A Phase II Study of Methotrexate (M), Vincristine (O), Pegylated L-Asparaginase (pA), and Dexamethasone (MOpAD) in Patients with Relapsed and/or Refractory Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4308-4308
Author(s):  
Tapan M. Kadia ◽  
Jorge E. Cortes ◽  
Deborah Thomas ◽  
Farhad Ravandi ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
Side Effects ◽  
Phase Ii ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Median Number ◽  
Cell Transplant ◽  
Dependent Manner ◽  
Salvage Regimen ◽  
Term Survival

Abstract Abstract 4308 Introduction Adults with relapsed or refractory (R/R) ALL have a poor prognosis, with low rates of complete remission (CR) to standard salvage therapy and long term survival of less than 5%. L-asparaginase has a unique mechanism of action and is highly active in ALL, but its use in adults has been limited by concerns for side effects. A new pegylated (peg) preparation bestows a longer half-life, less immunogenicity, and better tolerance. Additionally L-asparaginase has a significant synergy when combined with methotrexate in schedule-dependent manner. Methods Patients with previously treated, R/R ALL (including Burkitt's and Philadelphia [Ph] positive) with adequate organ function, and PS ≤ 3 were enrolled on a phase II clinical trial to determine the efficacy and safety of MOpAD. Patients were stratified in two groups: 1st salvage or3 2nd salvage. They were treated on the following schedule: methotrexate 200 mg/m2/d IV on days 1 & 15; vincristine 1.4 mg/m2/d (max 2 mg) IV on days 1,8, & 15; peg-asparaginase 2500 IU/m2/d on days 2 and 16; and dexamethasone 40 mg IV or PO daily on days 1–4 and 15–18. Patients with CD20+ ALL could receive rituximab 375 mg/m2/d IV on days 1 & 15 for the first 4 cycles (1 cycle=28 d). A later amendment allowed patients with Ph+ ALL to also receive daily imatinib, dasatinib, or nilotinib in conjunction with MOAD. Results A total of 27 patients (37% female) with R/R ALL have been enrolled thus far, with a median age of 41 (range, 24–68) and median PS of 1 (0–3). Eighteen pts (67%) had B-ALL (including 6 with Ph+ ALL), and 9 (33%) had T-ALL. The median number of prior therapies is 2 (1–6), and the breakdown by salvage is as follows: 1st salvage: 10 (37%); ≥ 2nd salvage: 17 (63%). 5 pts received rituximab, and 2 of 6 Ph+ pts received a tyrosine kinase inhibitor (TKI) (1 each of dasatinib and nilotinib). The overall response rate (ORR) was (12/27) 44%, with 8 CR (30%), 1 CRi (4%), and 3 CRp (11%). The ORR by salvage status was 25% in 1st salvage and 47% in ≥ 2nd salvage. The ORR by phenotype: Ph(−) B-ALL: 17%, Ph+ B-ALL: 67%, and T-ALL: 67%. All 6 patients (100%) with T-ALL who responded were able to go on to stem cell transplant. Response predicted for improved OS: median 9 months vs. 1 month in responders vs. non-responders. The most common grade 3/4 adverse events included low fibrinogen (44%), elevated bilirubin (37%), transaminitis (26%), elevated amylase/lipase without pancreatitis (15%), and thrombosis (11%). Side effects were manageable overall, myelosuppression was universal, and there were 3 early deaths (11%). Conclusions The non-anthracycline-based combination of MOpAD is a safe and effective salvage regimen in adult patients with relapsed ALL, particularly those with T-ALL or Ph+ disease. The chemotherapy backbone can be combined safely with rituximab and TKIs in this setting. Patients continue to be enrolled and updated results will be presented. Disclosures: Kadia: GSK: Research Funding. Borthakur:Sigma Tau: Research Funding.

