Publications by authors named "Leslie Andritsos"

93 Publications

Phase 2 Study of Ibrutinib in Classic and Variant Hairy Cell Leukemia.

Blood 2021 Mar 22. Epub 2021 Mar 22.

Ohio State University, Colmubus, Ohio, United States.

Hairy cell leukemia is a rare B-cell malignancy where there is a need for novel treatments for patients who do not benefit from purine analogues. Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signaling pathway, is highly effective in several malignancies. Its activity in HCL was unknown. Therefore, we conducted a multisite phase 2 study (NCT01841723) of oral ibrutinib in patients with either relapsed classic or variant hairy cell leukemia. The primary outcome measure was the overall response rate at 32 weeks with response at 48 weeks and best response during treatment also assessed. Key secondary objectives were characterization of toxicity and determination of progression-free and overall survival. Thirty-seven patients were enrolled (24 at 420mg, 13 at 840mg). The median duration of follow-up was 3.5 years (range 0-5.9). The overall response rate at 32 weeks was 24% which increased to 36% at 48 weeks. The best overall response rate was 54%. The estimated 36-month progression-free and overall survivals were 73% and 85%, respectively. The most frequent adverse events were diarrhea (59%), fatigue (54%), myalgia (54%), and nausea (51%). Hematologic adverse events were common with anemia (43%), thrombocytopenia (41%), and neutropenia (35%). Ibrutinib can be safely administered to hairy cell leukemia patients with objective responses and results in prolonged disease control. While the initial primary outcome objective of the study was not met, the observation of objective responses in heavily pretreated patients coupled with a favorable progression-free survival suggest that ibrutinib may be beneficial in these patients.
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http://dx.doi.org/10.1182/blood.2020009688DOI Listing
March 2021

Current and Emerging Therapeutic Options for Hairy Cell Leukemia Variant.

Onco Targets Ther 2021 9;14:1797-1805. Epub 2021 Mar 9.

Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.

Hairy cell leukemia variant (HCL-v) is a rare B-cell lymphoproliferative disorder with distinct immunophenotypic and molecular characteristics when compared to classical hairy cell leukemia (HCL-c). In contrast to the enormous progress in therapeutic options for HCL-c, HCL-v remains a therapeutic challenge due to inferior outcomes with standard chemoimmunotherapy and BCR signaling pathway inhibitors, and due to the fact that HCL-v has limited molecular therapeutic targets. In addition, because of the rarity of the disease, there is a paucity of later phase studies or multicenter trials to guide treatment decisions. In this article, we briefly review the diagnostic criteria and clinical characteristics of HCL-v and present a comprehensive overview of current therapeutic options in HCL-v.
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http://dx.doi.org/10.2147/OTT.S242247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955867PMC
March 2021

A Phase 1b Study to Evaluate the Safety and Efficacy of Durvalumab in Combination With Tremelimumab or Danvatirsen in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

Clin Lymphoma Myeloma Leuk 2020 Dec 17. Epub 2020 Dec 17.

Division of Hematology & Oncology, MUSC Health Hollings Cancer Center, Charleston, SC.

Background: Despite recent advances, outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) remain poor. Immune checkpoint inhibitors have shown limited efficacy in this setting, but combinations with novel agents may enhance benefit. Combination therapy with durvalumab, an anti-programmed death ligand 1 (PD-L1) antibody, and danvatirsen (AZD9150; an antisense oligonucleotide inhibiting signal transducer and activator of transcription 3 [STAT3]) or tremelimumab (an anti-cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] antibody) may augment endogenous antitumor activity.

Patients And Methods: In this phase 1b dose escalation and dose expansion study, we evaluated durvalumab 20 mg/kg every 4 weeks plus either tremelimumab 1 mg/kg every 4 weeks or danvatirsen 2 or 3 mg/kg (administered on days 1, 3, 5, 8, 15, and 22, then every week). Treatment continued until disease progression. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics, and immunogenicity.

Results: As of April 4, 2019, 32 patients were enrolled and treated, receiving a median of 2 prior lines of systemic therapy. Treatment-related adverse events occurred in 21 patients (65.6%), most commonly alanine aminotransferase/aspartate aminotransferase increased (grade 1-3), anemia (grade 1-3), and fatigue (grade 1). The overall objective response rate was 6.3%, with 2 partial responses. Median time to response was 11.0 weeks (range, 7.7-14.3 weeks). Median progression-free survival was 7.4 weeks (range, 0.1-31.4 weeks), and median overall survival was 28.0 weeks (range, 1.9-115.4 weeks).

