B-cell Acute Lymphoblastic Lymphoma Research Articles

Outcomes for Hispanic Patients with Acute Leukemia Treated at Academic Centers

▪Introduction: Health disparities for underrepresented U.S. minority populations with hematologic cancers contribute to differential treatment and higher death rates. The Hispanic population (including people of Mexican, South/Central American, Cuban, Puerto Rican, or other Spanish-speaking cultures, regardless of race) collectively constitutes the largest minority group in the United States. Hispanic patients have been reported to have an increased incidence of B-cell acute lymphoblastic lymphoma (B-ALL) and acute promyelocytic leukemia (APL). While APL is associated with favorable outcomes compared to other acute leukemias, registry data suggest poorer outcomes in Hispanic patients with both acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML). The Hispanic paradox is an epidemiological paradox that refers to the finding that Hispanic patients have paradoxically comparable, or better, health outcomes compared to their U.S. non-Hispanic White counterparts despite barriers to care such as lower socioeconomic status. This paradox has also been reported in hematologic malignancies. Definitive data regarding differences in outcome between Hispanic and non-Hispanic patients with acute leukemias (AL) are lacking.We sought to compare outcomes of Hispanic patients and non- Hispanic patients with acute leukemia with access to care, and examine whether the Hispanic paradox reported in hematologic malignancies is attributable to enrichment of patients with highly curable disease such as APL.Methods: Using data from a Vizient Clinical Data Base, a healthcare claims database, we identified patients with leukemia using ICD 10 codes for acute leukemia. Adult patients with AL, ages 18-89 who were treated between January 2020 and June 2021 were evaluated. Data from 121 academic centers was included. We focused on academic centers to limit the impact of access to care . Demographic information was obtained from the registry, to which ethnicity was self-reported. Patients were stratified by age, and we compared complication rates, number of complications, number of deaths, percent deaths and mortality index between Hispanic and non-Hispanic patients. The key metric used to compare outcomes of Hispanic patients with non-Hispanic patients was the severity adjusted mortality index, which is the ratio of observed mortality over expected mortality for patients with the same diagnosis in this registry. Chi-squared test is used for to determine the statistical significance of differences in mortality (by age group) in Hispanics v. non-Hispanic patients. Initial analysis included all patients with acute leukemias, and the data was subsequently reanalyzed excluding patients with APL, as APL is known to portend a favorable prognosis.Results: A total of 29,967 patients were with acute leukemia were evaluated; of these patients, 2903 identified as Hispanic and 27,064 were non- Hispanic. As seen in table 1, patients of Hispanic origin generally had lower treatment related complication rates in all age groups compared to their age matched non-Hispanic counterparts. Except for the 51-64 and 80-84 age groups the mortality index was lower in Hispanic patients compared to non-Hispanic peers. Differences in mortality between Hispanic and non-Hispanic patients in all age groups were not statistically significant. Trends to a lower mortality index in Hispanic patients are highlighted in green in table 1. When patients with APL were excluded from the analysis, the trend lower mortality in Hispanic patients in most age groups persisted. Again, the mortality index was comparatively higher in hispanic patients in the 51-64 and 80-84 age groups, but differences in mortality between Hispanic and non- Hispanic patients were not statistically significant. Exclusion of APL patients did not have a significant impact on the complication rate or mortality supporting that the Hispanic paradox is independent of higher rates of very favorable risk myeloid malignacies in this population.Conclusions: Hispanic patients with access to academic cancer centers have the potential for non-inferior outcomes compared to non-Hispanic patients. Equivalent outcomes as assessed by mortality index were not attributable solely to the higher incidence of very favorable risk disease such as APL in the Hispanic population. [Display omitted] DisclosuresWatts: Takeda: Consultancy, Research Funding; Genentech: Consultancy; Rafael Pharma: Consultancy; Celgene/BMS: Consultancy. Bradley: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sekeres: Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

LINC-34. OPTIC NERVE INFILTRATION: RARE MANIFESTATION OF CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA IN REMISSION

