scholarly journals Autoantibody Inhibitor Eradication In Acquired Hemophilia Associated with Cancer: a Retrospective Analysis.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1418-1418 ◽  
Author(s):  
Khendi T White ◽  
Anita Aggarwal ◽  
Marisanta Napolitano ◽  
Craig M. Kessler
Keyword(s):  
B Cell ◽  
Solid Tumor ◽  
Research Funding ◽  
Hematologic Malignancies ◽  
Acquired Hemophilia ◽  
Term Survival ◽  
Fviii Inhibitor ◽  
Underlying Malignancy ◽  
Fviii Activity

Abstract Abstract 1418 Introduction: Acquired hemophilia (AH), a rare autoimmune disorder primarily of adults, is typically characterized by the presence of IgG oligoclonal antibodies to the clotting factor VIII protein (FVIII). About 10–15% of patients with AH have an underlying malignancy, but the etiologic relationship of cancer to formation of FVIII inhibitor is yet to be determined. To date, there have been no published, comprehensive reviews on the efficacy of various treatments for AH in the context of either solid tumor or hematologic malignancies. Therefore, we have systematically reviewed 86 patients with cancer-associated AH from our own cancer center and from the published literature. Methods: The literature search for this systematic review was performed using PubMed MEDLINE, Ovid MEDLINE, CINAHL, SCOPUS, and Embase. The search terms included various combinations of “acquired”, “cancer”, “factor VIII”, “hemophilia A”, “autoantibodies”, and “treatment.” The major criterion for inclusion was a diagnosis of cancer before or within three months after appearance of acquired inhibitor. Both solid and hematologic malignancies were included. Any report that did not document a FVIII inhibitor titer and/or FVIII activity was excluded. Success in inhibitor eradication has been defined as undetectable inhibitor and normalization of FVIII activity. All articles with an abstract in English published in the period from January 1985 to July 2010 were considered. Results: 86 cases of AH were collected and analyzed according to classification of cancer and efficacy of treatments for inhibitor and malignancy. The mean age is 67.8 years. 74% of patients were of Caucasian or European background, 8% were of Asian descent, and 2% were of African descent. AH was associated with solid malignancy in 50 cases (58%) and hematologic malignancy in 36 cases (42%). Among all AH cases, 15% and 14% of patients had lymphoma and CLL, respectively. Of the solid tumors, lung and prostate carcinoma (each 12%) occurred with the greatest frequency followed by colorectal (9%) and bladder (5%). Not all patients had treatment for their underlying cancer, bleeding and/or inhibitor. Complete eradication (CE) of inhibitor was achieved in 48 patients (56%), no eradication (NE) in 22 (26%), and 16 (18%) had unknown status. Of the 73% of patients with CE, 22 were treated with chemotherapy, 10 were treated with surgery, and 1 with both (Table 1). In this series, there was a trend towards successful inhibitor eradication with treatment of B-cell lymphoproliferative malignancies as well as lung and prostate cancer. Long term survival was best achieved when successful CE and treatment of underlying malignancy occurred concurrently. Conclusions: This literature and case series suggests that AH is associated almost equally with hematological and solid tumor malignancies. These retrospective data suggest that treatment of the cancer with chemotherapy or surgery is very likely to induce eradication of the autoantibody inhibitor. There is a trend for increased success in CE in B-cell lymphoproliferative malignancies and selected solid tumors. Long term survival appears dependent on concurrent CE and treatment of the cancer. Disclosures: Kessler: Grifols S.A.: Research Funding; Baxter-Immuno: Research Funding; NovoNordisk: Research Funding.

scholarly journals Aggressive Combination Treatment for Invasive Fungal Sinusitis in Immunocompromised Patients

2000 ◽  
Vol 79 (4) ◽  
pp. 278-285 ◽  
Author(s):  
Samieh S. Rizk ◽  
Dennis H. Kraus ◽  
Goetz Gerresheim ◽  
Satvinder Mudan
Keyword(s):  
Hematologic Malignancies ◽  
Fungal Disease ◽  
Fungal Sinusitis ◽  
Granulocyte Colony Stimulating Factor ◽  
Term Survival ◽  
Invasive Fungal Sinusitis ◽  
Aggressive Management ◽  
Underlying Malignancy ◽  
Stimulating Factor

