Dr. Bita Fakhri is Assistant Professor of Medicine in the Division of Hematology at Stanford University School of Medicine. She specializes in the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), hairy cell leukemia, and other hematologic malignancies. As a clinical scientist, Dr. Fakhri is dedicated to caring for patients, teaching trainees, and researching novel therapies for patients with CLL/SLL. Dr. Fakhri has co-authored numerous publications on topics including CLL, novel targeted agents, and cellular therapies for patients with hematologic malignancies. Currently, Dr. Fakhri is the director of the CLL clinical trial portfolio at Stanford, and serves on the National Comprehensive Cancer Network CLL panel.
- clinical trials
- hairy cell leukemia
- indolent lymphomas
Assistant Professor - University Medical Line, Medicine - Hematology
Honors & Awards
Junior Faculty Career Development Award, University of California, San Francisco (2020)
Division of Hematology and Oncology Annual Teaching Award, University of California, San Francisco (2021)
Boards, Advisory Committees, Professional Organizations
Panel Member, CLL and Hairy Cell Leukemia Guidelines Committee, National Comprehensive Cancer Network (2022 - Present)
Panel Member, B Cell Lymphomas Guidelines Committee, National Comprehensive Cancer Network (2019 - 2022)
Board Certification, American Board of Internal Medicine, Medical Oncology (2018)
Board Certification, American Board of Internal Medicine, Hematology (2018)
Board Certification, American Board of Internal Medicine, Internal Medicine (2015)
Certificate, Washington University School of Medicine, Clinical Investigation (2018)
Fellowship, Washington University School of Medicine, Hematology and Medical Oncology (2018)
Residency, Boston University Medical Center, Internal Medicine (2015)
MPH, Yale School of Public Health, Epidemiology and Biostatistics (2011)
MD, Iran University of Medical Sciences, Medicine (2009)
Value of embedded palliative care: outpatient palliative care and healthcare utilization for hematologic malignancies.
View details for DOI 10.1182/bloodadvances.2022009039
View details for PubMedID 36809787
SOHO State of the Art Updates and Next Questions: New Targetable Pathways in Chronic Lymphocytic Leukemia.
Clinical lymphoma, myeloma & leukemia
Regulatory approvals of Bruton tyrosine kinase (BTK) inhibitors and BCL2 inhibitors have transformed the therapeutic paradigm in chronic lymphocytic leukemia (CLL). However, despite significant improvement, treatment discontinuations due to an acquired resistance mutation or intolerance to these agents are common. Those who are refractory and/or intolerant to both these classes of drugs - the "double exposed/refractory" patients - pose a real challenge in clinical practice and are in dire need of novel therapeutic approaches. In this manuscript, we review the ongoing efforts addressing this unmet clinical need including the ongoing development of non-covalent BTK inhibitors, BTK degraders, novel BH3-mimetics, therapeutic antibodies targeting novel antigens and immune cell enabling therapies.
View details for DOI 10.1016/j.clml.2023.01.009
View details for PubMedID 36754692
Copy Number Loss at Chromosome 14q11.2 Correlates With the Proportion of T Cells in Biopsies and Helps Identify T-Cell Neoplasms.
Archives of pathology & laboratory medicine
Evidence of T-cell clonality is often critical in supporting a T-cell lymphoma.To retrospectively explore the significance of copy number losses at the 14q11.2 T-cell receptor α locus in relation to the presence of a T-cell neoplasm and proportion of T cells by targeted next-generation sequencing.Targeted next-generation sequencing data from 139 tissue biopsies including T-cell lymphomas, B-cell lymphomas, classic Hodgkin lymphomas, nonhematopoietic malignancies, and normal samples were reviewed for copy number losses involving the T-cell receptor α gene segments at chr14q11.2.We found that biallelic or homozygous deletion of 14q11.2 was found in most (28 of 33, 84.8%) T-cell lymphomas. The magnitude of 14q11.2 loss showed a statistically significant correlation with the proportion of T cells in lymphoma tissue samples. Copy number losses could also be detected in other lymphomas with high number of T cells (8 of 32, 25% of B-cell lymphomas, 4 of 4 classical Hodgkin lymphomas), though biallelic/homozygous deletion of 14q11.2 was not significantly observed outside of T-cell lymphomas. Most nonhematopoietic neoplasms and normal tissues (59 of 64, 92.2%) showed no significant copy number losses involving the T-cell receptor α locus at chr14q11.2.Analysis of copy number losses at the T-cell receptor α locus chr14q11.2 with targeted next-generation sequencing can potentially be used to estimate the proportion of T cells and detect T-cell neoplasms.
