Rituximab, Ifosfamide, Carboplatin And Etoposide Research Articles

A Phase I/II Trial to Evaluate the Safety, Pharmacokinetics, and Efficacy of Glofitamab As Monotherapy and in Combination with R-ICE Chemoimmunotherapy in Children and Young Adults with Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (iMATRIX-GLO)

Background: Although rare,relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) in children, adolescents, and young adults is an area of high unmet need, with 1-year overall survival rates of <30% and complete remission (CR) rates of 27% after treatment with R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) chemoimmunotherapy (Burke et al. Leukemia 2020). New treatment regimens are urgently needed (Woessmann et al. Blood 2020; Burkhardt et al. Cancers (Basel) 2021). T-cell engagers have been identified as medicinal products with the greatest probability of being beneficial for the pediatric population (Pearson et al. Eur J Cancer 2019). Glofitamab is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate B cells and is currently under investigation as monotherapy and in combination with chemoimmunotherapy for the treatment of adults with R/R B-NHL, with encouraging clinical activity and a manageable safety profile. Known risks associated with glofitamab are cytokine release syndrome (CRS), febrile neutropenia, tumor flare, tumor lysis syndrome, pyrexia, and infections. The safety profile of glofitamab in children is expected to be similar to that seen in adults. Study Design and Methods: iMATRIX-GLO (NCT05533775) is a Phase I/II, open-label, single-arm, two-part trial to evaluate the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of glofitamab as monotherapy in children 6 months to <18 years of age with second and higher R/R B-NHL (i.e. relapse after 2 or more lines of treatment), or in combination with R-ICE in children and young adults ≤30 years of age with first R/R disease (i.e. relapse after the first line of treatment). Patients with a histologically confirmed diagnosis of CD20-positive R/R B-NHL are eligible. Study treatment is administered with a single dose of obinutuzumab pretreatment followed by glofitamab step doses and repeated glofitamab full doses every 21 days as monotherapy or in combination with R-ICE. Primary objectives and endpoints are the achievement of CR after up to three cycles of combination therapy (glofitamab plus R-ICE) as determined by the investigator according to the International Pediatric NHL Response Criteria for pediatric participants and Lugano Classification for young adult participants, evaluation of glofitamab safety (CRS by ASTCT 2019 criteria, otherwise by NCI CTCAE v5.0 criteria), tolerability, and PK as monotherapy and as combination therapy. The first patient was enrolled in November 2022 and the study is ongoing. The study is planned at 23 sites in 9 countries (Europe, Australia, North America, South Korea, and China).

Trial in Progress: Pomalidomide Plus Rituximab, Ifosfamide, Carboplatin, and Etoposide for Relapsed or Refractory Diffuse Large B-Cell Lymphoma (PRIDE)

Backgrounds: Relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) patients have limited treatment options and are associated with poor prognosis. Patients generally receive salvage therapy as rituximab, ifosfamide, carboplatin and etoposide (R-ICE), followed by consolidation with high-dose therapy (HDT) and autologous stem cell transplantation (ASCT). However, only approximately 50% of patients can proceed to ASCT and only half of these achieve durable remission post-transplant. New therapeutic strategies are needed to improve response rates and to prevent recurrence following ASCT. The immunomodulatory agent lenalidomide has demonstrated direct anti-tumor effects in lymphoma. Some studies found that the addition of lenalidomide to the widely used R-ICE salvage regimen is feasible and results in promising response rates in R/R DLBCL patients. Pomalidomide is a third-generation immunomodulatory drug that has shown excellent therapeutic activity against relapsed/refractory primary central nervous system lymphoma (PCNSL) and primary vitreoretinal lymphoma (PVRL) with an acceptable toxicity profile. We aim to determine the safety, tolerability and efficacy of pomalidomide in combination with R-ICE in R/R DLBCL patients.Study Design and Methods: PRIDE (ChiCTR2100049327) is a phase I/II trial of pomalidomide plus R-ICE (PR-ICE) as a salvage regimen for first-relapse or primary refractory DLBCL. In phase I of the study, patients receive escalating doses of pomalidomide (2mg, 3mg or 4mg daily on d1-10) along with R-ICE therapy every 21 days by standard 3+3 design until the MTD has been determined. In stage II, all subjects receive three cycles of R-ICE plus pomalidomide, dosing as RP2D. Patients with CR or PR but not eligible for ASCT receive continuous pomalidomide as maintenance therapy for 12 months. Key eligibility criteria are as follows: histologically confirmed DLBCL; relapsed or refractory after one prior treatment for DLBCL; age 18-75 years; absolute neutrophil count >1500 /mm 3; platelet count > 75,000/mm 3; calculated creatinine clearance of over 60 mL/min by Cockroft-Gault formula; total bilirubin < 1.5×ULN; AST and ALT < 3×ULN. The primary endpoint of phase II is the CR rate after PR-ICE induction treatment. The CR rate for R-ICE in R/R DLBCL was estimated to be approximately 35%. We hypothesize that the addition of POM to R-ICE could increase the CR rate by approximately 20%. For phase II, it requires a sample size of 44 evaluable patients (one-sided alpha = 0.05, power 80%, dropout rate of 15%). Eligible patients who receive at least one dose of PRICE will be included in the efficacy and safety analyses. The 95% CI of CR was calculated using Clopper-Pearson method. The Kaplan-Meier method was used to estimate PFS and OS. All these analyses were conducted using SAS 9.4 software. Enrollment for phase I will begin in Q4 of 2021. [Display omitted] DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:Pomalidomide is indicated for the treatment of adult patients: in combination with dexamethasone, for patients with multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy in China. The abstract presents the rationale for the use of generic pomalidomide in combination with R-ICE, a combination that is not approved in China at present.

