Publications by authors named "Bita Fakhri"

23 Publications

  • Page 1 of 1

Survival after autologous versus allogeneic transplantation in patients with relapsed and refractory Hodgkin lymphoma.

Leuk Lymphoma 2021 May 14:1-8. Epub 2021 May 14.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

For relapsed Hodgkin lymphoma, salvage chemotherapy followed by auto-HCT is the standard of care. It is important to identify subpopulations who could benefit from allo-HCT. This retrospective analysis included 277 patients with rrHL who underwent first transplant with auto-HCT or allo-HCT between 2007-2017. Patients in the auto-HCT cohort ( = 218) were older, more likely to be in CR at the time of transplant and receive maintenance therapy post-transplant. Patients who underwent allo-HCT ( = 59) had a higher MSKCC relapse score. Factors associated with an inferior PFS and OS included early relapse, advanced stage, extranodal involvement and not achieving CR following salvage chemotherapy. After controlling for these 4 risk factors and MSKCC score, PFS ( = 0.112) or OS ( = 0.256) was not affected by the choice of transplant. In patients with ≥ 3 high risk features, the 4-year PFS was 51% in the allo-HCT vs. 39% ( = 0.107) in the auto-HCT cohort.
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http://dx.doi.org/10.1080/10428194.2021.1927016DOI Listing
May 2021

Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study.

Lancet 2021 Mar;397(10277):892-901

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Covalent Bruton's tyrosine kinase (BTK) inhibitors are efficacious in multiple B-cell malignancies, but patients discontinue these agents due to resistance and intolerance. We evaluated the safety and efficacy of pirtobrutinib (working name; formerly known as LOXO-305), a highly selective, reversible BTK inhibitor, in these patients.

Methods: Patients with previously treated B-cell malignancies were enrolled in a first-in-human, multicentre, open-label, phase 1/2 trial of the BTK inhibitor pirtobrutinib. The primary endpoint was the maximum tolerated dose (phase 1) and overall response rate (ORR; phase 2). This trial is registered with ClinicalTrials.gov, NCT03740529.

Findings: 323 patients were treated with pirtobrutinib across seven dose levels (25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day) with linear dose-proportional exposures. No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. The recommended phase 2 dose was 200 mg daily. Adverse events in at least 10% of 323 patients were fatigue (65 [20%]), diarrhoea (55 [17%]), and contusion (42 [13%]). The most common adverse event of grade 3 or higher was neutropenia (32 [10%]). There was no correlation between pirtobrutinib exposure and the frequency of grade 3 treatment-related adverse events. Grade 3 atrial fibrillation or flutter was not observed, and grade 3 haemorrhage was observed in one patient in the setting of mechanical trauma. Five (1%) patients discontinued treatment due to a treatment-related adverse event. In 121 efficacy evaluable patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) treated with a previous covalent BTK inhibitor (median previous lines of treatment 4), the ORR with pirtobrutinib was 62% (95% CI 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (53 [67%] of 79), covalent BTK inhibitor intolerance (22 [52%] of 42), BTK C481-mutant (17 [71%] of 24) and BTK wild-type (43 [66%] of 65) disease. In 52 efficacy evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but eight remain progression-free to date.

Interpretation: Pirtobrutinib was safe and active in multiple B-cell malignancies, including patients previously treated with covalent BTK inhibitors. Pirtobrutinib might address a growing unmet need for alternative therapies for these patients.

Funding: Loxo Oncology.
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http://dx.doi.org/10.1016/S0140-6736(21)00224-5DOI Listing
March 2021

The role of acalabrutinib in adults with chronic lymphocytic leukemia.

Ther Adv Hematol 2021 5;12:2040620721990553. Epub 2021 Feb 5.

Department of Medicine, Division of Hematology/Blood and Marrow Transplantation, University of California, San Francisco, CA, USA.