Outcome of Patients with Chronic Myeloid Leukemia (CML) with Multiple ABL1 Kinase Domain Mutations during Tyrosine Kinase Inhibitor Therapy.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2111-2111
Author(s):  
Alfonso Quintas-Cardama ◽  
Hagop M. Kantarjian ◽  
Gautam Borthakur ◽  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Amino Acid ◽  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Kinase Domain ◽  
Molecular Response ◽  
Cell Transplant ◽  
Term Survival ◽  
2Nd Generation ◽  
Kinase Domain Mutations

Abstract BACKGROUND: BCR-ABL1 kinase domain mutations are the main mechanism of resistance to tyrosine kinase inhibitors (TKIs) by destabilizing the inactive conformation of the enzyme or by causing steric hindrance. Although mutations usually affect one amino acid residue within the ABL1 kinase domain, some patients have been shown to carry multiple ABL1 mutations (MAMs). The outcome of these patients is not well defined. OBJECTIVES: To define the clinical characteristics and outcome of patients harboring MAMs detected by direct sequencing during TKI therapy. RESULTS: MAMs were detected in 24 patients (5%) among a series of 502 patients assayed during TKI therapy: 22 with CML and 2 with BCR-ABL1-positive acute lymphoblastic leukemia (Ph+ALL). Median age was 57 years (range, 27–92). Median time from diagnosis to ABL1 mutation detection was 54 months (range, 8–254) and to detection of MAMs 77 months (range, 8–261). Overall, 21 different mutations affecting 15 amino acid residues were detected. The most frequent mutations were M351T (n=7), T315I (n=6), Y253H (n=6), G250E (n=6), and F317L (n=5). P-loop mutations (residues 244–255) were found in 16 (67%) patients. At the time of detection of MAMs, 13 patients were in CP, 4 in AP, and 7 in BP. Patients had received a median of 5 prior therapies (range, 2–9), including 2 TKIs (range, 1–4). Best response to TKI therapy prior to detection of MAMs (24 imatinib, 10 nilotinib, 15 dasatinib, 6 SKI- 606, 1 INNO-406, 1 MK-0457) was complete hematologic response (CHR) in 16 (67%) and cytogenetic response in 7 (29%; complete [CCyR] in 4, partial [PCyR] in 1, minor [mCyR] in 1). One patient had achieved a complete molecular response (CMR). The median follow-up from the detection of MAMs was 10 months (range, 1–51). Twenty-two patients received a 2nd generation TKI after imatinib failure. Among 13 with MAMs prior to start of 2nd generation TKI, 7 (54%) responded (5 CHR, 1 return to CP, and 1 CCyR) for a median of 6.5 months (range, 2–31). By contrast, all 9 (100%) patients without MAMs prior to 2nd generation TKI responded (4 CHR, 3 CCyR, 1 PCyR, 1 CMR) for a median of 43 months (range, 7–48) (p=0.005). Although most patients with MAMs prior to 2nd generation TKIs start had short-lived responses to those agents, those were sustained for significant periods of time in 3 patients: one in BP harboring simultaneously M244V and M351T achieved a CHR and a mCyR with dasatinib 35mg twice daily, sustained for 8 months. A second patient acquired M351T and F359V while receiving imatinib 800mg/d in CP. Therapy with bosutinib 300mg/d rendered a mCyR that has been sustained for more than 9 months. A third patient in AP receiving imatinib 800mg/d acquired G250E and F317L mutations. Therapy with nilotinib 800mg/d resulted in CCyR for 33 months; although F317L became undetectable, CCyR was lost and later regained and has been ongoing for the last 11 months on bosutinib 500mg/d. Four patients underwent allogeneic stem cell transplant (allo-SCT) and 2 are alive: 1 in CHR 2+ months after allo-SCT and 1 who relapsed 3 months post transplant and is currently in CCyR (BCR-ABL1/ABL1 ratio 0.55%) after 19+ months on dasatinib. Ten (42%) of the 24 patients died. The 2-year survival for patients in CP, AP, or BP at the time of detection of MAMs was 86%, 50%, and 0%, respectively. CONCLUSION: Patients expressing more than 1 ABL1 kinase domain mutation respond poorly to TKI therapy. Responses to 2nd generation TKIs, when they occur, are mostly hematologic and typically last <12 months. The long-term survival of patients with MAMs is highly influenced by CML phase.

