Publications by authors named "Tanya Siddiqi"

65 Publications

Cost Effectiveness of Second-Line Axicabtagene ciloleucel in Relapsed Refractory Diffuse Large B-cell Lymphoma.

Blood 2022 Aug 1. Epub 2022 Aug 1.

Loma Linda University School of Medicine, Loma Linda, California, United States.

The ZUMA-7 study demonstrated that Axicabtagene ciloleucel (axi-cel) improved event-free survival (EFS) compared to standard of care (SOC) salvage chemoimmunotherapy followed by autologous stem cell transplant in primary refractory/early relapsed diffuse large B-cell lymphoma (DLBCL) leading to its recent FDA approval in this setting. We modeled a hypothetical cohort of US adults (mean age, 65 years) with primary refractory/early relapsed DLBCL by developing a Markov model (lifetime horizon) to model the cost-effectiveness of second-line axi-cel compared to SOC using a range of plausible long-term outcomes. EFS and OS were estimated from ZUMA-7. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay (WTP) threshold of $150,000/quality-adjusted life-year (QALY). Assuming a 5-year EFS of 35% with second-line axi-cel and 10% with SOC, axi-cel was cost-effective at a WTP of $150,000/QALY ($93,547/QALY). Axi-cel was no longer cost-effective if its 5-year EFS was ≤ 26.4% or if it cost more than $972,061 at a WTP of $150,000. Second-line axi-cel was the cost-effective strategy in 73% of the 10,000 Monte-Carlo iterations at a WTP of $150,000. If the absolute benefit in EFS is maintained over time, second-line axi-cel for aggressive RR-DLBCL is cost-effective when compared to SOC at WTPs of $150,000/QALY. However, its cost-effectiveness is highly dependent on long-term outcomes. Routine usage of second-line CAR-T would add significantly to healthcare expenditures in the USA (>$1 billion each year), even when used in a high-risk subpopulation. Further reductions in the cost of CAR-T are needed to be affordable in many regions of the world.
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http://dx.doi.org/10.1182/blood.2022016747DOI Listing
August 2022

Total marrow and lymphoid irradiation as conditioning in haploidentical transplant with posttransplant cyclophosphamide.

Blood Adv 2022 07;6(14):4098-4106

Department of Pediatrics, City of Hope National Medical Center, Duarte, CA.

Posttransplant cyclophosphamide (PTCy) platform has shown low rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after haploidentical hematopoietic cell transplantation (HaploHCT). However, because of the limited disease control, relapse rate remains a major cause of treatment failure in high-risk patients. Total marrow and lymphoid irradiation (TMLI) allows for delivery of high radiation to bone marrow and other targeted structures, without increasing off-target radiation exposure and toxicity to end organs. In this phase 1 trial, 31 patients with high-risk and/or active primary refractory leukemias or myelodysplastic syndrome underwent peripheral blood stem cell HaploHCT with TMLI, fludarabine, and cyclophosphamide as the conditioning regimen. Radiation dose was escalated in increments of 200 cGy (1200-2000 cGy). GVHD prophylaxis was PTCy with tacrolimus/mycophenolate mofetil. Grade 2 toxicities by the Bearman scale were mucositis (n = 1), hepatic (n = 3), gastrointestinal (n = 5), and cardiac (n = 2). One patient (1800 cGy) experienced grade 3 pulmonary toxicity (dose-limiting toxicity). At a follow-up duration of 23.9 months for the whole cohort; 2-year NRM was 13%. Cumulative incidence of day 100 grade 2 to 4 and 3 to 4 acute GVHD was 52% and 6%, respectively. Chronic GVHD at 2 years was 35%. For patients treated with 2000 cGy, with a median follow-up duration of 12.3 months, 1-year relapse/progression, progression-free survival, and overall survival rates were 17%, 74%, and 83%, respectively. In conclusion, HaploHCT-TMLI with PTCy was safe and feasible in our high-risk patient population with promising outcomes.
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http://dx.doi.org/10.1182/bloodadvances.2022007264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9327543PMC
July 2022

PD-1 Blockade After Avelumab in Relapsed/Refractory Classical Hodgkin Lymphoma.

Clin Lymphoma Myeloma Leuk 2022 Jun 6. Epub 2022 Jun 6.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA. Electronic address:

Background: Anti-PD-1 directed therapy is safe and effective in patients with relapsed/refractory (r/r) cHL and is currently being studied in the frontline setting. There are currently little data regarding the safety and efficacy of PD-1 blockade after prior PD-L1 blockade with agents such as avelumab.

Methods: This is a retrospective case series evaluating r/r cHL patients treated with avelumab who subsequently received at least 1 dose of PD-1 blockade. Primary objective is efficacy as measured by overall response rate. Secondary objectives include duration of response and time to progression on PD-1 blockade as well as safety as evaluated by incidence and severity of immune-related adverse events (irAE) with PD-1 blockade.

Results: There were 7 patients treated with PD-1 blockade after avelumab, of whom 4 were re-treated. The median follow-up was 46.8 months. At the time of PD-1 blockade initiation median age was 36.6 years, all patients had advanced stage, 1 patient had B symptoms, and 4 patients had extranodal disease. Patients received median 7 prior lines of therapy including avelumab. Median duration on anti-PD-1 treatment was 15.9 months. A response was observed in 86% of patients with median duration of response of 26.4 months and median time to progression of 22.2 months. Only 1 patient experienced an irAE (grade 2 pneumonitis).

