Chemotherapy-refractory Lymphoma Research Articles

Radiation and Chimeric Antigen Receptor T-cell Therapy in B-cell Non-Hodgkin Lymphomas.

Chimeric antigen receptor T-cell therapy (CAR-T) is a revolutionary advancement in the management of chemotherapy refractory B-cell non-Hodgkin lymphomas representing a potentially curative therapy in scenarios that were previously only palliative. CAR-T cell therapy is associated with unique toxicities as well as practical challenges. One of those challenges is how to manage active lymphoma during the weeks-long CAR-T manufacturing process. Radiation therapy, steroids, and systemic therapy have all been used for what would be considered "bridging therapy" during this time frame. Radiation therapy is a particularly attractive strategy given its proven efficacy in chemotherapy refractory lymphomas; ability to stabilize patients, debulk disease, and palliate symptoms; as well as its potential to enhance the expansion and activity of CAR-T cells. Optimal dose, timing, and method of delivery are yet to be established though there is consensus that it should occur after apheresis if being used as a pre-treatment bridge. Another practical challenge is the management of patients in whom CAR-T cells fail. There is a potential emerging role for salvage radiation therapy, in select patients, for either palliation or as a means to get patients another potentially curative therapy. Collaborative well-designed prospective clinical trials are needed to definitively establish the role for radiation therapy (before or after CAR-T therapy) as well as define the impact on CAR-T cell activity/persistence and associated toxicity.

Drug Repurposing Patent Applications October-December 2020.

Drug Repurposing Patent Applications October-December 2020.

Yescarta: A New Era for Non-Hodgkin Lymphoma Patients.

The use of conventional therapeutic approaches in patients with lymphoma demonstrates significant drug resistance leading to poor prognosis with reduced median survival period. T-cell immunotherapy has diverted huge attention of the researchers in recent times to engage in the stated research studies in the pool of chemotherapy-refractory lymphoma patients. B-cell antigen CD19-targeted chimeric antigen receptor (CAR) T-cell products are approved for the treatment of non-Hodgkin B-cell refracting or relapsing lymphoma. The aim of this article is to give an idea about the use of FDA-approved anti-cancer gene therapy, Axicabtagene ciloleucel, marketed under the name of Yescarta®. Axicabtagene ciloleucel is developed from the patients’ mononuclear peripheral blood cells during which T cells are orchestrated to articulate a CAR that diverts them to identify CD19-expressing cells. It is used in patients with non-Hodgkin B-cell refracting or relapsing lymphoma who had no response to prior therapeutic regiment involving the use of chemotherapeutics. Here, we review the mode of action, safety, and efficacy of Yescarta.

Clinical anti-lymphoma effect of T cells expressing an anti-CD19 chimeric antigen receptor in synthetic biology optimizing system.

e20021 Background: Anti-CD19 chimeric antigen receptor (CAR) T cells for relapse/refractory B-cell malignancies has been remarkably effective in previous clinical trials. However, most of subjects has severe adverse effect even though the infusion of CAR T cells is at the low dose. Herein, we investigated the safety of administering CAR T cells which express the anti-CD19 chimeric antigen receptor in synthetic biology optimizing system. Methods: We designed an anti-CD19 CAR with FMC63 Scfv (KD-019). This CAR has a CD8 hinge and transmembrane domains and a 4-1BB costimulatory domain; T cells expresses CAR in synthetic biology optimizing system. A phase I dose-escalation trial was conducted to investigate the safety of KD-019 CAR T cells and to assess efficacy for patients with previously treated B-cell lymphoma. The patient at the 76 years old received Flu/Cy chemotherapy to enhance CAR T cells activity. Two days after the completion of chemotherapy, about 3 million KD-019 CAR T cells were infused. Results: The patient who has chemotherapy-refractory lymphoma has received KD-019 CAR T cells infusion. Post infusion KD-019 CAR T cells expansion were observed; peak CAR T cells level occurred between Day 3 and 10, and CAR T cells were still detected on Day 243. In addition, we found that CD3+CD8+ T cells level peaked on Day 15. Moreover, after infusion of CAR-T cells, the right peripheral pulmonary lymphaden and visible nodules were respectively shrunk by 53% and 85% on Day 28; and some peripheral pulmonary nodules were obviously reduced and nearly disappeared. We also found that pelvic effusion was significantly reduced, and pain symptoms of the left hip and leg were reduced by 50%. Exhilaratingly, our KD-019 CAR therapy has no obvious cytokine release syndrome (CRS) and central nervous system toxicity. Conclusions: KD-019 CAR T cells express an anti-CD19 chimeric antigen receptor in synthetic biology optimizing system. this innovative KD-019 product can offer significant clinical benefit for NHL patients at the low dose without fever and neurotoxicity. Clinical trial information: NCT03854994. Clinical trial information: NCT03854994 .

