A Proposal for Institutional Antimicrobial Prophylaxis

Guidelines for Patients with Hematologic Malignancies

Joel Brothers, MD Hematology/Oncology Fellow

Olive View-UCLA Medical Center January 2018

Updated May 2019

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1. Introduction

Patients undergoing treatment for hematologic malignancies are at risk for life-threatening infectious complications due to a combination of predisposing factors. Patients may have deficient humoral and cellular immunity as a consequence of their underlying malignancy. Often, patients will undergo treatment with immunosuppressive therapies which can lead to prolonged cytopenias. Chemotherapy can cause direct mucosal injury, disrupting the first-line of defense against a variety of pathogens. High doses of corticosteroids are frequently a part of treatment regimens for hematologic malignancies and have profound immunosuppressive effects. Lastly, treatments that weaken humoral immunity (i.e. rituximab) can lead to reactivation of latent infections such as hepatitis B or tuberculosis.

Given the significant risk of infection in patients with hematologic malignancies, a proactive approach aimed at preventing infectious complications is warranted. National guidelines are available through the National Comprehensive Cancer Network (NCCN) and the Infectious Disease Society of America (IDSA) which provide guidance on prevention and management of the most common type of infections (1) (2). However, despite the availability of these guidelines, there is significant variability in clinical practice. Furthermore, these guidelines do not take into account institution-specific factors such as epidemiologic data, resistance patterns, and costs of medications. Other large institutions have developed institution specific guidelines which take such factors into account (3); these guidelines are easy to access, interpret, and use. Due to the wide variability of clinical practice among practicing hematology physicians and trainees at our institution, we have developed standardized a set of guidelines regarding antimicrobial prophylaxis in patients with hematologic malignancies. Enclosed is a summary of the available data and the rationale for our recommendations in preventing the following types of infections: fungal infections, herpes viruses, pneumocystis jirovecii, hepatitis B, and latent tuberculosis. Antimicrobial prophylaxis for patients undergoing hematopoietic stem cell transplant or alemtuzumab is not addressed in these guidelines.

2. Bacterial infections:

Recommendations:

A. Routine use of bacterial prophylaxis is not recommended.

Rationale:

Bacterial infections are common in patients with prolonged neutropenia, and a large body of research is available regarding antibiotic prophylaxis against bacterial infections in cancer patients with neutropenia. Despite the abundance of data, it is difficult to make definitive recommendations regarding the utility of antibacterial prophylaxis.

Several meta-analyses suggest a benefit with the use of antimicrobial prophylaxis. A 1998 meta-analysis included 18 randomized trials with over 1,400 patients comparing quinolone prophylaxis to either placebo or trimethoprim/sulfamethoxazole (TMP/SMX) prophylaxis in cancer patients with neutropenia (4). Quinolone prophylaxis resulted in a 79% relative reduction in gram-negative bacterial infections and a 15% reduction in fevers, but it did not alter the incidence of clinically documented infections or infection-related death. A 2005 meta-analysis included 95 randomized trials between 1973 and 2004 comparing any microbial prophylaxis to placebo, no intervention, or other antibiotic

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prophylaxis (5). The authors reported a reduction in all-cause mortality (relative risk [RR] 0.67, 95% CI [confidence interval] 0.55-0.81) using any bacterial prophylaxis, and a relative risk of 0.52 (CI 0.35-0.77) specifically using quinolone prophylaxis. There were significant reductions in fever, infection-related mortality, and documented infections. There was a non-significant risk for colonization with quinolone resistant bacteria (RR 1.69, CI 0.73-3.92). An updated Cochrane review published in 2012 by many of the same authors reported a similar improvement in all-cause mortality (RR 0.66, CI 0.55-0.79) (6). There was no significant difference in mortality with quinolone prophylaxis compared to TMP/SMX, but quinolone prophylaxis was associated with greater tolerability and less resistance.

