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PDF file - 255 KB, Figure 1. Flavopiridol conditional weighted residuals vs. time with a smoothed loess line. Figure 2. Flavopiridol conditional weighted residuals vs. population predicted values with a smoothed loess line. Figure 3. Visual predictive check (VPC) plots for flavopiridol stratified by body weight. Open circles, observed data; grey solid line, median of observed data at nominal time; grey dashed line, 95% confidence interval (CI) of observed data at nominal time; black solid line, median of simulated data at nominal time; black dashed line, 95% prediction interval (PI) of simulated data at nominal time; grey area, 95% CI around median or 95% PI of simulated time. Figure 4. Flavopiridol-glucuronide (Flavo-G) conditional weighted residuals vs. time with a smoothed loess line. Figure 5. Flavopiridol-glucuronide (Flavo-G) conditional weighted residuals vs. population predicted values with a smoothed loess line. Figure 6. Predicted median TLS probability vs. observed TLS probability with a line of unity. Figure 7. TLS probability vs. median parent drug (flavopiridol) AUC.

Supplementary table 1. Selected early phase clinical trials evaluating Reolysin single-agent and combination treatment regimens. Abbreviations: SD = stable disease, PR = partial response, CR = complete response; ER = endoplasmic reticulum.

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Purpose: Flavopiridol, the first clinically evaluated cyclin-dependent kinase inhibitor, shows activity in patients with refractory chronic lymphocytic leukemia, but prevalent and unpredictable tumor lysis syndrome (TLS) presents a major barrier to its broad clinical use. The purpose of this study was to investigate the relationships between pretreatment risk factors, drug pharmacokinetics, and TLS.Experimental Design: A population pharmacokinetic/pharmacodynamic model linking drug exposure and TLS was developed. Plasma data of flavopiridol and its glucuronide metabolite (flavo-G) were obtained from 111 patients treated in early-phase trials with frequent sampling following initial and/or escalated doses. TLS grading was modeled with logistic regression as a pharmacodynamic endpoint. Demographics, baseline disease status, and blood chemistry variables were evaluated as covariates.Results: Gender was the most significant pharmacokinetic covariate, with females displaying higher flavo-G exposure than males. Glucuronide metabolite exposure was predictive of TLS occurrence, and bulky lymphadenopathy was identified as a significant covariate on TLS probability. The estimated probability of TLS occurrence in patients with baseline bulky lymphadenopathy less than 10 cm or 10 cm or more during the first 2 treatments was 0.111 (SE% 13.0%) and 0.265 (SE% 17.9%), respectively, when flavo-G area under the plasma concentration versus time curve was at its median value in whole-patient group.Conclusions: This is the first population pharmacokinetic/pharmacodynamic model of TLS. Further work is needed to explore potential mechanisms and to determine whether the associations between TLS, gender, and glucuronide metabolites are relevant in patients with chronic lymphocytic leukemia treated with other cyclin-dependent kinase inhibitors. Clin Cancer Res; 19(5); 1269–80. ©2012 AACR.

Purpose: Reolysin, a proprietary isolate of reovirus type III dearing, enters and preferentially induces apoptosis of malignant cells. RAS pathway activation has been associated with more efficient reoviral infectivity and enhanced oncolysis. Reovirus is currently in advanced solid tumor phase I-II trials; no clinical trials have been conducted in patients with hematologic malignancies.Experimental Design: A phase I trial treated 12 relapsed myeloma patients at two dose levels. Reolysin was infused daily for 5 days every 28 days. Bone marrow specimens were examined by in situ-based hybridization (ISH) for CD138, p38, caspase-3, reoviral RNA, and capsid protein at screening and cycle 1 day 8. Junctional adhesion molecule 1 (JAM-1) and cancer upregulated gene 2 (CUG2) were evaluated in patient samples and multiple myeloma cell lines. Neutralizing anti-reovirus antibody assay was performed weekly during cycle 1.Results: There were no dose-limiting toxicities, patients reached the 3 × 1010 TCID50 daily on days 1 to 5 dose level, and grade 3 laboratory toxicities included neutropenia, thrombocytopenia, and hypophosphatemia. ISH demonstrated reoviral genome confined in multiple myeloma cells. Reoviral capsid protein and caspase-3 were rarely identified within reoviral RNA-positive cells. The longest durations of stable disease were 4, 5, and 8 months.Conclusions: Treatment with single-agent Reolysin was well tolerated and associated with avid reoviral RNA myeloma cell entry but only minimal intracellular reoviral protein production within multiple myeloma cells. Our data support that in multiple myeloma cells, Reolysin-induced oncolysis requires combination therapy, similar to other cancers. Clin Cancer Res; 20(23); 5946–55. ©2014 AACR.

