Real-world use of venetoclax in the treatment of paediatric and teenage/young adult haematological malignancies.

Early-phase trials of venetoclax in children and teenagers/young adults with leukaemia have yielded promising results, but there remains a paucity of real-world data. To address this, we report a cohort of 41 children treated with venetoclax for a range of haematological malignancies, demonstrating complete remission in 43.6%, with most achieving minimal residual disease (MRD) negativity. Venetoclax was particularly effective as a bridge to transplant, with bridging successful in 75% of patients. Patients with MRD <1% at initiation of venetoclax were more likely to achieve MRD negativity (81.8% vs. 34.5%, p = 0.007) and had improved overall survival (54.5% vs. 17.9%, p = 0.004).

High dose total marrow irradiation (TMI) does not increase long-term toxicity of myeloablative fludarabine/busulfan (FluBu4) conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT).

OBJECTIVES: Based on a previous phase 1 study, total marrow irradiation (TMI) at 9Gy was added to a myeloablative FluBu4 conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for myeloid malignancies. Here, we report on the long-term toxicity of TMI combined with FluBu4 and compare it to patients who received only FluBu4. METHODS: We retrospectively analyzed 38 consecutive patients conditioned with FluBu4/TMI (n = 15) or FluBu4 (n = 23, control group) who had at least 1 year follow-up post-transplant. The rate of long-term adverse events that have been previously associated with total body irradiation (TBI) was analyzed in the two groups. RESULTS: The baseline characteristics did not differ between the two groups. The control group had a longer median follow-up (71.2 mo) than the TMI group (38.5 mo) (p = .004). The most common adverse events were xerostomia, dental complications, cataracts, or osteopenia and did not differ between the two groups. Cognitive dysfunction or noninfectious pneumonitis, often detected after high dose TBI, were also not different in the two groups (p = .12 and p = .7, respectively). There was no grade 4 adverse event. CONCLUSION: Our results suggest that a conditioning regimen with TMI 9Gy and FluBu4 does not increase long-term adverse events after allogeneic HSCT.

Patterns of prescription opioid use and opioid-related harms among adult patients with hematologic malignancies.

INTRODUCTION: Treatment advances for hematologic malignancies (HM) have dramatically improved life expectancy, necessitating greater focus on long-term cancer pain management. This study explored real-world patterns of opioid use among patients with HM. METHODS: This retrospective cohort study identified adults diagnosed with HM from January 1, 2013 through December 31, 2019 using the Truven MarketScan Commercial Claims and Encounters database. Across several HM types, we described rates of high-risk opioid use (based on Pharmacy Quality Alliance measures) and opioid-related harms, including incident opioid use disorder (OUD) diagnoses and opioid-related hospitalizations or emergency department (ED) visits. We used multivariable Cox regression to generate adjusted hazard ratios and 95% confidence intervals comparing the risk of opioid-related harms between patients with versus without high-risk opioid use. RESULTS: Our sample included 43,190 patients with HM. Median age at HM diagnosis was 54 years (interquartile range = 44-60). Most patients (61.9%) were diagnosed with lymphoma. Approximately half (49.2%) had an opioid dispensed in the follow-up period. Among all patients, 20.0% met criteria for high-risk opioid use, 0.9% had an OUD diagnosis, and 0.3% experienced an opioid-related hospitalization/ED visit in follow-up. High-risk opioid use increased the risk of an OUD diagnosis by 3.3 times (p < 0.0001) and an opioid-related hospitalization/ED visit 4.2 times (p < 0.0001). CONCLUSION: High-risk opioid use was prevalent among patients with HM and significantly increased the risk of opioid-related harms. However, rates of opioid-related harms were low. These findings highlight the importance of continually monitoring pain and opioid use throughout HM survivorship to provide safe, effective HM pain management.

Dual-detection approach for a charge variant analysis of monoclonal antibody combination products using imaged capillary isoelectric focusing.

