Maintenance Therapies in Indolent Lymphomas: should Recent Data Change the Standard of Care?

OPINION STATEMENT: The overall benefit of maintenance therapy for patients with an indolent lymphoma continues to go unanswered. A myriad of variables contribute to the lack of clear clinical guidance. First, the disease course is slow and treatment may not be required for years, requiring a long follow-up to prospectively study. Second, due to the long lag time from study initiation to conclusion, many of the induction therapies used at the onset of the study may not be favored at present, providing a conclusion that cannot be reconciled with current clinical practice. For example, bendamustine and rituximab are typically the favored initial treatment agents in follicular lymphoma, which was not true when many maintenance trials were initiated. Third, several studies' inclusion criteria allow for patient enrollment at both initial diagnosis as well as at disease recurrence. In some studies, patients who are asymptomatic are started on therapy, counter to the accepted watch and wait approach. This contributes to the difficulty of generalizing results. The question of the benefit of maintenance therapy has been studied enough, and there may not be a smoking gun in the foreseeable future. However, what does hold promise is focusing on the patients with minimum residual disease after conclusion of chemotherapy. This may be a population that could receive benefit from a prolonged treatment approach. In the meantime, maintenance therapy should not be used in all patients, and the rationale for use should be data-driven, as well as an assessment of a patient's potential intolerability of cytotoxic chemotherapy.

Novel Pharmacotherapies for B-Cell Lymphomas and Leukemias.

Novel pharmacotherapeutic agents were recently approved for treatment of low-grade B-cell neoplasms, and many other agents are under investigation. Several agents have demonstrated impressive activity in targeting malignant B-cell processes and specific pathways, all with the potential to expand our ability to effectively treat B-cell malignancies. The inhibitors of several cell regulatory proteins, including Bruton tyrosine kinase (Btk), phosphoinositide 3-kinase (PI3-K), B-cell lymphoma/leukemia-2 (Bcl-2), and histone deacetylases, as well as immunomodulatory agents are a few of the many pharmacotherapeutic agents under study. A comprehensive review and assessment is presented of the current pharmacotherapies under investigation targeting B-cell lymphomas and leukemias.

Novel Immunotherapies for B-Cell Lymphomas and Leukemias.

Current immunotherapeutic agents under investigation have the potential to significantly expand our ability to effectively treat B-cell malignancies. New disease targets, novel strategies to deliver therapy, and advanced agents that work to manipulate the immune system are a few of the ways immunotherapy has quickly evolved. Novel targeted and immune-modifying therapies may demonstrate early potential but unique toxicities and other limitations, such as difficulties in administration, must also be acknowledged. This review provides a comprehensive assessment of the current immunotherapies under investigation against B-cell malignancies.

Remission of severe myasthenia gravis after autologous stem cell transplantation.

OBJECTIVE: Myasthenia gravis (MG) is an autoantibody-mediated neuromuscular junction disorder involving the acetylcholine receptors on the motor endplate. The safety and response to high-dose chemotherapy (HDIT) and autologous hematopoietic cell transplantation (HCT) were assessed in a patient with severe refractory MG. METHODS: As part of a pilot study of HDIT/HCT for patients with treatment-resistant autoimmune neurological disorders, a patient with severe refractory MG underwent treatment. After mobilization of hematopoietic stem cells with rituximab, prednisone, and G-CSF, the patient had HDIT consisting of carmustine, etoposide, cytarabine, melphalan, and rabbit antithymocyte globulin, followed by autologous HCT. The effect of treatment on the autoantibody to the acetylcholine receptor (AChR) was assessed. RESULTS: The patient had been diagnosed with AChR antibody-positive MG 14 years before HDIT/HCT and had failed thymectomy, therapeutic plasma exchange, and multiple immunomodulatory agents. The Myasthenia Gravis Foundation of America (MGFA) clinical classification was IVb before HDIT/HCT. She tolerated HDIT/HCT well and started to improve clinically within days of treatment. At both 1 and 2 years after HDIT/HCT, patients remained symptom-free. After HDIT/HCT, AChR-binding autoantibodies persisted, and the relative frequency of immune cell subtypes shifted. INTERPRETATION: HDIT/HCT induced a complete response of disease activity in a patient with severe refractory MG. This response may suggest that a cell-mediated etiology may be a significant contributing factor in refractory MG cases. A phase 2 clinical trial is warranted to establish if HDIT/HCT can be an effective therapy for severe refractory MG and to gain a further understanding of disease pathogenesis.

Outcomes Among Classical Hodgkin Lymphoma Patients After an Interim PET Scan: A Real-World Experience.