BACKGROUNDOptic nerve infiltration in acute lymphoblastic leukemia is a rare manifestation. This infiltration may appear months in advance as an isolated sign of extramedullary relapse and considered as one of the significant clinical findings of central nervous system leukemia. AIM: To describe a case of rapidly progressive optic nerve infiltration in a girl with ALL in remission. CASE: A 13-year-old girl in full remission following treatment for B-cell acute lymphoblastic leukemia presented with decreased vision and proptosis on the left eye. She completed the chemotherapy course two years before. On physical examination, we found the optic disc swelling in her left eyes. There were no signs of relapse from the hematological, cerebrospinal fluid analysis, and bone marrow aspiration. The orbital CT found a mass on the left retrobulbar (size 29x48x32 mm), suspected of optic nerve glioma. The mass has grown rapidly in a month, and she lost her left sight. The involved eye was exenterated (60x55x40 mm). The histopathology and immunohistochemistry showed the B-cell acute lymphoblastic lymphoma. Unfortunately, the patient could not come for further follow up due to the COVID-19 large-scale social distancing. Two months later, she came with pallor and pain in all of her body. The bone marrow aspiration showed leukemic relapse and she is undergoing chemotherapy.CONCLUSIONOptic nerve infiltration by leukemia requires both diagnostic certainty and urgent management. A routine ophthalmic assessment is recommended in patients with a history of acute lymphoblastic leukemia to diagnose optic nerve involvement due to leukemic infiltration.

Pathogenesis of pediatric B-cell acute lymphoblastic leukemia: Molecular pathways and disease treatments.

B-cell acute lymphoblastic lymphoma (B-ALL) is a disease found mainly in children and in young adults. B-ALL is characterized by the rapid proliferation of poorly differentiated lymphoid progenitor cells inside the bone marrow. In the United States, ~4,000 of these patients are diagnosed each year, accounting for ~30% of childhood cancer types. The tumorigenesis of the disease involves a number of abnormal gene expressions (including TEL-AML1, BCR-ABL-1, RAS and PI3K) leading to dysregulated cell cycle. Risk factors of B-ALL are the history of parvovirus B 19 infection, high birth weight and exposure to environmental toxins. These risk factors can induce abnormal DNA methylation and DNA damages. Treatment procedures are divided into three phases: Induction, consolidation and maintenance. The goal of treatment is complete remission without relapses. Apart from traditional treatments, newly developed approaches include gene targeting therapy, with the aim of wiping out leukemic cells through the inhibition of mitogen-activated protein kinases and via c-Myb inhibition enhancing sensitivity to chemotherapy. To evaluate the efficacy of ongoing treatments, several indicators are currently used. The indicators include the expression levels of microRNAs (miRs) miR-146a, miR-155, miR-181a and miR-195, and soluble interleukin 2 receptor. Multiple drug resistance and levels of glutathione reductase can affect treatment efficacy through the increased efflux of anti-cancer drugs and weakening the effect of chemotherapy through the reduction of intracellular reactive oxygen species. The present review appraised recent studies on B-ALL regarding its pathogenesis, risk factors, treatments, treatment evaluation and causes of disease relapse. Understanding the mechanisms of B-ALL initiation and causes of treatment failure can help physicians improve disease management and reduce relapses.

PBI36 REVIEW AND COMPARISON OF OVERALL SURVIVAL EXTRAPOLATION IN HEALTH TECHNOLOGY ASSESSMENTS FOR CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPIES (CAR-TS)

