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John J Rossi - One of the best experts on this subject based on the ideXlab platform.
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lymphoma remissions caused by anti cd19 chimeric antigen receptor t cells are associated with high serum interleukin 15 levels
Journal of Clinical Oncology, 2017Co-Authors: James N Kochenderfer, Robert Somerville, James Chihhsin Yang, Richard M Sherry, Victoria Shi, Adrian Bot, John J Rossi, Allen Xue, Stephanie L Goff, Christopher A KlebanoffAbstract:PurposeT cells genetically modified to express chimeric antigen receptors (CARs) targeting CD19 (CAR-19) have potent activity against acute lymphoblastic leukemia, but fewer results supporting treatment of lymphoma with CAR-19 T cells have been published. Patients with lymphoma that is Chemotherapy refractory or relapsed after autologous stem-cell transplantation have a grim prognosis, and new treatments for these patients are clearly needed. Chemotherapy administered before adoptive T-cell transfer has been shown to enhance the antimalignancy activity of adoptively transferred T cells.Patients and MethodsWe treated 22 patients with advanced-stage lymphoma in a clinical trial of CAR-19 T cells preceded by Low-Dose Chemotherapy. Nineteen patients had diffuse large B-cell lymphoma, two patients had follicular lymphoma, and one patient had mantle cell lymphoma. Patients received a single dose of CAR-19 T cells 2 days after a Low-Dose Chemotherapy conditioning regimen of cyclophosphamide plus fludarabine.Resu...
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anti cd19 chimeric antigen receptor t cells preceded by low dose Chemotherapy to induce remissions of advanced lymphoma
Journal of Clinical Oncology, 2016Co-Authors: James N Kochenderfer, Robert Somerville, James Chihhsin Yang, Christopher A Klebanoff, Udai S Kammula, Richard M Sherry, Victoria Shi, Adrian Bot, Stephanie L Goff, John J RossiAbstract:LBA3010Background: T cells genetically-modified to express chimeric antigen receptors (CARs) targeting CD19 have potent activity against a variety of B-cell malignancies. Chemotherapy is administered prior to CAR T cells because depletion of recipient leukocytes enhances the anti-malignancy efficacy of adoptively-transferred T cells; an increase in serum interleukin (IL)-15 is one mechanism for this enhancement. Previously, we (Kochenderfer et al. Journal of Clinical Oncology, 2015) and others have reported patients treated with high-dose Chemotherapy prior to anti-CD19 CAR T-cell infusions. This report describes treatment of 22 patients with Low-Dose conditioning Chemotherapy followed by infusion of anti-CD19 CAR T-cells. Methods: Eighteen of 22 treated patients received 300 mg/m2 of cyclophosphamide (cy) daily for 3 days; 4 patients received 500 mg/m2 of cy on the same schedule. All patients received fludarabine 30 mg/m2daily for 3 days on the same days as cy. Patients received a single dose of CAR T ce...
Christopher A Klebanoff - One of the best experts on this subject based on the ideXlab platform.
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lymphoma remissions caused by anti cd19 chimeric antigen receptor t cells are associated with high serum interleukin 15 levels
Journal of Clinical Oncology, 2017Co-Authors: James N Kochenderfer, Robert Somerville, James Chihhsin Yang, Richard M Sherry, Victoria Shi, Adrian Bot, John J Rossi, Allen Xue, Stephanie L Goff, Christopher A KlebanoffAbstract:PurposeT cells genetically modified to express chimeric antigen receptors (CARs) targeting CD19 (CAR-19) have potent activity against acute lymphoblastic leukemia, but fewer results supporting treatment of lymphoma with CAR-19 T cells have been published. Patients with lymphoma that is Chemotherapy refractory or relapsed after autologous stem-cell transplantation have a grim prognosis, and new treatments for these patients are clearly needed. Chemotherapy administered before adoptive T-cell transfer has been shown to enhance the antimalignancy activity of adoptively transferred T cells.Patients and MethodsWe treated 22 patients with advanced-stage lymphoma in a clinical trial of CAR-19 T cells preceded by Low-Dose Chemotherapy. Nineteen patients had diffuse large B-cell lymphoma, two patients had follicular lymphoma, and one patient had mantle cell lymphoma. Patients received a single dose of CAR-19 T cells 2 days after a Low-Dose Chemotherapy conditioning regimen of cyclophosphamide plus fludarabine.Resu...