The clinical benefits of treatments with a combination of two or more therapeutic monoclonal antibodies (mAbs) have emerged in recent years. Imaged capillary isoelectric focusing is a frequently used technology in the biopharmaceutical industry for charge variant analysis of protein therapeutics. However, with the wide concentration ranges of combination products, one component may fall within the linear detection range, whereas the other does not. Here, we report a novel methodology to explore charge variants of mAb mixtures using multiple detection techniques simultaneously. We use ultraviolet absorbance to monitor the charge variants of the high-concentration component and native fluorescence (FL) to monitor the variants of the low-concentration one. Charge variants of mixtures that span 40-fold in ratio differences can be accurately quantified with this approach. In contrast to the conventional methods, it is not necessary to prepare and analyze two samples at different concentrations and combine the results for combination product testing. Additionally, the use of FL detection enables the charge variant analysis of highly potent/low abundant mAbs in a mixture. This methodology is more quality-control friendly and efficient for the charge variant analysis of combination products with wide ratios.

A comparison of four leukapheresis methods to harvest an optimal dose of CD34+ cells: A single center experience.

BACKGROUND: Chemokine receptor CXCR4 antagonist plerixafor (Px) as well as high volume (HV) leukapheresis have been shown to reduce hematopoietic stem progenitor cell (HSPC) mobilization failure rates. However, no direct comparisons of such methods currently exists. METHODS AND MATERIALS: We compared the HSPC collection yield based on basal peripheral blood CD34+ cell numbers in patients diagnosed with multiple myeloma or non-Hodgkin's lymphoma undergoing autologous stem cell transplantation in a retrospective chart review. The leukapheresis methods used included HV versus regular volume (RV) with or without Px. There were 116 patients in the study group while the historical control group had 34 patients. RESULTS AND CONCLUSIONS: Control group underwent RV leukapheresis without Px. Addition of Px or HV in the study group failed to display significant improvement in CD34+ cell collection yield; however, when basal CD34+ cell numbers were taken into account, both Px + RV and HV without Px increased CD34+ cell collection yield. The collection failure rates of HV without Px group were comparable to Px + RV when the basal CD34+ cell numbers were over 20/µl. Of interest, multivariate linear regression analysis did not detect any significant difference between HV versus Px + RV or other leukapheresis methods in CD34 yields or collection failure rates from a single collection after controlling for other factors (sex, age, or underlying disease). In multivariate analysis, pre apheresis CD34+ cell number was significantly and positively associated with the CD34+ cell yields from a single apheresis. In our studies, the majority of patients can be rescued without Px by HV alone as a potential cost saving approach. In summary, trend in our studies reflects that both Px and HV are capable of reducing the mobilization failure rates except the poorest mobilizers, which will need to be validated in larger studies.

Race/ethnicity and underlying disease influences hematopoietic stem/progenitor cell mobilization response: A single center experience.

BACKGROUND: Whether race/ethnicity plays a role in hematopoietic stem/progenitor cells (HSPC) mobilization in autologous donors has not been studied. We hypothesize that donor characteristic including race/ethnicity, age, sex, body mass index, and diagnostic groups influences HSPC mobilization. Diagnostic groups include healthy allogeneic donors, autologous multiple myeloma (MM) and non-MM donors. STUDY DESIGN AND METHODS: Here, we conducted a single-center retrospective study in 64 autologous patients and 48 allogeneic donors. Autologous donors were patients diagnosed with MM or non-MM. All donors were grouped as African American (AA), White (W), or "Other"(O). RESULTS: Multivariate analysis demonstrated diagnostic group differences for CD34+ cell yields between race/ethnicity. Specifically, non-MM patients had the lowest CD34+ cell yields in AA and O, but not in W. For pre-apheresis peripheral blood (PB) CD34+ cell numbers, race/ethnicity had a significant effect both in bivariate and multivariate analyses. Non-MM patients had the lowest, and AA patients had the highest PB CD34+ cells. The results support the view that past therapies used in MM are likely more conducive of recovery of HSPC. CONCLUSIONS: Our study shows that race/ethnicity and diagnostic group differences influenced CD34+ cell mobilization response across donor types. Interestingly, autologous MM donors with the aid of plerixafor displayed comparable CD34 yields to allogeneic donors. Even though both MM and non-MM donors received plerixafor, non-MM donors had significantly lower CD34 yields among AA and O donors but not in W donors. Larger studies would be required to validate the role of diagnostic groups and race/ethnicity interactions.

Predictors of increased melphalan exposure correlate with overall survival, nonrelapse mortality, and toxicities in patients undergoing reduced-intensity allogeneic stem cell transplantation with fludarabine and melphalan.

