Tag: Non-Hodgkin Lymphoma

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 the 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 (RITUXAN®-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.

MYC is a proto-oncogene and transcription factor and is rearranged in up to 15% of patients with DLBCL. MYC activation is an important adverse prognostic feature and results in aggressive cellular proliferation associated with DNA replication and transcription, protein synthesis, and altered cellular metabolism. BCL2 is a potent anti-apoptotic factor and dual rearrangement of MYC with BCL2 and less commonly, BCL6, occurs in 5% to 7% of cases of DLBCL. Further, both MYC and BCL2 proteins can be overexpressed, either with or without the underlying respective chromosomal rearrangements, in about 30% of patients with DLBCL.

The combination of MYC activation and anti-apoptosis (BCL2) results in a clinically aggressive phenotype called Double-Hit Lymphoma (DHL), which is associated with poor long-term survival after standard chemoimmunotherapy. Similar poor outcomes have been noted in patients with MYC activation along with BCL2, and BCL6 rearrangement, known as Triple Hit Lymphoma (THL).

The long term survival for patients with DHL or THL treated with R-CHOP is less than 20%. Patients are therefore often treated with more intensive regimens such as R-EPOCH (Rituximab, Etoposide, Prednisone, Vincristine, Cyclophosphamide, and Doxorubicin), although prospective data supporting the use of one regimen over another are limited.

The present study was conducted to compare Overall Survival of patients with advanced stage MYC-rearranged DLBCL and DHL/THL who were treated with R-CHOP versus R-EPOCH. The researchers analyzed de-identified data from a nationwide Flatiron Health Electronic Health Record database on patients diagnosed with DLBCL at 280 cancer clinics in the U.S. between January 2011, and June 2020. Among 6,809 total DLBCL patients, 443 (6.5%) were found to have MYC-rearranged DLBCL. Among these, 218 patients had advanced Stage (III/IV) disease at diagnosis, 64 patients had MYC-rearranged DLBCL only, and 117 and 37 had DHL or THL, respectively. Among those patients with DHL/THL, 43 patients (median age 73 years) were treated with R-CHOP and 111 patients (median age 67 years) received R-EPOCH. Among those with MYC-rearranged DLBCL only, 36 received R-CHOP (median age 70 years), and 28 received R-EPOCH (median age 61 years).

The investigators found no difference in the 4-year Overall Survival rates between the R-CHOP and R-EPOCH treatment arms in different patient groups. Among the MYC-rearranged DLBCL cohort, the 4-year Overall Survival rates were 32.8% with R-CHOP versus 30.4% with R-EPOCH regimens. In the DHL/THL group of patients, the 4-year Overall Survival rates were 54.5% with R-CHOP versus 49.6% with R-EPOCH. Among DHL/THL patient group, 89% of deaths occurred within 2 years of diagnosis, and among MYC- rearranged DLBCL, 78% of deaths occurred in the first 2 years. ECOG Performance Status score of 2 or more and elevated LDH were independently associated with worse mortality for these patients, by multivariate analysis.

It was concluded from this analysis that Overall Survival outcomes were similar between patients with MYC-rearranged Diffuse Large B-Cell Lymphoma and Double-Hit lymphoma/Triple-Hit Lymphoma (THL) who were treated with R-CHOP versus R-EPOCH. The authors suggested that further studies are needed to better risk stratify patients with DLBCL, for optimizing outcomes.

No difference in overall survival between R-CHOP and R-EPOCH among patients with advanced stage MYC-rearranged, double hit, or triple hit diffuse large B-cell lymphoma. Magnusson T, Narkhede M, Mehta A, et al. Abstract #S224. Presented at the EHA2021 Virtual Congress, June 9-17, 2021.

SUMMARY: The FDA on April 23, 2021 granted accelerated approval to ZYNLONTA® (Loncastuximab tesirine-lpyl ), a CD19-directed antibody and alkylating agent conjugate, for adult patients with Relapsed or Refractory Large B-Cell Lymphoma after two or more lines of systemic therapy, including Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified, DLBCL arising from Low Grade Lymphoma, and High Grade B-Cell Lymphoma.

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 the 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 (RITUXAN®-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. For patients who fail first line therapy, outcomes are poor, worsening with each line of therapy, and the chance for cure or long term disease-free survival diminishes. There is a significant unmet need for patients with Relapsed/Refractory DLBCL.

ZYNLONTA® is a CD19-directed Antibody Drug Conjugate comprised of a humanized anti-CD19 antibody, conjugated through a linker to a potent pyrrolobenzodiazepine (PBD) dimer toxin. Once bound to a CD19-expressing cell, ZYNLONTA® is internalized by the cell following which the toxic payload is released. The potent toxin then binds irreversibly to DNA to create highly potent interstrand cross-links that block DNA strand separation, thereby disrupting essential DNA metabolic processes such as replication and ultimately resulting in cell death. CD19 is a clinically validated target for the treatment of B-cell malignancies.

The present FDA approval of ZYNLONTA® was based on LOTIS-2, which is an open-label, single arm trial in which 145 adult patients who had Relapsed or Refractory DLBCL or High Grade B-Cell Lymphoma were included. This study included transplant eligible and ineligible patients, patients with double or triplet-hit lymphoma, and patients who previously received stem cell transplant or CD 19-targeted CAR-T cell therapy. Patients received ZYNLONTA® 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles. Treatment was continued until progressive disease or unacceptable toxicity. Enrolled patients had at least two prior systemic regimens. The main efficacy outcome measure was Overall Response Rate (ORR). Pre-specified analyses of ORR and Duration of Response (DoR) by demographic and clinical characteristics were performed, and ORR was assessed by independent reviewer according to the Lugano response criteria.