Long-term follow-up of anti-CD19 CAR T-cell therapy for B-cell lymphoma and chronic lymphocytic leukemia.

3012 Background: T cells expressing anti-CD19 chimeric antigen receptors (CARs) can cause complete remissions of relapsed lymphoma. We conducted the first clinical trial of anti-CD19 CAR T cells to show responses against lymphoma. This CAR was later developed as axicabtagene ciloleucel. Here, we aimed to assess the long-term durability of remissions and the long-term adverse effects after anti-CD19 CAR T-cell therapy. Methods: Between 2009 and 2015, we treated 43 patients with anti-CD19 CAR T cells preceded by conditioning chemotherapy of cyclophosphamide plus fludarabine (NCT00924326). Three patients were re-treated for a total of 46 CAR T-cell treatments. Twenty-eight patients had aggressive lymphoma (diffuse large B-cell lymphoma or primary mediastinal B cell lymphoma), eight patients had low-grade lymphoma (five with follicular lymphoma and 1 each with splenic marginal zone lymphoma, mantle cell lymphoma, and unspecified low-grade non-Hodgkin lymphoma), and seven patients had chronic lymphocytic leukemia (CLL). Patients were treated in three cohorts that differed in the CAR T-cell production process and conditioning chemotherapy dose. Results: Of the 43 treated patients, 63% had chemotherapy-refractory lymphoma. Patients had received a median of 4 previous lines of therapy. The median CAR+ T cell dose per kilogram was 2X10^6. The overall remission rate was 76% with 54% complete remissions (CR) and 22% partial remissions (PR). Patients with CR had higher median peak blood CAR levels (86 CAR+ cells/µL) than those who did not have CR (16 CAR+ cells/µL, P= 0.0041). Long-term adverse effects were rare except for B-cell depletion and hypogammaglobulinemia, which both improved over time. Conclusions: This is the longest follow-up study of patients who received anti-CD19 CAR T cells. Anti-CD19 CAR T cells cause highly durable remissions of relapsed B-cell lymphoma and CLL, and long-term adverse effects of anti-CD19 CAR T cells were rare and usually mild. Clinical trial information: NCT00924326 . [Table: see text]

CAR-T cell Therapy for Non-Hodgkin Lymphomas: A New Treatment Paradigm.

The majority of patients with B-cell non-Hodgkin lymphoma (NHL) can be cured with standard chemoimmunotherapy. However, patients who fail first line therapy have dismal outcomes, particularly if they have disease that is resistant to salvage therapy, including chemoimmunotherapy, radiation and/or autologous stem cell transplantation. Indolent B-NHLs, such as follicular lymphoma (FL), although not generally considered curable may be treated over many years with good prognosis. However, a subset of B-NHLs can undergo histologic transformation into more aggressive subtypes with outcomes similar to aggressive B-NHLs. In recent years, T cells genetically modified with chimeric antigen receptors (CARs), have demonstrated a remarkable capacity to induce complete and durable clinical responses in patients with chemotherapy-refractory lymphomas. Indeed, two autologous CD19-directed CAR-modified T cell products have now been FDA-approved for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) and transformed FL, while a plethora of other CAR-T cell targets are being explored in ongoing clinical trials. The purpose of this review is to summarize the clinical efficacy and unique toxicities of individually developed CAR-T cell products for the treatment of lymphomas, and their evolution from the laboratory bench to commercialization.

Chimeric antigen receptor T-cell therapies for lymphoma.

New therapies are needed for patients with Hodgkin or non-Hodgkin lymphomas that are resistant to standard therapies. Indeed, unresponsiveness to standard chemotherapy and relapse after autologous stem-cell transplantation are indicators of an especially poor prognosis. Chimeric antigen receptor (CAR) T cells are emerging as a novel treatment modality for these patients. Clinical trial data have demonstrated the potent activity of anti-CD19 CAR T cells against multiple subtypes of B-cell lymphoma, including diffuse large-B-cell lymphoma (DLBCL), follicular lymphoma, mantle-cell lymphoma, and marginal-zone lymphoma. Importantly, anti-CD19 CAR T cells have impressive activity against chemotherapy-refractory lymphoma, inducing durable complete remissions lasting >2 years in some patients with refractory DLBCL. CAR-T-cell therapies are, however, associated with potentially fatal toxicities, including cytokine-release syndrome and neurological toxicities. CAR T cells with novel target antigens, including CD20, CD22, and κ-light chain for B-cell lymphomas, and CD30 for Hodgkin and T-cell lymphomas, are currently being investigated in clinical trials. Centrally manufactured CAR T cells are also being tested in industry-sponsored multicentre clinical trials, and will probably soon become a standard therapy. Herein, we review the clinical efficacy and toxicity of CAR-T-cell therapies for lymphoma, and discuss their limitations and future directions with regard to toxicity management, CAR designs and CAR-T-cell phenotypes, conditioning regimens, and combination therapies.

