Category: Hem/Onc Updates

POLIVY® in Previously Untreated Diffuse Large B-Cell Lymphoma

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SUMMARY: The American Cancer Society estimates that in 2021, about 81,560 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,720 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphoma’s in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet.

DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using gene expression profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher five year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype. Approximately 30-40% of patients experience disease progression or relapse, during the first 2 years and attempts to improve on R-CHOP regimen have not been successful. Maintenance treatment strategy following R-CHOP, to better control the disease, delay disease progression and improve long term survival, have included Autologous Stem Cell Transplantation, maintenance treatment with agents such as oral protein kinase inhibitor Enzastaurin and Everolimus. Outcomes for transplant-ineligible patients with Relapsed/Refractory DLBCL patients remain poor.

CD79b is a B-cell specific surface protein, which is a component of the B-cell receptor and is ubiquitously expressed on the surface of malignant B cells. POLIVY® (Polatuzumab vedotin) is a CD79b-directed Antibody-Drug Conjugate (ADC) with activity against dividing B cells. It consists of three components: 1) the humanized ImmunoGlobulin G1 (IgG1) monoclonal antibody specific for human CD79b; 2) the small molecule anti-mitotic agent MMAE (monomethyl auristatin E) and 3) a protease-cleavable linker that covalently attaches MMAE to the Polatuzumab antibody. Upon binding to CD79b, POLIVY® is internalized, and the linker is cleaved by lysosomal proteases thus enabling intracellular delivery of MMAE. MMAE then binds to microtubules and kills dividing cells by inhibiting cell division and inducing apoptosis. POLIVY® demonstrated efficacy in patients with Relapsed or Refractory DLBCL, resulting in significantly longer Overall Survival when combined with Bendamustine and Rituximab, compared to Bendamustine and Rituximab alone. Based on these finding, the FDA granted accelerated approval to POLIVY® in June 2019.

In a Phase Ib-II study POLIVY® in combination with Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (pola-R-CHP) resulted in a 89% Overall Response rate and 77% Complete Responses when given as first line therapy, in patients with DLBCL. In this study, Vincristine was excluded from the regimen owing to the risk of overlapping neurotoxicities with POLIVY®. The present POLARIX trial was conducted to evaluate the efficacy and safety of pola-R-CHP as compared with R-CHOP, in patients with previously untreated DLBCL.

The POLARIX is a randomized, double-blind, placebo-controlled, International Phase III trial in which a total of 879 treatment naïve, CD20-positive, intermediate or high-risk DLBCL patients were randomly assigned in a 1:1 ratio to receive 6 cycles of either pola-R-CHP (N=440) or R-CHOP (N=439). Patients on Day 1 of each 21 day cycle, received POLIVY® 1.8 mg/kg IV and a placebo matching Vincristine IV (pola-R-CHP group) or a placebo matching POLIVY® and intravenous Vincristine at a dose of 1.4 mg/m2 (maximum of 2 mg) (R-CHOP group), along with Rituximab 375 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV and Doxorubicin 50 mg/m2 IV. All the patients also received Prednisone 100 mg orally once daily on Days 1-5 of each of the first six cycles. During cycles 7 and 8, patients in both treatment groups received Rituximab monotherapy at 375 mg/m2 IV. The median patient age was 65 years and stratification was based on IPI score and presence or absence of bulky disease, Subtypes of DLBCL were centrally evaluated and were balanced between the two treatment groups. Patients were eligible regardless of the Cell of Origin or the presence of rearrangements in MYC, BCL2, BCL6, or a combination of these. Patients with known CNS involvement were excluded but CNS prophylaxis with intrathecal chemotherapy was permitted, in accordance with institutional practice guidelines. The use of Granulocyte Colony-Stimulating Factor (G-CSF) was required during the first six cycles of treatment for primary prophylaxis against neutropenia and consolidative radiotherapy to initial sites of bulky disease or extranodal sites was allowed at the discretion of the investigator. The Primary end point was Progression Free Survival (PFS). Secondary end points included Overall Survival (OS) and Safety.

At a median follow up of 28.2 months, the PFS was significantly higher in the pola-R-CHP group compared to the R-CHOP group. The PFS at 2 years was 76.7% in the pola-R-CHP group versus 70.2% in the R-CHOP group (stratified HR=0.73; P=0.02). Treatment with pola-R-CHP resulted in a risk of disease progression, relapse, or death that was 27% lower, compared to R-CHOP. Patient subgroups that did not show a clear benefit with pola-R-CHP included patients 60 years of age or younger, patients with the Germinal Center B-cell-like subtype of DLBCL, patients who had bulky disease, and patients who had lower IPI scores. Overall Survival at 2 years did not differ significantly between the treatment groups and the researchers attributed the lack of a significant difference between the two groups in Overall Survival, to the availability of new, effective treatments for relapsed or refractory DLBCL, as well as short duration of follow up at the time of this reporting. The safety profile was similar in the two treatment groups.

The authors concluded that among patients with previously untreated intermediate-risk or high-risk DLBCL, the risk of disease progression, relapse, or death was lower among those who received pola-R-CHP than among those who received R-CHOP.

Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. Tilly H, Morschhauser F, Sehn LH, et al. December 14, 2021. DOI: 10.1056/NEJMoa2115304

Risk of Cardiovascular Diseases among Older Breast Cancer Survivors

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence.