The utility of quinolone prophylaxis was studied in two more recent, large, randomized controlled studies. In the first study, 760 cancer patients with expected neutropenia for more than seven days were randomized to levofloxacin prophylaxis or placebo (7). The majority of patients had hematologic malignancies. Levofloxacin prophylaxis resulted in a reduction in fevers (absolute reduction 20%), and microbiologically documented infections (i.e. culture positivity), but there was no difference in clinically documented infections or mortality. In patients with microbiologically documented infections quinolone resistance was present in 87% of patients receiving levofloxacin and 47% of patients receiving placebo. A second study compared the use of levofloxacin prophylaxis in low risk patients expected to have short durations of neutropenia, the majority of whom had solid tumors (8). Levofloxacin showed a small but significant reduction in fever (10.8% v. 15.2%) and in hospitalizations (15.7% v. 21.6%), but there was no difference in mortality.

In summary, quinolone prophylaxis appears to reduce the rate of fevers and documented bacteremia, but may not improve the rate of clinical infections. Large meta-analyses suggest a mortality benefit in patients receiving antibacterial prophylaxis, but meta-analyses are subject to bias, and a mortality benefit was not observed in a large, well designed, placebo controlled trial involving high-risk hematology patients. Levofloxacin, appears to increase the risk of colonization with resistant bacteria (9), and levofloxacin resistance predominates in patients receiving prophylaxis that develop a bacterial infection (7). Also, fluoroquinolone prophylaxis may increase the rate of gram positive infections (10).

Despite the published guidelines from the NCCN and IDSA (1) (2), we do not recommend routine use of bacterial prophylaxis at our institution. In our experience, patients undergoing treatment for hematologic malignancies are monitored closely for infection, and empiric antibiotics are initiated at the first documented fever or sign of infection. Our experience suggests that rapid initiation of systemic antibiotics is effective in reducing morbidity and mortality in patients with neutropenic infections. Furthermore, routine use of bacterial prophylaxis contributes to antimicrobial resistance (11) and has not been convincingly been shown to improve meaningful clinical outcomes.

One possible exception to this recommendation is for patients expected to have profound neutropenia for longer than 7 days who are treated in the outpatient setting (i.e. Hyper-CVAD regimen for lymphoma, HIDAC for AML consolidation). These patients are not rigorously monitored for fever and may experience delays in receiving appropriate antibiotics. In such instances, a reduction in the risk of infection using fluoroquinolone prophylaxis may be considered on a case-by-case basis. For patient who do receive prophylaxis, we prefer levofloxacin over ciprofloxacin due to its improved spectrum of activity for gram positive organisms, namely viridans streptococcus.

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3. Fungal infections

Recommendations:

A. In patients undergoing treatment for acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL), antifungal prophylaxis with voriconazole 200 mg BID should be administered while the patient is neutropenic (ANC <500/microL).

a. In patients undergoing induction treatment for AML with “3+7,” voriconazole prophylaxis should begin on day 4 (following completion of anthracycline therapy)

b. In patients undergoing treatment with vincristine, voriconazole should not be administered 48 hours before and 96 hours after vincristine administration. Voriconazole should also not be co-administered with tyrosine kinase inhibitors (i.e. dastinib) for patient with Ph positive ALL. Micafungin 50 mg daily or fluconazole 200mg daily may be substituted in patients deemed to be at high risk for fungal infection during this time period.

c. Voriconazole should not be used in patients with hepatic insufficiency. Micafungin 50 mg daily may be substituted.

d. For patients who experience visual hallucinations while on voriconazole, an empiric 25% dose reduction should be considered.

B. Voriconazole 200mg BID should be administered in patients with myelodysplastic syndrome or aplastic anemia with expected prolonged neutropenia (ANC <500/microL).

C. Patients receiving Hyper-CVAD for lymphoma should receive candida prophylaxis with fluconazole 200 mg daily while neutropenic.