Invasive sinonasal fungal disease is a potentially fatal complication of chemotherapy-induced immunosuppression and neutropenia. We reviewed the outcomes of seven cancer patients who had been diagnosed with invasive fungal sinusitis; six patients had hematologic malignancies and one had breast cancer. At the time of their sinus diagnosis, all patients had been hospitalized and were receiving combination chemotherapy for their underlying malignancy. Impairment of their immune function was characterized by an absolute neutrophil count of less than 1,000/mm3. Aggressive management of their sinonasal fungal disease consisted of surgical debridement and systemic amphotericin B for all patients, and treatment with granulocyte colony-stimulating factor for two patients. Invasive Aspergillus infection was identified in six patients and invasive Candida albicans infection in one. Although the prognosis for these patients was poor and two patients died of the fungal infection, the aggressive treatment strategy resulted in long-term survival for the remaining five patients.

Antibody-Interferon-Alpha Fusion Protein Therapy for the Treatment of B-Cell Non-Hodgkin Lymphoma: Enhanced ADCC, Inhibition of Proliferation, and In Vivo Eradication of CD20+ Human Lymphomas

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2762-2762 ◽  
Author(s):  
John M. Timmerman ◽  
Kristopher K Steward ◽  
Reiko E Yamada ◽  
Patricia A Young ◽  
Dena M. Minning ◽  
...  
Keyword(s):  
Fusion Protein ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Term Survival ◽  
Equity Ownership

Abstract Background: Interferon-alpha (IFNα) is a pleiotrophic cytokine with direct anti-tumor and immunostimulatory effects. Currently IFNα is approved for the treatment of multiple hematologic malignancies, including non-Hodgkin lymphoma (NHL). However, its clinical utility has been hindered by dose-limiting toxicitiy due to systemic activation of the interferon receptor. To overcome this limitation, we engineered anti-tumor antibody-IFNα fusion proteins to selectively increase delivery of IFN to the tumor site and reduce systemic toxicity. We previously reported that IGN002, an anti-CD20-IFNα fusion protein, exhibits enhanced complement-dependent cytotoxicity (CDC) compared to rituximab, and inhibits proliferation and induces apoptosis of human B-cell NHL (Yamada et al, ASCO 2013). We now extend these previous findings and show that IGN002 possesses enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) effector function and superior in vivo anti-tumor activity against B-cell NHL, compared to rituximab. Methods: IGN002 was evaluated against a panel of human Burkitt and diffuse large B-cell lymphoma (DLBCL) cell lines. Proliferation was measured by [3 H]-thymidine incorporation, STAT1 activation by flow cytometry, ADCC by lactate dehydrogenase release using human PBMC effectors, and IFN bioactivity by encephalomyocarditis (EMC) viral protection assay. NHL xenografts were grown in SCID mice. Results: IGN002 more potently inhibited the growth of NHL cell lines expressing CD20 than rituximab or unfused IFNα. Intrinsic IFNα activity of IGN002 was reduced in viral protection and anti-proliferation assays using cells lacking CD20 expression. STAT1 activation by IGN002 was enhanced on cells expressing the target antigen, whereas a control antibody-IFNα fusion protein showed reduced STAT activation activity compared to unfused IFNα. Together, these results indicate that fusion of IFNα to the antibody results in reduced IFN effects on cells not bearing the tumor antigen target. IGN002 exhibited enhanced ADCC activity compared to rituximab against Daudi, Ramos, and Raji NHL cells in long-term (overnight incubation) assays, demonstrating both higher potency and higher maximal cytotoxicity. This result is possibly due to activation of the effector cell populations by the fused IFNα moiety, as IFN is known to activate both NK cells and monocytes. The in vivo anti-tumor efficacy of IGN002 was compared to rituximab and a control antibody-IFNα fusion protein against 10-day established Raji NHL xenografts. IGN002 was superior to both rituximab and the control fusion protein, achieving a longer median survival and higher long-term survival rate (p = 0.0015 and < 0.0001 vs. rituximab and control fusion protein, respectively). The in vivo anti-tumor efficacy of IGN002 was also compared to rituximab at three equimolar dose levels (5 mg/kg, 1 mg/kg, and 0.2 mg/kg antibody) against 10-day established Daudi NHL xenografts. IGN002 showed superior efficacy compared to rituximab at all doses (p < 0.001), achieving tumor eradication (100% long-term survival) in all mice treated at all three dose levels, whereas rituximab only delayed tumor progression. Conclusions: IGN002 demonstrated more robust direct anti-proliferative and antibody effector functions than rituximab against human NHL cells in vitro, and also showed the ability to eradicate established NHL xenografts in vivo. Against cells expressing the CD20 target antigen, IGN002 exhibited greater anti-proliferative potency than unfused IFNα. In contrast, the anti-proliferative and anti-viral potency of IGN002 was reduced against cells lacking CD20, compared to unfused IFNα. These findings support the hypothesis that tumor antigen-targeted IFN therapeutics may possess a broader therapeutic index than unfused IFNα, inhibiting tumor growth by multiple mechanisms while reducing systemic toxicity. These results support the further development of IGN002 for the treatment of B-cell NHL, and a first-in-human phase I clinical study will begin later this year in the United States. Disclosures Timmerman: Janssen: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Valor Biotherapeutics: Research Funding. Steward:ImmunGene, Inc.: Employment. Minning:Valor Biotherapeutics, LLC: Consultancy. Sachdev:ImmunGene, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Gresser:ImmunGene, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Valor Biotherapeutics: Membership on an entity's Board of Directors or advisory committees. Khare:Valor Biotherapeutics: Membership on an entity's Board of Directors or advisory committees; ImmunGene, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Morrison:ImmunGene, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Selective B-cell depletion with rituximab for the treatment of patients with acquired hemophilia