The US Institute for Clinical and Economic Review (ICER) and the UK National Institute for Health and Care Excellence (NICE) recently evaluated chimeric antigen receptor T-cell therapies (CAR-Ts) for pediatric B-cell acute lymphoblastic lymphoma (B-ALL), and diffuse large B-cell lymphoma (DLBCL) in adults. We reviewed and compared assessments of CAR-Ts from ICER and NICE, focusing on the extrapolation of overall survival (OS). One ICER evaluation and three NICE technology assessments (TAs) of the cost effectiveness of CAR-Ts in B-ALL and DLBCL were identified. Methods used for extrapolation of OS were compared. For both B-ALL and DLBCL populations in ICER’s assessment, standard parametric survival curves were extrapolated for 5 years, after which survivors were considered cured and followed general population mortality. In NICE TA559 and TA554, mixture-cure models were used for modelling OS. Here, a cure fraction was derived; cured patients followed general population mortality, whereas patients who were not followed fitted parametric survival curves. The Committee considered this method appropriate, but also found the cure fraction, a key driver of results, to be highly uncertain. The Committee for NICE TA567 considered a 1-knot spline extrapolation appropriate but insisted more long-term data were needed to decide the point after which patients are assumed to follow general population mortality. In all three NICE TAs, CAR-Ts were recommended for the Cancer Drugs Fund due to uncertainties in OS data. While ICER’s assessment yielded favorable cost-effectiveness results, nine of 13 voters stressed the significant uncertainty around long-term clinical benefits. Both ICER and NICE noted the uncertainty with extrapolating short-term survival data beyond trial period for CAR-Ts but appeared to accept the use of mixture-cure and spline models over traditional parametric survival modelling to represent their potential curative nature. Longer follow-up data should be collected to confirm long-term survival benefit of CAR-Ts.

Successful Anti-CD 19 CAR-T Cell Therapy in Jehovah Witness Patient with Relapsed Refractory B-ALL

Topic Significance & Study Purpose/Background/Rationale Jehovah Witness is a minority Christian denomination whose members do not accept blood products. The population of Jehovah witness is approximately 1 million in the USA and 8 million worldwide. They are likely to be excluded from most clinical trials, including trials evaluating chimeric antigen receptor (CAR) T‐cell therapies for relapsed/refractory hematological malignancies. Methods, Intervention, & Analysis We hereby report a case of 20-year-old female, Jehovah Witness patient, with relapsed refractory B Cell Acute lymphoblastic lymphoma (B-ALL) who was successfully treated with anti‐CD19 CAR T‐cell product Tisagenlecleucel. The patient was initially diagnosed at age 13 in 2012 with B-ALL. She received treatment on a pediatric protocol and stayed in remission until 9/20/2018 when she presented with fatigue and Bone marrow biopsy with relapsed disease (85% B-ALL). Cytogenetics were 46XY and FISH negative for BCR/ABL. NGS was negative for a pathogenic variant, and Cerebrospinal fluid analysis was negative for B-ALL The patient was refractory to Inotuzumab and became eligible for Tisagenlecleucel. She underwent T-cell apheresis, lymphodepletion and CAR-T cell infusion per protocol Findings & Interpretation She had no cytokine release syndrome or Immune effector cell-associated neurotoxicity syndrome She developed pancytopenia and received supportive care with Epoetin alfa, Folic acid, Vitamin B12, Ferrous sulfate, vitamin and Provera daily to suppress menses. We also minimize blood loss by using pediatric size collection tubes. She is currently at 6 months and remains in complete remission with count recovery. Discussion & Implications We present a case of a Jehovah witness patient with relapsed B-ALL successfully treated Tisagenlecleucel. Per a report from Maude et' al, CAR-T therapy has induced 90% complete remission rates among 30 children with relapsed refractory B-ALL, of whom 15 did not receive additional treatment. This is especially pertinent for our patient who could not have tolerated allogeneic stem cell transplant without transfusion support.

A Case of Precursor B-cell Acute Lymphoblastic Leukemia Occurre d with Rapid Hip Bone Destruction and Femoral Neck Fracture