Anti-CD19 chimeric antigen receptor T cells preceded by low-dose chemotherapy to induce remissions of advanced lymphoma.

LBA3010 Background: T cells genetically-modified to express chimeric antigen receptors (CARs) targeting CD19 have potent activity against a variety of B-cell malignancies. Chemotherapy is administered prior to CAR T cells because depletion of recipient leukocytes enhances the anti-malignancy efficacy of adoptively-transferred T cells; an increase in serum interleukin (IL)-15 is one mechanism for this enhancement. Previously, we (Kochenderfer et al. Journal of Clinical Oncology, 2015) and others have reported patients treated with high-dose chemotherapy prior to anti-CD19 CAR T-cell infusions. This report describes treatment of 22 patients with low-dose conditioning chemotherapy followed by infusion of anti-CD19 CAR T-cells. Methods: Eighteen of 22 treated patients received 300 mg/m2 of cyclophosphamide (cy) daily for 3 days; 4 patients received 500 mg/m2 of cy on the same schedule. All patients received fludarabine 30 mg/m2daily for 3 days on the same days as cy. Patients received a single dose of CAR T cells 2 days after completion of chemotherapy. Blood CAR T cells and serum cytokines were analyzed in all patients. Results: Nineteen patients with various subtypes of diffuse large B-cell lymphoma (DLBCL) had the following responses: 8 CR, 5 PR, 2 SD, and 4 PD. One patient with mantle cell lymphoma obtained a CR. Two patients with follicular lymphoma both obtained CRs. Durations of response currently range from 1 to 20 months; 10 remissions are ongoing. All but 4 patients had either chemotherapy-refractory lymphoma or lymphoma that had relapsed after autologous stem cell transplant. The most prominent toxicities were various neurological toxicities. Other toxicities included fever and hypotension. The median peak blood CAR+ cell level was 47/μL (range 4-1217/μL). Patients obtaining CRs or PRs had higher peak blood CAR+ cell levels than patients experiencing SD or PD. The mean serum IL-15 level was 4 pg/mL before the conditioning chemotherapy and 32 pg/mL after chemotherapy (P < 0.0001). Conclusions: Anti-CD19 CAR T cells can induce remissions of advanced B-cell lymphoma when administered after low-dose chemotherapy. In the near future, CAR T cells will likely be a standard therapy for lymphoma. Clinical trial information: NCT00924326.

CMV-Replication After Allogeneic Stem Cell Transplantation Is Associated with a Gvhd-Independent Reduced Relapse Risk in Lymphoma

