Daniel O Persky

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Journals/Publications

• Alrawashdh, N., Persky, D. O., McBride, A., Sweasy, J., Erstad, B., & Abraham, I. (2021). Comparative Efficacy of First-Line Treatments of Chronic Lymphocytic Leukemia: Network Meta-Analyses of Survival Curves. Clinical lymphoma, myeloma & leukemia, 21(11), e820-e831.
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  Multiple treatment options in first-line chronic lymphocytic leukemia (CLL) pose a challenge in identifying the best treatment. We performed novel network meta-analyses (NMA; 8 trials, 11 treatments) on the Kaplan-Meier curves to compare treatments for fludarabine-ineligible patients on progression-free survival (PFS), time-to-next-treatment (TTNT) and overall survival (OS).
• Alrawashdh, N., Sweasy, J., Erstad, B., McBride, A., Persky, D. O., & Abraham, I. (2021). Survival trends in chronic lymphocytic leukemia across treatment eras: US SEER database analysis (1985-2017). Annals of hematology, 100(10), 2501-2512.
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  In this population-based study, we used the SEER database (1985-2015) to examine survival outcomes in chronic lymphocytic leukemia (CLL) patients followed up to the era of advanced treatments including targeted therapies. Data were extracted for patients 15 years or older with a primary diagnosis of CLL. A period analysis was performed to estimate 5- and 10-year relative survival rates for patients diagnosed during different calendar periods from 1985 to 2015. A mixture cure model was used to examine long-term survivors' proportions among patients diagnosed in 1985-2015 and for two cohorts diagnosed in 2000-2003, followed up to 2012 and 2004-2007, and followed up to 2015. Cox proportional hazard modeling was used for the two cohorts to estimate hazard ratios (HRs) of death adjusted for gender and age. The 5-year and 10-year age-adjusted relative survival rate ranged between 73.7 and 89.4% and from 51.6% to "not reached," respectively, for calendar periods of 1985-1989 to 2010-2014. The long-term survivor proportions varied by age and gender from 0 to 59%. The HRs (95%CI) for the 2004-2007 cohort in comparison to the 2000-2003 cohort were 0.58 (0.43-0.78), 0.58 (0.48-0.70), 0.57 (0.49-0.0.67), 0.68 (0.54-0.85), and 0.83 (0.68-1.02) for the age categories of 45-54, 55-64, 65-74, 75-84, and ≥ 85 years, respectively. Overall, relative survival improved significantly for CLL patients diagnosed between 1985 and 2015. These improvements were markedly better following the introduction of targeted therapies.
• Gordon, M. J., Kaempf, A., Sitlinger, A., Shouse, G., Mei, M., Brander, D. M., Salous, T., Hill, B. T., Alqahtani, H., Choi, M., Churnetski, M. C., Cohen, J. B., Stephens, D. M., Siddiqi, T., Rivera, X., Persky, D., Wisniewski, P., Patel, K., Shadman, M., , Park, B., et al. (2021). The Chronic Lymphocytic Leukemia Comorbidity Index (CLL-CI): A Three-Factor Comorbidity Model. Clinical cancer research : an official journal of the American Association for Cancer Research, 27(17), 4814-4824.
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  Comorbid medical conditions define a subset of patients with chronic lymphocytic leukemia (CLL) with poor outcomes. However, which comorbidities are most predictive remains understudied.
• Islam, S., Espitia, C. M., Persky, D. O., Carew, J. S., & Nawrocki, S. T. (2021). Targeting JAK/STAT Signaling Antagonizes Resistance to Oncolytic Reovirus Therapy Driven by Prior Infection with HTLV-1 in Models of T-Cell Lymphoma. Viruses, 13(7).
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  Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that infects at least 10 million people worldwide and is associated with the development of T-cell lymphoma (TCL). The treatment of TCL remains challenging and new treatment options are urgently needed. With the goal of developing a novel therapeutic approach for TCL, we investigated the activity of the clinical formulation of oncolytic reovirus (Reolysin, Pelareorep) in TCL models. Our studies revealed that HTLV-1-negative TCL cells were highly sensitive to Reolysin-induced cell death, but HTLV-1-positive TCL cells were resistant. Consistent with these data, reovirus displayed significant viral accumulation in HTLV-1-negative cells, but failed to efficiently replicate in HTLV-1-positive cells. Transcriptome analyses of HTLV-1-positive vs. negative cells revealed a significant increase in genes associated with retroviral infection including interleukin-13 and signal transducer and activator of transcription 5 (STAT5). To investigate the relationship between HTLV-1 status and sensitivity to Reolysin, we infected HTLV-1-negative cells with HTLV-1. The presence of HTLV-1 resulted in significantly decreased sensitivity to Reolysin. Treatment with the JAK inhibitor ruxolitinib suppressed STAT5 phosphorylation and expression of the key anti-viral response protein MX1 and enhanced the anti-TCL activity of Reolysin in both HTLV-1-positive and negative cells. Our data demonstrate that the inhibition of the JAK/STAT pathway can be used as a novel approach to antagonize the resistance of HTLV-1-positive cells to oncolytic virus therapy.
• Kittai, A. S., Best, S., Thurlow, B., Lam, V., Hashiguchi, T., Goodyear, S., Persky, D. O., Okada, C., Park, B., Spurgeon, S. E., & Danilov, A. V. (2021). Entospletinib and obinutuzumab in patients with relapsed/refractory chronic lymphocytic leukemia and B-cell malignancies. Haematologica, 106(7), 2022-2025.
• McBride, A., Alrawashdh, N., Bartels, T., Moore, L., Persky, D., & Abraham, I. (2021). Same-day versus next-day pegfilgrastim or pegfilgrastim-cbqv in patients with lymphoma receiving CHOP-like chemotherapy. Future oncology (London, England), 17(26), 3485-3497.
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  To compare the incidence of febrile neutropenia and related outcomes of prophylactic same-day versus next-day pegfilgrastim/pegfilgrastim-cbqv in patients with lymphoma receiving cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone (CHOP)-like chemotherapy. Retrospective, real-world, single-institution study. 93 patients received 460 cycles of CHOP-like chemotherapy. The incidence of febrile neutropenia and grade 3/4 chemotherapy-induced neutropenia was 5 and 16.5%, respectively. In 401 cycles pegfilgrastim was administered same-day versus 12 cycles next-day. Febrile neutropenia occurred in 17 cycles versus 0 cycles (p = 1.00) and grade 3/4 chemotherapy-induced neutropenia in 65 cycles (16.2%) versus 1 cycle (16.7%; p = 1.00) with same-day versus next-day pegfilgrastim administration, respectively. Pegfilgrastim may be safely administered on the same day as chemotherapy in patients with lymphoma receiving CHOP-like chemotherapy.
• McBride, A., Persky, D. O., Kumar, A., Abraham, I. L., Bartels, T., & Moore, L. (2021). Outcomes of primary and secondary prophylaxis of chemotherapy induced and febrile neutropenia in bendamustine plus rituximab regimens in patients with lymphoma and chronic lymphocytic leukemia.. Supportive Care in Cancer.
• Moore, L., Bartels, T., Persky, D. O., Abraham, I., Kumar, A., & McBride, A. (2021). Outcomes of primary and secondary prophylaxis of chemotherapy-induced and febrile neutropenia in bendamustine plus rituximab regimens in patients with lymphoma and chronic lymphocytic leukemia: real-world, single-center experience. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 29(8), 4867-4874.
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  To examine the outcomes associated with granulocyte colony stimulating factors (G-CSFs) administered as primary versus secondary prophylaxis in setting of bendamustine plus rituximab (BR) regimens.
• Carreau, N. A., Armand, P., Merryman, R. W., Advani, R. H., Spinner, M. A., Herrera, A. F., Ramchandren, R., Hamid, M. S., Assouline, S., Santiago, R., Wagner-Johnston, N., Paul, S., Svoboda, J., Bair, S. M., Barta, S. K., Nathan, S., Karmali, R., Torka, P., David, K., , Lansigan, F., et al. (2020). Checkpoint blockade treatment sensitises relapsed/refractory non-Hodgkin lymphoma to subsequent therapy. British journal of haematology.
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  Patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) have limited options for salvage, and checkpoint blockade therapy (CBT) has little efficacy. Usage in solid malignancies suggests that CBT sensitises tumours to subsequent chemotherapy. We performed the first analysis of CBT on subsequent NHL treatment. Seventeen North American centres retrospectively queried records. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment. Secondary aims included progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Fifty-nine patients (68% aggressive NHL, 69% advanced disease) were included. Patients received a median of three therapies before CBT. Fifty-three (90%) discontinued CBT due to progression. Post-CBT regimens included chemotherapy (49%), targeted therapy (30%), clinical trial (17%), transplant conditioning (2%) and chimeric antigen receptor T cell (CAR-T) therapy (2%). The ORR to post-CBT treatment was 51%, with median PFS of 6·1 months. In patients with at least stable disease (SD) to post-CBT, the median DOR was significantly longer than to pre-CBT (310 vs. 79 days, P = 0·005) suggesting sensitisation. Nineteen patients were transplanted after post-CBT therapy. Median overall survival was not reached, nor affected by regimen. Prospective trials are warranted, as this may offer R/R NHL patients a novel therapeutic approach.
• Carreau, N. A., Pail, O., Armand, P., Merryman, R., Advani, R. H., Spinner, M. A., Herrera, A., Chen, R., Tomassetti, S., Ramchandren, R., Hamid, M. S., Assouline, S., Santiago, R., Wagner-Johnston, N., Paul, S., Svoboda, J., Bair, S., Barta, S., Liu, Y., , Nathan, S., et al. (2020). Checkpoint Blockade Treatment May Sensitize Hodgkin Lymphoma to Subsequent Therapy. The oncologist.
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  Targeted therapies and checkpoint blockade therapy (CBT) have shown efficacy for patients with Hodgkin lymphoma (HL) in the relapsed and refractory (R/R) setting, but once discontinued owing to progression or side effects, it is unclear how successful further therapies will be. Moreover, there are no data on optimal sequencing of these treatments with standard therapies and other novel agents. In a multicenter, retrospective analysis, we investigated whether exposure to CBT could sensitize HL to subsequent therapy.
• Gordon, M. J., Sitlinger, A., Salous, T., Alqahtani, H., Churnetski, M., Rivera, X., Wisniewski, P., Cohen, J., Patel, K., Shadman, M., Choi, M., Hill, B., Stephens, D., Persky, D., Brander, D., & Danilov, A. V. (2020). A simplified prognostic index for chronic lymphocytic leukemia treated with ibrutinib: Results from a multicenter retrospective cohort study. Leukemia research, 89, 106302.
• Islam, S., Espitia, C. M., Persky, D. O., Carew, J. S., & Nawrocki, S. T. (2020). Resistance to histone deacetylase inhibitors confers hypersensitivity to oncolytic reovirus therapy. Blood advances, 4(20), 5297-5310.
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  Despite the promising antilymphoma activity of histone deacetylase (HDAC) inhibitors as a drug class, resistance is a significant clinical issue. Elucidating the molecular mechanisms driving HDAC inhibitor resistance and/or the specific targets that are altered in drug-resistant cells may facilitate the development of strategies that overcome drug resistance and are more effective for refractory patients. We generated novel T-cell lymphoma (TCL) cell line models of acquired resistance to the HDAC inhibitor belinostat to identify potential effective therapies. Belinostat-resistant cells displayed significant cross-resistance to other HDAC inhibitors including romidepsin, panobinostat, and vorinostat. Consistent with a lack of sensitivity to HDAC inhibitors, the resistant cells failed to induce increased acetylated histones. Drug-resistant cells featured significantly decreased expression of the key antiviral mediators IRF1 and STAT1. On the basis of these findings, we investigated the efficacy of the clinical formulation of reovirus (Reolysin) in parental and drug-resistant models. Our investigation revealed that HDAC inhibitor-resistant cells displayed enhanced vulnerability to reovirus replication and cell death in both in vitro and in vivo models compared with their parental counterparts. Importantly, Reolysin also significantly increased the antilymphoma activity of belinostat in HDAC inhibitor-resistant cells. Our data demonstrate that Reolysin alone or in combination with belinostat is a novel therapeutic strategy to treat TCL patients who develop resistance to HDAC inhibitors.
