Updates and Next Questions: Novel Therapies in Development for Myelofibrosis

Myeloproliferative neoplasms research has entered a dynamic and exciting era as we witness exponential growth of novel agents in advanced/early phase clinical trials for myelofibrosis (MF). Building on the success and pivotal role of ruxolitinib, many novel agents, spanning a wide range of mechanisms/targets (epigenetic regulation, apoptotic/intracellular signaling pathways, telomerase, bone marrow fibrosis) are in clinical development; several are studied in registrational trials and hold great potential to expand the therapeutic arsenal/shift the treatment paradigm if regulatory approval is granted. Insight into MF pathogenesis and its molecular underpinnings, preclinical studies demonstrating synergism of ruxolitinib with investigational agents, urgent unmet clinical needs (cytopenias, loss of response to JAK inhibitors); and progressive disease fueled the rapid rise of innovative therapeutics. New strategies include pairing ruxolitinib with erythroid maturation agents to manage anemia (luspatercept), designing rational combinations with ruxolitinib to boost responses in both the frontline and suboptimal response settings (pelabresib, navitoclax, parsaclisib), treatment with non-JAK inhibitor monotherapy in the second-line setting (navtemadlin, imetelstat), novel JAK inhibitors tailored to subgroups with challenging unmet needs (momelotinib and pacritinib for anemia and thrombocytopenia, respectively); and agents potentially enhancing longevity (imetelstat).Beyond typical endpoints evaluated in MF clinical trials (spleen volume reduction ≥ 35%, total symptom score reduction ≥ 50%) thus far, emerging endpoints include overall survival, progression-free survival, transfusion independence, anemia benefits, bone marrow fibrosis and driver mutation allele burden reduction. Novel biomarkers and additional clinical features are being sought to assess new agents and tailor emerging therapies to appropriate patients. New strategies are needed to optimize the design of clinical trials comparing novel combinations to standard agent monotherapy.     

SOHO State of the Art Updates and Next Questions: IDH Inhibition

There has been extraordinary progress in the field of targeted therapy for myeloid malignancies in the last few years, especially due to the approval of various agents that can be used as monotherapy or in combination as first-line treatment or when facing a refractory or relapsed disease. Many successful trials have been conducted recently, and a consistent body of work about the efficacy of novel molecules is now available. In this review, we sought to explain how enasidenib and ivosidenib have changed the face of myeloid neoplasm treatment through isocitrate dehydrogenase inhibition and to summarize the trials results that have led to the current commercial indications for the two molecules.     

SOHO State of the Art Updates and Next Questions: Hodgkin Lymphoma

Until recently, advances in classic Hodgkin lymphoma (HL) treatment primarily consisted of minor modifications of highly effective decades-old chemotherapy and radiation approaches. In early-stage disease, excellent outcomes have been reported with fewer cycles of chemotherapy, lower doses, smaller radiation fields and in some circumstances, radiation elimination. In advanced-stage disease, maintaining the dose intensity of standard chemotherapy regimens has resulted in modest improvements in outcomes. During the past decade, the use of early interim positron emission tomography (PET) scans to escalate or de-escalate treatment has been the subject of intense investigation with the goal of maximizing efficacy and minimizing toxicity. Important updates from recent PET-directed trials include; elimination of bleomycin in patients with advanced-stage HL and negative interim PET findings, the benefit of therapy escalation in patients with unfavorable early-stage HL and positive interim PET findings, and the minimal benefit of consolidative radiotherapy in patients with unfavorable early-stage HL and negative interim PET findings. A more nuanced approach to consolidative radiotherapy is required for patients with favorable early-stage disease based on age, disease sites, secondary cancer risk, and cardiovascular disease. Brentuximab vedotin and nivolumab/pembrolizumab have provided promising new options with surprisingly high response rates and modest toxicity for patients with relapsed HL whose disease does not respond to standard treatments. Incorporating these agents into earlier therapy is an area of active investigation for all stages of HL. Although the overall prognosis for HL patients has seen incremental improvement, efforts to optimize treatment with more effective and less toxic approaches continue.     

SOHO State of the Art Updates and Next Questions: Harnessing Apoptosis in AML

The treatment landscape for acute myeloid leukemia has expanded significantly in the past 5 years with the approval of several therapeutic small molecules. While agents such as FLT3 inhibitors and IDH inhibitors are restricted for patients with specific mutations, the selective BCL-2 inhibitor venetoclax combined with a hypomethylating agent or low-dose cytarabine was approved after demonstrating frontline efficacy across a molecularly heterogenous group of patients. Currently, venetoclax is being investigated in combination with multiple other therapies as the role of the intrinsic apoptotic pathway in acute myeloid leukemia continues to be explored.     