Abstract 1635 Background:We have previously showed that a CMV- reactivation after allogeneic HSCT is associated with a reduced risk for leukemic relapse and improved overall survival in patients with AML (Elmaagacli et al Blood 2011). Further, experimental data in a lymphoma mice model reported from Erlach et al. showed that coinfection with murine CMV revealed a strong anti-lymphoma effect by induction of apoptosis in lymphoma cells and improving rate of overall survival in mice after transplant. Methods:This prompted us to investigate the influence of early replicative CMV infection in 94 (median age [years]: 45, 18 – 70) patients with lymphoma, who received transplants from unrelated (n=67) or related (n=27) donors. Patients were transplanted from HLA-identical (n=74), HLA-mismatched (n=20). 13 patients were transplanted for indolent lymphoma (FL n=11, CLL n=2), 67 patients for aggressive lymphoma (B-lineage n=35, T-lineage n=27, transformed n=5), 11 patients for MCL and 3 patients for HD. The disease stages of patients at HSCT were CR in 20 patients, PR in 40 patients, refractory in 30 patients and untested in 2 patients. 55 patients (59%) received previous autograft and 82 patients (87%) were treated prior to transplant with at least 3 chemotherapy lines. The hematopoietic cell transplantation specific comorbidity index (HCT-CI) were 0–2 in 76 patients (81%) and 3+ in 18 patients (19%). Myeloablative preparative regimen was applied in 60 patients (64%) while 34 patients (36%) received a RIC. Sixty-eight % of patients (n=48) were at risk for CMV reactivation based on either patient or donor pretransplant CMV serostatus. CMV replication as detected by pp65 antigenemia assay occurred in 34 patients (36%). Results:Taking all competing risks into account, the cumulative incidence of progressive free survival (PFS) at 5 years after alloSCT was 38 % (95 % confidence limit [95 % CL]: 31 – 45) in patients without as compared to 20 % (95 % CL: 9 – 31) in patients with early pp65 antigenemia (p<0.018). In multivariate analysis including parameters as grades II-IV acute graft-versus-host disease (GvHD), chronic GvHD, disease stage, chemorefractory, previous chemotherapy lines and pp65 antigenemia, CMV replicative status was confirmed as a strong independent predictor of PFS (hazard ratio [HR]: 0.29, 95 % CL: 0.08 – 1.00, p<0.049) together with chronic GvHD (HR: 0.32, 95 % CL: 0.13 – 0.80, p<0.016), and chemorefractory HR: 3.3, 95 % CL: 1.28 – 8.4, p<0.013). The anti-lymphoma effect was detectable across all lymphoma subsets and was most pronounced in patients with chemotherapy refractory lymphoma or refractory disease of lymphoma. However, Overall survival rate did not differ in both groups (51.9% for patients with CMV-replication versus 50.7% without n.s.) Conclusions:This is the first report which demonstrates a strong and independent effect of early CMV replication on the PFS in patients with lymphoma. This effect deserves further and more comprehensive studies with regard to its clinical relevance and the underlying anti-lymphoma mechanisms.Cumulative incidence of progression-free survival (PFS) stratified by posttransplant HCMV pp65-antigenemia and cell type of aggressive lymphoma. Disclosures:No relevant conflicts of interest to declare.

P-0136 10 Cases of Non-Hodgkin's Lymphoma that Caused Gastrointestinal Perforation - Experience in our Department

ABSTRACT Introduction It is common that malignant lymphoma infiltrates the digestive tract. It may also cause gastrointestinal perforation after initial chemotherapy, resulting from its good response to the therapy. We report our experience with 10 patients who developed gastrointestinal perforation while being observed for malignant lymphoma. Methods In the case that hematologic malignancy was diagnosed in our hospital by 1990 from 2011. We intended to consider the 10 cases of gastrointestinal perforation about diagnosis, age, gender, pathological classification, clinical stage of malignant lymphoma, time of perforation, location, therapy and prognosis. Results The ratio of men to women was 8:2 and the median age was 64 years (range: 40 to 77 years). The histopathologic type was non-Hodgkin's lymphoma in all cases, with a subtype of T-cell leukemia/lymphoma (ATLL) in 1 case, follicular lymphoma (grade 2) in 1 case, diffuse large B-cell lymphoma in 6 cases, diffuse large T-cell lymphoma in 1 case, and diffuse mixed lymphoma (B-cell ) in 1 case. According to the Ann Arbor staging system, the clinical stage was IA in 1case, IE in 1 case, IIIE in 1 case, IVA in 3 cases, and IVB in 4 cases. Perforation occurred prior to chemotherapy in 2 cases, after completion of the first cycle of chemotherapy in 3 cases, after 4 cycles in 1 case, after 6 cycles in 2 cases, during the advanced stage of chemotherapy-refractory lymphoma in 1 case, and during recurrence after complete response in 1 case. The site of perforation was the stomach in 2 cases, the duodenum in 1 case, the jejunum in 2 cases, and the ileum in 5 cases. After the occurrence of perforation, a total of 8 patients underwent urgent laparotomy. Causes of death and duration of survival after perforation, of the 10 patients, 7 patients died. The cause of death was diffuse peritonitis in 4 cases and side effect of postoperative chemotherapy in 2 cases such as gastrointestinal hemorrhage, serious infection, 1 case achieved unconfirmed complete remission, but relapsed after 2years and indicated refractory to chemotherapy and died. 3 cases achieved complete response after finishing seven cycles of chemotherapy following emergency surgery. These cases are now being followed on an outpatient basis. The median survival in all patients was 13 days (range: 6 to 716 days). Conclusion The reason for the relatively high frequency of small intestine perforation is that the small intestine is originally devoid of cell-to-cell adhesiveness and lymphocytes, which do not produce extracellular matrix and proliferate without producing connective tissues involving the whole thickness, resulting in coarse cell junctions in the intestinal tract wall. In conclusion, according to our experience, it was suggested that curative resection is not mandatory in patients undergoing surgery for gastrointestinal perforation associated with malignant lymphoma and it is important to start chemotherapy in the early postoperative period and select a safer surgical procedure, such as limited surgery, that prioritizes patients' survival according to their individual general condition, flexibly assessing the necessity of removing the lesions.

