Acute Lymphoblastic Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) provide recommendations for management of ALL, with a focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. This selection from the NCCN Guidelines for ALL focuses on treatment recommendations for adults with newly diagnosed Ph-negative ALL based on current evidence.

Results from phase 1 of the MANIFEST clinical trial to evaluate the safety and tolerability of pelabresib in patients with myeloid malignancies.

Pelabresib (CPI-0610), a BET protein inhibitor, is in clinical development for hematologic malignancies, given its ability to target NF-κB gene expression. The MANIFEST phase 1 study assessed pelabresib in patients with acute leukemia, high-risk myelodysplastic (MDS) syndrome, or MDS/myeloproliferative neoplasms (MDS/MPNs) (NCT02158858). Forty-four patients received pelabresib orally once daily (QD) at various doses (24-400 mg capsule or 225-275 mg tablet) on cycles of 14 d on and 7 d off. The most frequent drug-related adverse events were nausea, decreased appetite, and fatigue. The maximum tolerated dose (MTD) was 225 mg tablet QD. One patient with chronic myelomonocytic leukemia (CMML) showed partial remission. In total, 25.8% of acute myeloid leukemia (AML) patients and 38.5% of high-risk MDS patients had stable disease. One AML patient and one CMML patient showed peripheral hematologic response. The favorable safety profile supports the ongoing pivotal study of pelabresib in patients with myelofibrosis using the recommended phase 2 dose of 125 mg tablet QD.CLINICAL TRIAL REGISTRATION: NCT02158858.

IDH2-mutated near ETP-ALL with aggressive leukemia cutis and brisk response to venetoclax and decitabine.

Near early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a rare hematologic malignancy, for which second line therapeutic options are limited. T-cell leukemias are also rarely associated with leukemia cutis, which is more often seen in leukemias of myeloid origin. We present the case of an adult male diagnosed with near ETP-ALL, with IDH2 and DNMT3A mutations, suggestive of a myeloid origin, and leukemia cutis. After the patient progressed on hyper-CVAD and nelarabine, we treated him with the BCL-2 inhibitor venetoclax and the hypomethylating agent decitabine. The regimen induced a rapid bone marrow response and resolution of the leukemia cutis.

Acute Myeloid Leukemia, Version 3.2023, NCCN Clinical Practice Guidelines in Oncology.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.

Clofarabine and Busulfan Myeloablative Conditioning in Allogeneic Hematopoietic Cell Transplantation for Patients With Active Myeloid Malignancies.

Patients with refractory or relapsed and refractory myeloid malignancies have a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning (MAC) in patients with active, chemotherapy-refractory myeloid disease is historically associated with high rates of relapse and nonrelapse mortality (NRM). A MAC regimen combining clofarabine with busulfan (Clo/Bu4) has been reported to exhibit antileukemic activity with acceptable toxicity in patients age ≤70 years. Here we describe the clinical outcomes of a real-world population of patients with active myeloid malignancies undergoing allogeneic HCT with Clo/Bu4 MAC. In a single-center retrospective descriptive analysis, we identified patients who underwent HCT for myeloid malignancies not in remission using Clo/Bu4 MAC between 2012 and 2020. We report event-free survival (EFS) and overall survival (OS), cumulative incidences of relapse and NRM, and the incidence and severity of acute and chronic graft-versus-host disease (GVHD). We identified 69 patients with a median age of 60 years (range, 22 to 70 years). Most patients had relapsed/refractory or primary refractory acute myelogenous leukemia (AML; n = 55) or refractory myelodysplastic syndrome (MDS; n = 12); 1 patient had chronic myelogenous leukemia, and 1 patient had a blastic plasmacytoid dendritic cell neoplasm. Fifty patients (72.5%) had complete remission at day 100 post-transplantation. Two-year EFS and OS were 30% (95% confidence interval [CI], 20% to 44%) and 40% (95% CI, 29% to 54%), respectively. Patients with AML had a 2-year EFS and OS of 28% (95% CI, 18% to 44%) and 38% (95% CI, 27% to 54%), respectively; those with MDS had a 2-year EFS and OS of 47% (95% CI, 25% to 88%) and 56% (95% CI, 33% to 94%), respectively. The cumulative incidence of relapse at 2 years was 39% (95% CI, 27% to 51%) for all patients, including 45% (95% CI, 31% to 58%) in the patients with AML and 18% (95% CI, 2% to 45%) in those with MDS. NRM at 2 years was 31% (95% CI, 20% to 42%), including 27% (95% CI, 15% to 39%) in patients with AML and 35% (95% CI, 10% to 63%) in those with MDS. The total incidence of acute GVHD (aGVHD) of any severity was 80%, and the incidence of grade III-IV aGVHD was 22%. In patients who achieved remission, those who required systemic immunosuppression for aGVHD (58%) had poorer 2-year EFS (29% versus 54%; P = .05) and 2-year OS (39% versus 70%; P = .04) compared to those who did not. The 2-year cumulative incidence of chronic GVHD was 44% (95% CI, 28% to 58%). Clo/Bu4 MAC followed by allogeneic HCT for patients with active myeloid malignancies is an effective transplantation strategy for patients up to age 70, particularly those with advanced MDS. The high incidence of and poor outcomes associated with aGVHD highlight the importance of optimizing preventative strategies.

