A multicenter study of venetoclax-based treatment for patients with Richter transformation of chronic lymphocytic leukemia.

ABSTRACT: Patients with chronic lymphocytic leukemia (CLL) who develop Richter transformation (RT) have a poor prognosis when treated with chemoimmunotherapy regimens used for de novo diffuse large B-cell lymphoma. Venetoclax, a BCL2 inhibitor, has single-agent efficacy in patients with RT and is potentially synergistic with chemoimmunotherapy. In this multicenter, retrospective study, we evaluated 62 patients with RT who received venetoclax-based treatment outside of a clinical trial, in combination with a Bruton tyrosine kinase inhibitor (BTKi; n=28), rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=13), or intensive chemoimmunotherapy other than R-CHOP (n=21). The best overall and complete response rates were 36%/25%, 54%/46%, and 52%/38%, respectively. The median progression-free and overall survival estimates for the same treatment groups were 4.9/14.3 months, 14.9 months/not reached, and 3.3/9 months, respectively. CLL with del(17p) was associated with a lower complete response rate in the total cohort (odds ratio [OR] 0.15; 95% confidence interval [CI] 0.04-0.6; p=0.01) and venetoclax-naïve subgroup (OR 0.13; 95%CI 0.02-0.66; p=0.01). TP53 mutated CLL was associated with a lower complete response rate (OR 0.15; 95%CI 0.03-0.74; p=0.02) and shorter progression-free survival (hazard ratio 3.1; 95%CI 1.21-7.95; p=0.02) only in venetoclax-naïve subgroup. No other clinical or baseline characteristics, including prior venetoclax treatment for CLL, showed statistically significant association with outcomes. Grade 3-4 neutropenia and thrombocytopenia events were most frequent with intensive chemoimmunotherapy + venetoclax; grade 3-4 infection rates were similar across treatment groups. In this difficult-to-treat RT patient population, venetoclax-based combination regimens achieved high response rates, with durable remission and survival observed in a subset of patients.

Refining prognosis in chronic lymphocytic leukemia with normal Fluorescence in situ hybridization results.

Fluorescence in situ hybridization (FISH) to detect the recurrent cytogenetics abnormalities deletion 13q, trisomy 12, deletion 11q, and deletion 17p is important for prognostication in chronic lymphocytic leukemia (CLL). A subset of patients are negative for each of these abnormalities (normal 12/13/11/17 FISH), and outcomes are heterogenous within this group. To elucidate variables important for prognostication in this subgroup we conducted a retrospective analysis of 280 treatment-naïve CLL patients with normal standard CLL FISH results. In a multivariable model, advanced Rai stage (p = 0.04, hazard ratio [HR] 1.24 (95% confidence interval [CI] 1.01-1.53)), unmutated immunoglobulin heavy chain gene (IGHV) (p < 0.0001, HR 5.59 (95% CI 3.63-8.62)) and IGH rearrangement by FISH (p = 0.02, HR 2.56 (95% CI 1.20-5.48)) were significantly associated with shorter time to first treatment. In a multivariable model for overall survival, increasing age at 5-year increments (p < 0.0001, HR 1.55 (95% CI 1.25-1.93)), unmutated IGHV (p = 0.01, HR 5.28 (95% CI 1.52-18.35)) and gain of REL (p = 0.01, HR 4.08 (5% CI 1.45-11.49)) were significantly associated with shorter survival. Our study identifies variables important for refining prognosis for CLL patients with normal standard CLL FISH results.

Clinical prediction of bacteremia and early antibiotics therapy in patients with solid tumors.

OBJECTIVE: To investigate the relationship between the systemic inflammatory response syndrome (SIRS), early antibiotic use, and bacteremia in solid-tumor patients. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective observational study of adults with solid tumors admitted to a tertiary-care hospital through the emergency department over a 2-year period. Patients with neutropenic fever, organ transplant, trauma, or cardiopulmonary arrest were excluded. METHODS: Rates of SIRS, bacteremia, and early antibiotics (initiation within 8 hours of presentation) were compared using the χ2 and Student t tests. Binomial regression and receiver operator curves were analyzed to assess predictors of bacteremia and early antibiotics. RESULTS: Early antibiotics were administered in 507 (37%) of 1,344 SIRS-positive cases and 492 (22%) of 2,236 SIRS-negative cases (P < .0001). Of SIRS-positive cases, 70% had blood cultures drawn within 48 hours and 19% were positive; among SIRS negative cases, 35% had cultures and 13% were positive (19% vs 13%; P = .003). Bacteremic cases were more often SIRS positive than nonbacteremic cases (60% vs 50%; P =.003), but they received early antibiotics at similar rates (50% vs 49%, P = .72). Three SIRS components predicted early antibiotics: temperature (OR, 1.7; 95% CI, 1.31-2.29; P = .0001), tachycardia (OR, 1.4; 95% CI, 1.10-1.69; P < .0001), and white blood-cell count (OR, 1.8; 95% CI, 1.56-2.14; P < .0001). Only temperature (OR, 1.6; 95% CI, 1.09-2.41; P = .01) and tachycardia (OR, 1.5; 95% CI, 1.09-2.06; P = .01) predicted bacteremia. SIRS criteria as a composite were poorly predictive of bacteremia (AUC, 0.57). CONCLUSIONS: SIRS criteria are frequently used to determine the need for early antibiotics, but they are poor predictors of bacteremia in solid-tumor patients. More reliable models are needed to guide judicious use of antibiotics in this population.