Synergistic cytotoxicity of the DNA alkylating agent busulfan, nucleoside analogs and suberoylanilide hydroxamic acid in lymphoma cell lines

Hematopoietic stem cell transplant (HSCT) is a promising treatment for lymphomas. Its success depends on effective pre-transplant conditioning regimens. We previously reported on the efficacy of DNA alkylating agent–nucleoside analog (NA) combinations for conditioning in acute myeloid leukemia (AML). We hypothesized that a similar combinatory approach can be used for lymphomas. A combination of busulfan (Bu) with two NAs - clofarabine (Clo), fludarabine (Flu) or gemcitabine (Gem) - resulted in synergistic cytotoxicity in lymphoma cell lines. We demonstrated that the [2 NAs + Bu] combination activates a DNA damage response through the ATM-CHK2 and ATM-CHK1 pathways, leading to cell cycle checkpoint activation and apoptosis. Histone modifications and KAP1 phosphorylation are indicative of chromatin relaxation mediated by the nucleoside analogs, which sequentially increase Bu alkylation. Addition of suberoylanilide hydroxamic acid (SAHA) enhanced chromatin relaxation through increased histone acetylation and further augmented the cytotoxicity of [2 NAs + Bu]. Our results provide a preclinical basis for a clinical trial on using [2 NAs + Bu ± SAHA] combinations as conditioning therapy for patients with chemotherapy-refractory lymphoma undergoing HSCT.

Hepatosplenic T-cell lymphoma associated to thiopurine in Ulcerative Colitis patient from Brazil: A case report

Hepatosplenic T-cell lymphoma (HSTCL) is a rare and usually fatal peripheral T-cell lymphoma that primarily affects men younger than 35 years old. Treatment with thiopurines of patients with inflammatory bowel disease (IBD) has been associated with HSTCL, especially when submitted to a combined therapy with antibodies to tumor necrosis factor (anti-TNFs). Herein, we describe the case of an 25-year-old man with diagnosis of Ulcerative Colitis disease since 2003. He was initially treated with sulfasalazine 6g/dia, interspersed with prednisone during episodes of exacerbation. In July 2007 he started treatment with 50mg of azathioprine after a disease exacerbation. The dose was adjusted by the weight through 150mg/day, maintaining remission. Within 3 years and 3 months under azathioprine therapy he started to show changes in blood count and leukopenia. After an hematology evaluation, there was a diagnose of HSTCL. He died 8 months after diagnosis from chemotherapy-refractory lymphoma. Through a literature review, we identified 16 cases of HSTCL in patients with Inflammatory Bowel Disease treated with azathioprine or 6-mercaptopurine alone. Only 06 of these patients had the diagnosis of Ulcerative Colitis. The median age at diagnosis of HSTCL was 24 years (range, 15-35 years). The median duration of thiopurine exposure was 06 years (range, 3-17 years). 11 of these patients died, with only 04 patients achieving remission. Despite the known benefits in the treatment of IBD, additional research is needed to better understand the role of thiopurines and TNF-alpha inhibitors in promoting HSTCL. The absolute risk and the frequency of HSTCL is very low. With respect to safety, however, special caution in prescribing this therapy to male 35 years-old and younger IBD patients should be recommended, mainly during a period of 24 months or more.

Hepatosplenic T-Cell Lymphoma in a Young Man With Crohn's Disease: Case Report and Literature Review

Hepatosplenic T-cell lymphoma (HSTCL) is a rare form of peripheral T-cell lymphoma. It is associated with an aggressive clinical course, a poor response to conventional treatment, and an exceedingly high mortality rate. Recent reports suggest an excessive number of cases of HSTCL in young patients with Crohn's disease who are treated with thiopurines (azathioprine or 6-mercaptopurine [6-MP]) either in conjunction with or without agents that inhibit tumor necrosis factor-alpha (TNF-alpha). Herein, we describe the case of an 18-year-old man with Crohn's disease who developed HSTCL after 5 years of 6-MP treatment. He died 7 months after diagnosis from chemotherapy-refractory lymphoma. Through a literature review, we identified 28 cases of HSTCL in Crohn's patients. All patients were treated with azathioprine or 6-MP; 22 of 28 (79%) received concomitant treatment with infliximab, and 3 of these 22 patients later received treatment with adalimumab. The median age at diagnosis of HSTCL was 22 years (range, 12-40 years). The median survival for all patients was 8 months (range, 5 days-31+ months), with only 1 patient achieving remission. Additional research is needed to better understand the role of thiopurines and TNF-alpha inhibitors in promoting HSTCL and what can be done to prevent and treat this devastating malignancy in young patients with Crohn's disease.