The reduced-intensity conditioning regimen, fludarabine and melphalan 140 mg/m2 (FM140), is widely adopted in practice. Pharmacokinetic studies report 10-fold interpatient variability in melphalan exposure. We identified low hemoglobin (Hb) and/or creatinine clearance (CrCl), determinants of melphalan pharmacokinetic, as strong predictors of outcomes after high-dose melphalan and autologous transplant. We hypothesized that these variables could predict for outcomes after FM140. Overall survival was shorter in patients with a lower Hb (113 vs. 2536 days; p = 0.004), due to an increased rate of nonrelapse mortality (NRM) (p = 0.0005). Overall survival was also worse in patients with lower CrCl (75 vs. 317 days; p = 0.003), with a significantly worse nonrelapse mortality (p = 0.0023). In a multivariate analysis, a higher Hb and CrCl predicted for better overall survival (p = 0.017). In patients with a lower Hb, the median duration of hospitalization (p = 0.02) and the mean duration of diarrhea (p = 0.008) were longer. In patients with a lower CrCl, the median duration of hospitalization (p = 0.06) and the mean duration of diarrhea (p = 0.0009) longer, and the rate of infection was higher (p = 0.02). We show for the first time that Hb and CrCl represent important determinants of outcomes after FM140, suggesting that pharmacokinetic-directed dosing may be beneficial in achieving optimal outcomes.

Targets of biologic disease-modifying antirheumatic drugs and risk of multiple myeloma.

Several commonly used immune-suppressing biologic drugs target proteins and cytokines involved in myeloma pathogenesis. Our objective was to determine whether targeted biologic disease-modifying antirheumatic drugs (DMARDs) are associated with risk of multiple myeloma (MM). We conducted a nested case-control study within a retrospective cohort of 56,886 commercially insured adults undergoing treatment for rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis between 2009 and 2015 using the Truven Health MarketScan Databases. MM cases (n = 287) were matched to up to 10 controls (n = 2,760) on age, sex and rheumatologic indication using incidence density sampling without replacement. Our exposures of interest were biologic DMARDs targeting tumor necrosis factor-alpha, interleukin 6, cytotoxic t-lymphocyte-associated protein-4 and depletion of B cells. Relative risks were estimated as adjusted odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression models. Cases and controls were similar with respect to use of prescription NSAIDs and concurrent conventional-synthetic DMARDs. Cases had slightly fewer etanercept users (4% vs. 7%) and slightly more tocilizumab users (1.4% vs. 0.4%). Compared to patients treated with only conventional-synthetic DMARDs, those receiving concomitant conventional-synthetic plus biologic DMARDs had lower risk of developing MM (OR = 0.48; 95% CI 0.30-0.88; p = 0.02). Risks differed by drug target with an inverse association observed with use of etanercept inhibiting tumor necrosis factor-alpha (OR = 0.55; 95% CI 0.30-1.02; p = 0.06) and a positive association with tocilizumab inhibiting interleukin-6 (OR = 4.33; 95% CI 1.33-14.19; p = 0.02) compared to biologic DMARD-naïve patients. Further investigation is warranted to understand the roles of drugs suppressing tumor necrosis factor-alpha and interleukin-6 in myeloma pathogenesis.

PARP Inhibition Synergizes with Melphalan but Does not Reverse Resistance Completely.