SOHO State of the Art Updates and Next Questions: Novel Transplant and Post-Transplant Options in Acute Lymphoblastic Leukemia

Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative treatment approach for patients with high-risk acute lymphoblastic leukemia (ALL). Despite development of several novel therapies targeting B-cell ALL, alloHCT continues to play an essential role in management, but the identification of patients who are most likely to benefit from alloHCT in first or subsequent remissions continues to evolve. Broader donor options, including haploidentical donors and umbilical cord blood, have enabled alloHCT for more patients, but improvements in front-line therapy and increasing use of high-sensitivity measurable residual disease (MRD) quantification continue to modify the calculus for selecting which patients require transplantation. MRD quantification has become increasingly important as a prognostic indicator, as well as a trigger for therapeutic intervention, since the achievement of MRD negative complete remission is well-established to be associated with improved transplant outcomes. ALL remains the only malignancy with approved therapy for MRD positivity after achievement of remission, and use of Blinatumomab in this setting currently appears to be most effective when used as a bridge-to-transplant, rather than a destination or purely consolidative therapy. Expanding options for those with relapsed/refractory disease, including chimeric antigen receptor (CAR)-T cells, also render more patient in suitably deep remissions to enable alloHCT with a high likelihood of success. It remains unclear whether CAR-T cell therapies may obviate the need for alloHCT in some patients, and currently available data suggest there remains a role for alloHCT after CAR-T. Together, these therapeutic advances appear to be improving post-transplant outcomes. Nevertheless, more remains to be studied regarding how to optimize use of available and emerging cellular and immune modulating therapies to maximize the likelihood of long-term post-alloHCT remission in high-risk ALL.     

SOHO State of the Art Updates and Next Questions: Managing Relapsed Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma i.e., incurable with current therapies. While some patients experience prolonged remissions following initial therapy, most will have a relapsing-remitting course requiring several lines of treatment over the course of their disease. Several targeted therapies are now available to treat patients with relapsed MCL. The Bruton's tyrosine kinase (BTK) inhibitors, including ibrutinib, acalabrutinib, and zanubrutinib, are highly active in MCL and currently approved for treating patients with relapsed disease. Bortezomib and lenalidomide are available as monotherapy or in combination with other agents. Venetoclax is active and can be considered for use in relapsed MCL, although it is not currently approved by regulatory agencies. Chimeric antigen receptor T-cell (CAR-T) therapy with brexucabtagene autoleucel yields high response rates and is now approved for patients with relapsed MCL. Allogeneic stem cell transplant remains an option for a small subset of medically fit and motivated patients who have progressed through multiple lines of therapy, although its use is limited by substantial toxicity. There is currently no standard approach to sequencing therapies for patients with relapsed MCL, and the ability to utilize disease biologic and clinical characteristics to guide treatment decisions in this setting remains limited. In this review, we summarize the current evidence to guide the management of patients with relapsed MCL, review emerging agents and combination therapies that are under investigation, and outline our current treatment approach for these patients.     

SOHO State of the Art Updates and Next Questions: Clonal Evolution in Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is an indolent disease with a long-lasting clinical course, with indication for treatment only when symptomatic. Its clinical heterogeneity is widely reported, with some patients requiring treatment soon after diagnosis because of development of cytopenia or bulky lymphadenopathy, and others showing a stable or a slowly progressive disease not requiring treatment for decades. Longitudinal sampling of peripheral blood, with accessible tumor cells and circulating tumor DNA, enabled the analysis of disease growing dynamics and the characterization of clonal evolution. Here we describe the main known features of CLL genomics and its shaping upon treatment, which can lead to progression, treatment refractoriness, or transformation into an aggressive lymphoma.     

SOHO State of the Art Updates and Next Questions: Treatment of Lower Risk Myelodysplastic Syndromes

MDS is a clonal stem cell neoplasm with a spectrum from lower risk disease to short term life threatening higher risk disease. The disease risk is dictated by clinical and molecular features. Majority of MDS patients including lower risk disease unfortunately succumb from disease related complications namely cytopenia. While cytopenias may be mild early upon diagnosis and can be surveilled, ultimately treatment is required. Anemia is the hall mark of disease and most common indication to treat in lower risk MDS. Erythroid stimulating agents are used in the first line setting. Treatment can be a personalized approach as in select patient such as patients with del(5q) and those with ringed sideroblasts, lenalidomide, and luspatercept can be extremely effective respectively at improving cytopenias. Younger patients and hypoplastic MDS have also shown and improved response to immunosuppressive therapy. Hypomethylating agents can be option for patients with higher risk features or thrombocytopenia/neutropenia. Refractory cytopenias still poses frustration as options are limited and there is need to add more treatments to our armamentarium.     