A multicentre phase II clinical experience with the novel aza‐epothilone Ixabepilone (BMS247550) in patients with relapsed or refractory indolent non‐Hodgkin lymphoma and mantle cell lymphoma

The epothilones represent a novel group of microtubule stabilization agents that appear to retain activity even in chemotherapy-resistant cell lines and animal models. Because of their ability to overcome chemotherapy resistance, we conducted a phase II study of Ixabepilone in patients with indolent non-Hodgkin lymphoma and mantle cell lymphoma (MCL). Ixabepilone was given at a dose of 25 mg/m(2) weekly for three of four consecutive weeks. Patients were required to have received < or =4 prior chemotherapy regimens, with an interval of at least one month since the last treatment, 3 months from prior rituximab, and 7 d from prior steroids, an absolute neutrophil count >1 x 10(9)/l and a platelet count >50 x 10(9)/l. Dose reductions were allowed. The overall response rate in assessable patients was 27% in this otherwise heavily treated population. One patient with chemotherapy-refractory follicular lymphoma attained a complete remission that lasted approximately 8 months. Three responses were also seen in refractory MCL and one in small lymphocytic lymphoma. The duration of response ranged from 2 to 8 months. Major toxicities included fatigue, myelosuppression and neuropathy. These data suggest that Ixabepilone has activity in chemotherapy-refractory lymphoma.

Human soluble TRAIL/Apo2L induces apoptosis in a subpopulation of chemotherapy refractory nodal diffuse large B‐cell lymphomas, determined by a highly sensitive in vitro apoptosis assay

Resistance to chemotherapy in therapy-refractory diffuse large B-cell lymphomas (DLBCL) is related to inhibition of the intrinsic apoptosis pathway. Human soluble tumour necrosis factor (TNF)-related apoptosis-inducing ligand (hsTRAIL/Apo2L) induces apoptosis via the alternative, death-receptor mediated apoptosis pathway and might be an effective alternative form of therapy for these lymphomas. This study investigated whether hsTRAIL/Apo2L could actually induce apoptosis in isolated lymphoma cells of DLBCL biopsies of patients with chemotherapy-refractory DLBCL. Twelve out of a total of 22 DLBCL samples were sensitive to hsTRAIL/Apo2L. These sensitive lymphomas included seven clinically chemotherapy-refractory lymphomas. Furthermore, hsTRAIL/Apo2L induced apoptosis in DLBCL cells and in B-cell lines that showed high expression levels of inhibitors of the intrinsic apoptosis pathway: Bcl-2 and/or X-linked inhibitor of apoptosis (XIAP). hsTRAIL/Apo2L-sensitive lymphoma cells showed expression of the TRAIL receptors R1 and/or R2 and absence of R3 and R4. We conclude that hsTRAIL/Apo2L induced apoptosis in a subpopulation of chemotherapy-refractory nodal DLBCL and that disruption of the intrinsic apoptosis-mediated pathway and expression of Bcl-2 and XIAP did not confer resistance to hsTRAIL/Apo2L-induced apoptosis in DLBCL. Thus, based on our results, further exploration of hsTRAIL/Apo2L as an alternative treatment for patients with chemotherapy-refractory DLBCL should be considered.

Risk Adapted Dose Intensive DICEP Salvage Chemotherapy Prior to Autologous Stem Cell Transplantation Yields Successful Outcomes in Chemotherapy Refractory Lymphoma.

