Improving outcomes after autologous transplantation in relapsed/refractory Hodgkin lymphoma: a European expert perspective.

Autologous stem cell transplantation (ASCT) is a well-established approach to treatment of patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) recommended by both the European Society for Medical Oncology and the National Comprehensive Cancer Network based on the results from randomized controlled studies. However, a considerable number of patients who receive ASCT will progress/relapse and display suboptimal post-transplant outcomes. Over recent years, a number of different strategies have been assessed to improve post-ASCT outcomes and augment HL cure rates. These include use of pre- and post-ASCT salvage therapies and post-ASCT consolidative therapy, with the greatest benefits demonstrated by targeted therapies, such as brentuximab vedotin. However, adoption of these new approaches has been inconsistent across different centers and regions. In this article, we provide a European perspective on the available treatment options and likely future developments in the salvage and consolidation settings, with the aim to improve management of patients with HL who have a high risk of post-ASCT failure. CONCLUSIONS: We conclude that early intervention with post-ASCT consolidation improves outcomes in patients with R/R HL who require ASCT. Future approvals of targeted agents are expected to further improve outcomes and provide additional treatment options in the coming age of personalized medicine.

Should rituximab replace splenectomy in the management of splenic marginal zone lymphoma?

BACKGROUND: SMZL is a relatively rare low grade B-cell lymphoma, characterized usually by an indolent clinical behavior. Since there is no prospective randomized trials to establish the best treatment approach, decision on therapeutic management should be based on the available retrospective series. Based on these data, rituximab and splenectomy appear to be the most effective. Splenectomy represented the standard treatment modality until early 2000s. More than 90% of the patients present quick amelioration of splenomegaly related symptoms along with improvement of cytopenias related to hypersplenism. The median progression free survival was 8.25 years in the largest series of patients published so far, while the median 5- and 10- year OS were 84% and 67%, respectively. Responses to splenectomy are not complete since extrasplenic disease persists. Patients with heavy bone marrow infiltration, lymphadenopathy or other disease localization besides the spleen are not good candidates for splenectomy. Furthermore splenectomy is a major surgical procedure accompanied by acute perioperative complications as well as late toxicities mainly due to infections. For that reasons splenectomy is not appropriate for elderly patients or patients with comorbidities with a high surgical risk. On the other hand rituximab monotherapy displays high efficacy with minimal toxicity. Several published series have shown an ORR more than 90%, with high CR rates (∼50%). The 10-year PFS and OS were 63% and 85%, respectively in a series of 104 SMZL patients. The role of rituximab maintenance has been investigated by only one group. Based on these data, maintenance with rituximab further improved the quality of responses by increasing significantly the CR rates (from 42% at the end of induction to 71% at the end of maintenance treatment), as well as the duration of responses: 7-year PFS was 75% for those patients who received maintenance vs 39% for those who did not (p < 0.0004). However no difference in OS has been noticed between the two groups, so far. Summarizing the above data, it is obvious that Rituximab monotherapy is associated with high response rates, long response duration and favorable safety profile, rendering it as the treatment of choice in SMZL.

Immune cell response to strenuous resistive breathing: comparison with whole body exercise and the effects of antioxidants.

Background/hypothesis: Whole body exercise (WBE) changes lymphocyte subset percentages in peripheral blood. Resistive breathing, a hallmark of diseases of airway obstruction, is a form of exercise for the inspiratory muscles. Strenuous muscle contractions induce oxidative stress that may mediate immune alterations following exercise. We hypothesized that inspiratory resistive breathing (IRB) alters peripheral blood lymphocyte subsets and that oxidative stress mediates lymphocyte subpopulation alterations following both WBE and IRB. Patients and methods: Six healthy nonathletes performed two WBE and two IRB sessions for 45 minutes at 70% of VO2 maximum and 70% of maximum inspiratory pressure (Pimax), respectively, before and after the administration of antioxidants (vitamins E, A, and C for 75 days, allopurinol for 30 days, and N-acetylcysteine for 3 days). Blood was drawn at baseline, at the end of each session, and 2 hours into recovery. Lymphocyte subsets were determined by flow cytometry. Results: Before antioxidant supplementation at both WBE end and IRB end, the natural killer cell percentage increased, the T helper cell (CD3+ CD4+) percentage was reduced, and the CD4/CD8 ratio was depressed, a response which was abolished by antioxidants only after IRB. Furthermore, at IRB end, antioxidants promoted CD8+ CD38+ and blunted cytotoxic T-cell percentage increase. CD8+ CD45RA+ cell percentage changes were blunted after antioxidant supplementation in both WBE and IRB. Conclusion: We conclude that IRB produces (as WBE) changes in peripheral blood lymphocyte subsets and that oxidative stress is a major stimulus predominantly for IRB-induced lymphocyte subset alterations.

Cost-Effectiveness Analysis of Rivaroxaban for Treatment of Deep Vein Thrombosis and Pulmonary Embolism in Greece.