Conclusion: The primary endpoint was met, with durvalumab plus tremelimumab/danvatirsen generally well tolerated in patients with relapsed/refractory DLBCL; however, antitumor activity was limited.
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http://dx.doi.org/10.1016/j.clml.2020.12.012DOI Listing
December 2020

Early Intervention with Lenalidomide in Patients with High-risk Chronic Lymphocytic Leukemia.

Clin Cancer Res 2020 Dec 21;26(23):6187-6195. Epub 2020 Sep 21.

Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.

Purpose: Infectious complications constitute a leading cause of morbidity and mortality in chronic lymphocytic leukemia (CLL). Patients respond poorly to vaccines, particularly pneumococcal polysaccharide and influenza vaccines. In addition, patients with genetically high-risk disease are at increased risk for early disease progression and death. Lenalidomide, an oral immunomodulatory agent with demonstrated clinical activity in CLL, can potentially restore immune system dysfunction associated with CLL while improving disease outcomes.

Patients And Methods: Phase II study randomized 49 patients with genetically high-risk CLL or small lymphocytic lymphoma [SLL; defined as unmutated Ig heavy chain variable region, deletion(17p) or (11q), and/or complex abnormal karyotype], to receive lenalidomide either concurrent (arm A) or sequential to (arm B) two doses of 13-valent protein-conjugated pneumococcal vaccine (PCV13) administered 2 months apart, in patients not meeting International Workshop on Chronic Lymphocytic Leukemia treatment criteria.

Results: Four serotypes (3, 4, 5, 6B) achieved the additional seroprotection definition of a fourfold increase in arm A, and six serotypes (3, 4, 5, 6B, 19A, 19F) in arm B. All patients achieved the defined concentration of 0.35 μg/mL for at least one serotype tested. No significant difference was observed with the addition of lenalidomide. At median time on treatment of 3.6 years, median progression-free survival (PFS) was 5.8 years [95% confidence interval (CI), 3.1-not reached]. PFS at 1, 2, and 3 years was 85% (95% CI, 72-93), 79% (95% CI, 64-88), and 72% (95% CI, 57-83), respectively.

Conclusions: Lenalidomide is efficacious with manageable toxicities as an early intervention strategy in patients with high-risk CLL, but did not enhance humoral response to PCV13 vaccine.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1280DOI Listing
December 2020

Prognostic significance of translocations in the presence of mutated IGHV and of cytogenetic complexity at diagnosis of chronic lymphocytic leukemia.

Haematologica 2020 05 15. Epub 2020 May 15.

Department of Hematology, The Ohio State University Wexner Medical Center, Columbus, USA.

Mutations of the IGH variable region in patients with chronic lymphocytic leukemia (CLL) are associated with a favorable prognosis. Cytogenetic complexity (>3 unrelated aberrations) and translocations have been associated with an unfavorable prognosis. While mutational status of IGHV is stable, cytogenetic aberrations frequently evolve. However, the relationships of these features as prognosticators at diagnosis are unknown. We examined the CpG-stimulated metaphase cytogenetic features detected within one year of diagnosis of CLL and correlated these features with outcome and other clinical features including IGHV. Of 329 untreated patients, 53 (16.1%) had a complex karyotype (16.1%), and 85 (25.8%) had a translocation. Median time to first treatment (TFT) was 47 months. In univariable analyses, significant risk factors for shorter TFT (p<0.05) were Rai stage 3-4, beta2-microglobulin >3.5, log-transformed WBC, unmutated IGHV, complex karyotype, translocation, and FISH for trisomy 8, del(11q) and del(17p). In multivariable analysis, there was significant effect modification of IGHV status on the relationship between translocation and TFT (p=0.002). In IGHV mutated patients, those with a translocation had over 3.5 times higher risk of starting treatment than those without a translocation (p<0.001); however, in IGHV unmutated patients, a translocation did not significantly increase the risk of starting treatment (HR 1.00, p=0.99). Rai Stage 3-4, log-transformed WBC and complex karyotype remained statistically significant; however, del(17p) did not (p=0.51). In summary, the presence of a translocation in IGHV mutated patients appeared to negate the improved prognosis of mutated IGHV, but the presence of a translocation did not have an effect on TFT in high-risk IGHV unmutated patients.
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http://dx.doi.org/10.3324/haematol.2018.212571DOI Listing
May 2020

Adverse event rates and economic burden associated with purine nucleoside analogs in patients with hairy cell leukemia: a US population-retrospective claims analysis.

Orphanet J Rare Dis 2020 02 13;15(1):47. Epub 2020 Feb 13.

Division of Hematology and Oncology, The University of New Mexico, Albuquerque, NM, USA.

