Publications by authors named "Loretta Nastoupil"

146 Publications

Radiation and CAR T-cell Therapy in Lymphoma: Future Frontiers and Potential Opportunities for Synergy.

Front Oncol 2021 25;11:648655. Epub 2021 Mar 25.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

CAR T-cell therapy has revolutionized the treatment approach to patients with relapsed/refractory hematologic malignancies; however, there continues to be opportunity for improvement in treatment toxicity as well as response durability. Radiation therapy can play an important role in combined modality treatments for some patients undergoing CAR T-cell therapy in various clinical settings. In this review, we discuss the current evidence for RT in the setting of CAR T-cell therapy for patients with hematologic malignancies and propose potential opportunities for future investigation of RT and CAR T-cell treatment synergy. Future research frontiers include investigation of hypotheses including radiation priming of CAR T-cell mediated death, pre-CAR T-cell tumor debulking with radiation therapy, and selection of high risk patients for early radiation salvage after CAR T cell therapy.
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http://dx.doi.org/10.3389/fonc.2021.648655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027336PMC
March 2021

When to Use Targeted Therapy for the Treatment of Follicular Lymphoma.

Curr Hematol Malig Rep 2021 Apr 2. Epub 2021 Apr 2.

Department of Lymphoma/Myeloma, UT MD Anderson Cancer Center, Houston, TX, USA.

Purpose Of Review: Follicular lymphoma is a common indolent non-Hodgkin lymphoma with survival improving in the modern era. Despite favorable responses and improving remission duration, FL remains largely incurable with patterns of relapsing and remitting disease with many patients requiring multiple lines of therapy. As our understanding of the malignant B-cell biology evolves, more targeted therapies have emerged for the treatment of follicular lymphoma.

Recent Findings: Targeted therapies entering the treatment landscape of follicular lymphoma include lenalidomide in combination with rituximab based on the randomized AUGMENT. Tazemetostat, an EZH2 inhibitor, joins the list of targeted therapies approved based on single-arm phase 2 studies in the relapsed setting. There are three PI3K inhibitors currently approved and more under development. Herein, I will review the available evidence that supports the use of targeted therapy across the disease course of follicular lymphoma.
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http://dx.doi.org/10.1007/s11899-021-00617-5DOI Listing
April 2021

Subtype-specific and co-occurring genetic alterations in B-cell non-Hodgkin lymphoma.

Haematologica 2021 Apr 1. Epub 2021 Apr 1.

Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, TX.

B-cell non-Hodgkin's lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL such as diffuse large B-cell lymphoma (DLBCL) have been comprehensively interrogated at the genomic level. But rarer subtypes such as mantle cell lymphoma (MCL) remain sparsely characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth; including DLBCL, MCL, follicular lymphoma (FL), and Burkitt lymphoma (BL). We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumor from each subtype, including the frequent genetic deregulation of the ubiquitin proteasome system (UPS). In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.
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http://dx.doi.org/10.3324/haematol.2020.274258DOI Listing
April 2021

Copanlisib for the Treatment of Malignant Lymphoma: Clinical Experience and Future Perspectives.

Target Oncol 2021 Mar 9. Epub 2021 Mar 9.

Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Dysregulation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin signaling is common in both indolent and aggressive forms of malignant lymphoma, for which several targeted therapies have been developed. Copanlisib is a highly selective and potent intravenous pan-class I PI3K inhibitor that has demonstrated durable objective responses and a manageable safety profile in heavily pre-treated patients with indolent lymphomas. As a result, copanlisib monotherapy received accelerated approval from the US Food and Drug Administration for the treatment of adults with relapsed follicular lymphoma who have received at least two systemic therapies, and breakthrough designation for patients with pre-treated relapsed or refractory marginal zone lymphoma. Hyperglycemia and hypertension are among the most frequently reported adverse events with copanlisib monotherapy, and are infusion-related, transient, and manageable with standard therapies. Mild diarrhea is also a common adverse event with copanlisib monotherapy; there is no evidence of worsening severity of diarrhea, or serious gastrointestinal toxicities such as colitis or severe liver enzyme elevations, which have been reported with orally administered PI3K inhibitors. The intravenous route of administration and intermittent dosing schedule of copanlisib may support a favorable tolerability profile over continually administered oral alternatives. Ongoing studies of copanlisib in combination with rituximab and standard-of-care chemotherapy in patients with relapsed indolent lymphoma have the potential to support the use of copanlisib in the second-line setting, providing a much-needed additional therapeutic option in this underserved patient population.
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http://dx.doi.org/10.1007/s11523-021-00802-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941125PMC
March 2021

Prognostic Impact of Corticosteroids on Efficacy of Chimeric Antigen Receptor T-cell Therapy in Large B-cell Lymphoma.