The treatment landscape of chronic lymphocytic leukemia (CLL) has significantly changed in the past decade. This paradigm shift is due to the introduction of novel agents to the field. The two major classes of drugs that have contributed to this dramatic evolution include the Bruton tyrosine kinase (BTK) inhibitors and BCL2 inhibitors. Ibrutinib was the first-in-class drug which was initially approved by the US Food and Drug Administration (FDA) for the treatment of patients with relapsed/refractory and later for patients with treatment-naïve CLL. Despite encouraging efficacy outcomes, its use has been associated with cardiovascular and gastrointestinal toxicities likely due to off-target inhibition of ITK, TEC and EGFR family kinases. The next generation of BTK inhibitors was developed to be more selective with less off-target inhibition with the prospect to improve tolerability without compromising efficacy. Acalabrutinib, a selective covalent BTK inhibitor, is a second generation BTK inhibitor. The focus of this review is on two major phase III trials that resulted in the FDA approval of acalabrutinib in 2019. The ELEVATE TN trial investigated acalabrutinib with or without obintuzumab chlorambucil-obinutuzumab in older and frail patients with previously untreated CLL. The ASCEND trial explored acalabrutinib chemoimmunotherapy in patients with relapsed/refractory CLL. Both trials demonstrated superiority of the acalabrutinib-containing arms in terms of both efficacy and tolerability. Unfortunately, the availability of new generation BTK inhibitors has not resulted in mitigating the financial toxicities associated with these potentially life-long treatments.
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http://dx.doi.org/10.1177/2040620721990553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871059PMC
February 2021

Carfilzomib in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma: A Phase I Trial.

Clin Lymphoma Myeloma Leuk 2021 Mar 24;21(3):139-146. Epub 2020 Dec 24.

Department of Medicine, Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA. Electronic address:

Introduction: We designed a multicenter, phase Ib dose-escalation trial of carfilzomib with bendamustine and rituximab in patients with relapsed/refractory non-Hodgkin lymphoma (NCT02187133) in order to improve the response rates of this difficult-to-treat population. Chemoimmunotherapy with bendamustine and rituximab has shown activity in a variety of lymphomas, and proteasome inhibitors have demonstrated pre-clinical synergy and early clinical activity in this population. The objectives were to determine the maximum tolerated dose of carfilzomib and the preliminary efficacy of this combination.

Patients And Methods: The protocol followed a 3+3 design of carfilzomib dose escalation combined with standard doses of bendamustine and rituximab. Patients were treated for up to 6 cycles with an interim positron emission tomography/computed tomography after cycle 3.

Results: Ten patients were treated on the dose-escalation phase. The study was terminated at a carfilzomib dose of 56 mg/m, and the maximum tolerated dose was not reached. The most common grade 3/4 adverse event was thrombocytopenia. There was 1 dose-limiting toxicity observed, grade 3 febrile neutropenia, and there were no treatment-related deaths. The overall response rate was 40% (complete response rate, 30%), with a median duration of response of 12 months and a median progression-free survival of 2.1 months.

Conclusion: Carfilzomib in combination with bendamustine and rituximab is a safe and well-tolerated treatment for patients with relapsed/refractory non-Hodgkin lymphoma. Preliminary data indicate that this combination may have efficacy with an acceptable side effect profile in this heavily pre-treated patient population with limited treatment options.
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http://dx.doi.org/10.1016/j.clml.2020.12.020DOI Listing
March 2021

Ofatumumab, Etoposide, and Cytarabine Intensive Mobilization Regimen in Patients with High-risk Relapsed/Refractory Diffuse Large B-Cell Lymphoma Undergoing Autologous Stem Cell Transplantation.

Clin Lymphoma Myeloma Leuk 2021 Apr 11;21(4):246-256.e2. Epub 2020 Nov 11.