Efficacy of Salvage Chemotherapy in Diffuse Large B Cell Lymphoma with Primary Treatment Failure According to Putative Cell of Origin

Efficacy of Salvage Chemotherapy in Diffuse Large B Cell Lymphoma with Primary Treatment Failure According to Putative Cell of Origin

Non-Effectiveness of Using RICE Post RDHAP or RDHAP Post RICE after Failure of First Line Salvage Therapy in DLBCL Patients Who Are Eligible for ASCT

Background: The treatment of relapsed or refractory diffuse large B cell lymphoma (DLBCL) remains challenging. The use of salvage chemotherapy followed by autologous stem cell transplantation (ASCT) in young and fit patients is considered the standard of care. RDHAP (rituximab, dexamethasone, high dose cytosine arabinoside and cisplatin) and RICE (rituximab, ifosfamide, carboplatin, and etoposide) are the two most commonly used salvage-regimens with comparable efficacy (CORAL study). However, nearly 40% of the patients do no respond to these regimens and subsequently they do not proceed to ASCT. There are no guidelines concerning the choice of a second-line salvage regimen. There are sparse data in the literature concerning the best choice if the first salvage regimen fails. The aim of our study was to investigate the potential role of a second salvage regimen, before intensification, by RICE or RDHAP in patients with DLBCL refractory to the first line salvage therapy by RDHAP or RICE, respectively.Methods: We retrospectively included all patients aged 18 years and above who had a relapsed or refractory DLBCL and who were eligible for an autologous stem cell transplant (ASCT) between the years 2008 and 2017. They should have had progressive or stable disease (PD/SD) following first-line salvage based on RICE (group 1) or RDHAP (group 2) and should have received a second-line salvage based on RDHAP or RICE, respectively. Patients who received carboplatin or oxaliplatin instead of cisplatin in the RDHAP protocol were also included. All cases were discussed at a tumor board and the revised International Working Group response criteria for Malignant lymphoma were used to assess the response to chemotherapy. Information were collected using electronic medical record. Ethics committee approval was not necessary.Results: 100 patients' medical files were reviewed, out of which 69 were excluded for the following reasons: 5 patients lacked necessary information; 13 patients were treated for a non-DLBCL; 30 patients could not receive second line salvage therapy because of deterioration of their performance status; 21 patients because they received a bridging therapy (other than RICE or RDHAP) before second line salvage therapy. The study included 31 patients with 19 (61.3%) males and 12 (38.7%) females. The median age was equal to 59 years (standard deviation 14). DLBCL was at the initial diagnosis in all but 6 patients in whom DLBCL developed after an indolent lymphoma (follicular lymphoma in 4 and marginal zone lymphoma in 2). 70% had germinal centre B-cell subtype, while 30% had activated B-cell subtype. 70% were refractory to the primary therapy (CR not attained on primary therapy or relapsed within 6 months) and 30% recurred after a CR lasting more than 6 months. All patients included in group 1 (n=5) have received cisplatin during the treatment with the RDHAP regimen. Among the 26 patients included in the second group, 19 (73.1%) have received cisplatin, 4 (15.4%) oxaliplatin, and 3 (11.5%) carboplatin in first line salvage. No patient in group 1 responded to RICE and eventually no patient proceeded to ASCT. In the second group, 2 patients (7.7%) deceased after the first cycle of RDHAP because of drug related toxicities (1 due to ifosfamide-induced encephalopathy and 1 due to septic choc following febrile neutropenia). Ten patients (38.5%) responded to RDHAP, in whom an ASCT was planned. However, 2 patients could not proceed to ASCT because of peripheral stem cell collection failure. After a median follow up of 8.7 months, the median progression free survival (PFS) of the 8 patients who proceeded to ASCT was 6.3 months (CI 95% 2.6-10.1). Only 1 patient had a tumor response lasting more than 30 months. No factor was found to be associated with PFS on cox regression analysis (which included age, sex, type of DLBCL, and refractory or recurrent status).Conclusion: There is little information regarding the effectiveness of a second-line salvage therapy in patients not responding to first line intensification. All except one patient either could not proceed to ASCT or had a limited response (less than 3 months) post ASCT. In addition, the toxicity was not negligible considering that 2 patients died because of drug related events. This study suggests that patients with DLBCL who failed to respond to first line salvage by RDHAP or RICE should be considered for investigational therapies rather than second line rescue. DisclosuresRibrag:pharmamar: Other: travel; MSD: Honoraria; BMS: Consultancy, Honoraria, Other: travel; Roche: Honoraria, Other: travel; Amgen: Research Funding; argenX: Research Funding; Servier: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; Incyte Corporation: Consultancy; Gilead: Consultancy, Honoraria; Infinity: Consultancy, Honoraria; epizyme: Consultancy, Honoraria.