Nonperturbative Double Copy in Flatland.

We derive a nonperturbative, Lagrangian-level formulation of the double copy in two spacetime dimensions. Our results elucidate the field theoretic underpinnings of the double copy in a broad class of scalar theories which can include masses and higher-dimension operators. An immediate corollary is the amplitudes-level double copy at all orders in perturbation theory. Applied to certain integrable models, the double copy defines an isomorphism between Lax connections, Wilson lines, and infinite towers of conserved currents. We also implement the double copy at the level of nonperturbative classical solutions, both analytically and numerically, and present a generalization of the double copy map that includes a fixed tower of higher-dimension corrections given by the Moyal algebra.

Age-Adjusted Schedules of Venetoclax and Hypomethylating Agents to Treat Extremely Elderly Patients with Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is associated with particularly poor outcomes in the elderly population, in whom the disease is most prevalent. BCL-2 has been identified as an antiapoptotic protein and promotes survival of leukemia stem cells. Recently, the United States FDA has approved venetoclax, a selective oral BCL-2 inhibitor, for use in conjunction with hypomethylating agents (azacitidine or decitabine) or low-dose cytarabine as a first-line treatment option for those AML patients ineligible for standard induction chemotherapy. However, there are nuances and challenges when using this regimen in the extremely elderly AML patients. Given the widespread adoption of this regimen and increasing prevalence of patients who are well into their 80 s, it is important to evaluate and understand how to safely use this regimen in this so-called "extremely elderly" population. We present here 3 case studies involving AML patients >85 years of age who were treated with venetoclax plus HMA and provide clinical knowledge on how this population should be appropriately managed.

NCCN Guidelines® Insights: Myelodysplastic Syndromes, Version 3.2022.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and management of patients with MDS based on a review of clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts meets on an annual basis to update the recommendations. These NCCN Guidelines Insights focus on some of the updates for the 2022 version of the NCCN Guidelines, which include treatment recommendations both for lower-risk and higher-risk MDS, emerging therapies, supportive care recommendations, and genetic familial high-risk assessment for hereditary myeloid malignancy predisposition syndromes.

Letermovir vs. high-dose valacyclovir for cytomegalovirus prophylaxis following haploidentical or mismatched unrelated donor allogeneic hematopoietic cell transplantation receiving post-transplant cyclophosphamide.