• Kumar, A., & Persky, D. O. (2020). Treatment of Early (Limited)-Stage DLBCL. Clinical lymphoma, myeloma & leukemia, 20 Suppl 1, S34-S36.
• Merryman, R. W., Carreau, N. A., Advani, R. H., Spinner, M. A., Herrera, A. F., Chen, R., Tomassetti, S., Ramchandren, R., Hamid, M., Assouline, S., Santiago, R., Wagner-Johnston, N., Paul, S., Svoboda, J., Bair, S. M., Barta, S. K., Liu, Y., Nathan, S., Karmali, R., , Burkart, M., et al. (2020). Impact of Treatment Beyond Progression with Immune Checkpoint Blockade in Hodgkin Lymphoma. The oncologist, 25(6), e993-e997.
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  Atypical response patterns following immune checkpoint blockade (ICB) in Hodgkin lymphoma (HL) led to the concept of continuation of treatment beyond progression (TBP); however, the longitudinal benefit of this approach is unclear. We therefore performed a retrospective analysis of 64 patients treated with ICB; 20 who received TBP (TBP cohort) and 44 who stopped ICB at initial progression (non-TBP cohort). The TBP cohort received ICB for a median of 4.7 months after initial progression and delayed subsequent treatment by a median of 6.6 months. Despite receiving more prior lines of therapy, the TBP cohort achieved longer progression-free survival with post-ICB treatment (median, 17.5 months vs. 6.1 months, p = .035) and longer time-to-subsequent treatment failure, defined as time from initial ICB progression to failure of subsequent treatment (median, 34.6 months vs. 9.9 months, p = .003). With the limitations of a retrospective study, these results support the clinical benefit of TBP with ICB for selected patients.
• Persky, D. O., Li, H., Stephens, D. M., Park, S. I., Bartlett, N. L., Swinnen, L. J., Barr, P. M., Winegarden, J. D., Constine, L. S., Fitzgerald, T. J., Leonard, J. P., Kahl, B. S., LeBlanc, M. L., Song, J. Y., Fisher, R. I., Rimsza, L. M., Smith, S. M., Miller, T. P., & Friedberg, J. W. (2020). Positron Emission Tomography-Directed Therapy for Patients With Limited-Stage Diffuse Large B-Cell Lymphoma: Results of Intergroup National Clinical Trials Network Study S1001. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 38(26), 3003-3011.
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  Diffuse large B-cell lymphoma (DLBCL) presents as a limited-stage disease in 25% to 30% of patients, with better overall survival (OS) than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of positron emission tomography (PET)-directed treatment approaches, we designed a National Clinical Trials Network (NCTN) study to improve outcomes and decrease toxicity.
• Persky, D. O., Smith, S. M., LeBlanc, M. L., & Friedberg, J. W. (2020). Reply to E. Hawkes et al. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 38(35), 4222-4223.
• Forero-Torres, A., Ramchandren, R., Yacoub, A., Wertheim, M. S., Edenfield, W. J., Caimi, P., Gutierrez, M., Akard, L., Escobar, C., Call, J., Persky, D., Iyer, S., DeMarini, D. J., Zhou, L., Chen, X., Dawkins, F., & Phillips, T. J. (2019). Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies. Blood, 133(16), 1742-1752.
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  This phase 1/2 study assessed parsaclisib (INCB050465), a next-generation, potent, and highly selective phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor, in patients with relapsed or refractory B-cell malignancies, alone or in combination with a Janus kinase 1 inhibitor (itacitinib) or chemotherapy (rituximab, ifosfamide, carboplatin, and etoposide). Seventy-two patients received parsaclisib monotherapy (5-45 mg once daily). Expansion doses were 20 and 30 mg once daily; intermittent dosing at 20 mg (once daily for 9 weeks, then once weekly) was explored. No dose-limiting toxicities were identified, and maximum tolerated dose was not reached. Most common nonhematologic treatment-emergent adverse events (TEAEs) were diarrhea/colitis (36%), nausea (36%), fatigue (31%), and rash (31%). Grade 3/4 neutropenia occurred in 19% of patients. Serious TEAEs (>2 patients) were diarrhea/colitis (n = 9), pyrexia (n = 4), hypotension (n = 3), and sepsis (n = 3). Aspartate and alanine transaminase elevations occurring before treatment discontinuation were grade 1, except 1 grade 3 event each, secondary to sepsis. Two patients experienced 3 fatal parsaclisib-unrelated TEAEs (respiratory failure; respiratory failure and sepsis). In non-Hodgkin lymphoma (NHL), objective response rates to monotherapy were 71% in follicular lymphoma, 78% in marginal zone lymphoma, 67% in mantle cell lymphoma, and 30% in diffuse large B-cell lymphoma; 93% of responses occurred at first assessment (∼9 weeks). Parsaclisib has demonstrated antitumor activity in relapsed or refractory B-cell NHL with the potential for improved long-term patient outcomes. Phase 2 studies in relapsed or refractory B-cell NHL subtypes are ongoing. This trial was registered at www.clinicaltrials.gov as #NCT02018861.
• Matasar, M. J., Luminari, S., Barr, P. M., Barta, S. K., Danilov, A. V., Hill, B. T., Phillips, T. J., Jerkeman, M., Magagnoli, M., Nastoupil, L. J., Persky, D. O., & Okosun, J. (2019). Follicular Lymphoma: Recent and Emerging Therapies, Treatment Strategies, and Remaining Unmet Needs. The oncologist, 24(11), e1236-e1250.
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  Follicular lymphoma (FL) is a heterogeneous disease with varying prognosis owing to differences in clinical, laboratory, and disease parameters. Although generally considered incurable, prognosis for early- and advanced-stage disease has improved because of therapeutic advances, several of which have resulted from elucidation of the biologic and molecular basis of the disease. The choice of treatment for FL is highly dependent on patient and disease characteristics. Several tools are available for risk stratification, although limitations in their routine clinical use exist. For limited disease, treatment options include radiotherapy, rituximab monotherapy or combination regimens, and surveillance. Treatment of advanced disease is often determined by tumor burden, with surveillance or rituximab considered for low tumor burden and chemoimmunotherapy for high tumor burden disease. Treatment for relapsed or refractory disease is influenced by initial first-line therapy and the duration and quality of the response. Presently, there is no consensus for treatment of patients with early or multiply relapsed disease; however, numerous agents, combination regimens, and transplant options have demonstrated efficacy. Although the number of therapies available to treat FL has increased together with an improved understanding of the underlying biologic basis of disease, the best approach to select the most appropriate treatment strategy for an individual patient at a particular time continues to be elucidated. This review considers prognostication and the evolving treatment landscape of FL, including recent and emergent therapies as well as remaining unmet needs. IMPLICATIONS FOR PRACTICE: In follicular lymphoma, a personalized approach to management based on disease biology, patient characteristics, and other factors continues to emerge. However, application of current management requires an understanding of the available therapeutic options for first-line treatment and knowledge of current development in therapies for previously untreated and for relapsed or refractory disease. Thus, this work reviews for clinicians the contemporary data in follicular lymphoma, from advances in characterizing disease biology to current treatments and emerging novel therapies.
• Persky, D. O. (2019). A Phase 1/2 Study of MT-3724 To Evaluate Safety, Pharmacodynamics And Efficacy of MT-3724 For The Treatment Of Patients With Relapsed Or Refractory Diffuse Large B Cell Lymphoma. Hematological Oncology, 37(52), 566-566.
• Persky, D. O. (2019). A Phase I/II Study of the SYK Inhibitor Entospletinib In Combination With Obinutuzumab In Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL): PS1155. HemaSphere, 3, 524.
• Persky, D. O. (2019). Abstract CT028: Drug-drug interaction potential of EZH2 inhibitor tazemetostat (TAZ). AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. doi:DOI: 10.1158/1538-7445.AM2019-CT028
• Barr, P. M., Li, H., Burack, W. R., LeBlanc, M., Smith, S. M., Gopal, A. K., Floyd, J. D., Persky, D. O., Press, O. W., Fisher, R. I., & Friedberg, J. W. (2018). R-CHOP, radioimmunotherapy, and maintenance rituximab in untreated follicular lymphoma (SWOG S0801): a single-arm, phase 2, multicentre study. The Lancet. Haematology.
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  Despite an abundance of therapeutic options, advanced-stage follicular lymphoma remains incurable. Furthermore, the ideal sequence and absolute benefit of post-induction therapy is unclear. We designed SWOG S0801 to assess the efficacy and safety of consolidative radioimmunotherapy and sequential maintenance rituximab following chemoimmunotherapy.
• Gordon, M. J., Churnetski, M., Alqahtani, H., Rivera, X., Kittai, A., Amrock, S. M., James, S., Hoff, S., Manda, S., Spurgeon, S. E., Choi, M., Cohen, J. B., Persky, D., & Danilov, A. V. (2018). Comorbidities predict inferior outcomes in chronic lymphocytic leukemia treated with ibrutinib. Cancer.
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  Most patients with chronic lymphocytic leukemia (CLL) present with multiple comorbidities. Although comorbidities negatively affect outcomes for patients treated with chemoimmunotherapy, their impact on patients who receive targeted therapies is unknown.
• Kelly, K. R., Friedberg, J. W., Park, S. I., McDonagh, K. T., Hayslip, J., Persky, D., Ruan, J., Puvvada, S., Rosen, P. J., Padmanabhan Iyer, S., Stefanovic, A., Bernstein, S. H., Weitman, S., Karnad, A. B., Monohan, G., VanderWalde, A., Mena, R., Schmelz, M., Spier, C., , Groshen, S., et al. (2018). Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/vincristine in Relapsed/refractory Aggressive B-cell Lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research.
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  The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin's lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab ± vincristine in patients with relapsed/refractory aggressive B-NHL.
• McBride, A., Campen, C. J., Camamo, J., Maloney, M., Persky, D., Kurtin, S. E., Barket, N. L., Krishnadasan, R., Elquza, E., Anwer, F., & Weibel, K. (2018). Implementation of a pharmacy-managed program for the transition of chemotherapy to the outpatient setting. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 75(9), e246-e258.
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  Implementation of a pharmacy-managed program for the transition of chemotherapy to the outpatient setting is described.
• Mori, S., Patel, R. D., Ahmad, S., Varela, J., Smith, T., Altoos, R., Shen, Q., Goldstein, S. C., & Persky, D. O. (2018). Aggressive Leukemic Non-Nodal Mantle Cell Lymphoma With P53 Gene Rearrangement/Mutation is Highly Responsive to Rituximab/Ibrutinib Combination Therapy. Clinical lymphoma, myeloma & leukemia.
• Persky, D. O. (2018). A phase I/II trial of vorinostat (SAHA) in combination with rituximab‐CHOP in patients with newly diagnosed advanced stage diffuse large B‐cell lymphoma (DLBCL): SWOG S0806. American journal of hematology, 93(4), 486-493. doi:https://doi.org/10.1002/ajh.25010
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  Loss of major histocompatibility Class II expression (MHCII) in diffuse large B‐cell lymphoma (DLBCL) correlates with decreased survival. MHCII transcription is in part regulated by histone acetylation. We tested the hypothesis that combination of histone deacetylase inhibitor (HDACI) with standard chemotherapy would improve outcomes in DLBCL in part through increased MHCII expression. S0806 was a single arm phase I/II trial of vorinostat given at 400 mg po daily on days 1‐9 (subsequently amended to days 1‐5 due to toxicity), combined with R‐CHOP given on day 3 of a 21‐day cycle for 8 cycles, with primary phase II endpoint of 2‐year progression free survival (PFS). With 72 evaluable patients, at median follow up of 3 years, 2‐year PFS estimate was 73%, and OS estimate was 86%. Considering that the regimen fell short of predefined efficacy improvement and was associated with high rates of febrile …
• Persky, D. O. (2018). Comorbidities predict inferior outcomes in chronic lymphocytic leukemia treated with ibrutinib. Cancer, 124(15), 3192-3200. doi:https://doi.org/10.1002/cncr.31554
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  Most patients with chronic lymphocytic leukemia (CLL) present with multiple comorbidities. Although comorbidities negatively affect outcomes for patients treated with chemoimmunotherapy, their impact on patients who receive targeted therapies is unknown.
