Publications by authors named "Michael R Grever"

146 Publications

The revised guidelines for the diagnosis and management of hairy cell leukaemia and the hairy cell leukaemia variant.

Br J Haematol 2020 Dec 23. Epub 2020 Dec 23.

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

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http://dx.doi.org/10.1111/bjh.17201DOI Listing
December 2020

A phase I study of lenalidomide plus chemotherapy with idarubicin and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome.

Am J Hematol 2020 12 19;95(12):1457-1465. Epub 2020 Sep 19.

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

Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and hematopoietic cell transplantation (HCT) is the only curative treatment. New targeted therapies improved survival in select patients with specific mutations, however management of patients without these molecular alterations is an unmet need. We conducted a phase one study of lenalidomide in combination with cytarabine/idarubicin salvage chemotherapy in patients with R/R AML and high-risk myelodysplastic syndromes. A total of 33 patients were enrolled in the study (30 AML, 3 MDS), and treated at three dose levels with 3 + 3 design. Dose-limiting toxicity (DLT) was seen in eight patients, including four hematologic DLTs. The most commonly observed non-hematologic serious adverse events were febrile neutropenia, rash, sepsis and renal injury. Dose level -1, consisting of 25 mg/d lenalidomide D1-21, 1 g/m cytarabine D5-8, and 8 mg/m idarubicin D5-7 was determined to be the maximum tolerated dose. Note, 15/33 (45%) of patients were able to receive pre-planned 21 days of lenalidomide. Overall, 18 patients achieved complete remission (CR) (n = 14) or CR with incomplete count recovery (CRi) (n = 4) with total CR/CRi rate of 56%. The 1-year and 2-year overall survival (OS) were 24% and 10%, respectively. Among responders, 10/18 underwent allogeneic HCT and had a 1-year OS of 40%. There was no molecular pattern associated with response. These data demonstrate that the combination had clinical activity in R/R AML. This regimen should be further investigated for patients who relapsed after HCT, and as a bridge therapy to HCT. (ClinicalTrials.gov identifier: NCT01132586).
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http://dx.doi.org/10.1002/ajh.25958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821016PMC
December 2020

Second cancer incidence in CLL patients receiving BTK inhibitors.

Leukemia 2020 12 23;34(12):3197-3205. Epub 2020 Jul 23.

Department of Internal Medicine, Division of Hematology, Arthur G James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Chronic lymphocytic leukemia (CLL) is associated with perturbed immune function and increased risk for second primary malignancies (SPM). Ibrutinib and acalabrutinib (BTKi) are effective therapies for CLL resulting in partial restoration of immune function. The incidence of and risk factors for SPM in CLL patients receiving BTKi are not yet characterized. We retrospectively determined the incidence of SPM in CLL patients treated with ibrutinib or acalabrutinib at our institution between 2009 and 2017, assessed for association between baseline characteristics and SPM incidence, and compared the observed to expected cancer incidence among age, sex, and year matched controls without CLL. After a median of 44 months follow-up, 64/691 patients (9%) were diagnosed with SPM (excluding non-melanoma skin cancer [NMSC]). The 3-year cumulative incidence rate was 16% for NMSC and 7% for other SPM. On multivariable analysis, smoking was associated with increased SPM risk (HR 2.8 [95% CI: 1.6-4.8]) and higher baseline CD8 count was associated with lower SPM risk (HR 0.9 for 2-fold increase [95% CI: 0.8-0.9]). The observed over expected rate of SPM was 2.2 [95% CI: 1.7-2.9]. CLL patients treated with BTKi remain at increased risk for SPM, and secondary cancer detection is an important consideration in this population.
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http://dx.doi.org/10.1038/s41375-020-0987-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688551PMC
December 2020

Clara D. Bloomfield, M.D. (1942-2020): Legacy in Leukemia Research.

Authors:
Michael R Grever

Oncologist 2020 06 28;25(6):543-544. Epub 2020 May 28.

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

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http://dx.doi.org/10.1634/theoncologist.2020-0369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288634PMC
June 2020

Phase I Study of Veliparib on an Intermittent and Continuous Schedule in Combination with Carboplatin in Metastatic Breast Cancer: A Safety and [18F]-Fluorothymidine Positron Emission Tomography Biomarker Study.

Oncologist 2020 08 17;25(8):e1158-e1169. Epub 2020 Jun 17.

Stefanie Spielman Comprehensive Breast Center, The Ohio State University, Columbus, Ohio, USA.