Rationale:

Patients with acute leukemia are at high risk of developing invasive fungal infections. During induction treatment, patients with acute leukemia develop profound neutropenia (ANC <100 cells/microL) which often lasts for several weeks. At our institution, we have typically used fluconazole at doses of 200 mg or 400 mg daily to prevent invasive fungal infections. This practice is based a randomized controlled trial that demonstrated a reduction in invasive fungal infections and infection related mortality in patients undergoing induction chemotherapy for acute leukemia (12), as well as a meta-analysis that showed a reduction in invasive fungal infections when the risk of systemic fungal infections is expected to be greater than 15% (13). Fluconazole prophylaxis is supported by the IDSA guidelines (2) and the NCCN guidelines (1). Indeed, using fluconazole prophylaxis, the observed risk of systemic candida infections in our patients undergoing induction chemotherapy is low.

However, fluconazole prophylaxis fails to provide protection against invasive mold species such as aspergillosis. We observed that 41.7% (5 of 12) of Olive View patients treated for acute leukemia between February - March 2017 also required treatment for suspected invasive mold infections. This percentage is consistent with reports form other institutions (14). Risk of mortality with invasive mold

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infections has been reported to be as high as 44% (15). Additionally, the cost for treatment of invasive mold infections averaged $4,596 (Table 1-2) per patient at our institution (16); please note, this estimate includes only the outpatient cost of medication, and does not include costs for hospitalization, laboratory testing, or diagnostic procedures.

The best data supporting the use of mold prophylaxis in leukemia patients comes from a randomized-controlled trial of 602 patients aged 13 years or older with AML or MDS undergoing treatment expected to cause neutropenia >7 days (17). Patient were randomized in a 1:1 fashion to posaconazole suspension versus either fluconazole or itraconazole. In this industry-sponsored study, there was an 6% absolute reduction (2% v. 8%) in incidence of invasive fungal infection during treatment with a number needed to treat (NNT) of 16. The study also showed a marginal survival benefit (relative risk reduction (RRR) 33%, p=0.04) favoring posaconazole. The cost of a course of prophylactic posaconazole is approximately $10,880 at our institution (Table 3), which corresponds to a cost of $174,080 to prevent one case of invasive fungal infection, assuming a NNT of 16. Using our incidence rate of invasive mold infection of 41.7%, and assuming a RRR of 75% with posaconazole, the incremental cost (compared to fluconazole) to prevent one invasive fungal infection decreases to $34,232 (Table 4); however, this cost remains prohibitively expensive.

Data regarding the use of other anti-mold agents for invasive fungal prophylaxis in acute leukemia are limited, but the concept of using a less expensive agent such as voriconazole is appealing. A meta-analysis of trials comparing anti-mold agents (i.e. echinocandins, voriconazole, posaconazole, amphotericin) versus fluconazole demonstrated a 29% RRR in invasive fungal infections, a 53% RRR in invasive aspergillus infections, and a 33% reduction in invasive fungal mortality, with no difference in overall survival (18). Another randomized control trial compared voriconazole versus fluconazole in 600 patients undergoing allogeneic stem cell transplant for 100 days post-transplant (19). There was no significant difference in invasive fungal-free survival at 180 days, but there was a trend toward reduction in aspergillus infections (3.0 v 5.8 %) and invasive fungal infections at 180 days (7.3% v. 11.2 %). The Kaplan Meier curves for fungal-free survival appear to separate for the first 100 days (while the patients are receiving active antifungal treatment) before converging at a later date Figure 1, panel B). Post-hoc analysis shows a trend toward reduction in proven or probable invasive fungal infection at 365 days (Risk ratio 0.56, 95% CI 0.3-1.07) (18). While limited, these data support the concept of anti-mold prophylaxis using agents other than posaconazole. Voriconazole is listed as an acceptable agent for mold prophylaxis by both the NCCN and IDSA (1) (2).