Background: Previous reports have suggested that patients with aggressive histology lymphoma who fail to respond to standard-dose salvage chemotherapy are unlikely to become long-term survivors with high-dose therapy. Thus, chemotherapy-refractory disease has traditionally been considered a contraindication for autologous transplantation. Whether the use of dose-intensified salvage chemotherapy prior to transplantation will alter outcomes is unknown.Patients and Methods: 207 patients with aggressive lymphoma (diffuse large cell B cell NHL n=137, Hodgkins Disease n=70) underwent autologous peripheral blood (n=192), bone marrow (n=7) or combined (n=8) transplantation at Hackensack University Medical Center between January 1997 and June 2004 using a regimen of BCNU 600 mg/m2, Etoposide 1600 mg/m2, Cytarabine 24 gms/m2 and Cyclophosphamide 90 mg/m2 (with dose attenuations for advanced age/poor performance status). All patients received a single cycle of DICE (Dexamethasone 160 mg, Ifosphamide 4 gm/m2, Cisplatin 100 mg/m2, Etoposide 400 mg/m2 in divided doses over 4 days) chemotherapy at the time of initial relapse. Restaging was performed and responding patients (n=142) received a second cycle of DICE prior to collection of stem cells. Patients not achieving at least a PR (>50% reduction in tumor bulk or only minimal residual for low volume disease) were considered to have chemotherapy refractory disease (n=65) and were given an intensified salvage regimen of DICEP (dose intensive Cyclophosphamide 5000 mg/m2, Etoposide 1500 mg/m2, Cisplatin 120 mg/m2 in divided doses over 3 days) prior to stem cell collection.Results: Chemotherapy refractory patients receiving dose intensified DICEP prior to autologous transplantation were able to achieve long-term survival. The 3 and 7-year Kaplan-Meier survival rates for DICEP treated refractory patients were 43% and 39%, respectively. This compares favorably, although less than, chemosensistive lymphoma patients treated with DICE salvage (3-yr: 65%, 7-yr: 52%; versus DICEP log-rank p=0.004). This difference in survival between refractory/sensitive patients held in both non-Hodgkins (refractory 3-yr: 47%, 7-yr 47%; sensitive 3-yr 61%, 7-yr: 47%; p=0.017) and Hodgkins Disease (refractory 3-yr: 48%, 7-yr: 39%; sensitive 3-yr: 74%, 7-yr: 61%; p=0.07). The most significant difference in outcomes by chemosensitivity was noted among patients with 1st relapse, with 3 and 7-year survivals of 70% and 58% in DICE sensitive and 32% and 32% in refractory patients requiring DICEP (p=0.0016). Minimal differences (p=0.36) were noted in Primary Induction Failure patients (7 yr survivals of 47% in both). Early (<100 day) all-cause mortality was similar among refractory (21.5%) and sensitive (14%; z=1.15; p=0.25) patients, although early relapse death rates trended higher in the refractory patients (15% vs 7%; z=1.63; p=0.10).Conclusions: Aggressive histology lymphoma patients not responding to standard-dose DICE salvage therapy may become long-term survivors with DICEP salvage followed by autologous transplantation, although outcomes are slightly inferior. A risk adapted strategy of dose intensified salvage in refractory lymphomas should be considered and transplant offered to chemotherapy refractory patients.

Establishment of early donor engraftment after reduced-intensity allogeneic hematopoietic stem cell transplantation to potentiate the graft-versus-lymphoma effect against refractory lymphomas

Reduced-intensity allogeneic hematopoietic stem cell transplantation (alloHSCT), which typically results in mixed chimerism initially after transplantation, has had limited efficacy in chemotherapy-refractory lymphomas. We hypothesized that the rapid establishment of complete donor chimerism would potentiate a graft-versus-lymphoma effect. Fifteen patients with chemotherapy-refractory lymphoma initially received induction with a conventional chemotherapy regimen (etoposide, prednisone, vincristine, cyclophosphamide, adriamycin, fludarabine [EPOCH-F]) to deplete host T cells and provide disease control prior to alloHSCT. Patients then received conditioning with fludarabine and cyclophosphamide followed by alloHSCT from HLA-matched siblings. Graft-versus-host disease prophylaxis consisted of cyclosporine alone. EPOCH-F resulted in 73% of patients having partial responses or stable disease. EPOCH-F depleted host CD4 + T cells from a median of 235 cells/μL to 56 cells/μL. Fourteen patients underwent alloHSCT, and all had >95% donor engraftment by day 14 after transplantation. The incidence of Grade II to III acute graft-versus-host disease was 71%. There were two therapy-related deaths. There were 8 partial responses and 3 complete responses (CRs) at day 28. Five additional CRs were observed at day 100 without withdrawal of cyclosporine or donor lymphocyte infusion. The rate of CRs for all 15 patients was 60%. The 1-year progression-free survival rate from time of study entry is 67% with only 1 relapse among 9 CRs. At a median potential follow-up of 28 months, the overall survival rate is 53%. These data demonstrate that a potent and durable graft-versus-lymphoma effect can occur against chemotherapy-refractory lymphomas and suggest that this effect may be associated with rapid, complete donor chimerism after reduced-intensity alloHSCT. © 2003 American Society for Blood and Marrow Transplantation Biology of Blood and Marrow Transplantation 9:162-169 (2003)

Reduced-intensity allogeneic transplantation for lymphoma.

