Risk factors for and risk reduction of IFDs in patients with AML or ALL
| Risk factors . | Risk reduction . |
|---|---|
| Pretreatment | |
| Net state of immunosupression | |
| Leukemia-related | |
| *Lower probability of CR32 AML: adverse cytogenetic/gene mutation profiles, WBC ≥50 000/µL, secondary leukemia, MDS or antecedent hematologic disorder >6 mo4,5 ALL: adverse cytogenetic/gene mutation profiles, WBC ≥30 000/µL, immunophenotype6 | Assess probability of CR and e-TRM42,43 Determine risk for IFDs: high, intermediate, or low, and manage accordingly. Primary mold-active prophylaxis for high-risk patients. Serial s-GMI tests Lower cytarabine consolidation for patients with favorable cytogenetics43 Better-tolerated antileukemic regiments if high risk for e-TRM64-68 |
| *Baseline neutropenia ANC <500/µL for ≥7 d,26 MDS-related phagocytic dysfunction | Manage as high risk for IFDs including mold-active prophylaxis G-CSF for patients with ALL,114 and GM-CSF for those with AML69 |
| *Leukemia status35 Relapse-refractory > first induction > consolidation | Manage as high risk for IFDs except for consolidation |
| Treatment-related | |
| *Corticosteroids (≥3 wk of >1 mg/kg per d of prednisone equivalent)25,33 | Reduce corticosteroid dose, provide antifungal and Pneumocystis prophylaxis |
| *Highly mucotoxic regimen36 Cumulative myelotoxicity from rapidly cycling chemotherapy courses | Fluconazole prophylaxis59 even if low risk for IFDs Adjust dose density and intensity based on likelihood of CR4243 and e-TRM43-45 |
| Host-related | |
| *Age >65 y (AML),44 >35 Y (ALL)115 ; Down syndrome Immunity polymorphisms31 ; pharmacogenomics of antineoplastic drugs117 | Manage as high risk for IFDs, including mold-active prophylaxis Consider better-tolerated therapies64-68 Avoid severe drug interactions and monitor clinical toxicity and drug levels31 |
| Organ dysfunction | |
| *High comorbidity scores118 and e-TRM risk43-45 | Improve organ function and consider better-tolerated regimens64-68 |
| *Chronic obstructive pulmonary disease,38 smoking,39 respiratory viral infection119 | Manage as high risk for IFDs, including mold-active antifungal prophylaxis During influenza season: immunize patient and close contacts vs influenza viruses, prophylaxis with neuraminidase inhibitors, avoid sick visitors,72 smoking cessation |
| *Poor physical functioning ECOG/WHO score,120 physiologic status, functional reserve, activities of daily living, gait speed, and others121 Hyperglycemia (blood glucose >200 mg/dL for >2 wk)122 | Preemptive physical and occupational therapy Monitor and correct blood glucose |
| Exposure to pathogenic fungi | |
| *Prior aspergillosis ± airway colonization by Aspergillus spp41,49 Room without HEPA filtration73 Building constructions or renovation74 Room without water precautions75 | Manage as high risk for IFDs, including mold-active antifungal secondary prophylaxis49,50 Provide HEPA filtration73 Ensure safe construction practices74 Provide water precautions21,75 |
| Posttreatment | |
| Net state of immunosupression | |
| Neutropenia, severe and prolonged35 (ANC <100/µL for >10 d) *Expected severe and prolonged neutropenia AML: low CR score,4-6 d 15 blasts >5%,48 no CR by end of induction ALL: no CR in 4 wk, persistent MRD32,48 Persistent lymphopenia (cells <300 µL) with normal WBC/ANC | Manage as high risk for IFDs, including mold-active antifungal prophylaxis Day-15 bone marrow biopsy for blast clearance and MRD48 G-CSF for patients with ALL114 and G-CSF for those with AML69 Reduce corticosteroid dose, antifungal and Pneumocystis prophylaxis |
| Organ dysfunction | |
| *Mucositis36 Severe, grade ≥3 for ≥7 d, especially if involving lower gut | Fluconazole prophylaxis |
| Exposure to pathogenic fungi | |
| Same as pretreatment *Multisite colonization by Candida species40 Central venous catheter123 | Same as pretreatment Fluconazole prophylaxis, unless a mold-active agent is indicated Optimal venous catheter care |
| Risk factors . | Risk reduction . |
|---|---|
| Pretreatment | |
| Net state of immunosupression | |
| Leukemia-related | |