BACKGROUND AND OBJECTIVE: Venous thromboembolism (VTE), comprising deep-vein thrombosis (DVT) and pulmonary embolism (PE), is a major healthcare concern that results in substantial morbidity and mortality with great economic burden for healthcare systems. Hence, the need for effective and efficient treatment of patients with VTE is important for both clinical and economic reasons. The objective of this study was to evaluate the cost effectiveness of rivaroxaban compared to standard of care (SoC) with enoxaparin followed by dose-adjusted vitamin-K antagonists for the treatment of DVT and PE in Greece. METHODS: An existing Markov model was locally adapted from a third-party payer perspective to reflect the management and complications of DVT and PE in the course of 3-month cycles, up to death. The clinical inputs and utility values were extracted from published studies. Direct medical costs, obtained from local resources, were incorporated in the model and refer to year 2017. Both costs and outcomes were discounted at 3.5%. The incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) gained was calculated. Probabilistic sensitivity analysis (PSA) was carried out to deal with uncertainty. RESULTS: The base-case analysis showed that rivaroxaban in 3- and 6-month treatment duration for DVT and PE, respectively, as this is the common clinical practice in Greece, was associated with a 0.02 and 0.01 increment in QALYs compared to SoC, respectively. Rivaroxaban was associated with a reduced total cost in DVT (€85) but with an additional total cost in PE (€2) compared to SoC. Therefore, rivaroxaban was a dominant (less costly, more effective) and cost-effective (ICER: €177) alternative over SoC for the management of DVT and PE, respectively. PSA revealed that the probability of rivaroxaban being cost effective at a threshold of €34,000 per QALY gained was 99% and 81% for DVT and PE, respectively. CONCLUSION: Rivaroxaban may represent a cost-effective option relative to SoC for the management of DVT and PE in Greece.

Treatment of splenic marginal zone lymphoma.

Splenic marginal zone lymphoma (SMZL) is a distinct lymphoma entity characterized by an indolent clinical course and prolonged survival. Treatment is not standardized, since there are no prospective randomized trials in large series of SMZL patients. Splenectomy and rituximab represent the most effective treatment strategies used so far. The addition of chemotherapy to rituximab has not further improved the outcome, although this issue requires further investigation. Rituximab monotherapy has been associated with high response rates (∼90%), with approximately half of these responses being complete, even at the molecular level. More importantly, many of these responses are long-lasting, with a reported 7-year progression-free survival (PFS) at the rate of 69%. Maintenance rituximab treatment has been associated with further improvement of the quality of response as well as longer response duration in studies derived from one group of investigators. Based on its high efficacy and the good safety profile, rituximab represent one of the best treatment options for SMZL patients. Moreover, rituximab retains its efficacy in the relapse setting in most cases. Splenectomy is a meaningful alternative to rituximab in patients with bulky splenomegaly and cytopenias, without extensive bone marrow infiltration, who are fit for surgery. However splenectomy cannot completely eradicate the disease and it is also associated with greater morbidity or even mortality compared to rituximab. The choice of one of these two treatment approaches (rituximab or splenectomy) should mainly be based on patient's characteristics and on the disease burden. Novel agents are currently testing in low grade lymphomas including a small number of SMZL patients with promising results.

Guanylyl cyclase activation reverses resistive breathing-induced lung injury and inflammation.

Inspiratory resistive breathing (RB), encountered in obstructive lung diseases, induces lung injury. The soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is down-regulated in chronic and acute animal models of RB, such as asthma, chronic obstructive pulmonary disease, and in endotoxin-induced acute lung injury. Our objectives were to: (1) characterize the effects of increased concurrent inspiratory and expiratory resistance in mice via tracheal banding; and (2) investigate the contribution of the sGC/cGMP pathway in RB-induced lung injury. Anesthetized C57BL/6 mice underwent RB achieved by restricting tracheal surface area to 50% (tracheal banding). RB for 24 hours resulted in increased bronchoalveolar lavage fluid cellularity and protein content, marked leukocyte infiltration in the lungs, and perturbed respiratory mechanics (increased tissue resistance and elasticity, shifted static pressure-volume curve right and downwards, decreased static compliance), consistent with the presence of acute lung injury. RB down-regulated sGC expression in the lung. All manifestations of lung injury caused by RB were exacerbated by the administration of the sGC inhibitor, 1H-[1,2,4]oxodiazolo[4,3-]quinoxalin-l-one, or when RB was performed using sGCα1 knockout mice. Conversely, restoration of sGC signaling by prior administration of the sGC activator BAY 58-2667 (Bayer, Leverkusen, Germany) prevented RB-induced lung injury. Strikingly, direct pharmacological activation of sGC with BAY 58-2667 24 hours after RB reversed, within 6 hours, the established lung injury. These findings raise the possibility that pharmacological targeting of the sGC-cGMP axis could be used to ameliorate lung dysfunction in obstructive lung diseases.

Treatment of splenic marginal zone lymphoma: should splenectomy be abandoned?