Safety and Efficacy of Venetoclax Combined with Rituximab, Ifosfamide, Carboplatin and Etoposide Chemoimmunotherapy (VICER) for Treatment of Relapsed Diffuse Large B Cell Lymphoma: Results from the Phase 1 Study

Safety and Efficacy of Venetoclax Combined with Rituximab, Ifosfamide, Carboplatin and Etoposide Chemoimmunotherapy (VICER) for Treatment of Relapsed Diffuse Large B Cell Lymphoma: Results from the Phase 1 Study

Co-expression of MYC and BCL2 predicts poorer outcomes for relapsed/refractory diffuse large B-cell lymphoma with R-ICE and intent to transplant.

Diffuse large B-cell lymphoma (DLBCL) with co-expression of MYC and BCL2 protein by immunohistochemistry (IHC) - that is, double-expresser lymphoma (DEL) - is associated with poor outcomes after standard frontline therapy. Less is known about the prognostic impact of DEL in patients with relapsed/refractory disease treated with salvage therapy and autologous stem cell transplantation (ASCT). We analyzed the outcomes of 167 patients with relapsed/refractory DLBCL treated with R-ICE (rituximab, ifosfamide, carboplatin and etoposide), of whom 111 patients (66%) underwent ASCT. Using predefined cutoffs for positivity by IHC at relapse for MYC and BCL2 of ⩾40% and ⩾50% of positive tumor cells, respectively, 26 patients (16%) were categorized as DEL and the rest as non-DEL. Overall and complete response rates to R-ICE did not differ between DEL and non-DEL. With a median follow up of 20 months, the 3-year progression-free survival (PFS) and overall survival (OS) rates for DEL were inferior compared to non-DEL (for PFS: 6% versus 33%, p = 0.044, for OS: 39% versus 56%, p = 0.03). The negative impact of DEL on PFS and OS remained significant on multivariable analysis. In conclusion, positive DEL status predicts poorer outcomes following salvage therapy.

Phase I Study Combining Ibrutinib with Rituximab, Ifosfamide, Carboplatin, and Etoposide (R-ICE) in Patients with Relapsed or Primary Refractory Diffuse Large B-Cell Lymphoma (DLBCL): NCI-Cancer Therapeutics Evaluation Program (CTEP) #9588

