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IntroductionCAR T-cell therapy has emerged as a promising new immuno-oncology treatment that engages the patient's immune system to fight certain hematological malignancies, including diffuse large B-cell lymphoma (DLBCL). In the European Union (EU), CAR T-cell therapies have been approved for relapsed/refractory (R/R) DLBCL patients since 2018, but patient access is often still limited or delayed. This paper is aimed at discussing challenges to access and possible solutions in the largest four EU countries. MethodsThe analysis relied on literature review, market data collection, since homogeneous data coming from registries were not available, and discussion with experts coming from all four countries. ResultsWe calculated that in 2020, between 58% and 83% of R/R DLBCL patients (EMA approved label population) or between 29% and 71% of the estimated medically eligible R/R DLBCL patients, were not treated with a licensed CAR T-cell therapy. Common challenges along the patient journey that may result in limited access or delays to CAR T-cell therapy were identified. These include timely identification and referral of eligible patients, pre-treatment funding approval by authorities and payers, and resource needs at CAR T-cell centers. DiscussionThese challenges, existing best practices and recommended focus areas for health systems are discussed here, with the aim to inform necessary actions for overcoming patient access challenges for current CAR T-cell therapies as well as for future cell and gene therapies.

INTRODUCTION: Chimeric antigen receptor (CAR) T-cell therapy is a relatively new cancer immunotherapy that is offering remarkable benefits for patients in the third line setting for relapsed/refractory aggressive large B-cell non-Hodgkin’s lymphoma (NHL). At one-month restaging post CAR T-cell therapy, approximately 30% of patients are found to be in a partial response (PR) or to have stable disease (SD) to therapy, and these patients diverge into 30% who deepen into a complete response (CR) and the remaining 70% who ultimately progress (PD). To date there has been no way to predict who will enter remission and who will progress. Our study seeks to better understand these diverging patient groups and identify early predictive markers of progression. Patients projected to progress could then be treated with adjuvant therapies that could both kill residual tumor cells and improve residual CAR T-cell activation in order to increase the probability of a deepening of response. METHODS: In this retrospective analysis, we evaluated 259 patients who were treated with anti-CD19 directed CAR T-cell therapy for r/r B-NHL at the Dana-Farber Cancer Institute between December 2017 and June 2021. Patients with a PR or SD at 1 month were further classified into two cohorts according to their subsequent response conversion. Those that are known to have progressed from their PR/SD were included in the PD cohort, and the rest of the PR/SD patients were included in the non-PD cohort. Early clinical and radiological parameters up to the 1 month restaging scan were included in our analysis. RESULTS: The overall response rate for our patient sample was 79% with a best response of CR in 64% of patients. At 1 month restaging 52% of patients were in CR, 28% in PR, 2% SD, and 18% PD. Median follow-up was 9 months. 41% of patients deepened their response from PR/SD into a CR, 90% of whom remain in a CR to last follow-up, and 42% were known to have progressed. The PD cohort had poorer progression-free survival (3 months vs. 11 months) and overall survival (11 months vs. not yet reached) than the non- PD cohort. Parameters significantly correlated to progression included poor performance status; high CRP and low Hgb at Day -30; high CRP at lymphodepletion; need for early admission; low Hgb, high LDH, and high ferritin on Day 0; CRS Lee grade 2+ and low albumin at CRS onset; high ferritin at time of CRS treatment; and Deauville score of 5 on restaging scan. High MTV and TLG on pre- and post-infusion PET scans also trended with those who progressed. CONCLUSIONS: The findings of our analysis that were correlated to progression are primarily related to poor lymphoma biology pre-therapy, residual lymphoma, and CRS onset kinetics. Notably, inflammatory markers and maximal CRS post-therapy were not significant. A primary difference between the two PR patient groups may thus relate to the tumor microenvironments pre-infusion with greater tumor bulk in the PD cohort possibly corresponding to tumor microenvironments that are more inflammatory and hostile to CAR T-cells. We therefore define a new prognostic scoring system, to be validated in future studies, that utilizes five early clinical parameters and establishes three risk groups with significantly different prognoses for PR/SD patients. Evaluation of post-infusion minimal residual disease, CD19 status, PD-L1 status, and other molecular markers could be useful in better understanding and differentiating the pathophysiologies characterizing these patient groups.