Blood 2021 Feb 3. Epub 2021 Feb 3.

The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.

Corticosteroids are commonly used for the management of severe toxicities associated with chimeric antigen receptor (CAR) T-cell therapy. However, it remains unclear whether their dose, duration, and timing may impact clinical efficacy. Here, we determined the impact of corticosteroids on clinical outcomes in patients with relapsed or refractory large B-cell lymphoma treated with standard of care anti-CD19 CAR T-cell therapy. Among 100 patients evaluated, 60 (60%) received corticosteroids for management of CAR T-cell therapy-associated toxicities. The median cumulative dexamethasone-equivalent dose was 186 mg (range, 8-1803 mg) and the median duration of corticosteroid treatment was 9 days (range 1-30). Corticosteroid treatment was started between days 0 and 7 in 45 (75%) patients and beyond day 7 in 15 (25%). After a median follow-up of 10 months (95% CI 8-12 months), use of higher cumulative dose of corticosteroids was associated with significantly shorter progression-free survival. More importantly, higher cumulative dose of corticosteroids, and prolonged and early use after CAR T-cell infusion were associated with significantly shorter overall survival. These results suggest that corticosteroids should be used at the lowest dose and for the shortest duration and their initiation should be delayed whenever clinically feasible, while managing CAR T-cell therapy-associated toxicities.
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http://dx.doi.org/10.1182/blood.2020008865DOI Listing
February 2021

The impact of cell-of-origin, MYC/Bcl-2 dual expression and rearrangement on disease relapse among early stage diffuse large B-cell lymphoma patients treated with combined modality therapy.

Leuk Lymphoma 2021 Jan 22:1-12. Epub 2021 Jan 22.

Departments of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

We addressed the prognostic impact of cell-of-origin (COO), MYC and Bcl-2 overexpression as well as isolated rearrangement among 111 patients with limited stage diffuse large B-cell lymphoma (DLBCL) treated with consolidative radiation therapy (RT) after a metabolic complete response to immunochemotherapy. With a median follow-up of 31.1 months (95% CI 27.4 - 34.8), 4 relapses occurred. The 3-year progression free survival (PFS), overall survival (OS), and loco-regional relapse free survival (LRFS) for the cohort were 95%, 96%, and 100%, respectively. There were no differences in OS, PFS, or LRFS based on COO or MYC/Bcl-2 dual expression (DE). Similarly, patients with translocations without or rearrangements did not have worse outcomes. Consolidative RT produced excellent local control, regardless of DLBCL biology, with one late in-field failure.
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http://dx.doi.org/10.1080/10428194.2020.1869965DOI Listing
January 2021

Disseminated ALK-positive histiocytosis with fusion in an adult.

Leuk Lymphoma 2020 Dec 22:1-7. Epub 2020 Dec 22.

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

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http://dx.doi.org/10.1080/10428194.2020.1861273DOI Listing
December 2020

A Prospective Trial of Radiation Therapy Efficacy and Toxicity for Localized Mucosa-associated Lymphoid Tissue (MALT) Lymphoma.

Int J Radiat Oncol Biol Phys 2021 Apr 10;109(5):1414-1420. Epub 2020 Dec 10.

The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: We report the long-term results of a prospective trial conducted to determine the efficacy and safety of radiation therapy (RT) alone in treating localized mucosa-associated lymphoid tissue (MALT) lymphoma.

Methods And Materials: Patients with localized MALT lymphoma were eligible and treated with involved field RT to doses of 24 to 39.6 Gy. Relapse-free survival (RFS) was the primary endpoint. Kaplan-Meier analysis was used to estimate RFS, progression-free survival (PFS), and overall survival (OS) defined from time of study entry. Preplanned subgroup analyses were performed based on site of involvement.

