Ivosidenib significantly reduces triazole levels in patients with acute myeloid leukemia and myelodysplastic syndrome.

BACKGROUND: Ivosidenib is primarily metabolized by CYP3A4; however, it induces CYP450 isozymes, including CYP3A4 and CYP2C9, whereas it inhibits drug transporters, including P-glycoprotein. Patients with acute myeloid leukemia are at risk of invasive fungal infections, and therefore posaconazole and voriconazole are commonly used in this population. Voriconazole is a substrate of CYP2C9, CYP2C19, and CYP3A4; therefore, concomitant ivosidenib may result in decreased serum concentrations. Although posaconazole is a substrate of P-glycoprotein, it is metabolized primarily via UDP glucuronidation; thus, the impact of ivosidenib on posaconazole exposure is unknown. METHODS: Patients treated with ivosidenib and concomitant triazole with at least one serum trough level were included. Subtherapeutic levels were defined as posaconazole <700 ng/mL and voriconazole <1.0 µg/mL. The incidences of breakthrough invasive fungal infections and QTc prolongation were identified at least 5 days after initiation of ivosidenib with concomitant triazole. RESULTS: Seventy-eight serum triazole levels from 31 patients receiving ivosidenib-containing therapy and concomitant triazole were evaluated. Of the 78 concomitant levels, 47 (60%) were subtherapeutic (posaconazole: n = 20 of 43 [47%]; voriconazole: n = 27 of 35 [77%]). Compared to levels drawn while patients were off ivosidenib, median triazole serum levels during concomitant ivosidenib were significantly reduced. There was no apparent increase in incidence of grade 3 QTc prolongation with concomitant azole antifungal and ivosidenib 500 mg daily. CONCLUSIONS: This study demonstrated that concomitant ivosidenib significantly reduced posaconazole and voriconazole levels. Voriconazole should be avoided, empiric high-dose posaconazole (>300 mg/day) may be considered, and therapeutic drug monitoring is recommended in all patients receiving concomitant ivosidenib.

Characteristics and clinical outcomes of patients with acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2).

Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) has a very poor prognosis. Determinants of clinical outcomes and optimal treatment remain uncertain. We retrospectively reviewed 108 cases of AML with inv(3)/t(3;3) and evaluated clinicopathological characteristics and clinical outcomes: 53 newly diagnosed (ND) AML and 55 relapsed/refractory (R/R) AML. Median age was 55 years. White blood cell (WBC) count ≥20x109/L and platelet count ≥140x109/L was observed in 25% and 32% of ND patients, respectively. Anomalies involving chromosome 7 were identified in 56% of patients. The most frequently mutated genes were SF3B1, PTPN11, NRAS, KRAS and ASXL1. In ND patients, the composite complete remission (CRc) rate was 46% overall; 46% with high-intensity treatments and 47% with lowintensity treatments. The 30-day mortality was 14% and 0%, with high- and low-intensity treatment, respectively. In R/R patients, the CRc rate was 14%. Venetoclax based-regimens were associated with a CRc rate of 33%. The 3-year overall survival (OS) was 8.8% and 7.1% in ND and R/R patients, respectively. The 3-year cumulative incidence of relapse was 81.7% overall. Older age, high WBC, high peripheral blast count, secondary AML and KRAS, ASXL1, DNMT3A mutations were associated with worse OS in univariable analyses. The 5-year OS rates were 44% and 6% with or without hematopoietic stem cell transplantation in CR1, respectively. AML with inv(3)/t(3;3) is associated with low CR rates, very high risk of relapse and dismal long-term survival. Intensive chemotherapy and hy pomethylating agents provide similar rates of remission and patients achieving CR benefit from hematopoietic stem cell transplantation in first CR.

Phase II study of cladribine, idarubicin, and ara-C (CLIA) with or without sorafenib as initial therapy for patients with acute myeloid leukemia.