PDF file - 79 KB, Supplementary Table 1. Patient Characteristics Supplementary Table 2. Summary of drop-outs in Cycle 1

Supplementary table 2. Five patients experienced at least grade 2 adverse events. Two of the 5 patients received at least 4 cycles of treatment, and the associated adverse events were noted after cycle 1. All cytopenias resolved prior to the completion of the cycle that adverse event occurred. Abbreviations: DL = dose level, m-protein = monoclonal protein, CXDX = cycle X, day X, NA = not available.

Supplementary figure 1. The top ten worst adverse events include grade 1 - 3 events. Grade 1 events included decreased neutrophil, white blood cell, lymphocyte, and platelet counts, increased aspartate aminotransferase and alkaline phosphatase, and nausea. Grade 2 events included decreased neutrophil, white blood cell, and platelet counts, anemia, and myalgia. Grade 3 events included decreased neutrophil, white blood cell, and platelet counts, and hypophosphatemia.

Complex karyotype, defined as ≥3 cytogenetic abnormalities, is prognostic of survival in patients treated with ibrutinib or venetoclax in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL). Recent studies re-evaluating this dichotomous variable have shown that higher numbers of cytogenetic abnormalities (ie, ≥5) have a worse overall survival in patients treated with chemoimmunotherapy. We sought to determine if increasing karyotypic complexity, treated as a continuous variable, was prognostic of survival for patients treated with ibrutinib for CLL. We conducted a retrospective analysis of all patients with CLL treated with single-agent ibrutinib or in combination with an anti–CD20 antibody at our institution. We included 456 patients with both treatment-naive and RR disease. Median number of prior therapies was 2 (range, 0-13), 30% of patients had presence of del(17p), and 75% expressed unmutated IGHV. Fifty percent had ≥3 cytogenetic abnormalities, including 30% with ≥5. In a multivariable analysis, increasing karyotypic complexity was an independent predictor of shorter progression-free survival (hazard ratio, 1.07; 95% confidence interval, 1.04-1.10; P < .0001) and overall survival (hazard ratio, 1.09; 95% confidence interval, 1.05-1.12; P < .0001). Furthermore, we found that presence of clonal evolution determined by cytogenetic analysis at progression was prognostic of subsequent survival (P = .02). This solidifies karyotypic complexity as an important prognostic factor for patients with CLL treated with ibrutinib. Further research should consider sequential karyotypic analysis as a determination of risk of progression and death in patients with CLL.

Chronic lymphocytic leukemia (CLL) transformation to aggressive lymphoma, known as Richter's Transformation (RT), has a dismal prognosis. There are limited data evaluating risk of RT in patients treated with ibrutinib. We performed a retrospective analysis to determine prognostic variables associated with development of RT and overall survival (OS) at progression after treatment with ibrutinib. We identified 559 patients with CLL treated with ibrutinib from 2010-2019. After a median follow-up of 44.5 months from ibrutinib start, 179 patients progressed and were included in our analysis. After a median follow-up of 20.8 months from progression, 54 out of 179 patients developed RT. Progression on treatment (hazard ratio [HR] 4.01 [1.60-10.00], p = .003), higher LDH (HR 1.80 for 2-fold increase [1.33-2.43], p = .0001), and lymphadenopathy without lymphocytosis (HR 2.88 [1.15-7.20], p = .02) were independent prognostic variables for the development of RT at progression. Progression with lymphadenopathy without lymphocytosis continued to be an independent prognostic variable of worse OS post-progression. In a subset analysis of 50 patients who obtained a PET-CT at progression, the median SUV

