Tocilizumab for Cytokine Release Syndrome Management After Haploidentical Hematopoietic Cell Transplantation With Post-Transplantation Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis.

Cytokine release syndrome (CRS) is a common complication after haploidentical hematopoietic cell transplantation (HaploHCT). Severe CRS after haploHCT leads to higher risk of non-relapse mortality (NRM) and worse overall survival (OS). Tocilizumab (TOCI) is an interleukin-6 receptor inhibitor and is commonly used as first-line for CRS management after chimeric antigen receptor T cell therapy, but the impact of TOCI administration for CRS management on Haplo HCT outcomes is not known. In this single center retrospective analysis, we compared HCT outcomes in patients treated with or without TOCI for CRS management after HaploHCT with post-transplantation cyclophosphamide- (PTCy-) based graft-versus-host disease (GvHD) prophylaxis. Of the 115 patients eligible patients who underwent HaploHCT at City of Hope between 2019 to 2021 and developed CRS, we identified 11 patients who received tocilizumab for CRS management (TOCI). These patients were matched with 21 patients who developed CRS but did not receive tocilizumab (NO-TOCI) based on age at the time of HCT (≤64 years or >65 years or older), conditioning intensity (myeloablative versus reduced-intensity/nonmyeloablative), and CRS grading (1, 2, versus 3-4). Instead of 22 controls, we chose 21 patients because there was only 1 control matched with 1 TOCI treatment patient in 1 stratum. With only 11 patients in receiving tocilizumab for CRS treatment, matching with 21 patients who developed CRS but did not receive tocilizumab, we had 80% power to detect big differences (hazard ratio [HR] = 3.4 or higher) in transplantation outcomes using a 2-sided 0.05 test. The power would be reduced to about 20% to 30% if the difference was moderate (HR = 2.0) using the same test. No CRS-related deaths were recorded in either group. Median time to neutrophil engraftment was 21 days (range 16-43) in TOCI and 18 days (range 14-23) in NO-TOCI group (HR = 0.55; 95% confidence interval [CI] = 0.28-1.06, P = .08). Median time to platelet engraftment was 34 days (range 20-81) in TOCI and 28 days (range 12-94) in NO-TOCI group (HR = 0.56; 95% CI = 0.25-1.22, P = .19). Cumulative incidences of day 100 acute GvHD grades II-IV (P = .97) and grades III-IV (P = .47) were similar between the 2 groups. However, cumulative incidence of chronic GvHD at 1 year was significantly higher in patients receiving TOCI (64% versus 24%; P = .05). Rates of NRM (P = .66), relapse (P = .83), disease-free survival (P = .86), and overall survival (P = .73) were similar at 1 year after HCT between the 2 groups. Tocilizumab administration for CRS management after HaploHCT appears to be safe with no short-term adverse effect and no effect on relapse rate. However, the significantly higher cumulative incidence of chronic GvHD, negates the high efficacy of PTCy on GvHD prophylaxis in this patient population. Therefore using tocilizumab for CRS management in the HaploHCT population with PTCy maybe kept only for patients with severe CRS. The impact on such approach on long term outcome in HaploHCT with PTCy will need to be evaluated in a larger retrospective study or a prospective manner.

Allogeneic transplant following CAR T-cell therapy for large B-cell lymphoma.

Allogeneic hematopoietic cell transplantation (alloHCT) can potentially salvage large B-cell lymphoma (LBCL) patients experiencing treatment failure after chimeric antigen receptor T-cell therapy (CAR T). Nonetheless, data on the efficacy and toxicities of alloHCT after receipt of CAR T are limited. We report a multicenter retrospective study assessing the safety, toxicities, and outcomes of alloHCT in LBCL patients following CAR T failure. Eighty-eight patients with relapsed, refractory LBCL received an alloHCT following anti-CD19 CAR T failure. The median number of lines of therapy between CAR T infusion and alloHCT was one (range, 0-7). Low intensity conditioning was used in 77% (n=68) and peripheral blood was the most common graft source (86%, n=76). The most common donor types were matched unrelated donor (39%), followed by haploidentical (30%) and matched related donor (26%). Median follow-up of survivors was 15 months (range, 1-72). One-year overall survival, progression-free survival, and graft-versus-host disease-free relapse-free survival were 59%, 45%, and 39% respectively. One-year non-relapse mortality and progression/relapse were 22% and 33% respectively. On multivariate analysis, <2 lines of intervening therapy between CAR T and alloHCT and complete response at time of alloHCT were associated with better outcomes. In conclusion, alloHCT after CAR T failure can provide durable remissions in a subset of patients.

A Case of Metastatic Gastric Leiomyosarcoma With Bilateral Adrenal Involvement and Complications.

Gastric leiomyosarcoma is a rare entity with only a handful of cases reported in the literature. Although this entity has been known to metastasize, there are currently no reported cases of metastatic leiomyosarcoma to the bilateral adrenal glands. We report a case of a 58-year-old woman with primary gastric leiomyosarcoma with bilateral metastasis to the adrenal gland. This case illustrates a presentation of gastric leiomyosarcoma with bilateral adrenal involvement, the challenges in its diagnosis, treatment, as well as a rare complication of primary adrenal insufficiency and adrenal crisis.

Autologous Stem Cell Transplantation in Hodgkin Lymphoma-Latest Advances in the Era of Novel Therapies.