Given the high rate of suspected or proven mold infection in Olive-View patients with acute leukemia, prevention of mold infections is desirable. The approximate cost to our hospital system for a course of voriconazole prophylaxis would be $696 per patient (Table 3) (16). Assuming a conservative 30% relative reduction in the risk of invasive mold infection with voriconazole prophylaxis, the incremental cost (compared to fluconazole) to prevent one case of invasive mold infection would be approximately $4,080 (Table 4), which is less than the cost of treatment for a single case of suspected mold infection. Therefore, we recommend anti-mold prophylaxis with voriconazole 200 mg BID for patients undergoing induction or consolidation treatment for acute leukemia during the duration of neutropenia. Please note, voriconazole does not protect against mucormycosis, although the risk of such infections in patients with acute leukemia is low.

Azoles are strong CYP 3A4 inhibitors and clinicians need to remain diligent about monitoring for drug-drug interactions. Most notably, voriconazole interacts with vincristine and can potentiate its neurotoxic effects. Based on the half-life of voriconazole (~6 hours) and vincristine (terminal half life ~85

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hours), we do not recommend administering voriconazole 48 hours before or 96 hours after administration of vincristine. Fluconazole or an echinocandin (i.e. micafungin 50 mg IV daily) can be substituted in patients at high risk of fungal infection. Voriconazole should also not be administered to patients receiving tyrosine kinase inhibitors (i.e. imatinib, dasatinib), which are commonly used in patient with Ph positive ALL. Voriconazole should not be administered in patients with severe hepatic impairment, and it can occasionally cause hepatic injury. In patients with AML voriconazole is typically administered on day 4, following completion of anthracycline therapy. Micafungin 50mg IV daily may be substituted in patients with hepatic impairment who are at high risk of fungal infection.

Voriconazole has been associated with neurologic and ophthalmic adverse advents, most notably visual hallucinations and vivid dreams (1). Voriconazole levels are commercially available; however, the delay in obtaining results limits clinical utility, and we recommend an empiric 25% dose reduction in patients who experience visual symptoms rather than checking levels. Prolonged voriconazole use is also associated with photosensitivity and increased risk of skin cancer.

Patients with aplastic anemia and myelodysplastic syndrome are at high risk of invasive fungal infection due to prolonged neutropenia (20). For such patients, we recommend voriconazole 200 mg BID. Additionally, patients undergoing Hyper-CVAD for Burkitt’s lymphoma are at increased risk for invasive fungal infection, with an induction mortality of 19% attributable to invasive fungal infections in patients 60 years of age or older (21). For lymphoma patients undergoing intensive treatment with Hyper-CVAD, we recommend candida prophylaxis with fluconazole 200 mg daily.

4. Herpes viruses:

Recommendations:

A. Patients undergoing treatment for acute leukemia should receive prophylaxis with acyclovir 400 mg BID to prevent reactivation of herpes simplex virus (HSV) and varicella zoster (VZV).

B. Patients receiving proteasome inhibitors (i.e. bortezomib, carfilzomib, ixazomib) should receive viral prophylaxis with acyclovir 400 mg BID to prevent reactivation of VZV.

C. Patients receiving intensified or salvage therapy for lymphoma (i.e. R-EPOCH, CHOEP, DHAP, GDP, ESHAP, ICE, maxi-CHOP/Nordic regimen, BEACOPP) should receive antiviral prophylaxis with acyclovir 400 mg BID.

D. Patients receiving purine analogs (i.e cladribine, fludarabine, nelarabine, pentostatin, bendamustine) should receive viral prophylaxis with acyclovir 400 mg BID. Viral prophylaxis should be continued at least 2 months past the last treatment received.

Rationale:

Patients with hematologic malignancies are at increased risk of reactivation of herpes viruses, including HSV and VZV. The risk of reactivation appears to be highest in patients undergoing induction for acute leukemia and in patients undergoing allogeneic hematopoietic stem cell transplantation, with up to 30% patients experiencing reactivation of VZV (22) and 60-80% of patients experiencing reactivation of HSV (1). Prophylaxis using acyclovir has been shown to be effective in the transplant setting in preventing HSV (23), and VZV (22). The dosing optimal dosing for acyclovir prophylaxis (400 mg

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v. 800 mg BID) has not been established. Studies of VZV prophylaxis in transplant patients used a dose of acyclovir 800 mg (22); however, we have not observed a significant risk of VZV or HSV reactivation at a dose of 400 mg.

