Received: February 10, 2018
Accepted: March 23, 2018
Mediterr J Hematol Infect Dis 2018, 10(1): e2018029 DOI 10.4084/MJHID.2018.029
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Blinatumomab is an anti-CD19 immunotherapy approved for
relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) with
significantly increased survival rate. While blinatumomab showed lower
rates of infection, neutropenia and mucosal barrier injury versus
chemotherapy, its infection risks are not well described.
Interestingly, in the phase 3 trial, blinatumomab group had numerically lower rates of infection (34.1% v. 52.3%), neutropenia (37.8% v. 57.8%), lymphopenia (1.5% v. 3.7%) and stomatitis (6.7% v. 12.8%) as compared to chemotherapy group.[1,3] However, complications from blinatumomab also included cytokine release syndrome (4.9% v. 0%), which mimics infection by mediating the production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T-cells, then ultimately lysis of CD19-positive cells. Furthermore, numerically higher rates of hypogammaglobulinemia (6.0% v. 0.9%), upper respiratory tract infection (7.1% v. 0.9%) and serious pneumonia (3.7% v. 1.8%) were observed with blinatumomab, which rose concerns for its infectious risks and complications. Of note, the phase 3 trial required antifungal prophylaxis primarily using posaconazole for the patients who previously underwent allogeneic hematopoietic stem-cell transplantation (HSCT) and presented with a medical history of graft-versus-host disease (GVHD), but the protocol does not discuss antibacterial prophylaxis. In the phase 2 trial, institutional guidelines for infections were followed when patients became neutropenic, but no details about antimicrobial prophylaxis were provided.
Currently, antiviral prophylaxis with acyclovir and anti-Pneumocystis jiroveci pneumonia prophylaxis with sulfamethoxazole-trimethoprim are recommended as per National Comprehensive Cancer Network (NCCN) guidelines for patients with active ALL. However, guidelines for anti-bacterial and anti-fungal prophylaxis are not well established in patients receiving blinatumomab. In this retrospective review, we intended to describe infectious risks and complications in these patients to assist in the supportive care from an Infectious Diseases standpoint including determination of appropriate antimicrobial prophylaxis regimen.
Patients and Methods
The study was approved by the Institutional Review Board of University of South Florida. For this type of study formal consent is not required; an informed consent waiver was granted as all data were currently in existence and no patient-specific interventions were conducted for the study. The collection of data was in compliance with the Health Insurance Portability and Accountability Act of 1996.
Patient Characteristics and Infectious Risks. Once patients were identified, the following characteristics were extracted from the medical records: age; gender; treatment phase (refractory to primary or salvage therapy, first relapse with remission <12 months, first relapse with remission >12 months, untreated second or greater relapse, relapse after HSCT or treatment with chimeric antigen receptor modified T-cells (CART), remission, or unspecified); prior chemotherapy regimens; other immunosuppressive comorbid conditions or treatment; recent infections within 7 days prior to initiation of blinatumomab; recent use of intravenous antimicrobials within 90 days prior to initiation of blinatumomab; days between prior cytotoxic chemotherapy and blinatumomab; total number of blinatumomab cycles and reasons for interrupted blinatumomab treatment if any; baseline absolute neutrophils (ANC) and lymphocyte (ALC) count; incidence, severity and duration of neutropenia and lymphopenia and whether there was a growth factor support or not.
Infectious Complications. Microbiological culture-proven infections and clinically diagnosed infections by imaging and physical exams were recorded. Nodular pneumonia defined as an opaque macronodule of ≥ 1cm in diameter, which is by far the most common CT finding in invasive aspergillosis and present in > 90% of patients, is assessed at baseline and every two weeks during the duration of neutropenia using CT thorax without contrast. Mortalities at 30 and 60 days after the end of the first cycle of blinatumomab were assessed.
Statistical Analysis. For bacteremia and nodular pneumonia suspicious for mold infection, the following characteristics were compared between the case and control groups using Mann-Whitney U test for the ordinal or non-normally distributed continuous variables and chi-square test for nominal variables: immunosuppressing conditions or treatments, cytotoxic chemotherapy prior to blinatumomab within 21 days, baseline neutrophil and lymphocyte counts, and incidence, severity and duration of neutropenia and lymphopenia. Multinomial logistic regression tests were performed after univariate analyses to evaluate risk factors associated with nodular pneumonia and bacteremia. A two-tailed P value of <0.05 was considered to be statistically significant. All data were analyzed using SPSS (IBM Corp. Released 2016. IBM SPSS Statistics for Windows, Version 24.0., Armonk, NY, USA).