Background: Poly(ADP-ribose) polymerase inhibitors (PARPis) are U.S. Food and Drug Administration (FDA) approved for treatment of BRCA-mutated metastatic breast cancer. Furthermore, the BROCADE studies demonstrated benefit of adding an oral PARPi, veliparib, to carboplatin and paclitaxel in patients with metastatic breast cancer harboring BRCA mutation. Given multiple possible dosing schedules and the potential benefit of this regimen for patients with defective DNA repair beyond BRCA, we sought to find the recommended phase II dose (RP2D) and schedule of veliparib in combination with carboplatin in patients with advanced breast cancer, either triple-negative (TNBC) or hormone receptor (HR)-positive, human epidermal growth receptor 2 (HER2) negative with defective Fanconi anemia (FA) DNA-repair pathway based on FA triple staining immunofluorescence assay.

Materials And Methods: Patients received escalating doses of veliparib on a 7-, 14-, or 21-day schedule with carboplatin every 3 weeks. Patients underwent [18]fluoro-3'-deoxythymidine ( FLT) positron emission tomography (PET) imaging.

Results: Forty-four patients (39 TNBC, 5 HR positive/HER2 negative with a defective FA pathway) received a median of 5 cycles (range 1-36). Observed dose-limiting toxicities were grade (G) 4 thrombocytopenia (n = 4), G4 neutropenia (n = 1), and G3 akathisia (n = 1). Common grade 3-4 toxicities included thrombocytopenia, lymphopenia, neutropenia, anemia, and fatigue. Of the 43 patients evaluable for response, 18.6% achieved partial response and 48.8% had stable disease. Median progression-free survival was 18.3 weeks. RP2D of veliparib was established at 250 mg twice daily on days 1-21 along with carboplatin at area under the curve 5. Patients with partial response had a significant drop in maximum standard uptake value (SUV ) of target lesions between baseline and early in cycle 1 based on FLT-PET (day 7-21; p  = .006).

Conclusion: The combination of continuous dosing of veliparib and every-3-week carboplatin demonstrated activity and an acceptable toxicity profile. Decrease in SUV on FLT-PET scan during the first cycle of this therapy can identify patients who are likely to have a response.

Implications For Practice: The BROCADE studies suggest that breast cancer patients with BRCA mutation benefit from addition of veliparib to carboplatin plus paclitaxel. This study demonstrates that a higher dose of veliparib is tolerable and active in combination with carboplatin alone. With growing interest in imaging-based early response assessment, the authors demonstrate that decrease in [18]fluoro-3'-deoxythymidine positron emission tomography (FLT-PET) SUV during cycle 1 of therapy is associated with response. Collectively, this study established a safety profile of veliparib and carboplatin in advanced breast cancer while also providing additional data on the potential for FLT-PET imaging modality in monitoring therapy response.
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http://dx.doi.org/10.1634/theoncologist.2020-0039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418347PMC
August 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

Population pharmacokinetics of lenalidomide in patients with B-cell malignancies.

Br J Clin Pharmacol 2019 05 27;85(5):924-934. Epub 2019 Feb 27.

Australian Centre for Pharmacometrics, School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Australia.

Aims: Lenalidomide is an immunomodulatory imide drug used broadly in the treatment of multiple myeloma and lymphoma. It continues to be evaluated in chronic lymphocytic leukaemia (CLL) at lower doses due to dose-related toxicities including tumour flare and tumour lysis syndrome. This study aimed to develop a population pharmacokinetic model for lenalidomide in multiple cancers, including CLL, to identify any disease-related differences in disposition.

Methods: Lenalidomide concentrations from 4 clinical trials were collated (1999 samples, 125 subjects), covering 4 cancers (multiple myeloma, CLL, acute myeloid leukaemia and acute lymphoblastic leukaemia) and a large dose range (2.5-75 mg). A population pharmacokinetic model was developed with NONMEM and patient demographics were tested as covariates.

Results: The data were best fitted by a 1-compartment kinetic model with absorption described by 7 transit compartments. Clearance and volume of distribution were allometrically scaled for fat-free mass. The population parameter estimates for apparent clearance, apparent volume of distribution and transit rate constant were 12 L/h (10.8-13.6), 68.8 L (61.8-76.3), and 13.5 h (11.9-36.8) respectively. Patients with impaired renal function (creatinine clearance <30 mL/min) exhibited a 22% reduction in lenalidomide clearance compared to patients with creatinine clearance of 90 mL/min. Cancer type had no discernible effect on lenalidomide disposition.

Conclusions: This is the first report of a lenalidomide population pharmacokinetic model to evaluate lenalidomide pharmacokinetics in patients with CLL and compare its pharmacokinetics with other B-cell malignancies. As no differences in pharmacokinetics were found between the observed cancer-types, the unique toxicities observed in CLL may be due to disease-specific pharmacodynamics.
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http://dx.doi.org/10.1111/bcp.13873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475687PMC
May 2019

Classic hairy cell leukemia complicated by pancytopenia and severe infection: a report of 3 cases treated with vemurafenib.