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4424-4428 ◽  
Author(s):  
Roberto Stasi ◽  
Maurizio Brunetti ◽  
Elisa Stipa ◽  
Sergio Amadori
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Complete Response ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Acquired Hemophilia ◽  
Durable Response ◽  
Fviii Inhibitor ◽  
Fviii Activity ◽  
Anti Cd20

Abstract The activity and safety profile of selective B-cell depletion with rituximab, an anti-CD20 monoclonal antibody, were evaluated in 10 patients with acquired hemophilia. Rituximab was given intravenously at the dose of 375 mg/m2 once weekly for 4 consecutive weeks. Infusion-related side effects were observed in 3 patients but were of mild intensity and did not require discontinuation of treatment. Eight patients with Factor VIII (FVIII) inhibitor titers between 4 and 96 Bethesda units per milliliter (BU/mL) achieved a complete remission, which was defined as a return to normal FVIII activity and undetectable FVIII inhibitor titers. Two more patients with inhibitor levels greater than 100 BU/mL experienced only a partial transient decrease of the inhibitor after rituximab alone, but they achieved a complete response after being challenged with a combination of rituximab plus pulse intravenous cyclophosphamide. With a median follow-up of 28.5 months (range, 12-41 months), 3 patients have thus far relapsed. Retreatment with the monoclonal antibody at the same dose and schedule resulted in a new sustained response in all these patients. In conclusion, rituximab appears an effective and well-tolerated treatment for patients with acquired hemophilia and low inhibitor titers. A reinforcement of therapy with other agents seems to be required to achieve a full and durable response in those patients with high inhibitor levels. (Blood. 2004;103:4424-4428)

scholarly journals Barriers to Referral for Chimeric Antigen Receptor T Cell (CAR-T) Therapies Among U.S. Community Hematologists/Oncologists (cH/O)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4010-4010
Author(s):  
Ajeet Gajra ◽  
Yolaine Jeune-Smith ◽  
Bruce A. Feinberg
Keyword(s):  
B Cell ◽  
Real World ◽  
Hematologic Malignancies ◽  
Term Survival ◽  
Specific Content ◽  
Intake Process ◽  
Primary Specialty ◽  
Car T ◽  
The U.S

