scholarly journals Expanding the Indications for Ibrutinib: Complete Remission Obtained By Induction with Ibrutinib Followed By Consolidative Ahsct in Refractory Primary CNS Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5631-5631 ◽  
Author(s):  
Cassidy Brothers
Keyword(s):  
Complete Remission ◽  
Disease Progression ◽  
Salvage Therapy ◽  
B Cell Lymphoma ◽  
Salvage Treatment ◽  
Severe Neutropenia ◽  
High Dose ◽  
Cell Transplant ◽  
Curative Intent ◽  
Hematopoietic Stem

Introduction Primary central nervous system lymphoma (PCNSL) is an exceedingly rare and aggressive sub-type of Non-Hodgkin's Lymphoma. Despite initial polychemotherapy that includes High-Dose Methotrexate (HD-MTX), over half of patients will develop recurrent or refractory disease that requires salvage therapy.1 Ibrutinib, a Bruton's tyrosine kinase inhibitor, has become an alternative for salvage treatment in relapsed or refractory PCNSL (RR-PCNSL) that is particularly useful in patients who are ineligible for re-induction with HD-chemo. In RR-PCNSL, Ibrutinib led to a progression free survival (PFS) of roughly 5 months when used as monotherapy2,3 and 15 months when used as add-on therapy.4 While its role as salvage treatment has been documented, its use to facilitate consolidative autologous hematopoietic stem cell transplant (AHSCT) in RR-PCNSL is not currently known. The following case describes the first known report of a patient with RR-PCNSL who achieved persistent complete remission following Ibrutinib salvage treatment and consolidative AHSCT. Case Description A 64-year-old male presented to the emergency department with a two-week history ptosis, visual abnormalities, confusion, and increasing fatigue. On physical exam, he was found to have bilateral mydriasis, left third nerve cranial palsy, severe left-sided ptosis, and restricted upwards and downward gaze of the right eye. A contrast-CT was performed which showed multiple areas of abnormal enhancement throughout the frontal lobes, corpus callosum, and midbrain associated with significant vasogenic edema. These findings were confirmed on MRI. He underwent a stereotactic guided burr hole biopsy which was consistent with diffuse large B-cell lymphoma (DLBCL). Immunohistochemistry performed on the tissue showed that the neoplastic cells were CD3(-), CD5(-), CD20(+), CD10(-), BCL2(subset +), BCL6(+), MUM1(+) and Cyclin D1(-). Staging CT and bone marrow biopsy showed no evidence of systemic disease. He was diagnosed with PCNSL and went on to receive induction therapy with Rituximab, Methotrexate, Procarbazine, and Vincristine (R-MPV) with curative intent and received a total of 7 cycles. Initially, he had a significant radiographic response with a repeat MRI post cycle 4 showing only a few small areas of residual enhancement. However, after completion of the 7 cycles of R-MPV, his MRI showed evidence of disease progression with both new and enlarging intra-axial lesions. Given his ECOG of 0 and lack of comorbidities, it was decided that he would proceed with salvage treatment with Cytarabine and Etoposide with curative intent for refractory PCNSL. Unfortunately, after only four weeks of receiving cycle one of Cytarabine and Etoposide, a repeat MRI showed evidence of disease progression. He was then transitioned to palliative therapy with prednisone up until December 2017, at which point he was able to obtain Ibrutinib on a compassionate basis. He was started on Ibrutinib salvage therapy and achieved radiographic evidence of complete remission after four months of treatment. There were minimal adverse effects of Ibrutinib therapy, most notably a severe neutropenia requiring a temporary discontinuation of therapy for two weeks. He underwent consolidative AHSCT with Thiotepa, Busulfan and Melphalan conditioning in August 2018. His post-transplant course was complicated by culture negative febrile neutropenia with a subsequent source determined to be Clostridium difficile for which he was treated. An MRI head performed 3 months after his AHSCT showed no evidence of recurrent or residual disease. He continues to be followed by the Hematology Service in Newfoundland and has remained in complete remission since. Conclusions This case demonstrates the feasibility of a salvage approach using Ibrutinib followed by AHSCT when standard salvage options have been exhausted in refractory PCNSL. OffLabel Disclosure: Ibrutinib's indications do not currently include use as a induction treatment prior to AHSCT in refractory/recurrent PCNSL.

scholarly journals Tumor Associated Antigen Specific T Cells Given in Combination with Nivolumab for the Treatment of Hodgkin Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-18 ◽  
Author(s):  
Hema Dave ◽  
Mimi Mai ◽  
Madeline Terpilowski ◽  
Keri Toner ◽  
Maja Stanojevic ◽  
...  
Keyword(s):  
T Cells ◽  
Complete Remission ◽  
Disease Progression ◽  
Hodgkin Lymphoma ◽  
Stable Disease ◽  
Peripheral Blood ◽  
Progressive Disease ◽  
Cell Transplant ◽  
Hematopoietic Stem