Blood Adv 2019 01;3(2):116-118

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

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http://dx.doi.org/10.1182/bloodadvances.2018027466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341189PMC
January 2019

Case 28-2018: A Man with Epistaxis, Pain and Erythema of the Forearm, and Pancytopenia.

N Engl J Med 2018 12;379(24):2381-2382

Ohio State University, Columbus, OH

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http://dx.doi.org/10.1056/NEJMc1813964DOI Listing
December 2018

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

A novel regimen for relapsed/refractory adult acute myeloid leukemia using a partial tandem duplication targeted therapy: results of phase 1 study NCI 8485.

Haematologica 2018 06 22;103(6):982-987. Epub 2018 Mar 22.

Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA.

partial tandem duplication occurs in approximately 5-10% of patients with acute myeloid leukemia and is associated with adverse prognosis. wild type is epigenetically silenced in partial tandem duplication; re-expression can be induced with DNA methyltransferase and/or histone deacetylase inhibitors , sensitizing myeloid blasts to chemotherapy. We hypothesized that epigenetic silencing of wildtype contributes to partial tandem duplication-associated leukemogenesis and pharmacologic re-expression activates apoptotic mechanisms important for chemoresponse. We developed a regimen for this unique molecular subset, but due to relatively low frequency of partial tandem duplication, this dose finding study was conducted in relapsed/refractory disease regardless of molecular subtype. Seventeen adults (< age 60) with relapsed/refractory acute myeloid leukemia were treated on study. Patients received decitabine 20 milligrams/meter daily on days 1-10 and vorinostat 400 milligrams daily on days 5-10. Cytarabine was dose-escalated from 1.5 grams/meter every 12 hours to 3 grams/meter every 12 hours on days 12, 14 and 16. Two patients experienced dose limiting toxicities at dose level 1 due to prolonged myelosuppression. However, as both patients achieved complete remission after Day 42, the protocol was amended to adjust the definition of hematologic dose limiting toxicity. No further dose limiting toxicities were found. Six of 17 patients achieved complete remission including 2 of 4 patients with partial tandem duplication. Combination therapy with decitabine, vorinostat and cytarabine was tolerated in younger relapsed/refractory acute myeloid leukemia and should be explored further focusing on the partial tandem duplication subset. ().
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http://dx.doi.org/10.3324/haematol.2017.186890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058798PMC
June 2018

BRAF accelerates disease progression and enhances immune suppression in a mouse model of B-cell leukemia.

Blood Adv 2017 Nov 30;1(24):2147-2160. Epub 2017 Oct 30.

Comprehensive Cancer Center.

Mutated mitogen-activated protein kinase (MAPK) pathway components promote tumor survival, proliferation, and immune evasion in solid tumors. MAPK mutations occur in hematologic cancers as well, but their role is less clear and few models are available to study this. We developed an in vivo model of disseminated BRAF B-cell leukemia to determine the effects of this mutation on tumor development and immune evasion. Mice with B-cell-restricted BRAF expression crossed with the Eµ-TCL1 model of chronic lymphocytic leukemia (CLL) developed leukemia significantly earlier (median, 4.9 vs 8.1 months; < .001) and had significantly shorter lifespan (median, 7.3 vs 12.1 months; < .001) versus BRAF wild-type counterparts. BRAF expression did not affect B-cell proliferation but reduced spontaneous apoptosis. BRAF-mutant leukemia produced greater T-cell effects, evidenced by exhaustion immunophenotype and CD44 T-cell percentage, as well as increased expression of PD-L1 on CD11b cells. Results were confirmed in syngeneic mice engrafted with BRAF leukemia cells. Furthermore, a BRAF-expressing CLL cell line more strongly inhibited anti-CD3/CD28-induced T-cell proliferation, which was reversed by BRAF inhibition. These results demonstrate the immune-suppressive impact of BRAF in B-cell leukemias and introduce a new model to develop rational combination strategies targeting both tumor cells and tumor-mediated immune evasion.
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http://dx.doi.org/10.1182/bloodadvances.2017006593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737117PMC
November 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

Biomedical Science Undergraduate Major: A New Pathway to Advance Research and the Health Professions.

Teach Learn Med 2018 Apr-Jun;30(2):184-192. Epub 2017 Nov 30.

c Department of Internal Medicine , The Ohio State University Wexner Medical Center , Columbus , Ohio , USA.

Problem: Many students entering professional degree programs, particularly M.D., Ph.D., and M.D./Ph.D., are not well prepared regarding the breadth of scientific knowledge required, communication skills, research experience, reading and understanding the scientific literature, and significant shadowing (for M.D.-related professions). In addition, physician scientists are a needed and necessary part of the academic research environment but are dwindling in numbers.

