Oral azacitidine in patients with relapsed or refractory follicular helper T-cell lymphoma.

• Highlight(s):  Follicular helper T-cell lymphomas (TFHL) harbor frequent alterations in genes that regulate DNA methylation. Preliminary reports suggest that treatment with 5-azacitidine has clinical activity in patients with relapsed or refractory TFHL. However, a recent phase 3 trial showed no superiority of azacitidine over investigator´s choice therapy (ICT). 

A phase 3 clinical trial (ORACLE) (Europe NCT03593018 and Japan NCT03703375) has been published. Patients with relapsed or refractory TFHL (angioimmunoblastic T-cell lymphoma, follicular lymphoma, or nodal T-cell lymphoma with phenotype) were randomly assigned 1:1 to treatment with either azacitidine (n=42) or ICT (gemcitabine, bendamustine, or romidepsin [n=44]). The primary endpoint was investigator-assessed progression-free survival (PFS). With a median follow-up of 27.4 months (interquartile range [IQR] 20.2–32.9), the median PFS was 5.6 months (95% confidence interval [CI] 2.7 –8.1) in the azacitidine group versus 2.8 months (1.9–4.8) in the ICT group (hazard ratio of 0.63 [95% CI 0.38–1.07]; 2-sided p=0.084). Thus, the criterion to declare superiority of azacitidine over ICT was not met. No significant difference was observed in the overall response rate or complete response rate at 3 and 6 months. No patient received an allogeneic hematopoietic stem cell transplantation (HSCT) as consolidation therapy, and only two patients, both in the azacitidine group, received an allogeneic HSCT after subsequent progression. Grade 3–4 adverse events were reported in 32 (76%) of 42 patients in the azacitidine group versus 42 (98%) of 43 patients in the ICT group. 

Risk stratification in Waldenström macroglobulinemia.

• Highlight(s): A new useful prognostic model (Modified Staging System for Waldenström macroglobulinemia [MSS-WM]) using age, albumin, and lactate dehydrogenase (LDH) risk-stratifies patients with symptomatic WM into four groups with distinct prognosis. 

Recently were published the results from a study of treatment-naïve patients with active WM, to identify clinical predictors of overall survival (OS). Patients with complete data for the parameters that were significant in the univariate analyses (n= 341) were included in a multivariable analysis to derive a prognostic model, subsequently validated in a multi-institutional cohort. In the derivation cohort (n= 341), age (hazard ratio [HR], 1.9 [95% CI, 1.2 to 2.1]; p=0.0009), serum lactate dehydrogenase (LDH) above upper limit of normal (HR, 2.3 [95% CI, 1.3 to 4.5]; p=0.007), and serum albumin <3.5 g/dL (HR, 1.5 [95% CI, 0.99 to 2.3]; p=0.056) were independently prognostic. By assigning a score of 1 point each to albumin <3.5 g/dL (HR, 1.5) and age 66-75 years (HR 1.4) and 2 points for age >75 years (HR, 2.6) or elevated LDH (HR, 2.3), four groups with distinct outcomes were observed based on the composite scores. Five-year OS was 93% for the low-risk (score 0), 82% for low-intermediate risk (score 1), 69% for intermediate-risk (score 2), and 55% for the high-risk (score ≥3; p<0.0001) groups. In the validation cohort (n=335), the model maintained its prognostic value, with a 5-year OS of 93%, 90%, 75%, and 57% for the four groups, respectively (p<0.0001).

VEXAS syndrome and thrombosis.

• Highlight(s): venous thromboembolism (VTE) is common in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, occurring in over 40% of patients with frequent recurrences; however, it is not associated with increased mortality. 