Division of Hematology/Oncology, Department of Medicine, UCSF Medical Center, San Francisco, CA; UCSF Helen Diller Family Comprehensive Cancer Center, UCSF Medical Center, San Francisco, CA. Electronic address:

Background: More than one-half of high-risk patients with relapsed/refractory (rr) diffuse large B-cell lymphoma (DLBCL) relapse after autologous hematopoietic cell transplantation (auto-HCT). In this phase II study, we investigate the long-term outcomes of high-risk patients with rrDLBCL receiving intensive consolidation therapy (ICT) with OVA (ofatumumab, etoposide, and high-dose cytarabine) prior to auto-HCT.

Patients And Methods: The primary endpoints were the ability of OVA to mobilize peripheral stem cells and the 2-year progression-free survival (PFS) rate following OVA. Secondary endpoints included safety, 2-year overall survival (OS), impact of cell of origin (COO), and the prognostic utility of next-generation sequencing minimal residual disease (MRD) testing. We simultaneously retrospectively assessed the outcomes of DLBCL patients who underwent ICT with a similar regimen at our institution.

Results: Twenty-seven patients received salvage chemotherapy, with a response rate of 25% in patients with germinal center B-cell (GCB)-DLBCL versus 92% in patients with non-GCB-DLBCL (P = .003). Nineteen responding patients underwent ICT with OVA (100% successful stem cell mobilization). The 2-year PFS and OS rate was 47% and 59%, respectively, with no difference based on COO. Similar findings were observed when the study and retrospective cohorts were combined. Neutropenia was the most common toxicity (47%). MRD-negative patients at the completion of salvage had a median OS of not reached versus 3.5 months in MRD-positive patients (P = .02).

Conclusions: OVA followed by auto-HCT is effective and safe for high-risk rrDLBCL. Patients with GCB-DLBCL had a lower response to salvage chemotherapy, but no difference in outcomes based on COO was seen after auto-HCT. MRD testing in the relapsed setting was predictive of long-term survival.
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http://dx.doi.org/10.1016/j.clml.2020.11.005DOI Listing
April 2021

Complexities in the diagnosis of large B-cell lymphomas, classic Hodgkin lymphomas and overlapping peripheral T-cell lymphomas simplified: An evidence-based guide.

Ann Diagn Pathol 2020 Jun 15;46:151534. Epub 2020 May 15.

Department of Pathology, University of California, San Francisco, CA 94143, United States of America. Electronic address:

The diagnosis of a large B-cell lymphoma and classic Hodgkin lymphoma (CHL) is often straightforward. However, in select circumstances, these simple diagnoses can be quite complex. In part, diagnostic difficulty may be due to uncertainty in the evaluation of morphologic and immunophenotypic features along a biologic continuum, or alternatively arise from uncertainty in predicting the behavior and outcomes of patients. Here, we systematically discuss and review areas of diagnostic difficulty in the diagnosis of large B-cell lymphomas (LBCL), classic Hodgkin lymphomas (CHL) and peripheral T-cell lymphomas (PTCL). We provide careful data-driven analyses and evidence-based approaches to help guide pathologists and clinicians. We discuss: 1) marginal zone lymphomas with increased large cells versus diffuse large B-cell lymphoma (DLBCL), 2) chronic lymphocytic leukemia with expanded proliferation centers versus diffuse large B-cell lymphoma (DLBCL), 3) chronic lymphocytic leukemia with Hodgkin/Reed-Sternberg-like cells versus CHL arising from chronic lymphocytic leukemia, 4) complex cases of follicular lymphoma versus DLBCL, 5) PTCL with large B-cell proliferations versus PTCL with LBCL, 6) PTCL with Hodgkin/Reed-Sternberg-like cells versus CHL, and finally 7) blastoid/pleomorphic mantle cell lymphoma versus DLBCL. Our evidence and data driven approach may serve as a useful diagnostic guide.
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http://dx.doi.org/10.1016/j.anndiagpath.2020.151534DOI Listing
June 2020

Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK Inhibition as an Effective Strategy.

