SOHO State of the Art Updates and Next Questions | Infections in Chronic Lymphocytic Leukemia Patients: Risks and Management

Although chronic lymphocytic leukemia (CLL) is a malignancy characterized by accumulation of tumor cells in the blood, bone marrow, lymph nodes and secondary lymphoid tissues, the hallmark of the disease and the major cause of death for patients with CLL is actually immune dysfunction and associated infections. Despite improvement in treatment based on combination chemoimmunotherapy and targeted treatment with BTK and BCL-2 inhibitors leading to longer overall survival for patients with CLL, the mortality due to infections have not improved over the last 4 decades. Thus, infections are now the main cause of death for patients with CLL, posing threats to the patient whether during the premalignant state of monoclonal B lymphocytosis (MBL), during the watch & wait phase for treatment naïve patients, or upon treatment in terms of chemoimmunotherapy or targeted treatment. To test whether the natural history of immune dysfunction and infections in CLL can be changed, we have developed the machine learning based algorithm CLL-TIM.org to identify these patients. The CLL-TIM algorithm is currently being used for selection of patients for the clinical trial PreVent-ACaLL (NCT03868722), testing whether short-term treatment with the BTK inhibitor acalabrutinib and the BCL-2 inhibitor venetoclax can improve immune function and decrease the risk of infections for this high-risk patient population. We here review the background for and management of infectious risks in CLL.     

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 | Mechanisms of Resistance to BCL2 Inhibitor Therapy in Chronic Lymphocytic Leukemia and Potential Future Therapeutic Directions

Chronic lymphocytic leukaemia (CLL) constitutively overexpresses B-cell lymphoma 2 (BCL2) with consequent dysregulation of intrinsic apoptosis leading to abnormal cellular survival. Therapeutic use of BCL2 inhibitors (BCL2i, eg, venetoclax) in CLL, as both continuous monotherapy or in fixed duration combination, has translated scientific rationale into clinical benefit with significant rates of complete responses, including those without detectable minimal residual disease. Unlike with chemotherapy, response rates to venetoclax do not appear to be influenced by pre-existing chromosomal abnormalities or somatic mutations present, although the duration of response observed remains shorter for those with traditional higher risk genetic aberrations. This review seeks to describe both the disease factors that influence primary venetoclax sensitivity/resistance and those resistance mechanisms that may be acquired secondary to BCL2i therapy in CLL. Baseline venetoclax-sensitivity or -resistance is influenced by the expression of BCL2 relative to other BCL2 family member proteins, microenvironmental factors including nodal T-cell stimulation, and tumoral heterogeneity. With selection pressure applied by continuous venetoclax exposure, secondary resistance mechanisms develop in oligoclonal fashion. Those mechanisms described include acquisition of BCL2 variants, dynamic aberrations of alternative BCL2 family proteins, and mutations affecting both BAX and other BH3 proteins. In view of the resistance described, this review also proposes future applications of BCL2i therapy in CLL and potential means by which BCL2i-resistance may be abrogated.     

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: 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 | Update on Treatment-Free Remission in Chronic Myeloid Leukemia (CML)

Tyrosine kinase inhibitor (TKI) discontinuation, also known as treatment-free remission (TFR) is currently one of the main goals of chronic myeloid leukemia (CML) therapy. TKI discontinuation should be considered in eligible patients for several reasons. Specifically, TKI therapy is associated with reduced quality of life, long-term side effects, and a heavy financial burden on both the patients and society. TKI discontinuation is a particularly important goal for younger patients diagnosed with CML because of the treatment's effects on their growth and development in addition to potential long-term side-effects. Numerous studies with thousands of patients have demonstrated the safety and feasibility of attempting TKI discontinuation in a select group of patients who have achieved a sustained deep molecular remission. With current TKIs, approximately 50% of patients will be eligible for attempting TFR of which only 50% will achieve a successful TFR. Therefore, in reality, only 20% of patients with newly diagnosed CML will achieve a successful TFR, and the majority of patients will need to continue TKI therapy indefinitely. However, several ongoing clinical trials are investigating treatment options for patients to achieve deeper remission with the ultimate goal of a cure, which is defined as being off drug with no evidence of disease.     