Conclusion: Our study suggests that PD-1 blockade after PD-L1 blockade in r/r cHL appears safe and may be effective with durable responses observed in a subset of patients.
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http://dx.doi.org/10.1016/j.clml.2022.06.004DOI Listing
June 2022

The use of chimeric antigen T-cell therapy in chronic lymphocytic leukemia.

Authors:
Tanya Siddiqi

Clin Adv Hematol Oncol 2022 06;20(6):366-368

Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, California.

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June 2022

NCCN Guidelines® Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 3.2022.

J Natl Compr Canc Netw 2022 06;20(6):622-634

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

The treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has significantly evolved in recent years. Targeted therapy with Bruton's tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors has emerged as an effective chemotherapy-free option for patients with previously untreated or relapsed/refractory CLL/SLL. Undetectable minimal residual disease after the end of treatment is emerging as an important predictor of progression-free and overall survival for patients treated with fixed-duration BCL-2 inhibitor-based treatment. These NCCN Guidelines Insights discuss the updates to the NCCN Guidelines for CLL/SLL specific to the use of chemotherapy-free treatment options for patients with treatment-naïve and relapsed/refractory disease.
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http://dx.doi.org/10.6004/jnccn.2022.0031DOI Listing
June 2022

Cost Effectiveness of Polatuzumab Vedotin Combined with Chemoimmunotherapy in Untreated Diffuse Large B-cell Lymphoma.

Blood 2022 Jun 14. Epub 2022 Jun 14.

Loma Linda University School of Medicine, Loma Linda, California, United States.

In patients with treatment-naive diffuse large B-cell lymphoma (DLBCL), the POLARIX study demonstrated a 6.5% improvement in the 2-year progression-free survival (PFS) with no difference in overall survival (OS) or safety using pola-R-CHP compared to standard R-CHOP. We evaluated the cost-effectiveness of pola-R-CHP for DLBCL. We modeled a hypothetical cohort of US adults (mean age, 65 years) with treatment-naïve DLBCL by developing a Markov model (lifetime horizon) to model the cost-effectiveness of pola-R-CHP and R-CHOP using a range of plausible long-term outcomes. Progression rates and OS were estimated from POLARIX. Outcome measures were reported in incremental cost-effectiveness ratios (ICERs), with a willingness-to-pay (WTP) threshold of $150,000/quality-adjusted life-year (QALY). Assuming a 5-year PFS of 69.6% with pola-R-CHP and 62.7% with R-CHOP, pola-R-CHP was cost-effective at a WTP of 150,000 (ICER $84,308/QALY). Pola-R-CHP was no longer cost-effective if its 5-year PFS was 66.1% or lower. One-way sensitivity analysis demonstrated that pola-R-CHP is cost-effective up to a cost of $276,312 at a WTP of $150,000. Pola-R-CHP was the cost-effective strategy in 56.6% of the 10,000 Monte-Carlo iterations at a WTP of $150,000. If the absolute benefit in PFS is maintained over time, pola-R-CHP is cost-effective when compared to R-CHOP at a WTP of $150,000/QALY. However, its cost-effectiveness is highly dependent on its long-term outcomes and CAR-T cost. Routine usage of pola-R-CHP would add significantly to healthcare expenditures. Price reductions or identification of subgroups that have maximal benefit would improve cost-effectiveness.
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http://dx.doi.org/10.1182/blood.2022016624DOI Listing
June 2022

Real-World Evidence of Axicabtagene Ciloleucel for the Treatment of Large B Cell Lymphoma in the United States.

Transplant Cell Ther 2022 May 21. Epub 2022 May 21.

Medical College of Wisconsin/Center for International Blood and Marrow Transplant Research, Milwaukee, Wisconsin. Electronic address:

Axicabtagene ciloleucel (axi-cel) is a standard-of-care for patients with relapsed or refractory (r/r) large B cell lymphoma who have received 2 or more lines of prior therapy. Patients receiving axi-cel in the real world could have broader a demographic, disease, and treatment profile compared with that of the cohort in the pivotal ZUMA-1 trial. The present study was conducted to evaluate the outcomes of axi-cel therapy in the real-world setting. A total of 1297 patients receiving commercial axi-cel between 2017 and 2020 were selected from the Center for International Blood and Marrow Transplant Research's data registry, of whom 739 (57%) would have been ineligible for inclusion in the ZUMA-1 cohort. Efficacy and safety outcomes were described for the entire cohort and by ZUMA-1 eligibility. Their associations with age, Eastern Cooperative Oncology Group Performance Score, and comorbidities were evaluated using multivariable logistic and Cox regressions. At a median follow-up of 12.9 months, the overall response rate (ORR) was 73%, with a 56% complete response (CR) rate. Median overall survival (OS) and progression-free survival (PFS) were 21.8 months (95% confidence interval [CI], 17.4 to 28.8 months) and 8.6 months (95% CI, 6.5 to 12.1 months), respectively. Duration of response (DOR) was comparable in the ZUMA-1 ineligible patients and ZUMA-1 eligible patients (62% by 1 year [95% CI, 57% to 66%] versus 67% [95% CI, 62% to 72%]). Patients age ≥65 years had favorable ORR (odds ratio [OR], 1.39; 95% CI, 1.05 to 1.83) despite having a higher risk of cytokine release syndrome (CRS) (OR, 1.41; 95% CI, 1.02 to 1.94) and immune effector cell-associated neurotoxicity syndrome (ICANS) (OR, 1.77; 95% CI, 1.39-2.26). Eastern Cooperative Oncology Group Performance Score ≥2 was associated with inferior efficacy outcomes (OR for ORR, 0.32; 95% CI, 0.18-0.56; hazard ratio [HR] for OS, 3.27; 95% CI, 2.37 to 4.52) and higher incidence of ICANS (OR, 2.63; 95% CI, 1.40 to 4.93). The patients ineligible for ZUMA-1 still had a durable response with axi-cel. Elderly patients had favorable efficacy outcomes despite higher rates of CRS and ICANS. Patient selection for standard-of-care axi-cel should consider comorbidities and risk-to-benefit ratio rather than be based strictly on ZUMA-1 eligibility.
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http://dx.doi.org/10.1016/j.jtct.2022.05.026DOI Listing
May 2022