Patients undergoing haploidentical or mismatched unrelated donor (haplo/MMUD) allogeneic hematopoietic cell transplantation (alloHCT) receiving post-transplant cyclophosphamide (PTCy) are at high risk of cytomegalovirus (CMV) infection. Experience with letermovir (LET) in this population is limited. This single center retrospective cohort study compared CMV and transplant outcomes between LET and a historical control with high-dose valacyclovir (HDV) prophylaxis in adults undergoing haplo/MMUD alloHCT. Thirty-eight CMV seropositive patients were included, 19 in each arm. LET reduced the incidence of CMV infection (5% vs. 53%, RR 0.01, 95% CI 0.014-0.71, p = .001) and need for CMV treatment by day +100 (5% vs. 37%, RR 0.14, 95% CI 0.18-0.99, p = .017) compared to HDV. Median CMV event-free-survival was improved with LET (not reached vs. 80 days, HR 0.114, 95% CI 0.07-0.61, p = .004). These data support the efficacy of LET in alternative donor transplants.

FMS-Like Tyrosine Kinase 3 Inhibitors for the Treatment of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is the most common acute leukemia of adults, with a five-year survival that remains poor (approximately 25%). Knowledge and understanding of AML genomics have expanded tremendously over the past decade and are now included in AML prognostication and treatment decisions. FMS-like tyrosine kinase 3 (FLT3) is a Class III receptor tyrosine kinase (RTK) expressed primarily in the cell membranes of early hematopoietic progenitor cells, found in 28% of all patients with AML. FLT3 is the second most frequent mutation in adult AML following Nuclear-cytoplasmic shuttling phosphoprotein (NPM1), which is found in 50% of cases.1 FLT3 inhibitors are promising new molecular therapeutics increasingly becoming standard of care for both newly diagnosed and relapsed/refractory FLT3 positive AML. This review will focus on the clinical trials/evidence, similarities, differences, clinical toxicities, and drug interactions relevant to treating clinicians as pertains to 5 FLT3-inhibitors: midostaurin, sorafenib, gilteritinib, crenolanib, and quizartinib.

Leucovorin Rescue After Methotrexate Graft-Versus-Host Disease Prophylaxis Shortens the Duration of Mucositis, Time to Neutrophil Engraftment, and Hospital Length of Stay.

Oropharyngeal mucositis (OPM) is common following conditioning for allogeneic hematopoietic cell transplantation (alloHCT) and results in pain, functional status decline, need for nutritional support, infections, and prolonged length of stay (LOS). Methotrexate (MTX) graft-versus-host disease (GVHD) prophylaxis exacerbates OPM and slows hematopoietic engraftment, which may prolong LOS. Previous studies have demonstrated reduced OPM and more rapid engraftment when leucovorin (LCV) is added following MTX GVHD prophylaxis, yet this practice is controversial. The primary objective of this study was to determine if the routine addition of LCV to MTX GVHD prophylaxis impacted the duration of grade 2 to 4 OPM. Secondary objectives included determination of the incidence of grade 2 to 4 and grade 3 to 4 OPM, time to engraftment, ability to receive all four planned MTX doses, use of total parenteral nutrition (TPN), use of patient-controlled analgesia (PCA), LOS, incidence of acute or chronic GVHD, relapse-free survival (RFS), and overall survival (OS). This single-center, retrospective cohort study compared alloHCT outcomes for 46 adult patients who received MTX 15 mg/m2 day +1; MTX 10 mg/m2 days +3, +6, and +11 (15-10-10-10); and LCV following days +3, +6, and +11 MTX compared to historical controls who did not. Patients who received myeloablative conditioning (MAC) and matched related donor (MRD) or matched unrelated donor (MUD) alloHCT were included. The addition of LCV resulted in significant reductions in the duration of grade 2 to 4 OPM (median, 6 days versus 10.5 days; P = .0004), duration of TPN (7 days versus 16 days; P = .001), PCA use (16% versus 39%; P = .0001), time to neutrophil engraftment (median, 18 versus 20 days; P = .008), and LOS (median, 27.5 versus 31 days; P = .017) compared to historical controls. Patients who received routine LCV had similar incidences of grade 2 to 4 acute GVHD (30% versus 28%; relative risk [RR], 1.08; 95% confidence interval [CI], .57 to 2.03; P = 1.0), grade 3 or 4 acute GVHD (2% versus 7%; RR, .33; 95% CI, .04 to 3.09; P = .62) and chronic GVHD (37% versus 30%; RR, 1.21; 95% CI, .67 to 2.16; P = .66) compared to historical controls. Graft failure occurred in 2% of patients in each group. In a multivariable logistic regression analysis, RFS was similar in the LCV group compared to historical controls (HR, .86; 95% CI, .24 to 1.2; P = .13); however, OS was improved in patients who received LCV (HR, .33; 95% CI, .13 to .83; P = .01). In patients undergoing MAC MRD/MUD alloHCT with four planned doses of MTX GVHD prophylaxis (15-10-10-10), LCV was associated with reduced duration of grade 2 to 4 OPM, faster neutrophil engraftment, reduced utilization of TPN and PCA, and shortened LOS compared to historical controls not receiving routine LCV. These benefits were apparent without an increased risk of acute or chronic GVHD or adverse effect on RFS. LCV improved OS; however, it is unclear if this was due to the intervention or an unmeasured confounder. A randomized, prospective trial of LCV prophylaxis in patients receiving MAC alloHCT and MTX 15-10-10-10 GVHD prophylaxis is warranted to confirm our findings.