Background: Hodgkin Lymphoma (HL) Reed Sternberg cells express tumor associated antigens (TAA) that are potential targets for cellular therapies. We recently demonstrated that TAA specific T cells (TAA-T) targeting WT1, PRAME and Survivin were safe and associated with prolonged time to progression in solid tumors (Hont JCO 2019). Hence, we evaluated whether TAA-T cells are safe and elicit anti-tumor effects in patients with relapsed/refractory (rel/ref) HL. We further evaluated the safety of Nivolumab following the TAA-T infusion and its effect on the persistence of the TAA-T cells in vivo. Methods: TAA-T products were generated from patients or healthy donors on 2 trials (NCT02203903; NCT03843294). Thirteen patients underwent procurement for product generation and 10 patients (2 allogeneic; 8 autologous) were infused TAA-T for rel/ref HL or as consolidation after autologous hematopoietic stem cell transplant (HSCT) at cumulative doses ranging from 0.5 X107 to 4 X107cells/m2. Patients were monitored for six weeks for safety and for response until disease progression. Seven patients received Nivolumab starting at 8 weeks after the first TAA-T infusion until disease progression or unacceptable toxicity. Results: TAA-T products (n=10) were polyclonal CD3+ T cells (Median 97%; 80.9-99.5%), comprised predominantly of CD4+ helper T cells (Median 10.5%; 1.74-20%) and CD8+ cytotoxic T cells (Median 70%; 29.3-87.5%). Specificity of TAA-T products was tested using Interferon-ϒ(INFϒ)-enzyme-linked immunospot (ELIspot) assay and defined as ≥ 2x spot-forming cells (SFC)/2.5X105cells against the tumor antigen as compared to irrelevant control antigen Actin(Figure 1). The median TAA specificity of the products was 2 antigens (range 0-3). All products were polyfunctional secreting INF-ϒ and TNF-α upon restimulation with tumor antigens (Fig 1). Median age of patients was 36yrs (range16-53). Patients had received a median 6 lines of therapy including HSCT prior to receiving TAA-T. Median follow-up post TAA-T#1 was 6 months (range 32 days-2.5yrs). There were no dose limiting toxicities observed within the 6 week safety monitoring period. In patients receiving Nivolumab post TAA-T, there were no increased immune related events over expected. One patient had Grade 3 seizures, possibly related to Nivolumab, 2 patients developed hypothyroidism requiring thyroid supplements and one patient developed myositis and discontinued Nivolumab after 5 months. The 2 patients who received TAA-T (1 donor derived and one autologous) as consolidation post HSCT achieved a continued complete remission (CCR) for 2+ years. Of the 8 patients with rel/ref HL at the time of infusion, 1 had disease progression at 6 weeks. He then received Nivolumab off protocol and achieved complete remission (CR) but developed Grade 4 GVHD. The remaining 7 patients had stable disease (SD) at 6 weeks. At a median follow-up of 6 months (32 days-2.5 years), 1 patient had progressive disease(PD) at 3 months, 1 patient had a complete metabolic response at 6 months and proceeded to allogeneic HSCT for definitive cure. 2 patients had PD at 6 months and the other 2 patients continue with SD at 6 months and remain on Nivolumab (Fig 1). All patients with objective responses (stable disease or better) recovered functional TAA-T cells in the peripheral blood at 3 months as detected by anti-Interferon-ϒ ELISPOT and reported as mean SFC/1 X105 cells for WT1(14±SD18.1); PRAME (17.4±15.3) and Survivin (4.5±7) compared to those with progressive disease with mean SFC/1 X105 cells for WT1 1.4(±2.3); PRAME (6.7±15.5) and Survivin (0.8±1.2). To evaluate TAA-T persistence, unique T cell receptor clonotypes defined in the TAA-T product and not present at baseline were detected in the peripheral blood 6 weeks post TAA-T, long-term persistence data and evaluating the effect on the TCR repertoire when adding nivolumab are pending. Conclusion: TAA-T cells given in combination with Nivolumab were safe when administered to patients with rel/ref HL with prolonged clinical responses (ranging from SD to CCR) observed in multiply relapsed patients. Disclosures Glenn: Genentech: Research Funding. Hanley:Mana Therapeutics: Honoraria, Other: Board Member; Cellevolve: Honoraria, Other: Board(Scientific Advisory Board). Bollard:Mana Therapeutics: Other: IP.