• Persky, D. O. (2018). Economic evaluation for the US of venetoclax (VEN) versus ibrutinib (IBR) versus allogeneic hematopoietic stem-cell transplantation (HSCT) for patients (pts) with relapsed or …. Journal of Clinical Oncology, 36, 7527-7527. doi:10.1200/JCO.2018.36.15_suppl.7527 Journal of Clinical Oncology 36, no. 15_suppl
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  Background: Prior to targeted agents, HSCT was the primary treatment for R/R CLL del 17p. VEN and IBR have been shown to improve progression free (PFS) and overall survival (OS). We performed an independent economic evaluation of VEN versus IBR versus HSCT in R/R CLL del 17p from the U.S. payer perspective. Methods: From published trial data we constructed a life-time horizon Markov model with 3 states: PFS; progression; and death. Kaplan-Meier PFS and OS curves for VEN, IBR and HSCT were digitized, and Weibull distributions fitted. The wholesale acquisition cost of VEN and IBR were sourced from RedBook. Costs of the HSCT (procedure, pre-conditioning, post-procedural adverse events [AE]) were estimated from published prediction equations and a claims database. EQ-5D utility values were sourced from literature. AE disutility values were assumed the same for the 3 interventions …
• Persky, D. O. (2018). Effect of concurrent CYP3A4 interacting medications on ibrutinib outcomes in patients with CLL.. Journal of Clinical Oncology, 36, e19514-e19514. doi:10.1200/JCO.2018.36.15_suppl.e19514 Journal of Clinical Oncology 36, no. 15_suppl
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  Background: Concurrent use of strong CYP3A4 inhibitors increases ibrutinib exposure 20-fold. Hence, use of strong CYP3A4 inhibitors/inducers is not recommended, and moderate inhibitors warrant ibrutinib dose reduction. Concurrent use of ibrutinib and CYP3A4 inducers/inhibitors is inevitable in clinical practice, and may result in adverse events. In this multicenter analysis, we investigated whether concurrent use of CYP3A4 interacting drugs impacts outcomes of ibrutinib therapy. Methods: We performed a retrospective analysis of 141 patients who received ibrutinib therapy for CLL at 4 academic centers. Survival time on ibrutinib was estimated in Cox proportional hazards model. Chi-squared test was used to evaluate discontinuation of ibrutinib due to side effects. Results: 141 patients were treated with ibrutinib, 26 (18%) were concurrently prescribed a moderate or strong inducer or inhibitor of CYP3A4 …
• Persky, D. O. (2018). Implementation of a hepatitis B screening process prior to CD20 therapy treatment in an oncology practice.. Journal of Clinical Oncology, 36, 287-287. doi:10.1200/JCO.2018.36.30_suppl.287 Journal of Clinical Oncology 36, no. 30_suppl
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  Background: Reactivation of hepatitis B virus (HBV) during or after chemotherapy is a serious complication of cancer treatment. Guidelines suggest hepatitis B testing prior to the initiation of CD20 based therapies. Black box warnings mandate clinicians screen patients for HBV before starting immunosuppressive therapy due to the risk of hepatitis B reactivation. We conducted a workflow implementation change at our infusion center sites to improve hepatitis B serological testing in patients receiving CD20 agents at our cancer center. Methods: For baseline evaluation, patients at The University of Arizona Cancer Center who were treated with CD20 agents between the years 2013 to April 2014 were retrospectively evaluated for HBV serology results prior to the initiation of first treatment. We implemented a pharmacy and nursing workflow process regarding chemotherapy orders and lab testing through the …
• Persky, D. O. (2018). Implementation of a pharmacy-managed program for the transition of chemotherapy to the outpatient setting. American Journal of Health-System Pharmacy, 75(9), e246-e258. doi:https://doi.org/10.2146/ajhp170138
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  The University of Arizona Cancer Center and Banner–University Medical Center Tucson are affiliated not-for-profit academic medical centers in Tucson, Arizona, whose facilities include a hospital and ambulatory care clinics that maintain 3 outpatient infusion centers. The cancer center pharmacy currently employs 25 pharmacists, with 4 clinical pharmacists serving both the inpatient and outpatient treatment sites. A multidisciplinary team of staff members was assembled to address the transition of chemotherapy from inpatient to outpatient that included physicians, ambulatory clinical oncology pharmacists, finance, social workers, pharmacy staff, nursing staff, and information technology. The program was initiated in May 2014, with a 2-year postimplementation evaluation of our …
• Persky, D. O. (2018). Limited-stage DLBCL: it's patient selection. Blood, 131(2), 155-156.
• Persky, D. O. (2018). Safety and efficacy of anti-CD20 immunotoxin MT-3724 in relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) in a phase I study.. Journal of Clinical Oncology, 36, 7580-7580. doi:10.1200/JCO.2018.36.15_suppl.7580 Journal of Clinical Oncology 36, no. 15_suppl
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  Background: MT-3724 is a novel recombinant fusion protein consisting of a CD20 binding variable fragment (scFv) fused to Shiga-like toxin-I A1. The SLT-I A1 forces MT-3724 internalization and irreversibly inactivates ribosomes triggering cell death. We present interim results from a Phase I study in patients (pts) with B-cell NHL who relapsed after prior response to anti-CD20 Mab and chemotherapy (NCT02361346). Methods: 24 pts were treated by 13FEB2018: 21 pts (12 DLBCL) at 5-100 µg/kg/dose in 6 dose escalation cohorts and 3 pts (all DLBCL) at 75 µg/kg/dose in MTD expansion cohort. MT-3724 was given as six 2-hr IV infusions on Days 1-12 of each cycle (C) for up to 5 cycles. Investigator assessed tumor response after C2, C4 and C5 using Cheson criteria. Results: Demographics in 24 evaluable pts were: 54% female, mean age 66 yrs (range 34-78); ≥4 prior NHL therapies in 67%; ECOG status 0 …
• Persky, D. O. (2018). Transition of dose-adjusted EPOCH therapy into the outpatient healthcare setting: Quality and cost considerations for outpatient treatment.. Journal of Clinical Oncology, 36(30_suppl), 110-110. doi:10.1200/JCO.2018.36.30_suppl.110 Journal of Clinical Oncology 36, no. 30_suppl
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  Background: Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH)-containing regimens are frequently utilized in lymphoma, however, outpatient EPOCH or modified inpatient/outpatient EPOCH has not been described extensively. We transitioned inpatient EPOCH to the outpatient setting and modified EPCOH to be given in the inpatient setting with rituximab outpatient to improve quality of care and access to patient assistance programs. We describe our institutional experiences with inpatient and modified EPOCH to the outpatient setting. Methods: A single-center, institutional review board-approved retrospective study was conducted for adults receiving EPOCH-based regimens. Clinical and financial data were collected by chart review for each patient. Descriptive statistics were utilized for analysis. Results: A total of 31 patients received 116 cycles of an EPOCH
• Puvvada, S. D., Guillen-Rodriguez, J., Kumar, A., Inclán, L., Heard, K., Rivera, X. I., Anwer, F., Schatz, J. H., Mahadevan, D., & Persky, D. O. (2018). Phase 2 Open-Label Study of Bortezomib, Cladribine, and Rituximab in Advanced, Newly Diagnosed, and Relapsed/Refractory Mantle-Cell and Indolent Lymphomas. Clinical lymphoma, myeloma & leukemia, 18(1), 58-64.
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  Mantle-cell lymphoma (MCL) and indolent non-Hodgkin lymphoma (iNHL) are incurable heterogeneous diseases characterized by relapse. There is a need for newer treatments in MCL and iNHL, especially in the relapsed/refractory (R/R) setting. We therefore investigated the novel combination of bortezomib (Velcade), cladribine, and rituximab (VCR) in front-line and R/R settings in MCL and iNHL (NCT00980395).
• Puvvada, S. D., Guillén-Rodríguez, J. M., Yan, J., Inclán, L., Heard, K., Rivera, X. I., Anwer, F., Mahadevan, D., Schatz, J. H., & Persky, D. O. (2018). Yttrium-90-Ibritumomab Tiuxetan (Zevalin®) Radioimmunotherapy after Cytoreduction with ESHAP Chemotherapy in Patients with Relapsed Follicular Non-Hodgkin Lymphoma: Final Results of a Phase II Study. Oncology.
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  Radioimmunotherapy (RIT) is effective in treating relapsed/refractory follicular lymphoma (FL), with durable remissions in first-line consolidation. We hypothesized that RIT with ibritumomab tiuxetan (Zevalin®) would result in durable remissions by eliminating minimal residual disease after cytoreduction.
• Rimsza, L. M., Li, H., Braziel, R. M., Spier, C. M., Persky, D. O., Dunlap, J., LeBlanc, M., Bartlett, N., Leonard, J. P., Smith, S. M., Press, O. W., & Friedberg, J. W. (2018). Impact of histologic grading on survival in the SWOG S0016 follicular lymphoma cohort. Haematologica.
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• Russ, A., Hua, A. B., Montfort, W. R., Rahman, B., Riaz, I. B., Khalid, M. U., Carew, J. S., Nawrocki, S. T., Persky, D., & Anwer, F. (2018). Blocking "don't eat me" signal of CD47-SIRPα in hematological malignancies, an in-depth review. Blood reviews.
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  Hematological malignancies express high levels of CD47 as a mechanism of immune evasion. CD47-SIRPα triggers a cascade of events that inhibit phagocytosis. Preclinical research supports several models of antibody-mediated blockade of CD47-SIRPα resulting in cell death signaling, phagocytosis of cells bearing stress signals, and priming of tumor-specific T cell responses. Four different antibody molecules designed to target the CD47-SIRPα interaction in malignancy are currently being studied in clinical trials: Hu5F9-G4, CC-90002, TTI-621, and ALX-148. Hu5F9-G4, a humanized anti-CD47 blocking antibody is currently being studied in four different Phase I trials. These studies may lay the groundwork for therapeutic bispecific antibodies. Bispecific antibody (CD20-CD47SL) fusion of anti-CD20 (Rituximab) and anti-CD47 also demonstrated a synergistic effect against lymphoma in preclinical models. This review summarizes the large body of preclinical evidence and emerging clinical data supporting the use of antibodies designed to target the CD47-SIRPα interaction in leukemia, lymphoma and multiple myeloma.
• Anwer, F., Shaukat, A. A., Zahid, U., Husnain, M., McBride, A., Persky, D., Lim, M., Hasan, N., & Riaz, I. B. (2017). Donor origin CAR T cells: graft versus malignancy effect without GVHD, a systematic review. Immunotherapy, 9(2), 123-130.
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  CD19, CD20 chimeric antigen receptor T (CAR T) cell therapy has shown promising results for the treatment of relapsed or refractory hematological malignancies. Best results have been reported in acute lymphoblastic leukemia patients with a complete response rate above 80%. Patients who received donor-derived CAR T cells for the relapsed malignancy after stem cell transplantation (allogenic hematopoietic stem cell transplant) were identified from the published trials. A total of 72 patients from seven studies were treated with donor-derived CAR T cells. Only five out of 72 patients (6.9%) developed graft versus host disease. Use of donor-derived CAR T cell for relapse prophylaxis, minimal residual disease clearance or salvage from relapse is therefore highly effective, and risk of graft versus host disease flare is very low. Side effects include cytokine release syndrome, tumor lysis syndrome, B-cell aplasia along with CNS toxicity.
• Kendrick, S., Rimsza, L. M., Scott, D. W., Slack, G. W., Farinha, P., Tan, K. L., Persky, D., Puvvada, S., Connors, J. M., Sehn, L., Gascoyne, R. D., & Schmelz, M. (2017). Aberrant cytoplasmic expression of MHCII confers worse progression free survival in diffuse large B-cell lymphoma. Virchows Archiv : an international journal of pathology, 470(1), 113-117.