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anti cd19 chimeric antigen receptor t cells preceded by low dose Chemotherapy to induce remissions of advanced lymphoma
Journal of Clinical Oncology, 2016Co-Authors: James N Kochenderfer, Robert Somerville, James Chihhsin Yang, Christopher A Klebanoff, Udai S Kammula, Richard M Sherry, Victoria Shi, Adrian Bot, Stephanie L Goff, John J RossiAbstract:LBA3010Background: T cells genetically-modified to express chimeric antigen receptors (CARs) targeting CD19 have potent activity against a variety of B-cell malignancies. Chemotherapy is administered prior to CAR T cells because depletion of recipient leukocytes enhances the anti-malignancy efficacy of adoptively-transferred T cells; an increase in serum interleukin (IL)-15 is one mechanism for this enhancement. Previously, we (Kochenderfer et al. Journal of Clinical Oncology, 2015) and others have reported patients treated with high-dose Chemotherapy prior to anti-CD19 CAR T-cell infusions. This report describes treatment of 22 patients with Low-Dose conditioning Chemotherapy followed by infusion of anti-CD19 CAR T-cells. Methods: Eighteen of 22 treated patients received 300 mg/m2 of cyclophosphamide (cy) daily for 3 days; 4 patients received 500 mg/m2 of cy on the same schedule. All patients received fludarabine 30 mg/m2daily for 3 days on the same days as cy. Patients received a single dose of CAR T ce...
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anti cd19 car t cells administered after low dose Chemotherapy can induce remissions of Chemotherapy refractory diffuse large b cell lymphoma
Blood, 2014Co-Authors: James N Kochenderfer, Robert Somerville, Alex Iwamoto, James Chihhsin Yang, Christopher A Klebanoff, Udai S Kammula, Richard M Sherry, Shi Victoria, Constance Yuan, Steven R FeldmanAbstract:We have treated a total of 30 patients with autologous T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19; 22 of 27 evaluable patients obtained either complete remissions (CR) or partial remissions (PR). Ten patients remain in ongoing CRs of 1 to 37 months duration. The CAR was encoded by a gammaretroviral vector and included the variable regions of an anti-CD19 antibody along with CD28 and CD3-zeta moieties. The first 21 patients treated on this protocol have been reported (Kochenderfer et al. Blood 2010, Blood 2012, and Journal of Clinical Oncology 2014). To enhance the activity of the transferred CAR T cells, T-cell infusions in the previously reported patients were preceded by a Chemotherapy regimen of high-dose cyclophosphamide (60-120 mg/kg) plus fludarabine. In an attempt to reduce the overall toxicity of our anti-CD19 CAR treatment protocol, we substantially reduced the doses of Chemotherapy administered before CAR T-cell infusions. This abstract communicates results from 9 patients with B-cell lymphoma who received a single infusion of 1x106 anti-CD19-CAR-expressing T cells/kg bodyweight preceded by a Low-Dose Chemotherapy regimen consisting of cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 (Table). Each Chemotherapy agent was administered daily for 3 days. Eight of the 9 treated patients had DLBCL (diffuse large B-cell lymphoma) that was refractory to Chemotherapy (chemo-refractory) or that had relapsed less than 1 year after autologous stem cell transplantation (ASCT). Both of these clinical situations carry a grim prognosis, with median overall survivals of only a few months. Despite the very poor prognoses of our patients, one patient with DLBCL obtained a CR and 4 DLBCL patients obtained PRs. In some patients, PRs included resolution of large lymphoma masses. Compared to our previous experience with anti-CD19 CAR T cells preceded by high-dose Chemotherapy, toxicity was reduced when CAR T cells were infused after Low-Dose Chemotherapy. None of the 9 patients treated with Low-Dose Chemotherapy and CAR T cells required vasopressor drugs or