Vinorelbine, Paclitaxel, Etoposide, Cisplatin and Cytarabine (VTEPA) Is An Effective Salvage Therapy for Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL) but Not for R/R Diffuse Large B Cell Lymphoma (DLBCL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1628-1628 ◽  
Author(s):  
Rajni Sinha ◽  
Nassoma King ◽  
Pareen J Shenoy ◽  
Mary Jo Lechowicz ◽  
Kevin Bumpers ◽  
...  
Keyword(s):  
Stem Cell ◽  
Salvage Therapy ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Electrolyte Imbalance ◽  
Stage Iii ◽  
High Dose ◽  
Cell Transplant ◽  
Refractory Disease ◽  
Relapsed Disease

Abstract Abstract 1628 Introduction: Historically, relapsed DLBCL and HL has been associated with a high cure rate with salvage regimens followed by high dose chemotherapy and stem cell transplant (ASCT). However, patients (pts) who relapse early following upfront chemotherapy and pts who fail to respond to salvage have a poor overall response rate (ORR) with additional salvage regimens and a poor prognosis even when consolidated with ASCT (von Tresckow & Engert, 2011; Gisselbrecht et al., 2010). At present there is no standard therapy in the third-line setting for pts with DLBCL and HL. We designed a regimen: vinorelbine (30mg/m2) & paclitaxel (175mg/m2) given on day 1; etoposide (100mg/m2) & cisplatin (20mg/m2) given on days 2–5; and cytarabine (2000mg/m2) on days 4 and 5 (VTEPA) for treatment of lymphoma pts with 1° refractory disease or relapse following salvage. In phase 1, VTEPA was safe with a 33% ORR following 1 cycle (Lonial et al, 2006). Design and Methods: To examine the effectiveness of VTEPA, we conducted an IRB approved retrospective review of consecutive cases of relapsed/refractory DLBCL and HL identified from our database from 1999–2011. All pts had evidence of primary refractory disease or stable or progressive disease following first line salvage therapy. Responses following salvage VTEPA were retrospectively assessed using International Working Group Criteria (JCO 1999) for all pts. Responding pts proceeded to ASCT. Survival curves were constructed using the Kaplan-Meier method and compared with the log-rank test. Results: 74 pts (44 DLBCL and 30 HL) with a median age at diagnosis of 30 years (range 18–63) for HL and 49 years (range 20–68) for DLBCL were included. 67% of HL pts had primary refractory disease and 33% of pts had relapsed disease; 60% were stage III/IV at diagnosis. 75% of DLBCL pts had primary refractory disease and 25% of pts had relapsed disease; 73% stage III/IV. Pts received a median of 2 prior therapies (range 1–4). 63% pts with HL received prior salvage therapy with ifosfamide, carboplatin, and etoposide (ICE) and 13% with other regimens. 16 pts with HL received 1 cycle of VTEPA, 13 received 2 cycles and 1 pt received 3 cycles of VTEPA. 70% pts with DLBCL had received prior salvage therapy with rituximab (R) + ICE and 16% received other salvage regimens. 32 pts with DLBCL received 1 cycle of R-VTEPA and 12 pts received 2 cycles. The most common reported grade 3/4 toxicities were pancytopenia (97%), nausea/vomiting (58%), fatigue (30%), infectious complications (26%), diarrhea (24%), electrolyte imbalance (19%), and mucositis (16%). 70 pts (43 DLBCL and 27 HL) were evaluable for response. The ORR for DLBCL pts was 44% (9% CR and 35% PR) while that for HL pts was 70% (26% CR and 44% PR, p=0.04). 4 DLBCL pts had treatment related mortality. 34 pts went on to collect ≥2 × 106 CD34+ cells/kg; 3 pts had inadequate stem cell collection. In 23 pts collection was not attempted, and 14 pts collected stem cells prior to R+/−VTEPA. 37 pts (47%) went onto planned ASCT, and 4 pts underwent allogeneic transplantation. The PFS at 2 years for pts with HL was 68% vs. 49% for pts with DLBCL (p<0.001, Figure 1). Similarly the OS at 2 years for pts with HL was 79% vs. 41% for pts with DLBCL (p<0.001, Figure 2). Conclusions: Treatment with VTEPA for heavily pretreated relapsed/refractory HL and DLBCL pts is feasible with manageable side effects, a high ORR, and permits transplantation for nearly ½ of pts. Nevertheless, outcomes for pts with refractory DLBCL is exceedingly poor compared to refractory pts with HL treated with the same approach. While there remains a great need for novel agents to aid DLBCL pts who are chemotherapy and R refractory, the favorable PFS and OS for relapsed/refractory HL pts suggest VTEPA is a promising salvage regimen for this disease. Disclosures: Sinha: Celgene: Research Funding. Kaufman:Millenium; Onxy; Novartis; Keryx: Research Funding; Merk, Celgene: Research Funding. Flowers:Spectrum: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Celgene: Consultancy; Genentech/Roche (unpaid): Consultancy; Novartis: Research Funding; Seattle Genetics: Consultancy.