Intervention: In response to predictions of critical shortages of clinician investigators and the lack of proper preparation as undergraduates for these professions, the Biomedical Science (BMS) undergraduate major was created at The Ohio State University to attract incoming college freshmen with interests in scientific research and the healthcare professions. The intent of this major was to graduate an elite cohort of highly talented individuals who would pursue careers in the healthcare professions, biomedical research, or both.

Context: Students were admitted to the BMS major through an application and interview process. Admitted cohorts were small, comprising 22 to 26 students, and received a high degree of individualized professional academic advising and mentoring. The curriculum included a minimum of 4 semesters (or 2 years) of supervised research experience designed to enable students to gain skills in clinical and basic science investigation. In addition to covering the prerequisites for medicine and advanced degrees in health professions, the integrated BMS coursework emphasized research literacy as well as skills related to work as a healthcare professional, with additional emphasis on independent learning, teamwork to solve complex problems, and both oral and written communication skills. Supported by Ohio State's Department of Internal Medicine, a unique clinical internship provided selected students with insights into potential careers as physician scientists.

Outcome: In this educational case report, we describe the BMS undergraduate major and its outcomes after 10 years of implementation. Major outcomes include the strength of the major's matriculates (average ACT score = 32.6; average high school class percentile rank = 95.5) and the high percentage of BMS students who pursued graduate/professional degrees (91%; n = 110). Other markers of success include the strong focus on research, which resulted in 120 articles published by graduates to date (range = 0-12/student; 43% with at least 1 peer-reviewed journal article).

Lessons Learned: Based on its successes, adoption of a similar program at other academic medical centers would help feed the pipeline of well-trained health professionals and biomedical researchers.
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http://dx.doi.org/10.1080/10401334.2017.1361827DOI Listing
September 2018

BTK-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia.

J Clin Oncol 2017 May 13;35(13):1437-1443. Epub 2017 Feb 13.

All authors: The Ohio State University, Columbus, OH.

Purpose Therapeutic targeting of Bruton tyrosine kinase (BTK) with ibrutinib in chronic lymphocytic leukemia has led to a paradigm shift in therapy, and relapse has been uncommon with current follow-up. Acquired mutations in BTK and PLCG2 can cause relapse, but data regarding the prevalence and natural history of these mutations are limited. Patients and Methods Patients accrued to four sequential studies of ibrutinib were included in these analyses. Deep sequencing for BTK and PLCG2 was performed retrospectively on patients who experienced relapse and prospectively on a screening population. Results With a median follow-up time of 3.4 years, the estimated cumulative incidence of progression at 4 years is 19% (95% CI, 14% to 24%). Baseline karyotypic complexity, presence of del(17)(p13.1), and age less than 65 years were risk factors for progression. Among patients who experienced relapse, acquired mutations of BTK or PLCG2 were found in 85% (95% CI, 71% to 94%), and these mutations were detected an estimated median of 9.3 months (95% CI, 7.6 to 11.7 months) before relapse. Of a group of 112 patients examined prospectively, eight patients have experienced relapse, and all of these patients had acquired resistance mutations before relapse. A resistance mutation was detected in an additional eight patients who have not yet met criteria for clinical relapse. Conclusion Relapse of chronic lymphocytic leukemia after ibrutinib is an issue of increasing clinical significance. We show that mutations in BTK and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.
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http://dx.doi.org/10.1200/JCO.2016.70.2282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455463PMC
May 2017

The long noncoding RNA, treRNA, decreases DNA damage and is associated with poor response to chemotherapy in chronic lymphocytic leukemia.

Oncotarget 2017 Apr;8(16):25942-25954

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

The study of long noncoding RNAs (lncRNAs) is an emerging area of cancer research, in part due to their ability to serve as disease biomarkers. However, few studies have investigated lncRNAs in chronic lymphocytic leukemia (CLL). We have identified one particular lncRNA, treRNA, which is overexpressed in CLL B-cells. We measured transcript expression in 144 CLL patient samples and separated samples into high or low expression of treRNA relative to the overall median. We found that high expression of treRNA is significantly associated with shorter time to treatment. High treRNA also correlates with poor prognostic indicators such as unmutated IGHV and high ZAP70 protein expression. We validated these initial findings in samples collected in a clinical trial comparing the nucleoside analog fludarabine alone or in combination with the alkylating agent cyclophosphamide in untreated CLL samples collected prior to starting therapy (E2997). High expression of treRNA was independently prognostic for shorter progression free survival in patients receiving fludarabine plus cyclophosphamide. Given these results, in order to study the role of treRNA in DNA damage response we generated a model cell line system where treRNA was over-expressed in the human B-CLL cell line OSU-CLL. Relative to the vector control line, there was less cell death in OSU-CLL over-expressing treRNA after exposure to fludarabine and mafosfamide, due in part to a reduction in DNA damage. Therefore, we suggest that treRNA is a novel biomarker in CLL associated with aggressive disease and poor response to chemotherapy through enhanced protection against cytotoxic mediated DNA damage.
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http://dx.doi.org/10.18632/oncotarget.15401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432228PMC
April 2017

Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia.