Background: Purine nucleoside analogs (PNAs) are the recommended first-line treatment for patients with hairy cell leukemia (HCL), but they are associated with adverse events (AEs). Due to a lack of real-world evidence regarding AEs that are associated with PNAs, we used commercial data to assess AE rates, AE-related health care resource utilization (HCRU), and costs among PNA-treated patients with HCL. Adults aged ≥18 years with ≥2 claims for HCL ≥30 days apart from 1 January 2006 through 31 December 2015 were included. Included patients had ≥1 claim for HCL therapy (cladribine ± rituximab or pentostatin ± rituximab [index date: first claim date]) and continuous enrollment for a ≥ 6-month baseline and ≥ 12-month follow-up period. Patient sub-cohorts were based on the occurrence of myelosuppression and opportunistic infections (OIs). Generalized linear models were used to compare HCRU and costs.

Results: In total, 647 PNA-treated patients were identified (mean age: 57.1 years). Myelosuppression and OI incidence were 461 and 42 per 1000 patient-years, respectively. Adjusted results indicated that those with myelosuppression had higher rates of hospitalization (47.4% vs 12.4%; P < .0001) and incurred higher mean inpatient costs ($23,517 vs $12,729; P = .011) and total costs ($57,325 vs $34,733; P = .001) as compared with those without myelosuppression. Similarly, patients with OIs had higher rates of hospitalization (53.8% vs 30.8%; P = .025) and incurred higher mean inpatient costs ($21,494 vs $11,229; P < .0001) as compared with those without OIs.

Conclusions: PNA therapy is highly effective but associated with significant toxicities that increase costs; these findings indicate a need for therapies with improved toxicity profiles and better risk stratification of patients at risk of developing myelosuppression and OIs.
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http://dx.doi.org/10.1186/s13023-020-1325-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020358PMC
February 2020

Ruxolitinib In The Treatment Of Polycythemia Vera: An Update On Health-Related Quality Of Life And Patient-Reported Outcomes.

J Blood Med 2019 14;10:381-390. Epub 2019 Nov 14.

University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA.

Polycythemia vera (PV) is a rare myeloproliferative neoplasm (MPN) associated with significant impairment in quality of life (QoL) due to disease-related symptoms and complications. Assessment of disease burden constitutes standard monitoring of symptoms and response. Conventional treatments for MPN, such as hydroxyurea, phlebotomy, or interferon, have not shown a significant impact in QoL or patient-reported outcomes (PRO). Ruxolitinib (RUX) is a JAK2 inhibitor approved for patients intolerant or resistant to hydroxyurea (HA). We conducted a systematic review of clinical trials of RUX in patients with PV that incorporated PRO measures to evaluate the effects on PRO and QoL. Three randomized Phase 3 studies reported in four publications were relevant for analysis. Although the small number of trials and potential for treatment bias in the review, treatment with RUX was associated with improved QoL and PRO in PV patients intolerant or resistant to hydroxyurea.
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http://dx.doi.org/10.2147/JBM.S177692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861552PMC
November 2019

Spontaneous resolution of untreated diffuse large B-cell lymphoma of maxillary bone after incisional biopsy.

Clin Case Rep 2019 Nov 27;7(11):2082-2086. Epub 2019 Sep 27.

University of New Mexico Comprehensive Cancer Center Albuquerque New Mexico.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of lymphomas which require multiagent therapy for remission induction and are associated with relapse in more than 40% of patients. Spontaneous remission of diffuse large B-cell lymphoma (DLBCL) is a rare occurrence.
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http://dx.doi.org/10.1002/ccr3.2408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878081PMC
November 2019

Clinical and cost outcomes of pre-emptive plerixafor administration in patients with multiple myeloma undergoing stem cell mobilization.

Leuk Res 2019 10 9;85:106215. Epub 2019 Aug 9.

University of Arizona Cancer Center, Tucson, AZ, USA; Department of Pharmacy Practice and Science, University of Arizona, Tucson, AZ, USA; Banner University Medical Center, Tucson, AZ, USA. Electronic address:

Purpose: The stem cell mobilization agent plerixafor significantly improves CD34 stem cell procurement in patients with multiple myeloma undergoing autologous stem cell transplant. We compared mobilization success rates and costs of two regimens of plerixafor administration: pre-emptive (P-PL, initiated the evening prior to the first day of stem cell collection) and standard (S-PL, initiated the evening prior to the second day of stem cell collection in the event of inadequate collection on the first day).

Methods: Patients with multiple myeloma undergoing mobilization were categorized as either P-PL or S-PL. Stem cell collection success was evaluated using logistic regression models. Associated costs were aggregated in terms of average collections per patient in each mobilization option (patient level), and escalated to a panel of 5000 patients (population level).