Phase II Study Of Combination Of Hyper-CVAD With Ponatinib In Front Line Therapy Of Patients (pts) With Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2663-2663
Author(s):  
Elias Jabbour ◽  
Hagop Kantarjian ◽  
Deborah A. Thomas ◽  
Farhad Ravandi ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Phase Ii ◽  
Cytogenetic Analysis ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Cytogenetic Response ◽  
Banding Technique ◽  
High Dose ◽  
Cell Transplant ◽  
Platelet Recovery ◽  
Cd20 Expression

Abstract Background Combination of cytotoxic chemotherapy with imatinib or dasatinib is effective in the treatment of Ph+ ALL. Ponatinib is a more potent BCR-ABL inhibitor. It also suppresses the T315I clones, a common cause of relapse in pts with Ph+ ALL. Clinical trials of ponatinib have demonstrated its high activity and limited toxicity in Ph+ leukemias. The complete cytogenetic response (CCyR) rate is 40% to 50% in patients failing 2-3 TKIs and in those with a T315I mutation. The combinations of chemotherapy and ponatinib may be associated with better response rates and higher likelihood of eradication of minimal residual disease (MRD) than those reported with imatinib or dasatinib. Methods In this phase II trial, pts with newly diagnosed Ph+ ALL received 8 cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternating with high dose methotrexate (MTX) and cytarabine every 21 days. Ponatinib was given at 45 mg po daily for the first 14 days of cycle 1 then continuously for the subsequent 7 cycles. Rituximab was administered during the first 4 cycles in pts with CD20 expression ≥20%. Pts in CR received maintenance with ponatinib 45 mg po daily and vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. MRD monitoring was conducted. Results To date 28 pts with untreated Ph+ ALL and 2 pts previously treated (1 with prior cycle of chemotherapy before Ph+/BCR-ABL status was known not in CR, and 1 post HCVAD-dasatinib in CR) have received a median of 6 cycles (1-8) of therapy; 10 pts are receiving maintenance in CR. Median age was 55 years (28–75). Median WBC at diagnosis was 3.55 x 109/L (1.6 -629 x 109/L). CD20 expression was reported positive in 11 pts (37%). 2 (7%) had concomitant CNS disease at diagnosis. All pts were in CR after cycle 1. 24 of the 26 pts (92%) with Ph+ metaphases (at least 20 metaphases analyzed) by cytogenetic analysis at baseline achieved a CCyR after 1 cycle; 1 had a minor cytogenetic response only and one had no cytogenetic analysis at CR, both of them achieved a CCyR after cycle 2; 4 had a diploid karyotype at the start of therapy (one in CCyR post previous chemotherapy and 3 diploid by standard G-banding technique and positive by FISH and PCR). To date, 26 pts (93%) have achieved a MMR, of whom 19 (70%) have achieved a CMR at a median of 10 weeks from initiation of treatment (2 -28). MRD assessment by flow cytometry is negative in 26 (90%) pts at a median of 3 weeks (3-14). Median time to neutrophil and platelet recovery for cycle 1 was 18 and 23 days, and 16 and 22 days for subsequent cycles, respectively. Grade ≥ 3 toxicity included increase of LFT’s in 11 pts (37%), thrombotic events in 3 (10%, 1 renal vein thrombosis and 2 pulmonary emboli), myocardial infarction (MI) in 3 (10%, 1 unexplained, 1 with history of cardiomyopathy, and 1 in the context of sepsis ), skin rash in 3 (15%), and pancreatitis in 2 (7%). 11 pts (37%) had their dose reduced to 30 mg and 2 pts (10%) switched to dasatinib (n=1) or imatinib (n=1). With a median follow up of 7 months (1-20), 21 pts are alive and in CR; 1 pt died in CR from an unrelated cardiac event after being taken off therapy and placed on imatinib, 1 pt died from multiple organ failure post sepsis (C2D13), and 1 from non ST elevation MI (NSTEMI) post cycle 2 (C2D41). 6 pts have undergone an allogeneic stem cell transplant. The 1-year progression-free and overall survival rates were 100% and 88% respectively. Conclusion The combination of hyperCVAD with ponatinib is safe and highly effective in achieving molecular remissions in pts with Ph+ ALL. Disclosures: Jabbour: Ariad: Consultancy; Novartis: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Ravandi:Sunesis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Teva: Consultancy, Honoraria; Pfizer: Honoraria; Merck: Research Funding; Bayer/Onyx: Consultancy, Honoraria; EMD Serono: Research Funding; Medimmune: Research Funding; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Cortes:Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Novartis: Research Funding; BMS: Research Funding. Faderl:Sanofi-Aventis: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Encapsulation of Imatinib in Targeted KIT-5 Nanoparticles for Reducing its Cardiotoxicity and Hepatotoxicity