Results: From 2000 to 2012, 75 patients were accrued; 73 received protocol-specified RT. Median follow-up was 9.8 years. Thirty-four patients had gastric MALT, 17 orbital, 13 head and neck nonorbit, 4 skin, and 5 disease of other sites. Thirteen of 34 patients with gastric MALT were Helicobacter pylori positive at the time of initial diagnosis and underwent 1 to 3 courses of triple antibiotic therapy. All gastric MALT patients had documented persistent MALT without H. pylori on endoscopy before enrollment in the study. All patients achieved a complete response with a median time of 3 months. Eleven patients (15%) had disease relapse, 9 of which were at sites outside the RT field with median time to progression of 38.3 months. Median PFS was 17.5 years, and median RFS and OS were not reached. The 10-year relapse-free rate was 83% (95% confidence interval [CI], 74%-93%). The 10-year PFS rate was 71% (95% CI, 60%-84%). The 10-year OS rate was 86% (95% CI, 77%-96%). RFS, PFS, and OS did not differ by disease site (P = .17, .43, and .50, respectively). All relapses were successfully salvaged. One patient developed metastatic gastric adenocarcinoma and was found to also have recurrent MALT on biopsy. Otherwise, all relapsed patients were alive without evidence of disease at last follow-up, and no patient died of MALT lymphoma. Sixty-seven patients (92%) experienced acute toxicity during radiation, all of which were grade 1 and 2, with only 1 grade 3 toxicity. Twenty-two patients (30%) experienced late toxicity, with only 1 grade 3 toxicity.

Conclusions: This prospective study confirms that RT for MALT lymphoma provides excellent long-term RFS with acceptable rates of toxicity. Current efforts are focused on RT de-escalation in an effort to further avoid treatment-related morbidity. CLINICALTRIALS.GOV: NCT04465162.
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http://dx.doi.org/10.1016/j.ijrobp.2020.11.070DOI Listing
April 2021

Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas.

Nat Med 2020 12 5;26(12):1878-1887. Epub 2020 Oct 5.

Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Autologous chimeric antigen receptor (CAR) T cell therapies targeting CD19 have high efficacy in large B cell lymphomas (LBCLs), but long-term remissions are observed in less than half of patients, and treatment-associated adverse events, such as immune effector cell-associated neurotoxicity syndrome (ICANS), are a clinical challenge. We performed single-cell RNA sequencing with capture-based cell identification on autologous axicabtagene ciloleucel (axi-cel) anti-CD19 CAR T cell infusion products to identify transcriptomic features associated with efficacy and toxicity in 24 patients with LBCL. Patients who achieved a complete response by positron emission tomography/computed tomography at their 3-month follow-up had three-fold higher frequencies of CD8 T cells expressing memory signatures than patients with partial response or progressive disease. Molecular response measured by cell-free DNA sequencing at day 7 after infusion was significantly associated with clinical response (P = 0.008), and a signature of CD8 T cell exhaustion was associated (q = 2.8 × 10) with a poor molecular response. Furthermore, a rare cell population with monocyte-like transcriptional features was associated (P = 0.0002) with high-grade ICANS. Our results suggest that heterogeneity in the cellular and molecular features of CAR T cell infusion products contributes to variation in efficacy and toxicity after axi-cel therapy in LBCL, and that day 7 molecular response might serve as an early predictor of CAR T cell efficacy.
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http://dx.doi.org/10.1038/s41591-020-1061-7DOI Listing
December 2020

Assessment of Radiation Doses Delivered to Organs at Risk Among Patients With Early-Stage Favorable Hodgkin Lymphoma Treated With Contemporary Radiation Therapy.

JAMA Netw Open 2020 09 1;3(9):e2013935. Epub 2020 Sep 1.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston.

Importance: Response-adapted randomized trials have used positron emission tomography-computed tomography to attempt to identify patients with early-stage favorable Hodgkin lymphoma (ESFHL) who could be treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) without radiation therapy (RT). While maximal efficacy is demonstrated with combined modality therapy, RT is often omitted in fear of late adverse effects; however, the application of modern RT could limit these toxic effects.

Objective: To determine the radiation doses delivered to organs at risk with modern involved-site RT among patients with ESFHL treated with 20 Gy after 2 cycles of ABVD.

Design, Setting, And Participants: This case series included 42 adult patients with ESFHL (according to the German Hodgkin Study Group criteria) who were treated between 2010 and 2019, achieved complete response by positron emission tomography-computed tomography (1-3 on 5-point scale) following 2 cycles of ABVD, and then received consolidative RT. The study was conducted at a single comprehensive cancer center.

Exposures: 2 cycles of chemotherapy followed by 20-Gy involved-site RT.

Main Outcomes And Measures: The medical records of patients with ESFHL were examined. Organs at risk were contoured, and doses were calculated. Progression-free survival, defined from date of diagnosis to disease progression, relapse, or death, and overall survival were estimated using the Kaplan-Meier method.