Background: In the post-rituximab era, half the patients with relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) fail to achieve a chemosensitive response with standard salvage therapy, and are thus ineligible to proceed to consolidative autologous stem cell transplantation (ASCT) with curative intent. The Bruton's tyrosine kinase inhibitor ibrutinib demonstrates single-agent activity in rel/ref DLBCL, predominately of the non-germinal center B-cell (non-GCB) phenotype, with minimal toxicity. This single center, NCI-CTEP sponsored phase I study is the first to evaluate the combination of ibrutinib with standard salvage therapy of rituximab, ifosfamide, carboplatin and etoposide (R-ICE) in transplant-eligible rel/ref DLBCL patients.Methods: Patients with rel/ref DLBCL, including transformed B-cell non-Hodgkin lymphoma, are eligible for study. The phase I study design is a standard 3 x 3 dose escalation of ibrutinib at 420 mg (dose level [DL] #1), 560 mg (DL #2) and 840 mg (DL #3) on days 1-21 with standard dosing of R-ICE for 3 cycles, every 21 days. The primary objective is to determine safety and the maximum tolerated dose (MTD) of ibrutinib in combination with R-ICE. Secondary objectives include response rate according to computed tomography (CT) and functional imaging (FDG-PET) per Deauville criteria.Results: To date, 16 patients are evaluable for toxicity, and 15 are evaluable for response. The median age of the 16 evaluable patients is 51 years (range 19-75 years). Histologies of the patients evaluable for response are: GCB DLBCL n=3, non-GCB DLBCL n=4, primary mediastinal large B-cell lymphoma n=4, and transformed chronic lymphocytic leukemia/small lymphocytic lymphoma (tCLL/SLL) n=4. There were no dose-limiting toxicities (DLTs) seen at DL #1 (n=3), 2 (n=3), or 3 (n=10, currently in expansion). Of the 16 patients evaluable for toxicity, 15 experienced expected and transient grade 3 or 4 hematologic toxicities with hematopoietic recovery prior to each cycle. The median number of cumulative platelet transfusions per patient for 3 cycles was 2 (range 0-11). Eleven of the 15 patients evaluable for response underwent chemotherapy-primed CD34+ hematopoietic progenitor cells (HPCs) apheresis procedures on study; 10 of the 11 patients successfully collected HPCs with a median of 5.6 x 106CD34+/kg (range 1.7-8.6). The only patient that failed to collect HPCs was an HIV-positive patient at DL #3 in the setting of febrile illness. One patient experienced grade 3 atrial fibrillation/flutter and was subsequently removed from study per treating physician's decision. Per CT criteria, five patients achieved complete remission (CR), eight patients achieved partial remission (PR), and two patients had stable disease for an overall response rate of 87%. All eight patients with non-GCB DLBCL and tCLL/SLL that were evaluable for response achieved chemosensitive remission per CT criteria (CR=4, PR=4). Seven of the 15 total patients (47%) evaluable for response achieved a complete metabolic remission (Deauville 1-3) per FDG-PET, including all 4 patients of non-GCB phenotype.Conclusions: Currently, no DLTs have been observed with ibrutinib at dosing up to 840 mg daily in combination with R-ICE. We are currently expanding DL #3. Manageable and expected hematologic toxicities have been observed. Importantly, hematologic toxicity has not resulted in failure to complete protocol therapy on-schedule or mobilize HPCs. Encouragingly, 87% of patients achieved a CT response (CR/PR) and 47% of patients achieved a complete metabolic remission per FDG-PET, including 100% of patients with non-GCB phenotype. These results compare favorably to historic cohorts. Given the safety and efficacy observed in this phase I, later phase studies for this treatment program are warranted. DisclosuresNo relevant conflicts of interest to declare.

Relapsed/refractory pediatric B-cell non-Hodgkin lymphoma treated with rituximab combination therapy: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group.

Pediatric relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) has been reported to be extremely difficult to cure, but rituximab is expected to be effective in improving the prognosis of pediatric R/R B-NHL patients. Here, we assessed the treatment and prognosis of pediatric R/R B-NHL in the rituximab era in Japan. We collected information on patients with R/R B-NHL who were registered with the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) B-NHL03 protocol, a nationwide multicenter trial for newly diagnosed patients. We assessed the treatment and outcome of 33 pediatric R/R B-NHL cases. Twenty-eight patients received rituximab combination therapy as salvage treatment. R-ICE (rituximab, ifosfamide, carboplatin, and etoposide), the most common regimen, was used in 22 patients as first-line salvage therapy. Twenty-three patients received hematopoietic stem cell transplantation (HSCT). Among all 33 patients, 23 (70.0%) achieved partial remission or complete remission. Their 5-year overall survival rate was 48.5%, which was far superior to that in both our previous study and in another study on pediatric R/R B-NHL. Four toxic deaths associated with viral infection occurred after allogeneic HSCT following on rituximab combined salvage therapy. Risk factor multivariate analysis for survival in patients receiving rituximab combination therapy showed central nervous system combined relapse had inferior outcome. The prognosis of pediatric R/R B-NHL in a Japanese cohort remained poor but is showing improvement in the rituximab era. Rituximab combination therapy is effective for R/R B-NHL patients who did not receive rituximab as primary treatment. We need to consider possible viral infections in allogeneic HSCT after rituximab treatment.