Bortezomib Consolidation Following Upfront ASCT for Multiple Myeloma Deepens Disease Response and MRD-Negative Rate without Compromising Response to Subsequent Bortezomib Salvage: Results of a Phase II Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4508-4508 ◽  
Author(s):  
Oliver C Cohen ◽  
Neil Rabin ◽  
Nicholas Counsell ◽  
Roger G Owen ◽  
Bilyana Popova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Disease Progression ◽  
Phase Ii ◽  
Salvage Therapy ◽  
Progression Free Survival ◽  
Patient Choice ◽  
High Dose ◽  
Cell Transplant ◽  
Second Line ◽  
Disease Response

Abstract Background: Consolidation after high dose therapy and autologous stem cell transplant (ASCT) for multiple myeloma (MM) can improve response depth and prolong progression free survival (PFS), but it is important to ensure good quality of life (QoL) and responsiveness to further salvage therapy. We conducted a single-arm Phase II weekly bortezomib consolidation trial (BCT) to assess outcomes in MM patients receiving upfront ASCT. Methods: Bortezomib-na•ve patients with at least stable disease at 3-4 months post-high dose melphalan 200mg/m2 with ASCT received up to 8 cycles of bortezomib (1.3mg/m2 days 1,8,15,22 in a 4-week cycle), 17 intravenously (IV) and 23 subcutaneously (SC). The primary endpoint was disease response (IMWG) at 6 and 12 months post-ASCT. Other endpoints were MRD by multiparametric flow cytometry (patient 15 onwards) at 6 and 12 months post-ASCT, toxicity, PFS, overall survival, osteoblast function and Qol (EORT-QLQ-C30). Serum basic alkaline phosphatase (bALP) and ostocalcin (OC) were measured by ELISA. Results: The study recruited 40 patients between December 2009 and March 2014 at a median of 3.4 months post-ASCT. The median age was 61 years (range 43-69); 55% male; isotypes were: 22 (59%) IgG, 9 (24%) IgA, 1 (3%) IgD, 5 (14%) light chain only, 1 non-secretory and 2 unknown. Induction regimens pre-ASCT were thalidomide (33, 87%), idarubicin and dexamethasone (5, 13%). and unknown in 2. One patient was withdrawn prior to commencement (unfit for treatment) and 3 patients stopped trial treatment after 1 cycle (2 toxicity, 1 disease progression). Of 36 patients who completed >1 cycle of bortezomib, 10 stopped treatment early (5 toxicity, 4 patient choice, 1 disease progression); median number of cycles received was 8. Eleven (28%) patients experienced a total of 15 grade 3 adverse events (AE); 6 (neuropathy, 3 in IV group, 18% cf 3 in SC group, 13%), 4 (infection), 1 (fatigue), 2 (haematological), 2 other. One patient had a grade 4 infection (cycle 1, treatment discontinued) and 1 grade 4 back pain. EORTC-QLQ-C30 scores for global health status and physical, emotional and social functioning did not change significantly throughout treatment. After a median follow up of 44.4 months, 18 (45%) are alive without progression, 20 (50%) are alive with progression and 2 (5%) died after progression. BCT improved response depth in assessable patients who completed >1 cycle (n=34). Disease response at trial entry: 4 (12%) sCR/CR, 19 (56%) VGPR, 10 (29%) PR, 1(3%) SD, cf. response at 12 months post-ASCT: 7 (21%) sCR/CR, 22 (65%) VGPR, 4 (12%) PR, 1(3%) PD. Biochemical response depth improved in 12 patients. 19 patients had MRD testing at 3 (where available) or 6 months post-ASCT and again at 12 months, 10 were MRD+ at the earlier time point, of whom 4 converted to MRD- at 12 months. Of the 9 MRD- patients, all remained negative at 12 months. 15 patients (44%) had improvement in biochemical and/or MRD response at 12 months. Median PFS was 38.5 months (95%CI 29.1-47.9)(Figure). Patients who were MRD- at 12 months had median PFS of 49.2 months (95%CI 35.3-63.2) compared with 22.0 months (95%CI 21.5-22.6) in MRD+ patients (p=0.03). Of the 22 patients who relapsed, 12 received bortezomib-based salvage regimens, 5 received carfilzomib-based regimens and 5 have not started second-line therapy. Disease responses in patients receiving bortezomib salvage was 8 (67%) VGPR, 4 (33%) PR. Four patients went on to have a 2nd ASCT. In the 17 patients receiving salvage, median 2nd PFS from start of second line was 14.8 months (95%CI 8.2-18.0). At 3 months post-ASCT, levels of the osteoblast markers bALP and OC were significantly higher in CR/VGPR patients, compared to patients with PR or less (p=0.04 and 0.03, respectively). Neither marker changed significantly following BCT. Conclusions: For patients with MM, consolidation with weekly bortezomib post-ASCT is well tolerated and deepens disease response and MRD negativity without compromising the response to subsequent bortezomib-based salvage therapy. Patients who are MRD- at 12 months enjoy a median PFS of 4 years. This low intensity post-ASCT strategy deserves further study in the context of current and evolving protocols for newly diagnosed patients. Figure Figure. Disclosures Yong: Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding.

scholarly journals Prolonged Progression-Free Survival Is Possible in Patients with Diffuse Large B-Cell Lymphoma Receiving > 1 Salvage Therapies before Autologous Stem Cell Transplant

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5825-5825
Author(s):  
Abigail G Kettle ◽  
Jeffrey Switchenko ◽  
Oscar Calzada ◽  
Anh Thuy Phan ◽  
Monique Farone ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Board Of Directors ◽  
Salvage Therapy ◽  
Research Funding ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Salvage Treatment ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Free Survival

