CD22-directed chimeric antigen receptor (CAR) T-cell therapy (CAR22) for large B-cell lymphomas (LBCL) progressing after CD19-directed CAR T-cell therapy (CAR19): a dose-finding phase 1 study. 

Highlight(s):  This trial identifies CD22 as an immunotherapeutic target in LBCL and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy.

In this single-center, open-label, dose-escalation phase 1 trial (NCT04088890), CAR22 at two dose levels (1 million and 3 million CAR22-positive T cells per kg of body weight) were administered to adult patients who relapsed after CAR19 or had CD19-negative LBCL. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose.  40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. 11 (29%) had refractory disease to all previous therapies. Patients had received a median of four lines of prior treatment (range 3–8). 37 of 38 patients treated (97%) had relapsed after previous CAR19. The maximum tolerated dose identified was 1 million CAR T-cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome.

Improved prevention and treatment strategies for differentiation syndrome (DS) contribute to reducing early mortality in patients with acute promyelocytic leukemia (APL): a clinical trial.

Highlight(s):  Rapid resolution of symptoms was observed in only 56% of DS patients who received preemptive dexamethasone with continuous all-trans

retinoic acid (ATRA) therapy. The efficacy of ruxolitinib for steroid-refractory DS was 67% when ATRA was maintained. Personalized strategies including steroids and ruxolitinib for managing DS in APL, resulted in a reduction in early death.

This multicenter single-arm APL-01 trial (NCT04446806) enrolled 111 previously untreated patients with APL from 14 centers in China, with a median follow-up of 34 months. All patients received induction treatment with ATRA along with either intravenous arsenic trioxide (ATO) or oral tetra-arsenic tetra-sulfide. The prevention regimen for DS was based on the white blood cell count at presentation and after the initiation of ATRA, which included cytoreductive agents and dexamethasone. The diagnosis and grading criteria for DS were consistent with those of the PETHEMA group.

When DS was suspected, prompt initiation of treatment with intravenous dexamethasone (20 mg/day) was administered. If a favorable response was achieved, dexamethasone could be gradually tapered. However, if the symptoms/signs did not improve within 24 hours or worsened in 8 hours, ruxolitinib (5-20 mg bid) should be initiated promptly, with the dosage determined by the severity of DS, age, weight, general condition, and accompanying comorbidities. Once significant improvement was observed, the doses of dexamethasone and ruxolitinib could be alternately reduced (see Fig 1 of the original article). Once symptoms had completely resolved, ATRA/arsenic could be restarted.

The primary study endpoint was the incidence of DS and severe DS, as well as early death.  Among these patients (111), 33 were classified as high-risk and 78 as low-risk patients. All high-risk patients and 57 out of 78 (73%) low-risk patients received dexamethasone (5-10 mg/day) for DS prophylaxis. Preemptive therapy with dexamethasone (10 mg every 12 hours) was administered to 65 patients (40 low-risk and 25 high-risk) due to suspected DS. Among the total 111 patients, 41 (36.9%) were ultimately diagnosed with DS, with 25 (22.5%) classified as moderate cases and 16 (14.4%) as severe cases. The incidence of DS and severe DS was higher in high-risk patients compared to low-risk patients (48.5% vs. 32.1%, 24.2% vs. 10.3%), but these differences were not statistically significant (p= 0.057, p= 0.056). DS occurred at a median of 8 days after the initiation of ATRA administration, with a range of 2-21 days. The most common features of DS included weight gain (85%), pulmonary opacities (78%), and dyspnea (71%). Additionally, patients with severe DS exhibited a higher prevalence of dyspnea (p= 0.013), pleuropericardial effusion (p= 0.018), and acute renal dysfunction (p= 0.009) compared to moderate cases. 23 out of the 41 patients with DS experienced rapid remission with preemptive treatment. However, the condition of the remaining patients with severe DS (12 patients) and moderate DS (6 patients) worsened. They all received ruxolitinib, with 12 responding well, while the other 6 required non-invasive mechanical ventilation and discontinued ATRA. Five of them recovered within 72 hours, and one patient was successfully weaned from the ventilator 10 days later. After discontinuing ATRA therapy, the remaining patients recovered. The median duration of ruxolitinib treatment was 12.5 days (range 8 to 17).

The overall 30-day mortality rate was 1.8% (2/111), with two high-risk patients succumbing to intracranial hemorrhage. There were no deaths attributed to DS or infection. The overall complete response rate was 98.2%.

Response-Adapted Ultralow-Dose Radiation Therapy (RT) for Orbital Indolent B-Cell Lymphoma (BCL): A Phase 2 Nonrandomized Controlled Trial.

Highlight(s):  RT to doses of 24 to 36 Gy is currently used to treat indolent BCL of the ocular adnexa; however, ocular adverse effects are common. Response-adapted ultralow-dose RT (4 Gy) is an effective approach for indolent orbital BCL, conferring high rates of local control and sparing most patients from standard radiation doses.

