Tag: Non-Hodgkin Lymphoma

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

SUMMARY: The FDA on July 31, 2020, granted accelerated approval to MONJUVI® (Tafasitamab-cxix), a CD19-directed cytolytic antibody, in combination with REVLIMID® (Lenalidomide), for adult patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) Not Otherwise Specified, including DLBCL arising from low grade lymphoma, and who are not eligible for Autologous Stem Cell Transplant.

The American Cancer Society estimates that in 2020, about 77,240 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,940 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. 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.

REVLIMID® (Lenalidomide) is an oral immunomodulatory agent with activity in lymphoid malignancies, primarily through immune modulation (repair T-cell immune synapse dysfunction and Natural Killer cell/T-cell effector augmentation). It additionally has antiproliferative effects. REVLIMID® was shown to have significant activity in relapsed DLBCL when given alone or along with RITUXAN®. MONJUVI® is an investigational humanized Fc-engineered monoclonal antibody directed against CD19. MONJUVI® incorporates an XmAb(R) engineered Fc domain, which is intended to lead to a significant potentiation of Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP), thus improving tumor cell kill. Preclinical data suggested that MONJUVI® might act synergistically with REVLIMID®.

L-MIND is an ongoing , multicenter, single arm, open-label, Phase II study, investigating the combination of MONJUVI® and REVLIMID® in patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL), after up to two prior lines of therapy, including an anti-CD20 targeting therapy (such as Rituximab), who are not eligible for high-dose chemotherapy and subsequent Autologous Stem Cell Transplantation. This study enrolled 81 patients and patients received 28-day cycles of MONJUVI® 12 mg/kg IV once weekly during Cycles 1-3 with a loading dose on Cycle 1 Day 4, then every 2 weeks during Cycles 4-12, along with REVLIMID® 25 mg orally daily on Days 1-21 of Cycles 1-12. After Cycle 12, progression-free patients received MONJUVI® every 2 weeks until disease progression. Eighty patients (N=80) received at least one dose of both MONJUVI® and REVLIMID®. The Primary endpoint was Objective Response Rate (ORR). Secondary endpoints included Duration of Response (DoR), Progression-Free Survival (PFS) and Overall Survival (OS).

In this long-term analysis after a minimum of two years follow-up, outcomes from the L-MIND study were consistent with the primary analysis. Assessment by an Independent Review Committee at data cut-off showed an ORR of 58.8% and a Complete Response (CR) rate of 41.3%. Median Duration of Response was 34.6 months. The median OS was 31.6 months and median PFS was 16.2 months. The safety profile was consistent with that observed in previously reported studies of MONJUVI® in combination with REVLIMID®. The most common Grade 3 or worse Adverse Events were cytopenias and febrile neutropenia.

To determine the the contribution of MONJUVI® in the combination with REVLIMID® and to prove its synergistic effect, an observational retrospective study was conducted (Re-MIND) to compare real-world response data of patients with Relapsed or Refractory DLBCL who received REVLIMID® monotherapy with the efficacy outcomes of the MONJUVI®- REVLIMID® combination, as investigated in the L-MIND trial. In this study, efficacy data was collected from 490 R/R DLBCL patients in the US and EU. Qualification criteria for matching patients of both studies were pre-specified. As a result, 76 eligible Re-MIND patients were identified and matched 1:1 to 76 of 80 L-MIND patients based on important baseline characteristics. Objective response rates (ORR) were validated based on this subset of 76 patients in Re-MIND and L-MIND, respectively. The Primary endpoint of Re-MIND was met and shows a statistically significant superior best ORR of the MONJUVI®/ REVLIMID® combination compared to REVLIMID® monotherapy. Further, there was a significant difference in OS as well as CR rates, favoring the L-MIND cohort over the observational cohort.

It was concluded that MONJUVI® in combination with REVLIMID® resulted high Complete Response rates, as well Durable Responses and improved survival, in a significant proportion of patients with relapsed or refractory Diffuse Large B-Cell Lymphoma, ineligible for Autologous Stem Cell Transplantation, and might represent a new therapeutic option in this clinical setting.

Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Salles G, Duell J, Barca EG, et al. Lancet Oncol. 2020 Jul;21:978-988.