Characterization of low-grade arthralgia, myalgia, and musculoskeletal pain with ibrutinib therapy: pooled analysis of clinical trials in patients with chronic lymphocytic leukemia and mantle cell lymphoma.

Leuk Lymphoma 2022 07 28;63(7):1580-1588. Epub 2022 Feb 28.

UC Irvine, Chao Family Comprehensive Cancer Center, Irvine, CA, USA.

Joint and muscle pain, including arthralgia, myalgia, and musculoskeletal pain, are among the common adverse events (AEs) reported for ibrutinib, a once-daily Bruton's tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). This pooled analysis from nine clinical trials of ibrutinib in CLL and MCL ( = 1178) evaluated patterns of these AEs. Any grade arthralgia, myalgia, and musculoskeletal pain occurred in 18%, 10%, and 6% of patients, respectively. AEs were primarily low-grade (grade 1/2: 97‒99%) and occurred during the first year of treatment; most resolved (67%-80%) at first occurrence. Few (<5%) patients required ibrutinib dose modification; no patients discontinued ibrutinib due to these AEs. Among patients evaluated for concomitant medication use, all those receiving concomitant medications after the first AE occurrence experienced AE resolution. These data suggest that these AEs were not treatment-limiting during ibrutinib therapy.
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http://dx.doi.org/10.1080/10428194.2022.2038372DOI Listing
July 2022

Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort.

Blood 2022 06;139(22):3278-3289

Università Vita-Salute San Raffaele, Milan, Italy; and.

CAPTIVATE (NCT02910583) is an international phase 2 study in patients aged ≤70 years with previously untreated chronic lymphocytic leukemia (CLL). Results from the cohort investigating fixed-duration (FD) treatment with ibrutinib plus venetoclax are reported. Patients received 3 cycles of ibrutinib lead-in then 12 cycles of ibrutinib plus venetoclax (oral ibrutinib [420 mg/d]; oral venetoclax [5-week ramp-up to 400 mg/d]). The primary endpoint was complete response (CR) rate. Hypothesis testing was performed for patients without del(17p) with prespecified analyses in all treated patients. Secondary endpoints included undetectable minimal residual disease (uMRD) rates, progression-free survival (PFS), overall survival (OS), and safety. Of the 159 patients enrolled and treated, 136 were without del(17p). The median time on study was 27.9 months, and 92% of patients completed all planned treatment. The primary endpoint was met, with a CR rate of 56% (95% confidence interval [CI], 48-64) in patients without del(17p), significantly higher than the prespecified 37% minimum rate (P < .0001). In the all-treated population, CR rate was 55% (95% CI, 48-63); best uMRD rates were 77% (peripheral blood [PB]) and 60% (bone marrow [BM]); 24-month PFS and OS rates were 95% and 98%, respectively. At baseline, 21% of patients were in the high tumor burden category for tumor lysis syndrome (TLS) risk; after ibrutinib lead-in, only 1% remained in this category. The most common grade ≥3 adverse events (AEs) were neutropenia (33%) and hypertension (6%). First-line ibrutinib plus venetoclax represents the first all-oral, once-daily, chemotherapy-free FD regimen for patients with CLL. FD ibrutinib plus venetoclax achieved deep, durable responses and promising PFS, including in patients with high-risk features.
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http://dx.doi.org/10.1182/blood.2021014488DOI Listing
June 2022

Management of Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma in the Era of Targeted Therapies.

Curr Hematol Malig Rep 2022 02 13;17(1):39-45. Epub 2022 Jan 13.

Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, 1500 E Duarte Rd., Duarte, CA, 91010, USA.

Purpose Of Review: The treatment landscape for relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has changed substantially over the past decade and continues to evolve. Despite the emergence of targeted therapies that are well tolerated and prolong survival, the disease remains incurable and relapse is common particularly in individuals with high-risk features. Herein, we review the key literature about the current options for relapsed disease and explore the emerging role of cellular therapies.

Recent Findings: Clinical trials have established the role of Bruton tyrosine kinase inhibitors, selective BCL-2 inhibition, and anti-CD20 monoclonal antibodies as treatment options for CLL/SLL. The role of chimeric antigen receptor T cells has shown promise in individuals with CLL/SLL in early phase clinical trials. Novel therapeutic approaches with targeted therapies have redefined the management of CLL/SLL in both the front-line and relapsed/refractory settings. Optimal management in terms of sequencing or combining therapies, especially in individuals with high-risk features, remains a challenge. The emerging role of cellular therapies has the potential to build upon and further improve the current treatment paradigm.
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http://dx.doi.org/10.1007/s11899-021-00652-2DOI Listing
February 2022

Venetoclax in Previously Treated Waldenström Macroglobulinemia.

J Clin Oncol 2022 01 18;40(1):63-71. Epub 2021 Nov 18.

Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA.

Purpose: BCL2 is overexpressed and confers prosurvival signaling in malignant lymphoplasmacytic cells in Waldenström macroglobulinemia (WM). Venetoclax is a potent BCL2 antagonist and triggers in vitro apoptosis of WM cells. The activity of venetoclax in WM remains to be clarified.

Patients And Methods: We performed a multicenter, prospective phase II study of venetoclax in patients with previously treated WM (NCT02677324). Venetoclax was dose-escalated from 200 mg to a maximum dose of 800 mg daily for up to 2 years.

Results: Thirty-two patients were evaluable, including 16 previously exposed to Bruton tyrosine kinase inhibitors (BTKis). All patients were -mutated, and 17 carried mutations. The median time to minor and major responses was 1.9 and 5.1 months, respectively. Previous exposure to BTKis was associated with a longer time to response (4.5 1.4 months; < .001). The overall, major, and very good partial response rates were 84%, 81%, and 19%, respectively. The major response rate was lower in those with refractory versus relapsed disease (50% 95%; = .007). The median follow-up time was 33 months, and the median progression-free survival was 30 months. mutations did not affect treatment response or progression-free survival. The only recurring grade ≥ 3 treatment-related adverse event was neutropenia (n = 14; 45%), including one episode of febrile neutropenia. Laboratory tumor lysis without clinical sequelae occurred in one patient. No deaths have occurred.

Conclusion: Venetoclax is safe and highly active in patients with previously treated WM, including those who previously received BTKis. mutation status did not affect treatment response.
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http://dx.doi.org/10.1200/JCO.21.01194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683218PMC
January 2022

Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL.

Blood 2022 03;139(12):1794-1806

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

Bruton tyrosine kinase inhibitors (BTKi) and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). However, most patients eventually develop resistance to these therapies, underscoring the need for effective new therapies. We report results of the phase 1 dose-escalation portion of the multicenter, open-label, phase 1/2 TRANSCEND CLL 004 (NCT03331198) study of lisocabtagene maraleucel (liso-cel), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory CLL/SLL. Patients with standard- or high-risk features treated with ≥3 or ≥2 prior therapies, respectively, including a BTKi, received liso-cel at 1 of 2 dose levels (50 × 106 or 100 × 106 CAR+ T cells). Primary objectives included safety and determining recommended dose; antitumor activity by 2018 International Workshop on CLL guidelines was exploratory. Minimal residual disease (MRD) was assessed in blood and marrow. Twenty-three of 25 enrolled patients received liso-cel and were evaluable for safety. Patients had a median of 4 (range, 2-11) prior therapies (100% had ibrutinib; 65% had venetoclax) and 83% had high-risk features including mutated TP53 and del(17p). Seventy-four percent of patients had cytokine release syndrome (9% grade 3) and 39% had neurological events (22% grade 3/4). Of 22 efficacy-evaluable patients, 82% and 45% achieved overall and complete responses, respectively. Of 20 MRD-evaluable patients, 75% and 65% achieved undetectable MRD in blood and marrow, respectively. Safety and efficacy were similar between dose levels. The phase 2 portion of the study is ongoing at 100 × 106 CAR+ T cells. This trial was registered at clinicaltrials.gov as NCT03331198.
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http://dx.doi.org/10.1182/blood.2021011895DOI Listing
March 2022

Cancer-Associated Venous Thromboembolic Disease, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2021 10 15;19(10):1181-1201. Epub 2021 Oct 15.

National Comprehensive Cancer Network.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease focus on the prevention, diagnosis, and treatment of patients with cancer who have developed or who are at risk for developing venous thromboembolism (VTE). VTE is a significant concern among cancer patients, who are at heightened risks for developing as well as dying from the disease. The management of patients with cancer with VTE often requires multidisciplinary efforts at treating institutions. The NCCN panel comprises specialists from various fields: cardiology, hematology/hematologic oncology, internal medicine, interventional radiology, medical oncology, pharmacology/pharmacy, and surgery/surgical oncology. This article focuses on VTE prophylaxis for medical and surgical oncology inpatients and outpatients, and discusses risk factors for VTE development, risk assessment tools, as well as management methods, including pharmacological and mechanical prophylactics. Contraindications to therapeutic interventions and special dosing, when required, are also discussed.
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http://dx.doi.org/10.6004/jnccn.2021.0047DOI Listing
October 2021

Chronic Lymphocytic Leukemia (CLL): Biology and Therapy.

Authors:
Tanya Siddiqi

Cancer Treat Res 2021 ;181:133-149

City of Hope Medical Center, 1500 E Duarte Rd., Duarte, CA, 91010, USA.

Chronic lymphocytic leukemia (CLL), the most common leukemia in the western world, is characterized by the accumulation of monoclonal B-lymphocytes in the bone marrow and lymphoid organs. Signaling via the B-cell receptor and Bruton tyrosine kinase (BTK) as well as resistance to apoptosis mediated by Bcl-2 are hallmarks of CLL biology and have been exploited in recent years to revolutionize management. As a result of the development of novel therapies, most CLL patients now can be spared conventional chemotherapy and can be treated using highly effective regimens consisting of BTK inhibitors, the Bcl-2 inhibitor venetoclax, and anti -CD20 monoclonal antibodies. The impact of novel therapies is particularly pronounced for high-risk cases including those with TP53 deletions/mutations who previously had a dismal outcome with conventional chemoimmunotherapy. Allogeneic HCT is a potentially curative option for selected younger patients with multiply relapsed high-risk disease.
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http://dx.doi.org/10.1007/978-3-030-78311-2_8DOI Listing
November 2021

Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia: Primary Analysis Results From the Minimal Residual Disease Cohort of the Randomized Phase II CAPTIVATE Study.