Abstract Introduction While 50-60% of patients with diffuse large B-cell lymphoma (DLBCL) are cured with initial chemoimmunotherapy such as R-CHOP, many patients will relapse and require additional therapy. Historically, autologous stem cell transplant (ASCT) has been utilized in chemo-sensitive patients with relapsed DLBCL although the role of ASCT in patients who require > 1 salvage treatment to achieve remission is less defined due to concerns about the likelihood of long-term remission in that population. We evaluated the outcome of ASCT in patients who required >1 salvage therapy. Methods We included all patients undergoing ASCT for relapsed/refractory DLBCL at our site between 2005-2016 who received > 1 salvage treatment before transplant, with radiation therapy considered a salvage treatment if given after relapse but before ASCT. We collected demographic, clinical, laboratory and pathologic data on all patients. We defined progression-free survival (PFS) as time from ASCT to date of progression or death from any cause and overall survival (OS) as time from ASCT to date of death from any cause. Living patients were censored at the time of their last follow up. Univariate Cox proportional hazards models of PFS and OS were fit and Kaplan-Meier plots were developed to estimate the impact of variables of interest on survival. Results Out of 259 patients undergoing ASCT for DLBCL, 43 received > 1 salvage treatment, the median age was 51 years and 23 patients were male. Twenty patients had stage III/IV disease at diagnosis. The median time to relapse from the time of diagnosis was 9.3 months, and 42% of patients experienced a relapse > 12 months after diagnosis. Twenty-six patients (60%) received radiation as one of their salvage therapies, 25 patients (58%) received R-ICE as their first salvage therapy and 10 (23%) patients received R-ICE as their second salvage treatment. All patients received either 2 (n=39) or 3 (n=4) salvage therapies before ASCT, and the response to the initial salvage therapy received was CR in 4 patients, PR in 14 patients, SD in 1 patient, and PD in 14 patients, with initial response to salvage therapy missing in 10 patients. The median PFS for all patients was 15.9 months and the median OS was 57.2 months (Figure 1a). Receipt of radiation and having disease sensitive to treatment at the time of ASCT were the only factors associated with prolonged PFS and OS. Median PFS has not been achieved in patients who received radiation while patients who did not receive radiation had a median PFS of 4.2 months (HR = 0.36, p = 0.014; Figure 1b). Patients who had a chemo sensitive disease status at transplant had a median PFS of 22.6 months; however, patients with refractory disease at transplant only achieved a median PFS of 3.6 months (HR = 0.30, p=0.008). Remaining factors including conditioning regimen, time to relapse, and number of salvage therapies were not significantly associated with PFS or OS. Conclusions ASCT can result in prolonged PFS/OS in patients requiring > 1 salvage therapy especially in the case of sensitive disease. Radiation as an additional line of therapy is associated with improved PFS/OS, suggesting this can be included to induce remission in patients who fail to achieve CR with initial salvage treatment. While uncommon, patients with chemo-refractory disease can also have durable survival and should not be excluded from transplant. Figure 1a Progression-free survival for all patients with DLBCL receiving > 1 salvage therapy. Figure 1a. Progression-free survival for all patients with DLBCL receiving > 1 salvage therapy. Figure 1b Progression-free survival for all patients with DLBCL receiving > 1 salvage therapy based on receipt of radiation therapy. Figure 1b. Progression-free survival for all patients with DLBCL receiving > 1 salvage therapy based on receipt of radiation therapy. Disclosures Calzada: Seattle Genetics: Research Funding. Flowers:Spectrum, Janssen, Infinity, AbbVie, Acerta, Pharmacyclics, TG Therapeutics: Research Funding; Celgene Corporation: Consultancy, Honoraria; Optum Rx, Seattle Genetics, Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Seattle Genetics: Research Funding. Cohen:Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals 1090. HHV-6 Encephalitis following Chimeric Antigen Receptor T-cell Therapy: Report of 2 Cases

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S574-S574
Author(s):  
Melanie T Rebechi ◽  
Jacqueline Bork ◽  
David J Riedel
Keyword(s):  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Human Herpesvirus ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Cell Transplant ◽  
T Cell Therapy ◽  
Hematopoietic Stem ◽  
Car T