Results: 299 patients were evaluable; 241 received P-PL and 58 received S-PL. Patients receiving P-PL had higher median CD34 count pre-collection and higher median total CD34 cell harvest on the first collection (6.75 × 10/kg for P-PL, 1.96 × 10/kg for S-PL; P<0.01). In multivariable analyses, P-PL remained significantly associated with the ability to collect ≥2 × 10/kg CD34 on the first day (OR = 4.05, 95% CI, 1.19-13.83, P = 0.03) and ≥5 × 10/kg CD34 in total (OR = 3.09, 95% CI, 1.04-9.23, P = 0.04). P-PL saved $11,248 (46%) per patient compared with S-PL.

Conclusion: P-PL significantly enhanced collection efficiency, with most patients completing collection in 1 day, resulting in substantial cost savings.
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http://dx.doi.org/10.1016/j.leukres.2019.106215DOI Listing
October 2019

A multicenter phase 1 study of plerixafor and rituximab in patients with chronic lymphocytic leukemia.

Leuk Lymphoma 2019 12 27;60(14):3461-3469. Epub 2019 Jul 27.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

CXCR4 directs chronic lymphocytic leukemia (CLL) trafficking within protective tissue niches, and targeting CXCR4 with plerixafor may enhance drug sensitivity. We performed a phase 1 dose escalation study of plerixafor (NCT00694590) with rituximab in 24 patients with relapsed/refractory CLL. Patients received rituximab 375 mg/m on days 1, 3, and 5, followed by bi-weekly rituximab plus dose-escalated plerixafor for 4 weeks. The maximum tolerated dose of plerixafor was 320 µg/kg. The most common toxicities were fatigue (13 patients, 57%), nausea (11, 48%), chills (10, 43%), and diarrhea and dyspnea (seven, 30% each). No patients developed symptomatic hyperleukocytosis or tumor lysis syndrome. A median 3.3-fold increase (range 1.2-12.4) in peripheral blood CLL was seen following the first dose of plerixafor, confirming CLL cell mobilization. The overall response rate was 38% and correlated with higher doses of plerixafor. Plerixafor is well-tolerated in patients with CLL; further tumor sensitization studies with CXCR4 antagonists are warranted.
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http://dx.doi.org/10.1080/10428194.2019.1643463DOI Listing
December 2019

Clinical utilization of Chimeric Antigen Receptor T-cells (CAR-T) in B-cell acute lymphoblastic leukemia (ALL)-an expert opinion from the European Society for Blood and Marrow Transplantation (EBMT) and the American Society for Blood and Marrow Transplantation (ASBMT).

Bone Marrow Transplant 2019 11 15;54(11):1868-1880. Epub 2019 May 15.

Division of Hematology, Ohio State University Wexner Medical Center, Columbus, OH, USA.

On August 30, 2017, the U.S. Food and Drug Administration (US-FDA) approved tisagenlecleucel (KYMRIAH, Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor-T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring and disease assessments. To address these issues, experts representing the American Society for Blood and Marrow Transplant (ASBMT), the European Group for Blood and Marrow Transplantation (EBMT), the International Society of Cell and Gene Therapy (ISCT), and the Foundation for the Accreditation of Cellular Therapy (FACT), formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.
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http://dx.doi.org/10.1038/s41409-019-0451-2DOI Listing
November 2019

Tocilizumab as first-line therapy for steroid-refractory acute graft-versus-host-disease: analysis of a single-center experience.

Leuk Lymphoma 2019 09 15;60(9):2223-2229. Epub 2019 Feb 15.

Department of Pharmacy, The James Cancer Hospital, The Ohio State University Comprehensive Cancer Center , Columbus , Ohio , 43210 , USA.

Acute graft-versus-host-disease (aGVHD) is a complication after allogeneic stem cell transplant. After the failure of treatment with high dose corticosteroids, steroid-refractory aGVHD (SR aGVHD) is associated with high rates of mortality. Tocilizumab has evidence of activity in SR aGVHD. For patients ineligible for trials, the OSU James Comprehensive Cancer Center has been utilizing tocilizumab as first-line therapy for SR aGVHD. We retrospectively report on 15 patients who received tocilizumab. aGVHD grading and responses were based on consensus criteria. Median age at transplant was 49 years. Median time to tocilizumab administration was 9 days (range, 3-16). Six patients had complete responses (40%) with a resolution of aGVHD. From the last contact, median overall survival for responders was not yet reached vs. 31 days for non-responders ( = .0002). Patients with skin and/or GI aGVHD demonstrated the greatest benefit. Patients with liver aGVHD did not respond. Future studies are needed to evaluate tocilizumab prior to steroid failure.
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http://dx.doi.org/10.1080/10428194.2019.1573996DOI Listing
September 2019

Anti-BAFF-R antibody VAY-736 demonstrates promising preclinical activity in CLL and enhances effectiveness of ibrutinib.