The ORR was 48.3% with a Complete Response Rate of 24.1%. The Partial Response (PR) rate was 24.1%. Patients had a median time to response of 1.3 months and the median Duration of Response for the 70 responders was 10.3 months (inclusive of patients who were censored). The most common Grade 3 or higher treatment-related adverse events included neutropenia with a low incidence of febrile neutropenia, thrombocytopenia, Gamma-Glutamyl Transferase increase, and anemia.

The authors concluded that ZYNLONTA® had substantial single-agent antitumor activity in patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma, with encouraging and durable responses noted in patients with high-risk characteristics.

Efficacy and Safety of Loncastuximab Tesirine (ADCT-402) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma. Caimi PF, Ai WZ, Alderuccio JP, et al. Presented at the 62nd ASH Annual Meeting and Exposition, December 5-8,2020. Abstract#1183

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 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.

High incidence of persistent COVID-19 among patients with lymphoma treated with B-cell depleting immunotherapy. Lamure S, Dulery R, Delord M, et al. AACR Virtual Meeting: COVID-19 and Cancer. Abstract S09-02. Presented on February 5, 2021.

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 Non-Hodgkin Lymphoma diagnosed in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 yrs or older at the time of diagnosis and the incidence is likely to increase with the 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 (RITUXAN®-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. The MInT trial (MabThera International Trial Group) published in The Lancet Oncology in 2006 established that for a subgroup of young DLBCL patients with favorable prognosis (age-adjusted International Prognostic Index (aaIPI) of 0 and no bulky disease, 6 cycles CHOP-like chemotherapy plus RITUXAN® resulted in a 3-year Event Free Survival of 89%, Progression Free Survival of 95% and Overall Survival of 98% (Lancet Oncol 2006;7:379-391).

Approximately 25-30% of DLBCL present as limited stage. Three cycles of Rituximab (RITUXAN®) along with CHOP plus Radiation Therapy (RT) is the standard treatment approach for limited stage DLBCL based on SWOG S0014 study. Data from retrospective studies suggested that 80% of patients were PET negative after 3 cycles of R-CHOP (defined as Deauville score 1-2), on a mid-treatment interim PET/CT scan, and only 8% of them relapsed after receiving 1 additional cycle of R-CHOP without RT.

S1001 is a prospective, Phase II, Intergroup, National Clinical Trials Network, PET-directed study, designed to tailor therapy for patients with limited-stage DLBCL after 3 cycles of R-CHOP. The goal of this study was to eliminate toxicities associated with RT, for the majority of patients with a negative PET scan after 3 cycles of R-CHOP and to improve the outcome in the minority of patients with a positive interim PET scan.

This study included 132 eligible, treatment naïve, Stage I/II, CD20-positive, DLBCL patients, with nonbulky (less than 10 cm) disease. All patients received 3 cycles of standard R-CHOP treatment given every 3 weeks, with Rituximab 375 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m2 IV, Vincristine 1.4 mg/m2 (capped at 2 mg) IV, and Prednisone 100 mg orally daily for 5 days. Patients had an interim PET scan between days 15 and 18 of cycle 3, which was centrally reviewed in real time. Patients with a negative PET, defined as Deauville score 1-3, proceeded with 1 additional cycle of R-CHOP. Patients with a positive PET (Deauville score 4-5) initiated 36 Gy of involved field radiation therapy, plus an additional boost of up to 9 Gy to FDG-avid areas, within 5 weeks of cycle 3 of R-CHOP. Three to 6 weeks after completing radiation therapy, patients received ZEVALIN® (Ibritumomab tiuxetan) administered per standard protocol, with Rituximab 250 mg/m2 IV given on day 1 and day 7, 8, or 9, and ZEVALIN® 0.4 mCi/kg on day 7, 8, or 9, after Rituximab. A final PET scan was performed 12 weeks after treatment completion. Patients were followed up with clinical examination and testing, including CT scans every 6 months for the first 2 years and then annually for up to 7 years or death.

The median age was 62 years, 62% of patients had Stage I disease, 17% had B symptoms, 43% had extranodal involvement, 66% had exclusive involvement of the head and neck region, and 10% had fully resected disease at baseline. Stage-modified IPI score was 0 in 27%, 1 in 42%, 2 in 28%, and 3 in 4% of the patients. Overall, 72% of the patients had DLBCL-Not Otherwise Specified, 17% had high-grade B-cell lymphoma–Not Otherwise Specified, and 3% had high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-hit lymphoma or triple-hit lymphoma). Among 87 patients for whom Cell of Origin could be assessed, 68% had Germinal Center B-cell (GCB), 23% had Activated B-Cell (ABC), and 9% were unclassifiable.

With a median follow up of 4.92 years, only 6 of 132 eligible patients progressed, and 3 died as a result of lymphoma, for a 5-year Progression Free Survival (PFS) estimate of 87% and an Overall Survival (OS) estimate of 89%. Eighty-nine percent of the patients with a negative interim PET/CT received R-CHOP × 4, whereas only 11% had a positive interim PET/CT and required radiation-based therapy, with both groups having excellent outcomes.

The authors concluded that, this largest prospective study in the US of limited-stage DLBCL establishes R-CHOP × 4 alone as the new standard treatment for the absolute majority of patients.

Positron Emission Tomography–Directed Therapy for Patients With Limited-Stage Diffuse Large B-Cell Lymphoma: Results of Intergroup National Clinical Trials Network Study S1001. Persky DO, Li H, Stephens DM, et al. J Clin Oncol. 2020;38:3003-3011