One of the most frequently transformed signaling networks in cancer is the PI3K/mTOR /eIF4F signaling pathway. Through harmonized regulation of mTOR and eIF4F, as well as other overlapping signaling pathways, cancer cells achieve elevated proliferation, cell growth (increase in size), metabolism and survival. The key aim of this dissertation work is to identify and characterize critical signaling components of the PI3K/mTOR/eIF4F signaling pathway using both aggressive non-Hodgkin’s lymphoma (NHL) and Philadelphia chromosome-positive (Ph+) acute leukemia models. Our goal is to identify molecular mechanisms that could be exploited in order to improve responses to specific targeted agents: venetoclax (BCL2 inhibitor) in the case of aggressive NHL (chapter 2), and the tyrosine kinase inhibitor dasatinib for Ph+ acute leukemia (chapter 3).The BCL2 inhibitor venetoclax has shown efficacy in several hematologic malignancies, with the greatest response rates in indolent blood cancers such as chronic lymphocytic leukemia (CLL). In aggressive NHL, including diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), there is a lower response rate to venetoclax monotherapy. At the same time, indications about the importance of mTOR signaling pathway and regulation of mRNA translation via eIF4F complex assembly have been accumulating. In chapter 2 of this work, we demonstrate that small molecule inhibitors of cap-dependent mRNA translation sensitize NHL cells to apoptosis induced by venetoclax. We compared the mTOR kinase inhibitor (TOR-KI) MLN0128 with SBI-756, a compound targeting eukaryotic translation initiation factor 4G1 (eIF4G1), a scaffolding protein in the eIF4F complex. Treatment of NHL cells with SBI-756 synergized with venetoclax to induce apoptosis in vitro, and enhanced venetoclax efficacy in vivo at a tolerable dose. SBI-756 prevented eIF4E-eIF4G association and cap-dependent translation in a dose-dependent manner, while retaining mTOR substrate phosphorylation – indication of a great advantage over TOR-KIs. In addition, SBI-756 retained its ability to sensitize DLBCL cells to venetoclax even when those cells were lacking eIF4E binding protein-1 (4E-BP1), while these cells were insensitive to TOR-KI treatment. Moreover, SBI-756 treatment selectively reduced translation of mRNAs encoding ribosomal proteins and translation factors, hence leading to a delayed suppression in protein synthesis rates in sensitive cells. Furthermore, when human peripheral blood mononuclear cells were treated with SBI-756, only B lymphocytes had displayed reduced viability. Moreover, we show the importance of eIF4E to support B-ALL survival. In chapter 3 of this work we demonstrate that treatment of Ph+ B-ALL cells with SBI-756 was able to reduce eIF4F complex formation (prevention of eIF4E-eIF4G interaction) in vitro and in vivo. At the same time, we developed a novel inducible system which enabled control of eIF4E availability. In both chemical and genetic approaches, we have shown that reduction of eIF4F complex formation sensitizes Ph+ B-ALL cells to dasatinib treatment. Similarly to the findings in NHL, both chemical and genetic suppression of eIF4F complex formation have resulted in reduced protein synthesis, reduced survival and sensitization to dasatinib. Lastly, treatment with SBI-756 was found cytotoxic with selectivity for B cells, while the compound was well tolerated in vivo.Together, our findings using both NHL and B-ALL systems indicate that the eIF4F complex formation is an “Achilles heel” of aggressive blood malignancies and could be exploited for targeted therapy. Specifically, our abilities (chemically and genetically) to reduce eIF4F complex formation and mRNA translation provide a druggable and specific target with potential to improve treatment of NHL, B-ALL patients, and maybe others as well.