The addition of cladribine, or sorafenib to standard chemotherapy have each demonstrated improved survival in patients with newly-diagnosed acute myeloid leukemia (AML). We studied the combination of cladribine, idarubicin, and intermediate-dose cytarabine (CLIA) in patients ≤65 years of age with newly diagnosed AML, fit to receive intensive therapy. Cladribine (5 mg/m2) IV was administered on days (D)1-5, cytarabine (1 g/m2) on D1-5, and idarubicin (10 mg/m2) on D1-3. Sorafenib was added to the CLIA backbone for patients with FLT3-ITD mutated AML. 80 patients were enrolled: 65 with newly diagnosed AML and 15 with AML arising from previously treated MDS (ts-AML). The median age was 55 years (range, 21-65). CR + CRi was 83% (54/65) and 27% in the untreated and ts-AML cohorts, respectively; 74% and 75% of responding patients, respectively, had undetectable measurable residual disease (MRD). Among patients with FLT3-ITD mutated AML receiving CLIA+sorafenib, the CR + CRi rate was 95%, with 81% negative for MRD. With a median follow-up of 76 months, the 2- and 4-year OS of 57% and 50% compared to 20%, and 13% for ts-AML, respectively. Patients treated with CLIA+sorafenib had 2- and 5-year OS rates of 63% and 59%, respectively. The most common Grade ≥3 adverse events were infection/fever, elevated bilirubin, rash, and nausea. CLIA was safe and effective in young, fit patients with newly diagnosed AML with inferior outcomes among patients with ts-AML. The addition of sorafenib to CLIA in FLT3-ITD mutated AML resulted in high rates of durable remission and excellent long-term survival.

Comparison of Mold Active Triazoles as Primary Antifungal Prophylaxis in Patients With Newly Diagnosed Acute Myeloid Leukemia in the Era of Molecularly Targeted Therapies.

BACKGROUND: Multiple factors influence the choice of primary antifungal prophylaxis (PAP) in patients with acute myeloid leukemia (AML) undergoing remission induction chemotherapy (RIC) given the recent incorporation of targeted leukemia therapies into these regimens. METHODS: We evaluated the incidence and characteristics of breakthrough invasive fungal infections (bIFI) in 277 adult patients with newly diagnosed AML undergoing RIC with high-intensity, or low-intensity venetoclax-containing therapy. Patients receiving posaconazole (PCZ), voriconazole (VCZ), or isavuconazole (ISA) for > 5 days as PAP during RIC were included. Echinocandin use prior to, but not concomitantly with, the PAP azole was allowed. IFI (modified EORTC/MSG criteria) occurring after > 5 days of continuous azole exposure or within 14 days of discontinuation were considered bIFI. RESULTS: Proven or probable bIFI were observed in 11 patients (4%). The incidence of bIFI was 2.9% for PCZ, 4.8% for VCZ, and 5.7% for ISA (P = .55). In total, 161 patients (58%) received echinocandin prophylaxis prior to azole initiation. Neither echinocandin exposure nor chemotherapy intensity impacted bIFI rate. Patients with bIFI had a lower rate of absolute neutrophil count recovery > 1000 cells/µL (64% vs 90%, P = .021) or complete remission (CR; 18% vs 66%, P = .002) after RIC. Thirty-eight patients (14%) discontinued PAP due to toxicity, most often hepatotoxicity. Discontinuation due to hepatotoxicity was similar among azoles (PCZ: 13%; VCZ: 15%; ISA: 13%). CONCLUSIONS: The rate of bIFI is low during RIC in patients with newly diagnosed AML receiving any of the mold-active triazoles as PAP. Neutrophil recovery and achievement of CR are important for bIFI risk.

Urgent cytoreduction for newly diagnosed acute myeloid leukemia patients allows acquisition of pretreatment genomic data and enrollment on investigational clinical trials.