Splenic marginal zone lymphoma (SMZL) is a rare chronic B-cell lymphoproliferative disorder recognized as a distinct entity in the World Health Organization (WHO) classification. SMZL usually runs an indolent clinical course with a median survival of more than 10 years. However, in a proportion of patients (10-20%) SMZL behaves more aggressively, with a median survival of less than 4 years. Many efforts are ongoing to establish commonly accepted prognostic factors as a guide to therapy for this disorder. Data on the treatment of SMZL come from reported retrospective series including relatively limited numbers of patients. Despite these limitations, much progress has recently been made in the management of patients with SMZL. The oldest and most commonly used first-line therapeutic modality is splenectomy, which offers rapid alleviation of splenomegaly-related symptoms along with an improvement of cytopenias in the majority of patients, with a median PFS of 5 years. However, SMZL is a systemic disease, and splenectomy is not carried out with eradicative intent. Furthermore, splenectomy is a major surgical procedure with significant morbidity or even mortality, especially in older patients. Chemotherapy has only moderate activity in this form of MZL. Recent data suggest that rituximab is a very effective therapy with minimal toxicity and could replace splenectomy as first-line treatment. The overall response rate is > 90%, with almost half of responses being complete, while the 5-year progression-free survival is approximately 70%. The combination of rituximab with chemotherapy requires further evaluation. Based on the current data, splenectomy could be abandoned as first-line treatment for patients with SMZL.

Antioxidant supplementation alters cytokine production from monocytes.

We studied in 10 healthy subjects the effect of chronic enteral supplementation of antioxidants (vitamins E, C, A, allopurinol, and N-acetylcysteine) on cytokine production by monocytes at rest, end exercise (60-min cycling at 60% of maximum oxygen consumption), and 60 min post-exercise (recovery). The percentage and the mean fluorescent intensity (MFI) of both unstimulated and lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6-producing monocytes were detected using flow cytometry. Antioxidants decreased the percentage of unstimulated IL-6-producing monocytes following exercise, while their MFI increased at rest. The percentage of LPS-stimulated monocytes increased after exercise and they produced more IL-6 both at rest and following exercise. The percentage of unstimulated and LPS-stimulated IL-1beta-producing monocytes was not affected by antioxidants. The MFI of IL-1beta-produced unstimulated monocytes was increased after antioxidants both at rest and following exercise. After antioxidants, LPS-stimulated monocytes produced more IL-1beta following exercise. Antioxidants decreased the percentage of TNF-alpha spontaneously-produced monocytes following exercise, which produced more TNF-alpha at recovery. Antioxidants did not affect the percentage of LPS-stimulated monocytes producing TNF-alpha, while LPS-stimulated production of TNF-alpha increased both at rest and following exercise. Antioxidants differentially affect TNF-alpha, IL-1beta, and IL-6 production by monocytes, with a general tendency of augmenting cytokine production.

Safety and efficacy of low-dose bexarotene and PUVA in the treatment of patients with mycosis fungoides.

BACKGROUND: The new rexinoid bexarotene is a retinoid X receptor antagonist and immune response modifier. Although combinations of oral bexarotene and psoralen plus UVA (PUVA) have been tried in patients with all stages of mycosis fungoides (MF), the dosage of bexarotene used in these combination regimens has been variable. OBJECTIVE: To assess the efficacy and safety of low-dose oral bexarotene and PUVA in patients with relapsed or treatment-refractory MF following monotherapy with multiple agents including PUVA, narrow-band UVB, interferon-alpha, oral bexarotene, and topical corticosteroids. METHOD: Combination therapy with PUVA three times weekly and low-dose oral bexarotene (150 or 300 mg/day, depending on physicians' preference) was administered to 14 patients, seven men and seven women (median age 49.5 years, range 30-75 years), with relapsed or refractory MF stages I-III. All responders received maintenance treatment at the same bexarotene dose that induced remission until progression or unacceptable toxicity. RESULTS: Low-dose oral bexarotene combined with PUVA was associated with an overall response rate (complete response or partial response) in 67% of the nine patients with refractory MF who completed the treatment course. Of these nine patients, four had a complete response, two had a partial response, one had stable disease, and two had progressive disease. Five patients withdrew because of hyperlipidemia. Oral bexarotene was continued as maintenance therapy in three of the four complete responders (one refused); two of these patients relapsed 2-10 months after PUVA discontinuation. Patients with partial response or stable disease received the combination for 3-5 months and were switched to another treatment regimen because of lack of further response. Therapy was fairly well tolerated. CONCLUSION: In a select population of patients who had not responded to at least one monotherapy for early-stage MF, a combination of low-dose oral bexarotene and PUVA was successful in achieving a satisfactory overall response rate in 67% of patients who completed the treatment course and was fairly well tolerated. Limitations of the study include the small number of patients evaluated, its retrospective nature, and the fact that patients were commenced on different bexarotene starting doses (150 or 300 mg/day), depending on physicians' preference.