INTRODUCTION: The utility of dose escalation after positive positron emission tomography following 2 cycles of ABVD (PET2) for Hodgkin Lymphoma (HL) remains controversial. We describe the United States real-world practice patterns for PET2 positive patients. PATIENTS AND METHODS: Data was collected from 15 sites on PET2 positive HL patients after receiving frontline treatment between January, 2015 and June, 2019. Descriptive analyses between those with therapy change and those continuing initial therapy were assessed. RESULTS: A total of 129 patients were identified; 111 (86%) were treated with ABVD therapy and 18 (14%) with an alternate regimen. At PET2 assessment, 74.4% (96/129) had Deauville score (DS) 4 and 25.6% (33/129) had DS 5. Of the 66 limited stage (LS) patients with PET2 DS score of 4/5, 77.3% (51/66) continued initial therapy and 22.7% (15/66) changed to escalated therapy. The 12-month progression-free survival (PFS) for DS 4/5 LS patients was 67.0% (95% CI; 54.9-81.7) for patients without escalation compared with 51.4% (95% CI; 30.8-85.8) for those who escalated. Of the 63 DS 4/5 patients with advanced stage (AS) disease, 76.2% (48/63) continued initial therapy and 23.8% (15/63) changed to escalated therapy. The 12-month PFS for DS 4/5 AS patients was 38.3% (95% CI: 26.3%-55.7%) for patients without escalation compared with 57.1% (95% CI: 36.3-89.9) for those with escalation. CONCLUSION: A minority of PET2 positive HL patients undergo therapy escalation and outcomes remain overall suboptimal. Improved prognostics markers and better therapeutics are required to improve outcomes for high-risk PET2 positive HL patients.

Hurricane Katrina-related maternal stress, maternal mental health, and early infant temperament.

To investigate temperament in infants whose mothers were exposed to Hurricane Katrina and its aftermath, and to determine if high hurricane exposure is associated with difficult infant temperament. A prospective cohort study of women giving birth in New Orleans and Baton Rouge, LA (n = 288) in 2006-2007 was conducted. Questionnaires and interviews assessed the mother's experiences during the hurricane, living conditions, and psychological symptoms, 2 months and 12 months postpartum. Infant temperament characteristics were reported by the mother using the activity, adaptability, approach, intensity, and mood scales of the Early Infant and Toddler Temperament Questionnaires, and "difficult temperament" was defined as scoring in the top quartile for three or more of the scales. Logistic regression was used to examine the association between hurricane experience, mental health, and infant temperament. Serious experiences of the hurricane did not strongly increase the risk of difficult infant temperament (association with three or more serious experiences of the hurricane: adjusted odds ratio (aOR) 1.50, 95% confidence interval (CI) 0.63-3.58 at 2 months; 0.58, 0.15-2.28 at 12 months). Maternal mental health was associated with report of difficult infant temperament, with women more likely to report having a difficult infant temperament at 1 year if they had screened positive for PTSD (aOR 1.82, 95% confidence interval (CI) 0.61-5.41), depression, (aOR 3.16, 95% CI 1.22-8.20) or hostility (aOR 2.17, 95% CI 0.81-5.82) at 2 months. Large associations between maternal stress due to a natural disaster and infant temperament were not seen, but maternal mental health was associated with reporting difficult temperament. Further research is needed to determine the effects of maternal exposure to disasters on child temperament, but in order to help babies born in the aftermath of disaster, the focus may need to be on the mother's mental health.

Chronic lymphocytic leukemia and small lymphocytic lymphoma: two faces of the same disease.

INTRODUCTION: Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are considered indolent lymphocytic malignancies, more often requiring active surveillance rather than intervention. Despite the indolent nature of CLL/SLL, treatment is likely indicated in a patients' lifetime. Recent changes in the therapeutic landscape have created more options to the clinician. Areas covered: The authors provide a broad assessment of the current state of disease, including the work-up, prognostic features, and mutational aspects of the disease that should be acknowledged when developing a rational treatment plan. Key studies, guideline recommendations, and expert analysis are used to create this update on CLL/SLL. Expert commentary: The recent pace of treatment additions in CLL/SLL is a welcome addition. Moving forward, it is anticipated that treatment modalities will continue to evolve, leading to additional management options that truly would define CLL/SLL as a chronic disease.

Efficacy of hypomethylating agents in therapy-related myelodysplastic syndromes.

We retrospectively assessed morphologic and cytogenetic responses to 5-azacytidine and decitabine in a cohort of 42 adult therapy-related myelodysplastic syndromes (tMDS) patients treated at Memorial Sloan-Kettering Cancer Center and in 2 industry-sponsored decitabine trials (D0007 and DACO-020). The overall response rate (complete remission+marrow CR+hematologic improvement) was 38%, including 6 patients with complete remission (14%), 6 with marrow CR with or without hematologic improvement (14%), and 4 with hematologic improvement alone (10%). We conclude that DNA methyltransferase inhibitors showed activity in tMDS that is roughly comparable to that seen in de novo MDS.