High-dose melphalan (MEL) and autologous stem cell transplantation (ASCT) is the standard of care in the treatment of multiple myeloma (MM). Resistance to MEL has been linked to increased DNA repair. Here we sought to identify whether inhibition of poly(ADP-ribose) polymerase (PARP) synergizes with MEL and can overcome resistance. We tested the synergistic cytotoxicity of 3 inhibitors of PARP (PARPi)-veliparib (VEL), olaparib (OLA), and niraparib (NIRA)-combined with MEL in RPMI8226 and U266 MM cell lines, as well as in their MEL resistance counterparts, RPMI8226-LR5 (LR5) and U266-LR6 (LR6). The addition of VEL, OLA, and NIRA to MEL reduced the half maximal inhibitory concentration (IC50) in RPMI8226 cells from 27.8 µM to 23.1 µM, 22.5 µM, and 18.0 µM, respectively. Similarly, the IC50 of MEL in U266 cells was decreased from 6.2 µM to 3.2 µM, 3.3 µM, and 3.0 µM, respectively. In LR5 and LR6 cells, PARPi did not reverse MEL resistance. We confirmed this in a NOD/SCID/gamma null xenograft mouse model with either MEL-sensitive (RPMI8226) or MEL-resistant (LR5) MM. Treatment with a MEL-VEL combination prolonged survival compared with MEL alone in RPMI8226 mice (107 days versus 67.5 days; P = .0009), but not in LR5 mice (41 versus 39 days; P = .09). We next tested whether 2 double-stranded DNA repair mechanisms, homologous recombination (HR) and nonhomologous end-joining (NHEJ), cause MEL resistance in LR5 and LR6 cells. In an HR assay, LR6 cells had a 4.5-fold greater HR capability than parent U226 cells (P = .05); however, LR5 cells had an equivalent HR ability as parent RPMI8226 cells. We hypothesized that NHEJ may be a mediator of MEL resistance in LR5 cells. Given that DNA-PK is integral to NHEJ and may be a therapeutic target, we treated LR5 cells with the DNA-PK inhibitor NU7026 in combination with MEL. Although NU7026 alone at 2.5 µM had no cytotoxicity, in combination it completely reversed resistance to MEL (MEL IC50, 46.4 µM versus 14.4 µM). We examined the clinical implications of our findings in a dataset of 414 patients treated with tandem ASCT. High PARP1 expressers had lower survival compared with patients with low expression (median 42.7 months versus median not reached; P = .003). We hypothesized that combined expression of the HR gene BRCA1, the NHEJ gene PRKDC (DNA-PK), and PARP1 may predict survival and found that overexpression of 0 (n = 101), 1 or 2 (n = 287), or all 3 (n = 26) genes had a negative impact on median survival (undefined versus 57.8 months versus 14.8 months; P < .0001). Here we demonstrate that PARPi synergized with MEL, but that resistance (which may be due to HR and NHEJ pathways) is not completely reversed by PARPi. In addition, we observed that a 3-gene analysis may be tested to identify patients resistant or sensitive to high-dose MEL.

Self-reported health and survival in older patients diagnosed with multiple myeloma.

PURPOSE: Patient-reported outcomes such as self-reported health (SRH) are important in understanding quality cancer care, yet little is known about links between SRH and outcomes in older patients with multiple myeloma (MM). We evaluated associations between SRH and mortality among older patients with MM. METHODS: We analyzed a retrospective cohort of patients ages ≥ 65 years diagnosed with first primary MM using the Surveillance, Epidemiology, and End Results (SEER)-Medicare Health Outcomes Survey (MHOS) data resource. Pre-diagnosis SRH was grouped as high (excellent/very good/good) or low (fair/poor). We used Cox proportional hazards models to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations between SRH and all-cause and MM-specific mortality. RESULTS: Of 521 MM patients with mean (SD) age at diagnosis of 76.8 (6.1) years, 32% reported low SRH. In multivariable analyses, low SRH was suggestive of modest increased risks of all-cause mortality (HR 1.32, 95% CI 1.02-1.71) and MM-specific mortality (HR 1.22, 95% CI 0.87-1.70) compared to high SRH. CONCLUSION: Findings suggest that low pre-diagnosis SRH is highly prevalent among older patients with MM and is associated with modestly increased all-cause mortality. Additional research is needed to address quality of life and modifiable factors that may accompany poor SRH in older patients with MM.

Development of a method for clinical pharmacokinetic testing to allow for targeted Melphalan dosing in multiple myeloma patients undergoing autologous transplant.

AIMS: High dose melphalan (HDM) and autologous stem cell transplant (ASCT) is standard of care for multiple myeloma (MM), but there is significant variability in melphalan exposure (area under the plasma drug concentration-time curve, AUC) when using body surface area-based dosing. Our aim was to establish a method of pharmacokinetic (PK) testing for real-time melphalan dose adjustments. METHODS: We performed a prospective PK study of melphalan 140 or 200 mg/m2 in MM patients undergoing ASCT. Twenty MM patients were administered HDM on days -2 and - 1, with PK sampling at 8-10 time points. PK testing was performed on day -2 in all patients, and on day -1 in 5 patients. RESULTS: Less than 20% interpatient variation in the day -2 and - 1 AUC was observed. The day -2 range in AUC (4.95-11.28 mg h/L) confirmed significant interpatient variability. The hypothetical total dose ranged from 133-302 mg/m2 to achieve the total median AUC. A 4-time point AUC (0, 30, 150 and 240 min) highly correlated with the AUC from the 8-time point schedule. A higher AUC correlated with increased risk of febrile neutropenia (P = .05). CONCLUSION: Here we outline the methods to establish novel melphalan dosing using PK testing in MM patients undergoing ASCT to target a desired melphalan AUC.