Background: Precursor B-cell lymphoblastic lymphoma is a rare subtype of acute lymphoblastic lymphoma and sometimes presents as lytic bone lesions. Diagnosis and treatment of lytic bone lesions are always challenging. This is a rare case of delayed leukemic change of precursor B-cell acute lymphoblastic lymphoma presented with a rapid hip bone destruction.Case presentation: A 12-year-old Japanese girl presented with progressive left hip pain, and bone destruction of her left hip two months after the onset of symptoms. She had no past medical or family history of malignancy and had no genetic abnormality. Radiograph and MRI examination showed bone destruction and osteolytic lesions in her left femoral neck and pelvis. Blast cells were not found in our initial examination of the peripheral blood and aspirated bone marrow cells. The case was finally diagnosed as Precursor B-cell lymphoblastic lymphoma as the results of bone biopsy, and blast cells were then detected after preforming multiple bone marrow aspirations. She also had pathological femoral neck fracture, but after treatment regimen by chemotherapy, her osteolytic lesions cured with obtainment of femoral neck fusion. She could walk at the final period.Conclusion: This case highlights the importance of early diagnosis of this disease for greater curing rates. Diagnosis of Precursor B-cell lymphoblastic lymphoma was finally made based on the results of biopsy of tissues because of the delayed appearance of leukemic changes. Orthopaedic surgeons should be aware of Precursor B-cell lymphoblastic lymphoma, when making diagnosis of patients exhibiting a rapid hip bone destruction.

Clinical Implications of Anti-CD19 Chimeric Antigen Receptors (CAR) T Cell Therapy in Acute Lymphoblastic Leukemia (ALL)

Acute Lymphoblastic Leukemia (ALL) is a cancer of white blood cells that is most prevalent among young children. Several environmental and genetic factors contribute to the occurrence of ALL, including radiation exposure, ethnicity, gender, and other genetic traits. Traditional treatment options include chemotherapy, radiation, and bone marrow transplant. More recently, a form of antibody-mediated immunotherapy using genetically engineered chimeric antigen receptor (CAR) T-cells has been used in several clinical trials with encouraging results. CAR T-cells allow for highly targeted treatment by inducing activation of the modified T-cells and stimulating an apoptotic response in target B-cells upon ligation with a given antigen target. Typically, modified CAR T-cells are capable of specific recognition of the B-cell surface marker CD19, a universally expressed oncogenic antigen found in many forms of B-cell acute lymphoblastic lymphoma. Because CD19 is not expressed in hematopoietic cells, successful CD19-targeted treatment would eradicate cancerous cells without damaging the hematopoietic system. Hematopoietic cells can therefore regenerate normal CD19+ B-cells following treatment, as these are also depleted by anti-CD19 CAR T-cells. With limited toxicities and significant efficacy, CD19-targeted CAR T-cell immunotherapy is a promising treatment approach for ALL.

Outcome Of Patients With Double-Hit Lymphomas Treated With CODOX-M/IVAC + R Followed By Hematopoietic Stem Cell Transplantation In British Columbia