Significant progress in breast cancer screening techniques, as well as new and novel therapies, have resulted in early cancer detection and improvement in the breast cancer 5-year survival rate in the US from 75% in the 1970s to 91% in the 2010s. Cardiovascular Disease (CVD) is the most frequent cause of noncancer-related death, and cardiotoxicities associated with cancer treatments may increase cardiovascular risk in this population of breast cancer survivors. However, few studies have in detail quantified the risks of the different clinically important cardiovascular outcomes. The authors therefore assessed the prevalence of the different clinically specific cardiovascular outcomes at breast cancer diagnosis, and their incidence after diagnosis, among survivors 65 years or older in the US, and compared this with similar women without cancer.

The researchers performed a matched cohort study using prospectively collected data from the SEER-Medicare linked claims-based database and identified all women older than 65 years of age with an incident Stage I-III breast cancer diagnosis in 2004 through 2013. Each patient with breast cancer was matched at diagnosis with 5 cancer-free female counterparts. Baseline prevalence of specific cardiovascular outcomes was measured, and the risk for individual cardiovascular outcomes during follow up was calculated, taking into consideration time since diagnosis, race/ethnicity, prior Cardiovascular Disease (CVD), and age. This study included a total of 91,473 women with breast cancer and 454,197 without breast cancer.

It was noted that women with breast cancer had lower baseline prevalence of all CVDs. Breast cancer survivors had substantially increased risks of Deep Vein Thrombosis and pericarditis, compared with cancer-free female counterparts. There was also evidence of smaller increased risks of sudden cardiac arrest, arrhythmia, heart failure, and valvular heart disease. The increased risks of arrhythmia, heart failure, pericarditis, and Deep Vein Thrombosis were most pronounced in the first year and persisted for more than 5 years after cancer diagnosis. There was evidence of a decreased risk of incident angina, myocardial infarction, revascularization, peripheral vascular disease, and stroke in breast cancer survivors, although this was not constant over time.

The CVD risk during follow up was consistently higher in African American women diagnosed with breast cancer compared with Caucasian women, regardless of whether there was an overall increased or decreased risk of outcomes during the entire follow up period, and this is consistent with racial differences in overall CVD risk in the US.

Finally, there was consistently a greater risk of all cardiovascular outcomes in those diagnosed with Stage III, Grade 3, and ER/PR-negative breast cancer, which may be a reflection of the more aggressive cancer treatment regimens used in these subtypes.

The authors concluded that there is evidence of increased risk of several cardiovascular diseases in elderly women diagnosed with breast cancer in the US, compared with similar women without cancer, with this risk persisting for several years after diagnosis. They added that these results highlight the importance of periodic cardiovascular evaluation throughout the long term follow up of women diagnosed with breast cancer.

Risk of Cardiovascular Diseases Among Older Breast Cancer Survivors in the United States: A Matched Cohort Study. Matthews AA, Hinton SP, Stanway S, et al. J Natl Compr Canc Netw 2021;19:275-284.

KRAS Variant Status and Outcomes with Immune Checkpoint Inhibitor-Based Therapy in Advanced Non Small Cell Lung Cancer

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SUMMARY: The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Patients with advanced NSCLC without a driver mutation and with Programmed cell Death Ligand 1 (PD-L1) expression of 50% or greater, are often treated first line with Immune Checkpoint Inhibition (ICI) monotherapy or ICI in combination with chemotherapy. The choice between these two treatment regimens is usually based on tumor burden and patient comorbidities, as there are presently no biomarkers available to predict the risk and benefit of these treatment interventions. The KEYNOTE-042 study demonstrated that single agent Pembrolizumab given as first line therapy demonstrated Overall Survival (OS) benefit over chemotherapy, in patients with previously untreated advanced NSCLC, with PD-L1 expression of 1% or greater. In an exploratory analysis, this benefit was seen regardless of KRAS status, but was more pronounced in patients with KRAS variants than those without KRAS variants.

The KRAS (kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. When mutated, KRAS oncogene has the potential to change normal cells cancerous. KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS-G12C mutation occurs in approximately 12-15% of NSCLC and in 3-5% of Colorectal cancers and other solid cancers. KRAS G12C is one of the most prevalent driver mutations in NSCLC and accounts for a greater number of patients than those with ALK, ROS1, RET, and TRK 1/2/3 mutations combined. KRAS G12C cancers are genomically more heterogeneous and occur more frequently in current or former smokers, and are likely to be more complex genomically than EGFR mutant or ALK rearranged cancers.

The authors conducted this study to evaluate the association of KRAS status with outcomes following ICI monotherapy versus chemoimmunotherapy in patients with PD-L1 of 50% or greater. The researchers used the Flatiron Health database, comprising 280 cancer clinics across the US and analyzed 1127 patients with advanced non-squamous NSCLC with PD-L1 expression of 50% or greater, known KRAS variant status, and no alteration in EGFR, ALK, or ROS1, who were treated with first line ICI monotherapy or chemoimmunotherapy between January 2016 and May 2020. Of the patients analyzed, 50.8% had KRAS variant status and 49.2% had KRAS wild type status. Patients with KRAS variant status were more likely to be female (58.7% versus 47.1%; P =0.002) and had smoking history (96.4% versus 87.7%; P < .001). Other patient demographics and patient characteristics, including age, race, ethnicity, Performance Status, and stage at diagnosis, were well balanced among the groups analyzed. Patient groups were stratified by treatment type and KRAS status (variant or wild type), and Overall Survival (OS) was compared between the treatment groups. Adjusted Hazard ratios for death associated with KRAS status and treatment regimen was estimated, using Cox proportional hazards models.