• Landsburg, D. J., Falkiewicz, M. K., Maly, J., Blum, K. A., Howlett, C., Feldman, T., Mato, A. R., Hill, B. T., Li, S., Medeiros, L. J., Torka, P., Hernandez-Ilizaliturri, F., Reddy, N. M., Singavi, A., Fenske, T. S., Chavez, J. C., Kaplan, J. B., Behdad, A., Petrich, A. M., , Bast, M. A., et al. (2017). Outcomes of Patients With Double-Hit Lymphoma Who Achieve First Complete Remission. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 35(20), 2260-2267.
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  Purpose Patients with double-hit lymphoma (DHL) rarely achieve long-term survival following disease relapse. Some patients with DHL undergo consolidative autologous stem-cell transplantation (autoSCT) to reduce the risk of relapse, although the benefit of this treatment strategy is unclear. Methods Patients with DHL who achieved first complete remission following completion of front-line therapy with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or intensive front-line therapy, and deemed fit for autoSCT, were included. A landmark analysis was performed, with time zero defined as 3 months after completion of front-line therapy. Patients who experienced relapse before or who were not followed until that time were excluded. Results Relapse-free survival (RFS) and overall survival (OS) rates at 3 years were 80% and 87%, respectively, for all patients (n = 159). Three-year RFS and OS rates did not differ significantly for autoSCT (n = 62) versus non-autoSCT patients (n = 97), but 3-year RFS was inferior in patients who received R-CHOP compared with intensive therapy (56% v 88%; P = .002). Three-year RFS and OS did not differ significantly for patients in the R-CHOP or intensive therapy cohorts when analyzed by receipt of autoSCT. The median OS following relapse was 8.6 months. Conclusion In the largest reported series, to our knowledge, of patients with DHL to achieve first complete remission, consolidative autoSCT was not associated with improved 3-year RFS or OS. In addition, patients treated with R-CHOP experienced inferior 3-year RFS compared with those who received intensive front-line therapy. When considered in conjunction with reports of patients with newly diagnosed DHL, which demonstrate lower rates of disease response to R-CHOP compared with intensive front-line therapy, our findings further support the use of intensive front-line therapy for this patient population.
• Persky, D. O., Li, H., Rimsza, L. M., Barr, P. M., Popplewell, L. L., Bane, C. L., Von Gehr, A., LeBlanc, M., Fisher, R. I., Smith, S. M., & Friedberg, J. W. (2017). A Phase I/II Trial of Vorinostat (SAHA) in Combination with Rituximab-CHOP in Patients with Newly Diagnosed Advanced Stage Diffuse Large B-Cell Lymphoma (DLBCL): SWOG S0806. American journal of hematology.
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  Loss of major histocompatibility Class II expression (MHCII) in diffuse large B-cell lymphoma (DLBCL) correlates with decreased survival. MHCII transcription is in part regulated by histone acetylation. We tested the hypothesis that combination of histone deacetylase inhibitor (HDACI) with standard chemotherapy would improve outcomes in DLBCL in part through increased MHCII expression. S0806 was a single arm phase I/II trial of vorinostat given at 400 mg po daily on days 1-9 (subsequently amended to days 1-5 due to toxicity), combined with R-CHOP given on day 3 of a 21-day cycle for 8 cycles, with primary phase II endpoint of 2-year progression free survival (PFS). With 72 evaluable patients, at median follow up of 3 years, 2-year PFS estimate was 73%, and OS estimate was 86%. Considering that the regimen fell short of pre-defined efficacy improvement and was associated with high rates of febrile neutropenia (38%) and sepsis (19%), it cannot be recommended for general use. Consistent with our hypothesis, patients with low MCHII expression on S0806 had numerically superior outcomes compared to those from trial S0433 which did not use an HDACI, but the difference was not statistically significant. Current studies are focused on finding biomarkers of response to HDACI. This article is protected by copyright. All rights reserved.
• Puvvada, S. D., Guillén-Rodríguez, J. M., Rivera, X. I., Heard, K., Inclan, L., Schmelz, M., Schatz, J. H., & Persky, D. O. (2017). A Phase II Exploratory Study of PXD-101 (Belinostat) Followed by Zevalin in Patients with Relapsed Aggressive High-Risk Lymphoma. Oncology.
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  Aggressive lymphomas (aNHL) including diffuse large B-cell lymphoma (DLBCL) have poor outcomes in relapsed refractory patients. Prior studies have demonstrated that loss of major histocompatibility complex class II (MHCII) expression in DLBCL is associated with poor survival. The objective of this single-arm phase II study was to evaluate if PXD-101 would increase MHCII expression, synergize with Zevalin, and improve clinical outcomes.
• Akhenblit, P. J., Hanke, N. T., Gill, A., Persky, D. O., Howison, C. M., Pagel, M. D., & Baker, A. F. (2016). Assessing Metabolic Changes in Response to mTOR Inhibition in a Mantle Cell Lymphoma Xenograft Model Using AcidoCEST MRI. Molecular imaging, 15.
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  AcidoCEST magnetic resonance imaging (MRI) has previously been shown to measure tumor extracellular pH (pHe) with excellent accuracy and precision. This study investigated the ability of acidoCEST MRI to monitor changes in tumor pHe in response to therapy. To perform this study, we used the Granta 519 human mantle cell lymphoma cell line, which is an aggressive B-cell malignancy that demonstrates activation of the phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway. We performed in vitro and in vivo studies using the Granta 519 cell line to investigate the efficacy and associated changes induced by the mTOR inhibitor, everolimus (RAD001). AcidoCEST MRI studies showed a statistically significant increase in tumor pHe of 0.10 pH unit within 1 day of initiating treatment, which foreshadowed a decrease in tumor growth of the Granta 519 xenograft model. AcidoCEST MRI then measured a decrease in tumor pHe 7 days after initiating treatment, which foreshadowed a return to normal tumor growth rate. Therefore, this study is a strong example that acidoCEST MRI can be used to measure tumor pHe that may serve as a marker for therapeutic efficacy of anticancer therapies.
• Kumar, A., Sundararajan, S., Puvvada, S., & Persky, D. O. (2016). Limited Stage Aggressive Non-Hodgkin Lymphoma: What Is Optimal Therapy?. Current treatment options in oncology, 17(9), 45.
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  The seminal SWOG trial S8736 trial established the success of a short course of chemotherapy followed by involved field radiation in treating limited stage aggressive NHL lymphoma. Addition of rituximab offered a surprisingly modest improvement in this disease subset. Radioimmunotherapy could hold a slight advantage over rituximab, but that should be investigated in a randomized trial setting. The role of radiation therapy continues to be widely debated, with interpretation complicated by different trial populations, methods of assessing risk, as well as by differences in timing and dose of radiation. Prolonged course of chemotherapy followed by radiation is certainly not justified in all patients with limited stage disease. Three to four cycles of R-CHOP followed closely by IFRT/ISRT, or six cycles of R-CHOP chemoimmunotherapy (based on the MInT trial) are acceptable options. PET/CT scans may further limit radiation to minority of patients who have residual PET-positive masses. PET/CT-directed treatment strategy is being tested in a US intergroup trial. There is evidence that localized DLBCL has a different biology as compared to advanced stage disease. This relates to propensity of limited stage disease to be proportionately more germinal center B-cell like (GCB) and to have late relapses beyond 5 years. Both biology and imaging need to be integrated in the study of limited stage disease without presumption that it should be approached the same as advanced stage disease.
• Puvvada, S. D., Li, H., Rimsza, L. M., Bernstein, S. H., Fisher, R. I., LeBlanc, M., Schmelz, M., Glinsmann-Gibson, B., Miller, T. P., Maddox, A., Friedberg, J. W., Smith, S. M., & Persky, D. O. (2016). A phase II study of belinostat (PXD101) in relapsed and refractory aggressive B-cell lymphomas: SWOG S0520. Leukemia & lymphoma, 1-11.
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  Recent advances in diffuse large B-cell lymphomas (DLBCL) have underscored the importance of tumor microenvironment in escaping host anti-tumor responses. One mechanism is loss of major histocompatibility Class II antigens (MHCII) associated with decreased tumor infiltrating T lymphocytes (TIL) and poor survival. Transcription of MHCII is controlled by CIITA which in turn is regulated by histone acetylation. In this study, we hypothesized that HDAC inhibition with belinostat increases MHCII, CIITA expression, TIL and improves patient outcomes. Primary objective was evaluation of toxicity and response. Twenty-two patients were enrolled for the study. Belinostat was well tolerated with mild toxicity. Two partial responses were observed at 5, 13 months after registration for an overall response rate (ORR) (95% CI) of 10.5% (1.3-33.1%), and three patients had stable disease for 4.7, 42.3+, and 68.4 + months with minimum 3-year follow-up. Included correlative studies support the hypothesis and serve as the basis for SWOG S0806 combining vorinostat with R-CHOP.
• Stephens, D. M., Li, H., LeBlanc, M. L., Puvvada, S. D., Persky, D., Friedberg, J. W., & Smith, S. M. (2016). Continued Risk of Relapse Independent of Treatment Modality in Limited-Stage Diffuse Large B-Cell Lymphoma: Final and Long-Term Analysis of Southwest Oncology Group Study S8736. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 34(25), 2997-3004.
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  Utility of combined-modality therapy for patients with limited-stage diffuse large B-cell lymphoma (DLBCL) was shown in the Southwest Oncology Group (SWOG) S8736 study, where three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus radiotherapy (CHOP3RT) improved 5-year progression-free (PFS) and overall survival (OS) compared with eight cycles of CHOP (CHOP8). Subsequent analysis showed an unexpected overlap of the PFS curves. We aimed to confirm and investigate this observation by performing long-term analysis of SWOG S8736 and evaluating these data alongside data from similar patients receiving rituximab and CHOP3RT (SWOG S0014 study).
• Taverna, J. A., Yun, S., Jonnadula, J., Saleh, A., Riaz, I. B., Abraham, I., Yeager, A. M., Persky, D. O., McBride, A., Haldar, S., & Anwer, F. (2016). Role of Maintenance Therapy after High-Dose Chemotherapy and Autologous Hematopoietic Cell Transplantation in Aggressive Lymphomas: A Systematic Review. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.
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  Significant uncertainty exists in regard to the efficacy of maintenance therapy after high-dose chemotherapy (HDC) as well as autologous stem cell transplantation (ASCT) for the treatment of patients with aggressive lymphoma. A systematic review was performed to evaluate the effectiveness of post-ASCT maintenance therapy in patients with relapsed/refractory lymphoma. A comprehensive literature search yielded 4476 studies and a total of 42 studies (11 randomized controlled trials [RCT], 9 retrospective comparative studies, and 22 single-arm studies) were included in the systematic review. There was significant heterogeneity in study design, chemotherapeutic regimens, post-ASCT maintenance strategies, patient enrollment criteria, and study endpoints. Our findings suggest that post-ASCT maintenance immune-targeting strategies, including PD-1/PD-L1 blocking antibodies, rituximab, and brentuximab, may improve progression-free survival but not overall survival. Collectively, the results indicate a need for testing new strategies with well-designed and adequately powered RCTs to better address the role of post-ASCT maintenance in relapsed/refractory lymphomas.
• Danilov, A. V., & Persky, D. O. (2021). Incorporating acalabrutinib, a selective next-generation Bruton tyrosine kinase inhibitor, into clinical practice for the treatment of haematological malignancies. British journal of haematology.
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  Greater understanding of the mechanisms involved in the disease progression of haematological malignancies has led to the introduction of novel targeted therapies with reduced toxicity compared with chemotherapy-based regimens, which has expanded the treatment options for patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). Ibrutinib is a first-in-class Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of patients with CLL/SLL or relapsed/refractory MCL. However, next-generation BTK inhibitors have been developed with improved specificity and the potential to reduce the off-target toxicity observed with ibrutinib. Acalabrutinib is a highly selective, next-generation BTK inhibitor, which was granted accelerated approval by the US Food and Drug Administration in 2017 for the treatment of adult patients with MCL who have received at least one prior therapy. In November 2019, it was also granted approval for the treatment of adult patients with CLL/SLL on the basis of two phase 3 clinical trials. This review describes the current understanding of acalabrutinib according to clinical study data for the treatment of MCL and CLL/SLL and shares recommendations from our practice on how it should be used when treating patients in the clinic, including dosing, administration and management of adverse events.
