Introduction: Anti-CD38 monoclonal antibodies have led to improved response rates, progression-free and overall survival in randomized clinical trials (RCTs) of multiple myeloma (MM) patients. However, CD38 is expressed on both malignant and normal plasma cells, so anti-CD38 therapy can lead to hypogammaglobulinemia (HGG). Already present at baseline in many MM patients, HGG can increase the risk of infections. In RCTs, daratumumab containing arms have been associated with an increased risk of infections, particularly in the respiratory tract. To date, there have been no studies on interventions to reduce this risk. In this retrospective case-crossover study of patients receiving daratumumab, we compared the rates of infection while on and off intravenous immunoglobulin (IVIG) replacement therapy. Methods: We retrospectively identified consecutive MM patients who received at least 3 doses of IVIG while receiving daratumumab. Patients served as their own controls and time periods were divided between 'ON IVIG', defined as within 30 days of last IVIG administration, and observation periods ('OFF IVIG'). The evaluation period for each patient began at the time of first daratumumab dose and ended 6 months after the last dose to account for lasting effects. HGG was defined as IgG< 700 mg/dL for non-IgG MM, and [IgG - M-spike mg/dL] < 700 mg/dL qfor IgG MM to account for the nonfunctional, monoclonal IgG. Infections were identified by new antimicrobial prescriptions and microbiological data. Baseline characteristics, infections during daratumumab treatment along with concurrent MM treatments and labs were collected. The primary outcome was annualized rate of infection ON IVIG vs OFF IVIG, with a secondary outcome comparing rates of grade 3-5 infections (per Common Terminology Criteria for Adverse Events v5.0). Generalized Estimating Equations with a log link function and Poisson distribution were used to compute incidence rate ratios (IRR) and the corresponding 95% confidence intervals to compare infection rates between ON and OFF IVIG periods. Results: 43 patients met the inclusion criteria. Baseline characteristics are listed in Table 1. Median age was 66 years (range, 37-85) and 44% were female. 37%/21% had light chain only/IgA MM, 46% had high-risk cytogenetics, and patients had a median of 2 prior lines of therapy (range, 0-9), with broad prior exposures to common MM agents. 56% had prior autologous stem cell transplant at a median of 35 months (range, 3-153) prior to daratumumab therapy. The median number of infections in the 12 months preceding daratumumab was 2 (range, 0-6). The median functional IgG at the start of daratumumab was 566 mg/dL (range, 115-1108 mg/dL). Patients were on daratumumab for a median of 21.1 months (range, 3-61 months) and on the present study period of interest for a median of 27.1 months (range, 9-62.6). The median proportion of time ON IVIG was 35% (range, 8-93%). 98% of patients had HGG at any point during the study and the median functional IgG prior to start of IVIG was 363 mg/dL (range, 200-1104 mg/dL). There were a total of 176 infections during the evaluation period, most commonly in the upper respiratory tract (53%) and lower respiratory tract (35%). There were no deaths due to infections. The median time to first infection on daratumumab was 2.5 months (range, 0.1-18.7); at which time the median absolute neutrophil and lymphocyte counts were 2.8 and 0.9 x103/uL respectively. The annualized rate of infections ON IVIG was 1.21, compared with 1.96 OFF IVIG (IRR 0.61 [0.45-0.83], p=0.0015) [Figure 1]. There were a total of 54 grade 3-4 infections, with an annual rate of 0.20 ON IVIG vs 0.71 OFF IVIG (IRR 0.28 [0.15-0.55], p=0.0002). Discussion: Use of IVIG during daratumumab treatment for MM was associated with a 39% reduction in all infections and a 72% reduction in serious (grade 3-4) infections. Despite the small cohort, the results are highly statistically significant. While the case-crossover design allows each patient to serve as an internal control, this study is limited by its retrospective nature, and IVIG was initiated at the discretion of the treating physicians. While additional retrospective or, preferably, prospective studies are needed to confirm these findings, IVIG may have the potential to significantly reduce the risk of infections during treatment with daratumumab. Disclosures Jagannath: BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Madduri:Janssen: Consultancy; BMS: Consultancy; Takeda: Consultancy; Legend: Consultancy; Sanofi: Consultancy; GSK: Consultancy; Foundation Medicine: Consultancy; Kinevant: Consultancy. Parekh:Karyopharm: Research Funding; Celgene: Research Funding; Foundation Medicine: Consultancy. Richter:Adaptive biotechnologies: Consultancy; Secura bio: Consultancy; Astra Zeneca: Consultancy; Celgene: Consultancy, Speakers Bureau; Oncopeptides: Consultancy; X4 pharmaceuticals: Consultancy; Sanofi: Consultancy; Janssen: Consultancy, Speakers Bureau; Karyopharm: Consultancy; Antengene: Consultancy; BMS: Consultancy. Chari:Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy; Karyopharm: Consultancy; Sanofi Genzyme: Consultancy; Seattle Genetics: Consultancy, Research Funding; Oncopeptides: Consultancy; Takeda: Consultancy, Research Funding; Secura Bio: Consultancy; Novartis: Honoraria; Array BioPharma: Honoraria; The Binding Site: Honoraria; Glaxo Smith Kline: Consultancy; Antengene: Consultancy; Adaptive Biotechnology: Honoraria; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.