Standard treatment for relapsed and/or refractory (r/r) Hodgkin lymphoma (HL) consists of salvage therapy, historically consisting of multiagent cytotoxic chemotherapy, followed by autologous stem cell transplantation (autoHCT) in responding patients. With this approach, most patients can proceed to autoHCT, of whom approximately half are cured. However, the introduction of the novel agents brentuximab vedotin (BV) and the checkpoint inhibitors (CPI) nivolumab and pembrolizumab has changed the decision making and peri-transplant decision making, as early incorporation of one or more of these agents can reduce or even eliminate the need for cytotoxic chemotherapy prior to autoHCT. Furthermore, post-autoHCT maintenance therapy with BV has also been shown to decrease relapse in high-risk rel/ref HL patients. In this review, we survey the current data regarding autoHCT in HL with a focus on pre-autoHCT salvage as well as maintenance strategies, and we also talk about the emerging data challenging the long-held dogma of chemosensitivity being a requirement for successful autoHCT.

Polatuzumab Vedotin for Relapsed/Refractory Aggressive B-cell Lymphoma: A Multicenter Post-marketing Analysis.

INTRODUCTION: Polatuzumab vedotin is approved therapy in the United States for relapsed/refractory diffuse large B-cell lymphoma in combination with bendamustine and rituximab (Pola+BR). However, the safety and efficacy of Pola+BR outside of a clinical trial setting is unknown. PATIENTS AND METHODS: We analyzed use of pola-based therapy at 5 centers in the United States, including dose, response rates, progression-free survival (PFS), survival, and toxicity. RESULTS: Sixty-nine patients with aggressive B-cell lymphoma, including 66 with diffuse large B-cell lymphoma/high-grade B-cell lymphoma and 84% refractory to prior therapy, were treated. Responses occurred in of 50%, including 24% complete response. Median duration of response was 5.1 months, PFS was 2.0 months, and survival was 5.3 months, at 4 months median follow-up. Inferior PFS was associated with prior refractory disease (median, 57 days vs. not reached; P = .003) and lack of response to Pola+BR (PFS, 27 days vs. 152 days; P < .001). Discontinuation owing to planned cellular therapy was seen in 36% and owing to toxicity occurred in 12%; unplanned hospitalizations occurred in 36%. CONCLUSIONS: We conclude that commercial Pola is applied to highly refractory lymphomas at our centers, often with intent to bridge to subsequent therapy. Although some clinical benefit was observed, efficacy was inferior to clinical trial data, especially among those with refractory disease.

Acute autoimmune myocarditis and hepatitis due to ipilimumab monotherapy for malignant melanoma.

An important agent in melanoma therapy, ipilimumab is associated with autoimmune toxicity. Two cases of autoimmune pericarditis and large pericardial effusion have been documented with its use. Reports of myocardial toxicity have surfaced with this agent, mainly when used in combination with PD1 blockade. We present herein a case of autoimmune myocarditis leading to biventricular failure after four doses of IV ipilimumab 3 mg/kg as a single agent. Furthermore, this toxic effect may be anticipated with PD1 inhibitors. Increased clinical suspicion, prompt diagnosis, and steroid therapy are crucial to ensure a favorable clinical outcome.

Systemic therapy for relapsed/refractory meningioma: Is there potential for antiangiogenic agents?

Effective therapies for relapsed/refractory meningioma after surgery and radiation therapy represent an unmet need. Most meningiomas are highly vascularized tumors and, therefore, potentially amenable to antiangiogenic therapy. Herein, we review comprehensively the scientific literature on systemic therapy options for relapsed, persistent or metastatic meningioma, not amenable to local therapy. Also, this review offers insights into the function of vascular endothelial growth factor/receptor pathway both in health and disease. Further, we address the current status of the preclinical and clinical studies targeting vascular endothelial growth factor/receptor signaling in meningioma. Most relevant publications were identified through searching the PubMed/Medline database for articles published from inception to 1 February 2018. Vascular endothelial growth factor pathway activation might represent the primary driver of angiogenesis in meningioma. Positive findings of two prospective phase II trials, supported by the results of several retrospective cohorts, suggest a clinical benefit for the vascular endothelial growth factor inhibitor bevacizumab in refractory meningioma. Bevacizumab causes both peritumoral brain edema reduction and true meningioma shrinkage. Patients with WHO grades II-III meningioma appear to benefit more than patients with grade I disease. Similarly, responses have been documented with certain oral targeted anti-vascular endothelial growth factor/receptor agents. Further exploration of the role of vascular endothelial growth factor/receptor inhibitors in refractory meningioma seems warranted.

Paraneoplastic Erythema Nodosum as a Prelude to Hodgkin Lymphoma.

Erythema nodosum is currently thought to represent a delayed hypersensitivity reac- tion to deposition of circulating immune complexes, followed by neutrophilic infiltration of the septa in the subcutaneous tissue. We describe a patient with advanced Hodgkin lymphoma with B symptoms, preceded by erythema nodosum of the left shin by 12 weeks. This dermatologic entity cleared after the treatment for Hodgkin lymphoma, suggesting a true paraneoplastic reaction. Given its known temporal association with Hodgkin lymphoma, we believe that this link deserves more exploration in both re- search laboratories and clinical practice.

SLIT/ROBO1 signaling suppresses mammary branching morphogenesis by limiting basal cell number.

In the field of breast biology, there is a growing appreciation for the "gatekeeping function" of basal cells during development and disease processes yet mechanisms regulating the generation of these cells are poorly understood. Here, we report that the proliferation of basal cells is controlled by SLIT/ROBO1 signaling and that production of these cells regulates outgrowth of mammary branches. We identify the negative regulator TGF-ß1 upstream of Robo1 and show that it induces Robo1 expression specifically in the basal layer, functioning together with SLIT2 to restrict branch formation. Loss of SLIT/ROBO1 signaling in this layer alone results in precocious branching due to a surplus of basal cells. SLIT2 limits basal cell proliferation by inhibiting canonical WNT signaling, increasing the cytoplasmic and membrane pools of ß-catenin at the expense of its nuclear pool. Together, our studies provide mechanistic insight into how specification of basal cell number influences branching morphogenesis.