VEXAS syndrome is an autoinflammatory disorder caused by somatic mutations in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene leading to upregulation of inflammatory pathways. VEXAS syndrome has diverse systemic manifestations, including cytopenias, myelodysplastic syndrome, and plasma cell dyscrasias. Recently, a study that included 119 patients with VEXAS syndrome showed that thrombosis occurred in 49% of patients, mostly VTE (41%). Almost two-thirds of VTEs were unprovoked, 41% were recurrent, and 20% occurred despite anticoagulation. The cumulative incidence of VTE was 17% at 1 year from symptom onset and 40% by 5 years. Cardiac and pulmonary inflammatory manifestations were associated with time to VTE. The cumulative incidence of arterial thrombosis was 6% at 1 year and 11% at 5 years. The overall survival of the entire patient cohort at a median follow-up time of 4.8 years was 88%, and there was no difference in survival between patients with or without thrombosis (p=0.8). 

Tattoos as a risk factor for malignant lymphoma.

• Highlight(s): Pigments in tattoos appear to be associated with the presence of lymphoma in a Swedish case-control study and the association was strongest for diffuse large B-cell lymphoma and follicular lymphoma.

Carcinogenic substances are frequently found in tattoo ink. The long-term health effects of tattoo pigment in lymph nodes remain unexplored. A Swedish case-control study which explored the association between tattoos and lymphoma was recently published. Identified were all incident cases of lymphoma diagnosed between 2007 and 2017 in individuals aged 20–60 years in the Swedish National Cancer Register. Three random age- and sex-matched controls per case were sampled from the total population register. Exposure was assessed through a questionnaire and data on potential confounders were retrieved from registers. The study population consisted of 11,905 individuals and the response rate was 54% among cases (n = 1398) and 47% among controls (n = 4193).

The tattoo prevalence was 21% among cases and 18% among controls. Tattooed individuals had a higher adjusted risk of overall lymphoma (incidence rate ratio [IRR= incidence rate in the exposed / incidence rate in the unexposed] = 1.21; 95% confidence interval [CI] 0.99–1.48). The risk of lymphoma was highest in individuals with less than two years between their first tattoo and the index year (IRR = 1.81; 95% CI 1.03–3.20). No evidence was found of increasing risk with a larger area of total tattooed body surface. The risk associated with tattoo exposure seemed to be highest for diffuse large B-cell lymphoma (IRR 1.30; 95% CI 0.99–1.71) and follicular lymphoma (IRR 1.29; 95% CI 0.92–1.82). Causality cannot be conferred from a single epidemiologic study and the results need to be confirmed by further research. 

Consensus guidelines and recommendations for the management and response assessment of chimeric antigen receptor (CAR)-T cell therapy in clinical practice for relapsed and refractory multiple myeloma.

A panel of experts from the International Myeloma Working Group (IMWG) was assembled to provide guidance for clinical use of CAR-T cell therapy in myeloma. Panel 1 of the original paper summarizes the main recommendations. Here is a summary of some of the most relevant key points.

Recommendations for patient selection:

• Although experience remains limited with patients on dialysis, growing experience in patients with renal dysfunction suggests feasibility of CAR-T cell therapy using renal dose adjusted fludarabine. 

• Previous exposure to other B-cell maturation antigen (BCMA)-targeted therapy could negatively affect clinical response to CAR-T cells. Due to the absence of a clinically available test for BCMA loss, consideration should be given whenever available for therapy targeting a different antigen at first relapse.

Recommendations for myeloma treatment before CAR-T cell therapy:

• Avoid lymphotoxic drugs, such as bendamustine and high-dose cyclophosphamide, where possible.

• A washout period of 14 days for chemotherapy drugs should be used, when possible, to allow for T cell count recovery. For radiation that involves less than 5% of the bone marrow, a washout period might not be needed.

• For corticosteroids and immunomodulatory drugs with a short half-life, the washout period can be reduced to 7 days. 

• For patients with low disease burden that is not rapidly progressing, consider the minimum bridging therapy needed to limit disease progression during CAR-T cell manufacturing, which could include continuing the same regimen before leukapheresis. For patients with high disease burden or rapidly progressing disease, priority should be placed on a regimen involving agents to which a patient’s disease has not become refractory. 

• Preclinical data suggest immunomodulatory drugs and anti-CD38 antibodies might improve T cell function and CAR-T cell activities; these drugs can be used with consideration for washout as needed, to allow count recovery before lymphodepletion chemotherapy. 