Blood 2017 02 30;129(5):553-560. Epub 2016 Nov 30.

Institute of Hematology, Department of Medicine, University and Hospital of Perugia, Perugia, Italy.

Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.
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http://dx.doi.org/10.1182/blood-2016-01-689422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290982PMC
February 2017

BRAF inhibitor: targeted therapy in hairy cell leukemia.

Authors:
Michael R Grever

Blood 2016 06;127(23):2784-5

THE OHIO STATE UNIVERSITY COMPREHENSIVE CANCER CENTER.

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http://dx.doi.org/10.1182/blood-2016-03-704262DOI Listing
June 2016

A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy.

Ann Hematol 2016 Jun 27;95(7):1137-43. Epub 2016 Apr 27.

Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, 320 W. 10th Avenue, Columbus, Ohio, 43210, USA.

Patients with chronic lymphocytic leukemia (CLL) who receive chemoimmunotherapy and do not achieve complete remission experience significantly shortened progression-free interval (PFS). Additionally, the majority of patients treated for relapsed disease demonstrate evidence of measurable disease. Eradication of minimal residual disease (MRD) results in improved PFS and overall survival. Maintenance therapy might result in eradication of MRD and improve response duration but might be associated with an increase in incidence of infectious complications. Flavopiridol is a broad cyclin-dependent kinase (CDK) inhibitor with established safety and efficacy in patients with relapsed CLL, particularly patients with high-risk cytogenetic features. A pharmacologically derived schedule was utilized as consolidation therapy in this phase I study to assess the safety and feasibility of outpatient therapy with flavopiridol in patients with low tumor burden. Flavopiridol was administered as a 30-min loading dose of 30 mg/m(2) followed by a 4-h infusion of 30 mg/m(2) once weekly for 3 weeks every 5 weeks (1 cycle) for planned 2 cycles in ten patients. Therapy was extremely well tolerated and no patient developed acute tumor lysis syndrome. The most common toxicities were gastrointestinal. Of the patients, 22 % improved their response from a PR to CR. Eighty-eight percent experienced a reduction in tumor burden as measured by extent of bone marrow involvement including patients with del17p and complex karyotype. The study establishes the safety and efficacy of flavopiridol as consolidation therapy after chemoimmunotherapy for patients with CLL. Further evaluation is required in larger trials for the utility of CDK inhibitors as consolidation or maintenance strategies.Registration number at ClinicalTrials.gov: NCT00377104.
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http://dx.doi.org/10.1007/s00277-016-2683-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981588PMC
June 2016

Historical overview of hairy cell leukemia.

Best Pract Res Clin Haematol 2015 Dec 26;28(4):166-74. Epub 2015 Oct 26.

Department of Internal Medicine, The Ohio State University, 395 W 12th Avenue #392, Columbus, OH 43210, USA. Electronic address:

Since its discovery in 1923 and further characterization in 1958, hairy cell leukemia (HCL) has undergone enormous advances in the understanding of the biology and treatment of the disease. Initially a uniformly fatal disease, new therapies in rapid succession transformed HCL into a chronic disease with a normal life expectancy in many cases. More recently, the identification of BRAFV600E mutations in the majority of patients with classic HCL have enabled targeted therapies as a therapeutic option. Additional discoveries into the biology of the disease have identified new subtypes of HCL. Modern approaches to the evaluation and treatment of HCL include detailed molecular analysis which informs therapeutic options, which may consist of traditional therapies such as purine nucleoside analogs, or targeted therapies with antibodies, BTK inhibitors, or BRAF inhibitors, or combination therapy. Because HCL is a rare disease, continued progress depends on patients being enrolled on clinical trials whenever possible.
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http://dx.doi.org/10.1016/j.beha.2015.10.018DOI Listing
December 2015

Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia.

N Engl J Med 2015 Oct 9;373(18):1733-47. Epub 2015 Sep 9.