Standard treatment options in classic HCL (cHCL) result in high response rates and near normal life expectancy. However, the disease itself and the recommended standard treatment are associated with profound and prolonged immunosuppression, increasing susceptibility to infections and the risk for a severe course of COVID-19. The Hairy Cell Leukemia Foundation (HCLF) has recently convened experts and discussed different clinical strategies for the management of these patients. The new recommendations adapt the 2017 consensus for the diagnosis and management with cHCL to the current COVID-19 pandemic. They underline the option of active surveillance in patients with low but stable blood counts, consider the use of targeted and non-immunosuppressive agents as first-line treatment for cHCL, and give recommendations on preventive measures against COVID-19.

Hairy cell leukemia (HCL) is a rare chronic B cell lymphoproliferative disorder characterized by high prevalence of BRAF V600E mutation.1,2 Purine nucleoside analogues can achieve an overall response rate (ORR) of 90 to 100% and complete responses (CR) of 80 to 95% and remain the mainstay of first-line treatment in HCL.3,4 However, approximately 30-40% patients will experience recurrent disease and relapse-free survival rates decrease with repeated courses of purine analogue-based treatments with cumulative myelotoxicity and immune suppression.5,6 The genetic basis of HCL was first uncovered a decade ago when Tiacci and colleagues reported that BRAF V600E is a key mutation in HCL,7 a finding that was further validated by subsequent studies.8,9 Based on these findings, we conducted a multicenter phase 2 clinical trial in the U.S. evaluating the efficacy and safety of vemurafenib, an oral BRAF inhibitor, in patients with relapsed/ refractory (R/R) HCL. We previously published the initial outcome of 26 U.S. patients together with the Italian study conducted by Tiacci et al.7 Vemurafenib monotherapy induced 96-100% ORR and 35-42% CR rates in both studies. With a median follow-up duration of 11.7 months, we observed relapses in 29% of the patients but the long-term clinical outcome and response or acquired resistance to vemurafenib retreatment have not been previously reported. Herein, we report the long-term follow-up data of the entire patient cohort in the completed U.S. clinical trial (NCT01711632) including the ORR, relapse free survival, clinical factors associated with improved survival as well as outcomes after retreatment with vemurafenib or alternative agents.