Venous thromboembolism following pegaspargase in adults receiving antithrombin supplementation.

Pegaspargase (PEG) increases venous thromboembolism (VTE) in acute lymphoblastic leukemia (ALL) potentially due to depletion of anticoagulation factors, including antithrombin (AT). The benefit and cost of AT supplementation in adults is unclear. We aimed to characterize VTE incidence and risk factors following AT and determine the characteristics and costs of supplementation. Fifty-three adults received PEG and AT. VTE occurred in 21% (grade ≥3 8%). T cell ALL and patients receiving prednisone during induction were at highest risk. Repeat AT levels post supplementation were subtherapeutic forty-four percent of the time. A median of 18 days elapsed between PEG and two sequential therapeutic AT levels despite supplementation. Patients received a median of 2 AT doses per PEG dose at a median cost of $11,145. VTE remains common in adults despite AT supplementation. More aggressive AT supplementation may reduce VTE but warrant prospective evaluation given the significant cost.

Risk of invasive fungal infections in patients with high-risk MDS and AML receiving hypomethylating agents.

Invasive fungal infections (IFI) are a significant source of morbidity and mortality for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Given the heterogeneity of the population receiving hypomethylating agents (HMA), it is difficult for clinicians to accurately assess their patients' risk of infection. Literature on the incidence of IFI following HMA is limited to several studies of azacitidine. The primary objective of this retrospective study was to establish the incidence of IFI in HMA treated AML/MDS patients at a large U.S. comprehensive cancer center. Secondary objectives included comparing incidence of IFI among pre-specified subgroups to identify potential risk factors for IFI. Two hundred three patients with AML, intermediate to very high risk MDS or chronic myelomonocytic leukemia who received at least two cycles of HMA were included. The incidence of IFI, as defined by the European Organization for Research and Treatment of Cancer / Invasive Fungal Infections Cooperative Group criteria, was 9.6%, with 20 IFI diagnosed following HMA (three proven, four probable, 13 possible). Among the proven cases of IFI, molds included Scedosporium and Fusarium spp. Eleven patients who developed IFIs were neutropenic upon initiating HMA. The majority (17/20) of infections occurred during the first four cycles. Given this incidence, mold-active prophylaxis can be considered in patients who are neutropenic at the start of therapy.

Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic Leukemia.