J Clin Oncol 2021 12 7;39(34):3853-3865. Epub 2021 Oct 7.

Peter MacCallum Cancer Center and St Vincent's Hospital and the University of Melbourne, Melbourne, VIC, Australia.

Purpose: CAPTIVATE (NCT02910583), a randomized phase II study, evaluates minimal residual disease (MRD)-guided treatment discontinuation following completion of first-line ibrutinib plus venetoclax treatment in patients with chronic lymphocytic leukemia (CLL).

Methods: Previously untreated CLL patients age < 70 years received three cycles of ibrutinib and then 12 cycles of combined ibrutinib plus venetoclax. Patients in the MRD cohort who met the stringent random assignment criteria for confirmed undetectable MRD (Confirmed uMRD) were randomly assigned 1:1 to double-blind placebo or ibrutinib; patients without Confirmed uMRD (uMRD Not Confirmed) were randomly assigned 1:1 to open-label ibrutinib or ibrutinib plus venetoclax. Primary end point was 1-year disease-free survival (DFS) rate with placebo versus ibrutinib in the Confirmed uMRD population. Secondary end points included response rates, uMRD, and safety.

Results: One hundred sixty-four patients initiated three cycles of ibrutinib lead-in. After 12 cycles of ibrutinib plus venetoclax, best uMRD response rates were 75% (peripheral blood) and 68% (bone marrow). Patients with Confirmed uMRD were randomly assigned to receive placebo (n = 43) or ibrutinib (n = 43); patients with uMRD Not Confirmed were randomly assigned to ibrutinib (n = 31) or ibrutinib plus venetoclax (n = 32). Median follow-up was 31.3 months. One-year DFS rate was not significantly different between placebo (95%) and ibrutinib (100%; arm difference: 4.7% [95% CI, -1.6 to 10.9]; = .15) in the Confirmed uMRD population. After ibrutinib lead-in tumor debulking, 36 of 40 patients (90%) with high tumor lysis syndrome risk at baseline shifted to medium or low tumor lysis syndrome risk categories. Adverse events were most frequent during the first 6 months of ibrutinib plus venetoclax and generally decreased over time.

Conclusion: The 1-year DFS rate of 95% in placebo-randomly assigned patients with Confirmed uMRD suggests the potential for fixed-duration treatment with this all-oral, once-daily, chemotherapy-free regimen in first-line CLL.
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http://dx.doi.org/10.1200/JCO.21.00807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8713593PMC
December 2021

CD19-directed CAR T-cell therapy for treatment of primary CNS lymphoma.

Blood Adv 2021 10;5(20):4059-4063

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA.

CD19-directed chimeric antigen receptor (CD19CAR) T-cell therapy has been successful in treating several B-cell lineage malignancies, including B-cell non-Hodgkin lymphoma (NHL). This modality has not yet been extended to NHL manifesting in the central nervous system (CNS), primarily as a result of concerns for potential toxicity. CD19CAR T cells administered IV are detectable in cerebrospinal fluid (CSF), suggesting that chimeric antigen receptor (CAR) T cells can migrate from the periphery into the CNS, where they can potentially mediate antilymphoma activity. Here, we report the outcome of a subset of patients with primary CNS lymphoma (PCNSL; n = 5) who were treated with CD19CAR T cells in our ongoing phase 1 clinical trial. All patients developed grade ≥ 1 cytokine release syndrome and neurotoxicity post-CAR T-cell infusion; toxicities were reversible and tolerable, and there were no treatment-related deaths. At initial disease response, 3 of 5 patients (60%; 90% confidence interval, 19-92%) seemed to achieve complete remission, as indicated by resolution of enhancing brain lesions; the remaining 2 patients had stable disease. Although the study cohort was small, we demonstrate that using CD19CAR T cells to treat PCNSL can be safe and feasible. This trial was registered at www.clinicaltrials.gov as #NCT02153580.
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http://dx.doi.org/10.1182/bloodadvances.2020004106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8945630PMC
October 2021

Comparison of 2-year outcomes with CAR T cells (ZUMA-1) vs salvage chemotherapy in refractory large B-cell lymphoma.

Blood Adv 2021 10;5(20):4149-4155

Hôpital Saint Louis, Paris, France.

The SCHOLAR-1 international retrospective study highlighted poor clinical outcomes and survival among patients with refractory large B-cell lymphoma (LBCL) treated with conventional chemotherapy. Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, demonstrated durable responses in patients with refractory LBCL in the pivotal phase 1/2 ZUMA-1 study (NCT02348216). Here, we compared SCHOLAR-1 with the 2-year outcomes of ZUMA-1. Prior to comparison of clinical outcomes, propensity scoring (based on a broad set of prognostic covariates) was used to create balance between ZUMA-1 and SCHOLAR-1 patients. In the pivotal phase 2 portion of ZUMA-1, 101 patients received axi-cel and were evaluable for response and survival. In SCHOLAR-1, 434 and 424 patients were evaluable for response and survival, respectively. ZUMA-1 patients were more heavily pretreated than were SCHOLAR-1 patients. The median follow-up was 27.1 months in ZUMA-1. The objective response rate (ORR) and complete response rate were 83% and 54% in ZUMA-1 vs 34% and 12% in SCHOLAR-1, respectively. The 2-year survival rate was 54% in ZUMA-1 and 20% in SCHOLAR-1, and a 73% reduction in the risk of death was observed in ZUMA-1 vs SCHOLAR-1. These results were consistent with those of an additional standardization analysis in which strata were limited to 2 prognostic factors (refractory categorization and presence/absence of stem cell transplant after refractoriness to chemotherapy) to conserve sample size. Despite the limitations of a nonrandomized analysis, these results indicate that axi-cel produces durable responses and a substantial survival benefit vs non-CAR T-cell salvage regimens for patients with refractory LBCL.
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http://dx.doi.org/10.1182/bloodadvances.2020003848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8945634PMC
October 2021

The Chronic Lymphocytic Leukemia Comorbidity Index (CLL-CI): A Three-Factor Comorbidity Model.