Treatment with the proteasome inhibitor bortezomib has been associated with a high risk of VZV reactivation (24), and acyclovir prophylaxis has been shown to be beneficial in this setting (25).

The rate of HSV reactivation in patients with lymphoma has been reported to be approximately 12% (26); however, this is a very heterogenous population. We recommend acyclovir prophylaxis in patients undergoing intensified or salvage therapy with the regiments listed above, based on guidelines from other institutions (3).

Purine analogs have been shown to impair cellular immunity which places patients at risk for viral reactivation (1), and HSV prophylaxis is warranted.

5. Pneumocystis Jirovecii

Recommendations:

A. All patients with acute lymphoblastic leukemia should receive pneumocystis (PCP) prophylaxis throughout all anti-leukemic therapy.

B. Patients receiving greater than the equivalent of 20 mg of prednisone daily for 4 or more weeks (i.e. multiple myeloma patients receiving more than 20 mg of dexamethasone weekly) should receive pneumocystis prophylaxis.

C. Patients receiving purine analogs (i.e cladribine, fludarabine, nelarabine, pentostatin, bendamustine) should receive pneumocystis prophylaxis during treatment and for at least 2 months following the completion of treatment.

D. Lymphoma patients receiving the PI3K inhibitors idelalisib or copanlisib for treatment of lymphoma should receive pneumocystis prophylaxis.

E. Patients with lymphoma receiving the following regimens should receive pneumocystis prophylaxis: R-DA-EPOCH, Hyper-CVAD.

F. The preferred regimens for PCP prophylaxis are one double strength tablet of trimethoprim/sulfamethoxazole (TMP/SMX) three times weekly or one single strength tablet of TMP/SMX daily.

G. Patients intolerant of TMP/SMX should receive dapsone 100 mg (if G6PD normal). If G6PD deficient, then atovaquone 1,500 mg daily.

Rationale:

Pneumocystis jirovecii pneumonia (PCP) is a severe pulmonary infection with significant risk of mortality. Although it is classically described in the HIV population, PCP can also develop in patients with impaired CD4+ cellular immunity from other causes. Antimicrobial prophylaxis with TMP/SMX is highly

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effective for prevention of PCP. Its effectiveness is described by a 2014 Cochrane review, which included trials with ALL, solid organ transplantation, and autologous stem cell transplant patients (27). TMP/SMX prophylaxis demonstrated an 85% relative reduction in the risk of PCP. Acute lymphoblastic leukemia patients are at high risk of PCP, and prophylaxis should be administered throughout all leukemic therapy (1).

PCP has been reported in patients receiving high dose glucocorticoids (28), and PCP prophylaxis is recommended in patients receiving the equivalent of 20mg of prednisone daily or greater for more than four weeks (1). In hematologic patients, this scenario most commonly applies to patients with multiple myeloma who are receiving standard doses of dexamethasone 40 mg weekly (20 mg of prednisone daily roughly corresponds to 21 mg of dexamethasone weekly). Patients with CNS or spinal involvement of lymphoma who are on high doses of corticosteroids may also be candidates for PCP prophylaxis.

PCP can develop patients receiving purine analogs, which are known cause CD4+ cell depletion, and has been described in CLL (29). Patients undergoing treatment with purine analogs should receive PCP prophylaxis until CD4+ cell counts recover, approximately 2 months after completion of therapy. Bendamustine is a chemotherapy agent with a dual mechanism of action including purine analog properties and DNA alkylation. Patients, undergoing treatment with bendamustine appear to have an increased risk of PCP (30) and should also receive PCP prophylaxis.