Table 1. (continued) Appropriateness of Order Median time to colonoscopy, days (IQR) 53 (27-95) Adequate bowel preparation (%) 47 (84) Documentation of cecal intubation (%) 55 (98) Documentation of appendiceal orifice and IC valve visualization (%) 48 (94) Documentation of right colon retroflexion (%) 44 (83) Advanced adenoma found on colonoscopy (%) 16 (29) Other adenoma or sessile polyp found on colonoscopy (%) 19 (34) Negative (%) 409 (85) Documentation of a 3-year follow-up screening recommendation (%) 369 (80) S297
Introduction: Lower gastrointestinal (GI) bleeding is a common occurrence, with the vast majority of cases being due to diverticula, vascular ectasias, cancers, and hemorrhoids. In rare cases, a large vessel can form a fistula with the GI tract, causing bleeding. We present a case where an abscess surrounding a failed transplant kidney eroded into the external iliac vein and presented as a slow lower GI bleed. Case Description/Methods: A 65-year-old man with a failed renal transplant and known colovesicular fistula presented with hypotension. Labs showed a significant leukocytosis, an elevated lactate, and a hemoglobin of 6.3 g/dL. He was started on broad spectrum antibiotics, and then developed intermittent episodes of small-volume bright red blood per rectum. The patient had an upper endoscopy and colonoscopy one month prior for GI bleeding which had not identified a source. Computed tomography angiography of the abdomen and pelvis revealed a fistulous communication between the sigmoid colon and a multiloculated right lower quadrant collection (Figure). The collection encased the transplanted kidney and right iliac vasculature. Extraluminal extravasation of intra-arterial contrast was noted, concerning for either active arterial bleed or pseudoaneurysm. The patient underwent emergent exploratory laparotomy which revealed a necrotic transplant kidney densely adhered to the surrounding colon and a right external iliac artery pseudoaneurysm. Bleeding was noted from a defect in the right external iliac vein. The kidney was removed, the pseudoaneurysm was stented, and the vein defect was oversewn. Unfortunately, the patient had a complicated post operative course and died. Discussion: In patients with evidence of small-volume rectal bleeding but a clinical picture concerning for a more significant bleed, cross-sectional imaging can be necessary to make the appropriate diagnosis. In this case, imaging identified the abscess-enteric fistula, and laparoscopy revealed that the bleeding was due to a defect in the iliac vein. Abscess-enteric fistulas are associated with post-surgical states or small localized perforations. This patient likely developed a microperforation that infected the failed transplant kidney, creating an abscess which eroded into the iliac vein. GI bleeding was only intermittent and a source was not identified on prior luminal imaging, possibly due to the small size of the fistula tract. This pathology is unfortunately not amenable to endoscopic intervention and often requires surgery.[2692] Figure 1. Computed tomography angiography of the abdomen and pelvis with a multiloculated right lower quadrant collection encasing a transplanted kidney and right iliac vasculature.
Figure 1. Image 1: Left: H&E stain of esophageal mass biopsy revealing tumor cells that are small with scant cytoplasm, salt and pepper chromatin, inconspicuous nucleoli, nuclear molding and smudging. Right: CT chest revealing for 4.2 x 3.0 cm distal esophageal mass. There is circumferential wall thickening involving the mid and lower esophagus.
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