Abstract Introduction: As of July 31, 2021, 5 CAR-T therapies have been approved in the U.S. to treat lymphomas (large B cell, follicular, and mantle cell), acute lymphoblastic leukemia, and multiple myeloma. These individualized, autologous cell therapies are expensive; involve complex manufacturing, transportation, and storage requirements; and have a unique set of serious adverse events associated with their use. Thus, the use of CAR-T therapies is limited mainly to tertiary care centers that have been licensed to administer these agents. Over half of all U.S. patients with cancer are treated in community-based oncology practices. Understanding the adoption of novel therapies by community hematologists/oncologists (cH/O) is critical to assessing their future utilization and impact on clinical outcomes in the real-world setting. We have assessed CAR-T adoption among cH/O in lymphoma (Gajra et al. Immunotherapy. PMID: 32552151) and with the expansion in number of agents and indications, we sought to assess the evolution of their use of, referrals for, and barriers to CAR-T therapy. Methods: Between January and April 2021, oncologists from across the U.S. were invited to complete a web-based survey about their CAR-T therapy utilization, referral patterns, barriers experienced, and overall impression of this class of therapy. Participant demographics and practice characteristics were also captured in the survey. Participants were not aware of the specific content of the survey as other areas in hematology/oncology were also addressed. Participants were compensated for their participation. Responses were aggregated and analyzed using descriptive statistics. Results: Of the 371 cH/O invited, 100% completed the survey; 63% identified their primary specialty as hematology oncology and 36% medical oncology. The median time in practice was 16 years with a median of 20 patients seen per day on clinic days. The top 3 hematologic malignancies treated by survey participants are CLL, AML, and B-cell NHL. Among the participants, 72% and 53% have referred patients for CAR-T therapy since the first approval and the preceding 6 months respectively; 16% of those who referred in preceding 6 months, reported that none of their referrals ultimately received the CAR-T product infusion. The top 2 barriers impacting timely referral for these participants include a slow approval process by payers (34%) and a slow intake process at the CAR-T center itself (23%). While patient deterioration is a significant challenge to 40% of the participants, other CAR-T center-related challenges perceived by the participants include the CAR-T product not being manufactured, lack of communication from the CAR-T center during the process, and lack of clear instructions to the referring oncologist about follow-up care. Common perceived barriers to prescribing/recommending CAR-T therapy include lack of long-term survival data (14%), therapy-related toxicity (30%), cumbersome logistics of administration (37%), and cost (39%). Among 309 participants queried about cost, 60% feel the price is acceptable for this breakthrough therapy. To facilitate their prescribing/recommendation of CAR-T therapies, the participants agreed that better support to community providers regarding post therapy management, easier referral process to CAR-T centers, timelier approval from payers, and more long-term clinical trial and real-world data are needed. As more CAR-T therapies gain approval and come to market, additional resources requested by the participants included more financial aid/support for patients (59%), more education for prescribing physicians (53%) and patients (29%), more decision support tools (38%), and better coordination and communication between community physicians and sites of care (37%). Conclusions: Most cH/O surveyed have referred patients for CAR-T therapies in hematologic malignancies but there is room for improvement in the referral and intake process as well as the treatment and post-infusion phase. Significant barriers of logistics and cost are potential deterrents to appropriate use. cH/O would welcome additional resources to aid the utilization of CAR-T. These results can inform stakeholders (manufacturers, payers, hospitals, and practices) regarding the need to improve processes and develop payment models to address cost in order to facilitate access of these agents to the appropriate patients. Figure 1 Figure 1. Disclosures Gajra: Cardinal Health: Current Employment, Current equity holder in publicly-traded company. Jeune-Smith: Cardinal Health: Current Employment. Feinberg: Cardinal Health: Current Employment.

scholarly journals Most up-to-Date Long Term Survival Estimates for Common Hematologic Malignancies Using the Boomerang Method

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2409-2409 ◽  
Author(s):  
Dianne Pulte ◽  
Lina Jansen ◽  
Hermann Brenner
Keyword(s):  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Relative Survival ◽  
Hematologic Malignancies ◽  
Lymphoid Leukemia ◽  
Term Survival ◽  
Long Term Survival ◽  
Increased Risk