mechanical ventilation, although some patients did have short-term neurological toxicity. Cytopenias were mild with a mean of only 1.4 days of blood neutrophils<500/microliter. Blood anti-CD19 CAR T-cell levels were assessed in 6 patients with a quantitative PCR assay; we detected CAR+ cells in the blood of all 6 patients. The mean peak absolute number of blood CAR+ T cells was 73 cells/microliter. Six months after infusion, persisting CAR+ T cells were detected in a lymphoma-involved lymph node by flow cytometry. These results demonstrate that anti-CD19 CAR T cells administered after Low-Dose Chemotherapy have significant activity against chemo-refractory DLBCL and could potentially become a standard treatment for aggressive lymphoma. | Patient | Age/Gender | Malignancy | Number of Prior Therapies | Clinical Situation | Response (Duration in Months) | || | 1 | 66/M | DLBCL | 3 | Post ASCT relapse | PR (7) | | 2[*][1] | 63/F | DLBCL | 2 | Chemo-refractory | PR (7+) | | 3 | 63/M | FL | 7 | Not chemo-refractory | PR (6+) | | 4[*][1] | 22/M | DLBCL | 6 | Chemo-refractory | Progression | | 5 | 65/M | DLBCL | 4 | Post ASCT relapse | PR (5+) | | 6 | 47/M | DLBCL | 2 | Chemo-refractory | PR (1) | | 7 | 28/M | DLBCL | 7 | Chemo-refractory | Progression | | 8 | 62/M | DLBCL | 7 | Post ASCT relapse | CR (1+) | | 9 | 54/M | DLBCL | 3 | Chemo-refractory | Progression | * [↵][2]* Compassionate exemption was obtained from regulatory agencies to enroll these patients because their poor performance status precluded standard enrollment; M = male; F = female; FL = follicular lymphoma; + indicates ongoing response Table Disclosures Rosenberg: Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding. [1]: #fn-2 [2]: #xref-fn-2-1
Robert S Kerbel - One of the best experts on this subject based on the ideXlab platform.
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in vitro procoagulant activity induced in endothelial cells by Chemotherapy and antiangiogenic drug combinations modulation by lower dose Chemotherapy
Cancer Research, 2005Co-Authors: Giulio Francia, Daniel J Hicklin, Alicia Viloriapetit, Jeanne Michelle Du Manoir, Robert S KerbelAbstract:One of the emerging problems concerning the use of antiangiogenic drugs, when used in combination with certain Chemotherapy regimens, is enhanced rates and severity of adverse clotting events. For as yet unknown reasons, certain drugs and particular combinations can induce an elevated incidence of thromboembolic events in treated cancer patients [e.g., SU5416, a vascular endothelial cell growth factor receptor-2 (VEGFR-2) antagonist, when combined with gemcitabine and cisplatin (CDDP)]. Such results highlight the need to develop assays capturing the essence of enhanced clot formation under such combination treatment and which may have predictive potential as well. Here, we report the possibility of such an assay (i.e., the ratio of tissue factor over tissue factor pathway inhibitor expression or activity in cultured human endothelial cells calculated as a coagulation index). A marked increase in coagulation index was observed after exposure to SU5416 and the CDDP/gemcitabine Chemotherapy combination in contrast to either of these treatments used alone. Substitution of SU5416 with any one of ZD6474, SU6668, IMC-1121, a monoclonal antibody to VEGFR-2, or an antibody to VEGF (bevacizumab) did not cause a marked increase in the coagulation index, nor did the combination of SU5416 with 5-fluorouracil and leucovorin. Finally, we noted that reducing the concentrations of gemcitabine and CDDP (i.e., use of “metronomic dosing” in vitro) significantly attenuated the coagulation index increase induced by these drugs, suggesting that use of Low-Dose Chemotherapy regimens might be an approach to consider for reducing the incidence of adverse clotting events associated with Chemotherapy alone or in conjunction with antiangiogenic drug combination therapies.