Clin Cancer Res 2020 07 20;26(14):3589-3596. Epub 2020 Mar 20.

Division of Malignant Hematology, Moffitt Cancer Center, Tampa, Florida.

Purpose: Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood.

Experimental Design: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies].

Results: We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve ( = 130), and 81% were idelalisib naïve ( = 263). ORR to BTKi was 84% ( = 44) in BTKi-naïve patients versus 54% ( = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.

Conclusions: For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3815DOI Listing
July 2020

Immune-related Adverse Events Associated With Checkpoint Inhibition in the Setting of CAR T Cell Therapy: A Case Series.

Clin Lymphoma Myeloma Leuk 2020 03 26;20(3):e118-e123. Epub 2019 Dec 26.

Division of Hematology/Oncology, Department of Medicine, University of California San Francisco Medical Center, San Francisco, CA; University of California San Francisco Helen Diller Family Comprehensive Center, San Francisco, CA.

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http://dx.doi.org/10.1016/j.clml.2019.12.014DOI Listing
March 2020

CLL14 Trial: Fixed-Duration Chemotherapy-Free Regimen for Frail Patients with Treatment-Naïve CLL.

Oncology (Williston Park) 2019 Nov 14;33(11). Epub 2019 Nov 14.

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November 2019

Measuring cardiopulmonary complications of carfilzomib treatment and associated risk factors using the SEER-Medicare database.

Cancer 2020 02 13;126(4):808-813. Epub 2019 Nov 13.

Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.

Background: Carfilzomib improves survival in patients with recurrent myeloma. Given the strict eligibility criteria in clinical trials, the actual frequency of cardiac adverse events (CAEs) and pulmonary adverse events (PAEs) and the risk factors associated with these AEs in the general population need to be established.

Methods: The authors extracted myeloma cases in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database from 2000 through 2013 and corresponding claims through 2014. They then identified patients who received carfilzomib during their disease course. Subsequently, the International Classification of Diseases, Ninth Revision (ICD-9) was used to identify all the codes for CAEs, PAEs, and respiratory infections associated with carfilzomib use. Preexisting diagnoses corresponding to the CAEs and PAEs of interest were excluded to distinguish toxicity from comorbidity. Multivariate Cox regression was performed to determine those variables independently associated with the development of CAEs and PAEs.

Results: Of the 635 patients analyzed, the median age was 72 years (range, 36-94 years); 55% of the patients were male and 79% were white. The median duration of carfilzomib treatment was 58 days (range, 1-716 days). Overall, approximately 66% of the patients had codes for either CAEs or PAEs. In terms of CAEs, approximately 22% of patients developed hypertension, 15% developed peripheral edema, and 14% experienced heart failure. With regard to PAEs, approximately 28% of patients developed dyspnea, 15% developed cough, and 15% developed pneumonia. Only chronic obstructive pulmonary disease (COPD) was found to be independently associated with the development of CAEs. Patients with preexisting COPD were found to have a 40% increase in their hazard of developing CAEs (adjusted hazard ratio, 1.40; 95% CI, 1.03-1.90).

Conclusions: In older adults with myeloma who are undergoing treatment with carfilzomib, new cardiac and pulmonary diagnoses were common. Patients with preexisting COPD were found to be at an increased risk of developing CAEs.
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http://dx.doi.org/10.1002/cncr.32601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992490PMC
February 2020

Outcomes in patients with aggressive B-cell non-Hodgkin lymphoma after intensive frontline treatment failure.

Cancer 2020 01 30;126(2):293-303. Epub 2019 Sep 30.

Center for Lymphoid Malignancies, Department of Medicine, and Department of Pathology and Cell Biology, Columbia University Medical Center , New York.

Background: Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown.

Methods: Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy.