Improved Outcome of Relapsed or Refractory Pediatric B-Cell Non-Hodgkin Lymphoma in Japan

IntroductionRelapsed or refractory pediatric B-cell non-Hodgkin lymphoma (B-NHL) has been reported to be extremely difficult to cure. We previously conducted a retrospective study of pediatric relapsed or refractory B-NHL in Japan between 1996 and 2004 and found that the four-year overall survival rate was only 20.5% (Fujita N. e al. PBC. 2008). Rituximab, a chimeric anti-CD20 monoclonal antibody, is expected to be effective in improving the prognosis of pediatric relapsed or refractory B-NHL and was approved for use in 2003 in Japan. Here, we retrospectively assessed the treatment and prognosis of pediatric relapsed or refractory pediatric B-NHL in the rituximab era in Japan.MethodsWe collected relapsed pediatric B-NHL cases from patients enrolled in our current study, JPLSG B-NHL03 study, which was the first nationwide multicenter trial for newly diagnosed pediatric B-NHL. We collected information on treatment and outcome after induction failure or relapse.ResultsIn 33 patients enrolled this study, the median age at diagnosis was 9.7 years and male predominance was observed. Nine cases were pathologically subclassified initially as diffuse large B-cell lymphoma, 11 as Burkitt lymphoma, 11 as Burkitt Leukemia and two as others. According to initial Murphy staging, most cases were in the advanced stage. The most common site of relapse was abdomen (8 cases), followed by bone marrow (8 cases) and central nervous system (7 cases). Twenty-three cases relapsed in one site while 10 did so in multiple sites. Among them, 20 relapsed within six months after initial diagnosis.Among them, 28 patients received some rituximab combined treatment as salvage therapy. R-ICE (rituximab, ifosfamide, carboplatin and etoposide) regimen was the most popular and used in 22 patients as first-line salvage therapy. As a result, 22 patients (66.7%) achieved complete remission (CR) by some salvage therapy. 23 received hematopoietic stem cell transplantation (HSCT). Their 5-year overall survival rate was 48.5%, which was far more superior to both our previous study (Figure 1) and another on relapsed or refractory B-NHL in childhood.In risk factor analysis for survival, rituximab combined treatment and HSCT did not influence the outcome, but achievement of CR after salvage treatment resulted in significantly better survival (68.2% vs 9.1%, p=0.001). These results suggest that the advent of rituximab induced an improvement of CR rate for relapsed paediatric B-NHL, which resulted in an improvement of the survival rate.ConclusionIn conclusion, the prognosis of the pediatric relapsed or refractory B-NHL in a Japanese cohort remained poor but is showing improvement in the rituximab era. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Addition of lenalidomide to rituximab, ifosfamide, carboplatin, etoposide (RICER) in first‐relapse/primary refractory diffuse large B‐cell lymphoma

Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) is associated with a poor prognosis. Outcomes are particularly poor following immunochemotherapy failure or relapse within 12 months of induction. We conducted a Phase I/II trial of lenalidomide plus RICE (rituximab, ifosfamide, carboplatin, and etoposide) (RICER) as a salvage regimen for first-relapse or primary refractory DLBCL. Dose-escalated lenalidomide was combined with RICE every 14 d. After three cycles of RICER, patients with chemosensitive disease underwent stem cell collection and consolidation with BEAM [BCNU (carmustine), etoposide, cytarabine, melphalan] followed by autologous stem cell transplantation (autoSCT). Patients who recovered from autoSCT toxicities within 90 d initiated maintenance treatment with lenalidomide 25 mg daily for 21 d every 28 d for 12 months. No dose-limiting or unexpected toxicities occurred with lenalidomide 25 mg plus RICE. Grade 3/4 haematological toxicities resolved appropriately, and planned dose density and dose intensity of RICER were preserved. No lenalidomide or RICE dose reductions were required in any of the three cycles. After two cycles of RICER, nine of 15 patients (60%) achieved a complete response, and two achieved a partial response (13%). Combining lenalidomide with RICE is feasible, and results in promising response rates (particularly complete response rates) in high-risk DLBCL patients.

Transformed Diffuse Large B-Cell Lymphoma (DLBCL) Patients Treated With Salvage Rituximab, Ifosfamide, Carboplatin and Etoposide (R-ICE) Have Superior Overall Survival Than Patients With De Novo DLBCL