This single-institution, phase 2 prospective nonrandomized controlled trial (NCT02494700) of a response-adapted strategy involved 50 evaluable patients with stage I to IV indolent BCL of the ocular adnexa. This treatment approach was also retrospectively evaluated with a separate 55-patient cohort. Patients were treated with RT to 4 Gy in 2 fractions and assessed for response at 3-month intervals. Patients with persistent orbital lymphoma were offered an additional 20 Gy in 10 fractions to complete the response-adapted treatment. The primary end point was 2-year local orbital control within the irradiated field after response-adapted RT. Among the 50 patients, 32 (64%) had mucosa-associated lymphoid tissue (MALT) lymphoma, 12 (24%) had follicular lymphoma, and 6 (12%) had unclassifiable low-grade BCL. Thirty-one patients (62%) had stage I disease, and 36 (72%) were newly diagnosed. At a median follow-up of 37.4 (95% confidence interval [CI], 33.7-52.5) months, the 2-year local control rate was 89.4% (95%CI, 81.0%-98.7%); 45 patients (90.0%; 95%CI, 78.2%-96.7%) experienced a complete response (CR) to response-adapted RT, including 44 patients with a CR to ultralow-dose RT and 1 patient with a CR after an additional 20 Gy. No local recurrences were observed among patients with a CR to response-adapted RT. No grade 3 or higher toxic effects were observed. In a planned subset analysis of 22 patients with newly diagnosed, untreated stage I MALT lymphoma, the 2-year local control rate was 90.7%(95%CI, 79.2%-100%), and the 2-year freedom from distant relapse rate was 95.2%(95%CI, 86.6%-100%). Additional follow-up will also permit comprehensive assessment of long-term ocular toxic effects, which is expected to be minimal after 4 Gy but requires confirmation.

An open-label, prospective trial to evaluate the efficacy and safety of ixazomib in combination with cyclophosphamide and dexamethasone (ICD) in patients with newly diagnosed POEMS syndrome.

Highlight(s): The combination of ICD demonstrated both efficacy and safety in newly diagnosed POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes), making it a viable treatment option.

This open-label, prospective trial evaluated the combination of ICD in 12 newly diagnosed POEMS syndrome patients from Shanghai. The treatment protocol consisted of 12 cycles of the ICD regimen compromising ixazomib (4 mg on Days 1, 8 and 15), oral cyclophosphamide (300 mg on Days 1, 8 and 15) and dexamethasone (20 mg weekly). A total of 12 patients received a median of 10 (range: 3–23) cycles of the ICD regimen. The hematological response (based on the

Llight- chain amyloidosis response criteria) could be evaluated in 10 patients. The overall hematological response rate was 80% (8/10), with 30% (3/10) achieving complete hematological response, and the overall serum vascular endothelial growth factor response rate and neurological response were 100% and 83.3%, respectively. The ICD regimen was well tolerated, and no patient discontinued treatment due to treatment-related adverse events. Two patients experienced grade 3/4 adverse events, including diarrhea (n = 1) and leukopenia (n = 1). The median follow-up time was 36 (range: 25–57) months. One patient died at 30 months after being diagnosed with a pulmonary infection. Three patients developed progressive disease, with two of them experiencing disease progression during ICD treatment, and the other one after stopping ICD treatment. The median overall survival was not reached, and the median progression-free survival was 53.2 months.

The origin of ferritin reference intervals: a systematic review.

Highlight(s): The use of evidence-based laboratory clinical decision limits to diagnose iron deficiency. Data driven ferritin reference intervals are at high risk of bias given lack of exclusion of individuals at risk for iron deficiency in the presumed normal sample and lack of adherence to reference interval establishment standards.

A serum ferritin concentration of less than 30 μg/L has a high specificity and sensitivity for diagnosing iron deficiency in adults, but the laboratory reported lower limit of normal (LLN) is typically lower.  A systematic review was done (per systematic reviews and meta-analysis guidelines) to identify studies that determined ferritin reference intervals in healthy adults and a search of gray literature for the five most common ferritin assays. The objectives were to systematically summarize the ferritin reference intervals and to do a methodological quality assessment of the included studies. 37 studies were eligible for analysis of the ferritin LLN in the general population. The population sample comprised a total of 21,882 female and 23,650 male participants. The median ferritin LLN was 8 μg/L (interquartile range [IQR]  5–15) and mean ferritin LLN was 9 μg/L (standard deviation [SD] 11) in females and respective values for males were 25 μg/L (IQR 16–44) and 25 μg/L (SD 29). Thirty of 61 studies (49%) did not explicitly screen for patients at risk of iron deficiency, and 32 (52%) did not refer to a reference interval establishment guideline. The five most used commercial ferritin laboratory assays reported reference intervals with a median LLN of 11 (IQR 9–12) and mean of 9 μg/L (SD 4) for females and median of 22 (IQR 22–24) and mean of 23 μg/L (SD 4) for males. In the literature, serum ferritin reference intervals in healthy adults consistently report a LLN of less than 30 μg/L. These findings provide a compelling argument for the need for equitably designed studies looking to define laboratory reference intervals for conditions that more commonly affect vulnerable populations, such as women.