BackgroundDouble-hit (DHIT) lymphoma is a heterogeneous group of non-Hodgkin lymphomas characterized by concurrent translocations involving MYC and BCL2 and typified by aggressive behavior and poor prognosis with only rare long-term survivors. There is no established treatment for DHIT lymphoma. Since 2003, the British Columbia Cancer Agency (BCCA) has adopted the use of intensive chemotherapy CODOX-M/IVAC combined with rituximab (R) followed by high-dose chemotherapy and hematopoietic cell transplantation (HSCT) as definitive treatment for DHIT lymphoma. In younger patients, an ablative matched sibling donor allotransplant (AlloSCT) is preferred over an autotransplant (AutoSCT). For all patients over the age of 60 years only AutoSCT is offered. Total Body Irradiation (TBI) is used as a part of the conditioning regimen for patients younger than 60 years of age. Here we report our provincial experience with this strategy, focusing on the ability to deliver this treatment and survival outcomes. MethodsThe Leukemia/BMT Program of British Columbia database and the BCCA Lymphoid Cancer Database were searched to identify all patients diagnosed with non-Hodgkin lymphomas with concurrent translocation of MYC and BCL2 (DHIT lymphoma) diagnosed between January 2003-September 2012. Results27 cases of DHIT lymphoma were identified with the following characteristics: median age at diagnosis was 55.8 years (range 35.5-70.9 years); 19 (70%) were male; 26 (96%) patients had stage 3/4 disease; 16 (59%) had bone marrow involvement. All cases were HIV negative. Histological diagnosis based on the WHO 2008 classification were: diffuse large B-cell lymphoma (DLBCL) n=8 (30%); B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (BCL-U) n=17 (63%); B-cell acute lymphoblastic lymphoma (ALL) n=1; high-grade B-cell lymphoma, not otherwise specified (NOS) n=1. 13 cases (48%) were transformed from an underlying indolent B-cell lymphoma (12 follicular lymphoma, 1 low-grade B-cell lymphoma NOS). CODOX-M/IVAC + R was administered in 20 patients (74%). 7 patients received alternative chemotherapy regimen (5 R-CHOP, 1 R-CVP, 1 R-ICE) due to patient and/or physician preference. 14 patients (52%) underwent HSCT (7 AutoSCT, 7 AlloSCT), including 11 patients treated CODOX-M/IVAC + R pre-transplant, and 3 patients who received other therapy. 13 patients did not undergo HSCT: primary refractory disease n=7; patient preference n=2; deconditioning n=1; age > 65 and poor performance status n=3. The clinical status at time of transplantation was CR in 5 patients (19%), PR in 8 (30%), progressive disease in 1 (4%). The conditioning regimens included: cyclophosphamide/TBI n=6, VP-16/cyclophosphamide/TBI n=4, BEAM n=3, busulfan/cyclophosphamide n=1. At last follow-up, 15 (56%) patients have died, 14 from disease progression and 1 from complications of AlloSCT. 10 (37%) patients are alive and in remission and 2 patients are alive but have relapsed. 8 of 14 HSCT recipients (6 AutoSCT, 2 AlloSCT) remain alive and free of disease compared with 2 of 13 patients who did not receive HSCT; both disease free survivors received CODOX-M/IVAC + R. Median follow-up for living patients was 31 months (range 6.5-67.3 months). 2-year EFS and OS from the diagnosis of all DHIT lymphoma patients were 35% (95% CI 16%-54%) and 45% (95% CI 20%-65%), respectively. For patients who received CODOX-M/IVAC + R, the 2-year EFS was 37%. For patients who received CODOX-M/IVAC + R followed by SCT, the 2-year EFS was 43%. Patients with BCLU/ALL/High-grade lymphoma NOS had a 2-year EFS of 27% and patients with DLBL had a 2 –year EFS of 50%. ConclusionPatients with DHIT lymphoma treated with CODOX-M/IVAC + R followed by SCT can have durable remissions. Regardless, progression during initial therapy prior to SCT remains a significant problem. Patients with DLBCL histology may have a more favorable outcome than those with BCLU.▪ Disclosures:Savage:Eli-Lilly: Consultancy. Toze:Roche Canada: Research Funding; F Hoffmann-La Roche: Research Funding. Sehn:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Connors:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Gerrie:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Sutherland:Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Villa:Roche: Honoraria, Research Funding; Lundbeck: Honoraria; Celgene: Honoraria. Song:Roche: Research Funding.

PAX2 Expression in Wilms Tumors and Other Childhood Neoplasms

PAX2 plays an important role in kidney development; although small studies have demonstrated PAX2 expression in Wilms tumors (WT), comprehensive studies on formalin-fixed tissue are lacking. Thus, we systematically evaluated PAX2 immunohistochemical staining in a retrospective study of pediatric WT, as compared with other pediatric tumors. We stained formalin-fixed, paraffin-embedded sections from 39 WT, 6 nephrogenic rests, 8 non-Wilms renal tumors, and 43 nonrenal pediatric small round cell tumors with 2 different PAX2 polyclonal antibodies. PAX2 demonstrated strong, diffuse staining of epithelial and blastema components of WT (97% of cases). PAX2 stained WT stroma in fewer cases (23%), but 80% of anaplastic foci were positive. Nephrogenic rests, 1 case of metanephric adenoma, and 1 pediatric renal cell carcinoma were also PAX2 positive; other pediatric renal tumors were negative. Neuroblastoma, primitive neuroectodermal tumor/Ewings, and T-cell acute lymphoblastic lymphoma (ALL) were PAX2 negative. However, PAX2 weakly stained some cases of B-cell ALL rhabdomyosarcoma (RMS) was also stained, especially alveolar RMS (83%), with less staining of embryonal RMS (13%). One of the antibodies also stained maturing myoid cytoplasm of WT and RMS. This study shows that PAX2 is a sensitive marker of WT (sensitivity 97%), but PAX2 shows weak-to-moderate-intensity nuclear staining of RMS and B-cell ALL, somewhat limiting its utility. However, PAX2 may be a helpful marker in certain diagnostic situations. We speculate that RMS and B-cell ALL staining could be due to antibody cross-reactivity with PAX family members with known expression in RMS and B-cell ALL.