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maximum tolerable dose and low dose metronomic Chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells
Cancer Research, 2003Co-Authors: Francesco Bertolini, Saki Paul, Patrizia Mancuso, Silvia Monestiroli, Alberto Gobbi, Yuval Shaked, Robert S KerbelAbstract:There is growing evidence that vasculogenesis (progenitor cell-derived generation of new blood vessels) is required for the growth of some neoplastic diseases. Here we show that the administration of cyclophosphamide (CTX) at the maximum tolerable dose with 21-day breaks or at more frequent Low-Dose (metronomic) schedules have opposite effects on the mobilization and viability of circulating endothelial progenitors (CEPs) in immunodeficient mice bearing human lymphoma cells. Animals treated with the maximum tolerable dose CTX experienced a robust CEP mobilization a few days after the end of a cycle of drug administration, and tumors rapidly became drug resistant. Conversely, the administration of metronomic CTX was associated with a consistent decrease in CEP numbers and viability and with more durable inhibition of tumor growth. Our findings suggest that metronomic Low-Dose Chemotherapy regimens are particularly promising for avoiding CEP mobilization and, hence, to potentially reduce vasculogenesis-dependent mechanisms of tumor growth.
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protracted low dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs
Cancer Research, 2002Co-Authors: Guido Bocci, K C Nicolaou, Robert S KerbelAbstract:Recent preclinical studies have shown that frequent administration in vivo of low doses of chemotherapeutic drugs (“metronomic” dosing) can affect tumor endothelium and inhibit tumor angiogenesis, reducing significant side effects (e.g., myelosuppression) involving other tissues, even after chronic treatment. This suggests that activated endothelial cells may be more sensitive, or even selectively sensitive, to protracted (“high-time”) Low-Dose Chemotherapy compared with other types of normal cells, thus creating a potential therapeutic window. To examine this hypothesis, we assessed the effects of several different chemotherapeutic drugs—namely paclitaxel, 4-hydroperoxycyclophosphamide, BMS-275183 (an oral taxane), doxorubicin, epothilone B (EpoB) and its analogue 5-methylpyridine EpoB—on human microvascular or macrovascular endothelial cells, fibroblasts, and drug-sensitive or multidrug-resistant breast cancer cell lines in cell culture, using both short-term (24 h) versus long-term (144 h), continuous exposures, where drug-containing medium was replaced every 24 h. Whereas little differential and only weak effects were observed using the short-term exposure, a striking trend of comparative vascular endothelial cell hypersensitivity was induced using the continuous long-term exposure protocol. Potent differential growth inhibition effects as well as induction of apoptosis were observed with IC50 values in the range of 25–143 pm for paclitaxel, BMS-275183, EpoB, and 5-methylpyridine-EpoB. In contrast, the IC50 values for tumor cells and fibroblasts tested were in the range of 500 pm to >1 nm for these drugs. Similar differential IC50 values were noted using 4-hydroperoxycyclophosphamide. The results are consistent with the possibility that continuous Low-Dose therapy with various chemotherapeutic drugs may have a highly selective effect against cycling vascular endothelial cells, and may be relevant to the use of continuous or frequent administration of low doses of certain types of drugs as an optimal way of delivering antiangiogenic therapy.