PURPOSE: The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential in adults. We report outcomes for adults with r/r ALL treated with an optimized CTL019 dosing and CRS management strategy. METHODS: Adults with r/r B-cell ALL received CTL019 in 1 of 2 trials. Patients received lymphodepletion followed by CTL019 as either a one-time infusion or fractionated infusions split over 3 days (day 1, 10%; day 2, 30%; day 3, 60%), which allowed for day 2 and day 3 doses to be held for early CRS. Total planned CTL019 dose varied with adaptive protocol modifications in response to efficacy and CRS toxicity. RESULTS: Thirty-five adults with r/r ALL received CTL019 in 1 of 3 dosing cohorts. The low-dose cohort (n = 9) received single or fractionated dosing and had manageable toxicity with a 33% complete remission (CR) rate. In the high-dose single infusion cohort, 3 of 6 patients with refractory CRS concurrent with culture-positive sepsis died, and 3 achieved CR. The 20 patients in the high-dose fractionated (HDF) cohort had a 90% CR rate and manageable CRS. The HDF cohort had the highest survival, with a 2-year overall survival of 73% (95% CI, 46% to 88%) and event-free survival of 49.5% (95% CI, 21% to 73%). CONCLUSION: Fractionated dosing of CTL019 with intrapatient dose modification optimizes safety without compromising efficacy in adults with r/r ALL.

Persistent Mixed Donor Chimerism following Double Umbilical Cord Transplantation in a Patient with T-Cell Prolymphocytic Leukemia.

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive postthymic T-cell neoplasm with an associated survival time of 1 year when left untreated. Current standard of care for T-PLL is with alemtuzumab, followed by allogeneic or autologous stem cell transplant. Little is found in the literature about alternative donor transplantation in T-PLL. Here, we present the case of a patient treated with double umbilical cord blood transplantation, which resulted in initial complete remission. An unusual outcome of this case is that coengraftment of both cords was established. After 16 months, the patient had relapse of the disease, unfortunately, prompting treatment with alemtuzumab and pentostatin, which resulted in remission once again. Here, we report a unique phenomenon whereby single-cord dominance occurred after treatment with these agents, suggesting that anti-T-cell therapy after transplant may help achieve single-unit dominance. A second relapse of the disease occurred six months thereafter, ultimately resulting in the patient's death, highlighting the aggressive nature of this disease.

Tocilizumab for the treatment of severe steroid-refractory acute graft-versus-host disease of the lower gastrointestinal tract.

Steroid-refractory (SR) acute gastrointestinal (GI) graft-versus-host disease (GVHD) is associated with significant mortality in allogeneic hematopoietic cell transplantation recipients. We retrospectively evaluated the efficacy of tocilizumab for the treatment of SR biopsy-proven acute lower GI GVHD in 16 consecutive adult transplant recipients between October 2015 and July 2016. Tocilizumab 8 mg/kg was administered every 2 weeks until achievement of complete response, defined as resolution of all manifestations of GI GVHD, or until patients had progression or initiation of other therapy. Ten of 16 patients (62.5%; 95% CI, 0.39-82) achieved a complete response after a median time of 11 days (range, 2-28 days) from tocilizumab initiation. The median time to response onset (improvement in stage by at least 1) was 1 day (range, 1-4 days). Tocilizumab was administered at a median of 9 days (range, 3-75 days) from GVHD diagnosis and 10 days (range, 3-75 days) from initiation of high-dose steroids. At a median follow-up of 7.6 months (range, 0.8-27.7 months) from initiation of tocilizumab, 6/16 (37.5%) patients are alive and free of their underlying hematologic malignancy. Tocilizumab appears to be a highly active agent for the treatment of severe SR lower GI acute GVHD.

Extended CCR5 Blockade for Graft-versus-Host Disease Prophylaxis Improves Outcomes of Reduced-Intensity Unrelated Donor Hematopoietic Cell Transplantation: A Phase II Clinical Trial.