A multi-institutional comparison of mitoxantrone, etoposide, and cytarabine vs high-dose cytarabine and mitoxantrone therapy for patients with relapsed or refractory acute myeloid leukemia.

Relapsed or refractory acute myeloid leukemia (R/R AML) has a poor prognosis and is best treated with salvage chemotherapy as a bridge to allogeneic stem cell transplant (alloSCT). However, the optimal salvage therapy remains unknown. Here we compared two salvage regimens; mitoxantrone, etoposide, and cytarabine (MEC) and mitoxantrone and high-dose Ara-C (Ara-C couplets). We analyzed 155 patients treated at three academic institutions between 1998 and 2017; 87 patients received MEC and 68 received Ara-C couplets. The primary endpoint was overall response (OR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of hospitalization, hematologic and nonhematologic toxicities, and success in proceeding to alloSCT. Baseline characteristics of the cohorts were well matched, though patients receiving Ara-C couplets had more co-morbidities (48.5% vs 33%; P = .07). OR was achieved in 43.7% of MEC and 54.4% of Ara-C couplets patients (P = .10). Ara-C couplets patients also trended towards a longer OS and PFS, more frequently proceeded to alloSCT (31% vs 54.4%; P = .003), and experienced less febrile neutropenia (94% vs 72%; P < .001) and grade 3/4 gastrointestinal toxicities (17.2% vs 2.94%; P = .005). No significant differences in other toxicities or median duration of hospitalization were noted. This is the first multi-institutional study directly comparing these regimens in a racially diverse population of R/R AML patients. Although these regimens have equivalent efficacy in terms of achieving OR, Ara-C couplets use is associated with significant reductions in toxicities, suggesting it should be used more frequently in these patients.

Depressive symptoms, mental health-related quality of life, and survival among older patients with multiple myeloma.

PURPOSE: To examine the impact of pre-diagnosis depressive symptoms and mental health-related quality of life (HRQOL) on survival among older patients with multiple myeloma (MM). METHODS: We performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results-Medicare Health Outcomes Survey data resource. Patients aged 65 years and older diagnosed with first primary MM between 1998 and 2014 were identified, and presence of depressive symptoms was determined based on responses to 3 depression screening questions prior to MM diagnosis. Veterans RAND 12 mental component summary (MCS) scores were analyzed to evaluate mental HRQOL. We used multivariable Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for risks of all-cause and cancer-specific mortality. RESULTS: Of 522 patients, mean (SD) age at diagnosis was 76.9 (6.1) years and 158 (30%) reported depressive symptoms. Patients with depressive symptoms had a higher number of comorbid conditions and nearly all (84%) scored below the median MCS. Pre-diagnosis depressive symptoms were not associated with all-cause (HR = 1.01, 95% CI 0.79-1.29) or cancer-specific mortality (HR = 0.94, 95% CI 0.69-1.28). MM patients scoring in the second MCS tertile (vs the highest tertile) had a modestly increased risk of all-cause (HR = 1.19, 95% CI 0.91-1.55) and cancer-specific mortality (HR = 1.17, 95% CI 0.86-1.60), but these estimates were not statistically significant. CONCLUSION: Pre-diagnosis depressive symptoms and lower mental HRQoL did not impact survival among older MM patients. Highly prevalent depressive symptoms among older MM patients deserve clinical attention. Such efforts can inform clinicians in tailoring care for this vulnerable population.

Polypharmacy and potentially inappropriate medication use is highly prevalent in multiple myeloma patients and is improved by a collaborative physician-pharmacist clinic.