Results: The cohort comprised 42 patients with ESFHL (median [range] age at diagnosis, 35 [18-74] years; 18 [43%] women; 24 [57%] with stage II disease). At a median follow-up of 44.6 (95% CI, 27.6-61.6) months, the 3-year progression-free survival and overall survival rates were 91.2% (95% CI, 74.9%-97.1%) and 97.0% (95% CI, 80.4%-99.6%), respectively. The mean heart dose was less than 5 Gy (mean, 0.8 Gy; SD, 1.5 Gy; range, 0-4.8 Gy) in all patients. The mean (SD) breast dose for both breasts was 0.1 (0.2) Gy (left breast range, 0-1.0 Gy; right breast range, 0-0.9 Gy).

Conclusions And Relevance: In this study, combined modality therapy with 2 cycles of ABVD and 20 Gy for ESFHL was highly effective and avoided excess doses to organs at risk, which may limit long-term toxic effects.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.13935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525355PMC
September 2020

Initial report of a phase II study with R-FND followed by ibritumomab tiuxetan radioimmunotherapy and rituximab maintenance in patients with untreated high-risk follicular lymphoma.

Leuk Lymphoma 2021 01 14;62(1):58-67. Epub 2020 Sep 14.

The University of Texas MD Anderson Cancer Center, Houston, Texas.

R-FND (rituximab, fludarabine, mitoxantrone, and dexamethasone) can induce molecular remissions in indolent lymphoma. The addition of yttrium ibritumomab tiuxetan (YIT) radioimmunotherapy following first-line induction treatment in patients with advanced follicular lymphoma (FL) may improve remission rates. We now report 10-year follow-up results from our sequential treatment approach with an abbreviated regimen of R-FND followed by YIT consolidation and rituximab maintenance. Forty-nine patients were enrolled; 47 received treatment. Patients had high-risk (FLIPI score ≥3) FL of grade 1-3A and stage III/IV with adequate hematologic function. Following R-FND, the complete and partial response rates were 91% and 8.5%, respectively. After YIT consolidation, the CR rate increased to 97%. The 10-year PFS rate was 49%. The most common non-hematologic, grade 3 or 4 adverse events were fatigue, dyspnea, and myalgia. Five developed myelodysplastic syndrome (MDS). This treatment approach is most appropriate in FLIPI-based high-risk patients whose outlook with standard therapy is inadequate.
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http://dx.doi.org/10.1080/10428194.2020.1821005DOI Listing
January 2021

Partial omission of bleomycin for early-stage Hodgkin lymphoma patients treated with combined modality therapy: Does incomplete ABVD lead to inferior outcomes?

EJHaem 2020 Jul 7;1(1):272-276. Epub 2020 Feb 7.

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

Classical Hodgkin lymphoma (HL) patients achieve excellent outcomes; therefore, treatment de-escalation strategies to spare toxicity have been prioritized. In a large randomized trial of early stage HL patients, omission of chemotherapeutic agents including bleomycin from the standard ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen was not found to be non-inferior; however the effect of partial omission is unknown. We investigated the effect of bleomycin omission on outcome for 150 early stage HL patients. At eight years, freedom from relapse was 99% for both patients who received complete or incomplete bleomycin, which is reassuring for patients requiring bleomycin omission due to toxicity.
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http://dx.doi.org/10.1002/jha2.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455016PMC
July 2020

Clinical and radiologic correlates of neurotoxicity after axicabtagene ciloleucel in large B-cell lymphoma.

Blood Adv 2020 08;4(16):3943-3951

Department of Neuro-Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Neurotoxicity or immune effector cell-associated neurotoxicity syndrome (ICANS) is the second most common acute toxicity after chimeric antigen receptor (CAR) T-cell therapy. However, there are limited data on the clinical and radiologic correlates of ICANS. We conducted a cohort analysis of 100 consecutive patients with relapsed or refractory large B-cell lymphoma (LBCL) treated with standard of care axicabtagene ciloleucel (axi-cel). ICANS was graded according to an objective grading system. Neuroimaging studies and electroencephalograms (EEGs) were reviewed by an expert neuroradiologist and neurologist. Of 100 patients included in the study, 68 (68%) developed ICANS of any grade and 41 (41%) had grade ≥3. Median time to ICANS onset was 5 days, and median duration was 6 days. ICANS grade ≥3 was associated with high peak ferritin (P = .03) and C-reactive protein (P = .001) levels and a low peak monocyte count (P = .001) within the 30 days after axi-cel infusion. Magnetic resonance imaging was performed in 38 patients with ICANS and revealed 4 imaging patterns with features of encephalitis (n = 7), stroke (n = 3), leptomeningeal disease (n = 2), and posterior reversible encephalopathy syndrome (n = 2). Abnormalities noted on EEG included diffuse slowing (n = 49), epileptiform discharges (n = 6), and nonconvulsive status epilepticus (n = 8). Although reversible, grade ≥3 ICANS was associated with significantly shorter progression-free (P = .02) and overall survival (progression being the most common cause of death; P = .001). Our results suggest that imaging and EEG abnormalities are common in patients with ICANS, and high-grade ICANS is associated with worse outcome after CAR T-cell therapy in LBCL patients.
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http://dx.doi.org/10.1182/bloodadvances.2020002228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448589PMC
August 2020