It was noted that among patients treated with ICI monotherapy, KRAS variant status was associated with superior median survival compared with KRAS wild type (21.1 months versus 13.6 months; HR=0.77; P=0.03), and this was statistically significant. However, among patients treated with chemoimmunotherapy, there was no significant median survival difference between patients with KRAS variant and KRAS wild type status (20.0 months versus 19.3 months; HR=0.99; P=0.93).

Among patients with KRAS variant status, the median OS did not differ between those treated with ICI monotherapy and chemoimmunotherapy (21.1 months versus 20.0 months; P =0.78), whereas among patients with KRAS wild type status, those treated with ICI monotherapy had numerically worse median survival than those treated with chemoimmunotherapy, although this difference was not statistically significant (13.6 months versus 19.3 months; HR=1.19; P =0.06).

In conclusion, this data suggests that chemoimmunotherapy might be favored over ICI monotherapy for patients with KRAS wild type tumors associated with high PD-L1 expression. The authors caution that in this analysis KRAS variant subtype and co-mutation status including TP53 and STK11 was unknown, and further investigation is needed to selection appropriate therapies for patients with PD-L1 High NSCLC.

Association Between KRAS Variant Status and Outcomes With First-line Immune Checkpoint Inhibitor–Based Therapy in Patients With Advanced Non–Small-Cell Lung Cancer. Sun L, Hsu M, Cohen RB, et al. JAMA Oncol. 2021;7:937-939.

Duration of Adjuvant Aromatase Inhibitor Therapy in Postmenopausal Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence.

Luminal breast cancer is the most prevalent molecular subtype in postmenopausal females, accounting for over 70%. Despite substantial improvements in adjuvant therapies, the risk of disease recurrence continues indefinitely, with more than half the recurrences occurring after the first 5 years following diagnosis. Following initial adjuvant endocrine therapy with Tamoxifen for 5 years, the addition of extended adjuvant therapy has resulted in 40% longer Disease Free Survival (DFS), when compared to placebo or no extended therapy. However the benefit of extending adjuvant Aromatase Inhibitor therapy for 5 years beyond the initial 5-year duration regimen is less well established. Further, the most effective duration of such extended adjuvant endocrine therapy remains unclear. Added to this dilemma are the side effects associated with Aromatase Inhibitor therapy including hot flushes, arthralgia, and bone pain, as well as treatment-induced osteoporosis, which can have a significant impact on patient’s quality of life. Researchers in the Secondary Adjuvant Long-Term Study with Arimidex [Anastrozole] (SALSA) prospectively investigated whether an additional 2 years or 5 years of Anastrozole therapy would result in better outcomes, following the initial 5 years of endocrine therapy, in postmenopausal women with Hormone Receptor-positive breast cancer.

The authors conducted a prospective, multicenter, randomized, Phase III trial, which included 3,470 eligible postmenopausal women with Stages I, II or III early stage breast cancer with no evidence of recurrence. Enrolled patients had invasive Hormone Receptor-positive breast cancer, and had received 5 years (plus or minus 12 months) of adjuvant endocrine therapy with Tamoxifen, Aromatase Inhibitors, or both sequentially, up until 12 months before randomization. Patients were randomly assigned 1:1 to receive Anastrozole 1 mg, orally daily, for either 2 additional years for a total of 7 years (N=1732) or 5 additional years for a total of 10 years (N=1738). The two treatment groups were well balanced. The median age at the time of randomization was 64 years, 72% of patients had tumors that were smaller than 2 cm, 66% had node-negative disease, and 19% had high-grade tumors. Stratification criteria included pathological tumor stage, pathological node stage, primary adjuvant endocrine therapy and adjuvant chemotherapy.

The primary analysis included all the patients who were still participating in the study (N=3208), including 1,603 in the 2-year group versus 1,605 in the 5-year group. In the primary analysis population of 3208 patients, 51% had received Tamoxifen alone for the initial 5 years, 7.3% had received an Aromatase Inhibitor alone, and 41.7% had received an Aromatase Inhibitor in combination with Tamoxifen. The Primary end point was Disease Free Survival (DFS). Secondary end points were Overall Survival (OS), contralateral breast cancer, second primary cancer, and clinical bone fracture. The median follow-up after randomization was 118 months.

The researchers observed no difference in DFS with 2 versus 5 additional years of adjuvant endocrine therapy with Anastrozole. The DFS 10 years since randomization was 73.6% in the 2-year group versus 73.9% in the 5-year group (HR=0.99; P=0.90). Contralateral breast cancer occurred in 2.2% versus 2.1% of patients (HR= 1.15), and local recurrence occurred in 3% versus 2.4% in the 2 year and 5 year groups, respectively. There was no difference noted for Overall Survival at 8 years between the two treatment groups (87.5% in the 2-year group and 87.3% in the 5-year group, HR for death from any cause=1.02). The risk of clinical bone fracture however was higher in the 5-year group than in the 2-year group (HR=1.35).

It was concluded from this study that in postmenopausal women with Hormone Receptor positive breast cancer who had received 5 years of adjuvant endocrine therapy, extending endocrine therapy with an Aromatase Inhibitor by an additional 5 years provided no benefit over a 2-year extension, but was associated with a greater risk of bone fracture.

Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer. Gnant M, Fitzal F, Rinnerthaler G, et al. N Engl J Med 2021; 385:395-405.

Updated Data on Fixed Duration VENCLEXTA® for Frontline Chronic Lymphocytic Leukemia

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SUMMARY: The American Cancer Society estimates that for 2021, about 21,250 new cases of CLL will be diagnosed in the US and 4320 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children.