2020 ◽  
Vol 20 (16) ◽  
pp. 1966-1980
Author(s):  
Jaleh Varshosaz ◽  
Saeedeh Fardshouraki ◽  
Mina Mirian ◽  
Leila Safaeian ◽  
Setareh Jandaghian ◽  
...  
Keyword(s):  
Controlled Release ◽  
Side Effects ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Drug Carrier ◽  
Free Drug ◽  
Jurkat Cells ◽  
Targeted Nanoparticles ◽  
Inhibitor Drug ◽  
Histopathological Results

Background: Using imatinib, a tyrosine kinase inhibitor drug used in lymphoblastic leukemia, has always had limitations due to its cardiotoxicity and hepatotoxicity side effects. The objective of this study is to develop a target-oriented drug carrier to minimize these adverse effects by the controlled release of the drug. Methods: KIT-5 nanoparticles were functionalized with 3-aminopropyltriethoxysilane and conjugated to rituximab as the targeting agent for the CD20 positive receptors of the B-cells. Then they were loaded with imatinib and their physical properties were characterized. The cell cytotoxicity of the nanoparticles was studied by MTT assay in Ramos (CD20 positive) and Jurkat cell lines (CD20 negative) and their cellular uptake was shown by fluorescence microscope. Wistar rats received an intraperitoneal injection of 50 mg/kg of the free drug or targeted nanoparticles for 21 days. Then the level of aspartate Aminotransferase (AST), alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP) and Lactate Dehydrogenase (LDH) were measured in serum of animals. The cardiotoxicity and hepatotoxicity of the drug were also studied by hematoxylin and eosin staining of the tissues. Results: The targeted nanoparticles of imatinib showed to be more cytotoxic to Ramos cells rather than Jurkat cells. The results of the biochemical analysis displayed a significant reduction in AST, ALT, ALP, and LDH levels in animals treated with targeted nanoparticles, compared to the free drug group. By comparison with the free imatinib, histopathological results represented less cardiotoxicity and hepatotoxicity in the animals, which received the drug through the current designed delivery system. Conclusion: The obtained results confirmed that the rituximab targeted KIT-5 nanoparticles are promising in the controlled release of imatinib and could decrease its cardiotoxicity and hepatotoxicity side effects.

scholarly journals Impact of Induction Treatment on Stem Cell Collection: A COVID Related Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4848-4848
Author(s):  
Brad Rybinski ◽  
Ashraf Z. Badros ◽  
Aaron P. Rapoport ◽  
Mehmet Hakan Kocoglu
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Research Funding ◽  
Median Number ◽  
Cell Transplant ◽  
Cd34 Cells ◽  
Significant Difference ◽  
Number Of Cycles ◽  
Time Required ◽  
Stem Cell Collection