Blood Adv 2019 02;3(3):447-460

Division of Hematology, Department of Internal Medicine, College of Medicine and OSU Comprehensive Cancer Center.

The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib has transformed chronic lymphocytic leukemia (CLL) therapy but requires continuous administration. These factors have spurred interest in combination treatments. Unlike with chemotherapy, CD20-directed antibody therapy has not improved the outcome of BTKi treatment. Whereas CD20 antigen density on CLL cells decreases during ibrutinib treatment, the B-cell activating factor (BAFF) and its receptor (BAFF-R) remain elevated. Furthermore, BAFF signaling via noncanonical NF-κB remains elevated with BTKi treatment. Blocking BAFF interaction with BAFF-R by using VAY-736, a humanized defucosylated engineered antibody directed against BAFF-R, antagonized BAFF-mediated apoptosis protection and signaling at the population and single-cell levels in CLL cells. Furthermore, VAY-736 showed superior antibody-dependent cellular cytotoxicity compared with CD20- and CD52-directed antibodies used in CLL. VAY-736 exhibited in vivo activity as a monotherapy and, when combined with ibrutinib, produced prolonged survival compared with either therapy alone. The in vivo activity of VAY-736 is dependent upon immunoreceptor tyrosine-based activation motif (ITAM)-mediated activation of effector cells as shown by using an ITAM-deficient mouse model. Collectively, our findings support targeting the BAFF signaling pathway with VAY-736 to more effectively treat CLL as a single agent and in combination with ibrutinib.
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http://dx.doi.org/10.1182/bloodadvances.2018025684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373734PMC
February 2019

BEAM or BUCYVP16-conditioning regimen for autologous stem-cell transplantation in non-Hodgkin's lymphomas.

Bone Marrow Transplant 2019 10 4;54(10):1553-1561. Epub 2019 Feb 4.

Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.

High-dose chemotherapy followed by autologous hematopoietic cell transplantation (AHCT) is an effective salvage therapy for patients with relapsed chemosensitive non-Hodgkin's lymphoma (NHL). However, the optimal conditioning regimen is unclear. Different conditioning regimens prior to AHCT have been used with the two most common being BEAM (carmustine, etoposide, cytarabine, and melphalan) and BUCYVP16 (busulfan, cyclophosphamide, and etoposide). We sought to compare the two regimens for patients with relapsed NHL undergoing AHCT. We retrospectively compared the outcomes of patients treated with BEAM (N = 269) at The Ohio State University and BUCYVP16 (N = 409) at the Cleveland Clinic followed by AHCT between 2006 and 2014. The primary endpoints were progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR). Patient characteristics between the two groups were similar. After a median follow-up of 3.9 years for BEAM and 4.3 years for BUCYVP16 from AHCT, the rate of relapse (p = 0.69), PFS (p = 0.52), and OS (p = 0.11) were similar between the two conditioning regimens. No differences in survival outcomes were seen in disease subtypes. Multivariable analysis showed significant association toward improved OS with BEAM (HR: 1.56, 95% CI 1.16-2.10) (p < 0.01). Even though the study is limited by its retrospective nature and some differences in cohort, the findings indicate that BEAM could serve as an alternative conditioning regimen prior to AHCT for NHL.
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http://dx.doi.org/10.1038/s41409-019-0463-yDOI Listing
October 2019

BEAM versus BUCYVP16 Conditioning before Autologous Hematopoietic Stem Cell Transplant in Patients with Hodgkin Lymphoma.

Biol Blood Marrow Transplant 2019 06 1;25(6):1107-1115. Epub 2019 Feb 1.

Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio. Electronic address:

High-dose chemotherapy followed by autologous hematopoietic stem cell transplant (AHSCT) is a standard of care for patients with relapsed Hodgkin lymphoma. Different conditioning regimens before AHSCT have been used, with the 2 most common being BEAM (carmustine, etoposide, cytarabine, and melphalan) and BUCYVP16 (busulfan, cyclophosphamide, and etoposide). We retrospectively compared the outcomes of patients treated with BEAM (n = 128) or BUCYVP16 (n = 105) followed by AHSCT. After a median follow-up of 4.2 years for BEAM and 3.8 for BUCYVP16 from AHSCT, the 5-year cumulative incidence of relapse was 29% with BEAM compared with 56% with BUCYVP16 (P < .001). Median progression free survival (PFS) and overall survival (OS) were not reached with BEAM and were 2.0 and 7.8 years with BUCYVP16, respectively. Improved PFS (P < .001) and OS (P = .001) were observed with BEAM for patients who needed transplant within 24 months from diagnosis and for patients not in complete remission (non-CR; P = .001 and P < .001, respectively) at AHSCT. In this large retrospective comparison the use of BEAM conditioning before AHSCT resulted in a statistically significant improved PFS and OS and lower relapse compared with BUCYVP16. This supports the use of BEAM as a frontline conditioning regimen before AHSCT for early relapsed and non-CR Hodgkin lymphoma.
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http://dx.doi.org/10.1016/j.bbmt.2019.01.032DOI Listing
June 2019