Results: In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse <12 months from completion of first-line therapy) experienced inferior median PFS (2.8 vs 23 months; P < .001) and OS (6 months vs not reached; P < .001) compared with patients with late treatment failure. Although the 17% of patients with early failure who achieved a complete response to second-line immunochemotherapy experienced prolonged survival, this outcome could not be predicted by clinicopathologic features at the start of second-line immunochemotherapy.

Conclusions: Patients with early treatment failure after intensive first-line immunochemotherapy experience poor outcomes after receiving standard second-line immunochemotherapy. The use of standard-of-care or experimental therapies currently available in the third-line setting and beyond should be investigated in the second-line setting for these patients.
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http://dx.doi.org/10.1002/cncr.32526DOI Listing
January 2020

Fifty Shades of GATA2 Mutation: A Case of Plasmablastic Lymphoma, Nontuberculous Mycobacterial Infection, and Myelodysplastic Syndrome.

Clin Lymphoma Myeloma Leuk 2019 09 29;19(9):e532-e535. Epub 2019 May 29.

Division of Oncology, Siteman Cancer Center, Washington University School of Medicine, St Louis, MO. Electronic address:

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http://dx.doi.org/10.1016/j.clml.2019.05.015DOI Listing
September 2019

Maintenance rituximab or observation after frontline treatment with bendamustine-rituximab for follicular lymphoma.

Br J Haematol 2019 02 21;184(4):524-535. Epub 2018 Dec 21.

Washington University School of Medicine, Saint Louis, MO, USA.

Bendamustine (B) with rituximab (R) is a standard frontline treatment for medically fit follicular lymphoma (FL) patients. The safety and efficacy of maintenance rituximab (MR) after BR induction has not been formally compared to observation for FL, resulting in disparate practice patterns. Prospective trials have shown benefit of MR after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or R-CVP (rituximab, cyclophosphamide, vincristine, prednisone), yet recent data from the GALLIUM study comparing outcomes of patients treated with chemotherapy with R or obinutuzumab (G) showed higher than anticipated fatal adverse events with BR/BG. In order to assess the efficacy and tolerability of MR after BR, we retrospectively collected data on 640 newly diagnosed patients treated with FL. We found that patients who achieved partial remission (PR) after ≥4 cycles of BR had improved duration of response (DOR) with MR vs. no maintenance, whereas those in complete remission did not. These findings were confirmed in a validation cohort. In the entire study population, the known fatal adverse event rate after BR was 2·5% and did not significantly differ in those receiving MR versus no maintenance. [Correction added on 14 January 2019, after online publication: The preceding sentence has been corrected in this current version.] Within the limitations inherent to retrospective analysis, these data suggest that FL patients with a PR to BR experience prolongation of remission with MR with an acceptable safety profile.
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http://dx.doi.org/10.1111/bjh.15720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486816PMC
February 2019

Bones in Multiple Myeloma: Imaging and Therapy.

Am Soc Clin Oncol Educ Book 2018 May;38:638-646

From the "Seràgnoli" Institute of Hematology, Bologna University School of Medicine, Bologna, Italy; Washington University School of Medicine, St. Louis, MO; Indiana University Simon Cancer Center, Indianapolis, IN.

Bone disease is the most frequent disease-defining clinical feature of multiple myeloma (MM), with 90% of patients developing bone lesions over the course of their disease. For this reason, imaging plays a major role in the management of disease in patients with MM. Although conventional radiography has traditionally been the standard of care, its low sensitivity in detecting osteolytic lesions has called for more advanced imaging modalities. In this review, we discuss the advantages, indications, and applications of whole-body low-dose CT (WBLDCT), F-fluorodeoxyglucose (FDG)-PET/CT, MRI, and other novel imaging modalities in the management of disease in patients with plasma cell dyscrasias. We also review the state of the art in treatment of MM bone disease (MMBD) and the role of bisphosphonates and denosumab, a monoclonal antibody that binds and blocks the activity of receptor activator of nuclear factor-kappa B ligand (RANKL), which was recently approved by the U.S. Food and Drug Administration for MMBD.
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http://dx.doi.org/10.1200/EDBK_205583DOI Listing
May 2018

Undertreatment of Older Patients With Newly Diagnosed Multiple Myeloma in the Era of Novel Therapies.