7511 Background: Patients (pts) with chronic lymphocytic leukemia (CLL) suffer morbidity and mortality from CLL and increased risk for second primary neoplasia (SPN). BTK inhibitors (BTKi) are highly effective for the treatment (tx) of CLL and are associated with partial restoration of immune function with ongoing tx. The impact of BTKi on the risk for and patterns of SPN is yet to be characterized. Methods: CLL pts treated with ibrutinib or acalabrutinib at our center were identified retrospectively. Baseline (bl) and outcome data were collected including incidence (inc) of Richter’s transformation (RT), non-melanoma skin cancer (NMSC), and SPN. Standard inc ratio (SIR) with 95% confidence intervals (CI) were calculated using expected inc rates from the Surveillance, Epidemiology, and End Results Program, assuming a Poisson distribution for the observed inc. Cumulative inc (CIR) of SPN (excluding RT and NMSC) was calculated from BTKi start date to the diagnosis of SPN; death was a competing risk and pts without event were censored at last follow-up (f/u). SPN was correlated with bl data using the Fine-Gray model. Results: 691 pts were included; median age was 64 years (y), median prior lines of treatment (tx) was 2 (20% tx-naïve, 66% with prior chemo-immunotherapy), and 56% were never smokers. At median f/u of 44 months, 68 pts (10%) were diagnosed (dx) with SPN (SIR 2.4, CI 1.9-3.0) including 13 lung (SIR 3.2, CI 1.7-5.5), 9 melanoma (SIR 6.9, CI 3.1-13), 9 prostate (SIR 1.4, CI 0.6-2.6), 7 bladder (SIR 5.2, CI 2.1-10.6) cancers. CIR of SPN at 3 y was 7.6% (Table). Smoking (hazard ratio (HR) 2.9, CI 1.7-5.0, p < .01) and low bl CD8 count (HR 0.9 for 2-fold increase, CI 0.8-0.9, p < .01) were associated with higher inc of SPN. RT was dx in 58 pts (8%) and NMSC in 138 pts (20%). 179 pts had died with 3 y overall survival of 79% (CI 76-82); the most common causes of death were CLL/RT (57%) and SPN (13%). Conclusions: The inc of SPN in pts treated with BTKi for CLL is increased relative to the general population. With a 5 y CIR of NMSC and SPN of 23% and 12%, these data support consideration of intensive cancer screening for CLL pts receiving BTKi. [Table: see text]

Mutations of the IGH variable region in patients with chronic lymphocytic leukemia are associated with a favorable prognosis, whereas cytogenetic complexity (≥3 unrelated aberrations) and translocations have been associated with an unfavorable prognosis. While mutational status of IGHV is stable, cytogenetic aberrations frequently evolve. However, the relationships of these features as prognosticators at diagnosis are unknown. We examined the CpG-stimulated metaphase cytogenetic features detected within 1 year of diagnosis of chronic lymphocytic leukemia and correlated these features with outcome and other clinical features including IGHV mutational status. Of 329 untreated patients, 53 (16.1%) had a complex karyotype, and 85 (25.8%) had a translocation. The median time to first treatment (TFT) was 47 months. In univariable analyses, significant risk factors for shorter TFT (P3.5 mg/L, log-transformed white blood cell count, unmutated IGHV, a complex karyotype, a translocation, and trisomy 8, del(11q) or del(17p) detected by fluorescence in situ hybridization. In multivariable analysis, there was a significant effect modification of IGHV status on the relationship between translocation and TFT (P=0.002). In IGHV-mutated patients, those with a translocation had an over 3.5 times higher risk of starting treatment than those without a translocation (P