| *Lower probability of CR32 AML: adverse cytogenetic/gene mutation profiles, WBC ≥50 000/µL, secondary leukemia, MDS or antecedent hematologic disorder >6 mo4,5 ALL: adverse cytogenetic/gene mutation profiles, WBC ≥30 000/µL, immunophenotype6 | Assess probability of CR and e-TRM42,43 Determine risk for IFDs: high, intermediate, or low, and manage accordingly. Primary mold-active prophylaxis for high-risk patients. Serial s-GMI tests Lower cytarabine consolidation for patients with favorable cytogenetics43 Better-tolerated antileukemic regiments if high risk for e-TRM64-68 |
| *Baseline neutropenia ANC <500/µL for ≥7 d,26 MDS-related phagocytic dysfunction | Manage as high risk for IFDs including mold-active prophylaxis G-CSF for patients with ALL,114 and GM-CSF for those with AML69 |
| *Leukemia status35 Relapse-refractory > first induction > consolidation | Manage as high risk for IFDs except for consolidation |
| Treatment-related | |
| *Corticosteroids (≥3 wk of >1 mg/kg per d of prednisone equivalent)25,33 | Reduce corticosteroid dose, provide antifungal and Pneumocystis prophylaxis |
| *Highly mucotoxic regimen36 Cumulative myelotoxicity from rapidly cycling chemotherapy courses | Fluconazole prophylaxis59 even if low risk for IFDs Adjust dose density and intensity based on likelihood of CR4243 and e-TRM43-45 |
| Host-related | |
| *Age >65 y (AML),44 >35 Y (ALL)115 ; Down syndrome Immunity polymorphisms31 ; pharmacogenomics of antineoplastic drugs117 | Manage as high risk for IFDs, including mold-active prophylaxis Consider better-tolerated therapies64-68 Avoid severe drug interactions and monitor clinical toxicity and drug levels31 |
| Organ dysfunction | |
| *High comorbidity scores118 and e-TRM risk43-45 | Improve organ function and consider better-tolerated regimens64-68 |
| *Chronic obstructive pulmonary disease,38 smoking,39 respiratory viral infection119 | Manage as high risk for IFDs, including mold-active antifungal prophylaxis During influenza season: immunize patient and close contacts vs influenza viruses, prophylaxis with neuraminidase inhibitors, avoid sick visitors,72 smoking cessation |
| *Poor physical functioning ECOG/WHO score,120 physiologic status, functional reserve, activities of daily living, gait speed, and others121 Hyperglycemia (blood glucose >200 mg/dL for >2 wk)122 | Preemptive physical and occupational therapy Monitor and correct blood glucose |
| Exposure to pathogenic fungi | |
| *Prior aspergillosis ± airway colonization by Aspergillus spp41,49 Room without HEPA filtration73 Building constructions or renovation74 Room without water precautions75 | Manage as high risk for IFDs, including mold-active antifungal secondary prophylaxis49,50 Provide HEPA filtration73 Ensure safe construction practices74 Provide water precautions21,75 |
| Posttreatment | |
| Net state of immunosupression | |
| Neutropenia, severe and prolonged35 (ANC <100/µL for >10 d) *Expected severe and prolonged neutropenia AML: low CR score,4-6 d 15 blasts >5%,48 no CR by end of induction ALL: no CR in 4 wk, persistent MRD32,48 Persistent lymphopenia (cells <300 µL) with normal WBC/ANC | Manage as high risk for IFDs, including mold-active antifungal prophylaxis Day-15 bone marrow biopsy for blast clearance and MRD48 G-CSF for patients with ALL114 and G-CSF for those with AML69 Reduce corticosteroid dose, antifungal and Pneumocystis prophylaxis |
| Organ dysfunction | |
| *Mucositis36 Severe, grade ≥3 for ≥7 d, especially if involving lower gut | Fluconazole prophylaxis |
| Exposure to pathogenic fungi | |
| Same as pretreatment *Multisite colonization by Candida species40 Central venous catheter123 | Same as pretreatment Fluconazole prophylaxis, unless a mold-active agent is indicated Optimal venous catheter care |
Risk stratification is done prior to treatment and on day-15 bone marrow examination. Risk factors are shown according to type: immunosuppression, organ dysfunction, exposure to pathogenic fungi, and to timing (pretreatment or posttreatment). Yeast infections are typically caused by Candida species, whereas aspergillosis is the most common mold infection. ECOG, Eastern Cooperative Oncology Group; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; HEPA, high-efficiency particulate air; MRD, minimal residual disease; WBC, white blood cell; WHO, World Health Organization. *Most important risk factors.