Barely benign: The dangers of BB and other nonpowder guns.

OBJECTIVE: To characterize the risks of nonpowder guns commonly used by children for recreation. METHODS: We conducted a retrospective review of children ≤18 years of age treated for nonpowder gun injuries at a pediatric level I trauma center during 2013-2017. Demographics, injury characteristics, treatments, and outcomes were reviewed and analyzed using descriptive statistics. RESULTS: Forty-six cases were identified; of these, 78% were male and the median age was 10 years (IQR 7-13). All guns were either ball-bearing or pellet guns. Eighty-five percent (38/46) of injuries were penetrating. The most common location was the head and neck (28%), followed by the anterior torso (26%) and eye (24%). Significant injuries that penetrated organs or body cavities occurred in 39% (18/46) and included subarachnoid hemorrhage; lung, liver, and kidney lacerations; pulmonary artery injury; and tracheal injury. Nine percent (4/26) were admitted to the intensive care unit, 37% (17/46) underwent surgery, and there were no deaths. DISCUSSION: Injuries from recreational nonpowder guns such as ball-bearing or pellet guns can cause severe injuries in children. A thorough penetrating trauma workup should always be undertaken. Safety precautions should be taken when using these guns and access to young children should be restricted. LEVEL OF EVIDENCE: Prognosis level IV.

The significance of abdominal radiographs with paucity of gas in pediatric adhesive small bowel obstruction.

PURPOSE: Management of children with adhesive small bowel obstruction (ASBO) is often based on abdominal radiographs (AXR). Our purpose was to determine the significance of paucity of gas on initial AXR. METHODS: Retrospective, single center review of children with ASBO between 2011 and 2015. Analysis included chi-square, non-parametric tests and multivariate regression. RESULTS: Of 207 cases, 99 were operative. Initial AXR showed paucity of gas in 41% and gaseous loops in 59%. Paucity was more common in operative patients (49% vs. 32%, p = 0.01). At operation, 71% of patients with paucity had closed loop or high-grade obstruction, compared to 29% of patients with gaseous loops (p = <0.001). CONCLUSION: For children with ASBO with paucity of gas on AXR, complicated obstruction (closed loop or high-grade) should be considered. In children with high clinical suspicion of complicated obstruction, additional imaging with CT or SBFT may clarify the clinical picture.

Management of Pediatric Adhesive Small Bowel Obstruction: Do Timing of Surgery and Age Matter?

BACKGROUND: Adhesive small bowel obstruction (ASBO) in children is generally managed with initial observation. However, no clear guidelines exist regarding indications to operate. Our purpose was to compare outcomes of ASBO management to determine whether timing of surgery and patient age should affect management. MATERIALS AND METHODS: A retrospective review of children admitted to a tertiary care children's hospital for ASBO between 2011 and 2015 was performed. Data included demographics, imaging, operative findings, and clinical management, which were analyzed using χ2 test, Fischer's exact test, t-test, analysis of variance, or logistic regression when appropriate. RESULTS: We identified 258 admissions for 202 patients. Urgent operation was performed in 12% and the rest had nonoperative management (NOM), which was successful in 54%. Patients younger than 1 y of age were more likely to require operation (odds ratio 3.71, 95% confidence interval [CI] 1.69-8.15; P < 0.01), and patients with prior ASBO were less likely to require operation (odds ratio 0.51, 95% CI 0.31-0.84; P < 0.01). At presentation, fever was most common in patients who had urgent operation (22.3% versus failure of NOM 7.6% versus successful NOM 6.6%; P = 0.02), but there were no differences in leukocytosis or abdominal pain. Excluding urgent operations, bowel resection was more common when operation was delayed more than 48 h (32.6% versus 15.3%; P = 0.04). CONCLUSIONS: In children with adhesive small bowel obstruction, NOM can be successful, but when failure is suspected, early operation before 48 h should be considered to avoid bowel loss, especially in children younger than 1 y of age.