Background: Acalabrutinib (A) is a next-generation, highly selective, covalent Bruton tyrosine kinase (BTK) inhibitor approved for marketing by the US FDA in patients (pts) with chronic lymphocytic leukemia (CLL). While responses to A monotherapy are durable in CLL, response depth may be enhanced with combination therapy and potentially allow treatment discontinuation. The safety and efficacy of A plus a CD20 antibody (obinutuzumab [O] or rituximab [R]) and the BCL-2 inhibitor venetoclax (V) were examined in a phase 1b study (CL-003; NCT02296918) in relapsed/refractory (R/R) or treatment-naïve (TN) CLL pts. Methods: Pts were aged ≥18 years with intermediate or high-risk CLL (R/R or TN) and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Prior BTK inhibitor treatment was allowed for R/R pts if discontinuation was not due to CLL progression. R/R CLL pts received oral (PO) A 100 mg twice daily (BID) until progression, plus intravenous (IV) R 375 mg/m2 for 9 infusions (cycles 2-7), plus V PO daily per standard dosing (cycles 3-15). TN CLL pts received PO A and V (as above) plus IV O per standard dosing (cycles 2-7). The primary endpoint was safety. Secondary endpoints included investigator-assessed overall response rate (ORR, partial response [PR] or better) at cycle 16, complete response (CR) rate, undetectable minimal residual disease (uMRD) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and pharmacokinetics (PK). Results: Twelve pts were included in each cohort (R/R: male, n=9 [75%], median [range] age: 66 [55-72] y; TN: male, n=9 [75%], median [range] age: 61 [42-73] y). All pts had ECOG PS ≤1; 6/8 (75%) R/R and 8/10 (80%) TN pts had unmutated IGHV ( At a median follow-up of 23.2 mo (range: 19.8-25.3) in R/R pts and 22.0 mo (range: 19.5-24.4) in TN pts, 11 (92%) and 10 (83%) pts remained on treatment, respectively. Reasons for treatment discontinuation were adverse events (AEs) in 1 pt (8%) in each cohort (R/R: grade 1 purpura; TN: grade 2 head discomfort), and withdrawal by 1 pt (8%) in the TN cohort. The median number of treatment cycles in R/R pts was 23 (range: 14.9-27.5) for A, 6 (6-6) for R, and 13 (10.0-13.7) for V, and in TN pts was 23 (18.0-24.8) for A, 6 (6-6) for O, and 13 (13.0-13.5) for V. Reported AEs were similar to the individual agents' toxicity profiles (Table 1). Among AEs of interest, 7 R/R pts (58%) and 4 TN pts (33%) had cardiac AEs; grade ≥3 cardiac AEs were reported in 1 pt (8%). Atrial fibrillation was reported in 1 pt (grade 3; R/R pt with prior atrial fibrillation history). No ventricular arrhythmias were reported. Three R/R pts (25%) and 7 TN pts (58%) had hypertension AEs; none were grade ≥3. The most frequent infections (≥40%) were upper respiratory tract infection (URTI; 50%) in R/R pts and URTI (67%), sinusitis (42%), and nasopharyngitis (42%) in TN pts. Grade ≥3 infections occurred in 3 TN pts (lung infection, n=2 [17%]; prostate infection, staphylococcal bacteremia, staphylococcal sepsis, n=1 [8%] each) and no R/R pts. Six R/R pts (50%) and 3 TN pts (25%) had infusion-related reactions; none were grade ≥3. One R/R pt (8%) and 6 TN pts (50%) had decreased neutrophil counts; all were grade ≥3. No tumor lysis syndrome AEs, Richter transformations, or deaths were reported. After 16 cycles, ORR was 92% (95% CI: 62-100) in R/R pts and 100% (95% CI: 74-100) in TN pts. At the time of data cutoff, 50% of pts in each cohort had achieved CR or CR with incomplete marrow recovery (CRi). All pts with CR or CRi achieved uMRD (10-4) in peripheral blood (PB) at the time of CR/CRi or earlier. Overall, 8 (67%) R/R and 9 (75%) TN pts achieved uMRD (10-4) in PB at cycle 10 (Table 2). Median DOR, PFS, and OS were not reached in either group. Estimated 18-mo PFS and OS rates were 100% (95% CI: not estimable) in both cohorts. The PK of A and its active metabolite, ACP-5862, were consistent when given as monotherapy or with V, R, or O. The PK of V remained within the range observed with monotherapy (Salem et al. J Clin Pharmacol. 2017;57:484-492) when given with A. Conclusions: Combination therapy with A plus an anti-CD20 antibody and BCL-2 inhibitor leads to a tolerable safety profile with high CR and uMRD rates in both R/R and TN CLL pts, with minimal to no drug-drug interactions. Disclosures Woyach: Pharmacyclics, Janssen, Morphosys, Karyopharm, Verastem, Abbvie, Lox: Research Funding; Pharmacyclics LLC, an AbbVie Company, AbbVie, Janssen, AstraZeneca, ArQule: Honoraria; Janssen, Pharmacyclics, AstraZeneca, Abbvie, Arqule: Consultancy. Blachly:AbbVie, AstraZeneca, KITE Pharma: Consultancy. Rogers:Janssen: Research Funding; AstraZeneca: Consultancy, Other: Travel Funding; Pharmacyclics: Consultancy; AbbVie: Consultancy, Research Funding; Genentech: Research Funding; Acerta Pharma: Consultancy. Lozanski:Genentech, Novartis, Beckman Coulter: Research Funding. Andersen:Ohio State University: Current Employment, Research Funding. Patel:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Munugalavadla:Acerta Pharma/AstraZeneca: Current Employment, Current equity holder in publicly-traded company; Gilead Sciences: Current equity holder in publicly-traded company, Other: Family Association. Butturini:Puma Biotechnology: Divested equity in a private or publicly-traded company in the past 24 months; Dynavax, Puma Biotechnology: Ended employment in the past 24 months; Roche/Genentech, Pfeizer, AstraZeneca, Amgen: Current equity holder in publicly-traded company; Acerta Pharma: Current Employment. Xu:Acerta Pharma: Current Employment, Research Funding; AstraZeneca: Research Funding. Wang:Acerta Pharma: Current Employment. Byrd:Acerta Pharma: Research Funding; Syndax: Research Funding; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Trillium: Research Funding; Leukemia and Lymphoma Society: Other; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other; Vincera: Research Funding.