Clin Lymphoma Myeloma Leuk 2018 03 31;18(3):219-224. Epub 2018 Jan 31.

Division of Oncology, Washington University School of Medicine, St. Louis, MO. Electronic address:

Background: With the expanding armamentarium of therapeutic agents for multiple myeloma (MM), it is important to identify any undertreated patient populations to mitigate outcome disparities.

Materials And Methods: We extracted the data for all plasma cell myeloma cases (International Classification of Disease for Oncology, third revision [ICD-O-3] code 9732) in the Surveillance, Epidemiology, End Results (SEER)-Medicare database from 2007 to 2011. The ICD-O-3 histologic code 9732 captures both active MM and smoldering/asymptomatic myeloma. We defined active MM as either claims indicating receipt of treatments approved for MM or ICD-9 codes for MM-defining clinical features, referred to as the CRAB criteria (calcium [elevated], renal failure, anemia, bone lesions). Multivariate logistic regression was performed to determine the variables that were independently associated with receipt of no treatment.

Results: Of the initial 4187 patients included in the present study, 373 had no claims indicating receipt of treatments approved for MM and had no ICD-9 codes associated with the CRAB criteria and were excluded from the analyses. Of the 3814 patients with active MM, 1445 (38%) did not have any claims confirming that they had received systemic treatment. Older age, poor performance indicators, comorbidities, African-American race, and lower socioeconomic status, including enrollment in Medicaid, were statistically significant factors associated with the receipt of no systemic treatment.

Conclusions: In the present retrospective study of data from the SEER-Medicare database, we found that age, health status, race, and socioeconomic status were associated with receipt of MM treatment. These factors have previously been linked to reduced usage of specific treatments for MM, such as stem cell transplantation. To the best of our knowledge, however, ours is the first study to show their association with the receipt of any MM therapy.
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http://dx.doi.org/10.1016/j.clml.2018.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837946PMC
March 2018

Current and emerging treatment options for mantle cell lymphoma.

Ther Adv Hematol 2017 Aug 7;8(8):223-234. Epub 2017 Jul 7.

660 South Euclid Ave, Campus Box 8056, Saint Louis, MO 63110, USA.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma with typically aggressive behavior. The genetic signature is the chromosomal translocation t(11;14)(q13;q32) resulting in overexpression of cyclin D1. Asymptomatic newly diagnosed MCL patients with low tumor burden can be closely observed, deferring therapy to the time of disease progression. Although MCL classically responds to upfront chemotherapy, it remains incurable with standard approaches. For patients in need of frontline therapy, the initial decision is whether to proceed with an intensive treatment strategy or a non-intensive treatment strategy. In general, given the unfavorable risk-benefit profile, older MCL patients should be spared intensive strategies, while younger and fit patients can be considered for intensive strategies. The bendamustine and rituximab (BR) regimen is becoming an increasingly popular treatment option among the elderly population, with improved progression-free survival (PFS) and acceptable side-effect profile. Although rituximab maintenance after R-CHOP improves survival outcomes in elderly patients, no clinical trial to date has shown statistical significance to support the use of rituximab maintenance after BR induction in older patients. In young and fit patients with MCL, an intensive strategy to maximize the length of first remission has emerged as a worldwide standard of care. With current high-dose cytarabine-containing immunochemotherapy regimens followed by autologous stem cell transplantation, the median PFS has exceeded 7 years. In the relapsed or refractory (R/R) setting, reduced intensity conditioning allogeneic hematopoietic stem cell transplantation may offer the highest likelihood of long-term survival in young R/R MCL patients, at the cost of increased risk of non-relapse mortality and chronic graft host disease. Novel agents targeting activated pathways in MCL cells, such as bortezomib, lenalidamide, ibrutinib and temsirolimus are now available for the management of R/R disease.
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http://dx.doi.org/10.1177/2040620717719616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544150PMC
August 2017

Molecular landscape and sub-classification of gastrointestinal cancers: a review of literature.

