TABLE 2.

Recommendations to Optimize Venetoclax Use in AML

Clinical Issues	Recommendations
Dose ramp-up	• Ramp-up over 3 or 4 d for target dose of 400 or 600 mg, respectively. • e.g., 100 mg on D1, 200 mg on D2, 400 mg on D3; 600 mg on D4
Inpatient monitoring	• Newly diagnosed AML → admit until hematologic recovery or for first cycle • Relapsed/refractory AML → admit for duration of venetoclax ramp-up
Outpatient monitoring	• Consider outpatient follow-up 3 to 1 time per week
Minimizing risk of TLS	• Identify high risk patients → renal dysfunction, hyperuricemia, high lactate dehydrogenase, sensitive mutations IDH1/2, NPM1 • Cytoreduction to WBC count <10 to 25 × 109/L prior to starting venetoclax • TLS prophylaxis prior to starting venetoclax and adequate hydration • TLS monitoring every 6–8 h until 24 h after reaching target dose • If significant biochemical, or clinical TLS → hold venetoclax until resolution
Premedications	• Antiemetic prophylaxis if used with HMA or intensive chemotherapy
Food and supplements	• Avoid grapefruit, starfruit, pomelo, Seville oranges, and St John's wort • Administer venetoclax 30 min after a meal with 1 cup of water
Washout	• 3-day washout for strong or moderate CYP3A4 inhibitor food or drug
Optimizing venetoclax dose	• Avoid CYP3A4 inhibitor during dose ramp-up • Ensure appropriate dose reduction with CYP3A4 or P-glycoprotein inhibitors
Renal impairment	• Avoid in glomerular filtration rate <30 mL/min due to lack of pharmacokinetic data
Liver dysfunction	• For severe liver dysfunction (Child-Pugh class C), reduce dose by 50%
Minimizing myelosuppression
Cycle 1 venetoclax duration	• Perform BM evaluation between days 14 and 28 depending on regimen • If BM shows ≤5% blasts consider “venetoclax holiday” until complete (CR) or at least partial (CRh) hematologic recovery • If BM shows persistent AML, continue venetoclax or start next cycle without interruption, depending on timepoint
Venetoclax duration during consolidation or maintenance	• Reduce venetoclax duration instead of dose in cases of myelosuppression • If marrow blasts ≤5% and grade 4 neutropenia for >7 d or hematologic recovery takes >14 d following venetoclax interruption → reduce venetoclax in stepwise manner from 21 d to 14 d to 7 d per cycle • For neutropenic fever or severe infections → hold venetoclax until resolution
Dose reduction of concomitant therapy	• For older patients with marrow blasts ≤5% and marrow cellularity 15%–30% → reduce HMA or LDAC dose to 50% • If marrow cellularity <15%, reduce HMA dose to 33% • For younger patients with prolonged myelosuppression or severe infections, consider decreasing subsequent chemotherapy dose by 20%–33%
Growth factor use	• For patients achieving remission or hypocellular or aplastic BM on day 21 or day 14, administer daily GCSF until ANC >1.5 × 109/L • For consolidation or maintenance, consider prophylactic peg-filgrastim 1 d after last dose of HMA, LDAC, or chemotherapy • For neutropenic fever or severe infections → use GCSF until ANC recovery
Minimizing infections	• “Triple antimicrobial” prophylaxis for all patients • Antibiotic → fluoroquinolone or oral third-generation cephalosporin • Antifungal → posaconazole, isavuconazole, or voriconazole • Antiviral → valacyclovir or acyclovir • For elevated liver function tests due to azoles → change to echinocandin
Triplet therapy with FLT3 inhibitor	• Perform BM evaluation on day 14 to assess for response • If BM blasts ≤5% blasts, hold venetoclax and FLT3 inhibitor until partial or complete hematologic recovery • For subsequent cycles administer FLT3 inhibitor at 1 lower dose level continuously and reduce venetoclax to ≤14 d, depending on response, county recovery, BM cellularity, and infectious complications
Duration of therapy	• Continue therapy for at least 2 cycles with lower-intensity regimens - Discontinue therapy if no blast reduction or clinical benefit after 3–4 cycles of lower-intensity therapy, provided alternative options or clinical trials are available - In the absence of SCT, lower-intensity regimens may be continued indefinitely • For intensive therapy-based regimens, we recommend discontinuation if no response after 2 cycles of induction. - In responding patients, continue up to 6 total cycles of therapy, if tolerated, followed by maintenance therapy indefinitely • For patients achieving response with severe or recurrent infections or significant myelosuppression, consider de-escalation of therapy

Modified with permission from DiNardo and Wei.⁶²