Graft-versus-host disease (GVHD) remains the most common treatment-related complication after allogeneic hematopoietic cell transplantation (allo-HCT). Lymphocyte migration plays a critical role in the pathogenesis of GVHD. A previous phase I/II trial demonstrated that CCR5 blockade with maraviroc in the first 30days after allo-HCT resulted in a low incidence of early acute GVHD, primarily in visceral organs, but with no impact on late acute or chronic GVHD. We conducted a phase II trial to examine the efficacy of an extended course of maraviroc, administered through post-transplantation day +90 in addition to standard prophylaxis in 37 recipients of reduced-intensity-conditioned unrelated donor allo-HCT performed to treat hematologic malignancies. Extended maraviroc treatment was safe and feasible. The primary study endpoint, day +180 rate of grade II-IV acute GVHD, was 22 ± 7%, liver GVHD was not observed, and gut GVHD was uncommon. The day +180 rate of grade III-IV acute GVHD was 5 ± 4%. The 1-year rate of moderate to severe chronic GVHD was 8 ± 5% and that of disease relapse was 30 ± 8%. Overall survival at 1 year was 70 ± 8%. Compared with the previously studied short course of maraviroc, the extended course resulted in a significantly higher GVHD-free, relapse-free survival (adjusted hazard ratio [HR], .45; 95% confidence interval [CI], .25 to .82; P = .009) and overall survival (adjusted HR, .48; 95% CI, .24 to .96; P = .037). A combined analysis of both trials showed that high maraviroc trough concentrations on the day of hematopoietic cell infusion were associated with lower rates of acute GVHD. An extended course of maraviroc after reduced-intensity-conditioned unrelated donor allo-HCT is safe and effective in preventing acute and chronic GVHD and is associated with favorable survival.

Oral Vancomycin Prophylaxis Is Highly Effective in Preventing Clostridium difficile Infection in Allogeneic Hematopoietic Cell Transplant Recipients.

BACKGROUND: Clostridium difficile infection (CDI) is a leading cause of infectious complications in allogeneic hematopoietic cell transplant recipients (alloHCT). We sought to evaluate whether prophylactic oral vancomycin reduces the incidence of CDI in alloHCT recipients. METHODS: We conducted a retrospective cohort study to examine the effectiveness of CDI prophylaxis with oral vancomycin, as compared to no prophylaxis, in 145 consecutive adult alloHCT recipients at the University of Pennsylvania between April 2015 and November 2016. Patients received oral vancomycin 125 mg twice daily, starting on admission and continuing until discharge. The primary outcome of interest was the association between oral vancomycin prophylaxis and CDI diagnosis. Secondary outcomes included graft-versus-host disease (GVHD) and relapse. RESULTS: There were no cases of CDI in patients that received prophylaxis (0/90, 0%), whereas 11/55 (20%) patients who did not receive prophylaxis developed CDI (P < .001). Oral vancomycin prophylaxis was not associated with a higher risk of acute, grades 2-4 GVHD (subhazard ratio [sHR] 1.59; 95% confidence interval [CI] 0.88-2.89; P = .12), acute, grades 3-4 GVHD (sHR 0.65; 95% CI 0.25-1.66; P = .36), or acute, grades 2-4 gastrointestinal GVHD (sHR 1.95; 95% CI 0.93-4.07; P = .08) at day 180 post-transplant. No associations between oral vancomycin and relapse or survival were observed. CONCLUSIONS: Prophylaxis with oral vancomycin is highly effective in preventing CDI in alloHCT recipients without increasing the risk of graft-versus-host disease or disease relapse. Further evaluation via a prospective study is warranted.

Dose-related periorbital edema following sorafenib in a patient with acute myeloid leukemia.

We describe a case of dose-related periorbital edema in a patient with FLT3-mutated acute myeloid leukemia taking sorafenib and voriconazole that resolved following sorafenib dose reduction. We hypothesize that the mechanism of this adverse event may be related to the inhibition of platelet-derived growth factor receptor (PDGFR) by sorafenib. Clinicians should be aware of this possible dose-related adverse event and the potential role of sorafenib dose reduction when on concurrent voriconazole.