J Gastrointest Oncol 2017 Jun;8(3):379-386

Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.

The historical approach of diagnosing cancer types based entirely on anatomic origin and histologic features, and the "one-size-fit-all" therapeutic approach, are inadequate in modern cancer treatment. From decades of research we now know that cancer is a highly heterogeneous disease driven by complex genetic or epigenetic alterations. The advent of various high throughput molecular tools has now enabled us to view and sub-classify each cancer type based on their distinct molecular features, in addition to histologic classification, with the promise of individualized treatment strategies tailored towards each specific subtype to improve patient outcomes. In this review, we have made an effort to systematically review the most up-to-date, leading literature in molecular analysis and/or subtyping of major gastrointestinal cancers. These include esophageal squamous cell carcinoma (ESCC), gastric cancer (GC) adenocarcinoma, pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC), gallbladder cancer (GBC), and colorectal cancer (CRC). For each cancer type we summarized the global mutational landscape, subgroup classification based on genomics, epigenetics, gene expression and/or proteomic analysis, and their salient clinicopathological features. We have highlighted the actionable mutations or mutational pathways that could help guide targeted therapies in the future.
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http://dx.doi.org/10.21037/jgo.2016.11.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506283PMC
June 2017

Donor-Derived Smoldering Multiple Myeloma following a Hematopoietic Cell Transplantation for AML.

Case Rep Hematol 2017 20;2017:3728429. Epub 2017 Feb 20.

Washington University School of Medicine, St. Louis, MO, USA; Siteman Cancer Center, St. Louis, MO, USA.

Posttransplant Lymphoproliferative Disorder (PTLD) is one of the most common malignancies complicating solid organ transplantation. In contrast, PTLD accounts for a minority of secondary cancers following allogeneic hematopoietic cell transplantation (HCT). Here we report on a 61-year-old woman who received an ABO-mismatched, HLA-matched unrelated donor hematopoietic cell transplantation from a presumably healthy donor for a diagnosis of acute myeloid leukemia (AML). Eighteen months following her transplant, she developed a monoclonal gammopathy. Bone marrow studies revealed 10% plasma cells, but the patient lacked clinical defining features of multiple myeloma (MM); thus a diagnosis of smoldering multiple myeloma (SMM) was established. Cytogenetic and molecular studies of the bone marrow confirmed the plasma cells were donor-derived. The donor lacks a diagnosis of monoclonal gammopathy of undetermined significance, SMM, or MM.
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http://dx.doi.org/10.1155/2017/3728429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337855PMC
February 2017

Clonal Evolution in Multiple Myeloma.

Clin Lymphoma Myeloma Leuk 2016 08;16 Suppl:S130-4

Division of Hematology and Oncology, Washington University School of Medicine, St Louis, MO. Electronic address:

Multiple myeloma (MM) is the second most common hematologic malignancy encountered among patients in the United States. The last decade has seen incremental improvements in the survival of patients with MM. These advances are, to a large extent, attributable to the addition of proteasome inhibitors and immunomodulatory drugs to the armamentarium of treatment options. The adoption of these drug classes was the result of an empiric research paradigm. However, with the application of next generation sequencing technologies, we are now starting to unravel the genomic landscape of MM. It is hoped that this will allow us to better disentangle the biology of the disease and allow for identification of new therapeutic targets. In this article, we review what we have learned to date about the mutational profile, clonal architecture, and evolution of the disease, and discuss the potential clinical implications of these findings.
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http://dx.doi.org/10.1016/j.clml.2016.02.025DOI Listing
August 2016

Variability in postpacing intervals predicts global ventricular activation pattern during tachycardia.