Clin Cancer Res 2021 09 24;27(17):4814-4824. Epub 2021 Jun 24.

Knight Cancer Institute, Portland, Oregon.

Purpose: Comorbid medical conditions define a subset of patients with chronic lymphocytic leukemia (CLL) with poor outcomes. However, which comorbidities are most predictive remains understudied.

Experimental Design: We conducted a retrospective analysis from 10 academic centers to ascertain the relative importance of comorbidities assessed by the cumulative illness rating scale (CIRS). The influence of specific comorbidities on event-free survival (EFS) was assessed in this derivation dataset using random survival forests to construct a CLL-specific comorbidity index (CLL-CI). Cox models were then fit to this dataset and to a single-center, independent validation dataset.

Results: The derivation and validation sets comprised 570 patients (59% receiving Bruton tyrosine kinase inhibitor, BTKi) and 167 patients (50% receiving BTKi), respectively. Of the 14 CIRS organ systems, three had a strong and stable influence on EFS: any vascular, moderate/severe endocrine, moderate/severe upper gastrointestinal comorbidity. These were combined to create the CLL-CI score, which was categorized into 3 risk groups. In the derivation dataset, the median EFS values were 58, 33, and 20 months in the low, intermediate, and high-risk groups, correspondingly. Two-year overall survival (OS) rates were 96%, 91%, and 82%. In the validation dataset, median EFS values were 81, 40, and 23 months (two-year OS rates 97%/92%/88%), correspondingly. Adjusting for prognostic factors, CLL-CI was significantly associated with EFS in patients treated with either chemo-immunotherapy or with BTKi in each of our 2 datasets.

Conclusions: The CLL-CI is a simplified, CLL-specific comorbidity index that can be easily applied in clinical practice and correlates with survival in CLL.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416936PMC
September 2021

Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer.

Mol Cell 2021 05 19;81(10):2094-2111.e9. Epub 2021 Apr 19.

Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. Electronic address:

Even though SYK and ZAP70 kinases share high sequence homology and serve analogous functions, their expression in B and T cells is strictly segregated throughout evolution. Here, we identified aberrant ZAP70 expression as a common feature in a broad range of B cell malignancies. We validated SYK as the kinase that sets the thresholds for negative selection of autoreactive and premalignant clones. When aberrantly expressed in B cells, ZAP70 competes with SYK at the BCR signalosome and redirects SYK from negative selection to tonic PI3K signaling, thereby promoting B cell survival. In genetic mouse models for B-ALL and B-CLL, conditional expression of Zap70 accelerated disease onset, while genetic deletion impaired malignant transformation. Inducible activation of Zap70 during B cell development compromised negative selection of autoreactive B cells, resulting in pervasive autoantibody production. Strict segregation of the two kinases is critical for normal B cell selection and represents a central safeguard against the development of autoimmune disease and B cell malignancies.
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http://dx.doi.org/10.1016/j.molcel.2021.03.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239336PMC
May 2021

Cytokine release syndrome and neurological event costs in lisocabtagene maraleucel-treated patients in the TRANSCEND NHL 001 trial.

Blood Adv 2021 03;5(6):1695-1705

Bristol-Myers Squibb, Princeton, NJ.

Chimeric antigen receptor (CAR) T-cell therapies have demonstrated high response rates in patients with relapsed/refractory large B-cell lymphoma (LBCL); however, these therapies are associated with 2 CAR T cell-specific potentially severe adverse events (AEs): cytokine release syndrome (CRS) and neurological events (NEs). This study estimated the management costs associated with CRS/NEs among patients with relapsed/refractory LBCL using data from the pivotal TRANSCEND NHL 001 trial of lisocabtagene maraleucel, an investigational CD19-directed defined composition CAR T-cell product with a 4-1BB costimulation domain administered at equal target doses of CD8+ and CD4+ CAR+ T cells. This retrospective analysis of patients from TRANSCEND with prospectively identified CRS and/or NE episodes examined relevant trial-observed health care resource utilization (HCRU) associated with toxicity management based on the severity of the event from the health care system perspective. Cost estimates for this analysis were taken from publicly available databases and published literature. Of 268 treated patients as of April 2019, 127 (47.4%) experienced all-grade CRS and/or NEs, which were predominantly grade ≤2 (77.2%). Median total AE management costs ranged from $1930 (grade 1 NE) to $177 343 (concurrent grade ≥3 CRS and NE). Key drivers of cost were facility expenses, including intensive care unit and other inpatient hospitalization lengths of stay. HCRU and costs were significantly greater among patients with grade ≥3 AEs (22.8%). Therefore, CAR T-cell therapies with a low incidence of severe CRS/NEs will likely reduce HCRU and costs associated with managing patients receiving CAR T-cell therapy. This clinical trial was registered at www.clinicaltrials.gov as #NCT02631044.
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http://dx.doi.org/10.1182/bloodadvances.2020003531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993105PMC
March 2021

A phase Ib, open label, dose escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia.