Abstract Background Human herpesvirus 6 (HHV-6) is the most common cause of infectious encephalitis following hematopoietic stem cell transplant. Chimeric antigen receptor T-cell (CAR-T) therapy is a novel cancer-directed immunotherapy; chemotherapy conditioning for CAR-T results in prolonged, severe immunosuppression. HHV-6 encephalitis has not been reported in patients after CAR-T therapy. Methods We report 2 cases of HHV-6 encephalitis after CAR-T therapy. Results Case 1: A 69 year old man underwent CAR-T therapy after fludarabine/cyclophosphamide (Flu/Cy) conditioning for relapsed diffuse large B cell lymphoma (DLBCL). His course was complicated by cytokine release syndrome (CRS) requiring tocilizumab and neurotoxicity requiring high dose dexamethasone. On day 29 he was febrile to 39.3℃, confused, and had difficulty speaking. Mental status (MS) worsened, so LP and MRI of the brain were performed. HHV-6 CSF PCR was positive, and ganciclovir (GCV) was started. He improved gradually over 10 days. At follow up, he reported mild short term memory difficulty but no focal deficits. Case 2: A 57 year old man underwent CAR-T therapy after Flu/Cy conditioning for refractory DLBCL. His course was complicated by CRS requiring tocilizumab. On day 6, he had difficulty concentrating, slowed thinking, stuttering and repetitive speech. MS continued to worsen, and dexamethasone and siltuximab were given for CAR-T neurotoxicity. After 1 week he was following commands. By week 3 he remained intermittently confused and agitated, so MRI and LP were performed. HHV-6 PCR was positive in the CSF. He was started on GCV and improved gradually over the next 2 weeks but remained dysarthric with slowed speech. On day 55, HHV-6 remained detectable in CSF but not quantifiable and GCV was discontinued despite persistent cognitive deficits. Table 1: Demographics and clinical characteristics of 2 patients with HHV-6 encephalitis following CAR-T therapy Conclusion Diagnosing HHV-6 encephalitis can be challenging after CAR-T therapy because altered MS is often attributed to CAR-T associated neurotoxicity. It is important to maintain a high index of suspicion for infectious causes of altered MS after CAR-T therapy, including HHV-6 encephalitis, especially in patients treated with further immunosuppression for CRS and CAR-T related neurotoxicity. Disclosures All Authors: No reported disclosures

Open-Label, Single-Arm, Phase II Study of Everolimus in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2717-2717 ◽  
Author(s):  
Patrick B. Johnston ◽  
Lauren Pinter-Brown ◽  
Jaqueline Rogerio ◽  
Ghulam Warsi ◽  
Anne Graham ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Disease Progression ◽  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
High Dose ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Pretreated Patients

Abstract Abstract 2717 Background: Dysregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signal transduction pathway, which is central to cellular growth, proliferation, metabolism, survival, and angiogenesis, is implicated in Hodgkin lymphoma (HL) pathogenesis. In a previous phase II study of patients with relapsed/refractory lymphomas, the oral mTOR inhibitor everolimus showed promising clinical activity and acceptable toxicity in a subgroup of 19 heavily pretreated patients with HL (Johnston et al. Am J Hematol 2010;85:320–4). The purpose of this study was to confirm the safety and efficacy of everolimus 10 mg/day in patients with relapsed/refractory classical HL. Methods: In this multicenter, US, phase II study, patients aged ≥18 years with classical HL whose disease progressed after high-dose chemotherapy with autologous hematopoietic stem cell transplant (AHSCT) and/or a gemcitabine-, vinorelbine-, or vinblastine-containing regimen were treated with oral everolimus 10 mg/day until disease progression or unacceptable toxicity. Radiological response was assessed every 12 weeks using integrated positron emission tomography/computed tomography with contrast or computed tomography with contrast. The primary endpoint was the overall response rate (ORR) evaluated using modified response criteria for malignant lymphoma (Cheson et al. J Clin Oncol 2007;25:579–86). Secondary endpoints included median progression-free survival (PFS). Adverse events (AEs) were assessed throughout the study and for ≥4 weeks after the last everolimus dose. Results: The results from 37 patients in the safety population with evaluable data are reported in this abstract. Among these 37 patients, 35% were male, and the median age was 32 years. The median times from initial diagnosis to the first and most recent recurrence/relapse were 9 and 38 months, respectively. Of the 37 patients, 54% were pretreated with AHSCT and 95% were pretreated with a gemcitabine-, vinorelbine-, or vinblastine-containing regimen. The percentage of patients who experienced disease progression during prior therapies or discontinued their previous treatment due to disease progression was 73%. The median number of prior medication regimens was 4.5. Twenty-two patients discontinued treatment, including 11 due to disease progression and 8 due to AEs. The ORR was 35%, and an additional 27% of patients had stable disease (Table). The median PFS was 7.2 months (Figure). The most common hematologic AEs were thrombocytopenia (38%) and anemia (22%), and the most common nonhematologic AEs were fatigue (43%), cough (27%), headache (22%), dyspnea (22%), and rash (22%). Grade 3 or 4 drug-related AEs were noted in 12 (32%) patients and most commonly included thrombocytopenia (16%), neutropenia (8%), and anemia (8%). Serious AEs were experienced by 19% of patients; no serious AE occurred in more than 1 patient. Conclusion: Everolimus was associated with a favorable ORR and median PFS duration in highly pretreated patients with relapsed/refractory classical HL, confirming results of a previous study. The AE profile was consistent with that previously observed for everolimus; most AEs were grade 1 or 2 and manageable. These results suggest that further study evaluating everolimus in HL is warranted. Disclosures: Pinter-Brown: Genentech: Speakers Bureau; Spectrum: Honoraria; Celgene: Consultancy; Merck: Consultancy; Allos: Consultancy. Rogerio:Novartis Pharmaceuticals Corporation: Employment. Warsi:Novartis Pharmaceuticals Corporation: Employment. Graham:Novartis Pharmaceuticals Corporation: Employment. Ramchandren:Seattle Genetics: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Celgene: Research Funding; Pfizer: Research Funding.