Clinical Utilization of Chimeric Antigen Receptor T Cells in B Cell Acute Lymphoblastic Leukemia: An Expert Opinion from the European Society for Blood and Marrow Transplantation and the American Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2019 03 18;25(3):e76-e85. Epub 2018 Dec 18.

Oncology Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia; Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address:

On August 30, 2017 the US Food and Drug Administration approved tisagenlecleucel (Kymriah; Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present, ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring, and disease assessments. To address these issues experts representing the American Society for Blood and Marrow Transplant, the European Society for Blood and Marrow Transplantation, the International Society of Cell and Gene Therapy, and the Foundation for the Accreditation of Cellular Therapy formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.
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http://dx.doi.org/10.1016/j.bbmt.2018.12.068DOI Listing
March 2019

Cutaneous adverse events associated with purine analogs in the treatment of hairy cell leukemia.

Int J Dermatol 2019 May 27;58(5):e109-e110. Epub 2018 Nov 27.

Division of Dermatology, Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, OH, USA.

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http://dx.doi.org/10.1111/ijd.14320DOI Listing
May 2019

Antibiotic exposure is associated with cutaneous adverse events in hairy cell leukemia patients treated with purine analogues.

J Am Acad Dermatol 2019 06 8;80(6):1762-1764. Epub 2018 Sep 8.

Division of Dermatology, Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio.

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http://dx.doi.org/10.1016/j.jaad.2018.07.066DOI Listing
June 2019

The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation.

Cancer Discov 2018 10 9;8(10):1300-1315. Epub 2018 Aug 9.

Department of Internal Medicine, Division of Hematology, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Targeted inhibition of Bruton tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has improved outcomes for patients with hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here, we describe preclinical investigations of ARQ 531, a potent, reversible inhibitor of BTK with additional activity against Src family kinases and kinases related to ERK signaling. We hypothesized that targeting additional kinases would improve global inhibition of signaling pathways, producing more robust responses. treatment of patient CLL cells with ARQ 531 decreases BTK-mediated functions including B-cell receptor (BCR) signaling, viability, migration, CD40 and CD86 expression, and NF-κB gene transcription. , ARQ 531 was found to increase survival over ibrutinib in a murine Eμ-TCL1 engraftment model of CLL and a murine Eμ-MYC/TCL1 engraftment model resembling Richter transformation. Additionally, ARQ 531 inhibits CLL cell survival and suppresses BCR-mediated activation of C481S BTK and PLCγ2 mutants, which facilitate clinical resistance to ibrutinib. This study characterizes a rationally designed kinase inhibitor with efficacy in models recapitulating the most common mechanisms of acquired resistance to ibrutinib. Reversible BTK inhibition is a promising strategy to combat progressive CLL, and multikinase inhibition demonstrates superior efficacy to targeted ibrutinib therapy in the setting of Richter transformation. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-1409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261467PMC
October 2018

Use of PD-1 (PDCD1) inhibitors for the treatment of Richter syndrome: experience at a single academic centre.

Br J Haematol 2019 04 20;185(2):363-366. Epub 2018 Jul 20.

Division of Hematology, The Ohio State University, Columbus, OH, USA.

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http://dx.doi.org/10.1111/bjh.15508DOI Listing
April 2019

Detection of toxigenic colonization in patients admitted to the hospital for chemotherapy or haematopoietic cell transplantation.

J Med Microbiol 2018 Jul;67(7):976-981

Division of Hematology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Increasing evidence suggests that asymptomatic carriers are an important source of healthcare-associated infection. However, it is not known which test for the detection of colonization is most sensitive in patients with haematological malignancies. We performed a prospective cohort study of 101 patients with haematological malignancies who had been admitted to the hospital for scheduled chemotherapy or haematopoietic cell transplantation. Each patient provided a formed stool sample. We compared the performance of five different commercially available assays, using toxigenic culture as the reference method. The prevalence of toxigenic colonization as determined by toxigenic culture was 14/101 (14 %). The Cepheid Xpert PCR /Epi was the most sensitive test for the detection of toxigenic colonization, with 93 % sensitivity and 99 % negative predictive value. Our findings suggest that the Xpert PCR /Epi could be used to rule out toxigenic colonization in this population.
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http://dx.doi.org/10.1099/jmm.0.000774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152365PMC
July 2018

Psychosocial risk predicts high readmission rates for hematopoietic cell transplant recipients.