Invest New Drugs 2021 08 8;39(4):1099-1105. Epub 2021 Mar 8.

Dana-Farber Cancer Institute, Boston, MA, USA.

BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a transmembrane protein expressed on normal and malignant B cells. This open-label, phase Ib, dose-escalation study was conducted to determine the recommended phase II dose (RP2D) of BI 836826 + ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Eligible patients received 420 mg/day of ibrutinib with escalating doses of BI 836826. BI 836826 was administered in 4-week cycles. After Cycle 12, patients achieving complete response (CR), CR with incomplete marrow recovery, or minimal residual disease-negative partial response could continue to receive BI 836826 + ibrutinib every 4 weeks for ≤ 12 additional cycles. Patients received either 100 mg (n = 3) or 200 mg (n = 3) BI 836826 + ibrutinib. In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. In the 200 mg BI 836826 cohort, patients received 12, 16 and 20 cycles of BI 836826, respectively. All patients discontinued BI 836826 and continued ibrutinib outside the trial. No dose-limiting toxicities were reported in the maximum tolerated dose (MTD) evaluation period. As the trial was discontinued before the MTD was reached, the RP2D was not determined. Grade 3/4 adverse events (AEs) were predominantly hematological. Pseudomonal bacteremia was the only drug-related AE of special interest. BI 836826 + ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL. However, RP2D and MTD were not formally established, as the sponsor discontinued the trial.
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http://dx.doi.org/10.1007/s10637-020-01056-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279974PMC
August 2021

Zanubrutinib for the treatment of MYD88 wild-type Waldenström macroglobulinemia: a substudy of the phase 3 ASPEN trial.

Blood Adv 2020 12;4(23):6009-6018

BeiGene USA, Inc., San Mateo, CA.

Patients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/refractory; 5 treatment-naïve) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.
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http://dx.doi.org/10.1182/bloodadvances.2020003010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724905PMC
December 2020

The Cerebroventricular Environment Modifies CAR T Cells for Potent Activity against Both Central Nervous System and Systemic Lymphoma.

Cancer Immunol Res 2021 01 22;9(1):75-88. Epub 2020 Oct 22.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.

Lymphomas with central nervous system (CNS) involvement confer a worse prognosis than those without CNS involvement, and patients currently have limited treatment options. T cells genetically engineered with CD19-targeted chimeric antigen receptors (CAR) are effective against B-cell malignancies and show tremendous potential in the treatment of systemic lymphoma. We aimed to leverage this strategy toward a more effective therapy for patients with lymphoma with CNS disease. NOD- IL2Rgamma (NSG) mice with CNS and/or systemic lymphoma were treated with CD19-CAR T cells via intracerebroventricular (ICV) or intravenous (IV) injection. CAR T cells isolated after treatment were rigorously examined for phenotype, gene expression, and function. We observed that CAR T cells infused ICV, but not IV, completely and durably eradicated both CNS and systemic lymphoma. CAR T cells delivered ICV migrated efficiently to the periphery, homed to systemic tumors, and expanded , leading to complete elimination of disease and resistance to tumor rechallenge. Mechanistic studies indicated that ICV-delivered CAR T cells are conditioned by exposure to cerebrospinal fluid in the ICV environment for superior antilymphoma activity and memory function compared with IV-delivered CAR T cells. Further analysis suggested that manipulating cellular metabolism or preactivating therapeutic CAR T cells with antigen may improve the efficacy of CAR T cells Our demonstration that ICV-delivered CD19-CAR T cells had activity against CNS and systemic lymphoma could offer a valuable new strategy for treatment of B-cell malignancies with CNS involvement.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008993PMC
January 2021

Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study.

Lancet 2020 09 1;396(10254):839-852. Epub 2020 Sep 1.

City of Hope National Medical Center, Duarte, CA, USA.

Background: Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas.

Methods: We did a seamless design study at 14 cancer centres in the USA. We enrolled adult patients (aged ≥18 years) with relapsed or refractory large B-cell lymphomas. Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed from any indolent lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B. Patients were assigned to one of three target dose levels of liso-cel as they were sequentially tested in the trial (50 × 10 CAR T cells [one or two doses], 100 × 10 CAR T cells, and 150 × 10 CAR T cells), which were administered as a sequential infusion of two components (CD8 and CD4 CAR T cells) at equal target doses. Primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate (assessed per Lugano criteria); endpoints were assessed by an independent review committee in the efficacy-evaluable set (comprising all patients who had confirmed PET-positive disease and received at least one dose of liso-cel). This trial is registered with ClinicalTrials.gov, NCT02631044.

Findings: Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR T cells (liso-cel), of whom 269 patients received at least one dose of liso-cel. Patients had received a median of three (range 1-8) previous lines of systemic treatment, with 260 (97%) patients having had at least two lines. 112 (42%) patients were aged 65 years or older, 181 (67%) had chemotherapy-refractory disease, and seven (3%) had secondary CNS involvement. Median follow-up for overall survival for all 344 patients who had leukapheresis was 18·8 months (95% CI 15·0-19·3). Overall safety and activity of liso-cel did not differ by dose level. The recommended target dose was 100 × 10 CAR T cells (50 × 10 CD8 and 50 × 10 CD4 CAR T cells). Of 256 patients included in the efficacy-evaluable set, an objective response was achieved by 186 (73%, 95% CI 66·8-78·0) patients and a complete response by 136 (53%, 46·8-59·4). The most common grade 3 or worse adverse events were neutropenia in 161 (60%) patients, anaemia in 101 (37%), and thrombocytopenia in 72 (27%). Cytokine release syndrome and neurological events occurred in 113 (42%) and 80 (30%) patients, respectively; grade 3 or worse cytokine release syndrome and neurological events occurred in six (2%) and 27 (10%) patients, respectively. Nine (6%) patients had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 × 10 CAR T cells.