• Li, L., Pongtornpipat, P., Tiutan, T., Kendrick, S. L., Park, S., Persky, D. O., Rimsza, L. M., Puvvada, S. D., & Schatz, J. H. (2015). Synergistic induction of apoptosis in high-risk DLBCL by BCL2 inhibition with ABT-199 combined with pharmacologic loss of MCL1. Leukemia, 29(8), 1702-12.
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  Better treatments are needed for patients with diffuse large B-cell lymphoma (DLBCL) at high risk of failing standard therapy. Avoiding apoptosis is a hallmark of cancer, and in DLBCL the redundantly functioning antiapoptotic proteins BCL2 and MCL1 are frequently expressed. Here we explore drugs that cause loss of MCL1, particularly the potent new cyclin-dependent kinase inhibitor dinaciclib, which knocks down MCL1 by inhibiting CDK9. Dinaciclib induces apoptosis in DLBCL cells but is completely overcome by increased activity of BCL2. We find that clinical samples have frequent co-expression of MCL1 and BCL2, suggesting that therapeutic strategies targeting only one will lead to treatment failures owing to activity of the other. The BH3 mimetic ABT-199 potently and specifically targets BCL2. Single-agent ABT-199 had modest antitumor activity against most DLBCL lines and resulted in compensatory upregulation of MCL1 expression. ABT-199 synergized strongly, however, when combined with dinaciclib and with other drugs affecting MCL1, including standard DLBCL chemotherapy drugs. We show potent antitumor activities of these combinations in xenografts and in a genetically accurate murine model of MYC-BCL2 double-hit lymphoma. In sum, we reveal a rational treatment paradigm to strip DLBCL of its protection from apoptosis and improve outcomes for high-risk patients.
• Majeed, A., Chan, O., Okolo, O., Shponka, V., Georgescu, A., & Persky, D. (2015). Hodgkin Lymphoma Mimicking Osteomyelitis. Case reports in oncology, 10(2), 542-547.
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  Hodgkin lymphoma with symptomatic osseous involvement can have a similar presentation to osteomyelitis. Common findings in symptoms, laboratory workup, and imaging can make it very difficult to distinguish between the two diseases. Excisional biopsy should be pursued if fine-needle biopsy is equivocal and suspicion of lymphoma is high. We report a case of a 40-year-old man who presented with a history of marine animal sting on his neck and later developed erythema in the area, chest pain, constitutional symptoms, adenopathy, and imaging classic for sternal osteomyelitis. Fortunately, initial biopsy prompted the possibility of lymphoma, and further workup was initiated, which confirmed Hodgkin lymphoma. This case is a good reminder that malignancies and infections can share many common features, and keeping a broad differential diagnosis can be lifesaving. Proper staging and risk stratification of Hodgkin lymphoma help determine the optimal treatment.
• Persky, D. O., Miller, T. P., Unger, J. M., Spier, C. M., Puvvada, S., Stea, B. D., Press, O. W., Constine, L. S., Barton, K. P., Friedberg, J. W., LeBlanc, M., & Fisher, R. I. (2015). Ibritumomab consolidation after 3 cycles of CHOP plus radiotherapy in high-risk limited-stage aggressive B-cell lymphoma: SWOG S0313. Blood, 125(2), 236-41.
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  In the S0313 trial, we evaluated the impact of adding ibritumomab tiuxetan consolidation to 3 cycles of standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy plus involved field radiotherapy (IFRT) in patients with limited-stage aggressive B-cell non-Hodgkin lymphoma (LD-NHL). Patients with at least 1 stage-modified adverse risk factor (nonbulky stage II, age >60 years, elevated lactate dehydrogenase, or World Health Organization performance status of 2) were treated with CHOP on days 1, 22, and 43, followed 3 weeks later by 40 to 50 Gy of IFRT. An ibritumomab tiuxetan regimen was initiated 3 to 6 weeks following IFRT. Forty-six patients were registered and eligible, with median follow-up of 7.3 years. The progression-free survival estimate is 89% at 2 years, 82% at 5 years, and 75% at 7 years. The overall survival estimate is 91% at 2 years, 87% at 5 years, and 82% at 7 years. Grade 4 adverse events occurring more than once included neutropenia (8), leukopenia (5), and lymphopenia (2). Febrile neutropenia was observed in 4 patients. No cases of treatment-related myeloid neoplasms were noted. In conclusion, patients with high-risk LD-NHL treated with 3 cycles of CHOP plus IFRT followed by ibritumomab tiuxetan consolidation had outcomes that compare favorably to our historical experience. The clinical trial was registered at www.clinicaltrials.gov as #NCT00070018.
• Roberts, A. W., Advani, R. H., Kahl, B. S., Persky, D., Sweetenham, J. W., Carney, D. A., Yang, J., Busman, T. B., Enschede, S. H., Humerickhouse, R. A., & Seymour, J. F. (2015). Phase 1 study of the safety, pharmacokinetics, and antitumour activity of the BCL2 inhibitor navitoclax in combination with rituximab in patients with relapsed or refractory CD20+ lymphoid malignancies. British journal of haematology, 170(5), 669-78.
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  The oral BCL2 inhibitor navitoclax has moderate single-agent efficacy in chronic lymphocytic leukaemia (CLL) and minor activity in lymphoma in Phase 1 trials. Navitoclax synergizes with rituximab in preclinical models of B-cell lymphoid cancers. We report the safety, pharmacokinetics and clinical activity of this combination. Patients received navitoclax (200-325 mg) daily and four standard weekly doses of rituximab. Twenty-nine patients were enrolled across three dose-escalation cohorts and a safety expansion cohort (250 mg/d navitoclax). The combination was well tolerated. Common toxicities were mild diarrhoea (79%) and nausea (72%). Grade 4 thrombocytopenia occurred in 17% of patients (dose limiting at 325 mg/d). CD19(+) counts were severely reduced, while CD3(+) cells (~ 20%) and serum immunoglobulin M levels (~ 33%) were also reduced during the first year. The maximum tolerated dose for navitoclax in combination was 250 mg/d. Pharmacokinetic analyses revealed no apparent interactions between the drugs. The response rate in patients with follicular lymphoma was 9/12, including five complete responses. All five patients with CLL/small lymphocytic leukaemia achieved partial responses. One of nine patients with aggressive lymphoma responded. The addition of rituximab to navitoclax 250 mg/d is safe; the combination demonstrates higher response rates for low-grade lymphoid cancers than observed for either agent alone in previous Phase 1 trials.
• Barr, P. M., Miller, T. P., Friedberg, J. W., Peterson, D. R., Baran, A. M., Herr, M., Spier, C. M., Cui, H., Roe, D. J., Persky, D. O., Casulo, C., Littleton, J., Schwartz, M., Puvvada, S., Landowski, T. H., Rimsza, L. M., Dorr, R. T., Fisher, R. I., Bernstein, S. H., & Briehl, M. M. (2014). Phase 2 study of imexon, a prooxidant molecule, in relapsed and refractory B-cell non-Hodgkin lymphoma. Blood, 124(8), 1259-65.
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  Lymphoma cells are subject to higher levels of oxidative stress compared with their normal counterparts and may be vulnerable to manipulations of the cellular redox balance. We therefore designed a phase 2 study of imexon (Amplimexon/NSC-714597), a prooxidant molecule, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Imexon was administered at 1000 mg/m(2) IV daily for 5 days in 21-day cycles. Gene expression analysis performed on pretreatment tumor specimens included 13 transcripts used to generate a redox signature score, previously demonstrated to correlate with lymphoma prognosis. Twenty-two patients were enrolled having follicular (n = 9), diffuse large B-cell (DLBCL) (n = 5), mantle cell (n = 3), transformed follicular (n = 2), small lymphocytic (n = 2), and Burkitt (n = 1) lymphoma. The most common grade 3/4 adverse events were anemia (14%) and neutropenia (9%). The overall response rate was 30%, including responses in follicular lymphoma (4 of 9) and DLBCL (2 of 5). Gene expression analyses revealed CD68 and the redox-related genes, GPX1 and SOD2, as well as a higher redox score to correlate with clinical responses. Therefore, pretreatment markers of oxidative stress may identify patients likely to respond to this therapeutic approach. This trial was registered at www.clinicaltrials.gov as #NCT01314014.
• Friedberg, J. W., Mahadevan, D., Cebula, E., Persky, D., Lossos, I., Agarwal, A. B., Jung, J., Burack, R., Zhou, X., Leonard, E. J., Fingert, H., Danaee, H., & Bernstein, S. H. (2014). Phase II study of alisertib, a selective Aurora A kinase inhibitor, in relapsed and refractory aggressive B- and T-cell non-Hodgkin lymphomas. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 32(1), 44-50.
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  Aurora A kinase (AAK) is overexpressed in aggressive lymphomas and can correlate with more histologically aggressive forms of disease. We therefore designed a phase II study of alisertib, a selective AAK inhibitor, in patients with relapsed and refractory aggressive non-Hodgkin lymphomas.
• Gustafson, H. L., Yao, S., Goldman, B. H., Lee, K., Spier, C. M., LeBlanc, M. L., Rimsza, L. M., Cerhan, J. R., Habermann, T. M., Link, B. K., Maurer, M. J., Slager, S. L., Persky, D. O., Miller, T. P., Fisher, R. I., Ambrosone, C. B., & Briehl, M. M. (2014). Genetic polymorphisms in oxidative stress-related genes are associated with outcomes following treatment for aggressive B-cell non-Hodgkin lymphoma. American journal of hematology, 89(6), 639-45.
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  Variable survival outcomes are seen following treatment for aggressive non-Hodgkin lymphoma (NHL). This study examined whether outcomes for aggressive B-cell NHL are associated with single nucleotide polymorphisms (SNPs) in oxidative stress-related genes, which can alter drug metabolism and immune responses. Genotypes for 53 SNPs in 29 genes were determined for 337 patients given anthracycline-based therapies. Their associations with progression-free survival (PFS) and overall survival (OS) were estimated by Cox proportional hazard regression; associations with hematologic toxicity were estimated by logistic regression. To validate the findings, the top three SNPs were tested in an independent cohort of 572 DLBCL patients. The top SNPs associated with PFS in the discovery cohort were the rare homozygotes for MPO rs2243828 (hazard ratio [HR] = 1.87, 95% confidence interval [CI] = 1.14-3.06, P = 0.013), AKR1C3 rs10508293 (HR = 2.09, 95% CI = 1.28-3.41, P = 0.0032) and NCF4 rs1883112 (HR = 0.66, 95% CI = 0.43-1.02, P = 0.06). The association of the NCF4 SNP with PFS was replicated in the validation dataset (HR = 0.66, 95% CI = 0.44-1.01, P = 0.05) and the meta-analysis was significant (HR = 0.66, 95% CI = 0.49-0.89, P < 0.01). The association of the MPO SNP was attenuated in the validation dataset, while the meta-analysis remained significant (HR = 1.64, 95% CI = 1.12-2.41). These two SNPs showed similar trends with OS in the meta-analysis (for NCF4, HR = 0.72, 95% CI = 0.51-1.02, P = 0.07 and for MPO, HR = 2.06, 95% CI = 1.36-3.12, P < 0.01). In addition, patients with the rare homozygote of the NCF4 SNP had an increased risk of hematologic toxicity. We concluded that genetic variations in NCF4 may contribute to treatment outcomes for patients with aggressive NHL.
• Mahadevan, D., Morales, C., Cooke, L. S., Manziello, A., Mount, D. W., Persky, D. O., Fisher, R. I., Miller, T. P., & Qi, W. (2014). Alisertib added to rituximab and vincristine is synthetic lethal and potentially curative in mice with aggressive DLBCL co-overexpressing MYC and BCL2. PloS one, 9(6), e95184.