Abstract Background: Five year survival has increased dramatically for most of the common hematologic malignancies in the early part of the 21st century, probably due to new therapeutic options. However, less is known about the effects recent changes in therapy have had on longer term survival. Here, we examine 10- and 20-year survival for patients with common hematologic malignancies including myeloma, acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), chronic lymphoid leukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma (HL). Methods: Data were extracted from the Surveillance, Epidemiology, and End Results (SEER9) database. Patients age 15+ with appropriate ICD-10 codes for the above malignancies were included, with exclusion of those patients diagnosed by death certificate only. The boomerang method1 was used to estimate 10 and 20-year relative survival for patients in two calendar periods, 1999-2003 and 2009-13. This recently described method has been demonstrated to more closely approximate actual observed survival for a given time period compared to other methods of estimation, including period analysis, by minimizing the contribution of earlier time periods to the estimation of survival. Results: Ten and 20-year survival increased for each malignancy examined, with increases ranging from +4.3 percent units for 20-year survival for myeloma to +28.4 percent units for 10-year survival for CML (see Table). Ten year relative survival was greater than 50% in 2009-13 for patients with CML, CLL, NHL, and HL, at 69.9%, 59.1%, 63.4%, and 63.1%, respectively. Major decreases in survival were observed between 10- and 20-year survival estimates for all malignancies except for AML, where 10- and 20-year relative survival estimates were virtually identical in 2009-13. Discussion: Long term survival is increasing for common hematologic malignancies, with particularly strong increases being observed for CLL, CML, and NHL. Major decreases in survival were observed between 10 and 20 years for most malignancies, including NHL and ALL, which are generally considered curable. This may be partly due to the effect of recent changes in therapy leading to underestimation of 20-year survival, even using the boomerang method, but further study of long-term outcomes in curable malignancies to determine whether there is an increased risk of specific issues later in life is indicated. Reference: 1. Brenner H, Jansen L. Timely disclosure of progress in long-term cancer survival: the boomerang method substantially improved estimates in a comparative study. J Clin Epidemiol. 2016;70:224-32. Disclosures Pulte: Selexys Pharmaceuticals: Research Funding; EBSCO: Other: Review of content for Dynamed medical reference product; ApoPharma: Research Funding.

scholarly journals Overshoot of FVIII Activity in Patients with Acquired Hemophilia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2497-2497
Author(s):  
Yoshiyuki Ogawa ◽  
Kunio Yanagisawa ◽  
Hiroaki Shimizu ◽  
Takuma Ishizaki ◽  
Akitada Ichinose ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Immunosuppressive Therapy ◽  
Research Funding ◽  
Coagulation Factor ◽  
Cytotoxic Agents ◽  
University Hospital ◽  
Hemorrhagic Diathesis ◽  
Acquired Hemophilia ◽  
Fviii Inhibitor ◽  
Fviii Activity

Abstract Background: Acquired hemophilia A (AHA) is a rare, life-threatening bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII) [J Thromb Haemost. 2011;9:226-235]. The disease is characterized by spontaneous hemorrhage or prolonged bleeding after surgery, trauma, or other invasive procedures in patients with neither family nor personal histories of hemorrhagic diathesis [BMC Res Notes. 2010;3:161]. The main goal of AHA therapy is arrest of bleeding by eliminating FVIII inhibitors. Once AHA is diagnosed, the patient should be placed on immunosuppressive therapy comprising corticosteroids either alone or in combination with effective cytotoxic agents such as cyclophosphamide, cyclosporine, azathioprine or, more recently, rituximab. Through these therapeutic interventions, 70-80% of patients with AHA reportedly achieve complete remission (CR) [Blood. 2007;109:1870-1877]. Overshoot of FVIII activity after achieving CR has been known anecdotally in some AHA patients, but the details remain unclear. Patients and methods: CR was defined when the following criteria were met: resolution of hemorrhagic signs; FVIII activity >60 IU/dl; and negative results for FVIII inhibitor. We treated a total of 20 patients with AHA between January 2009 and December 2017 at Gunma University Hospital (GUH). Data from the 15 AHA patients (median age, 74 years; range, 30-87 years; 10 males) who achieved CR under immunosuppressive therapy were retrospectively analyzed. Overshoot of FVIII activity was defined as a level ³150 IU/dl. All patients provided written informed consent for review of their medical records. The institutional review board at GUH approved the study protocol. Results: Baseline AHA-related parameters are shown below. All 15 patients showed a prolonged APTT (median, 77.0 s; range, 63.4-124.7 s). FVIII activity had decreased to <10 IU/dl in all patients (median, 2.3 IU/dl; range, <1.0-8.0 IU/dl), and two patients were very deficient in FVIII (<1.0 IU/dl). Median titer of FVIII inhibitor was 13.0 BU/mL (range, 2.0-234 BU/ml). Eleven patients required therapy with bypassing agents. Hemostatic therapy was generally effective and no deaths due to bleeding events were encountered. All 15 patients achieved CR by immunosuppressive therapy primarily due to steroids, within a median of 39 days (range, 19-173 days). Overshoot was observed in 10 patients (66.7%), with maximum FVIII activity >200 IU/dl in 5 patients. Median duration from CR to overshoot was 17 days (range, 0-154 days). Venous thromboembolism as a severe complication caused by overshoot was observed in one patient, with a giant hematoma compressing the left iliac vein. Discussion and Conclusion: We have provided, here, the first report on the frequency of FVIII overshoot after CR in AHA patients, revealing a higher than expected frequency. Most AHA patients are elderly, relatively inactive and receiving steroid therapy, and so are a prime group for developing thromboembolism. Some patients have been reported to develop thrombosis during AHA treatment [Haemophilia. 2007;13:451-461]. In addition, high FVIII activity (>150 IU/dl) has been reported as a risk factor for venous thromboembolism [Lancet. 1995;345:152-155]. Overshoot of FVIII activity after CR may risk thromboembolism when combined with other thrombotic triggers. Disclosures Handa: Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Long-Term Survival and Gradual Recovery of B Cells in Patients (Pts) with Refractory Large B Cell Lymphoma (LBCL) Treated with Axicabtagene Ciloleucel (Axi-Cel)