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continuous low dose therapy with vinblastine and vegf receptor 2 antibody induces sustained tumor regression without overt toxicity
Journal of Clinical Investigation, 2000Co-Authors: Giannoula Klement, Sylvain Baruchel, Janusz Rak, Shan Man, Katherine A Clark, Daniel J Hicklin, Peter Bohlen, Robert S KerbelAbstract:Various conventional chemotherapeutic drugs can block angiogenesis or even kill activated, dividing endothelial cells. Such effects may contribute to the antitumor efficacy of Chemotherapy in vivo and may delay or prevent the acquisition of drug-resistance by cancer cells. We have implemented a treatment regimen that augments the potential antivascular effects of Chemotherapy, that is devoid of obvious toxic side effects, and that obstructs the development of drug resistance by tumor cells. Xenografts of 2 independent neuroblastoma cell lines were subjected to either continuous treatment with low doses of vinblastine, a monoclonal neutralizing antibody (DC101) targeting the flk-1/KDR (type 2) receptor for VEGF, or both agents together. The rationale for this combination was that any antivascular effects of the Low-Dose Chemotherapy would be selectively enhanced in cells of newly formed vessels when survival signals mediated by VEGF are blocked. Both DC101 and Low-Dose vinblastine treatment individually resulted in significant but transient xenograft regression, diminished tumor vascularity, and direct inhibition of angiogenesis. Remarkably, the combination therapy resulted in full and sustained regressions of large established tumors, without an ensuing increase in host toxicity or any signs of acquired drug resistance during the course of treatment, which lasted for >6 months. This article may have been published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org. J. Clin. Invest. 105:R15–R24 (2000).
James N Kochenderfer - One of the best experts on this subject based on the ideXlab platform.
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lymphoma remissions caused by anti cd19 chimeric antigen receptor t cells are associated with high serum interleukin 15 levels
Journal of Clinical Oncology, 2017Co-Authors: James N Kochenderfer, Robert Somerville, James Chihhsin Yang, Richard M Sherry, Victoria Shi, Adrian Bot, John J Rossi, Allen Xue, Stephanie L Goff, Christopher A KlebanoffAbstract:PurposeT cells genetically modified to express chimeric antigen receptors (CARs) targeting CD19 (CAR-19) have potent activity against acute lymphoblastic leukemia, but fewer results supporting treatment of lymphoma with CAR-19 T cells have been published. Patients with lymphoma that is Chemotherapy refractory or relapsed after autologous stem-cell transplantation have a grim prognosis, and new treatments for these patients are clearly needed. Chemotherapy administered before adoptive T-cell transfer has been shown to enhance the antimalignancy activity of adoptively transferred T cells.Patients and MethodsWe treated 22 patients with advanced-stage lymphoma in a clinical trial of CAR-19 T cells preceded by Low-Dose Chemotherapy. Nineteen patients had diffuse large B-cell lymphoma, two patients had follicular lymphoma, and one patient had mantle cell lymphoma. Patients received a single dose of CAR-19 T cells 2 days after a Low-Dose Chemotherapy conditioning regimen of cyclophosphamide plus fludarabine.Resu...
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anti cd19 chimeric antigen receptor t cells preceded by low dose Chemotherapy to induce remissions of advanced lymphoma
Journal of Clinical Oncology, 2016Co-Authors: James N Kochenderfer, Robert Somerville, James Chihhsin Yang, Christopher A Klebanoff, Udai S Kammula, Richard M Sherry, Victoria Shi, Adrian Bot, Stephanie L Goff, John J RossiAbstract:LBA3010Background: T cells genetically-modified to express chimeric antigen receptors (CARs) targeting CD19 have potent activity against a variety of B-cell malignancies. Chemotherapy is administered prior to CAR T cells because depletion of recipient leukocytes enhances the anti-malignancy efficacy of adoptively-transferred T cells; an increase in serum interleukin (IL)-15 is one mechanism for this enhancement. Previously, we (Kochenderfer et al. Journal of Clinical Oncology, 2015) and others have reported patients treated with high-dose Chemotherapy prior to anti-CD19 CAR T-cell infusions. This report describes treatment of 22 patients with Low-Dose conditioning Chemotherapy followed by infusion of anti-CD19 CAR T-cells. Methods: Eighteen of 22 treated patients received 300 mg/m2 of cyclophosphamide (cy) daily for 3 days; 4 patients received 500 mg/m2 of cy on the same schedule. All patients received fludarabine 30 mg/m2daily for 3 days on the same days as cy. Patients received a single dose of CAR T ce...