OBJECTIVE: To compare polypharmacy and potentially inappropriate medication use in multiple myeloma patients receiving care under a traditional, physician-managed, or collaborative physician-pharmacist clinic. DESIGN: Retrospective chart review. SETTING: Urban academic cancer center. DATA SOURCE: Computerized electronic record. PATIENTS: Forty-four patients in the traditional physician-managed clinic and 57 patients in the collaborative physician-pharmacist clinic. MEASUREMENTS AND MAIN RESULTS: Patients in the collaborative clinic took fewer medications on average (9 vs. 7, p = 0.045). Although the median number of myeloma-related medications was higher (2 vs. 4, p < 0.0001), the number of non-myeloma-related medications was lower (7 vs. 3, p < 0.0001) in the collaborative clinic. Polypharmacy rates were high in both clinics (93% vs. 84%, p = 0.22). However, the collaborative clinic had a lower rate of polypharmacy of non-myeloma medications (71 vs. 33%, p = 0.0003), including both minor (five to nine medications, 48 vs. 28%, p = 0.06) and major (≥10 medications, 23 vs. 5%, p = 0.02) polypharmacy. Minor polypharmacy of myeloma-related medications was higher in the collaborative clinic (32 vs. 2%; p = 0.0002). Multivariate analysis showed a reduced risk of having a higher number of medications (Relative risk (RR) 0.79, 95% confidence interval 0.67-0.93; p = 0.004), a lower risk of having any polypharmacy of non-myeloma-related medications (RR 0.41, 95% confidence interval 0.25-0.67; p < 0.001) and a lower risk of receiving potentially inappropriate medication (RR 0.62, 95% confidence interval 0.41-0.95; p = 0.029) in the collaborative clinic. CONCLUSIONS: Multiple myeloma patients have a high rate of polypharmacy but comanagement with a pharmacist reduced the number of all medications, but in particular the number of non-myeloma-related medications.

Synergistic Cytotoxic Effect of Busulfan and the PARP Inhibitor Veliparib in Myeloproliferative Neoplasms.

Patients with high-risk myeloproliferative neoplasms (MPNs), and in particular myelofibrosis (MF), can be cured only with allogeneic hematopoietic stem cell transplantation (HSCT). Because MPNs and JAK2V617F-mutated cells show genomic instability, stalled replication forks, and baseline DNA double-strand breaks, DNA repair inhibition with poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors represents a potential novel therapy. Because the alkylating agent busulfan is integral in conditioning regimens for HSCT and leads to stalled replication forks through DNA strand cross-linking, we hypothesized that PARP inhibition with veliparib in combination with busulfan may lead to synergistic cytotoxicity in MPN cells. We first treated 2 MPN cell lines harboring the JAK2V617F mutation (SET2 and HEL) with veliparib at increasing concentrations and measured cell proliferation. SET2 and HEL cells were relatively sensitive to veliparib (IC50 of 11.3 µM and 74.2 µM, respectively). We next treated cells with increasing doses of busulfan in combination with 4 µM veliparib and found that the busulfan IC50 decreased from 27 µM to 4 µM in SET2 cells and from 45.1 µM to 28.1 µM in HEL cells. The mean combination index was .55 for SET2 cells and .40 for HEL cells. Combination treatment of SET2 cells caused G2M arrest in 53% of cells, compared with 30% with veliparib alone and 35% with busulfan alone. G2M arrest was associated with activation of the ATR-Chk1 pathway, as shown by an immunofluorescence assay for phosphorylated Chk1 (p-Chk1). We then tested in vivo the effect of combined low doses of busulfan and veliparib in a JAK2V617F MPN-AML xenotransplant model. Vehicle- and veliparib-treated mice had similar median survival of 39 and 40 days, respectively. Combination treatment increased median survival from 47 days (busulfan alone) to 50 days (P = .02). Finally, we tested the combined effect of busulfan and veliparib on CD34+ cells obtained from the bone marrow or peripheral blood of 5 patients with JAK2V617F-mutated and 2 patients with CALR-mutated MF. MF cells treated with the combination of veliparib and busulfan showed reduced colony formation compared with busulfan alone (87% versus 68%; P = .001). In contrast, treatment of normal CD34+ cells with veliparib did not affect colony growth. Here we show that in vivo confirmation that treatment with the PARP-1 inhibitor veliparib and busulfan results in synergistic cytotoxicity in MPN cells. Our data provide the rationale for testing novel pretransplantation conditioning regimens with combinations of PARP-1 inhibition and reduced doses of alkylators, such as busulfan and melphalan, for high-risk MPNs or MPN-derived acute myelogenous leukemia.