SOHO State of the Art Updates and Next Questions | Novel Approaches to Pediatric T-cell ALL and T-Lymphoblastic Lymphoma

While outcomes for children with T-cell acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LL) have improved significantly with contemporary therapy, outcomes for patients with relapsed or refractory (r/r) disease remain dismal. Improved risk stratification and the incorporation of novel therapeutics have the potential to improve outcomes further in T-ALL/T-LL by limiting relapse risk and improving salvage rates for those with r/r disease. In this review we will discuss the challenges and new opportunities for improved risk stratification in T-ALL and T-LL. We will further discuss the recent incorporation of the novel therapeutics nelarabine and bortezomib into front-line therapy for children with T-ALL and T-LL. Finally, we will address new classes of targeted small molecule inhibitors, immunotherapeutics, and chimeric antigen receptor T-cell therapies under investigation in r/r T-ALL and T-LL.     

SOHO State of the Art Updates and Next Questions: Tailoring Upfront Therapy in Mantle Cell Lymphoma

In this article, we will review current strategies for the front-line management of mantle cell lymphoma, an uncommon and biologically and clinically heterogeneous subtype of non-Hodgkin lymphoma that remains incurable with current therapies. Patients invariably relapse with time, and as a result, treatment strategies involve persistent therapy over the course of months to years, including induction, consolidation, and maintenance. Topics discussed include the historical development of various chemoimmunotherapy backbones with continued modifications to maintain and improve efficacy while limiting off-target, off-tumor effects. Chemotherapy-free induction regimens were developed initially for elderly or less fit patients though are now being utilized for younger, transplant-eligible patients due to deeper, more prolonged remission durations with fewer toxicities. The historic paradigm of recommending autologous hematopoietic cell transplant for fit patients in complete or partial remission is now being challenged based in part on ongoing clinical trials in which minimal residual disease directed approaches influence the consolidation strategy for any particular individual. The addition of novel agents, namely first and second generation Bruton tyrosine kinase inhibitors as well as immunomodulatory drugs, BH3 mimetics, and type II glycoengineered anti-CD20 monoclonal antibodies have been tested in various combinations with or without immunochemotherapy. We will attempt to help the reader by systematically explaining and simplifying the various approaches for treating this complicated group of disorders.     

SOHO State of the Art Update and Next Questions: IDH Therapeutic Targeting in AML

Mutations in isocitrate dehydrogenase isoform (IDH) 1 and 2 occur in approximately 25% of patients with acute myeloid leukemia (AML). These mutations lead to a block in myeloid differentiation and ultimately, to the development of AML. Inhibitors of mutant IDH1 and 2 have recently been approved by the US Food and Drug Administration and their use has led to clinical responses with prolonged duration of response. IDH inhibitors in combination with standard-of-care therapy and other small molecular inhibitors are now being used.     

SOHO State of the Art Updates and Next Questions: Prophylaxis and Management of Secondary CNS Lymphoma

Secondary CNS lymphoma (SCNSL) is a rare but frequently fatal complication of systemic lymphoma. There is no standard treatment for SCNSL, and patients who develop SCNSL at diagnosis or after frontline therapy often receive highly intensive chemotherapy regimens that are inactive against primary chemorefractory disease and too toxic for older, frail patients to tolerate. Because the prognosis of SCNSL is so poor, management has historically emphasized prevention, but the current methods of CNS prophylaxis are not universally effective. To improve both the prevention and management of SCNSL, better characterization of the molecular determinants of CNS invasion is needed. Novel treatments that are currently being studied in SCNSL include targeted pathway inhibitors and cellular therapy, but SCNSL patients are often excluded from clinical trials of promising new therapies.     

SOHO State of the Art Updates and Next Questions | Challenging Cases in Rare T-Cell Lymphomas

Mature T- and NK-cell neoplasms (MTNKN) collectively represent a rare disorder, representing less than 15% of all non-Hodgkin lymphoma (NHL) cases and qualifying for orphan disease designation by the U.S. Food and Drug Administration (FDA). These consist of 9 families in the fifth revised WHO classification of lymphoid neoplasms, which are made up of over 30 disease subtypes, underscoring the heterogeneity of clinical features, molecular biology, and genetics across this disease group. Moreover, the 5 most common subtypes (peripheral T-cell lymphoma, not otherwise specified; nodal TFH cell lymphoma, angioimmunoblastic type; extranodal NK-cell/T-cell lymphoma; adult T-cell leukemia/lymphoma; and ALK-positive or -negative anaplastic large cell lymphoma) comprise over 75% of MTNKN cases, so other subtypes are exceedingly rare in the context of all NHL diagnoses and consequently often lack consensus on best practices in diagnosis and management. In this review, we discuss the following entities–enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), hepatosplenic T-cell lymphoma (HSTCL), subcutaneous panniculitis-like T-cell lymphoma (SPTCL), and primary cutaneous ɣδ T-cell lymphoma (PCGD-TCL) – with an emphasis on clinical and diagnostic features and options for management.     