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anti cd19 car t cells administered after low dose Chemotherapy can induce remissions of Chemotherapy refractory diffuse large b cell lymphoma
Blood, 2014Co-Authors: James N Kochenderfer, Robert Somerville, Alex Iwamoto, James Chihhsin Yang, Christopher A Klebanoff, Udai S Kammula, Richard M Sherry, Shi Victoria, Constance Yuan, Steven R FeldmanAbstract:We have treated a total of 30 patients with autologous T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19; 22 of 27 evaluable patients obtained either complete remissions (CR) or partial remissions (PR). Ten patients remain in ongoing CRs of 1 to 37 months duration. The CAR was encoded by a gammaretroviral vector and included the variable regions of an anti-CD19 antibody along with CD28 and CD3-zeta moieties. The first 21 patients treated on this protocol have been reported (Kochenderfer et al. Blood 2010, Blood 2012, and Journal of Clinical Oncology 2014). To enhance the activity of the transferred CAR T cells, T-cell infusions in the previously reported patients were preceded by a Chemotherapy regimen of high-dose cyclophosphamide (60-120 mg/kg) plus fludarabine. In an attempt to reduce the overall toxicity of our anti-CD19 CAR treatment protocol, we substantially reduced the doses of Chemotherapy administered before CAR T-cell infusions. This abstract communicates results from 9 patients with B-cell lymphoma who received a single infusion of 1x106 anti-CD19-CAR-expressing T cells/kg bodyweight preceded by a Low-Dose Chemotherapy regimen consisting of cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 (Table). Each Chemotherapy agent was administered daily for 3 days. Eight of the 9 treated patients had DLBCL (diffuse large B-cell lymphoma) that was refractory to Chemotherapy (chemo-refractory) or that had relapsed less than 1 year after autologous stem cell transplantation (ASCT). Both of these clinical situations carry a grim prognosis, with median overall survivals of only a few months. Despite the very poor prognoses of our patients, one patient with DLBCL obtained a CR and 4 DLBCL patients obtained PRs. In some patients, PRs included resolution of large lymphoma masses. Compared to our previous experience with anti-CD19 CAR T cells preceded by high-dose Chemotherapy, toxicity was reduced when CAR T cells were infused after Low-Dose Chemotherapy. None of the 9 patients treated with Low-Dose Chemotherapy and CAR T cells required vasopressor drugs or mechanical ventilation, although some patients did have short-term neurological toxicity. Cytopenias were mild with a mean of only 1.4 days of blood neutrophils<500/microliter. Blood anti-CD19 CAR T-cell levels were assessed in 6 patients with a quantitative PCR assay; we detected CAR+ cells in the blood of all 6 patients. The mean peak absolute number of blood CAR+ T cells was 73 cells/microliter. Six months after infusion, persisting CAR+ T cells were detected in a lymphoma-involved lymph node by flow cytometry. These results demonstrate that anti-CD19 CAR T cells administered after Low-Dose Chemotherapy have significant activity against chemo-refractory DLBCL and could potentially become a standard treatment for aggressive lymphoma. | Patient | Age/Gender | Malignancy | Number of Prior Therapies | Clinical Situation | Response (Duration in Months) | || | 1 | 66/M | DLBCL | 3 | Post ASCT relapse | PR (7) | | 2[*][1] | 63/F | DLBCL | 2 | Chemo-refractory | PR (7+) | | 3 | 63/M | FL | 7 | Not chemo-refractory | PR (6+) | | 4[*][1] | 22/M | DLBCL | 6 | Chemo-refractory | Progression | | 5 | 65/M | DLBCL | 4 | Post ASCT relapse | PR (5+) | | 6 | 47/M | DLBCL | 2 | Chemo-refractory | PR (1) | | 7 | 28/M | DLBCL | 7 | Chemo-refractory | Progression | | 8 | 62/M | DLBCL | 7 | Post ASCT relapse | CR (1+) | | 9 | 54/M | DLBCL | 3 | Chemo-refractory | Progression | * [↵][2]* Compassionate exemption was obtained from regulatory agencies to enroll these patients because their poor performance status precluded standard enrollment; M = male; F = female; FL = follicular lymphoma; + indicates ongoing response Table Disclosures Rosenberg: Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding. [1]: #fn-2 [2]: #xref-fn-2-1
Martin S Tallman - One of the best experts on this subject based on the ideXlab platform.