Pacing Clin Electrophysiol 2010 Feb 18;33(2):129-34. Epub 2009 Nov 18.

Texas Heart Institute, St. Luke's Episcopal Hospital, Houston, TX 77060, USA.

Introduction: Assessment of ventricular activation pattern is critical to the successful ablation of ventricular tachycardia (VT). We have previously shown that the global atrial activation pattern during tachycardia can be rapidly and accurately assessed by calculating the postpacing interval variability (PPIV); PPIV was minimal in circuitous tachycardias and highly variable in centrifugal tachycardias. In the present study, we use the PPIV to determine the ventricular global activation pattern during VT.

Methods: Patients with mappable VT were included. We defined global ventricular activation as either centrifugal (arising from a focus with radial expansion) or circuitous (gross macro-reentrant circuit), based on the findings of electroanatomic mapping. PPIV was calculated as the difference in postpacing interval with right ventricular apical overdrive pacing during tachycardia at cycle lengths (CL) 10 ms and 30-ms shorter than tachycardia, regardless of the origin of the tachycardia. We studied 20 patients with 23 VTs (11 centrifugal, mean CL 390 +/- 36.1 ms; 12 circuitous, mean CL 418 +/- 75.7 ms).

Results: The mean PPIV was 45 +/- 16 ms for patients with centrifugal VT and 6.7 +/- 4.1 ms for patients with circuitous VT. Rank sum analysis of PPIV showed a significant difference between the two groups (P < 0.05).

Conclusions: Our data suggest that the global ventricular activation pattern during VT can be rapidly and accurately defined by assessing the PPIV. This technique allows for a rapid confirmation of the tachycardia activation and significantly facilitates mapping and ablation.
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http://dx.doi.org/10.1111/j.1540-8159.2009.02617.xDOI Listing
February 2010

Variability in post-pacing intervals predicts global atrial activation pattern during tachycardia.

J Cardiovasc Electrophysiol 2008 Feb 20;19(2):142-7. Epub 2007 Nov 20.

Texas Heart Institute, St. Luke's Episcopal Hospital, Houston, Texas, USA.

Introduction: Knowledge of the global atrial activation pattern is critical to ablation of an atrial arrhythmia. We hypothesized that the variability in post-pacing intervals (PPIs) with pacing at different cycle lengths (CLs) from the same pacing site, regardless of distance to the circuit, can be used to identify atrial activation patterns during tachycardia.

Methods And Results: Consecutive patients referred for ablation of organized atrial arrhythmias were included (n = 28, 31 total tachycardias). The variability in PPIs (PPIV) was calculated by comparing the difference in PPIs after overdrive pacing with 5-second trains 10, 20, and 30 ms shorter than the tachycardia cycle length (TCL). The global activation pattern was defined as circuitous (macroreentrant atrial circuit) or centrifugal (focal origin with centrifugal radiation) by electroanatomic mapping. Except for one case, all pacing was performed from the proximal coronary sinus bipole. Circuitous tachycardias (n = 17, all macro-reentrant) exhibited minimal variability with pacing at 10 ms and 30 ms shorter than TCL (6.0 +/- 2.5 ms), whereas centrifugal tachycardias (n = 14, 8 microreentrant) displayed a high degree of variability (56.5 +/- 20.6 ms). Rank sum analysis of PPIV suggests that the two groups are indeed distinct (P < 0.001). Using PPIV cutoffs of or=30 ms, circuitous and centrifugal activation patterns could be distinguished with a high degree of sensitivity (94% circuitous, 92.8% centrifugal) and 100% specificity.

Conclusions: Our data support the use of PPIV to rapidly and accurately predict the global activation pattern during atrial arrhythmia.
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http://dx.doi.org/10.1111/j.1540-8167.2007.01029.xDOI Listing
February 2008