Myelodysplastic syndrome and acute myeloid leukemia after receipt of granulocyte colony-stimulating factors in older patients with non-Hodgkin lymphoma.

BACKGROUND: Granulocyte colony-stimulating factors (G-CSFs), which are used for the prevention of complications from chemotherapy-related neutropenia, are linked to the risk of developing second primary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The objective of this study was to examine the correlation between using a specific G-CSF agent and the risk of MDS/AML among older patients with non-Hodgkin lymphoma (NHL). METHODS: This was a retrospective cohort study of adults aged >65 years who were diagnosed with first primary NHL between 2001 and 2011. With data from the Surveillance, Epidemiology, and End Results-Medicare-linked database, adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for the risk of MDS/AML associated with the receipt of G-CSF(filgrastim and pegfilgrastim) in Cox proportional-hazards models, which were stratified according to treatment accounting for confounding by indication. RESULTS: Among 18,245 patients with NHL patients who had a median follow-up of 3.5 years, 56% received chemotherapy and/or immunotherapy, and G-CSF was most commonly used in those who received rituximab plus multiple chemotherapy regimens (77%). Subsequent MDS/AML diagnoses were identified in 666 patients (3.7%). A modest increased risk of MDS/AML was observed with the receipt of G-CSF (HR, 1.28; 95% CI, 1.01-1.62) and a trend was observed with increasing doses (Ptrend < .01). When specific agents were analyzed, an increased risk of MDS/AML was consistently observed with filgrastim (≥10 doses: HR, 1.67; 95% CI, 1.25-2.23), but not with pegfilgrastim (≥10 + doses: HR, 1.11; 95% CI, 0.84-1.45). CONCLUSIONS: A higher of MDS/AML was observed in patients with NHL risk among those who received G-CSF that was specific to the use of filgrastim (≥10 doses), but not pegfilgrastim. Neutropenia prophylaxis is an essential component of highly effective NHL treatment regimens. The differential risk related to the types of G-CSF agents used warrants further study given their increasing use and newly available, US Food and Drug Administration-approved, biosimilar products.

A novel drug interaction between busulfan and blinatumomab.

Busulfan is an alkylating agent used in pre-transplant conditioning for patients undergoing hematopoietic stem cell transplantation. Several factors contribute to variations in busulfan drug disposition including bioavailability, age, liver function, genetic polymorphisms, and concurrent administration of other drugs. Busulfan is metabolized by hepatic oxidation via the cytochrome P450 3A4 system as well as through conjugation with glutathione. Interactions with drugs such as phenytoin, itraconazole, and metronidazole have been reported to alter busulfan clearance and result in sub- or supra-therapeutic concentrations. We report a case of a clinically significant drug interaction between intravenous busulfan and the bifunctional T-cell engager, blinatumomab, observed through busulfan therapeutic drug monitoring. We found that busulfan clearance was reduced resulting in a higher area under the concentration-time curve when it was administered 48 h after blinatumomab. Repeat busulfan pharmacokinetic testing two weeks later demonstrated increased clearance of the drug and a 31% higher dose recommendation. Similar to other protein therapeutics, cytokine elevations during blinatumomab treatment can lead to cytochrome 3A4 suppression. We hypothesize that the increased busulfan levels observed could be related to a cytokine-mediated CYP3A4 suppression. This represents a unique pharmacologic consideration in hematopoietic stem cell transplantation which would impact several drugs that undergo CYP3A4 metabolism, including calcineurin inhibitors, cyclophosphamide, sirolimus, and triazole antifungals. Additionally, this mechanism of CYP3A4 suppression may be relevant in treatments and disease states where cytokine levels are elevated such as haploidentical stem cell transplantation, graft-versus-host disease, and use of chimeric antigen receptor T-cell therapy.

Automatic Normalization of Anatomical Phrases in Radiology Reports Using Unsupervised Learning.