Abstract Introduction: Standard induction therapy for multiple myeloma consists of 3-6 cycles of bortezomib, lenalidomide, and dexamethasone (VRd) or carfilzomib, lenalidomide and dexamethasone (KRd). Receiving greater than 6 cycles of a lenalidomide containing regimen is thought to negatively impact the ability to collect sufficient CD34+ stem cells for autologous stem cell transplant (Kumar, Dispenzieri et al. 2007, Bhutani, Zonder et al. 2013). Due to the COVID-19 pandemic, at least 20 patients at University of Maryland Greenebaum Comprehensive Cancer Center (UMGCC) had transplant postponed, potentially resulting in prolonged exposure to lenalidomide containing induction regimens. Here, in the context of modern stem cell mobilization methods, we describe a retrospective study that suggests prolonged induction does not inhibit adequate stem cell collection for transplant. Methods: By chart review, we identified 56 patients with multiple myeloma who received induction with VRd or KRd and underwent apheresis or stem cell transplant at UMGCC between 10/1/19 and 10/1/20. Patients were excluded if they received more than 2 cycles of a different induction regimen, had a past medical history of an inborn hematological disorder, or participated in a clinical trial of novel stem cell mobilization therapy. We defined 1 cycle of VRd or KRd as 1 cycle of "lenalidomide containing regimen". In accordance with routine clinical practice, we defined standard induction as having received 3-6 cycles of lenalidomide containing regimen and prolonged induction as having received 7 or more cycles. Results: 29 patients received standard induction (Standard induction cohort) and 27 received prolonged induction (Prolonged induction cohort) with lenalidomide containing regimens. The median number of cycles received by the Standard cohort was 6 (range 4-6), and the median number of cycles received by the Prolonged cohort was 8 (range 7-13). The frequency of KRd use was similar between patients who received standard induction and prolonged induction (27.58% vs. 25.93%, respectively). Standard induction and Prolonged induction cohorts were similar with respect to clinical characteristics (Fig 1), as well as the mobilization regimen used for stem cell collection (p = 0.6829). 55/56 patients collected sufficient stem cells for 1 transplant (≥ 4 x 10 6 CD34 cells/kg), and 40/56 patients collected sufficient cells for 2 transplants (≥ 8 x 10 6 CD34 cells/kg). There was no significant difference in the total CD34+ stem cells collected at completion of apheresis between standard and prolonged induction (10.41 and 10.45 x 10 6 CD34 cells/kg, respectively, p = 0.968, Fig 2). Furthermore, there was no significant correlation between the number of cycles of lenalidomide containing regimen a patient received and total CD34+ cells collected (R 2 = 0.0073, p = 0.5324). Although prolonged induction did not affect final stem yield, prolonged induction could increase the apheresis time required for adequate collection or result in more frequent need for plerixafor rescue. There was no significant difference in the total number of stem cells collected after day 1 of apheresis between patients who received standard or prolonged induction (8.72 vs. 7.96 x 10 6 cells/kg, respectively, p = 0.557). However, patients who received prolonged induction were more likely to require 2 days of apheresis (44% vs. 25%, p = 0.1625) and there was a trend toward significance in which patients who received prolonged induction underwent apheresis longer than patients who received standard induction (468 vs 382 minutes, respectively, p = 0.0928, Fig 3). In addition, longer apheresis time was associated with more cycles of lenalidomide containing regimen, which neared statistical significance (R 2 = 0.0624, p = 0.0658, Fig 4). There was no significant difference between standard and prolonged induction with respect to the frequency of plerixafor rescue. Conclusions: Prolonged induction with lenalidomide containing regimens does not impair adequate stem cell collection for autologous transplant. Prolonged induction may increase the apheresis time required to collect sufficient stem cells for transplant, but ultimately clinicians should be re-assured that extending induction when necessary is not likely to increase the risk of collection failure. Figure 1 Figure 1. Disclosures Badros: Janssen: Research Funding; J&J: Research Funding; BMS: Research Funding; GlaxoSmithKline: Research Funding.

scholarly journals Daratumumab, Pomalidomide, and Dexamethasone (DPd) for the Treatment of Relapsed/Refractory Multiple Myeloma: A Single Institution Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5642-5642 ◽  
Author(s):  
Al-Ola Abdallah ◽  
Neil Dunavin ◽  
Brian McClune ◽  
Leyla Shune ◽  
Ajoy L. Dias ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Median Number ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Duration Of Treatment ◽  
Effective Treatment Option ◽  
Refractory Multiple Myeloma ◽  
Overall Response