High Dose Cytarabine, Mitoxantrone and L-Asparaginase (HAMA) Salvage For Relapsed Or Refractory Acute Myeloid Leukemia (AML) In The Elderly

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2700-2700 ◽  
Author(s):  
Tamjeed Ahmed ◽  
Scott Holwerda ◽  
Timothy Pardee ◽  
Scott Isom ◽  
Susan Lyerly ◽  
...  
Keyword(s):  
Complete Remission ◽  
Median Survival ◽  
Older Patients ◽  
The Elderly ◽  
High Dose ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Poor Risk ◽  
Elderly Aml ◽  
High Dose Cytarabine

Abstract AML is a disease of older adults with the median age at diagnosis of 68. Elderly AML, generally defined as patients ≥60 years of age, is a clinically distinct disease highlighted by worse overall survival (OS), lower complete remission (CR) rates, and higher treatment related toxicity. Most elderly AML patients who achieve a CR will eventually relapse and require further chemotherapy. Despite the central role of relapsed disease in elderly patients few studies have reported on outcomes using salvage chemotherapy in patients over 60 years of age and no standard regimen has been established. We retrospectively examined data for 108 consecutive relapsed or refractory AML patients treated with the HAMA regimen at Wake Forest between May, 1999 and December, 2010. This regimen consists of high dose cytarabine (3gm/m2 in patients <60, 1 to 3gm/m2 in patients ≥60) given Q12 hours for 5 doses, mitoxantrone at 6mg/m2 once daily for 3 days immediately following the cytarabine and a single dose of L-asparaginase at 6000 units/m2 following the last dose of mitoxantrone. We collected data on age, gender, race, comorbidities, baseline lab values, cytogenetics at relapse, length of first remission (CR1), attainment of second complete remission (CR2), further therapy received and survival. Statistical analysis was performed using Kaplan-Meier estimates and Cox proportional hazards models. Of the 108 patients analyzed, 75 were ≥60 years old and 33 were younger than 60 at the time of HAMA treatment. The median age for the younger cohort was 51 (range 20-59) and for the elderly cohort was 68 (range 60-84). Older patients were more likely to have refractory disease (25% vs 6%), one or more comorbidities (47% vs 12%) and poor risk cytogenetics (23% vs 16%). Early all cause mortality (30 and 60 day) was 13% and 22% respectively for all patients and 17% and 28% for those ≥60. The percentage of patients that died during hospitalization or were discharged to hospice was 25% for all patients (12% <60, 31% ≥60). CR2 was achieved in 41% of patients (49% <60, 37% ≥60). Median OS was 7 (2.1-14.3), 13.6 (4.9-68) and 5.8 (1.3-11.9) months for all patients, <60 and ≥60 cohorts respectively. For those patients ≥60 who achieved a CR median OS was 11.9 months. At 12 months 56% of patients <60 were alive compared with 24% for patients ≥60. By 24 months these numbers fell to 40% and 3% respectively. In the <60 cohort 27% (9/33) went on to allogeneic hematopoietic stem cell transplant (HCT) compared to 12% (9/75) in the ≥60 cohort. The only significant predictors for OS were cytogenetic risk score (p=0.0050) and length of first CR >1 year (p=0.0005). Of the 16 patients in the cytogenetic poor risk group only 12% (2/16) achieved CR2 and none were alive more than 14 months from relapse. Median survival for patients with CR1 >1 year was 13.6 (5.9-19.7) months compared to 5.8 (3.3-7.2) months for patients with CR1 <1 year. In conclusion, the HAMA salvage regimen when given to older patients results in a 37% complete remission rate with a median survival of almost one year in this subgroup, however only 12% went on to allogeneic HCT and only 3% were alive 24 months after relapse. Patients with poor risk cytogenetics regardless of age were not effectively salvaged with this regimen and should be offered experimental therapy when possible. Disclosures: No relevant conflicts of interest to declare.