Reduced-intensity allogeneic transplants are promising, increasingly used treatments for hematologic malignancies, exploiting graft-versus-tumor effects for eradicating malignancies. This article reviews approximately 40 published reports of reduced-intensity allogeneic transplants in lymphomas. Overall, reduced-intensity allogeneic transplants have been well tolerated and have produced encouraging results despite a diversity of transplant approaches used largely in heavily pretreated and older patients. Of 368 lymphoma patients who underwent reduced-intensity allogeneic transplants, 66.3% had responses, most of which were complete. Many had chemotherapy-refractory lymphomas, including some that relapsed after autologous transplants. Although the short follow-up periods of many studies do not permit assessments of response duration, protracted remissions were reported in some studies. Additionally, some patients entered molecular remissions, suggesting that graft-versus-tumor effects could, by themselves, cure some lymphomas. Graft-versus-host disease is the major risk of reduced-intensity allogeneic transplants, and treatment methods need refinement to reduce transplant risks while preserving graft-versus-tumor effects. Controlled trials involving patients with earlier-stage disease appear warranted to define better the role of reduced-intensity allogeneic transplants in treating lymphomas.

Dose-escalated total body irradiation and autologous stem cell transplantation for refractory hematologic malignancy

Purpose: To evaluate the feasibility of dose escalation of total body irradiation (TBI) above the previously reported maximally tolerated dose, we have undertaken a Phase I–II trial of dose-escalated TBI with autologous peripheral blood stem cell transplantation (PBSCT) for chemotherapy-refractory lymphoma. Methods and Materials: Nine lymphoma patients with primary refractory disease (PRD) or in resistant relapse (RR) received dose-escalated TBI and PBSCT. The three dose levels of fractionated TBI (200 cGy twice daily) were 1,600 cGy, 1,800 cGy, and 2,000 cGy. Lung blocks were used to reduce the TBI transmission dose by 50%, and the chest wall dose was supplemented to the prescribed dose using electrons. Shielding of the kidneys was performed to keep the maximal renal dose at 1,600 cGy. Three patients, two with non-Hodgkin’s lymphoma (NHL) in RR and one with PRD Hodgkin’s disease, received 1,600 cGy + PBSCT, three patients (two NHL in RR, one PRD) received 1,800 cGy + PBSCT, and three patients with NHL (two in RR, one PRD) received 2,000 cGy + PBSCT. Results: Toxicities associated with this high-dose TBI regimen included reversible hepatic veno-occlusive disease in 1 patient, Grade 2 mucositis requiring narcotic analgesics in 8 patients, and neurologic toxicities consisting of a symmetrical sensory neuropathy ( n = 4) and Lhermitte’s syndrome ( n = 1). Interstitial pneumonitis developed in 1 patient who received 1,800 cGy after receiving recombinant α-interferon (with exacerbation after rechallenge with interferon). Six (66%) patients achieved a response. Four (44%) patients achieved complete responses, three of which were of a duration greater than 1 year, and 2 (22%) patients achieved a partial response. One patient remains disease-free more than 5 years posttransplant. Corticosteroid-induced gastritis and postoperative infection resulted in the death of 1 patient in complete response, 429 days posttransplant. Conclusion: TBI in a dose range 1,600–2,000 cGy as preparative therapy for autologous PBSCT is feasible and has substantial activity in chemorefractory non-Hodgkin’s and Hodgkin’s lymphoma.

Treatment of patients with malignant lymphomas with monoclonal antibodies

Malignant lymphomas represent a heterogenous group of B and T cell-derived malignancies. Most lymphomas are sensitive to chemo- and radiotherapy, however many patients will eventually relapse. Immunotherapeutic approaches including monoclonal antibodies, cytokines or vaccination approaches may offer an alternative treatment of chemotherapy-resistant residual cells especially in cases with low tumor burden or residual disease following chemo- or radiotherapy. Monoclonal antibodies have been successfully applied in their native form, or coupled with radioisotopes or toxins to selectively destroy lymphoma cells and promising results in early clinical trials have been obtained. Alternatively, bispecific antibodies and idiotypic vaccination strategies are used to target autologous T cells to eliminate lymphoma cells. A humanized anti-CD20 antibody showed excellent results in chemotherapy refractory lymphomas and has recently been approved for clinical application in CD20 positive B cell lymphomas.