Abstract Background: Daratumumab triplet regimens containing dexamethasone and lenalidomide or bortezomib are an effective treatment option for patients with relapsed/refractory multiple myeloma (RRMM). Daratumumab was recently FDA-approved in combination with the second-generation immunomodulatory drug, pomalidomide, and dexamethasone based (DPd) on results of the EQUULEUS study where overall response rates (ORR) of 60% were seen. The goal of this retrospective study was to analyze clinical outcomes of the DPd triplet regimen in either a daratumumab and pomalidomide naïve or refractory population of heavily pretreated RRMM patients at our institution. Methods: Thirty-two patients with RRMM treated with DPd at the University of Kansas Health System between November 2015 and July 2018 were included in our analysis. DPd consisted of 28-day cycles of daratumumab 16 mg/kg intravenously (weekly for cycles 1 and 2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter until disease progression); pomalidomide 4 mg orally (PO)on Days 1-21 and adjusted for cytopenia or toxicities; and dexamethasone 40 mg PO weekly adjusted based on tolerance. based on age. Responses were evaluated using IMWG criteria. Patient characteristics, disease course, and outcomes were summarized with descriptive statistics. Kaplan-Meier analyses were used to estimate progression-free (PFS) and overall survival (OS). Results:The median age was 64 years (range 44-83). Twenty-three patients (72%) had IgG isotype, 11 patients (34 %) had ISS stage III disease at diagnosis, 13 patients (41%) had high risk cytogenetics, and 13 patients (41%) had extramedullary disease. Median number of previous lines of therapy was 4 (1-9). Twenty-two patients (69%) received ≥3 prior therapies. Twenty-three patients (72%) were proteasome inhibitor refractory, 28 patients (88%) were immunomodulator refractory, 9 patients (28%) were daratumumab refractory, and 3 patients (15%) were double refractory to daratumumab and pomalidomide. Twenty-eight patients (88%) had received autologous stem cell transplant (ASCT) prior to DPd; 12 patients (38%) had ≥2 prior transplants. Median number of DPd cycles received was 6 (2-30) and the median duration of treatment was 5 months (2-30). At a median follow-up of 8.4 months (range: 2-29), the overall response rate (ORR) for all patients was 72% which compares favorably to the ORR of 60% in the EQUULEUS study. However, about half of the responses were partial responses (PR) (47%). The ORR rate for those who were refractory to either pomalidomide or daratumumab was 65%. The PFS was 8.3 months, while the median OS was not reached. Conclusion: DPd was recently approved for the treatment of RRMM. Our ORR compares favorably to the EQUULEUS study, however about half of responses were partial responses or better. Surprisingly, our analysis shows an impressive ORR in patients with previous exposure to proteasome inhibitor and immunomodulatory therapies in RRMM population, suggesting a benefit of DPd even in patients who received prior pomalidomide or daratumumab. Disclosures McGuirk: Astellas Pharma: Research Funding; Gamida Cell: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Other: speaker, Research Funding; Pluristem Ltd: Research Funding; Kite Pharma: Honoraria, Other: travel accommodations, expenses, speaker ; Fresenius Biotech: Research Funding; Bellicum Pharmaceuticals: Research Funding. Ganguly:Daiichi Sankyo: Research Funding; Janssen: Consultancy; Amgen: Consultancy; Seattle Genetics: Speakers Bureau.