SOHO State of the Art Updates and Next Questions: The Conundrum in Assessing the Therapy Response of Patients With Chronic Lymphocytic Leukemia

In 2018, the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) updated the guidelines for diagnosis, indications for treatment, response assessment, and supportive management of patients with chronic lymphocytic leukemia. Included were definitions for response, which incorporated consideration of the significance of minimal residual disease. Here we discuss the clinical significance of complete response or partial response, as defined in the 2018 iwCLL guidelines, and the relative value of assessing for minimal residual disease.     

SOHO State of the Art Updates and Next Questions |The Role of Maintenance Therapy in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is an aggressive disease predominantly affecting the elderly population. Although, up to 65% of patients with AML achieve a complete remission with standard induction chemotherapy, the majority of patients will relapse and succumb to the disease. Although maintenance therapy is a component of standard management for various hematological malignancies, such as acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL) or multiple myeloma, past studies investigating the role of maintenance therapy in AML were unable to demonstrate an advantage in overall survival, and therefore, it has not been an established practice in the treatment of AML. For patients, who are not candidates for stem cell transplant, effective AML maintenance therapies are needed in order to reduce the risk of relapse. Over the past decades, many investigators have examined the role of various maintenance strategies in AML; with the intention to prolong remission and overall survival. This review will provide an overview of prior and ongoing approaches and strategies to maintenance therapy for AML.     

SOHO State of the Art Updates and Next Questions | Beyond BCL-2 Inhibition in Acute Myeloid Leukemia: Other Approaches to Leverage the Apoptotic Pathway

BCL-2 inhibition has transformed the therapeutic landscape of acute myeloid leukemia (AML) but is not curative for the majority of patients. Consequently, there has been growing interest in targeting other facets of the apoptotic machinery to improve outcomes. These approaches include targeting the intrinsic and extrinsic apoptotic pathway, inducing apoptosis via p53 activation, and others. Targeting the intrinsic apoptotic pathway includes MCL-1 antagonism and BCL-xL inhibition. MCL-1 can be targeted via direct inhibitors as well as via indirect mechanisms to downregulate MCL-1 including inhibition of cyclin dependent kinases and Nedd8 activating enzyme. The extrinsic apoptotic pathway could be harnessed via inhibition of inhibitor of apoptosis proteins, agonism of the TNF-related apoptosis-inducing ligand receptors and inhibiting FLICE-like inhibitor protein. Approaches inducing p53-mediated apoptosis are being evaluated using inhibitors of MDM2, dual inhibitor of MDM2/X in TP53 wild-type AML and p53 reactivators in TP53-mutant myeloid disorders. Several such agents are in early clinical development and rationale combinations of these agents may help improving outcomes for patients with AML.     

SOHO State of the Art Updates and Next Questions | Optimal Timing of Blinatumomab for the Treatment of B-Acute Lymphoblastic Leukemia

Blinatumomab is a CD19 targeting bi-specific T-cell engager antibody construct developed for the treatment of CD19 expressing B-cell malignancies. Numerous adult and pediatric B-ALL clinical trials have demonstrated blinatumomab's efficacy in the relapse setting as well as in patients with residual disease after upfront chemotherapy. The safety profile of blinatumomab is also favorable, making it a feasible option for most patients. Several key questions remain, including the role of blinatumomab as a replacement for toxic elements of standard chemotherapy regimens in the upfront setting, its role as a bridge to hematopoietic stem cell transplantation, or whether previous blinatumomab impacts the efficacy of subsequent CAR-T cell therapy.     

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 |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 | 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: 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 | 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: 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: 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: Management of Asparaginase Toxicity in Adolescents and Young Adults with Acute Lymphoblastic Leukemia

A wider use of L-asparaginase in the treatment of children with acute lymphoblastic leukemia has improved cure rates during recent decades and hence led to introduction of pediatric-inspired treatment protocols for adolescents and young adults. In parallel, a range of burdensome, often severe and occasionally life-threatening toxicities have become frequent, including hypersensitivity, hepatotoxicity, hypertriglyceridemia, thromboembolism, pancreatitis, and osteonecrosis. This often leads to truncation of asparaginase therapy, which at least in the pediatric population has been clearly associated with a higher risk of leukemic relapse. Many of the asparaginase induced toxicities are far more common in older patients, but since their relapse rate is still unsatisfactory, the decision to discontinue asparaginase therapy should balance the risk of toxicity with continued asparaginase therapy against the risk of relapse in the individual patient. The underlying mechanisms of most of the asparaginase induced side effects are still unclear. In this review we address the individual toxicities, known risk factors, and their clinical management.