The oral PI3K inhibitor idelalisib, used for treatment of refractory follicular lymphoma or chronic lymphocytic leukemia, has been associated with a 2.5% risk of developing PCP on therapy (31). This risk was reduced to approximately 1% with administration of PCP prophylaxis. As a result, PCP prophylaxis is recommended during active treatment with idelalisib (1). Copanlisib, an intravenous PI3K inhibitor approved in refractory lymphoma, appears to confer a lower risk of PCP than idelalisib (0.6% in a phase II study) (32); however due to similar mechanism of action, PCP prophylaxis should be considered in patients receiving copanlisib until further data are available.

Studies evaluating the chemotherapy regimens Hyper-CVAD and R-DA-EPOCH incorporated routine prophylaxis into the study protocol (33) (21). Therefore, it is reasonable to use PCP for patients being treated with these regimens, since the incidence of PCP without prophylaxis is unknown. The risk of PCP in lymphoma patients receiving standard R-CHOP appears to be low (34).

Accepted regimens for the prevention of PCP include one trimethoprim/sulfamethoxazole 80/400 mg (single strength) tablet daily or one 160/800 mg (double strength) tablet three times weekly. TMP/SMX is the preferred regimen for PCP prevention (1) (35). Due to lower cost and ease of administration, dapsone 100 mg PO daily is our preferred regimen in patients intolerant of TMP/SMX (36). In G6PD deficient patients, atovaquone 1,500 mg daily may be used (37). TMP/SMX should be held during treatment with high-dose methotrexate since it can potentiate its toxic effects.

6. Hepatitis B

Recommendations:

A. Patients with hematologic malignancies should be screened for evidence of prior hepatitis B (HBV) infection with the following tests: core antibody (cAb) total, surface antibody (sAb), surface antigen (sAg).

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B. Patients who are seropositive for hepatitis B core antibody or surface antigen should be tested for active viremia with a hepatitis B DNA PCR test.

C. Patients who are surface antigen seropositive or have a detectable hepatitis B DNA on PCR assay and who are going to receive treatment with with anti-CD20 therapy (i.e. rituximab, ofatumumab, obinutuzumab), cytotoxic chemotherapy or high-dose glucocorticoids (equivalent of >20 mg prednisone daily for 4 or more weeks) should receive hepatitis B prophylaxis.

D. Patient who are core antibody positive/surface antigen negative with undetectable hepatitis B DNA who will receive anti-CD20 therapy, cytotoxic chemotherapy or high dose glucocorticoids should undergo periodic monitoring of hepatitis B DNA (approximately every 3 months) while on treatment. If hepatitis B DNA is detected, the patient should undergo treatment for hepatitis B.

E. The preferred medication for hepatitis B treatment/prophylaxis is entecavir o.5 mg daily or tenofovir 300 mg daily. Prophylaxis should continue for six months past completion of anticancer treatment.

Rationale:

Patients with previous exposure to hepatitis B are at risk of viral reactivation during receipt of anti-cancer treatment. HBV reactivation can lead to significant transaminitis, which may limit the ability to safely give necessary chemotherapy, and may even result in fulminant hepatic failure and death. The risk of hepatitis B reactivation depends on the type of treatment used (i.e. anti-CD 20 therapy, cytotoxic chemotherapy, high dose glucocorticoids), the viral status of the patient (sAg positive v. sAg negative/cAb positive), and the presence of active viremia (38). Patients with the highest risk of reactivation are those who are sAg positive receiving anti-CD20 therapy, and have a reported risk of reactivation as high as 60% (38). Patients who are sAg negative/cAb positive receiving anti-CD20 therapy are also at risk of viral reactivation, with HBV reactivation reported in 25% (39) (40). It is unclear how surface antibody positivity affects the risk of reactivation.