Intravesicular Cidofovir in the Treatment of BK Virus-Associated Hemorrhagic Cystitis (BKV-HC) Following Allogeneic Hematopoietic Stem Cell Transplant (HSCT)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2085-2085
Author(s):  
Graham Tooker ◽  
Ashraf Z. Badros ◽  
Jennifer Nishioka ◽  
David Riedel
Keyword(s):  
Viral Load ◽  
Median Time ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Bk Virus ◽  
Response To Treatment ◽  
Cell Transplant ◽  
Initial Report ◽  
Hematopoietic Stem ◽  
Common Diagnosis

Abstract Background: BKV HC is a well-known complication following allo-SCT. Supportive care with bladder irrigation and blood transfusions were the only available treatment. Since our initial report (Bridges B et al. Am J Hematol 2006;81:535), several studies confirmed that intravesicular cidofovir is a potential effective treatment for BKV HC. In this study, we report a large series of consecutive patients who developed BKV HC following allo SCT and received intravesicular cidofovir. Methods: We conducted a retrospective review of allo SCT patients who developed BKV HC and were prescribed intravesicular cidofovir from 2012 to 2017. Results: 33 patients were diagnosed with BKV HC. The median age was 50 years (range=23-73), and 18 (55%) were male. Acute myeloid leukemia (n=12, 35%) was the most common diagnosis followed by non-Hodgkin lymphoma (n=7, 21%) and B cell acute lymphoblastic leukemia (n=4, 12%). Conditioning regimens were myeloablative (n=19, 58%) or reduced-intensity (n=14, 42%); 15 (45%) patients received cyclophosphamide, and 22 (67%) received total body irradiation. The median time to onset of HC symptoms following SCT was 37 days (range: 8-178); 17 (52%) patients had acute graft vs. host disease. HC symptom severity ranged from grade 0-4 (median=2). The median BK urine viral load pre-treatment was 100,000,000 IU/ml. Patients received a median of 2 intravesicular treatments (range=1-7) at a dose of 5 mg/kg. Four patients (12%) were also treated concurrently with intravenous cidofovir. 19 (59%) patients demonstrated complete clinical resolution of symptoms, 9 (28%) demonstrated partial response to treatment, and 4 (13%) had no change in symptoms following treatment. These improvements in clinical status were independent of viral load, though most had reductions in the viral load. The median time to symptom resolution was 17 days (range=7-53; n=28). 82% of patients had no recurrent symptoms of HC. The main side effect of intra-vesicular instillation was increased discomfort and bladder spasms; severe in 3 patients (9%). No patient had impaired renal function directly attributable to intra-vesicular cidofovir. At 12 months after BKV HC diagnosis, 26 (79%) patients were alive. Conclusions: To our knowledge this is the largest study of intravesicular cidofovir for BKV HC reported to date; 77% of patients with BVK HC achieved clinical improvement of symptoms with minimal side effects. Clinical trials of intravesicular cidofovir could provide further evidence for adding intravesicular cidofovir as a standard tool for the treatment of BKV HC. Disclosures Badros: Celgene: Consultancy, Research Funding; Karyopharm: Research Funding; GSK: Research Funding.

Initial Findings of the Phase 1 Trial of PBCAR0191, a CD19 Targeted Allogeneic CAR-T Cell Therapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4107-4107 ◽  
Author(s):  
Caron A. Jacobson ◽  
Alex F. Herrera ◽  
Lihua E Budde ◽  
Daniel J. DeAngelo ◽  
Christopher Heery ◽  
...  
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
Cell Expansion ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Preliminary Evidence ◽  
Cell Transplant ◽  
Car T Cell ◽  
Car T