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  Pearson correlation coefficient for expression analysis of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) demonstrated Aurora A and B are highly correlated with MYC in DLBCL and mantle cell lymphoma (MCL), while both Auroras correlate with BCL2 only in DLBCL. Auroras are up-regulated by MYC dysregulation with associated aneuploidy and resistance to microtubule targeted agents such as vincristine. Myc and Bcl2 are differentially expressed in U-2932, TMD-8, OCI-Ly10 and Granta-519, but only U-2932 cells over-express mutated p53. Alisertib [MLN8237 or M], a highly selective small molecule inhibitor of Aurora A kinase, was synergistic with vincristine [VCR] and rituximab [R] for inhibition of cell proliferation, abrogation of cell cycle checkpoints and enhanced apoptosis versus single agent or doublet therapy. A DLBCL (U-2932) mouse model showed tumor growth inhibition (TGI) of ∼ 10-20% (p = 0.001) for M, VCR and M-VCR respectively, while R alone showed ∼ 50% TGI (p = 0.001). M-R and VCR-R led to tumor regression [TR], but relapsed 10 days after discontinuing therapy. In contrast, M-VCR-R demonstrated TR with no relapse >40 days after stopping therapy with a Kaplan-Meier survival of 100%. Genes that are modulated by M-VCR-R (CENP-C, Auroras) play a role in centromere-kinetochore function in an attempt to maintain mitosis in the presence of synthetic lethality. Together, our data suggest that the interaction between alisertib plus VCR plus rituximab is synergistic and synthetic lethal in Myc and Bcl-2 co-expressing DLBCL. Alisertib plus vincristine plus rituximab [M-VCR-R] may represent a new strategy for DLBCL therapy.
• Taverna, J., Nair, A., Yun, S., Paulson, S., Schatz, J. H., Persky, D., Fuchs, D., & Puvvada, S. (2014). A rare presentation of in situ mantle cell lymphoma and follicular lymphoma: a case report and review of the literature. Case reports in hematology, 2014, 145129.
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  A 65-year-old gentleman presented with left groin swelling over the course of two months. Physical exam revealed nontender left inguinal adenopathy, and computed tomography scans detected multiple lymph nodes in the mesenteric, aortocaval, and right common iliac regions. An excisional lymph node biopsy was performed. Pathologic evaluation demonstrated follicular center site which stained positive for PAX5, CD20, CD10, Bcl-2, Bcl-6, and mantle zone cells. These findings demonstrated CCND1 and CD5 positivity, suggesting composite lymphoma comprising follicular lymphoma (FL) with in situ mantle cell lymphoma (MCLIS). FL is known as indolent non-Hodgkin lymphoma; however, the clinical significance of a coexisting MCLIS continues to be elusive, and optimal management of these patients remains largely unknown. This case illustrates the diagnostic and therapeutic challenges of composite lymphomas. This paper also discusses advances in molecular pathogenesis and lymphoma genomics which offer novel insights into these rare diseases.
• Cycon, K. A., Mulvaney, K., Rimsza, L. M., Persky, D., & Murphy, S. P. (2013). Histone deacetylase inhibitors activate CIITA and MHC class II antigen expression in diffuse large B-cell lymphoma. Immunology, 140(2), 259-72.
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  Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin's lymphoma (NHL) diagnosed in the USA, consists of at least two distinct subtypes: germinal centre B (GCB) and activated B-cell (ABC). Decreased MHC class II (MHCII) expression on the tumours in both DLBCL subtypes directly correlates with significant decreases in patient survival. One common mechanism accounting for MHCII down-regulation in DLBCL is reduced expression of the MHC class II transactivator (CIITA), the master regulator of MHCII transcription. Furthermore, reduced CIITA expression in ABC DLBCL correlates with the presence of the transcriptional repressor positive regulatory domain-I-binding factor-1 (PRDI-BF1). However, the mechanisms underlying down-regulation of CIITA in GCB DLBCL are currently unclear. In this study, we demonstrate that neither PRDI-BF1 nor CpG hypermethylation at the CIITA promoters are responsible for decreased CIITA in GCB DLBCL. In contrast, histone modifications associated with an open chromatin conformation and active transcription were significantly lower at the CIITA promoters in CIITA(-) GCB cells compared with CIITA(+) B cells, which suggests that epigenetic mechanisms contribute to repression of CIITA transcription. Treatment of CIITA(-) or CIITA(low) GCB cells with several different histone deacetylase inhibitors (HDACi) activated modest CIITA and MHCII expression. However, CIITA and MHCII levels were significantly higher in these cells after exposure to the HDAC-1-specific inhibitor MS-275. These results suggest that CIITA transcription is repressed in GCB DLBCL cells through epigenetic mechanisms involving HDACs, and that HDACi treatment can alleviate repression. These observations may have important implications for patient therapy.
• Mahadevan, D., Unger, J. M., Spier, C. M., Persky, D. O., Young, F., LeBlanc, M., Fisher, R. I., & Miller, T. P. (2013). Phase 2 trial of combined cisplatin, etoposide, gemcitabine, and methylprednisolone (PEGS) in peripheral T-cell non-Hodgkin lymphoma: Southwest Oncology Group Study S0350. Cancer, 119(2), 371-9.
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  Patients with peripheral T-cell lymphomas (PTCLs) have inferior progression-free survival (PFS) and overall survival (OS) compared with patients who have aggressive B-cell non-Hodgkin lymphoma. Because PTCLs over express multidrug resistance gene 1/P-glycoprotein (MDR-1/P-gp), we devised platinum, etoposide, gemcitabine, and methylprednisolone (PEGS) with agents that are not substrates of the efflux pump. Gemcitabine was included because of its excellent single-agent activity in PTCL.
• Qi, W., Spier, C., Liu, X., Agarwal, A., Cooke, L. S., Persky, D. O., Chen, D., Miller, T. P., & Mahadevan, D. (2013). Alisertib (MLN8237) an investigational agent suppresses Aurora A and B activity, inhibits proliferation, promotes endo-reduplication and induces apoptosis in T-NHL cell lines supporting its importance in PTCL treatment. Leukemia research, 37(4), 434-9.
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  Peripheral T-cell lymphomas (PTCL) are a diverse group of rare non-Hodgkin lymphomas (NHL) that carry a poor prognosis and are in need of effective therapies. Alisertib (MLN8237) an investigational agent that inhibits Aurora A Ser/Thr kinase has shown activity in PTCL patients. Here we demonstrate that aurora A and B are highly expressed in T-cell lymphoma cell lines. In PTCL patient samples aurora A was positive in 3 of 24 samples and co-expressed with aurora B. Aurora B was positive in tumor cells in 22 of 32 samples. Of the subtypes of PTCL, aurora B was over-expressed in PTCL (NOS) [73%], T-NHL [100%], ALCL (Alk-Neg) [100%] and AITL [100%]. Treatment with MLN8237 inhibited PTCL cell proliferation in CRL-2396 and TIB-48 cells with an IC50 of 80-100nM. MLN8237 induced endo-reduplication in a dose and time dependent manner in PTCL cell lines leading to apoptosis demonstrated by flow cytometry and PARP-cleavage at concentrations achieved in early phase clinical trials. Moreover, inhibition of HisH3 and aurora A phosphorylation was dose dependent and strongly correlated with endo-reduplication. The data provide a sound rationale for aurora inhibition in PTCL as a therapeutic modality and warrants clinical trial evaluation.
• Mahadevan, D., Stejskal, A., Cooke, L. S., Manziello, A., Morales, C., Persky, D. O., Fisher, R. I., Miller, T. P., & Qi, W. (2012). Aurora A inhibitor (MLN8237) plus vincristine plus rituximab is synthetic lethal and a potential curative therapy in aggressive B-cell non-Hodgkin lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research, 18(8), 2210-9.
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  Aurora A and B are oncogenic serine/threonine kinases that regulate mitosis. Overexpression of Auroras promotes resistance to microtubule-targeted agents. We investigated mechanistic synergy by inhibiting the mitotic spindle apparatus in the presence of MLN8237 [M], an Aurora A inhibitor with either vincristine [MV] or docetaxel [MD] in aggressive B-cell non-Hodgkin lymphoma (B-NHL). The addition of rituximab [R] to MV or MD was evaluated for synthetic lethality.
• Persky, D. O., Dornan, D., Goldman, B. H., Braziel, R. M., Fisher, R. I., Leblanc, M., Maloney, D. G., Press, O. W., Miller, T. P., & Rimsza, L. M. (2012). Fc gamma receptor 3a genotype predicts overall survival in follicular lymphoma patients treated on SWOG trials with combined monoclonal antibody plus chemotherapy but not chemotherapy alone. Haematologica, 97(6), 937-42.
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  Fc gamma receptor polymorphisms were linked to outcome in follicular lymphoma patients treated with single-agent rituximab, an anti-CD20 monoclonal antibody. In particular, 158F/F genotype of Fc gamma receptor 3A and 131R/R genotype of Fc gamma receptor 2A correlated with worse outcome compared to high-affinity 158V/V and 131H/H, respectively. We examined this association in the context of anti-CD20 monoclonal antibody combined with chemotherapy, as compared to chemotherapy alone, in follicular lymphoma patients treated on SWOG clinical trials.
• Qi, W., Liu, X., Cooke, L. S., Persky, D. O., Miller, T. P., Squires, M., & Mahadevan, D. (2012). AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas. International journal of cancer, 130(12), 2997-3005.
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  Aurora kinases are oncogenic serine/threonine kinases that play key roles in regulating the mitotic phase of the eukaryotic cell cycle. Auroras are overexpressed in numerous tumors including B-cell non-Hodgkin's lymphomas and are validated oncology targets. AT9283, a pan-aurora inhibitor inhibited growth and survival of multiple solid tumors in vitro and in vivo. In this study, we demonstrated that AT9283 had potent activity against Aurora B in a variety of aggressive B-(non-Hodgkin lymphoma) B-NHL cell lines. Cells treated with AT9283 exhibited endoreduplication confirming the mechanism of action of an Aurora B inhibitor. Also, treatment of B-NHL cell lines with AT9283 induced apoptosis in a dose and time dependent manner and inhibited cell proliferation with an IC(50) < 1 μM. It is well known that inhibition of auroras (A or B) synergistically enhances the effects of microtubule targeting agents such as taxanes and vinca alkaloids to induce antiproliferation and apoptosis. We evaluated whether AT9283 in combination with docetaxel is more efficient in inducing apoptosis than AT9283 or docetaxel alone. At very low doses (5 nM) apoptosis was doubled in the combination (23%) compared to AT9283 or docetaxel alone (10%). A mouse xenograft model of mantle cell lymphoma demonstrated that AT9283 at 15 mg/kg and docetaxel (10 mg/kg) alone had modest anti-tumor activity. However, AT9283 at 20 mg/kg and AT9283 (15 or 20 mg/kg) plus docetaxel (10 mg/kg) demonstrated a statistically significant tumor growth inhibition and enhanced survival. Together, our results suggest that AT9283 plus docetaxel may represent a novel therapeutic strategy in B-cell NHL and warrant early phase clinical trial evaluation.
• Qi, W., Cooke, L. S., Liu, X., Rimsza, L., Roe, D. J., Manziolli, A., Persky, D. O., Miller, T. P., & Mahadevan, D. (2011). Aurora inhibitor MLN8237 in combination with docetaxel enhances apoptosis and anti-tumor activity in mantle cell lymphoma. Biochemical pharmacology, 81(7), 881-90.
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  Auroras (A and B) are oncogenic serine/threonine kinases that play key roles in the mitotic phase of the eukaryotic cell cycle. Analysis of the leukemia lymphoma molecular profiling project (LLMPP) database indicates Aurora over-expression correlates with poor prognosis. A tissue microarray (TMA) composed of 20 paired mantle cell lymphoma (MCL) patients demonstrated >75% of patients had high levels Aurora expression. Aurora A and B were also found elevated in 13 aggressive B-NHL cell lines. MLN8237, an Aurora inhibitor induced G2/M arrest with polyploidy and abrogated Aurora A and histone-H3 phosphorylation. MLN8237 inhibited aggressive B-NHL cell proliferation at an IC(50) of 10-50 nM and induced apoptosis in a dose- and time-dependent manner. Low dose combinations of MLN8237+docetaxel enhanced apoptosis by ~3-4-fold in cell culture compared to single agents respectively. A mouse xenograft model of MCL demonstrated that MLN8237 (10 or 30 mg/kg) or docetaxel (10mg/kg) alone had modest anti-tumor activity. However, MLN8237 plus docetaxel demonstrated a statistically significant tumor growth inhibition and enhanced survival compared to single agent therapy. Together, our results suggest that MLN8237 plus docetaxel may represent a novel therapeutic strategy that could be evaluated in early phase trials in relapsed/refractory aggressive B-cell NHL.