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). VENCLEXTA® is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells.BCR-Signal-Pathways-and-MOA-of-New-Agents

CLL14 Trial is a prospective, multicenter, open-label, randomized Phase III study conducted in close collaboration with the German CLL Study Group (DCLLSG). This study was designed to evaluate the efficacy and safety of a fixed duration combination of VENCLEXTA® and GAZYVA® (Obinutuzumab) versus GAZYVA® and Chlorambucil in previously-untreated patients with CLL and coexisting medical conditions. In this trial, 432 treatment-naïve patients with CLL were randomized in a 1:1 ratio to receive fixed duration of 12 months of VENCLEXTA® in combination with six cycles of GAZYVA®, or 6 cycles of GAZYVA® in combination with Chlorambucil. Both treatment groups were well balanced and the median patient age was 72 years. The Primary endpoint was Progression Free Survival (PFS) assessed by an Independent Review Committee. Secondary endpoints included Minimal Residual Disease (MRD) status, Overall Response Rate, Complete Response, Complete Remission with Incomplete Hematologic Recovery (CRi), Overall Survival, duration of response, Time to Next CLL Treatment, and safety.

The median PFS was not reached in either treatment groups after a median follow-up of 28 months. The trial demonstrated a statistically significant improvement in PFS for patients who received VENCLEXTA® plus GAZYVA®, compared with those who received GAZYVA® plus Chlorambucil (HR 0.33; P<0.0001), suggesting a 67% reduction in the risk of progression or death with the VENCLEXTA® plus GAZYVA® combination. The Overall Response Rate was 85% in VENCLEXTA® plus GAZYVA® group compared to 71% in GAZYVA® plus Chlorambucil group (P=0.0007). Based on this data, the FDA in May 2019 approved VENCLEXTA® (Venetoclax) as frontline treatment for adult patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (SLL).

The authors in this presentation provided updated efficacy and safety data from the ongoing follow up of the CLL14 study, with all patients off study treatment for at least 3 years. After a median follow-up of 52.4 months, PFS continued to be superior for VENCLEXTA® plus GAZYVA® group, compared to GAZYVA® plus Chlorambucil (median Not Reached versus 36.4 months; HR=0.33 P<0.0001). At 4 years after randomization, the estimated PFS rate was 74.0% in the VENCLEXTA® plus GAZYVA® arm and 35.4% in the GAZYVA® plus Chlorambucil arm. This benefit was noted across all clinical and biological risk groups, including patients with TP53 mutation/deletion (4-year PFS 53.0% versus 20.8%) and unmutated IGHV status (4-year PFS 68.0% versus 19.8%). Time to Next Treatment was significantly longer in the VENCLEXTA® plus GAZYVA® group, compared to GAZYVA® plus Chlorambucil group (4-year TTNT 81.1% versus 59.9%; HR=0.46, P<0.0001). Further, majority of patients received and responded to BTK inhibitor monotherapy as a second-line treatment after progressive disease in both the treatment groups.

Assessment of MRD in peripheral blood 30 months after the end of treatment showed that 26.9% of patients in the VENCLEXTA® group still had undetectable MRD (less than 10-4), compared with 3.2% in the GAZYVA® plus Chlorambucil group. The median OS has not yet been reached in either treatment groups. No new safety signals were observed.

It was concluded that the fixed duration combination of VENCLEXTA® plus GAZYVA® continued to confer a PFS advantage over GAZYVA® plus Chlorambucil, for patients with previously untreated CLL, and remains an effective treatment for all patients with CLL and with coexisting conditions.

Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 4-year follow-up analysis of the randomized CLL14 study. Al-Sawaf O, Zhang C, Robrecht S, et al. Presented at: European Hematology Association 2021 Virtual Congress; June 9-17, 2021. Abstract S146.

Stereotactic Ablative Radiotherapy Non-Inferior to Surgery in Operable Stage I Non Small Cell Lung Cancer

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SUMMARY: The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer. Approximately 15% of patients present with early stage (T1-2 N0) disease, and these numbers are likely to increase with the implementation of Lung Cancer screening programs. Patients with early stage disease unless medically unfit, undergo surgical resection with a curative intent. Those who are not surgical candidates are often treated with conventional Radiation Therapy, over a period of 4 to 6 weeks.

Dating back to the 1930’s, the only hope for curing lung cancer has been surgery. However, important advances in the field of medical physics, computer science, and engineering have enabled significant progress in the field of Radiation Oncology, by better targeting the tumor and escalating the daily treatment doses. Surgery for Stage I NSCLC is now being challenged by these new Radiation Therapy techniques.

Stereotactic Ablative Radiotherapy (SABR) is a non-surgical procedure that allows delivery of significantly higher doses of precisely focused radiation to the tumor, compared to conventional Radiation Therapy, with less collateral damage to the surrounding normal tissue. The technologies used for SABR include GAMMA KNIFE® which uses highly focused gamma rays, Proton Beam therapy which uses ionized Hydrogen or Protons, Linear Accelerator (LINAC) and CYBER KNIFE® which use Photons, to target the tumor tissue. Because SABR is fractionated and delivered over 1-5 days, the short-and long-term side effects of radiation therapy are decreased and may allow higher total dosage to be given.

In a previously published pooled analysis of two independent, randomized, Phase III trials of SABR in patients with operable, clinical T1–2a (<4 cm), N0M0, Stage I NSCLC (STARS and ROSEL), Overall Survival (OS) was higher after Stereotactic Ablative Radiotherapy (SABR) than with surgery. This analysis had notable limitations and was closed early due to slow accrual. In the present study, the SABR group in the STARS trial was re-accrued with a larger sample size and the authors reported long-term results of the revised STARS trial, along with a protocol-specified propensity-matched comparison with a prospectively registered, contemporary institutional cohort of patients, who underwent Video-Assisted Thoracoscopic Surgical Lobectomy with Mediastinal Lymph Node Dissection (VATS L-MLND).