Hematopoietic recovery and immune reconstitution after axicabtagene ciloleucel in patients with large B-cell lymphoma.

Haematologica 2020 07 30. Epub 2020 Jul 30.

Dept. of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, USA;

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 may be associated with long-term adverse effects such as cytopenia and immune deficiency. To characterize these late events, we analyzed 31 patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel at our institution on 2 clinical trials, ZUMA-1 (NCT02348216) and ZUMA-9 (NCT03153462). Complete blood counts, lymphocyte subsets, and immunoglobulin levels were measured serially until month 24 or progression. Fifteen (48%) patients had grade 3-4 cytopenia, anemia (5 [16%]), neutropenia (9 [29%]), or thrombocytopenia (13 [42%]) at day 30. Cytopenia at day 30 was not significantly associated with later diagnosis of myelodysplasia. Among patients with ongoing remission, grade 3-4 cytopenias was observed in 1/9 (11%) at 2 years. While peripheral CD8+ T cells recovered early, CD4+ T cell recovery was delayed with a count of <200/μL in 3/9 (33%) patients at 1 year and 2/7 (29%) at 2 years. Immunoglobulin G levels normalized in 5/9 (56%) patients at 2 years. Thirteen (42%) patients developed grade 3-4 infectious complications, including herpes zoster and Pneumocystis jiroveci pneumonia. These results suggest the need for prolonged monitoring and prophylaxis against opportunistic infections in these patients to improve the long-term safety of axicabtagene ciloleucel therapy.
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http://dx.doi.org/10.3324/haematol.2020.254045DOI Listing
July 2020

Ibrutinib for central nervous system lymphoma: the Australasian Lymphoma Alliance/MD Anderson Cancer Center experience.

Br J Haematol 2021 Mar 16;192(6):1049-1053. Epub 2020 Jul 16.

Department of Haematology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.

Primary and secondary central nervous system lymphomas (PCNSL/SCNSL) are aggressive rare malignancies with dismal outcomes. Encouraging data have emerged from Phase I/II clinical trials treating relapsed/refractory PCNSL/SCNSL with ibrutinib. We analysed 33 patients who received ibrutinib, alone or with other therapies, for PCNSL (n = 9) or SCNSL (n = 24). The objective response rate was 58% (complete response 55%). The median progression-free survival and overall survival for patients with PCNSL were both 3·1 months; for SCNSL, 10·2 and 11·5 months respectively. Only one invasive fungal infection was observed, despite concurrent or recent use of dexamethasone 8-16 mg daily in 14 patients (42%). Ibrutinib has encouraging activity in these aggressive malignancies.
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http://dx.doi.org/10.1111/bjh.16946DOI Listing
March 2021

Bridging therapy prior to axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma.

Blood Adv 2020 07;4(13):2871-2883

Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX.

The impact of bridging therapy (BT) administered between leukapheresis and chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL) is unclear. We evaluated the influence of BT (systemic therapy [ST], radiation therapy [RT], or combined-modality therapy [CMT]) on outcomes of 148 LBCL patients who underwent leukapheresis for planned axicabtagene ciloleucel (axi-cel) infusion. The 55% (n = 81) of patients who received BT were more likely to have international prognostic index (IPI) score ≥3 (P ≤ .01), bulky disease (P = .01), and elevated lactate dehydrogenase (LDH; P ≤ .01). The 1-year progression-free (PFS) and overall survival (OS) rates were 40% and 65% in non-BT patients vs 21% and 48% in BT patients (P = .01 and .05, respectively). Twenty-four patients (16%) did not receive axi-cel, most commonly because of lymphoma progression (88%), despite 80% (n = 19) receiving BT. Among 124 patients who received axi-cel, 50% (n = 62) received BT with ST (n = 45), RT (n = 11), or CMT (n = 6); 1-year PFS and OS rates were not significantly different between BT and non-BT cohorts (P = .06 and .21, respectively). There was no difference in proportion of patients with IPI ≥3, limited-stage disease, or elevated LDH between ST, RT, and CMT groups. Compared with non-BT patients, 1-year PFS was inferior for ST-bridged patients (P = .01). RT-bridged patients had improved PFS compared with ST-bridged patients (P = .05). Despite the poor prognosis associated with requiring BT, RT can be an effective bridging strategy. Future studies are necessary to identify strategies that may improve access to CAR T-cell therapy and outcomes.
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http://dx.doi.org/10.1182/bloodadvances.2020001837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362355PMC
July 2020