Bone Marrow Transplant 2018 11 14;53(11):1418-1427. Epub 2018 Feb 14.

Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH, USA.

Hematopoietic cell transplantation (HCT) is an intensive treatment resulting in disease control however subsequent psychosocial distress is common. Screening for psychosocial risk factors that contribute to morbidity is underutilized; moreover, the value in screening is uncertain. We performed a retrospective study of 395 HCT patients who were screened for psychosocial risk using the Transplant Evaluation Rating Scale (TERS). Patients were classified by psychosocial risk as no-risk (TERS = 26.5, 52%) vs. at-risk (TERS > 26.5, 48%), with at-risk patients stratified by cumulative deficits into mild risk (TERS = 27-35.5, 39%) and moderate risk (TERS > 35.5, 9%). At-risk patients were more likely to be readmitted within 90 days (mild risk HR = 1.62, p = 0.02; moderate risk HR = 2.50, p = 0.002). Prior psychiatric history (HR = 1.81, p = 0.002) and poor coping skills (HR = 1.64, p = 0.04) also influenced readmission. At-risk patients were more likely to be readmitted for infection (no-risk = 12% vs. at-risk = 25%, p = 0.002). Pre-HCT screening with the TERS did not predict survival or length of stay although at-risk patients are at a heighted risk of readmission. Implementing strategies to reduce readmission in higher risk patients is warranted.
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http://dx.doi.org/10.1038/s41409-018-0118-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092254PMC
November 2018

Cumulative incidence, risk factors, and management of atrial fibrillation in patients receiving ibrutinib.

Blood Adv 2017 Sep 8;1(20):1739-1748. Epub 2017 Sep 8.

Division of Hematology, The James Cancer Hospital and Solove Research Institute at The Ohio State University, Columbus, OH.

Atrial fibrillation (AF) has been reported in up to 16% of patients taking ibrutinib. Data regarding the management of AF in this patient population are limited, and stroke prevention poses a challenge because of increased risk of bleeding with ibrutinib treatment. Our study sought to describe the incidence of AF in adult patients treated with ibrutinib for a hematologic malignancy, assess management strategies, evaluate stroke and bleeding outcomes, and identify risk factors for occurrence. Of 582 patients treated with ibrutinib, 76 developed AF. With a median follow-up of 32 months, the estimated cumulative incidence at 6 months, 1 year, and 2 years was 5.9% (95% confidence interval [CI]: 4.2-8.0), 7.5% (95% CI: 5.5-9.9), and 10.3% (95% CI: 8.0-13.0), respectively. Median time to onset of AF was 7.6 months. History of AF and Framingham Heart Study (FHS) AF risk score were found to be significant risk factors for development of AF. Most patients were treated with rate control-only strategies (61.8%), and concomitant aspirin or anticoagulant therapy with ibrutinib was used in 52.6% and 28.9% of patients, respectively. One patient on aspirin developed symptoms consistent with stroke. Nine major bleeds were noted in 7 patients, and 34 clinically relevant nonmajor bleeds were noted in 24 patients. Twenty-one bleeds (4 major bleeds) occurred in 18 patients on aspirin, and 10 bleeds (all clinically relevant nonmajor bleeds) occurred in 6 patients with anticoagulant therapy. These results provide risk factor assessment, impact of management strategies, and outcomes of patients with AF on ibrutinib and serve as basis for formal guidelines.
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http://dx.doi.org/10.1182/bloodadvances.2017009720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728342PMC
September 2017

Near-tetraploidy is associated with Richter transformation in chronic lymphocytic leukemia patients receiving ibrutinib.

Blood Adv 2017 Aug 21;1(19):1584-1588. Epub 2017 Aug 21.

Division of Hematology, Department of Internal Medicine.