This single-arm prospective trial done at the University of Texas MD Anderson Cancer Center did not include patients from the previous pooled analysis and enrolled 80 patients (N=80) with newly diagnosed and histologically confirmed NSCLC with N0M0 disease (squamous cell, adenocarcinoma, large cell, or NSCLC not otherwise specified), and a tumor diameter of 3 cm or less. SABR dosing for peripheral lesions was 54 Gy in three fractions and 50 Gy in four fractions for central tumors, with simultaneous integrated boost to gross tumor totaling 60 Gy.

For the propensity-matching analysis, the researchers used a surgical cohort from the MD Anderson Department of Thoracic and Cardiovascular Surgery’s prospectively registered, institutional review board-approved database of all patients with clinical Stage I NSCLC who underwent VATS L-MLND during the period of enrolment in this trial. Propensity matching consisted of determining a propensity score using a several covariates such as age, tumor size, histology, Performance Status, and the interaction of age and sex. The Primary endpoint was the 3-year Overall Survival. Non-inferiority could be claimed if the 3-year Overall Survival rate after SABR was lower than that after VATS L-MLND by 12% or less and the upper bound of the 95% CI of the Hazard Ratio (HR) was less than 1.965.

At a median follow-up time was 5.1 years, the OS with SABR was 91% at 3 years and 87% at 5 years. The OS in the propensity-matched VATS L-MLND cohort was 91% at 3 years and 84% at 5 years. Non-inferiority was claimed since the 3-year OS after SABR was not lower than that observed in the VATS L-MLND group. There was no significant difference in OS between the two patient cohorts from a multivariable analysis (HR=0.86; P=0•65). SABR was well tolerated with no Grade 4-5 toxicities.

It was concluded from this study that long term survival after SABR is non-inferior to VATS L-MLND for operable Stage IA Non Small Cell Lung Cancer. SABR remains promising for this patient group and the authors strongly recommend a multidisciplinary management approach .

Stereotactic ablative radiotherapy for operable stage I non-small-cell lung cancer (revised STARS): long-term results of a single-arm, prospective trial with prespecified comparison to surgery. Chang JY, Mehran RJ, Feng L, et al. Lancet Oncol. 2021;22:1448-1457.

Chemoradiotherapy Followed by Consolidation Chemotherapy as Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer

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SUMMARY: The American Cancer Society estimates that 45,230 new cases of rectal cancer will be diagnosed in the US in 2021. Based on the information from the SEER database, the 5-year relative survival rates for rectal cancer, all SEER stages combined is 67%.

Management of invasive locally advanced rectal cancer (LARC), defined as Stage II (T3-4, N0) or Stage III (T1-4, N+) disease, mandates a multidisciplinary approach, and neoadjuvant chemoradiation therapy (CRT) followed by Total Mesorectal Excision (TME) and adjuvant chemotherapy is often recommended , whereas standard therapy for early-stage lesions involves surgery with or without adjuvant chemoradiation. The trimodality treatment approach was established as the standard of care for LARC based on the findings from the landmark German trial. Preoperative neoadjuvant CRT decreased the local recurrence rate (7.1% vs 10.1%; P=.048) and was associated with lower rates of treatment-related toxicity. Long course Radiation Therapy (RT) remains the preferred approach in the United States, with short course RT as an alternative in selected patients. With regards to chemotherapy, 4 months of adjuvant systemic chemotherapy following 2 months of Fluoropyrimidine-based chemotherapy with concurrent RT and surgery, is the recommended guideline by the National Comprehensive Cancer Network.

Even though the current standard of care for LARC have demonstrated a significant decrease in local recurrence rates from 25% to less than 10%, the high rates of distant relapse of approximately 30% indicate that there is a need for the further optimization of treatment sequencing. Patients with rectal cancer should undergo accurate staging with MRI, as this can better determine the proximity of the primary tumor to the mesorectal fascia, the presence of extramural vascular invasion, and involvement of the extramesorectal pelvic lymph nodes and anterior peritoneal reflection, compared to endoscopic rectal ultrasound (ERUS).

More recently, optimizing the delivery of trimodality treatment by intensifying neoadjuvant treatment has gained popularity. This strategy called Total Neoadjuvant Therapy (TNT) involves moving chemotherapy from the postoperative (adjuvant) to the preoperative setting. The potential benefits of TNT include earlier administration of full doses of systemic treatment with fewer adverse events and better compliance, assessment of the tumor response after neoadjuvant therapy, down staging tumors to increase the likelihood of pathological Complete Response (pCR) and complete resection, opportunities for the selective omission of Radiation Therapy (RT) and potential nonoperative management through a Watch and Wait strategy. Further, earlier administration of uninterrupted systemic chemotherapy can potentially eradicate occult micrometastases and help assess chemosensitivity.

For patients receiving TNT, the optimal sequence of induction chemotherapy followed by ChemoRadiotherapy (CRT) versus CRT followed by consolidation chemotherapy, before Total Mesorectal Excision surgery, has remained unclear. Only two randomized trials, the Organ Preservation in Rectal Adenocarcinoma (OPRA) in the US, and the German Randomized Phase II Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer (CAO/ARO/AIO-12), have investigated this approach.