Antiviral therapy has shown to be effective for the prevention of hepatitis B reactivation. Most studies of HBV prophylaxis in cancer patients were performed using lamivudine. A systemic review of lamivudine prophylaxis in patients undergoing chemotherapy demonstrated a four- to sevenfold decrease in the rate of hepatis B reactivation (41). However, due to concerns about the development of resistance with lamivudine treatment, it is no longer recommended routinely (42). Entecavir was compared to lamivudine prophylaxis in patients seropositive for HBV sAg undergoing R-CHOP chemotherapy for DLBCL (43). Entecavir prophylaxis resulted in fewer cases of HBV reactivation (6.6% v. 30%) and HBV-related hepatitis (0% v. 13.3%). Entecavir and tenofovir are the preferred agents for prevention of hepatitis B reactivation.

Our recommendations for HBV prophylaxis are similar to the American Academy for the Study of Liver Disease (AASLD) guidelines (44). All patients who are undergoing cancer treatment should be screened for evidence of previous hepatitis B exposure with HBV sAg and core Ab (IgG or total) assays. Patients with evidence of prior exposure (sAg and/or cAb seropositive) should have a HBV DNA PCR level measured in order to establish a baseline and to assess for the presence of active viremia. Patients at highest risk of viral reactivation (sAg or HBV DNA positive receiving anti-CD20 therapy, chemotherapy, or prolonged glucocorticoids) should receive HBV prophylaxis with either entecavir or lamivudine. Patients at lower risk of HBV reactivation should have HBV DNA levels monitored periodically during cancer-

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treatment and receive HBV treatment if HBV DNA becomes detectable. In contrast to the AASLD guidelines, it was thought that patients receiving anti-CD20 therapy who are cAb positive with no detectable HBV viremia could be safely monitored with serial HBV DNA based on clinical experience at our institution

The optimum duration of HBV prophylaxis is unknown. Due to reports of HBV reactivation once lamivudine was withdrawn after completion of chemotherapy (median time to discontinuation, 3.1 months) (45), continuing HBV prophylaxis until six months after completion of chemotherapy seems reasonable.

7. Latent Tuberculosis

Recommendations:

A. Due to the high prevalence of prior tuberculosis (TB) exposure among patients at our institution, all patients should be screened for latent tuberculosis with an interferon gamma release assay prior to initiation of anti-cancer therapy.

B. Patients with a positive assay should be screened for signs and symptoms of active tuberculosis.

C. Patients undergoing cancer treatment should receive tuberculosis prophylaxis. Preferred regimens include the following:

a. Isoniazid (INH) 300 mg daily for 9 months

b. Isoniazid 900 mg weekly with rifapentine 900 mg weekly for 12 weeks

c. Rifampin 600 mg PO daily for 4 months

D. Patients receiving INH should receive pyridoxine 50 mg daily to prevent neurotoxicity. Patients should have LFTs checked monthly.

Rationale:

At our institution, we care for a large immigrant population, a substantial portion of which has been exposed to tuberculosis. Patients with hematologic malignancies receiving anti-cancer treatment with a history of tuberculosis exposure are at high risk for progression to active tuberculosis (46) (47). The interferon gamma release assay (IGRA) is the preferred method of screening for latent tuberculosis. It does not require a follow-up visit, and it is not affected by the BCG vaccination. A single positive test in patients at high risk for progression to active tuberculosis is sufficient to diagnose latent tuberculosis, and does not require confirmatory tuberculin skin testing (TST) (48). TST can be considered in patients with indeterminate IGRAs.