• Koreishi, A. F., Saenz, A. J., Persky, D. O., Cui, H., Moskowitz, A., Moskowitz, C. H., & Teruya-Feldstein, J. (2010). The role of cytotoxic and regulatory T cells in relapsed/refractory Hodgkin lymphoma. Applied immunohistochemistry & molecular morphology : AIMM / official publication of the Society for Applied Immunohistochemistry, 18(3), 206-11.
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  Recent data suggests the presence of cytotoxic (TIA-1 and granzyme B+) and regulatory T-cells (FOXP3+) in classical Hodgkin lymphoma (cHL) tissues has been shown to correlate with poor overall survival in mainly diagnostic biopsies. By tissue microarray analyses, we extend this observation to a cohort of relapsed/refractory cHL tissue biopsies and analyze immunohistochemical expression of FOXP3, TIA-1, and granzyme B in the inflammatory background and the tumor microenvironment. High expression of TIA-1 (>50%) correlated with poor overall survival (P
• Persky, D. O., Moskowitz, C. H., Filatov, A., Saxena, R., Cui, H., & Teruya-Feldstein, J. (2010). High dose chemoradiotherapy and ASCT may overcome the prognostic importance of biologic markers in relapsed/refractory Hodgkin lymphoma. Applied immunohistochemistry & molecular morphology : AIMM / official publication of the Society for Applied Immunohistochemistry, 18(1), 35-40.
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  Of about 20% of patients with relapsed/refractory Hodgkin lymphoma (HL), approximately half achieve long-term remissions after high-dose chemoradiotherapy and autologous stem cell transplantation (HDT/ASCT). Treatment with a comprehensive program using second-line chemotherapy with ICE (ifosfamide, carboplatin, etoposide) before HDT/ASCT identified a clinical prognostic model, but prognostic biologic markers in relapsed/refractory HL remain unclear. We sought to determine if we could identify such markers, and if our comprehensive second-line program could overcome their significance.
• Schaffel, R., Hedvat, C. V., Teruya-Feldstein, J., Persky, D., Maragulia, J., Lin, D., Portlock, C. S., Moskowitz, C. H., & Zelenetz, A. D. (2010). Prognostic impact of proliferative index determined by quantitative image analysis and the International Prognostic Index in patients with mantle cell lymphoma. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 21(1), 133-9.
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  The proliferative index (PI) is a powerful prognostic factor in mantle cell lymphoma (MCL); however, its utility is hampered by interobserver variability. The mantle cell international prognostic index (MIPI) has been reported to have prognostic importance. In this study, we determined the prognostic value of the PI as determined by quantitative image analysis in MCL.
• Stasik, C. J., Nitta, H., Zhang, W., Mosher, C. H., Cook, J. R., Tubbs, R. R., Unger, J. M., Brooks, T. A., Persky, D. O., Wilkinson, S. T., Grogan, T. M., & Rimsza, L. M. (2010). Increased MYC gene copy number correlates with increased mRNA levels in diffuse large B-cell lymphoma. Haematologica, 95(4), 597-603.
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  Translocations involving the MYC gene and increased MYC mRNA levels are associated with poor outcome in diffuse large B-cell lymphoma. However, the presence of increased MYC gene copy number and/or polysomy of chromosome 8 have not been previously described.
• Persky, D. O., & Miller, T. P. (2009). Localized large cell lymphoma: is there any need for radiation therapy?. Current opinion in oncology, 21(5), 401-6.
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  Diffuse large B-cell lymphoma is the most common lymphoma diagnosed in the United States and presents as localized disease in about 25% of the patients. The standard of care was established by Southwest Oncology Group trial 8736, which showed the superiority of a short course of chemotherapy followed by radiation over a longer course of chemotherapy alone. This review discusses the studies that followed with the intent to establish whether the standard of care has changed.
• Rkein, A. M., Harrigal, C., Friedman, A. C., Persky, D., & Krupinski, E. (2009). Comparison of the accuracy of CT volume calculated by circumscription to prolate ellipsoid volume (bidimensional measurement multiplied by coronal long axis). Academic radiology, 16(2), 181-6.
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  Tumor volume is one of the most important factors in evaluating the response to treatment of patients with cancer. The objective of this study was to compare computed tomographic (CT) volume calculation using a semiautomated circumscribing tracing tool (manual circumscription [MC]) to prolate ellipsoid volume calculation (PEVC; bidimensional measurement multiplied by coronal long axis) and determine which was more accurate and consistent.
• Stopeck, A. T., Unger, J. M., Rimsza, L. M., Bellamy, W. T., Iannone, M., Persky, D. O., Leblanc, M., Fisher, R. I., & Miller, T. P. (2009). A phase II trial of single agent bevacizumab in patients with relapsed, aggressive non-Hodgkin lymphoma: Southwest oncology group study S0108. Leukemia & lymphoma, 50(5), 728-35.
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  This is the first report of the Southwest oncology group phase II trial of single agent bevacizumab in patients with relapsed, aggressive non-Hodgkin lymphoma (NHL). Fifty-two patients in first or second relapse with diffuse large B-cell or mantle cell lymphoma were enrolled. Patients were treated with bevacizumab at 10 mg/kg every 2 weeks. Therapy was well tolerated with no unexpected toxicities observed. Six-month progression-free survival (PFS) was 16% with a response rate of 2% and median duration of response or stable disease of 5.2 months (range 3.5-72.7). Vascular endothelial growth factor A (VEGF) and VEGF receptor expression was observed in 70% and 65% of specimens, respectively. In an exploratory subgroup analysis, baseline urine VEGF and plasma vascular cell adhesion molecule-1 (VCAM) levels correlated with survival. Prolonged PFS in several patients as well as biomarker studies suggest the VEGF pathway plays an important role in aggressive NHL. Clinical trials combining active chemotherapy regimens with VEGF targeted agents are currently in progress.
• Persky, D. O., Unger, J. M., Spier, C. M., Stea, B., LeBlanc, M., McCarty, M. J., Rimsza, L. M., Fisher, R. I., Miller, T. P., & , S. O. (2008). Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 26(14), 2258-63.
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  To evaluate the effect of rituximab in limited-stage diffuse large B-cell lymphoma (DLBCL), we conducted a multicenter phase II trial combining rituximab with three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP) followed by involved-field radiation therapy (IFRT).
• Rimsza, L. M., Leblanc, M. L., Unger, J. M., Miller, T. P., Grogan, T. M., Persky, D. O., Martel, R. R., Sabalos, C. M., Seligmann, B., Braziel, R. M., Campo, E., Rosenwald, A., Connors, J. M., Sehn, L. H., Johnson, N., & Gascoyne, R. D. (2008). Gene expression predicts overall survival in paraffin-embedded tissues of diffuse large B-cell lymphoma treated with R-CHOP. Blood, 112(8), 3425-33.
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  Gene expression profiling (GEP) on frozen tissues has identified genes predicting outcome in patients with diffuse large B-cell lymphoma (DLBCL). Confirmation of results in current patients is limited by availability of frozen samples and addition of monoclonal antibodies to treatment regimens. We used a quantitative nuclease protection assay (qNPA) to analyze formalin-fixed, paraffin-embedded tissue blocks for 36 previously identified genes (N = 209, 93 chemotherapy; 116 rituximab + chemotherapy). By qNPA, 208 cases were successfully analyzed (99.5%). In addition, 15 of 36 and 11 of 36 genes, representing each functional group previously identified by GEP, were associated with survival (P < .05) in the 2 treatment groups, respectively. In addition, 30 of 36 hazard ratios of death trended in the same direction versus the original studies. Multivariate and variable cut-off point analysis identified low levels of HLA-DRB (< 20%) and high levels of MYC (> 80%) as independent indicators of survival, together distinguishing cases with the worst prognosis. Our results solve a clinical research problem by demonstrating that prognostic genes can be meaningfully quantified using qNPA technology on formalin-fixed, paraffin-embedded tissues; previous GEP findings in DLBCL are relevant with current treatments; and 2 genes, representing immune escape and proliferation, are the common features of the most aggressive DLBCL.

Proceedings Publications

• Recio Boiles, A., Alkhatib, N., McBride, A., Abraham, I. L., & Elquza, E. (2018, Winter). Recurrent venous thromboembolism, major bleeding, and associated cost of treatment with low molecular weight heparin or direct oral anticoagulant in patients with gastrointestinal malignancies: retrospective real-world analysis at a comprehensive cancer center. In Blood, 132(Suppl 1):, 5057.
• Persky, D. O. (2016, December). A Phase II, Open-Label Study of Bortezomib (Velcade®), Cladribine, and Rituximab (VCR) in Advanced, Newly Diagnosed and Relapsed/Refractory Mantle Cell and Indolent Lymphomas.. In American Society of Hematology, 128.
• Persky, D. O. (2016, December). Benefit of Consolidative Autologous Stem Cell Transplantation in First Complete Remission for Patients with Double Hit Lymphoma Appears Dependent on Induction Regimen Intensity. In American Society of Hematology, 128.
• Persky, D. O. (2016, December). Sequential RCHOP, Radioimmunotherapy and Rituximab Maintenance Improves Early Outcomes in Advanced Stage Follicular Lymphoma: 5 Year Outcomes from SWOG 0801.. In American Society of Hematology, 128, 1790.
• Persky, D. O. (2015, December 2015). A Phase I/II Trial of Vorinostat (SAHA) in Combination with Rituximab-CHOP in Patients with Newly Diagnosed Advanced Stage Diffuse Large B-Cell Lymphoma (DLBCL): SWOG S0806.. In ASH Annual Meeting, 126, 23.
• Persky, D. O. (2015, December 2015). Efficacy of Same-Day Vs. Next-Day Pegfilgrastim for the Prevention of Chemotherapy-Induced (Febrile) Neutropenia (CIN/FN): A Meta-Analysis.. In ASH Annual Meeting, 126, 23.

Presentations

• Persky, D. O. (2020, February/Winter). The Next Frontier: Therapeutic Advances in Relapsed/Refractory DLBCL. Med-IQ: A series of CME/CE accredited - deliver education on the lastest clinical data and emerging therapeutics strategies in relapsed/refractory DLBCL. Goodyear, AZ: Med-IQ.
• Persky, D. O. (2020, July/Summer). Lymphoma. ASCO Direct Highlights. Phoenix, AZ: ASCO.
• Persky, D. O. (2020, October/Fall). Lymphoma Overview. 25th Annual North American Educational Forum on Lymphoma: Lymphoma Foundation. virtual.
• Persky, D. O. (2020, October/Fall). Oral Agents. Lymphoma Research Foundation: 25th Annual North American Educational Forum on Lymphoma. virtual: LRF.
• Persky, D. O. (2020, September/Summer). Shifting Chemo Administration from inpatient to outpatient setting improves care and reduces costs. ACCC 37th National Oncology Conference. virtual.
• Persky, D. O. (2020, September/Summer). Treatment Of Early Stage DLBCL. Eighth Annual Meeting of the Society of Hematologic Oncology. virtual conference.
• Persky, D. O. (2020, September/Summer). University of Arizona Cancer Canter: Bearing Down on Cancer. 2nd Annual Drug Discovery & Development Summit. Tucson: UofA.
• Persky, D. O. (2019, December/Fall). PET-Directed Therapy for Patients with Limited-Stage Diffuse Large B-Cell Lymphoma – Results of Intergroup Nctn Study S1001. 61st ASH Annual Meeting. Orlando, FL: ASH.
• Persky, D. O. (2019, July/Summer). Lymphoma and Chronic Lymphocytic Lymphoma. Best of ASCO. Auston, TX: Best of ASCO.