The CAO/ARO/AIO-12 is a multicenter, randomized, Phase II trial, which included 306 eligible patients with rectal adenocarcinoma, up to 12 cm above the anal verge based on rigid rectoscopy. Enrolled patients had either clinical T3 tumor less than 6 cm from the anal verge, clinical T3 tumor in the middle third of the rectum (6 cm or more, up to 12 cm) with extramural tumor spread into the mesorectal fat of more than 5 mm (more than clinical T3b), clinical T4 tumors, or lymph node involvement, based on MRI. All enrolled patients had a CT of the chest and abdomen to exclude distant metastases.

Patients were randomly assigned to either Group A (N=156) for induction chemotherapy before CRT, or to Group B (N=150) for consolidation chemotherapy after CRT. Radiation therapy consisted of IMRT to the primary tumor and to mesorectal, presacral, and internal iliac lymph nodes, to a total dose of 50.4 Gy in 28 fractions. Concurrent chemotherapy with radiotherapy consisted of Fluorouracil 250 mg/m2 IV as a Continuous Infusion on days 1 thru 14 and days 22 thru 35, along with Oxaliplatin 50 mg/m2 IV, given as a 2-hour infusion on days 1, 8, 22, and 29 of radiotherapy. Induction and consolidation chemotherapy consisted of Oxaliplatin 100 mg/m2 IV, as a 2-hour infusion, followed by a Leucovorin 400 mg/m2 IV, given as a 2-hour infusion, followed by Fluorouracil 2400 mg/m2 IV, given as a continuous 46-hour infusion and repeated on day 15, for a total of 3 cycles. All patients underwent Total Mesorectal Excision (TME) independent of tumor response on approximately day 123 after initiation of TNT. Adjuvant chemotherapy after TME was not recommended. The Primary end point was pathological Complete Response (pCR) and Secondary end points included Disease Free Survival (DFS), cumulative incidence of locoregional recurrence and distant metastases, Overall Survival (OS), chronic toxicities, Quality of Life and stool incontinence.

The authors first reported the results of this study in 2019, and it was shown that up-front CRT followed by consolidation chemotherapy resulted in a higher pCR (25% versus 17%; combined pCR and clinical Complete Response 28% versus 21%).The rates of CRT-related Grade 3 or 4 toxicity were lower in the consolidation chemotherapy group (27% versus 37%) and compliance with CRT was better. However, compliance with chemotherapy was worse in the consolidation chemotherapy group than in the induction chemotherapy group.

The researchers in this publication presented long-term outcomes of this trial, including the secondary outcomes of DFS, chronic toxicity, Quality of Life (QoL), and stool incontinence. After a median follow-up of 43 months, the 3-year DFS was 73% in both groups (HR=0.95; P=0.82). The 3-year cumulative incidence of locoregional recurrence (6% versus 5%) and distant metastases (18% versus 16%) were not significantly different between the two treatment groups. At 3 years, chronic Grade 3-4 toxicities occurred in 11.8% of patients in group A and 9.9% of patients in group B. The Quality of Life score decreased after Total Mesorectal Excision but returned to pretreatment levels 1 year after randomization with no difference between the treatment groups. Stool incontinence deteriorated one year after randomization in both groups and only improved slightly at 3 years, but never reached baseline levels.

It was concluded from the secondary analysis of this randomized trial that CRT followed by chemotherapy before TME resulted in higher pathological Complete Response, without compromising DFS, toxicity, QoL, or stool incontinence. Based on these findings, the authors proposed that CRT followed by consolidation chemotherapy is the preferred Total Neoadjuvant Therapy sequence, if organ preservation is a priority.

Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer: Long-term Results of the CAO/ARO/AIO-12 Randomized Clinical Trial. Fokas E, Schlenska-Lange A, Polat B, et al. for the German Rectal Cancer Study Group. JAMA Oncol. Published online November 18, 2021. doi:10.1001/jamaoncol.2021.5445.

Sintilimab for Patients with Pretreated EGFR-Mutated Non Small Cell Lung Cancer

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SUMMARY: The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21. Patients with advanced EGFR-mutated NSCLC, following initial clinical response to first, second and third generation EGFR-TKIs therapies, will inevitably advance to a progressive disease course. These patients often receive platinum-based chemotherapy, with limited clinical benefit. Immune checkpoint inhibitors given alone have low efficacy in the treatment of patients with metastatic NSCLC with oncogenic-driven tumors. There is a highly unmet medical need for these patients with resistant disease.

Sintilimab is an immunoglobulin G4, anti-PD-1 monoclonal antibody, which binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

ORIENT-31 is a prospective, randomized, double-blind, multi-center Phase III study, which evaluated Sintilimab, with or without a Bevacizumab biosimilar injection (IBI305), in combination with chemotherapy (Pemetrexed and Cisplatin), in patients with EGFR-mutated locally advanced or metastatic non-squamous NSCLC, who have progressed following EGFR TKI treatment. Patients were randomized in a 1:1:1 ratio to receive Sintilimab 200 mg IV plus Bevacizumab biosimilar 15 mg/kg IV combined with Pemetrexed 500 mg/m2 IV and Cisplatin 75 mg/m2 IV (Arm A), Sintilimab combined with Pemetrexed and Cisplatin (Arm B), or chemotherapy alone with Pemetrexed and Cisplatin (Arm C), all agents administered every 3 weeks for 4 cycles followed by maintenance treatment with Sintilimab plus Bevacizumab and Pemetrexed in Arm A, Sintilimab and Pemetrexed in Arm B, and Pemetrexed alone in Arm C. Treatment was continued until radiographic disease progression or unacceptable toxicity. Eligible patients included patients with disease progression following first or second generation EGFR TKI and confirmed as T790M negative, or T790M positive but further progressed on third generation EGFR TKI, or patients with disease progression following third generation EGFR TKI as first line treatment. The median age was 57 years, 36% of patients had brain metastasis, 64% of patients had received First or Second generation TKIs without T790M mutation, 28% had received First or Second generation TKIs and then a Third generation TKI for T790M mutation, and 8% patients received first line Third generation TKI. The target accrual was 480 patients and by the data cutoff date of the first interim analysis, 444 patients were enrolled. The Primary endpoint was Progression Free Survival (PFS) as assessed by an Independent Radiographic Review Committee (IRRC). Secondary endpoints included Overall Survival (OS), PFS as assessed by investigators, Objective Response Rate (ORR) and Safety. The median follow up at first interim analysis was 9.8 months.