Background and objectivesApproximately 30% of diffuse large B-cell lymphoma (DLBCL) patients relapse following initial immuno-chemotherapy. DLBCL usually arises without a history of lymphoma (“de novo”), but can also transform from antecedent indolent lymphoma. There are limited data regarding the outcomes of the two subpopulations of transformed and de novo DLBCL patients treated with second-line chemotherapy regimens. We sought to compare the outcomes of relapsed/refractory transformed and de novoDLBCL patients after receiving frontline rituximab, cyclophosphamide, doxorubcin, vincristine and prednisone (R-CHOP) and second-line rituximab, ifosfamide, carboplatin and etoposide (R-ICE) chemotherapy prior to planned autologous stem cell transplant (ASCT). This analysis was performed on an intent-to-treat basis. MethodsThis retrospective review compared 100 consecutive DLBCL patients, 89 de novo and 11 transformed, at the Cleveland Clinic between 2000 and 2012. Inclusion criteria were: age ≥18 with relapsed/refractory DLBCL, prior treatment with R-CHOP and second-line R-ICE chemotherapy. Baseline characteristics were compared for categorical variables using the Chi-square test or Fisher's exact test; continuous and ordinal categorical variables were compared using the Wilcoxon rank sum test. Overall survival (OS) and progression-free survival (PFS) in transformed and de novorelapsed/refractory DLBCL patients were estimated using the Kaplan-Meier method and compared using the log-rank test. Stepwise multivariable analysis with a variable entry criterion of P<0.10 and a variable retention criterion of P<0.05 was used to identify multivariable prognostic factors. ResultsThe majority of patients had advanced stage (III or IV) disease at the time of diagnosis of DLBCL (62.5% for transformed and 68.5% de novo patients, P = 0.59).There was a male predominance in both groups, transformed (72.7%) and de novo (61.8%), P = 0.48. The median age at second-line was comparable between transformed and de novo patients (62 vs. 58 yrs, respectively, P = 0.66). The period of time between R-CHOP and R-ICE was significantly longer in transformed patients than those with de novo DLBCL (30.1 vs. 11.3 months respectively, P< 0.001). The number of cycles of R-ICE was comparable between the two groups and most commonly was 3. The percentage of patients who proceeded to a planned ASCT was comparable for transformed and de novo patients (45.5% vs. 47.2% respectively; P = 0.97). The molecular subtype for cases in which data were available was germinal center in 6 of 7 (85.7%) transformed patients and 32 of the 46 (69.6%) de novo cases as determined by the Hans immunohistochemistry algorithm (P = 0.66). Transformed patients had a statistically significant improvement in OS compared with de novo patients (77.8% vs. 27.4% 5 year OS, respectively, p=0.034). Death due to relapsed disease was comparable for both transformed and de novo patients (50% vs. 38.5% respectively). Transformed patients had marginally better PFS outcomes after 5 years (51.4%) than de novopatients (26.9%; p=0.18). In a multivariable analysis, transformed DLBCL was associated with a statistically significant odds ratio (OR) of 0.23 (95% confidence interval (C.I.) 0.05 – 0.95)1.05 -17.8) for OS (p=0.043). ASCT was associated with improved OS in multivariable analysis (OR = 0.57 (C.I. 0.33 – 1.00), p= 0.05). ConclusionsContrary to expectation, transformed DLBCL patients previously treated with R-CHOP have superior OS after second-line R-ICE than patients with de novo DLBCL. This may result from relatively longer period of time between initial treatment and the need for second-line and possibly an enrichment for cases with the more favorable germinal center molecular subtype. Improvements in second-line treatment for de novo relapsed/refractory DLBCL with novel agents are needed.▪ Disclosures:Hill:Celgene: Honoraria, Research Funding.

Ricer (Rituximab, Ifosfamide, Carboplatin, Etoposide, Revlimid) Is Well-Tolerated Salvage Regimen in First Relapse/Primary Refractory DLBCL Allowing Consolidation with Autologous Stem Cell Transplant