• Abraham, I. L., McBride, A., Persky, D. O., Alsaid, N., AlRawashdeh, N., Abraham, I. L., McBride, A., Persky, D. O., Alsaid, N., & AlRawashdeh, N. (2018, Winter). Economic evaluation for the US of ibrutinib versus acalabrutinib for patients with relapsed or refractory mantle cell lymphoma. American Society of Hematology. San Diego, CA: American Society of Hematology.
• Persky, D. O. (2018, February/Winter). Clinical Trials Update. External Advisory Board Meeting. Arizona Cancer Center: AZCC.
• Persky, D. O. (2018, February/Winter). Overview of Clinical Trials and Protocol Development. Clinical and Translational Research Curriculum for Hematology/Medical Oncology Fellowship. Arizona Cancer Center: AZCC.
• Persky, D. O. (2017, January/Winter). Treating Indolent Lymphoma. 14th Annual Review Course; Mayo Clinic Clinical and Multidisciplinary Hematology and Oncology. Scottsdale, AZ: Mayo.
• Persky, D. O. (2017, September/Fall). Limited Stage Diffuse Large B-Cell Lymphoma: is the problem solved?. Emil J. Freireich Grand Rounds; The University of Texas MD Andeson Cancer Center. Houston, TX: The University of Texas MD Anderson Cancer Center.
• Persky, D. O. (2020, September/Fall). Treatment of Early Stage DLBCL. SOHO 2020 Eighth Annual Meeting of the Society of Hematologic Oncology. Houston, TX: SOHO.

Poster Presentations

• Abraham, I. L., Erstad, B. L., Sweasy, J., Persky, D. O., McBride, A., & Alrawashdh, N. (2021). Survival trends in chronic lymphocytic leukemia across treatment eras: SEER database analyses (1985 to 2017).. American Society of Clinical Oncology Annual MeetingAmerican Society of Clinical Oncology.
• Persky, D. O. (2019, November/Fall). A Phase 2 Study of MT-3724 to Evaluate Safety, Pharmacodynamics and Efficacy of MT-3724 for the Treatment of Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma. American Society of HematologyBlood.
• Persky, D. O. (2019, November/Fall). Anti-CD47 Antibody, CC-90002, in Combination with Rituximab in Subjects with Relapsed and/or Refractory Non-Hodgkin Lymphoma (R/R NHL). American Society of HematologyBlood.
• Persky, D. O. (2019, November/Fall). Monotherapy Activity with the First CD20-Targeted Immunotoxin, MT-3724, in Subjects with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL). American Society of Hematology.
• Persky, D. O. (2019, November/Fall). Outcomes of Primary and Secondary Prophylaxis of Chemotherapy Induced and Febrile Neutropenia (CIN/FN) in Bendamustine Plus Rituximab (BR) Regimens in Patients with Lymphoma and Chronic Lymphocytic Leukemia (CLL): Real-World, Single-Center Experience. American Society of Hematology.
• Persky, D. O. (2019, November/Fall). SYK Inhibitor Entospletinib in Combination with Obinutuzumab Demonstrates Efficacy in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia. American Society of Hematology.
• Persky, D. O. (2019, November/Fall). The Chronic Lymphocytic Leukemia Comorbidity Index (CLL-CI): A Novel Comorbidity Score Derived from a Large Multicenter Retrospective Cohort Study of Patients Treated with Ibrutinib and/or Chemo-Immunotherapy (CIT). American Society of Hematology.
• Persky, D. O. (2018, January/Winter). A Phase II Intergroup Trial of PET-Directed Therapy for Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): SWOG Study S1001 (NCT01359592). Department of Medicine 2nd Annual PI Poster Session. Kiewit: DOM-UA.
• Persky, D. O. (2018, January/Winter). A Phase II Intergroup Trial of PET-Directed Therapy for Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): SWOG Study S1001. 2nd Annual PI Poster Session. Tucson: Department of Medicine.
• Persky, D. O. (2018, November/Winter). Checkpoint Blockade Therapy May Sensitize Aggressive and Indolent Non-Hodgkin Lymphoma to Subsequent Therapy. Blood.
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  Background: Outcomes to salvage therapy for patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) are suboptimal. Checkpoint blockade therapy (CBT) has been explored in the relapsed/refractory (R/R) NHL population, but response rates to single agent CBT therapy are modest. To date, there is no literature on whether treatment with CBT may sensitize NHL patients to subsequent therapy. We investigated the outcome of subsequent treatment in patients with R/R NHL who had received CBT in a large multicenter international retrospective analysis.
• Persky, D. O. (2018, November/Winter). Checkpoint Blockade Therapy May Sensitize Hodgkin Lymphoma to Subsequent Therapy. Blood.
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  Background: Relapsed or refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical problem. Recently checkpoint blockade therapy (CBT) has shown striking activity in this setting, but the complete response (CR) rate is modest. Patients who relapse after CBT have limited therapeutic options. A prior, retrospective study showed that after anti-PD-1 therapy the objective response rate to chemotherapy alone was 61% (Rossi et al 2017). We investigated the effect of treatment subsequent to CBT in a large international multicenter retrospective analysis.
• Persky, D. O. (2018, November/Winter). Economic Evaluation for the US of Ibrutinib Versus Acalabrutinib for Patients with Relapsed or Refractory Mantle Cell Lymphoma. Blood.
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  Introduction. Mantle cell lymphoma (MCL) is a rare subtype of Non-Hodgkin lymphoma (NHL) with a poor prognosis. Ibrutinib is an oral Bruton9s tyrosine kinase inhibitor (BTKi) approved in the US in 2013 for, among other indications, MCL patients with at least one prior therapy (i.e., relapsed/refractory [R/R] MCL). The BTKi acalabrutinib was approved in late 2017 specifically for this same indication. No studies have assessed the comparative efficacy and cost-effectiveness and cost-utility of both agents in the management of R/R MCL. We performed an indirect comparison of both agents in terms of progression-free survival (PFS) and overall survival (OS) to subsequently evaluate the relative cost-effectiveness and cost-utility of both treatment options of R/R MCL from a USA payer perspective.
• Persky, D. O. (2018, November/Winter). Impact of Individual Comorbidities on Treatment Outcomes in Chronic Lymphocytic Leukemia. Blood.
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  Introduction: Chronic lymphocytic leukemia (CLL) is a common leukemia which tends to occur late in life. Comorbidities are common, and the iwCLL guidelines recommend their assessment in patients (pts) enrolled on clinical trials. The Cumulative Illness Rating Scale (CIRS) is a rigorous tool designed to evaluate the burden of comorbidities, which has been employed in therapeutic studies. Our group and others demonstrated that CIRS score predicts survival in pts with CLL treated with either chemo-immunotherapy (CIT) or novel kinase inhibitors (KI; ibrutinib) (Manda et al, 2016 & Gordon et al, 2018). However, CIRS has not become part of common clinical practice, in part due to complexities in scoring. It is also unknown whether all of the 14 organ systems included in the score carry equal weight to determine prognosis. Here we report the impact of specific comorbidities from a multicenter retrospective cohort
• Persky, D. O. (2018, November/Winter). Oncolytic Reovirus Is an Effective Treatment for Histone Deacetylase Inhibitor Resistant T-Cell Lymphoma. Blood.
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  Aberrant gene expression plays a pivotal role during tumorigenesis and cancer progression. The acetylation status of histones is an important determinant of gene expression and is controlled by two opposing classes of enzymes: histones acetyl transferases (HATs) and histone deacetylases (HDACs). The deacetylation of histones is associated with repression of key tumor suppressor genes and has been linked to HDAC overexpression in multiple forms of cancer including lymphomas. Several HDAC inhibitors have been FDA approved for T‑cell lymphoma (TCL) therapy including belinostat, vorinostat, and romidepsin. Despite the promising anti‑lymphoma activity of HDAC inhibitors as a drug class, resistance is a significant clinical issue. Identification of new strategies that are more effective in the drug resistant patient population is a high priority, but the mechanisms underlying HDAC inhibitor‑induced cell death and the development of drug resistance are not completely understood. Elucidating the molecular mechanisms driving HDAC inhibitor resistance and/or the specific targets that are altered in drug‑resistant cells may facilitate the development of strategies that overcome drug resistance and are effective for refractory patients. To pursue this goal, we generated novel TCL cell line models of acquired HDAC inhibitor resistance through repeated exposure to belinostat. The sensitivity of parental and resistant TCL cells to belinostat and other clinically relevant HDAC inhibitors was initially characterized using cell viability and flow cytometric assays. Notably, belinostat‑resistant cells displayed significant
• Abraham, I. L., Kumar, A., Persky, D. O., & Anwar, F. (2017, December/Winter). 4678 Economic Evaluation for the US of Venetoclax Versus Allogeneic Hematopoietic Stem-Cell Transplantation for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia with 17p Deletion. ASH Annual Meeting. Atllanta, GA: ASH.
• Abraham, I. L., Kumar, A., Persky, D. O., & Anwar, F. (2017, December/Winter). 4679 Economic Evaluation for the US of Ibrutinib Versus Allogeneic Hematopoietic Stem-Cell Transplantation for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia with 17p Deletion. ASH Annual Conference. Atlanta GA: ASH.
• Persky, D. O. (2017, December/Winter). A Phase II Intergroup Trial of PET-Directed Therapy for Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL) (ASH Annual Meeting Poster Presentation) 2017, Abstract 1553. ASH Annual Meeting Poster Presentation. Atlanta, GA: ASH.

Reviews

• Diefenbach, C. S., Connors, J. M., Friedberg, J. W., Leonard, J. P., Kahl, B. S., Little, R. F., Baizer, L., Evens, A. M., Hoppe, R. T., Kelly, K. M., Persky, D. O., Younes, A., Kostakaglu, L., & Bartlett, N. L. (2017. Hodgkin Lymphoma: Current Status and Clinical Trial Recommendations.
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  The National Clinical Trials Network lymphoid malignancies Clinical Trials Planning Meeting (CTPM) occurred in November of 2014. The scope of the CTPM was to prioritize across the lymphoid tumors clinically significant questions and to foster strategies leading to biologically informed and potentially practice changing clinical trials. This review from the Hodgkin lymphoma (HL) subcommittee of the CTPM discusses the ongoing clinical challenges in HL, outlines the current standard of care for HL patients from early to advanced stage, and surveys the current science with respect to biomarkers and the landscape of ongoing clinical trials. Finally, we suggest areas of unmet need in HL and elucidate promising therapeutic strategies to guide future HL clinical trials planning across the NCTN.

Others

• Persky, D. O. (2017, December/Winter). Characteristics and Outcomes of Patients with Double-Protein Expression in Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of SWOG Study S1001 (NCT01359592) (ASH Annual Meeting Abstract), December 2017, abstract 4122. ASH Annual Meeting Abstract.
• Persky, D. O. (2017, December/Winter). Medical Comorbidities Assessed By CIRS Negatively Impact Survival in the Era of Targeted Therapies in CLL: A Multicenter Retrospective Analysis (ASH Annual Meeting Abstract), December 2017, abstract 918. ASH Annual Meeting.
• Persky, D. O. (2017, December/Winter). Results from a Phase 1/2 Study of INCB050465, a Highly Selective and Highly Potent PI3Kδ Inhibitor, in Patients with Relapsed or Refractory B-Cell Malignancies (CITADEL-101) (ASH Annual Meeting Abstracts), December 2017, abstract 410. ASH.
• Persky, D. O. (2016, December/Winter). Benefit of Consolidative Autologous Stem Cell Transplantation in First Complete Remission for Patients with Double Hit Lymphoma Appears Dependent on Induction Regimen Intensity. Blood (ASH Annual Meeting Abstracts), December 2016, abstract 3455. ASH Annual Meeting.
• Rivera, X., Ayala, A., Inclan, L., Schatz, J., Guillen-Rodriguez, J., Anwer, F., Kumar, A., Puvvada, S. D., Persky, D. O., Mahadevan, D., & Sundararajan, S. (2016, December). A phase II, open-label study of bortezomib (Velcade®), cladribine, and rituximab (VCR) in advanced, newly diagnosed and relapsed /refractory mantle Cell and indolent Lymphomas.