View details for DOI 10.5858/arpa.2022-0193-OA
View details for PubMedID 36445717
Outcomes of Therapies and Resistance Mutations Following Non-Covalent Bruton's Tyrosine Kinase Inhibitor Treatment for Patients with Chronic Lymphocytic Leukemia and Richter Transformation
AMER SOC HEMATOLOGY. 2022: 9885-9888
View details for DOI 10.1182/blood-2022-159133
View details for Web of Science ID 000893230302383
MCL-133 Pirtobrutinib, a Highly Selective, Non-Covalent (Reversible) BTK Inhibitor in Previously Treated Mantle Cell Lymphoma: Updated Results From the Phase 1/2 BRUIN Study.
Clinical lymphoma, myeloma & leukemia
2022; 22 Suppl 2: S394-S395
Covalent BTK inhibitors (BTKi) have transformed the management of mantle cell lymphoma (MCL), but most patients will require additional treatment. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that inhibits both wild-type and C481-mutated BTK with equal low nM potency.To evaluate pirtobrutinib safety and efficacy in patients with MCL.BRUIN is an ongoing multicenter phase 1/2 study (NCT03740529) of pirtobrutinib monotherapy.Global; community hospitals, academic medical centers.Patients with advanced B-cell malignancies.Oral pirtobrutinib, phase 1 dose-escalated in a standard 3+3 design, phase 2 continuous therapy, 28-day cycles.The primary phase 1 objective was to determine the recommended phase 2 dose (RP2D) and the primary phase 2 objective was overall response rate (ORR); secondary objectives included duration of response, progression-free survival, overall survival, safety/tolerability, and pharmacokinetics.As of 27 September 2020, 323 patients (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT, and 6 other NHL) were treated on 7 dose levels (25-300mg QD). No DLTs were reported and MTD was not reached (n=323). 200mg QD was selected as the RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent treatment-emergent adverse events regardless of attribution or grade seen in >10% of patients. The most common adverse event of grade ≥3 was neutropenia (10%). Five (1%) patients discontinued due to treatment-related adverse events. 52 prior BTKi treated MCL patients were efficacy evaluable with an ORR of 52% (95% CI 38-66; 13 CR [25%], 14 PR [27%], 9 SD [17%]), 11 PD [21%] and 5 [10%] discontinued prior to first response assessment). Median follow-up was 6 months (0.7-18.3+). Responses were observed in 9/14 patients (64%) with prior autologous or allogeneic stem cell transplant, and 2/2 with prior CAR-T cell therapy.Pirtobrutinib demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL following multiple prior lines of therapy, including a covalent BTKi. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 60 new patients with MCL and an additional 10 months since the prior data-cut will be presented.
View details for DOI 10.1016/S2152-2650(22)01569-5
View details for PubMedID 36164120
CLL-120 Pirtobrutinib, A Highly Selective, Non-Covalent (Reversible) BTK Inhibitor in Previously Treated CLL/SLL: Updated Results from the Phase 1/2 BRUIN Study.