Ibrutinib is a highly effective targeted therapy for chronic lymphocytic leukemia (CLL). However, ibrutinib must be discontinued in a subset of patients due to progressive CLL or transformation to aggressive lymphoma (Richter transformation). Transformation occurs early in the course of therapy and has an extremely poor prognosis. Thus, identification of prognostic markers associated with transformation is of utmost importance. Near-tetraploidy (4 copies of most chromosomes within a cell) has been reported in various lymphomas, but its incidence and significance in CLL has not been described. Using fluorescence in situ hybridization, we detected near-tetraploidy in 9 of 297 patients with CLL prior to beginning ibrutinib treatment on 1 of 4 clinical trials (3.0%; 95% confidence interval [CI], 1.4%-5.7%). Near-tetraploidy was associated with aggressive disease characteristics: Rai stage 3/4 ( = .03), deletion 17p ( = .03), and complex karyotype ( = .01). Near-tetraploidy was also associated with ibrutinib discontinuation due to Richter transformation ( < .0001), but not due to progressive CLL ( = .41). Of the 9 patients with near-tetraploidy, 6 had Richter transformation with diffuse large B-cell lymphoma. In a multivariable model, near-tetraploidy (hazard ratio [HR], 8.66; 95% CI, 3.83-19.59; < .0001) and complex karyotype (HR, 4.77; 95% CI, 1.42-15.94; = .01) were independent risk factors for discontinuing ibrutinib due to transformation. Our results suggest that near-tetraploidy is a potential prognostic marker for Richter transformation to assess in patients going on ibrutinib.
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http://dx.doi.org/10.1182/bloodadvances.2017007302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728464PMC
August 2017

A retrospective review of fall risk factors in the bone marrow transplant inpatient service.

J Oncol Pharm Pract 2018 Jun 16;24(4):272-280. Epub 2017 Mar 16.

4 The James Cancer Hospital and Solove Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Purpose The purpose of this study was to compare medications and potential risk factors between patients who experienced a fall during hospitalization compared to those who did not fall while admitted to the Blood and Marrow Transplant inpatient setting at The James Cancer Hospital. Secondary objectives included evaluation of transplant-related disease states and medications in the post-transplant setting that may lead to an increased risk of falls, post-fall variables, and number of tests ordered after a fall. Methods This retrospective, case-control study matched patients in a 2:1 ratio of nonfallers to fallers. Data from The Ohio State University Wexner Medical Center (OSUWMC) reported fall events and patient electronic medical records were utilized. A total of 168 adult Blood and Marrow Transplant inpatients with a hematological malignancy diagnosis were evaluated from 1 January 2010 to 30 September 2012. Results Univariable and multivariable conditional logistic regression models were used to assess the relationship between potential predictor variables of interest and falls. Variables that were found to be significant predictors of falls from the univariable models include age group, incontinence, benzodiazepines, corticosteroids, anticonvulsants and antidepressants, and number of days status-post transplant. When considered for a multivariable model age group, corticosteroids, and a cancer diagnosis of leukemia were significant in the final model. Conclusion Recent medication utilization such as benzodiazepines, anticonvulsants, corticosteroids, and antidepressants placed patients at a higher risk of experiencing a fall. Other significant factors identified from a multivariable analysis found were patients older than age 65, patients with recent corticosteroid administration and a cancer diagnosis of leukemia.
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http://dx.doi.org/10.1177/1078155217697485DOI Listing
June 2018

A single-institution retrospective cohort study of first-line R-EPOCH chemoimmunotherapy for Richter syndrome demonstrating complex chronic lymphocytic leukaemia karyotype as an adverse prognostic factor.

Br J Haematol 2018 01 28;180(2):259-266. Epub 2017 Nov 28.

Division of Hematology, The Ohio State University, Columbus, OH, USA.

Richter Syndrome, an aggressive lymphoma occurring in patients with chronic lymphocytic leukaemia (CLL), has a generally poor prognosis and anthracycline-based chemoimmunotherapy regimens designed to treat de novo diffuse large B-cell lymphoma achieve modest clinical benefit. R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) has demonstrated greater activity against aggressive B-cell histologies but has not been studied in Richter Syndrome. We conducted a retrospective cohort study of 46 Richter Syndrome patients treated with first-line R-EPOCH at our institution between 1 January 2006 and 31 May 2014. The median progression-free survival (PFS) was 3·5 months [95% confidence interval (CI): 2·0-7·6] and median overall survival (OS) was 5·9 months (95% CI: 3·2-10·3). Toxicity was high and 30% of patients died without progression or response. Patients with a complex CLL karyotype had significantly shorter PFS and OS (P = 0·005 and P = 0·002, respectively). Multivariable analysis identified complex CLL karyotype as the most significant predictor of decreased survival [Hazard ratio (HR) 2·72, 95% CI: 1·14-6·52, P = 0·025], adjusting for number of prior CLL treatments (P = 0·036). Richter Syndrome patients with complex CLL karyotype experience poor survival with R-EPOCH treatment and novel approaches are needed for these patients. In contrast, survival of patients without a complex CLL karyotype was similar to patients with de novo diffuse large B-cell lymphoma.
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http://dx.doi.org/10.1111/bjh.15035DOI Listing
January 2018