Sintilimab plus Bevacizumab biosimilar in combination with chemotherapy (Arm A), demonstrated a statistically significant and clinically meaningful improvement in PFS, compared with Arm C (chemotherapy alone group). The median PFS was 6.9 months in Arm A, and 4.3 months in Arm C (HR=0.46; P<0.0001). Additionally, the key Secondary endpoints of ORR and Duration of Response (DOR) were improved in Arm A compared with Arm C, and the results of PFS, ORR and DOR assessed by the investigator were consistent with the results assessed by IRRC. The prespecified PFS futility analysis that compares Arm A to Arm B (Sintilimab and chemotherapy group) did not cross futility stopping boundary. The PFS data of Arm B versus Arm C were immature.

The authors concluded that in this first prospective, double-blind, Phase III study among patients with EGFR mutated NSCLC who had progressed after EGFR TKIs, this quadruple regimen of Sintilimab plus Bevacizumab biosimilar in combination with chemotherapy, significantly improved Progression Free Survival, compared with chemotherapy alone.

VP9-2021: ORIENT-31: Phase III study of sintilimab with or without IBI305 plus chemotherapy in patients with EGFR mutated nonsquamous NSCLC who progressed after EGFR-TKI therapy. Lu S, Wu L, Jian H, et al. Published:November 19, 2021DOI:https://doi.org/10.1016/j.annonc.2021.10.007.

Anti-BCMA CAR T-Cell Therapy for Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,920 new cases will be diagnosed in 2021 and 12,410 patients are expected to die of the disease. Multiple Myeloma (MM) in 2021 remains an incurable disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The median survival for patients with myeloma is over 10 years. With the introduction of new combinations of antimyeloma agents in earlier lines of therapy, patients with Relapsed/Refractory myeloma often have disease that is refractory to multiple drugs. There is an urgent unmet medical need for agents with novel mechanisms of action that are safe and effective, for patients with aggressive and resistant disease.

Chimeric Antigen Receptor (CAR) T-cell therapy has been associated with long-term disease control in some hematologic malignancies and showed promising activity in a Phase 1 study involving patients with Relapsed or Refractory myeloma. B-cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and Multiple Myeloma.

Anti-BCMA CAR T-Cell Therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure. These T cells are then stimulated by treating with interleukin 2 (IL-2) and anti-CD3 antibodies in vitro, so that they will actively proliferate and expand to large numbers. These T cells are then genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR), by transducing with a gene encoding the engineered CAR, via a retroviral vector such as lentiviral vector. These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen such as BCMA on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen such as BCMA. The patient undergoes lymphodepletion chemotherapy with Fludarabine and Cytoxan prior to the introduction of the engineered CAR T-cells. By depleting the number of circulating leukocytes, cytokine production is upregulated and reduces competition for resources, which in turn promotes the expansion of the engineered CAR T-cells.
Anti-BCMA-CAR-T-Cell-Therapy-for-Multiple-Myeloma
ABECMA® (Idecabtagene vicleucel) is the first FDA approved cell-based gene therapy for multiple myeloma and was based on results from the pivotal, open-label, single-arm, multicenter, multinational, Phase II study (KarMMa trial), in which the efficacy and safety of ABECMA® was evaluated in adults with Relapsed and Refractory multiple myeloma. In this study, 128 patients with persistent disease after at least three previous regimens including a Proteasome Inhibitor, an immunomodulatory agent, and an anti-CD38 antibody, received ABECMA® target doses of 150×106 to 450×106 CAR-positive (CAR+) T cells, after receiving lymphodepleting chemotherapy. Lymphodepletion therapy consisted of Fludarabine 30 mg/m2 IV and Cyclophosphamide 300 mg/m2 IV given on 3 consecutive days, followed by 2 days of rest before ABECMA® infusion. The median patient age was 61 years and the median time from diagnosis was 6 years. About 51% of patients had a high tumor burden (50% or more bone marrow plasma cells), 39% had extramedullary disease and 35% had a high-risk cytogenetic abnormalities, defined as del(17p), t(4;14), or t(14;16). Patients had received a median of 6 previous antimyeloma regimens and 94% had received previous Autologous Hematopoietic Stem Cell Transplants. The Primary end point was an Overall Response Rate (ORR) as assessed by an Independent Review Committee (IRC) and key Secondary end point was a Complete Response or better (comprising complete and stringent Complete Responses). Other efficacy endpoints include Time to Response, Duration of Response, Progression Free Survival (PFS), Overall Survival (OS), Minimal Residual Disease (MRD) evaluated by Next-Generation Sequencing (NGS) assay, and Safety.