From the Institute of Hematology, Department of Medicine, and Centro di Ricerca Emato-Oncologico (CREO), University of Perugia, and Ospedale Santa Maria della Misericordia, Perugia (E.T., L.D.C., F.F., S.A., M.C., M.P.M., B.F.), the Department of Experimental, Diagnostic, and Specialty Medicine, Units of Hematology and Hematopathology, Bologna University School of Medicine, Bologna (A.B., S.A.P., P.L.Z.), Hematology Unit, Centro Trapianti e Terapie Cellulari Carlo Melzi, Dipartimento di Science Mediche Sperimentali e Cliniche, Azienda Ospedaliero Universitaria, Udine (F.Z.), the Department of Cellular Biotechnologies and Hematology, Division of Hematology, Sapienza University, Rome (A.P., R.F.), the Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Regionale San Carlo, Potenza (M.C.), the Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara (D.R.), Hematology Unit, Ospedale Ferrarotto, Catania (G.M.), the Department of Onco-Hematology, Fondazione IRCCS, Policlinico San Matteo, Pavia (M.V.), Hematology Unit, Spedali Civili, Brescia (A. Anastasia), the Department of Medicine, Section of Hematology, University of Verona, Verona (A. Ambrosetti), Onco-Hematology Unit, Fondazione di Ricerca e Cura S.S. Giovanni Paolo II, Campobasso (V.F.), Institute of Hematology 1, IRCCS, Azienda Ospedaliero Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa (A.M.C.), the Department of Hematology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Ancona (P.L.), and the Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy; Leukemia Service (J.H.P., S.S.C., R.L.L., O.A-W., M.S.T.,) and Dermatology Service (M.E.L.), the Department of Medicine, Human Oncology and Pathogenesis Program (S.S., Y.R.C., E.K., R.L.L., C.Y.P., M.F.B., O.A-W.), the Departments of Epidemiology and Biostatistics (S.D.), Pathology (C.Y.P.), and Pharmaco

Background: BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues.

Methods: We conducted two phase 2, single-group, multicenter studies of vemurafenib (at a dose of 960 mg twice daily)--one in Italy and one in the United States. The therapy was administered for a median of 16 weeks in the Italian study and 18 weeks in the U.S. study. Primary end points were the complete response rate (in the Italian trial) and the overall response rate (in the U.S. trial). Enrollment was completed (28 patients) in the Italian trial in April 2013 and is still open (26 of 36 planned patients) in the U.S. trial.

Results: The overall response rates were 96% (25 of 26 patients who could be evaluated) after a median of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12 weeks in the U.S. study. The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) in the two trials, respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free survival was 19 months among patients with a complete response and 6 months among those with a partial response; the median treatment-free survival was 25 months and 18 months, respectively. In the U.S. trial, at 1 year, the progression-free survival rate was 73% and the overall survival rate was 91%. Drug-related adverse events were usually of grade 1 or 2, and the events most frequently leading to dose reductions were rash and arthralgia or arthritis. Secondary cutaneous tumors (treated with simple excision) developed in 7 of 50 patients. The frequent persistence of phosphorylated ERK-positive leukemic cells in bone marrow at the end of treatment suggests bypass reactivation of MEK and ERK as a resistance mechanism.

Conclusions: A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy-cell leukemia. (Funded by the Associazione Italiana per la Ricerca sul Cancro and others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number NCT01711632.).
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http://dx.doi.org/10.1056/NEJMoa1506583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811324PMC
October 2015

BRAF induces ABCB1/P-glycoprotein expression and drug resistance in B-cells via AP-1 activation.

Leuk Res 2015 Sep 5. Epub 2015 Sep 5.

Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA; Department of Internal Medicine, College of Medicine; The Ohio State University, Columbus, OH, USA. Electronic address:

A subset of patients with chronic lymphocytic leukemia (CLL) and nearly all patients with classic hairy cell leukemia (HCL) harbor somatic BRAF activating mutations. However, the pathological role of activated BRAF in B-cell leukemia development and progression remains unclear. In addition, although HCL patients respond well to the BRAF inhibitor vemurafenib, relapses are being observed, suggesting the development of drug resistance in patients with this mutation. To investigate the biological role of BRAF in B-cell leukemia, we generated a CLL-like B-cell line, OSUCLL, with doxycycline-inducible BRAF expression. Microarray and real-time PCR analysis showed that ABCB1 mRNA is upregulated in these cells, and P-glycoprotein (P-gp) expression as well as function were confirmed by immunoblot and rhodamine exclusion assays. Additionally, pharmacological inhibition of BRAF and MEK alleviated the BRAF-induced ABCB1/P-gp expression. ABCB1 reporter assays and gel shift assays demonstrated that AP-1 activity is crucial in this mechanism. This study, uncovers a pathological role for BRAF in B-cell leukemia, and provides further evidence that combination strategies with inhibitors of BRAF and MEK can be used to delay disease progression and occurrence of resistance.
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http://dx.doi.org/10.1016/j.leukres.2015.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779435PMC
September 2015

Externally validated predictive clinical model for untreated del(17p13.1) chronic lymphocytic leukemia patients.

Am J Hematol 2015 Nov 12;90(11):967-9. Epub 2015 Oct 12.