Newly diagnosed acute myeloid leukemia is often deemed a medical emergency, requiring urgent treatment. This is in contradiction with the need for accurate cytogenetic and molecular data, which is not immediately available, to select optimal therapy. We hypothesized that cytoreduction with hydroxyurea or cytarabine would enable urgent disease control and provide a bridge to clinical trial enrollment. We analyzed three prospective frontline clinical trials that allowed the use of cytoreduction before treatment initiation. Among 274 patients with a median age of 62 (range, 18-89), there was no significant difference in short- and long-term outcome and safety among patients who did (CytoRed) or did not receive (NoCytoRed) cytoreduction. The overall response rate in CytoRed group was 91%, compared with 86% in NoCytoRed group (p = .264). The 30- and 60-day mortality rates were 2% and 7% in CytoRed group, compared with 2% (p = .978) and 6% (p = .652) in NoCytoRed group, respectively. There was no significant difference in overall survival (OS) between in CytoRed group compared with NoCytoRed group (Hazard ratio 0.97, 95% CI 0.70-1.37, p = .879). Results were unchanged after stratification by age (< or ≥65 years) or after multivariate analyses for OS. Our data suggests that urgent cytoreduction using hydroxyurea or cytarabine is a feasible and safe approach to facilitate acquisition of complete diagnostic information prior to treatment initiation on a clinical trial.

Isavuconazole as Primary Antifungal Prophylaxis in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome: An Open-label, Prospective, Phase 2 Study.

BACKGROUND: Mold-active primary antifungal prophylaxis (PAP) is routinely recommended in neutropenic patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) undergoing remission-induction chemotherapy (RIC). Isavuconazole (ISAV) is an extended spectrum mold-active triazole and has superior tolerability and fewer significant drug-drug interactions compared with other triazoles. METHODS: In our investigator-initiated, phase 2 trial, treatment-naive adult patients with AML or MDS starting RIC received ISAV per the dosing recommendations in the US label until neutrophil recovery (absolute neutrophil count [ANC] ≥ 0.5 × 109/L) and attainment of complete remission, occurrence of invasive fungal infection (IFI), or for a maximum of 12 weeks. The primary endpoint was the incidence of proven/probable IFI during ISAV PAP and up to 30 days after the last dose. RESULTS: Sixty-five of 75 enrolled patients received ISAV PAP (median age, 67 years, median ANC at enrollment, 0.72 × 109/L). Thirty-two patients (49%) received oral targeted leukemia treatments (venetoclax, FTL3 inhibitors). Including the 30-day follow-up period, probable/proven and possible IFIs were encountered in 4 (6%) and 8 patients (12%), respectively. ISAV trough serum concentrations were consistently > 1 µg/mL, showed low intraindividual variation, and were not significantly influenced by chemotherapy regimen. Tolerability of ISAV was excellent, with only 3 cases (5%) of mild to moderate elevations of liver function tests and no QTc prolongations. CONCLUSIONS: ISAV is a safe and effective alternative for PAP in patients with newly diagnosed AML/MDS undergoing RIC in the era of recently approved or emerging small-molecule antileukemia therapies. CLINICAL TRIALS REGISTRATION: NCT03019939.

Outcomes of TP53-mutant acute myeloid leukemia with decitabine and venetoclax.

BACKGROUND: TP53 mutation (TP53mut ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53mut confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53mut AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.gov identifier NCT03404193). METHODS: Patients with newly diagnosed AML received decitabine 20 mg/m2 for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53mut was identified in bone marrow samples using next-generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines. RESULTS: Among 118 patients (median age, 72 years; age range, 49-89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53mut AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%-65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53mut AML compared with those who had wild-type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60-day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53mut versus wild-type TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Outcomes with DEC10-VEN in patients with TP53mut AML were comparable to historical results with 10-day decitabine alone. CONCLUSIONS: Patients with TP53mut AML have lower response rates and shorter survival with DEC10-VEN.

Ten-day decitabine with venetoclax versus intensive chemotherapy in relapsed or refractory acute myeloid leukemia: A propensity score-matched analysis.