Novel Agents Beyond Immunomodulatory Agents and Phosphoinositide-3-Kinase for Follicular Lymphoma.

Hematol Oncol Clin North Am 2020 08 5;34(4):743-756. Epub 2020 May 5.

Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0429, Houston, TX 77030, USA. Electronic address:

Follicular lymphoma is the most common indolent non-Hodgkin lymphoma. Although median overall survival rates exceed 12 years with rituximab, follicular lymphoma remains largely incurable. The growing understanding of the molecular drivers of lymphomagenesis and the tumor microenvironment have led to novel therapies. Prognostic markers have identified a subset of patients with chemoresistant and/or refractory disease-associated poor outcomes. We identify the patients with follicular lymphoma in need of novel therapies, describe the drivers of lymphomagenesis and importance of the tumor microenvironment, and summarize the novel agents under investigation in relapsed/refractory and upfront follicular lymphoma.
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http://dx.doi.org/10.1016/j.hoc.2020.03.002DOI Listing
August 2020

Standard-of-Care Axicabtagene Ciloleucel for Relapsed or Refractory Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium.

J Clin Oncol 2020 09 13;38(27):3119-3128. Epub 2020 May 13.

Moffitt Cancer Center, Tampa, FL.

Purpose: Axicabtagene ciloleucel (axi-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory large B-cell lymphoma (LBCL) on the basis of the single-arm phase II ZUMA-1 trial, which showed best overall and complete response rates in infused patients of 83% and 58%, respectively. We report clinical outcomes with axi-cel in the standard-of-care (SOC) setting for the approved indication.

Patients And Methods: Data were collected retrospectively from all patients with relapsed/refractory LBCL who underwent leukapheresis as of September 30, 2018, at 17 US institutions with the intent to receive SOC axi-cel. Toxicities were graded and managed according to each institution's guidelines. Responses were assessed as per Lugano 2014 classification.

Results: Of 298 patients who underwent leukapheresis, 275 (92%) received axi-cel therapy. Compared with the registrational ZUMA-1 trial, 129 patients (43%) in this SOC study would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis. Among the axi-cel-treated patients, grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 7% and 31%, respectively. Nonrelapse mortality was 4.4%. Best overall and complete response rates in infused patients were 82% (95% CI, 77% to 86%) and 64% (95% CI, 58% to 69%), respectively. At a median follow-up of 12.9 months from the time of CAR T-cell infusion, median progression-free survival was 8.3 months (95% CI, 6.0 to15.1 months), and median overall survival was not reached. Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 and elevated lactate dehydrogenase had shorter progression-free and overall survival on univariable and multivariable analysis.

Conclusion: The safety and efficacy of axi-cel in the SOC setting in patients with relapsed/refractory LBCL was comparable to the registrational ZUMA-1 trial.
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http://dx.doi.org/10.1200/JCO.19.02104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499611PMC
September 2020

Chimeric Antigen Receptor T Cell Therapy During the COVID-19 Pandemic.

Biol Blood Marrow Transplant 2020 07 14;26(7):1239-1246. Epub 2020 Apr 14.

Hematopoietic Cellular Therapy Program, Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL. Electronic address:

The SARS-CoV-2 coronavirus (COVID-19) pandemic has significantly impacted the delivery of cellular therapeutics, including chimeric antigen receptor (CAR) T cells. This impact has extended beyond patient care to include logistics, administration, and distribution of increasingly limited health care resources. Based on the collective experience of the CAR T-cell Consortium investigators, we review and address several questions and concerns regarding cellular therapy administration in the setting of COVID-19 and make general recommendations to address these issues. Specifically, we address (1) necessary resources for safe administration of cell therapies; (2) determinants of cell therapy utilization; (3) selection among patients with B cell non-Hodgkin lymphomas and B cell acute lymphoblastic leukemia; (4) supportive measures during cell therapy administration; (5) use and prioritization of tocilizumab; and (6) collaborative care with referring physicians. These recommendations were carefully formulated with the understanding that resource allocation is of the utmost importance, and that the decision to proceed with CAR T cell therapy will require extensive discussion of potential risks and benefits. Although these recommendations are fluid, at this time it is our opinion that the COVID-19 pandemic should not serve as reason to defer CAR T cell therapy for patients truly in need of a potentially curative therapy.
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http://dx.doi.org/10.1016/j.bbmt.2020.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194685PMC
July 2020