C-MYC translocation in t(14;18) positive follicular lymphoma at presentation: An adverse prognostic indicator?

Follicular lymphoma (FL) is a common subtype of low grade B-cell non-Hodgkin lymphoma (NHL). Although this form of lymphoma often pursues an indolent course, in some cases it may behave in a more aggressive manner. Clinical and histological parameters have been shown to correlate with an adverse prognosis but a number of cytogenetic abnormalities may also be associated with aggressive disease. Although, the t(14;18) in itself does not affect outcome in cases of FL, secondary abnormalities that occur in a complex polyploid karyotype may identify cases with a poor prognosis. It is unusual to find both t(14;18) and C-MYC translocation in the same tumour; those cases in which it has been described include examples of high-grade B-cell NHL (either de novo or transformed FL) or B-cell acute lymphoblastic lymphoma. In this report, three cases of FL are described in which both t(14;18) and a C-MYC translocation were identified at presentation. We also summarize four further cases from the literature. This is a small series but one which raises the possibility that the presence of a C-MYC translocations at presentation may identify a particularly aggressive subtype of FL. Further studies are required to investigate the true incidence of this aberration, the impact on C-MYC regulation, clinical course and response to treatment.

Update of the M. D. Anderson Cancer Center Experience with Hyper-CVAD and Rituximab for the Treatment of Mantle Cell and Burkitt-Type Lymphomas

Mantle cell lymphoma (MCL) and Burkitt lymphoma respond to initial intense therapies, such as hyper-CVAD (hyperfractionated cyclophosphamide/ vincristine/doxorubicin/dexamethasone) alternating with high-dose methotrexate/cytarabine, to which the monoclonal antibody rituximab has recently been added. This report provides an update detailing the long-term outcome when this chemoimmunotherapy regimen is used as first-line therapy for newly diagnosed MCL, de novo Burkitt lymphoma, atypical Burkitt lymphoma, and mature B-cell acute lymphoblastic lymphoma (B-ALL). Ninetyseven patients with de novo MCL and 31 patients with Burkitt lymphoma, atypical Burkitt lymphoma, and B-ALL were treated with rituximab plus hyper-CVAD alternating with rituximab/methotrexate/cytarabine under different institutional trials approved by the University of Texas M. D. Anderson Cancer Center Institutional Review Board. Overall response rate (RR) for patients with MCL was 97% (complete response [CR]/unconfirmed CR rate, 87%). At a median follow-up of 4.8 months, the 5-year failure-free survival and OS rates were 48% and 65%, respectively. Among patients aged ≤ 65 years, the 5 year failure-free survival was 60%. Patients with blastoid morphology have a 7-year survival rate of 47%. Toxicity was mainly hematologic but significant. Overall RR for patients with Burkitt lymphoma/atypical Burkitt lymphoma/B-ALL was 97% (CR rate, 86%). With a median follow-up of 22 months, the estimated 3-year OS, disease-free survival, and event-free survival rates were 89%, 88%, and 80%, respectively. Rituximab plus hyper-CVAD alternating with rituximab/methotrexate/cytarabine is an effective dose-intense chemoimmunotherapy program for untreated MCL, Burkitt lymphoma, atypical Burkitt lymphoma, and B-ALL. Toxicity is mainly hematologic and significant, but expected.