BACKGROUND: Relapsed/refractory (R/R) acute myeloid leukemia (AML) has poor outcomes. Although lower-intensity venetoclax-containing regimens are standard for older/unfit patients with newly diagnosed AML, it is unknown how such regimens compare with intensive chemotherapy (IC) for R/R AML. METHODS: Outcomes of R/R AML treated with 10-day decitabine and venetoclax (DEC10-VEN) were compared with IC-based regimens including idarubicin with cytarabine, with or without cladribine, clofarabine, or fludarabine, with or without additional agents. Propensity scores derived from patient baseline characteristics were used to match DEC10-VEN and IC patients to minimize bias. RESULTS: Sixty-five patients in the DEC10-VEN cohort were matched to 130 IC recipients. The median ages for the DEC10-VEN and IC groups were 64 and 58 years, respectively, and baseline characteristics were balanced between the 2 cohorts. DEC10-VEN conferred significantly higher responses compared with IC including higher overall response rate (60% vs 36%; odds ratio [OR], 3.28; P < .001), complete remission with incomplete hematologic recovery (CRi, 19% vs 6%; OR, 3.56; P = .012), minimal residual disease negativity by flow cytometry (28% vs 13%; OR, 2.48; P = .017), and lower rates of refractory disease. DEC10-VEN led to significantly longer median event-free survival compared with IC (5.7 vs 1.5 months; hazard ratio [HR], 0.46; 95% CI, 0.30-0.70; P < .001), as well as median overall survival (OS; 6.8 vs 4.7 months; HR, 0.56; 95% CI, 0.37-0.86; P = .008). DEC10-VEN was independently associated with improved OS compared with IC in multivariate analysis. Exploratory analysis for OS in 27 subgroups showed that DEC10-VEN was comparable with IC as salvage therapy for R/R AML. CONCLUSION: DEC10-VEN represents an appropriate salvage therapy and may offer better responses and survival compared with IC in adults with R/R AML.

Duration of cytopenias with concomitant venetoclax and azole antifungals in acute myeloid leukemia.

BACKGROUND: Venetoclax (VEN) combined with the hypomethylating agent (HMA) azacitidine improves survival in patients aged ≥75 years with newly diagnosed acute myeloid leukemia (AML). VEN and HMA treatment can result in prolonged and often profound neutropenia, and this warrants antifungal prophylaxis. Azole antifungals inhibit cytochrome P450 3A4, the primary enzyme responsible for VEN metabolism; this results in VEN dose reductions for each concomitant antifungal. Limited clinical data exist on outcomes for patients treated with VEN, an HMA, and various azoles. METHODS: The time to neutrophil recovery (absolute neutrophil count [ANC] > 1000 cells/mm3 ) and platelet (PLT) recovery (PLT count > 100,000 cells/mm3 ) in 64 patients with newly diagnosed AML who achieved a response after course 1 of VEN plus an HMA were evaluated. HMA therapy included azacitidine (75 mg/m2 intravenously/subcutaneously for 7 days) or decitabine (20 mg/m2 intravenously for 5 or 10 days). RESULTS: Forty-seven patients (73%) received an azole: posaconazole (n = 17; 27%), voriconazole (n = 9; 14%), isavuconazole (n = 20; 31%), or fluconazole (n = 1; 2%). The median time to ANC recovery were similar for patients who did receive an azole (37 days; 95% confidence interval [CI], 34-38 days) and patients who did not receive an azole (39 days; 95% CI, 30 days to not estimable; P = .8). The median time to PLT recovery was significantly longer for patients receiving azoles (28 vs 22 days; P = .01). The median times to ANC recovery (35 vs 38 days) and PLT recovery (26 vs 32 days) were similar with posaconazole and voriconazole. CONCLUSIONS: VEN plus an HMA resulted in neutropenia and thrombocytopenia, with the latter prolonged in patients receiving concomitant azoles. Concomitant posaconazole or voriconazole and VEN (100 mg) resulted in similar ANC and PLT recovery times, suggesting the safety of these dosage combinations during course 1.

Venetoclax with decitabine vs intensive chemotherapy in acute myeloid leukemia: A propensity score matched analysis stratified by risk of treatment-related mortality.