2021 ◽  
Vol 27 (3) ◽  
pp. S404-S405
Author(s):  
Caron A. Jacobson ◽  
Frederick L. Locke ◽  
Armin Ghobadi ◽  
David B. Miklos ◽  
Lazaros J. Lekakis ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Term Survival ◽  
Long Term Survival ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals Non-Myeloablative Conditioning Regimen before T-Cell Replete Haploidentical Transplantation with Post-Transplant Cyclophosphamide for Advanced Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4614-4614
Author(s):  
Catalina Montes De Oca ◽  
Thomas Pagliardini ◽  
Stefania Bramanti ◽  
Sabine Furst ◽  
Jean Marc Schiano de Collela ◽  
...  
Keyword(s):  
Research Funding ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Research Support ◽  
Myeloablative Conditioning ◽  
Term Survival ◽  
Gvhd Prophylaxis ◽  
Increased Risk ◽  
Low Incidence

Introduction: allogeneic transplantation (allo-HSCT) is a curative treatment for patients with advanced lymphoma. Haploidentical (haplo-SCT) transplantation extended the accessibility to allo-HSCT, overcoming the issue of donor availability. However, alternative donor allo-HSCT is still considered at higher risk of non-relapse mortality due to the HLA disparity and thus an anticipated higher incidence of GVHD. In this context, the use of a non myeloablative conditioning (NMAC) regimen combined with post transplantation cyclophosphamide (PT-Cy) based GVHD prophylaxis may reduce procedure related toxicity. The aim was to evaluate the toxicity and efficacy of haplo-SCT using NMAC with PT-Cy in advanced lymphoma patients. Methods: We here report the retrospective experience of a bicentric transplantation program. We analyzed a cohort of lymphoma patients undergoing Haplo-SCT and homogeneously receiving NMAC and PT-Cy. Inclusion criteria were: 1) first allo-HSCT for advanced lymphoma between 2009 and 2018; 2) haploidentical donor; 3) NMAC (fludarabine cyclophosphamide and 2 gray TBI GVHD prophylaxis consisted of PT-Cy day+3 and +4 , cyclosporine A and MMF starting from day +5. Multivariate analyses included age, disease type (NHL vs HL), HCT-CI (< vs ≥ 3), graft source (PBSC vs BM), disease status at haplo-SCT (CR vs other). Results: One hundred forty seven patients (73 NHL; 74 HL) with a median age of 46 years (range: 19-71) were included. PBSC (peripheral blood stem cell) was used as graft source in 96 patients (65%). Patients received a median number of 3 conventional chemotherapy lines before haplo-SCT (1-8). Sixty-five (44%) had relapse after Auto-HCT. At the time of haplo-SCT, 96 patients (66%) were in complete remission. The cumulative incidences of day+100 grade 2-4 and 3-4 acute GVHD were 30% and 3%, respectively. The cumulative incidences of 2-year chronic and moderate or severe chronic GVHD were 13% and 8%, respectively. With a median follow up of 39 months (6-114), 2-year NRM was 14%, with a trend for higher risk in patients with HCT-CI ≥ 3 (HR 0.39, 95CI [0.15-1.04] p = 0.061) while age was not associated with an increased risk of NRM (HR 1.01, 95CI [0.98-1.05], p = 0.450). Two-year cumulative incidence of relapse (CIR) was 21% and 18% in HL and NHL patients, respectively. Disease status at the time of haplo-SCT was strongly associated with relapse (HR 2.99, 95CI [1.41-6.35], p = 0.004) In HL patients, 2-year PFS, OS and GRFS were 65%, 77% and 57%, respectively, while corresponding values in NHL patients were 65%, 69% and 55%, respectively. Two-year PFS and GRFS were significantly higher in patients who underwent haplo-SCT in CR (PFS: CR vs. no CR: 72% vs. 55%, p=0.045; GRFS: CR vs. no CR: 63% vs. 42%, p=0.010). There