SOHO State of the Art Updates and Next Questions |Treatment Approaches for Nodular Lymphocyte-Predominant Hodgkin Lymphoma

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare variant of Hodgkin lymphoma characterized by a persistent risk of relapse but an excellent overall survival. Historically, it was treated similarly to classic Hodgkin lymphoma, but efforts have been made to deintensify treatment due to risk of late toxicity associated with intensive therapy. For patients with completely resected stage IA NLPHL, no further treatment may be considered, particularly for pediatric patients. For those with stage I-II NLPHL without risk factors such as B symptoms, sites>2, or variant pattern histology, lower intensity treatment with radiotherapy or chemotherapy alone may be sufficient. However, combined modality therapy is a standard treatment for favorable and unfavorable risk stage I-II NLPHL associated with excellent progression-free and overall survival rates. For patients with advanced stage NLPHL, the optimal chemotherapy is not defined, but R-CHOP appears to be an effective treatment. Efforts to study NLPHL through multicenter collaborative efforts are crucial to develop evidence based and individualized treatments for patients with NLPHL.     

SOHO State of the Art Updates and Next Questions: Pathology and Pathogenesis of Nodal Peripheral T-Cell Lymphomas

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous and often clinically aggressive group of neoplasms derived from mature post-thymic T-lymphocytes. These neoplasms are rare and usually diagnostically challenging. Our understanding of the pathogenesis of PTCL is increasing and this improved knowledge is leading us to better molecular characterization, more objective and accurate diagnostic criteria, more effective risk assessment, and potentially better treatments. The focus of this paper is to present a brief overview of the current pathology criteria and molecular and genetic features of nodal peripheral T-cell lymphomas focusing on distinct genetically and molecularly defined subgroups that are being recognized within each major nodal PTCL category. It is expected that the molecular stratification will improve the diagnosis and will provide novel therapeutic opportunities (biomarker-driven and targeted therapies) that might benefit and change the outcomes of patients with these neoplasms.     

Society of Hematologic Oncology (SOHO) State of the Art Updates and Next Questions: Myelodysplastic Syndromes

In the past few months, 2 main streams of research have dominated the panorama of myelodysplastic syndrome (MDS) investigations: deepening the insight into the pathogenic role, hierarchy, and prognostic effect of somatic mutations and, as a consequence, into the effect of inherited congenital predisposing conditions and the second, quite interlinked with the first, analyzing inflammation and innate immunity in patients with MDS. The research devoted to clarifying the mechanisms of action and mechanisms of resistance to hypomethylating agents has also advanced, mostly resulting from different approaches to the study of DNA methylation. Recent observations have reinforced support for targeted therapies for selected subgroups of MDS patients.     

SOHO State of the Art Updates and Next Questions | Hyper-CVAD in 2022: Lessons Learned and New Approaches

Combination chemotherapy is the mainstay of treatment for acute lymphoblastic leukemia (ALL). The Hyper-CVAD regimen was developed in 1992 at MD Anderson Cancer Center and has since become a standard of care option for adult patients with ALL. Since its conception, a number of modifications have been implemented to customize the regimen for different patient populations and safely incorporate novel therapies without compromising tolerability. We aim to review the evolution of the Hyper-CVAD regimen over the past 3 decades, focusing on clinical pearls, as well as future directions.     

SOHO State of the Art Updates and Next Questions: Treatment of Older,Vulnerable Adults with Multiple Myeloma

Multiple myeloma is primarily a disease of the elderly, and optimal treatments must weigh the risks of toxicity with the benefits of therapy.  Frailty scales have been developed to aid treatment-decision making for older adults with MM.   This review provides a framework for incorporating frailty scales into clinical care and highlights how patient-aligned priorities for care can influence the management of older or more vulnerable adults with newly diagnosed multiple myeloma newly diagnosed multiple myeloma. We review the currently available systemic therapies for managing older or more vulnerable adults with newly diagnosed multiple myeloma otherwise considered ineligible for autologous stem cell transplantation.