Hypomethylating agents (HMA) with venetoclax is a new standard for older/unfit patients with acute myeloid leukemia (AML). However, it is unknown how HMA with venetoclax compare to intensive chemotherapy (IC) in patients who are "fit" or "unfit" for IC. We compared outcomes of older patients with newly diagnosed AML receiving 10-day decitabine with venetoclax (DEC10-VEN) vs IC. DEC10-VEN consisted of daily venetoclax with decitabine 20 mg/m2 for 10 days for induction and decitabine for 5 days as consolidation. The IC cohort received regimens containing cytarabine ≥1 g/m2 /d. A validated treatment-related mortality score (TRMS) was used to classify patients at high-risk or low-risk for TRM with IC. Propensity scores were used to match patients to minimize bias. Median age of the DEC10-VEN cohort (n = 85) was 72 years (range 63-89) and 28% patients were at high-risk of TRM with IC. The comparator IC group (n = 85) matched closely in terms of baseline characteristics. DEC10-VEN was associated with significantly higher CR/CRi compared to IC (81% vs 52%, P < .001), and lower rate of relapse (34% vs 56%, P = .01), 30-day mortality (1% vs 24%, P < .01), and longer overall survival (OS; 12.4 vs 4.5 months, HR = 0.48, 95%CI 0.29-0.79, P < .01). In patients at both at high-risk and low-risk of TRM, DEC10-VEN showed significantly higher CR/CRi, lower 30-day mortality, and longer OS compared to IC. Patients at both high-risk and low-risk of TRM had comparable outcomes with DEC10-VEN. In conclusion, DEC10-VEN offers better outcomes compared to intensive chemotherapy in older patients with newly diagnosed AML, particularly in those at high-risk of TRM.

Treating Leukemia in the Time of COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic poses several challenges to the management of patients with leukemia. The biology of each leukemia and its corresponding treatment with conventional intensive chemotherapy, with or without targeted therapies (venetoclax, FLT3 inhibitors, IDH1/2 inhibitors, Bruton's tyrosine kinase inhibitors), introduce additional layers of complexity during COVID-19 high-risk periods. The knowledge about COVID-19 is accumulating rapidly. An important distinction is the prevalence of "exposure" versus "clinical infectivity," which determine the risk versus benefit of modifying potentially highly curative therapies in leukemia. At present, the rate of clinical infection is <1-2% worldwide. With a mortality rate of 1-5% in CO-VID-19 patients in the general population and potentially of >30% in patients with cancer, careful consideration should be given to the risk of COVID-19 in leukemia. Instead of reducing patient access to specialized cancer centers and modifying therapies to ones with unproven curative benefit, there is more rationale for less intensive, yet effective therapies that may require fewer clinic visits or hospitalizations. Here, we offer recommendations on the optimization of leukemia management during high-risk COVID-19 periods.

The face of remission induction.

Acute myeloid leukaemia (AML) is a heterogeneous disease in which prognosis is determined by cytogenetic and molecular aberrations as well as patient-related factors, including age, prior haematologic disorders, and comorbidities. Despite the diverse disease biology, the standard of care for remission induction therapy has changed very little since its inception in 1973. Next generation sequencing has helped to increase our knowledge of the disease pathogenesis, allowing us to develop targeted and possibly more effective treatment options. Seven new agents have been approved for the treatment of AML since 2017, all of which are directed toward a specific molecular subtype or patient population. With the advent of these therapies, a more optimal, patient-specific approach rather than the historical 'one-size fits all' model can be utilised. This review will discuss the role of these novel therapies in the remission induction setting.

Cell cycle inhibitors for the treatment of acute myeloid leukemia: a review of phase 2 & 3 clinical trials.