AbstractAbstract 3710 Background:Relapsed/refractory DLBCL has poor prognosis in the rituximab era. Pts who failed Rituximab-containing initial chemo regimen within 12 mo do particularly poorly. (ORR 46–51% vs. 83–88%, EFS 20% vs. 45% at three years). Novel salvage therapies to overcome chemo resistance and maintain remission in post transplant setting are needed.The immunomodulatory agent lenalidomide has demonstrated direct tumoricidal and antiproliferative effects in lymphoma and clinical activity and safety in multiple phase II studies in aggressive NHL. Methods:We are conducting a phase I/II trial combining lenalidomide with RICE (rituximab, ifosfamide, carboplatin and etoposide) (RICER) as a salvage regimen in first relapse or primary refractory DLBCL. Four dose levels of lenalidomide are being evaluated in Phase I part of the study: 10mg, 15mg, 20mg, and 25mg given for 7 days (days 1–7) together with RICE. After three cycles of RICER patients with chemo sensitive disease proceed to stem cell collection (off 3rdRICE) and consolidation with BEAM followed by autologous SCT (ASCT). Patients who recover from ASCT toxicities within 90 days are started on maintenance with lenalidomide 25mg daily for 21 days every 28 days for 12 months. Results:13 patients have been enrolled. DLT was not seen at 25 mg (last dose level tested) of lenalidomide during the salvage part of RICER. No unexpected toxicities were observed by adding lenalidomide to RICE. Grade 3 and 4 hematologic toxicities were comparable to RICE alone and resolved appropriately and planned dose density and dose intensity of RICER were preserved. One episode of febrile neutropenia occurred during RICER administration. No new DVT’s occurred during lenalidomide administration either in salvage or in post ASCT maintenance part of the trial. Stem cell collection was successful in all but one patient. So far seven patients have completed ASCT and five patients were able to start on maintenance lenalidomide post transplantation. No unusual toxicities were observed in the peritransplantation period and there was no delay in engraftment: median days to ANC of >500 is 11, and to plts over 20K/mL is 11. In the maintenance post ASCT there was no infection but routine dose reductions were required because of myelotoxicity. Conclusions:1.Adding lenalidomide to RICE (RICER) is feasible salvage regimen with no increased toxicity.2.PET-CR rate is promising in this very refractory DLBCL population.3.While it is premature for any definitive conclusions regarding feasibility of maintenance lenalidomide in post transplant setting, trial is ongoing with expansion in additional institutions.Table 1Patient characteristicsNumber of patients13Male/female10/3Median age64 (47–75)Disease characteristicNumber of patientsStage at relapse III-IV8 out of 13Relapse IPI6Low, low intermediate7Intermediate high, highPrimary refractory6Relapse <12 months of initial therapy5Relapse >12 mo of initial therapy2Rituximab used with initial therapy13Initial therapy9R-CHOP3R-HCVAD/R-MA1R-CODOX-M/IVACOverall response (OR)9Complete response (CR)8Partial response (PR)1Stable disease (SD)3Progression of disease (PD)1Auto SCT characteristicsStem cell harvest5.24 mln/kg (range 3.37–12.8mln/kg)Median time to platelets recovery to 20,000/mL without transfusional support12 days (range 7 to 14)Median time to ANC >500/mL11 days (range 9 to 11) Disclosures:Feldman:allos: Speakers Bureau; merck: Speakers Bureau; celgene: Speakers Bureau; seattle genetics: Speakers Bureau. Off Label Use: Lenalidomide in combination with chemotherapy as salvage regimen for DLBCL. Mato:Celgene: Speakers Bureau; seattle genetics: Speakers Bureau; genentech: Speakers Bureau; millennium: Speakers Bureau. Goldberg:Eisai: Speakers Bureau. Vesole:Celgene Corp.: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Siegel:Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau. Goy:Milennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees; Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; J & J: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees.

Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Neurolymphomatosis: role of positron emission tomography in diagnosis

Dear Editor, A 49-year-old woman presented with stage IA diffuse large B cell lymphoma (DLBCL) of the uterine cervix. She received four courses of R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone) and two cycles of R-ICE (rituximab, ifosfamide, carboplatin, and etoposide), followed by local tomotherapy. A complete remission was achieved, as shown by 18F-fluorodeoxyglucose positron emission tomography–computed tomography (PET/CT). However, she developed gradually numbness over her right thoracic 10 dermatome. A magnetic resonance imaging (MRI) scan performed 4 months later showed abnormal signal intensity in the anterior and posterior wall of the lower thoracic cord, at the origin of cauda equina and at the anterior and posterior nerve roots of right thoracic 10 and thoracic 11 roots, suggestive of leptomeningeal deposits. Lumbar puncture showed normal cerebrospinal fluid, and although a dose of intrathecal methotrexate and cytarabine was given there was no symptomatic improvement. On referred 6 months after the onset of neurologic symptoms, another MRI focusing on the thoracic spine showed abnormal signal intensity in the anterior and posterior wall of the lower thoracic cord at the origin of cauda equina and at the anterior and posterior right thoracic 10 and thoracic 11 nerve roots (Fig. 1a, arrow). To resolve the nature of the lesion, a PET/CT scan was performed. It showed a hypermetabolic soft tissue nodule (standardized uptake value maximum, 4.2) extending across the right thoracic 10/11 neural foramen (Fig. 1b, arrow), suggesting a lymphomatous lesion. Fig. 1 Imaging studies in neurolymphomatosis. a MRI scan showing a lesion (arrow) at the anterior and posterior right thoracic 10 and thoracic 11 nerve roots. b Positron emission tomography/computed tomography, showing an isolated hypermetabolic lesion in the ... The surgical resection specimen showed the presence of atypical lymphoid cells among the neuroganglion tissue, which were CD20+, CD3−, and BCL-2+ (Fig. 2a–d). The overall features were consistent with DLBCL relapsing as neurolymphomatosis. Fig. 2 Histopathology of neurolymphomatosis. a Surgical specimen showing neuroganglion tissue diffusely infiltrated by abnormal lymphoid cells (hematoxylin–eosin). b Lymphoid cells were positive for CD20 (immunoperoxidase stain). c Lymphoid cells were ... Neurolymphomatosis refers to direct lymphomatous infiltration of the cranial and peripheral nerve and roots [1–3]. It is a very rare condition, with a recent study identifying merely 50 patients from 12 centers in 5 countries over a 16-year period [3]. Four different clinical presentations have been described: painful infiltration of nerves or roots; cranial neuropathy with or without pain; painless involvement of peripheral nerves; and painful or painless involvement of a single peripheral nerve [1]. Aggressive B cell lymphoma is the predominant underlying pathology [1–3]. Owing to the nonspecific presentation, the diagnosis is often delayed. Furthermore, biopsies are not feasible when deep-seated roots or cranial nerves are involved. Hence, when neurologic symptoms are the initial manifestation, the diagnosis of neurolymphomatosis may not be made until at post-mortem [1–3]. In a patient with a history of lymphoma, the diagnostic challenge is to distinguish neurolymphomatosis from other pathologies not due to direct nerve invasion, including leptomeningeal lymphoma, nerve compression from adjacent lymphoma masses, neuropathy related to chemotherapy and radiotherapy, lymphoma-associated vasculitis, and paraneoplastic syndromes [2]. Imaging studies are therefore very helpful in these differential diagnoses. Earlier studies have relied on MRI, which might not be able to distinguish between lymphomatous or a primary nervous tissue lesion. As shown in the present study, PET/CT allows the lesion to be accurately localized and gives an indication of the metabolic activity of the lesion [4], which provides useful information on the differential diagnosis of the nature of the pathology.