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how i treat acute promyelocytic leukemia
Blood, 2009Co-Authors: Martin S Tallman, Jessica K. AltmanAbstract:Acute promyelocytic leukemia is the first malignant disease highly curable with targeted therapy directed at a unique molecular abnormality. The characteristic bleeding diathesis is the most notorious manifestation of the disease, which historically has accounted for a high mortality rate during induction. Acute promyelocytic leukemia is one of the few hematologic diseases that must be recognized under the microscope by the practicing hematologist because early institution of all-trans retinoic acid (ATRA) at the first suspicion of the disease before confirmation of the diagnosis and aggressive blood product support are critical to reduce early mortality. ATRA plus anthracycline-based Chemotherapy for induction and consolidation followed by maintenance ATRA with Low-Dose Chemotherapy is currently the standard of care. However, the combination of ATRA and arsenic trioxide, with minimal Chemotherapy to control leukocytosis, is very effective therapy for newly diagnosed patients. This combination may replace conventional approaches for most, if not all, patients in the very near future. Acute promyelocytic leukemia should be considered in any patient with newly diagnosed acute myeloid leukemia because the treatment is urgent and different from all other subtypes.
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treatment of relapsed or refractory acute promyelocytic leukemia
Best Practice & Research Clinical Haematology, 2007Co-Authors: Martin S TallmanAbstract:Current treatment for acute promyelocytic leukemia (APL) usually includes an induction phase with all-trans retinoic acid (ATRA) and anthracycline-based Chemotherapy, followed by a consolidation phase of anthracycline-based Chemotherapy and maintenance therapy with ATRA with or without Low-Dose Chemotherapy for 1–2 years. This treatment strategy results in a high complete remission (CR) rate of about 90% and an overall survival rate of 80%. About 5%–30% of patients relapse, mainly patients with high-risk APL. Relapse at extramedullary sites, which occurs in approximately 3%–5% of patients, is emerging as a new issue. Treatment of relapsed/advanced APL includes the use of arsenic trioxide (ATO), gemtuzumab ozogamicin, and hematopoietic stem cell transplantation. ATO is currently the most effective therapeutic agent in relapsed APL. Hematopoietic stem cell transplantation is becoming a common strategy after achieving remission with ATO. Autologous transplant appears to have a more favorable outcome than allogeneic transplant in this setting, particularly when carried out during second remission, primarily because of significantly higher treatment-related mortality with allogeneic transplants. Allogeneic transplant, however, should be strongly considered for patients who remain molecularly positive. Future directions for APL therapy should include developing agents that can prevent relapse, particularly for high-risk patients. Other future treatment strategies may include use of ATO administered concomitantly or sequentially with Chemotherapy, gemtuzumab or FLT-3 inhibitors that may obviate the need for autologous transplantation, and posttransplant maintenance perhaps with FLT-3 inhibitors.