Introduction: Acute myeloid leukemia (AML) is a clinically heterogeneous hematologic malignancy with poor long term outcomes. Cytotoxic chemotherapy remains the backbone of therapy especially among younger patients; however the effective incorporation of targeted therapies continues to be an area of active research in an effort to improve response durations and survival. Cell cycle inhibitors (CCI) are a novel class of agents which may be of particular interest for development in patients with AML. Areas covered: We will review the concept of CCIs along with available pre-clinical and clinical data in the treatment of AML both in North America and abroad. Specific drug targets reviewed include cyclin D kinase, Aurora kinase, CHK1, and WEE1. Expert opinion: Utilization of CCIs in patients with AML is an emerging approach that has shown promise in pre-clinical models. It has been challenging to translate this concept into clinical success thus far, due to marginal single-agent activity and significant toxicity profiles, however clinical evaluation is ongoing. Addition of these agents to cytotoxic chemotherapy and other targeted therapies provides a potential combinatorial path forward for this novel class of therapies. Developing optimal combinations while balancing toxicity are among the top clinical challenges that must be overcome before we can anticipate adoption of these agents into the armamentarium of AML therapy.

Optimizing patient selection for treatment-free remission.

The advent of BCR-ABL1 tyrosine kinase inhibitors has revolutionized the treatment and prognosis of chronic myeloid leukemia. Life expectancy for patients with chronic phase chronic myeloid leukemia now nears that of the healthy population; however, optimal outcomes require continuous tyrosine kinase inhibitor administration, which can impact patient quality of life. Consequently, the concept of treatment-free remission has been explored in patients achieving and sustaining a deep molecular response. Heterogeneous data exist with multiple tyrosine kinase inhibitors; however, nilotinib is currently the only therapy that has been approved by the US Food and Drug Administration for treatment-free remission. The decision to pursue treatment-free remission is one that relies heavily on both patient- and disease-related factors. Herein, we will discuss relevant considerations to be made when determining an optimal candidate for treatment-free remission.

Tolerability of isavuconazole after posaconazole toxicity in leukaemia patients.

BACKGROUND: Posaconazole (PCZ) is widely used for prophylaxis or treatment of invasive fungal infections (IFIs) in leukaemia patients. However, issues with PCZ tolerability can result in treatment interruption. Isavuconazole (ISA) has a similar broad spectrum of activity to PCZ; however, real-world data regarding the tolerability of ISA after PCZ toxicity are lacking. OBJECTIVES: To describe the tolerability of ISA after PCZ toxicity in leukaemia patients. PATIENTS/METHODS: We retrospectively assessed tolerability of ISA after PCZ toxicity in adult leukaemia patients (March 2015 to November 2017). We included all patients who received ≥7 days of ISA within 48 hours of PCZ discontinuation. Laboratory markers for liver toxicity were collected at three time points: prior to PCZ, at switch to ISA and after ISA therapy. RESULTS: We identified 23 such patients. Increased liver function tests (LFTs) were noted in 20 patients on PCZ, while three patients had Grade 3/4 QTc prolongation. No patient discontinued subsequent ISA due to toxicity. Grade 3/4 elevations in LFTs were decreased after changing to ISA (30% after PCZ vs 5% after ISA). No patient had significant QTc prolongation after switching to ISA. CONCLUSIONS: Isavuconazole was well-tolerated in patients discontinuing PCZ due to toxicity, with no patient discontinuing ISA due to toxicity.

Prolonged voriconazole treatment in a patient with chronic lymphocytic leukemia resulting in a litany of chronic overlapping toxicities.

Voriconazole is a triazole antifungal with activity against a number of yeast and mold species including Candida, Aspergillosis, Fusarium, and Coccidioides. Invasive fungal infections are associated with high morbidity and mortality, prolonged treatment courses, and occasionally lifelong suppressive therapy. Voriconazole therapy can result in a number of acute toxicities that clinicians are frequently aware of including hepatotoxicity, visual disturbances, and hallucinations; however, there is limited experience with extended durations of voriconazole therapy. We describe the case of a 62-year-old man who developed Coccidioides meningitis as a result of prolonged neutropenia from treatment for chronic lymphocytic leukemia. He was initially treated with a number of different antifungal agents including voriconazole, liposomal amphotericin B, fluconazole, and itraconazole; however, he developed acute toxicity due to those agents. He was successfully re-challenged with voriconazole, and maintained therapeutic serum concentrations throughout treatment. As a result of prolonged voriconazole exposure of over 14 years, he has suffered a number of toxicities, most significantly including actinic keratosis, squamous cell carcinoma, and skeletal fluorosis. To our knowledge, this is the longest continuous use of voriconazole therapy currently in the literature.