In today's radiology workflow, free-text reporting is established as the most common medium to capture, store, and communicate clinical information. Radiologists routinely refer to prior radiology reports of a patient to recall critical information for new diagnosis, which is quite tedious, time consuming, and prone to human error. Automatic structuring of report content is desired to facilitate such inquiry of information. In this work, we propose an unsupervised machine learning approach to automatically structure radiology reports by detecting and normalizing anatomical phrases based on the Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT) ontology. The proposed approach combines word embedding-based semantic learning with ontology-based concept mapping to derive the desired concept normalization. The word embedding model was trained using a large corpus of unlabeled radiology reports. Fifty-six anatomical labels were extracted from SNOMED CT as class labels of the whole human anatomy. The proposed framework was compared against a number of state-of-the-art supervised and unsupervised approaches. Radiology reports from three different clinical sites were manually labeled for testing. The proposed approach outperformed other techniques yielding an average precision of 82.6%. The proposed framework boosts the coverage and performance of conventional approaches for concept normalization, by applying word embedding techniques in semantic learning, while avoiding the challenge of having access to a large amount of annotated data, which is typically required for training classifiers.

Tumor necrosis factor-alpha inhibitors and risk of non-Hodgkin lymphoma in a cohort of adults with rheumatologic conditions.

Based on limited evidence, the U.S. Food and Drug Administration (FDA) issued a black box warning for the use of tumor necrosis factor-alpha inhibitors (TNFIs) and risk of non-Hodgkin lymphoma (NHL). Our objective was to determine the risk of NHL associated with TNFI use by duration and type of anti-TNF agent. We performed a nested case-control study within a retrospective cohort of adults with rheumatologic conditions from a U.S. commercial health insurance database between 2009 and 2015. Use of TNFIs (infliximab, adalimumab, etanercept, golimumab and certolizumab pegol) and conventional-synthetic disease-modifying antirheumatic drugs (csDMARDs) was identified, and conditional logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL. From a retrospective cohort of 55,446 adult patients, 101 NHL cases and 984 controls matched on age, gender and rheumatologic indication were included. Compared to controls, NHL cases had greater TNFI use (33% vs. 20%) but were similar in csDMARD use (70% vs. 71%). TNFI ever-use was associated with nearly two-fold increased risk of NHL (OR = 1.93; 95% CI: 1.16-3.20) with suggestion of increasing risk with duration (P-trend = 0.05). TNF fusion protein (etanercept) was associated with increased NHL risk (OR = 2.73; 95% CI: 1.40-5.33), whereas risk with anti-TNF monoclonal antibodies was not statistically significant (OR = 1.77; 95% CI: 0.87-3.58). In sensitivity analyses evaluating confounding by rheumatologic disease severity, channeling bias was not likely to account for our results. Our findings support the FDA black box warning for NHL. Continued surveillance and awareness of this rare but serious adverse outcome are warranted with new TNFIs and biosimilar products forthcoming.

Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease.

We report on the screening and development of haploidentical hematopoietic stem cell transplantation (HSCT) for adult patients with clinically aggressive sickle cell disease (SCD) at our institution. Of 50 adult SCD patients referred for HSCT between January 2014 and March 2017, 20% were denied by insurance. Of 41 patients initially screened, 10% lacked an available haploidentical donor, 29% had elevated donor-specific antibodies (DSAs), and 34% declined to proceed to HSCT. All 10 patients who were transplanted received peripheral blood stem cells. The initial 2 were conditioned with alemtuzumab/total body irradiation (TBI) 3 Gy followed by post-transplant cyclophosphamide and failed to engraft. The next 8 patients received the regimen developed at Johns Hopkins University with TBI 3 Gy. Granulocyte colony-stimulating factor was administered from day +12 in those with HbS < 30%. All 8 patients engrafted with a median time to neutrophil >.5 × 109/L of 22 days (range, 18 to 23). One patient subsequently lost the graft, and 7 (87.5%) maintained >95% donor cell chimerism at 1-year post-HSCT. Two patients developed acute graft-versus-host disease (GVHD) of at least grade II. One had chronic GVHD and died >1 year after HSCT of unknown causes. With a median follow-up of 16 months (range, 11 to 29), 7 patients (87.5%) are alive. Our findings suggest that limited insurance coverage, high rate of DSAs, and patient declining HSCT may limit the availability of haploidentical HSCT in adult SCD patients. The modified Hopkins regimen used here demonstrates high engraftment and low morbidity rates and should be tested in larger, multicenter, prospective clinical trials.