Hairy cell leukemia (HCL) is a rare B-cell malignancy, and there is a need for novel treatments for patients who do not benefit from purine analogs. Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signaling pathway, is highly effective in several malignancies. Its activity in HCL was unknown, so we conducted a multisite phase 2 study of oral ibrutinib in patients with either relapsed classic or variant hairy cell leukemia. The primary outcome measure was the overall response rate (ORR) at 32 weeks, and we also assessed response at 48 weeks and best response during treatment. Key secondary objectives were characterization of toxicity and determination of progression-free survival (PFS) and overall survival (OS). Thirty-seven patients were enrolled at 2 different doses (24 at 420 mg, 13 at 840 mg). The median duration of follow-up was 3.5 years (range, 0-5.9 years). The ORR at 32 weeks was 24%, which increased to 36% at 48 weeks. The best ORR was 54%. The estimated 36-month PFS was 73% and OS was 85%. The most frequent adverse events were diarrhea (59%), fatigue (54%), myalgia (54%), and nausea (51%). Hematologic adverse events were common: anemia (43%), thrombocytopenia (41%), and neutropenia (35%). Ibrutinib can be safely administered to patients with HCL with objective responses and results in prolonged disease control. Although the initial primary outcome objective of the study was not met, the observation of objective responses in heavily pretreated patients coupled with a favorable PFS suggests that ibrutinib may be beneficial in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01841723.

Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and hematopoietic cell transplantation (HCT) is the only curative treatment. New targeted therapies improved survival in select patients with specific mutations, however management of patients without these molecular alterations is an unmet need. We conducted a phase one study of lenalidomide in combination with cytarabine/idarubicin salvage chemotherapy in patients with R/R AML and high‐risk myelodysplastic syndromes. A total of 33 patients were enrolled in the study (30 AML, 3 MDS), and treated at three dose levels with 3 + 3 design. Dose‐limiting toxicity (DLT) was seen in eight patients, including four hematologic DLTs. The most commonly observed non‐hematologic serious adverse events were febrile neutropenia, rash, sepsis and renal injury. Dose level −1, consisting of 25 mg/d lenalidomide D1‐21, 1 g/m2 cytarabine D5‐8, and 8 mg/m2 idarubicin D5‐7 was determined to be the maximum tolerated dose. Note, 15/33 (45%) of patients were able to receive pre‐planned 21 days of lenalidomide. Overall, 18 patients achieved complete remission (CR) (n = 14) or CR with incomplete count recovery (CRi) (n = 4) with total CR/CRi rate of 56%. The 1‐year and 2‐year overall survival (OS) were 24% and 10%, respectively. Among responders, 10/18 underwent allogeneic HCT and had a 1‐year OS of 40%. There was no molecular pattern associated with response. These data demonstrate that the combination had clinical activity in R/R AML. This regimen should be further investigated for patients who relapsed after HCT, and as a bridge therapy to HCT. (ClinicalTrials.gov identifier: NCT01132586).