|Table 1. Patient Characteristics.|
Infectious Complications. While six patients did not experience infections, 14 patients had a total of 26 infections, of which lower respiratory (n=9), gastrointestinal (n=6) and bacteremia (n=5) were most common during or 30 days after the blinatumomab treatment. Four patients had nodular, possible invasive mold pneumonia, three of which were newly developed on blinatumomab with normal baseline CT thorax. None of the four patients had met direct (i.e., cytology, direct microscopy, or culture-proven) nor indirect [i.e., Aspergillus galactomannan antigen (GM) or β-D-glucan test (BDG)] microbiological criteria for proven or probable invasive fungal infection,  but had host factors and radiologic evidence of invasive mold pneumonia (i.e. nodular consolidation with halo signs). One patient who already had possible mold pneumonia prior to blinatumomab received isavuconazole throughout blinatumomab treatment. Two patients were on micafungin and the last patient was on voriconazole followed by posaconazole as antifungal prophylaxis before the CT findings of possible mold pneumonia. Compared to patients without nodular, possible mold pneumonia, patients with nodular pneumonia had significantly lower ANC on the first day of blinatumomab (2319 v. 208/µL, p=0.011). In multinomial logistic regression, ANC on the first day of blinatumomab remained significantly associated with nodular pneumonia (p= 0.020) when controlled for other immunosuppressing conditions and cytotoxic chemotherapy within 21 days prior to blinatumomab.
There were 5 episodes of bacteremia from 4 patients, two of which were polymicrobial (Table 2). Three of the 4 patients received cytotoxic chemotherapy within 21 days of blinatumomab, and the timelines between the onset of bacteremia and cytotoxic chemotherapy are listed in the footnote (Table 2). One patient was discharged with no antibacterial prophylaxis since ANC recovered to >500 cells/µL, but developed Pseudomonal bacteremia on day 35 of blinatumomab with ANC~ 100 cells/µL. One patient expired within 30 days due to progressive leukemia.
|Table 2. Infectious complications.|
When factors associated for nodular, possible mold pneumonia were examined, baseline ANC and days to become severely neutropenic (ANC < 100 cells/µL) were significantly correlated to nodular pneumonia (Table 3), but the duration of lymphopenia nor the severity of lymphopenia were not related (data not shown). The similar analysis for bacteremia found no significantly associated factors.
|Table 3. Factors associated with nodular, possible mold pneumonia and bacteremia.|
Two patients were sent to hospice care by 30 days post blinatumomab with progressive disease, one of whom also had nodular, possible mold pneumonia and bacteremia. There were two other patients who expired in the 30 to 60-day range, one of whom experienced multiple infectious complications (i.e., pansinusitis, possible mold pneumonia, P. aeruginosa bacteremia and C. difficile colitis). Additional two patients were sent to hospice care by 60 days post blinatumomab with progressive disease.
On the other hand, the incidence of bacteremia was not significantly associated with the baseline ANC. Since chemotherapy-induced mucositis is associated with early onset of bacteremia and blinatumomab causes less stomatitis than conventional chemotherapy (6.7% v. 12.8%), we investigated the timing between the onset of bacteremia and other cytotoxic chemotherapy given pre and post blinatumomab (Table 2). While hydroxyurea is not considered conventional chemotherapy, it could cause severe mucositis, thus was counted as cytotoxic chemotherapy. Although 3 of the 4 bacteremic patients received cytotoxic chemotherapy prior to initiation of blinatumomab within 21 days, 2 of those 3 patients had bacteremia on day 35 of blinatumomab, which makes it less likely that the episodes of bacteremia were related to the cytotoxic chemotherapy that was received prior to blinatumomab. Furthermore, one of these two patients who had bacteremia on day 35 of blinatumomab, also received VXLD (dexamethasone, doxorubicin, vincristine, bortezomib and peg-asparaginase) on day 18 of blinatumomab, which is known to induce mucositis and bacterial translocation from the gut. Nonetheless, compared to non-bacteremic patients, numerically higher number of patients with bacteremia received cytotoxic chemotherapy ≤21 days of blinatumomab (Table 3). Other than mucositis, chemotherapy dose gram/m2, severe neutropenia of ANC <100 cell/µL, or previous use of antibacterial prophylaxis for neutropenia have been identified as risks for bacteremia. Understandably, one of our patients had hemorrhoids and developed two episodes of polymicrobial bacteremia. Another patient developed pseudomonal bacteremia when ANC dropped to around 100 cells/µL after being discharged post count recovery, i.e. ANC>500 cell/µL, without antibacterial prophylaxis. Fluctuation in ANC is not uncommon in relapsed or refractory disease, and ANC should be monitored closely during both inpatient and outpatient stays as neutropenia can unexpectedly develop after blinatumomab which may be compounded by the underlying disease and recent chemotherapy effects. While we did not identify specific risk factors associated with breakthrough bacteremia, we propose antibacterial prophylaxis to be individualized based on the degree of neutropenia, other recent cytotoxic chemotherapy, mucositis, previous bacterial infections and other risk factors such as hemorrhoids. For example, antibacterial prophylaxis may be initiated when ANC <100 cell/µL for most patients receiving blinatumomab treatment, but the ANC cut-off may be changed to <500 cell/µL if other risk factors coexist.
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