Comprehensive Cancer Center, Ohio State University, Columbus, Ohio.

Little is known about outcomes of patients with chronic lymphocytic leukemia (CLL) with del(17p13.1) karyotype at diagnosis. We reviewed 114 de novo del(17p13.1) CLL patients seen at our institution. Using proportional hazards models to identify pretreatment clinical variables significantly associated with treatment-free survival (TFS) and overall survival (OS), we developed a simplified risk score for de novo del(17p13.1) CLL patients to predict TFS and OS based on these variables. These scores, particularly the very highest, can be utilized to identify high-risk patients for expedient enrollment on clinical trials. Our data support careful observation for low-risk patients, potentially preventing unnecessary use of aggressive therapies.
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http://dx.doi.org/10.1002/ajh.24125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055503PMC
November 2015

Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia.

JAMA Oncol 2015 Apr;1(1):80-7

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

Importance: The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in patients with chronic lymphocytic leukemia (CLL). Reasons for discontinuing therapy with this drug and outcomes following discontinuation have not been evaluated outside of clinical trials with relatively short follow-up.

Objective: To determine features associated with discontinuation of ibrutinib therapy and outcomes.

Design, Setting, And Participants: A total of 308 patients participating in 4 sequential trials of ibrutinib at The Ohio State University Comprehensive Cancer Center were included. These clinical trials accrued patients included in this analysis from May 2010 until April 2014, and data were locked in June 2014.

Main Outcomes And Measures: Patients were evaluated for time to therapy discontinuation, reasons for discontinuation, and survival following discontinuation. For patients who discontinued therapy because of disease progression, targeted deep sequencing was performed in samples at baseline and time of relapse.

Results: With a median follow-up of 20 months, 232 patients remained on therapy, 31 had discontinued because of disease progression, and 45 had discontinued for other reasons. Disease progression includes Richter's transformation (RT) or progressive CLL. Richter's transformation appeared to occur early and CLL progressions later (cumulative incidence at 12 months, 4.5% [95% CI, 2.0%-7.0%] and 0.3% [95% CI, 0%-1.0%], respectively). Median survival following RT was 3.5 months (95% CI, 0.3-6.0 months) and 17.6 months (95% CI, 4.7 months-"not reached") following CLL progression. Sequencing on peripheral blood from 8 patients with RT revealed 2 with mutations in BTK, and a lymph node sample showed no mutations in BTK or PLCG2. Deep sequencing on 11 patients with CLL progression revealed BTK or PLCG2 mutations in all. These mutations were not identified before treatment in any patient.

Conclusions And Relevance: This single-institution experience with ibrutinib confirms it to be an effective therapy and identifies, for the first time, baseline factors associated with ibrutinib therapy discontinuation. Outcomes data show poor prognosis after discontinuation, especially for those patients with RT. Finally, sequencing data confirm initial reports associating mutations in BTK and PLCG2 with progression and clearly show that CLL progressions are associated with these mutations, while RT is likely not.

Trial Registrations: clinicaltrials.gov Identifiers:NCT01105247, NCT01217749, NCT01589302, and NCT01578707.
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http://dx.doi.org/10.1001/jamaoncol.2014.218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520535PMC
April 2015

Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study.

Blood 2015 Aug 26;126(7):842-50. Epub 2015 Jun 26.

Division of Hematology, Department of Medicine.

Ibrutinib represents a therapeutic advance in chronic lymphocytic leukemia (CLL) but as monotherapy produces few complete remissions in previously treated patients. Anti-CD20 antibodies have improved response and progression-free survival (PFS) when combined with chemotherapy. We evaluated the safety and activity of adding ofatumumab to ibrutinib in 3 different administration sequences. Patients with CLL/small lymphocytic lymphoma (SLL), prolymphocytic leukemia, or Richter's transformation who failed ≥2 prior therapies were enrolled. Patients received ibrutinib 420 mg daily and 12 doses of ofatumumab 300/2000 mg in 3 schedules: ibrutinib lead-in (group 1; n = 27), concurrent start (group 2; n = 20), or ofatumumab lead-in (group 3; n = 24). Seventy-one patients were treated; most had high-risk disease including del(17)(p13.1) (44%) or del(11)(q22.3) (31%). The most frequent adverse events (any grade) were diarrhea (70%), infusion-related reaction (45%), and peripheral sensory neuropathy (44%). Overall response rates in CLL/SLL patients (n = 66) were 100%, 79%, and 71% in groups 1, 2, and 3, respectively. Estimated 12-month PFSs for all patients were 89%, 85%, and 75%, respectively. Four patients in group 3 progressed prior to receiving ibrutinib. This study demonstrates the tolerability and clinical activity of this combination with quicker time to best response than single-agent ibrutinib and with durable responses. This trial was registered at www.clinicaltrials.gov as #NCT01217749.
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http://dx.doi.org/10.1182/blood-2014-12-617522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536539PMC
August 2015

Final results of EFC6663: a multicenter, international, phase 2 study of alvocidib for patients with fludarabine-refractory chronic lymphocytic leukemia.