Clinical lymphoma, myeloma & leukemia
2022; 22 Suppl 2: S268-S269
Covalent BTK inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but many patients (pts) will require additional treatment. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that inhibits both wild type and C481-mutated BTK with equal low nM potency.To evaluate the safety and efficacy of pirtobrutinib in previously treated CLL/SLL.BRUIN is a phase 1/2 multicenter study (NCT03740529) of oral pirtobrutinib monotherapy.Global; community hospitals, academic medical centers.Pts with advanced B-cell malignancies.Oral pirtobrutinib, phase 1 dose escalated in a standard 3+3 design, phase 2 continuous monotherapy, 28-day cycles.The primary objective for phase 1 was to determine the recommended phase 2 dose (RP2D). The primary objective of phase 2 was ORR. Secondary objectives included duration of response, progression-free survival, overall survival, safety and tolerability, and pharmacokinetics.As of 27 September 2020, 323 previously treated pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, and 66 other) were treated on 7 dose levels (25-300mg QD). No dose limiting toxicities were reported and MTD was not reached (n=323). 200mg QD was selected as RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent TEAEs regardless of attribution or grade seen in >10% pts. Most common AE of grade ≥3 was neutropenia (10%). 139 CLL/SLL pts were efficacy-evaluable with a median follow up time of 6 months (0.16-17.8+). ORR was 63% (95%CI 55-71) with 69 PRs (50%), 19 PR-Ls (14%), 45 SDs (32%) and 1 PD (1%), and 5 (4%) discontinued prior to first response assessment. Among 121 BTKi pretreated pts, ORR was 62% (95%CI 53-71). Responses deepened over time with an ORR of 86% among pts with >10 months follow-up. ORR was similar in pts who discontinued prior BTKi due to progression (67%), or adverse events or other (52%). Of 88 responding pts, all except 5 remained on therapy.Pirtobrutinib demonstrated promising efficacy in heavily pretreated CLL/SLL pts. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data from 252 efficacy evaluable BTK pre-treated CLL/SLL patients with a data cutoff date of 16 July 2021 will be presented.
View details for DOI 10.1016/S2152-2650(22)01327-1
View details for PubMedID 36163872
Evaluation of pulmonary toxicities in lymphoma patients receiving brentuximab vedotin.
Leukemia & lymphoma
View details for DOI 10.1080/10428194.2022.2100369
View details for PubMedID 35875857
Embedded outpatient palliative care for hematologic malignancies: Referral patterns and health care utilization.
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680300535
Toci or not toci: innovations in the diagnosis, prevention, and early management of cytokine release syndrome.
Leukemia & lymphoma
2021; 62 (11): 2600-2611
Cytokine release syndrome (CRS) remains a significant toxicity of chimeric antigen receptor T-cell (CAR-T) therapy for hematologic malignancies. While established guidelines exist for the management of Grade 2+ CRS with immunosuppressive agents such as tocilizumab or corticosteroids, the management of early-grade CRS (i.e. Grade 1 CRS with isolated fevers) has no such consensus beyond supportive care. In this review, we discuss early-grade CRS with an emphasis on its diagnosis, management, and prevention. Strategies to target early-grade CRS include immunosuppression preemptively (once CRS develops) or prophylactically (before CRS develops) as well as novel small-molecule inhibitors or fractionated CAR-T dosing. In the near future, next-generation CAR-T therapies may be able to target CRS precisely or obviate CRS entirely. If shown to prevent CRS-associated morbidity while maintaining therapeutic anti-neoplastic efficacy, these innovative strategies will enhance the safety of CAR-T therapy while also improving its operationalization and accessibility in the real-world setting.
View details for DOI 10.1080/10428194.2021.1924370
View details for PubMedID 34151714
Current and emerging treatment options in primary mediastinal B-cell lymphoma.
Therapeutic advances in hematology
2021; 12: 20406207211048959
Previously considered a subtype of diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) is now recognized by the World Health Organization as an independent entity. PMBCL has clinicopathologic features that are separate from systemic DLBCL and harbors some biologic characteristics which overlap with nodular sclerosing classic Hodgkin's lymphoma (cHL). Similar to cHL, copy number alterations of 9p24.1 are frequently seen in PMBCL, which leads to increased expression of key genes in the region, including programmed death-ligand 1( PD-L1), PD-L2, and JAK2. In addition, PMBCL cells express CD30 in a mostly patchy fashion. In the upfront setting, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (i.e., DA-EPOCH-R) is the only regimen that has been shown in a prospective setting to result in outstanding outcomes without consolidative radiation to the mediastinum, with a 5-year event-free survival rate of 93% and overall survival rate of 97%. Thus, in recent years, DA-EPOCH-R has been recognized as the preferred frontline regimen. Despite the encouraging results in the frontline setting, the outcomes in the relapsed/refractory setting remain poor. The current approach of salvage chemotherapy followed by autologous stem cell transplantation, as used in patients with DLBCL, does not result in high rates of cure in patients with rrPMBCL. In recent years, the characteristic molecular features identified in PMBCL have provided more treatment opportunities for this patient population. In the relapsed setting, single-agent PD-1 inhibitor pembrolizumab have demonstrated high and durable remission rates. Despite the expression of CD30, the CD30 antibody drug-conjugate brentuximab vedotin (BV) as a single agent has been deemed inactive in this disease. On the contrary, the combinations of BV and PD-1 inhibitor have shown higher response rates than PD-1 inhibitor alone. Moreover, anti-CD19 chimeric antigen receptor T-cell (CAR T-cell) therapy has been positioned as another successful strategy for patients with rrPMBCL. Axicabtagene ciloleucel and lisocabtagene maraleucel are two products used in rrPMBCL.