Poly(ADP-ribose) polymerase inhibitors are FDA-approved for treatment of BRCA mutated metastatic breast cancer (MBC). Prior studies demonstrated benefit of adding oral PARPi veliparib to carboplatin and paclitaxel in BRCA mutation positive patients with MBC. We sought to find the recommended phase II dose (RP2D) and schedule of veliparib in combination with carboplatin in patients with advanced breast cancer, either triple negative (TNBC) or hormone receptor (HR) positive, HER2-negative with defective functional Fanconi Anemia (FA) DNA-repair pathway. Patients received escalating doses of veliparib on a 7, 14, or 21-day schedule with carboplatin every 3 weeks. Patients underwent [18]fluoro-3’-deoxythymidine (18FLT) positron emission tomography (PET) imaging, assessed in a blinded fashion. Forty-four patients (39 TNBC, 5 HR-positive/HER2-negative with a defective FA pathway) received a median of 5 cycles (range 1-36). Observed DLTs were grade (G) 4 thrombocytopenia (N=4), G4 neutropenia (N=1) and G3 akathisia (N=1). Common grade 3-4 toxicities included thrombocytopenia, lymphopenia, neutropenia, anemia, and fatigue. Of 43 patients evaluable for response, 18.6% achieved partial response and 48.8% had stable disease. Median progression free survival was 18.3 weeks. RP2D of veliparib was established at 250 mg twice daily on days 1-21 along with carboplatin at AUC 5. Patients with partial response had significant drop in SUVmax of target lesions between baseline and early 18FLT-PET (day 7-21; ptrend=0.006). Continuous dosing of veliparib and every three week carboplatin demonstrated activity and acceptable toxicity. Decrease in SUVmax on 18FLT-PET scan during the first cycle of this therapy can identify patients likely to have a response.IMPLICATIONS FOR PRACTICEThe BROCADE studies suggest that patients with BRCA mutation benefit from addition of PARP inhibitor veliparib to carboplatin plus paclitaxel. In this study, we demonstrate that a higher dose of veliparib is tolerable and active in combination with carboplatin alone. With growing interest in imaging-based early response assessment, we demonstrate that decrease in 18FLT-PET SUVmax in the first cycle of therapy is significantly associated with response. Collectively, this study provides clarity on dosing of veliparib with carboplatin in advanced breast cancer while providing additional data on the potential for novel PET imaging modalities in monitoring therapy response.