Interpretation: Use of liso-cel resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory large B-cell lymphomas, including those with diverse histological subtypes and high-risk features. Liso-cel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies.

Funding: Juno Therapeutics, a Bristol-Myers Squibb Company.
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http://dx.doi.org/10.1016/S0140-6736(20)31366-0DOI Listing
September 2020

A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study.

Blood 2020 10;136(18):2038-2050

BeiGene USA, Inc, San Mateo, CA; and.

Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ≥1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P = .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached; 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ≥3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.
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http://dx.doi.org/10.1182/blood.2020006844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596850PMC
October 2020

Model of a Queuing Approach for Patient Accrual in Phase 1 Oncology Studies.

JAMA Netw Open 2020 05 1;3(5):e204787. Epub 2020 May 1.

Department of Medical Oncology, City of Hope, Duarte, California.

Importance: Phase 1 cancer studies, which guide dose selection for subsequent studies, are almost 3 times more prevalent than phase 3 studies and have a median study duration considerably longer than 2 years, which constitutes a major component of drug development time.

Objective: To discern a method to reduce the duration of phase 1 studies in adult and pediatric cancer studies without violating risk limits by better accommodating the accrual and evaluation process (or queue).

Design: The process modeled, the phase 1 queue (IQ), includes patient interarrival time, screening, and dose-limiting toxicity evaluation. For this proof of principle, the rules of the 3 + 3 and rolling 6 phase 1 designs were modified to improve patient flow through the queue without exceeding the maximum risk permitted in the parent designs. The resulting designs, the IQ 3 + 3 and the IQ rolling 6, were each compared with their parent design by simulations in 12 different scenarios.

Main Outcomes And Measures: (1) The time from study opening to determination of the maximum tolerated dose (MTD), (2) the number of patients treated to determine the MTD, and (3) the association of the design with the dose selected as the MTD.

Results: Based on 800 simulations, for all 12 scenarios considered, the IQ 3 + 3 and the IQ rolling 6 designs were associated with reduced expected study durations compared with the parent design. The expected IQ 3 + 3 reduction ranged from 1.6 to 10.4 months (with 3.7 months for the standard scenario), and the expected reduction associated with IQ rolling 6 ranged from 0.4 to 10.5 months (with 3.4 months for the standard scenario). The increase in the mean number of patients treated in the IQ 3 + 3 compared with the 3 + 3 ranged from 0.6 to 3.2 patients. No increase in the number of patients was associated with the IQ rolling 6 compared with the rolling 6 design. The probability of selecting a dose level as the MTD changed by less than 3% for all dose levels and scenarios in both parent designs.

Conclusions And Relevance: This study found that IQ designs were associated with reduced mean duration of phase 1 studies compared with their parent designs without changing the risk limits or MTD selection operating characteristics. These approaches have been successfully implemented in both hematology and solid tumor phase 1 studies.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.4787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221509PMC
May 2020

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 4.2020, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2020 02;18(2):185-217

National Comprehensive Cancer Network.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are characterized by a progressive accumulation of leukemic cells in the peripheral blood, bone marrow, and lymphoid tissues. Treatment of CLL/SLL has evolved significantly in recent years because of the improved understanding of the disease biology and the development of novel targeted therapies. In patients with indications for initiating treatment, the selection of treatment should be based on the disease stage, patient's age and overall fitness (performance status and comorbid conditions), and cytogenetic abnormalities. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.
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http://dx.doi.org/10.6004/jnccn.2020.0006DOI Listing
February 2020

Phase 1 study of the Aurora kinase A inhibitor alisertib (MLN8237) combined with the histone deacetylase inhibitor vorinostat in lymphoid malignancies.

Leuk Lymphoma 2020 02 16;61(2):309-317. Epub 2019 Oct 16.

Department of Medical Oncology, Division of Molecular Pharmacology, City of Hope, Duarte, CA, USA.

Alisertib, an Aurora kinase A inhibitor, was evaluated in a Phase 1 study in combination with the histone deacetylase inhibitor vorinostat, in patients with relapsed/refractory lymphoid malignancies ( = 34; NCT01567709). Patients received alisertib plus vorinostat in 21-day treatment cycles with escalating doses of alisertib following a continuous or an intermittent schedule. All dose-limiting toxicities (DLTs) were hematologic and there were no study-related deaths. The recommended phase 2 dose (RP2D) of the combination was 20 mg bid of alisertib and 200 mg bid of vorinostat on the intermittent schedule. A 13-patient expansion cohort was treated for a total of 18 patients at the RP2D. There were no DLTs at the RP2D, and toxicities were mainly hematologic. Two patients with DLBCL achieved a durable complete response, and two patients with HL achieved partial response. Alisertib plus vorinostat showed encouraging clinical activity with a manageable safety profile in heavily pretreated patients with advanced disease.
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http://dx.doi.org/10.1080/10428194.2019.1672052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982547PMC
February 2020
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