Treatment of relapsed/refractory acute lymphoblastic leukemia.

Patients with relapsed or refractory acute lymphoblastic leukemia (R/R ALL) have dismal outcomes, with survival of less than 6 months, and treatment options in the salvage setting have been limited to conventional cytotoxic chemotherapy with minimal activity. Advances in the development of novel targeted therapies have significantly improved outcomes in R/R ALL. Blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor (CAR) T-cell therapy constitute new treatment modalities that are challenging the historical regimens and paving a new path for treating patients with R/R ALL.

Breakthrough Fungal Infections in Patients With Leukemia Receiving Isavuconazole.

We retrospectively assessed breakthrough invasive fungal infections (b-IFIs) in 100 consecutive patients with leukemia receiving single-agent isavuconazole; 13 had documented b-IFIs (candidiasis in 6, mucormycosis in 4). All b-IFIs were observed in patients with prolonged neutropenia and active leukemia.

Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies.

INTRODUCTION: Venetoclax (VEN), a selective BCL2 inhibitor, has single-agent activity in relapsed and refractory (R/R) acute myeloid leukemia (AML), and efficacy in lower intensity combinations for treatment-naïve elderly AML patients. VEN treatment combinations in R/R AML have not been previously reported. METHODS: All R/R myeloid patients (including AML, myelodysplastic syndrome (MDS), and blastic plasmacytoid dendritic cell neoplasm (BPDCN)) treated with VEN combinations in the salvage setting were reviewed. RESULTS: Forty-three patients with median age 68 (range, 25-83) were treated for AML (91%), MDS (5%), or BPDCN (5%). Most (n = 36, 84%) were ≥ salvage-2 treatment status, including prior hypomethylating agent (HMA) in 77%. In combination with VEN, most patients received HMA therapy (n = 31, 72%); eight (19%) received low-dose cytarabine (LDAC). Patients received a median of 2 treatment cycles (range, 1-4). Objective response was observed in 9 (21%) patients, including 2 complete responses (CR), 3 CRi, and 4 morphologic leukemia-free state (MLFS). Median survival was 3.0 months (range, 0.5-8.0), and estimated 6-month survival was 24%. Responses were observed in five (24%) of 21 patients with intermediate-risk cytogenetics, 3 (27%) of 11 IDH1/2-mutant, and 4 (50%) of 8 RUNX1-mutated patients. Two (20%) of 10 TP53-mutated patients responded; both had concurrent RUNX1 mutations. Of the 3 (15%) responding patients with adverse cytogenetics, all had concurrent RUNX1 mutations. CONCLUSION: Low-intensity chemotherapy, including HMAs or LDAC, in combination with VEN is a viable salvage option, even in multiply relapsed/refractory patients with AML, MDS, and BPDCN. Notable responses were identified in patients with diploid/intermediate cytogenetics, RUNX1, and/or IDH1/2 mutations.

Treatment of adult acute lymphoblastic leukemia with inotuzumab ozogamicin.

Treatment of adult acute lymphoblastic leukemia (ALL) has largely relied on cytotoxic chemotherapy agents borrowed from successful treatment regimens of pediatric ALL. However, the high cure rates seen in pediatric ALL have not been replicated in adults. In recent years, the development of monoclonal antibodies targeting cell surface antigens, such as CD19 and CD20, have significantly improved outcomes when used alone or in combination with cytotoxic chemotherapy. With these novel agents come challenges in managing adverse events, understanding mechanisms of resistance and determining their optimal place in therapy alongside conventional chemotherapy and allogeneic stem cell transplant. Herein we discuss the above challenges with the next addition to the armamentarium of antileukemic agents, inotuzumab ozogamicin, an antibody-drug conjugate against CD22.