View details for DOI 10.1177/20406207211048959
View details for PubMedID 34659697
View details for PubMedCentralID PMC8511915
Survival after autologous versus allogeneic transplantation in patients with relapsed and refractory Hodgkin lymphoma.
Leukemia & lymphoma
2021; 62 (10): 2408-2415
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 (N = 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 (N = 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 (p = 0.112) or OS (p = 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% (p = 0.107) in the auto-HCT cohort.
View details for DOI 10.1080/10428194.2021.1927016
View details for PubMedID 33988071
Incidence, management and outcomes of arterial and venous thrombosis after chimeric antigen receptor modified T cells for B cell lymphoma and multiple myeloma.
Leukemia & lymphoma
2021; 62 (4): 1003-1006
View details for DOI 10.1080/10428194.2020.1852474
View details for PubMedID 33258699
View details for PubMedCentralID PMC8012226
Ofatumumab, Etoposide, and Cytarabine Intensive Mobilization Regimen in Patients with High-risk Relapsed/Refractory Diffuse Large B-Cell Lymphoma Undergoing Autologous Stem Cell Transplantation.
Clinical lymphoma, myeloma & leukemia
2021; 21 (4): 246-256.e2
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.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.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).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.
View details for DOI 10.1016/j.clml.2020.11.005
View details for PubMedID 33288485
Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study.
Lancet (London, England)
2021; 397 (10277): 892-901
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.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, NCT03740529.323 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.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.Loxo Oncology.
View details for DOI 10.1016/S0140-6736(21)00224-5
View details for PubMedID 33676628
Carfilzomib in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma: A Phase I Trial.
Clinical lymphoma, myeloma & leukemia
2021; 21 (3): 139-146
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.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.Ten patients were treated on the dose-escalation phase. The study was terminated at a carfilzomib dose of 56 mg/m2, 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.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.
View details for DOI 10.1016/j.clml.2020.12.020
View details for PubMedID 33478921
A Case of EBV-Negative Aggressive NK-cell Leukemia: Use of Next-Generation Sequencing in Demystifying a Diagnostic Dilemma and Guiding Clinical Care.
Clinical lymphoma, myeloma & leukemia
View details for DOI 10.1016/j.clml.2021.02.010
View details for PubMedID 33814335
The role of acalabrutinib in adults with chronic lymphocytic leukemia.
Therapeutic advances in hematology
2021; 12: 2040620721990553
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 versus chlorambucil-obinutuzumab in older and frail patients with previously untreated CLL. The ASCEND trial explored acalabrutinib versus 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.
View details for DOI 10.1177/2040620721990553
View details for PubMedID 33613932
View details for PubMedCentralID PMC7871059
NCCN Guidelines Insights: B-Cell Lymphomas, Version 5.2021.
Journal of the National Comprehensive Cancer Network : JNCCN
2021; 19 (11): 1218-1230
In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody-drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1-mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.
View details for DOI 10.6004/jnccn.2021.0054
View details for PubMedID 34781267
Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK Inhibition as an Effective Strategy.
Clinical cancer research : an official journal of the American Association for Cancer Research
2020; 26 (14): 3589-3596
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.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].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 (n = 130), and 81% were idelalisib naïve (n = 263). ORR to BTKi was 84% (n = 44) in BTKi-naïve patients versus 54% (n = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.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.See related commentary by Rogers, p. 3501.
View details for DOI 10.1158/1078-0432.CCR-19-3815
View details for PubMedID 32198151
View details for PubMedCentralID PMC8588795
Immune-related Adverse Events Associated With Checkpoint Inhibition in the Setting of CAR T Cell Therapy: A Case Series.
Clinical lymphoma, myeloma & leukemia
2020; 20 (3): e118-e123
View details for DOI 10.1016/j.clml.2019.12.014
View details for PubMedID 31948859
Measuring cardiopulmonary complications of carfilzomib treatment and associated risk factors using the SEER-Medicare database.