At a median follow up of 13.3 months, the ORR was 73%, and 33% had a complete or stringent Complete Response. Of those with a complete or stringent Complete Response, 79% had MRD-negative status at a sensitivity level of 10−5, corresponding to 26% of the treated population. This benefit was consistently observed in most subgroups examined, including older patients, those who received bridging therapy, and those with aggressive disease features, including high-risk cytogenetics, triple or penta-refractory disease, a high tumor burden, and extramedullary disease. The median time to first response was 1.0 month and the median time to a Complete Response or better was 2.8 months. The estimated median Duration of Response was 10.7 months for all patients and 11.3 months among those receiving the highest target dose. The response duration increased with the depth of response. The median PFS was 8.8 months for all patients and 20.2 months in patients having a complete or stringent Complete Response. Data on Overall Survival are immature. Cellular kinetic analysis confirmed CAR+ T cells in 59% at 6 months and 36% at 12 months after infusion. Common toxicities included neutropenia, anemia and thrombocytopenia. Cytokine Release Syndrome was reported in 84% of patients including 5% Grade 3 or higher events. Neurotoxic effects developed in 18% of patients.

It was concluded that ABECMA® induced deep and durable responses in majority of heavily pretreated patients with Refractory and Relapsed myeloma, and fulfills a highly unmet need for this patient group. It should however be noted that although some subsets of patients may have sustained responses for long periods of time, most patients eventually relapse. This has been attributed to the loss of CAR T-cells, loss of antigen expression on the tumor cell surface, or to impaired activity of T cells in an immunosuppressive microenvironment. Studies are underway to overcome these shortcomings by optimizing CAR design, as well as preventing antigen escape and developing combination therapies.

Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. Munshi NC, Anderson LD, Shah N, et al. N Engl J Med 2021; 384:705-716

Non Hodgkin Lymphoma Treated with B-Cell Depleting Immunotherapy May Result in Prolonged Hospital Stay and Higher Morbidity after Covid-19 Infection

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SUMMARY: The SARS-CoV-2 Coronavirus (COVID-19) induced pandemic first identified in December 2019 in Wuhan, China, has contributed to significant mortality and morbidity in the US, and the number of infections, continue to exponentially increase worldwide. Majority of the patients present with treatment-resistant pyrexia and respiratory insufficiency, with some of these patients progressing to a more severe systemic disease and multiple organ dysfunction.

Patients with lymphoproliferative disorders may be immune deficient due to their underlying disease or due to the therapies they receive, which in turn can increase the incidence and severity of infections. Patients with Non Hodgkin Lymphoma are often treated with CD20 targeted, B-cell depleting monoclonal antibodies such as RITUXAN® (Rituximab) or GAZYVA® (Obinutuzumab), as they were shown to improve survival among patients with B-cell Non-Hodgkin Lymphoma. Depleting B cells dampens the body’s ability to generate antibody responses to new pathogens, which may impact the clinical course of COVID-19. The authors in this study analyzed the clinical course of COVID-19 infection in hospitalized lymphoma patients, and characterized the determinants of worse outcomes.

It has been shown in several studies and registries that patients with hematologic malignancies including lymphomas have a higher incidence of death from COVID-19 compared with other types of cancer. Additional risk factors for COVID-19-related mortality include older age and relapsed or refractory disease. To better understand the risk factors associated with worse outcomes from COVID-19 in this patient population, the authors conducted a retrospective study of 111 patients with lymphoma, hospitalized for COVID-19, at any of the 16 French hospitals, during March and April 2020. The researchers specifically focused on identifying factors associated with prolonged hospital stay (longer than 30 days), or hospitalization for recurrent symptoms for more than 30 days and death, and used length of hospital stay as a proxy for persistent COVID-19 infection. Study patients included those formerly treated for lymphoma, those currently undergoing treatment, or had no treatment.

Of the 111 patients included in this study, 57% (N=63) had previously received B-cell-depleting therapy. The most common type of lymphoma was Diffuse Large B-Cell Lymphoma. Twenty nine percent (29%) of all patients required a prolonged hospital stay (longer than 30 days) due to severe COVID-19 symptoms and persistent disease. The median age of patients with persistent COVID-19 was 64 years and 63% were male. More than two-thirds (69%) had at least one significant comorbidity. None of the patients with T-cell lymphoma included in the study (N=8) experienced persistent COVID-19 infection.

At a median follow-up of 191 days, the 6-month Overall Survival for the entire cohort was 69%. Older age (70 years and over) as well as relapsed/refractory disease were both associated with worse survival and prolonged hospital stays. After adjusting for age, comorbidities, and the presence of relapsed/refractory disease, the researchers noted that receipt of B-cell-depleting treatment within the previous 12 months nearly doubled the likelihood of a prolonged hospital stay and more than doubled the risk of death. After 1 month, 41% of patients who received anti-CD20 monoclonal antibodies were still hospitalized for COVID-19 versus 13% not treated with those antibodies.

The authors concluded that standardized guidelines on the use of anti-CD20 therapies are needed to help us make decisions during the COVID-19 pandemic, and convalescent plasma may be a treatment consideration for B-cell-depleted patients with persistent COVID-19. Patients who recently received B-cell depleting therapies and have COVID-19 should be closely monitored. Additionally, the efficacy and timing of vaccination in this particular population needs further study.

Prolonged in-hospital stay and higher mortality after Covid-19 among patients with non-Hodgkin lymphoma treated with B-cell depleting immunotherapy. Dulery R, Lamure S, Delord M, et al. Am J Hematol. 2021;96:934-944.