Background Poly(ADP‐ribose) polymerase inhibitors (PARPis) are U.S. Food and Drug Administration (FDA) approved for treatment of BRCA‐mutated metastatic breast cancer. Furthermore, the BROCADE studies demonstrated benefit of adding an oral PARPi, veliparib, to carboplatin and paclitaxel in patients with metastatic breast cancer harboring BRCA mutation. Given multiple possible dosing schedules and the potential benefit of this regimen for patients with defective DNA repair beyond BRCA, we sought to find the recommended phase II dose (RP2D) and schedule of veliparib in combination with carboplatin in patients with advanced breast cancer, either triple‐negative (TNBC) or hormone receptor (HR)‐positive, human epidermal growth receptor 2 (HER2) negative with defective Fanconi anemia (FA) DNA‐repair pathway based on FA triple staining immunofluorescence assay. Materials and Methods Patients received escalating doses of veliparib on a 7‐, 14‐, or 21‐day schedule with carboplatin every 3 weeks. Patients underwent [18]fluoro‐3′‐deoxythymidine (18FLT) positron emission tomography (PET) imaging. Results Forty‐four patients (39 TNBC, 5 HR positive/HER2 negative with a defective FA pathway) received a median of 5 cycles (range 1–36). Observed dose‐limiting toxicities were grade (G) 4 thrombocytopenia (n = 4), G4 neutropenia (n = 1), and G3 akathisia (n = 1). Common grade 3–4 toxicities included thrombocytopenia, lymphopenia, neutropenia, anemia, and fatigue. Of the 43 patients evaluable for response, 18.6% achieved partial response and 48.8% had stable disease. Median progression‐free survival was 18.3 weeks. RP2D of veliparib was established at 250 mg twice daily on days 1–21 along with carboplatin at area under the curve 5. Patients with partial response had a significant drop in maximum standard uptake value (SUVmax) of target lesions between baseline and early in cycle 1 based on 18FLT‐PET (day 7–21; p trend = .006). Conclusion The combination of continuous dosing of veliparib and every‐3‐week carboplatin demonstrated activity and an acceptable toxicity profile. Decrease in SUVmax on 18FLT‐PET scan during the first cycle of this therapy can identify patients who are likely to have a response. Implications for Practice The BROCADE studies suggest that breast cancer patients with BRCA mutation benefit from addition of veliparib to carboplatin plus paclitaxel. This study demonstrates that a higher dose of veliparib is tolerable and active in combination with carboplatin alone. With growing interest in imaging‐based early response assessment, the authors demonstrate that decrease in [18]fluoro‐3′‐deoxythymidine positron emission tomography (FLT‐PET) SUVmax during cycle 1 of therapy is associated with response. Collectively, this study established a safety profile of veliparib and carboplatin in advanced breast cancer while also providing additional data on the potential for FLT‐PET imaging modality in monitoring therapy response., This phase I study of veliparib in combination with carboplatin in patients with metastatic triple negative or hormone receptor positive, HER2‐negative breast cancer with somatic deficiency in the Fanconi anemia pathway, established a safety profile and recommended phase II dose of the combination and provided new information on the use of novel PET imaging modalities in monitoring therapy response.

KMT2A partial tandem duplication occurs in approximately 5-10% of patients with acute myeloid leukemia and is associated with adverse prognosis. KMT2A wild type is epigenetically silenced in KMT2A partial tandem duplication; re-expression can be induced with DNA methyltransferase and/or histone deacetylase inhibitors in vitro, sensitizing myeloid blasts to chemotherapy. We hypothesized that epigenetic silencing of KMT2A wildtype contributes to KMT2A partial tandem duplication-associated leukemogenesis and pharmacologic re-expression activates apoptotic mechanisms important for chemoresponse. We developed a regimen for this unique molecular subset, but due to relatively low frequency of KMT2A partial tandem duplication, this dose finding study was conducted in relapsed/refractory disease regardless of molecular subtype. Seventeen adults (< age 60) with relapsed/refractory acute myeloid leukemia were treated on study. Patients received decitabine 20 milligrams/meter2 daily on days 1-10 and vorinostat 400 milligrams daily on days 5-10. Cytarabine was dose-escalated from 1.5 grams/meter2 every 12 hours to 3 grams/meter2 every 12 hours on days 12, 14 and 16. Two patients experienced dose limiting toxicities at dose level 1 due to prolonged myelosuppression. However, as both patients achieved complete remission after Day 42, the protocol was amended to adjust the definition of hematologic dose limiting toxicity. No further dose limiting toxicities were found. Six of 17 patients achieved complete remission including 2 of 4 patients with KMT2A partial tandem duplication. Combination therapy with decitabine, vorinostat and cytarabine was tolerated in younger relapsed/refractory acute myeloid leukemia and should be explored further focusing on the KMT2A partial tandem duplication subset. (clinicaltrials.gov identifier 01130506).

Key Points Infections are a major cause of morbidity and mortality in HCL patients, and myelosuppressive therapies increase the risk of poor outcomes. Vemurafenib achieves rapid hematologic improvement in HCL and may facilitate management during life-threatening infection.