Background: Adoptive engineered autologous cellular immunotherapy has had a significant impact on the lives of some patients with advanced hematologic malignancies. However, the use of these therapies on a larger proportion of patients has been limited by variability of the final cell product, feasibility concerns, cost, and toxicity. Off-the-shelf allogeneic (allo) products offer the opportunity to address some of these concerns. Allo products have their own theoretical limitations, including the potential for graft-versus-host disease (GvHD) causing additional toxicity and host-versus-graft rejection limiting efficacy. PBCAR0191, an anti-CD19 allogeneic CAR T cell, was designed to limit the risk of GvHD by specifically inserting a CD19 specific CAR into the TRAC (T cell receptor alpha constant) locus in cells harvested from healthy donors. Those cells are then expanded, a CD3 elimination step is performed, followed by another expansion, and then PBCAR0191 is vialed and frozen for shipment then thawing, dilution, and infusion at the treatment site. To reduce the risk of PBCAR0191 rejection and increase the chances of cell expansion, lymphodepletion prior to dosing is required. This phase 1 3+3 dose escalation study is designed to identify an optimal dose of PBCAR0191 for efficacy evaluation. Methods: In each of 3 dose levels (3 x 105, 1 x 106, and 3 x 106 CAR-T+ cells/kg), up to 6 patients may be enrolled in each of 2 cohorts (Non-Hodgkin Lymphoma (NHL) and Acute Lymphoblastic Leukemia (ALL)). Eligibility requirements include adequate organ function, confirmed diagnosis to fit one of the cohorts, evaluable disease, at least 2 prior standard treatment regimens, no immunodeficiencies, no CNS disease, no active infections or other major medical issues requiring intervention, and no active GvHD. Eligible patients may have received allogeneic stem cell transplant or another CAR-T therapy. Lymphodepletion was administered on day -5 to day -3 using fludarabine 30mg/m2/day and cyclophosphamide 500mg/m2/day. Cells were administered on day 0. Correlative serum and PBMC samples were taken, while patients remained on study, on days 0, 1, 3, 7, 10, 14, 28, 42, 60 and every 30 days until 180 and then every 90 days until day 360. Assessment of response compared to baseline was performed on day 14 (optional for NHL only), and days 28, 60, 90, 180, 270, and 360, until progression. Results: Three patients with advanced NHL were enrolled and treated in DL1 between April 25, 2019 and May 24, 2019. Two males (one MCL, one DLBCL) and 1 female (DLBCL) ages 34 - 64 (median 64) years were treated. Two screen failures occurred, both patients with ALL, due to non-compliance (1) and loss of CD19 surface expression (1). One patient enrolled post disease progression after treatment with Axicabtagene ciloleucel. No significant toxicity was observed, including no serious adverse events and no dose-limiting toxicities with all patients having a minimum follow-up of 28 days (median 60 days). Two of the three patients experienced objective tumor response by Lugano criteria, at day 14 and day 28, respectively. Both patients progressed due to new lesions (on day 28 and day 60, respectively). The third patient has not met the definition of response, but has had evidence of central necrosis, decreased tumor size, and decreased PET-avidity at day 28, in the context of post-infusion tumor site pain and mild CRS symptoms. Peripheral blood analysis for CAR-T expansion has identified preliminary evidence of cell expansion with a low absolute numbers quantified, likely due to the low dose level at which treatment was initiated. Peripheral blood serum analysis for IFN-gamma, IL-6, and IL-15 indicate preliminary evidence of cell expansion, though not definitive. Conclusions: Further enrollment of patients into DL2 is ongoing. Data from DL2 entered by early October will be included in a presentation in the meeting. Findings to date indicate preliminary evidence of short-lived cell-mediated anti-tumor effect and preliminary evidence of cell expansion in vivo, which will be evaluated more fully at DL2 and DL3. Disclosures Jacobson: Bayer: Consultancy, Other: Travel Expenses; Humanigen: Consultancy, Other: Travel Expenses; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel Expenses; Precision Biosciences: Consultancy, Other: Travel Expenses; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel Expenses. Herrera:Adaptive Biotechnologies: Consultancy; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Budde:F. Hoffmann-La Roche Ltd: Consultancy. DeAngelo:Amgen, Autolus, Celgene, Forty-seven, Incyte, Jazzs, Pfizer, Shire, Takeda: Consultancy; Novartis: Consultancy, Research Funding; Glycomimetics: Research Funding; Abbvie: Research Funding; Blueprint: Consultancy, Research Funding. Heery:Precision BioSciences: Employment. Stein:Amgen: Consultancy, Speakers Bureau; Stemline: Speakers Bureau; Celgene: Speakers Bureau. Jain:Kite/Gilead: Consultancy. Shah:Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria.

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