Recommendations for management of cytokine release syndrome (CRS): 

• Use of tocilizumab with or without dexamethasone for persistent grade 1 CRS, or for early or rapid onset CRS.

• There is a low threshold for tocilizumab use in grade 1 CRS, such as in patients who are frail, those with high disease burden, or high levels of inflammatory markers at the time of CAR-T cell infusion.

• Steroids should be added in grade 3 and higher CRS, and when CRS

persists despite two doses of tocilizumab.

• Consider adding alternative immunosuppressive agents once two or more doses of tocilizumab have been given.

• Consider tocilizumab with or without dexamethasone for the following, regardless of CRS grading, in addition to grading-based management: atrial fibrillation with rapid ventricular response, decrease in cardiac ejection fraction, grade 3 or higher transaminitis not attributable to other causes, grade 3 or higher renal dysfunction not attributable to other causes.

• Consider tocilizumab, dexamethasone, and anakinra for early signs of immune effector cell-associated hemophagocytic lymphohistiocytosis (HLH)-like syndrome (IEC-HS), macrophage activation like-syndrome, or persistent immune activation.

Recommendations for immune effector cell-associated neurotoxicity syndrome (ICANS) management: 

• Baseline brain imaging and comprehensive neurologic assessment by a neurologist before CAR-T cell infusion ensures accuracy in assessing new neurologic deficits post-CAR-T cell infusion.

• Handwriting changes can identify early onset of ICANS, and micrographia is an early change seen with the onset of Parkinsonism.

• Consider electroencephalogram, brain MRI, and intracranial pressure monitoring with the onset of altered levels of consciousness, focal motor weakness, or paresis.

• Prophylactic anti-seizure medications can be used in the first month after CAR-T cell infusion for patients at high risk for ICANS.

• ICANS most commonly occurs during or after CRS in the first 1–2 weeks post-infusion and is generally completely reversible. For ICANS with deficits measurable on immune effector cell encephalopathy (ICE) score that are improving on treatment:

  • De-escalate steroid as rapidly as tolerated if ICE score does not worsen.

  • For patients with persistent grade 1 ICANS for weeks to months with no effect on activities of daily living or safety, corticosteroids can be discontinued.

  • Rapid escalation of therapy should be considered for patients with grade 3 or 4 ICANS (anakinra can be useful), especially due to seizure and cerebral oedema that is not improving with corticosteroids.

• If occurring during CAR-T cell expansion or with evidence for rapid lymphocyte expansion, consider lymphotoxic drugs, such as high-dose cyclophosphamide or antithymocyte globulin.

• ICANS in the subacute to late onset setting: 

  • Guillain–Barré syndrome, cranial nerve palsies, and Parkinsonism have been reported.

  • Abstaining from operating motor vehicles for 8 weeks after CAR-T cell infusion.

Antimicrobial prophylaxis (Table 1 of original paper). In summary, the IMWG recommends antimicrobial prophylaxis with: 

• Valacyclovir (500 mgs twice a day and acyclovir 400-800 mgs twice a day from lymphodepletion for 1-year post-CAR-T cell therapy).

• Levofloxacin (500 mgs daily; not recommended by European Society for Blood and Marrow Transplantation).

• Fluconazole 400 mg daily (or equivalent [not EBMT]); prophylaxis against mold (e.g., Aspergillus) should be considered in high-risk situations.

• Sulfamethoxazole 800 mg and trimethoprim 160 mg three times a week pre-lymphodepletion until 6 months post-CAR-T cell therapy (EBMT: 1-year post-CAR-T cell therapy); alternatives could be considered in settings of cytopenia, allergy, or regional drug access; alternatives include monthly pentamidine nebulizer or atovaquone (1.5 g daily). 

• Consider immunoglobulin G (IgG) replacement if IgG <400 mg/dL with 400–500 mg/kg intravenous immunoglobulin every 4–6 weeks (EBMT: Consider in adults who have had encapsulated organism infections).