2020; 126 (4): 808-813
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.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.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).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.
View details for DOI 10.1002/cncr.32601
View details for PubMedID 31721140
View details for PubMedCentralID PMC6992490
Outcomes in patients with aggressive B-cell non-Hodgkin lymphoma after intensive frontline treatment failure.
2020; 126 (2): 293-303
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.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.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.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.
View details for DOI 10.1002/cncr.32526
View details for PubMedID 31568564
Complexities in the diagnosis of large B-cell lymphomas, classic Hodgkin lymphomas and overlapping peripheral T-cell lymphomas simplified: An evidence-based guide.
Annals of diagnostic pathology
2020; 46: 151534
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.
View details for DOI 10.1016/j.anndiagpath.2020.151534
View details for PubMedID 32473554
CLL14 Trial: Fixed-Duration Chemotherapy-Free Regimen for Frail Patients with Treatment-Naïve CLL.
Oncology (Williston Park, N.Y.)
2019; 33 (11)
View details for PubMedID 31769861
Fifty Shades of GATA2 Mutation: A Case of Plasmablastic Lymphoma, Nontuberculous Mycobacterial Infection, and Myelodysplastic Syndrome.
Clinical lymphoma, myeloma & leukemia
2019; 19 (9): e532-e535
View details for DOI 10.1016/j.clml.2019.05.015
View details for PubMedID 31279773
Maintenance rituximab or observation after frontline treatment with bendamustine-rituximab for follicular lymphoma.
British journal of haematology
2019; 184 (4): 524-535
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.
View details for DOI 10.1111/bjh.15720
View details for PubMedID 30575016
View details for PubMedCentralID PMC6486816
Bones in Multiple Myeloma: Imaging and Therapy.
American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting
2018; 38: 638-646
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), 18F-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.
View details for DOI 10.1200/EDBK_205583
View details for PubMedID 30231385
Undertreatment of Older Patients With Newly Diagnosed Multiple Myeloma in the Era of Novel Therapies.
Clinical lymphoma, myeloma & leukemia
2018; 18 (3): 219-224
With the expanding armamentarium of therapeutic agents for multiple myeloma (MM), it is important to identify any undertreated patient populations to mitigate outcome disparities.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.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.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.
View details for DOI 10.1016/j.clml.2018.01.005
View details for PubMedID 29429818
View details for PubMedCentralID PMC5837946
Current and emerging treatment options for mantle cell lymphoma.
Therapeutic advances in hematology
2017; 8 (8): 223-234
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 versus 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.
View details for DOI 10.1177/2040620717719616
View details for PubMedID 28811872
View details for PubMedCentralID PMC5544150
Molecular landscape and sub-classification of gastrointestinal cancers: a review of literature.
Journal of gastrointestinal oncology
2017; 8 (3): 379-386
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.
View details for DOI 10.21037/jgo.2016.11.01
View details for PubMedID 28736626
View details for PubMedCentralID PMC5506283
Donor-Derived Smoldering Multiple Myeloma following a Hematopoietic Cell Transplantation for AML.
Case reports in hematology
2017; 2017: 3728429
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.
View details for DOI 10.1155/2017/3728429
View details for PubMedID 28316846
View details for PubMedCentralID PMC5337855
Halfway there: the past, present and future of haploidentical transplantation.
Bone marrow transplantation
2017; 52 (1): 1-6
In recent years, the use of haploidentical donors for hematopoietic cell transplantation has expanded rapidly. Approximately 50% of patients requiring hematopoietic cell transplant lack a traditional donor. The use of HLA haploidentical-related donors is attractive due to nearly universal availability of this graft source. We summarize the current and future need for haploidentical donors and detail the rise of post-transplant cyclophosphamide as the dominant haploidentical approach. Further, we examine ongoing controversies in the field of haploidentical transplant, including conditioning regimens and graft source. Finally, we review the evidence available from preliminary comparative studies and discuss future direction of research.
View details for DOI 10.1038/bmt.2016.190
View details for PubMedID 27454072
Clonal Evolution in Multiple Myeloma.
Clinical lymphoma, myeloma & leukemia
2016; 16 Suppl: S130-4
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.
View details for DOI 10.1016/j.clml.2016.02.025
View details for PubMedID 27521309