This phase II, single-arm, multicenter study examined the efficacy and safety of coltuximab ravtansine (an anti-CD19 antibody drug conjugate) in 61 patients with histologically documented ( de novo2clinicaltrials.gov identifier: 01472887) or transformed) relapsed or refractory diffuse large B-cell lymphoma who had previously received rituximab-containing immuno-chemotherapy. Patients had received a median of 2.0 (range 0-9) prior treatment regimens for diffuse large B-cell lymphoma and almost half (45.9%) had bulky disease (≥1 lesion >5 cm) at trial entry. Patients received coltuximab ravtansine (55 mg/m) in 4 weekly and 4 biweekly administrations until disease progression or unacceptable toxicity. Forty-one patients were eligible for inclusion in the per protocol population. Overall response rate (International Working Group criteria) in the per protocol population, the primary end point, was 18/41 [43.9%; 90% confidence interval (CI:) 30.6-57.9%]. Median duration of response, progression-free survival, and overall survival (all treated patients) were 4.7 (range 0.0-8.8) months, 4.4 (90%CI: 3.02-5.78) months, and 9.2 (90%CI: 6.57-12.09) months, respectively. Common non-hematologic adverse events included asthenia/fatigue (30%), nausea (23%), and diarrhea (20%). Grade 3-4 adverse events were reported in 23 patients (38%), the most frequent being hepatotoxicity (3%) and abdominal pain (3%). Eye disorders occurred in 15 patients (25%); all were grade 1-2 and none required a dose modification. Coltuximab ravtansine monotherapy was well tolerated and resulted in moderate clinical responses in pre-treated patients with relapsed/refractory diffuse large B-cell lymphoma.

The efficacy of therapeutic modalities for non-Hodgkin’s lymphoma have been tested and improved throughout the 19th century through various series of drug trials aimed at eliminating cellular malignancies, first through chemotherapy treatment, and more recently through immunotherapy. While to an extent successful in eliminating cancerous lesions and affected cells, chemotherapy treatments have shown to influence the induction of new malignancies, through genetic mutation, as well as unwanted toxic effects of systemic poisoning. The purpose of this thesis is to compare treatment methods in terms of their biomolecular activity, precision of intended results, and possible drawbacks, as well as their application to specific populations of Non-Hodgkin lymphoma diagnoses, including Follicular and Diffuse Large B-Cell lymphomas. In the following sections on contributing factors specific to Diffuse Large B-Cell lymphomas and Follicular lymphoma, elements of disease prognosis will be analyzed from a molecular and clinical point of view. This includes a focus on the impact of genetic mutation, the immunohistochemical evidence these changes present, as well as the variances in immune cell functionality, and finally a description of symptoms with direction to specific underlying causes. An analysis of standard of care chemotherapy, and monoclonal antibody treatments will then be provided for each occurrence. The second segment will discuss novel techniques being developed for the treatment of lymphoma including but not limited to new monoclonal antibodies, synthetic lethality modulation, inhibition of selected chemokine receptors, DNA vector immunization for production of internal host antibodies, concepts of cell mediated bispecific antibody induced destruction, and new generations of Immunomodulatory drugs. With the recent development of cost effective sequencing technology, included is a discussion of the shift towards personalized medicine treatments, targeting appropriate phenotypic specific populations for optimal results, as it relates to therapies for Diffuse Large B-Cell lymphoma and Follicular lymphoma.