Imaging Surveillance of Limited-stage Classic Hodgkin Lymphoma Patients After PET-CT-documented First Remission.

Clin Lymphoma Myeloma Leuk 2020 08 20;20(8):533-541. Epub 2020 Feb 20.

Departments of Radiation Oncology, MD Anderson Cancer Center, Houston, TX. Electronic address:

Introduction: Early stage Hodgkin lymphoma (ESHL) is highly curable; however, 10% to 15% of patients experience relapse. We examined the utilization of follow-up imaging for patients with ESHL who achieved a metabolic complete response after upfront therapy.

Materials And Methods: The records of adult patients treated at a single institution between 2003 and 2014 were reviewed. Positron emission tomography-computed tomography (PET-CT) and CT scan frequency was quantified during the 2 years following treatment and subsequent visits beyond 2 years.

Results: The study cohort contained 179 patients. The median age was 31 years; bulky disease was present in 30%. ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or AVD (doxorubicin, vinblastine, and dacarbazine) was given in 97%; 75% received radiation therapy. At a median follow-up of 6.9 years, the 5-year progression-free and overall survival rates were 93.7% and 98.1%, respectively. Relapse occurred in 5% (n = 9) of patients at a median of 9.1 months (range, 4.6-27.2 months) from therapy. Two patients presented with symptoms prompting imaging in follow-up. Within 2 years after therapy, 376 PET-CT scans and 3325 CT scans were performed, yielding an average of 2.1 PET-CTs and 18.6 CTs per patient. Of the initial 179 patients, 113 had follow-up conducted beyond 2 years post-therapy; an average of 2.7 PET-CTs and 33.2 CTs were performed. In the 2-year post-therapy period, 463 scans were performed per relapse detected.

Conclusion: In this cohort of patients with ESHL who responded completely to frontline therapy, the relapse rate was low. Routine imaging surveillance lacks clinical benefit in this patient population.
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http://dx.doi.org/10.1016/j.clml.2020.02.008DOI Listing
August 2020

Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients.

Am J Hematol 2020 06 17;95(6):623-629. Epub 2020 Apr 17.

Department of Lymphoma and myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Venetoclax is effective in relapsed patients with mantle cell lymphoma (MCL). Mechanisms of resistance to venetoclax in MCL are poorly understood. We describe the clinical outcomes and genomic characteristics of 24 multiply relapsed patients (median of five prior lines of therapy) who received venetoclax-based therapies; 67% had progressed on BTK inhibitors (BTKi) and 54% had blastoid or pleomorphic histology. Median follow up after venetoclax treatment was 17 months. The overall response rate was 50% and complete response (CR) rate was 21%, 16 patients had progressed and 15 died. The median progression free, overall and post venetoclax survival were 8, 13.5 and 7.3 months respectively. Whole-exome sequencing (WES) was performed on samples collected from seven patients (including five pairs; before starting venetoclax and after progression on venetoclax). The SMARCA4 and BCL2 alterations were noted only after progression, while TP53, CDKN2A, KMT2D, CELSR3, CCND1, NOTCH2 and ATM were altered 2-4-fold more frequently after progression. In two patients with serial samples, we demonstrated clonal evolution of novel SMARCA4 and KMT2C/D mutations at progression. Mutation dynamics in venetoclax resistant MCL is demonstrated. Our data indicates that venetoclax resistance in MCL is predominantly associated with non-BCL2 gene mutations. Further studies are ongoing in MCL patients to evaluate the efficacy of venetoclax in combination with other agents and understand the biology of venetoclax resistance in MCL.
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http://dx.doi.org/10.1002/ajh.25796DOI Listing
June 2020

Cost-Effectiveness Analyses, Costs and Resource Use, and Health-Related Quality of Life in Patients with Follicular or Marginal Zone Lymphoma: Systematic Reviews.

Pharmacoecon Open 2020 Dec;4(4):575-591

Janssen R&D, Raritan, NJ, USA.