Everolimus (EVE) for relapsed/refractory classical Hodgkin lymphoma (cHL): Open-label, single-arm, phase II study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8028-8028 ◽  
Author(s):  
Patrick B. Johnston ◽  
Lauren C. Pinter-Brown ◽  
Jaqueline Willemann Rogerio ◽  
Ghulam Warsi ◽  
Quincy Chau ◽  
...  
Keyword(s):  
Disease Progression ◽  
Mammalian Target Of Rapamycin ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Cell Transplant ◽  
Open Label ◽  
Hematopoietic Stem ◽  
Positron Emission

8028 Background: Effective treatment for relapsed/refractory cHL is lacking. The oral mammalian target of rapamycin inhibitor EVE showed promising efficacy and acceptable toxicity in cHL. We conducted a study to confirm EVE safety and efficacy in relapsed/refractory cHL. Methods: In this multicenter, open-label, 2-step, phase 2 study, adults with cHL that progressed after high-dose chemotherapy with autologous hematopoietic stem cell transplant (AHSCT) or a gemcitabine-, vinorelbine-, or vinblastine-containing regimen received EVE 10 mg/d until disease progression or unacceptable toxicity. Response was assessed every 12 wk via integrated positron emission tomography/computed tomography (CT) with contrast or CT with contrast. Primary endpoint was overall response rate (ORR) per modified response criteria for malignant lymphoma. Adverse events (AEs) were assessed during, and for ≥4 wk after, EVE treatment. Results: 55 patients were enrolled. Of the 38 currently evaluable patients, 37% were men, median age was 32.5 y, 53% were pretreated with AHSCT, and 95% were pretreated with gemcitabine, vinorelbine, or vinblastine; 71% had disease progression during previous therapies or discontinued previous treatment due to progression. 23 patients discontinued treatment, most commonly due to disease progression (n = 11). ORR was 37% (Table). Median progression-free survival (PFS) was 7.2 mo. The most common hematologic AEs were thrombocytopenia (39%) and anemia (24%); the most common nonhematologic AEs were fatigue (47%), cough (29%), dyspnea (26%), headache (21%), and rash (21%). Grade 3/4 AEs, most commonly thrombocytopenia (18%), were observed in 45% of patients. Conclusions: EVE showed a favorable ORR and median PFS in the first 38 evaluable patients with highly pretreated, relapsed/refractory cHL. The AE profile was consistent with that previously observed for EVE. These preliminary results confirm those of an earlier study and support further evaluation of EVE in cHL. [Table: see text]

PROSPECTS FOR HIGH-DOSE CHEMOTHERAPY WITH AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN THE FIRST LINE OF THERAPY FOR AGGRESSIVE NON-HODGKIN’S LYMPHOMAS

2017 ◽  
Vol 63 (2) ◽  
pp. 326-328
Author(s):  
Larisa Filatova ◽  
Yevgeniya Kharchenko ◽  
Sergey Alekseev ◽  
Ilya Zyuzgin ◽  
Anna Artemeva ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Therapeutic Option ◽  
B Cell Lymphoma ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
First Line ◽  
Hematopoietic Stem ◽  
Hodgkin's Lymphomas

Currently there is no single approach to treatment for aggressive diffuse large-cell B-cell lymphoma (Double-HIT and Triple-HIT). Accumulated world data remain controversial and, given the unfavorable prognosis in this subgroup, high-dose chemotherapy with autologous stem cell transplantation in the first line of treatment is a therapeutic option.

scholarly journals Breakthrough Mucormycosis Developing on Mucorales-Active Antifungals Portrays a Poor Prognosis in Patients with Hematologic Cancer

2021 ◽  
Vol 7 (3) ◽  
pp. 217
Author(s):  
Dierdre B. Axell-House ◽  
Sebastian Wurster ◽  
Ying Jiang ◽  
Andreas Kyvernitakis ◽  
Russell E. Lewis ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Symptom Onset ◽  
Poor Prognosis ◽  
Treatment Initiation ◽  
Cox Regression ◽  
Severe Neutropenia ◽  
Apache Ii Score ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Cox Regression Analysis

Although breakthrough mucormycosis (BT-MCR) is known to develop on mold-active antifungals without Mucorales activity, it can also occur while on Mucorales-active antifungals. Herein, we retrospectively compared the characteristics and outcomes of patients with hematologic malignancies (HMs) or hematopoietic stem cell transplant (HSCT) who developed BT-MCR on mold-active antifungals with or without Mucorales activity. Of the patients developing BT-MCR, 16 were on Mucorales-active antifungals (9 isavuconazole, 6 posaconazole, 1 amphotericin B), and 87 were on other mold-active agents (52 voriconazole, 22 echinocandins, 8 itraconazole, 5 echinocandin + voriconazole). Both groups were largely comparable in clinical characteristics. Patients developing BT-MCR while on Mucorales-active antifungals had higher 42-day mortality, from either symptom onset (63% versus 25%, p = 0.006) or treatment initiation (69% versus 39%, p = 0.028). In multivariate Cox regression analysis, exposure to Mucorales-active antifungals prior to BT-MCR had a hazard ratio of 2.40 (p = 0.015) for 42-day mortality from treatment initiation and 4.63 (p < 0.001) for 42-day mortality from symptom onset. Intensive care unit (ICU) admission and APACHE II score at diagnosis, non-recovered severe neutropenia, active HM, and amphotericin B/caspofungin combination treatment were additional independent predictors of 42-day mortality. In summary, BT-MCR on Mucorales-active antifungals portrays poor prognosis in HM/HSCT patients. Moreover, improvements in early diagnosis and treatment are urgently needed in these patients.

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