Isoniazid is the most studied treatment for latent tuberculosis and is effective at reducing the risk of progression to active tuberculosis by about 60% (49). The optimum duration of isoniazid therapy is 9 months (50). Isoniazid is associated with hepatotoxicity, and liver function tests should be monitored at least monthly while on treatment. Isoniazid should be suspended or discontinued for AST/ALT increase 3-5 times the upper limit of normal. Isoniazid has been associated with neurotoxicity due to

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interference with vitamin B6 metabolism, which can be prevented using pyridoxine supplementation. Once-weekly rifapentine and isoniazid given for 12 weeks was found to be equally efficacious as daily isoniazid for 12 months in a randomized control study, and may be considered when a shorter duration of treatment is desired (51). This combination was well tolerated with low rates of hepatotoxicity (0.4%). Recently, rifampin at 600 mg daily for four months was shown to be non-inferior to nine months of INH isoniazid with improved compliance (52). The clinician needs to be diligent about monitoring for drug-drug interactions with rifampin, which is a CYP3A4 inducer.

8. Other infections

Recommendations:

A. Patients expected to receive cancer treatment for hematologic malignancies should be screened for the presence of HIV and Hepatitis C (HCV) infections.

B. Patients who screen positive for HIV should be tested for CD4 count and HIV viral load, and referred to an infectious disease specialist. Anti-retroviral medications should be started prior initiation of systemic anticancer treatment, if possible.

C. Patients who are seropositive for HCV should be tested for hepatitis C viral load as well as genotype. These patients should be referred for risk assessment and consideration of antiviral treatment.

Rationale:

These guidelines do not address the management of HIV and HCV in hematology patients. However, it is important to screen for the presence of these chronic infections prior to initiation of systemic cancer-treatment. Patients with HIV or HCV should be referred to the appropriate specialist for management.

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9. Tables and Figures

Table 1. Average Daily Cost of Antifungal Agents at DHS FacilitiesAgent Inpatient Hospital ClinicFluconazole (PO) $4 $1Voriconazozle (PO) $19 $1Posaconazole (DR tab) *$175 $99Isovuconazonium (PO) $119 $78Micafungin (IV) $61 N/A

DR: Delayed release, IV- Intravenous, PO: By mouth. Source: Department of Health Services Core Formulary Pocket Guide. 2017-2018. (16). *Personal communication with pharmacist.

Table 2. Cost of Treatment of Suspected Mold InfectionsCase # Diagnosis Phase of

Leukemia Treatment

Site of Infection

Duration of Voriconazole Treatment (months)

Duration of Isovuconazole Treatment (months)

Cost of Treatment

1 ALL Induction Lung 22 0 $6602 ALL Induction Lung 23 0 $6903 AML Consolidation Lung 7 2 $4,8904 AML Induction Liver 4 3 $7,1405 ALL Maintenance Lung 8 4 $9,600Average $4,596

Table 3. Cost of Antifungal ProphylaxisAcute Myeloid Leukemia (AML)

Acute Lymphoblastic Leukemia (ALL)

Average Comments

Weight 0.4 0.6 -Duration of treatment-induction (inpatient days)

25 25 25

Duration of treatment-consolidation (inpatient days)

15 5 9 AML- 3 consolidation blocks x5 days inpatientALL- majority given outpatient

Duration of treatment-consolidation (outpatient days)

27 65 50 AML- 3 consolidation blocks x14 days neutropenia (5 inpatient)ALL- 7 myelosuppresive consolidation blocks x10 days neutropenia (primarily outpatient)

Fluconazole Cost $187 $185 $186Voriconazole Cost $787 $635 $696Posaconazole Cost $9,673 $11,685 $10,880

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Table 4. Cost-Benefit of Anti-Mold ProphylaxisPosaconazole Voriconazole

Incidence of Invasive Mold Infection 41.7% 41.7%Relative Risk Reduction (RRR) 75% 30%Absolute Risk Reduction (ARR) 31.3% 12.5%Number Needed to Treat (NNT) 3.2 8Incremental Cost (compared to fluconazole prophylaxis) to prevent one case of mold infection

$34,222 $4,080

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Figure 1. Voriconazole Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplant Recipients

A) Incidence of invasive fungal infection B) Fungal free survival C) Overall Survival D) Relapse free survival. Reproduced from Wingard Et Al. Blood. 2010; 116(24): 5114. (19)

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Figure 2. Pocket Card with Summary of Recommendations

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