was a trend for better 2-year OS in CR (OS: CR vs. no CR: 78% vs. 63%, p=0.063. Conclusion: We confirm the feasibility of haplo-SCT using NMAC and PT-Cy with low incidence of GVHD (notably severe forms) and NRM. In addition, we observed a relatively low incidence of relapse (19%) in this cohort of heavily pretreated patients, underlining a potent graft-versus-lymphoma effect after haplo-SCT, leading to promising survivals, including high rate of GRFS (>50%), suggesting a preserved long term quality of life in survivors. We conclude that NMAC haplo-SCT with PT-Cy should be considered as a valuable curative option for advanced lymphoma patients, with a favorable toxicity profile and promising long term survival. Figure Disclosures Stoppa: celgene: Other: travel fees, lecture fees; takeda: Other: travel fees. Carlo-Stella:MSD: Honoraria; BMS: Honoraria; Janssen: Other: Travel, accommodations; Boehringer Ingelheim: Consultancy; Genenta Science sr: Consultancy; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; Servier: Consultancy, Honoraria, Other: Travel, accommodations; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Takeda: Other: Travel, accommodations; Janssen Oncology: Honoraria; AstraZeneca: Honoraria. Chabannon:EBMT: Other: Working Party Chair, Board member; Fresenius Kabi: Other: research support; Miltenyi Biotech: Other: research support; Terumo BCT: Other: speaker's fees; Celgene: Other: speaker's fees; Novartis: Other: speaker's fees; Gilead: Other: speaker's fees, hospitalities; Sanofi SA: Other: research support, speaker's fees, hospitalities. Santoro:Takeda: Speakers Bureau; BMS: Speakers Bureau; Roche: Speakers Bureau; Abb-Vie: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Servier: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Arqule: Consultancy, Speakers Bureau; Lilly: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Bayer: Consultancy, Speakers Bureau; MSD: Speakers Bureau; BMS: Consultancy. Blaise:Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria; Molmed: Consultancy, Honoraria; Pierre Fabre medicaments: Honoraria.

scholarly journals Translation of the Philadelphia chromosome into therapy for CML

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4808-4817 ◽  
Author(s):  
Brian J. Druker
Keyword(s):  
Cancer Research ◽  
Clinical Trials ◽  
Myeloid Leukemia ◽  
Therapeutic Agent ◽  
Philadelphia Chromosome ◽  
Hematologic Malignancies ◽  
Successful Development ◽  
Term Survival ◽  
Abl Tyrosine Kinase

AbstractThroughout its history, chronic myeloid leukemia (CML) has set precedents for cancer research and therapy. These range from the identification of the first specific chromosomal abnormality associated with cancer to the development of imatinib as a specific, targeted therapy for the disease. The successful development of imatinib as a therapeutic agent for CML can be attributed directly to decades of scientific discoveries. These discoveries determined that the BCR-ABL tyrosine kinase is the critical pathogenetic event in CML and an ideal target for therapy. This was confirmed in clinical trials of imatinib, with imatinib significantly improving the long-term survival of patients with CML. Continuing in this tradition of scientific discoveries leading to improved therapies, the understanding of resistance to imatinib has rapidly led to strategies to circumvent resistance. Continued studies of hematologic malignancies will allow this paradigm of targeting molecular pathogenetic events to be applied to many additional hematologic cancers.

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