Low Dose Lenalidomide Induces Remission in Therapy Related 5q- Acute Myeloid Leukemia (AML).

Treatment of 5q- myelodysplastic syndrome (MDS) with single agent lenalidomide therapy eliminates hematologic and cytogenetic abnormalities resulting in decreased transfusion requirements (NEJM 2005; 352(6):549–557). We report the induction and maintenance of disease remission by lenalidomide in a 20 year old white female with 5q- AML that developed following extensive treatment of stage 2A nodular sclerosing Hodgkin's Lymphoma (HL). Remission after initial HL therapy with COPP/ABV lasted 21 months. Following first relapse, she received gemcitabine and vinorelbine with local radiotherapy. HL recurred and progressed. Therefore, 36 months after initial diagnosis, she was given Dexa miniBEAM (BCNU, etoposide, cytarabine, and melphalan) followed by BEAC and autologous PBSC transplant. With localized HL relapse 12 months after autologous PBSC transplant, her bone marrow showed mild dyspoiesis and multiple cytogenetic abnormalities including 5q−, 7q−, der17 and t(5:17). She was given three courses of RICE (rituximab, ifosfamide, carboplatin, and etoposide) followed by reduced intensity busulfan, fludarabine, ATG conditioning and MUD PBSC transplant. Within 2 months of this second transplant, peripheral blood blasts were noted and bone marrow again showed the previously noted cytogenetic abnormalities with 13% blasts consistent with MDS. A second MUD PBSC transplant followed FLAG (fludarabine, cytarabine, G-CSF) conditioning. Early after transplant, there was 95% donor chimerism but low levels of the cytogenetically abnormal clone remained. Within 4 months of the third transplant, bone marrow was dyspoietic with 43% erythroid blasts morphologically consistent with erythroleukemia (AML-M6). Cytogenetic abnormalities persisted and VNTR analysis showed only 35% donor cells. Treatment was started with lenalidomide 5mg po daily for 3 weeks followed by a one week rest. During therapy, there was resolution of fatigue and generalized bone pain. Hgb increased and only mild thrombocytopenia and neutropenia were noted at the end of week 3, course 1. There was clearance of peripheral blood blasts. Lenalidomide 10mg po daily during course 2 was not tolerated due to severe nausea. With return to 5mg po daily on day 6, there were no further adverse reactions during course 2. Platelet count increased and there was no neutropenia. Lenalidomide 5mg po daily was again well tolerated during a third course. Hgb increased with stable to slightly decreased platelet and neutrophil counts. Bone marrow aspirate during week 2 of course 3, showed normal 46 XX karyotype and absence of 5q-abnormality by FISH. Flow cytometry did not reveal the abnormal leukemic phenotype. VNTR analysis showed 100% allogeneic MUD chimerism. Of interest was the development of persistent eosinophilia up to 54% (absolute eosinophil count 2408/ML) during course 2. In a previous report of Lenalidomide therapy for MDS, 2 of 3 patients with eosinophilia responded to the treatment (NEJM 2005; 352(6):549–557). This case demonstrates the efficacy of low dose Lenalidomide for AML developing from therapy related MDS in a heavily treated HL patient. To our knowledge, this is the first such case reported for a pediatric patient.