Leuk Res 2015 May 7;39(5):495-500. Epub 2015 Feb 7.

The Ohio State University, Columbus, OH, United States.

Early phase studies of alvocidib showed activity in relapsed CLL including patients with high risk genomic features and those refractory to fludarabine. A multi-center, international, phase II study of alvocidib in fludarabine refractory CLL was undertaken to validate these early results. Patients with fludarabine refractory CLL or prolymphocytic leukemia arising from CLL were treated with single agent alvocidib. The primary outcome measure was overall response rate, with secondary outcomes including survival, toxicity, and response duration. One hundred and sixty five patients were enrolled and 159 patients were treated. The median age was 61 years, the median number of prior therapies was 4, and 96% of patients were fludarabine refractory. The investigator-assessed overall response rate was 25%; the majority of responses were partial. Response rates were lower among patients with del(17p) (14%), but equivalent in patients with del(11q) or bulky lymphadenopathy. Median progression free and overall survival were 7.6 and 14.6 months, respectively. Tumor lysis occurred in 39 patients (25%), and 13 received hemodialysis. Diarrhea, fatigue, and hematologic toxicities were common. Alvocidib has clinical activity in patients with advanced, fludarabine refractory CLL. Future studies should focus on discovery of biomarkers of clinical response and tumor lysis, and enhanced supportive care measures.
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http://dx.doi.org/10.1016/j.leukres.2015.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557608PMC
May 2015

Cytogenetic prioritization with inclusion of molecular markers predicts outcome in previously untreated patients with chronic lymphocytic leukemia treated with fludarabine or fludarabine plus cyclophosphamide: a long-term follow-up study of the US intergroup phase III trial E2997.

Leuk Lymphoma 2015 30;56(11):3031-7. Epub 2015 Mar 30.

a Ohio State University Comprehensive Cancer Center , Columbus , OH , USA.

Fludarabine (F) and cyclophosphamide (C) remain backbones of up-front chemotherapy regimens for chronic lymphocytic leukemia (CLL). We report long-term follow-up of a randomized F vs. FC trial in untreated CLL (#) . With median follow-up of 88 months, estimated median progression-free survival (PFS) was 19.3 vs. 48.1 months for F (n = 109) and FC (n = 118), respectively (p < 0.0001), and median overall survival (OS) was 88.0 vs. 79.1 months (p = 0.96). In multivariable analyses, variables associated with inferior PFS and OS respectively were age (p = 0.002, p < 0.001), Rai stage (p = 0.006, p = 0.02) and sex (p = 0.03, PFS only). Del(17)(p13.1) predicted shorter PFS and OS (p < 0.0001 for each), as did del(11q)(22.3) (p < 0.0001, p = 0.005, respectively), trisomy 12 with mutated Notch1 (p = 0.003, p = 0.03, respectively) and unmutated IGHV (p = 0.009, p = 0.002, respectively), all relative to patients without these features. These data confirm results from shorter follow-up and further justify targeted therapies for CLL.
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http://dx.doi.org/10.3109/10428194.2015.1023800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688910PMC
September 2016

Reduced occurrence of tumor flare with flavopiridol followed by combined flavopiridol and lenalidomide in patients with relapsed chronic lymphocytic leukemia (CLL).

Am J Hematol 2015 Apr 25;90(4):327-33. Epub 2015 Feb 25.

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

Flavopiridol and lenalidomide have activity in refractory CLL without immunosuppression or opportunistic infections seen with other therapies. We hypothesized that flavopiridol treatment could adequately de-bulk disease prior to lenalidomide therapy, decreasing the incidence of tumor flare with higher doses of lenalidomide. In this Phase I study, the maximum tolerated dose was not reached with treatment consisting of flavopiridol 30 mg m(-2) intravenous bolus (IVB) + 30 mg m(-2) continuous intravenous infusion (CIVI) cycle (C) 1 day (D) 1 and 30 mg m(-2) IVB + 50 mg m(-2) CIVI C1 D8,15 and C2-8 D3,10,17 with lenalidomide 15 mg orally daily C2-8 D1-21. There was no unexpected toxicity seen, including no increased tumor lysis, tumor flare (even at higher doses of lenalidomide) or opportunistic infection. Significant clinical activity was demonstrated, with a 51% response rate in this group of heavily pretreated patients. Biomarker testing confirmed association of mitochondrial priming of the BH3 only peptide Puma with response.
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http://dx.doi.org/10.1002/ajh.23946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552311PMC
April 2015