Background: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are types of indolent non-Hodgkin lymphoma (NHL) that develop in the B lymphocytes (also known as B cells).

Objective: The aim of this study was to conduct a comprehensive review of studies relating to cost effectiveness, costs and resource use, and health-related quality of life (HRQoL) in patients with FL or MZL.

Methods: Three separate systematic reviews were conducted to identify all published evidence on cost effectiveness, costs and resource use, and HRQoL between 2007 and March 2017 using the MEDLINE, MEDLINE in-process, E-pubs ahead of print (Ovid SP), Embase (Ovid SP), NHS EED, and EconLit databases. Select congress proceedings were also searched. Two systematic reviewers independently reviewed titles, abstracts, and full papers against eligibility criteria. Relevant data were extracted into bespoke data extraction templates (DETs) by a single systematic reviewer; these data were then validated for accuracy by a second reviewer against clean copies of the relevant publications.

Results: A total of 25 cost-effectiveness studies (24 in FL; 1 in FL and MZL) met the eligibility criteria. Markov models were the most utilised cost-effectiveness model. US FL studies reported an incremental cost-effectiveness ratio (ICER) of $28,565/QALY for first-line rituximab-cyclophosphamide, vincristine, and prednisone (R-CVP) versus CVP, and $43,000/QALY for second-line obinutuzumab plus bendamustine (G + B) followed by G maintenance versus B. In the UK, ICERs were £1529-10,834/quality-adjusted life-year (QALY) for first-line rituximab + chemotherapy versus chemotherapy, £27,988/QALY for second-line G + B + G-maintenance versus B, and £62,653/QALY for second-line idelalisib versus chemotherapy and/or rituximab. Five costs/resource use and four HRQoL studies were identified in FL, and none in MZL. US mean lifetime costs in first-line patients ranged from $108,000 (rituximab) to $130,300 (rituximab-cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisolone [CHOP]), and from £2185 (watch-and-wait) to £17,054 (chemotherapy) in the UK. In a multinational study, more rituximab-refractory patients receiving G + B + G-maintenance reported a meaningful improvement in total FACT-Lym scores compared with patients receiving B. In the UK, total FACT-Lym scores were meaningfully higher for newly diagnosed patients compared with patients with progression (136.04 vs. 109.7).

Conclusions And Relevance: We found a small body of evidence of quality of life, and potentially cost-effective treatment options for FL; however, no evidence was reported on MZL specifically. The significant data gaps in knowledge in these diseases demonstrate a marked need for further studies.
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http://dx.doi.org/10.1007/s41669-020-00204-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688753PMC
December 2020

Genomic profiles and clinical outcomes of de novo blastoid/pleomorphic MCL are distinct from those of transformed MCL.

Blood Adv 2020 03;4(6):1038-1050

Department of Lymphoma and Myeloma.

Blastoid and pleomorphic mantle cell lymphomas (MCLs) are variants of aggressive histology MCL (AH-MCL). AH-MCL can arise de novo (AH-DN) or transform from prior classic variant MCL (AH-t). This study is the first integrated analysis of clinical and genomic characteristics of AH-MCL. Patient characteristics were collected from diagnosis (AH-DN) and at transformation (AH-t). Survival after initial diagnosis (AH-DN) and after transformation (AH-t) was calculated. Regression tree analysis was performed to evaluate prognostic variables and in univariate and multivariate analyses for survival. Whole-exome sequencing was performed in evaluable biopsy specimens. We identified 183 patients with AH-MCL (108 were AH-DN, and 75 were AH-t; 152 were blastoid, and 31 were pleomorphic). Median survival was 33 months (48 and 14 months for AH-DN and AH-t, respectively; P = .001). Factors associated with inferior survival were age (≥72 years), AH-t category, Ki-67 ≥50% and poor performance status. AH-t had a significantly higher degree of aneuploidy compared with AH-DN. Transformed MCL patients exhibited KMT2B mutations. AH-MCL patients with Ki-67 ≥50% had exclusive mutations in CCND1, NOTCH1, TP53, SPEN, SMARCA4, RANBP2, KMT2C, NOTCH2, NOTCH3, and NSD2 compared with low Ki-67 (<50%). AH-t patients have poor outcomes and distinct genomic profile. This is the first study to report that AH-MCL patients with high Ki-67 (≥50%) exhibit a distinct mutation profile and very poor survival.
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http://dx.doi.org/10.1182/bloodadvances.2019001396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094021PMC
March 2020