The dissemination in the central nervous system (CNS) is an uncommon but fatal complication occurring in patients with diffuse large B-cell lymphoma (DLBCL). Standard prophylaxis has been demonstrated to reduce CNS relapse and improve survival rates. Intrathecal (IT) liposomal cytarabine allows maintaining elevated drug levels in the cerebrospinal fluid for an extended period of time. Data on the efficacy and safety of liposomal cytarabine as CNS prophylaxis in patients with DLBCL are still insufficient. The objective of the present study was to evaluate the effectiveness and safety of the prophylaxis with IT liposomal cytarabine in prevention of CNS relapse in high-risk patients with DLBCL who were included in a trial of first line systemic therapy with 6 cycles of dose-dense R-CHOP every 14 days. Twenty-four (18.6 %) out of 129 patients were identified to have risk factors for CNS involvement, defined as follows: >30 % bone marrow infiltration, testes infiltration, retroperitoneal mass ≥10 cm, Waldeyer ring, or bulky cervical nodes involvement. Liposomal cytarabine (50 mg) was administered by lumbar puncture the first day of the 1st, 2nd, and 6th cycle of R-CHOP14 scheme. Among 70 IT infusions, grade 3–4 adverse events reported were headache (one patient) and nausea/vomiting (one patient). With a median follow-up of 40.1 months, no CNS involvement by DLBCL was observed in any patient. In conclusion, IT liposomal cytarabine is safe, feasible, and effective for CNS prophylaxis, causing few associated risks and little discomfort to patients with DLBCL.

Diffuse large B-cell lymphoma (DLBCL) patients failing rituximab-containing therapy have a poor outcome with the current salvage regimens. We conducted a phase 1b trial to determine the maximum tolerated dose (MTD) of lenalidomide in combination with R-ESHAP (rituximab, etoposide, cisplatin, cytarabine, methylprednisolone) (LR-ESHAP) in patients with relapsed or refractory DLBCL. Efficacy data were collected as a secondary objective. Subjects received 3 cycles of lenalidomide at escalating doses (5, 10 or 15 mg) given on days 1–14 of every 21-day cycle, in combination with R-ESHAP. Responding patients received BEAM (carmustine, etoposide, cytarabine, melphalan) followed by autologous stem-cell transplantation. Lenalidomide 10 mg/d was identified as the MTD because, in the 15 mg cohort, one patient experienced dose-limiting toxicity (grade 3 angioedema) and two patients had mobilization failure. A total of 19 patients (3, 12 and 4 in the 5, 10 and 15 mg cohorts, respectively) were evaluable. All toxicities occurring during LR-ESHAP cycles resolved appropriately and no grade 4–5 non-haematological toxicities were observed. The complete remission and overall response rates were 47·4% and 78·9%, respectively. With a median follow-up of 24·6 (17·4–38·2) months, the 2-year progression-free survival and overall survival were 44% and 63%, respectively. In conclusion, the LR-ESHAP regimen is feasible and yields encouraging outcomes.

High dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed or refractory (R/R) diffuse large B cell lymphoma (DLBCL) who are chemosensitive to salvage therapy. There is now evidence that the achievement of complete remission by PET scan (PET-CR) after salvage therapy is a favorable determinant of ASCT outcome, implying that PET response should be part of the prognostic assessment for patients considering ASCT. However, it is unclear whether other prognostic factors are still relevant in patients getting post-salvage PET scanning. Moreover, while ASCT is often also used for patients with R/R transformed indolent lymphoma (TIL), there are no data on whether prognostic factors that are important for DLBCL patients, especially PET response to salvage, are similarly prognostic in this population. We conducted a retrospective study of 143 patients with R/R DLBCL and TIL who were transplanted in the last decade and had a post-salvage PET scan prior to ASCT. We examined prognostic factors in both groups, and constructed a prognostic score for DLBCL patients. For patients with DLBCL, post-salvage PET response was an important prognostic factor. Advanced age and symptomatic relapse were also significantly associated with inferior outcome. A simple score could stratify patients into 3 risk groups with 4-year post-ASCT overall survival of 84%, 59%, and 10%, and 4-year progression-free survival of 67%, 41% and 0% (p

Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease with multiple distinct molecular subtypes. Increased NF-κB activity and expression of the microRNA miR-155 (product of the BIC gene) are associated with one subtype, called the activated B-cell (ABC) subtype. It is shown here that induction of NF-κB activity leads to increased miR-155 expression, the levels of miR-155 in a panel of B-lymphoma cell lines correlate with increased NF-κB activity, and the NF-κB p50/p65 heterodimer binds to a specific DNA site in the BIC promoter. Also described is a regulatory network wherein NF-κB-dependent up-regulation of miR-155 leads to reduced PU.1 transcription factor expression and consequently reduced PU.1-driven expression of B-lymphoma marker CD10 in the human B-lymphoma cell line BJAB. Genetic variation in DLBCL can be used to explain the response of individual patients to chemotherapy. One cancer therapeutic approach currently in clinical trials uses histone deacetylase inhibitors (HDACi's) as a monotherapy or in combination with other vi agents. It is shown here that two pan-HDACi's, trichostatin A and vorinostat, induce apoptosis in seven of eight human DLBCL cell lines. Ectopic over-expression of antiapoptotic proteins BCL-2 and BCL-XL or the pro-apoptotic protein BIM in select DLBCL cell lines can confer further resistance or sensitivity, respectively, to HDACi treatment. Additionally, the BCL-2 family antagonist ABT-737 can increase the sensitivity of several DLBCL cell lines to vorinostat-induced apoptosis, including the HDACi-resistant SUDHL6 cell line. Moreover, one vorinostat-resistant variant of the HDACi-sensitive cell line SUDHL4 has increased expression of anti-apoptotic proteins BCL-XL and MCL-1 and decreased sensitivity to ABT-737, and a second such variant cell line has increased expression of anti-apoptotic protein MCL-1. These results suggest that the balance of anti- to pro-apoptotic BCL-2 family protein expression is important in determining the sensitivity of DLBCL cell lines to HDACi-induced apoptosis. Thus, the sensitivity of DLBCL cell lines to treatment with HDACi's appears to depend on the complex regulation of BCL-2 family members, suggesting that the response of a subset of DLBCL patients to HDACi treatment may benefit from co-treatment with BCL-2 antagonists.

Introduction: Horner’s syndrome has a variety of etiologies ranging from benign to serious life-threatening conditions and has been infrequently reported as a presenting symptom of patients with lymphoid neoplasms. Only one case of Burkitt’s lymphoma presenting with toothache, paresthesia, and Horner’s syndrome has been described and no case reports of diffuse large B-cell lymphoma as the etiology of Horner’s syndrome currently exist in the literature. In addition, lymphoid neoplasms have rarely been reported to occur in patients with neurofibromatosis type 1 despite an increased risk of many types of cancer in such cases. Case presentation: A 28-year-old Thai man presented with a progressively enlarged left supraclavicular mass together with a significant weight loss and night sweating for four months. He also noticed hoarseness and ptosis of his left eye associated with double vision for two months. Physical examination revealed large supraclavicular lymphadenopathy and Horner’s syndrome (ptosis, miosis, and anhydrosis) on the left side of his face. A large mediastinal mass was clearly detected by chest X-ray and computed tomography and subsequent lymph node biopsy provided a diagnosis of diffuse large B-cell lymphoma. Interestingly, the patient was also definitely diagnosed with neurofibromatosis type 1 from multiple café au lait macules, axillary freckles, three neurofibromas, multiple Lisch nodules, and a history of affected family members. He subsequently received chemotherapy with a good response. Twenty-seven cases of various types of lymphoid neoplasms previously reported to occur in neurofibromatosis type 1 patients were also extracted from the literature. All cases were non-Hodgkin lymphoma and the major subtype was T-cell. Only nine cases were B-cell lymphoma. The majority of cases were young with a median age at lymphoma diagnosis of 9.4 years (range 1.1 to 77 years). Two-thirds of the cases were boys or men. Other concomitant malignancies were brain tumor, colorectal cancer, pheochromocytoma, and acute lymphoblastic leukemia. Conclusions: We describe for the first time a case of diffuse large B-cell lymphoma that occurred in a neurofibromatosis type 1 patient with Horner’s syndrome. Horner’s syndrome can be an initial manifestation of diffuse large B-cell lymphoma. Patients who present with a classical triad of Horner’s syndrome should always be fully investigated for lymphomatous involvement, especially in the thorax. The exact molecular mechanism for diffuse large B-cell lymphoma development in neurofibromatosis type 1 cases remains to be elucidated.