Tandem Autologous-Allogeneic Nonmyeloablative Sibling Transplant in Relapsed Follicular Lymphoma Leads to Impressive Progression Free Survival with Minimal Toxicity.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 50-50 ◽  
Author(s):  
Sandra Cohen ◽  
Lambert Busque ◽  
Thomas Kiss ◽  
Silvy Lachance ◽  
Denis-Claude Roy ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Median Time ◽  
Chronic Gvhd ◽  
Progression Free Survival ◽  
Disease Status ◽  
Allogeneic Transplant ◽  
Bulky Disease ◽  
Free Survival ◽  
Cd34 Cells

Abstract Abstract 50 High dose chemotherapy followed by autologous stem cell transplantation (ASCT) has been shown to prolong progression free survival (PFS) as well as overall survival (OS) in patients (pts) with relapsed follicular lymphoma (FL). However, ASCT is usually not considered curative. Myeloablative allogeneic transplant has produced long term PFS in a subgroup of pts but is hampered by significant transplant related mortality (TRM). Reduced intensity transplant has less TRM but reports suggest a higher relapse rate. We therefore hypothesized that a tandem strategy consisting of ASCT followed by nonmyeloablative allogeneic transplant (NMT) would mimic a myeloablative allogeneic transplant without the associated early toxicity. We initiated such a prospective protocol for pts with relapsed FL in 2003. Patients underwent ASCT with a chemotherapy based conditioning regimen; 3 months post ASCT, pts with a 6/6 related donor received an outpatient NMT with 5 days of fludarabine 30 mg/m2/d and cyclophosphamide 300 mg/m2/d followed by infusion of ≥4×106 donor CD34+ cells/kg. GVHD prophylaxis, selected to take advantage of the low incidence of acute and the putative protective effect of chronic GVHD (as we have previously published in BBMT 2009 Aug;15(8):919), consisted of tacrolimus 3 mg bid started on day (D)-8 to achieve levels of 10–15 nmol/L then tapered off by D+100 and mycophenolate mofetil 1 g bid from D+2 to D+50. Between 4/2003 and 10/2008, 27 pts (M/F: 19/8) underwent tandem transplant, including 25 with FL and 2 with histology compatible with either FL or marginal zone lymphoma; 6/27 had histological progression towards an aggressive lymphoma. Median age was 49 years (range 34–65). The pts had previously been treated with a median of 3 lines of therapy (range 2–6). Median time from diagnosis to transplant was 34 months (range 14–131); 8 patients had never been exposed to rituximab. Disease status prior to ASCT was: 8 CR, 14 PR and 5 refractory. Conditioning chemotherapy for ASCT was: BEAC (n=14) and BEAM (n=13). 23 pts received peripheral blood stem cells and 4 received bone marrow for their ASCT. 2 pts received radiotherapy after ASCT to sites of previously bulky disease. Median time between ASCT and NMT was 133 days (range: 75–285). Pre NMT disease status was: 14 CR, 8 PR, 3 refractory, and 2 unknown. Median number of CD34+ cells/kg infused for NMT was 8.2 ×106 (range 3.2–29.2). Engraftment was prompt in all pts. 5 pts (18%) developed acute GVHD: 1 grade II and 4 grade III (2 classic acute and 3 delayed onset). Overall, 18 (67%) pts developed extensive chronic GVHD requiring treatment. Disease status at last follow up was: 22 CR and 5 unconfirmed CR. To date, there has been no disease progression and only 1 patient has died from GVHD at +11 months. With a median follow-up of 34 months (range 11–70) OS and PFS are both 96% at 3 and 5 years. In conclusion: 1) ASCT followed by sibling NMT for relapsed FL appears to be safe and well tolerated. 2) Disease response and PFS are excellent even in refractory and transformed cases of FL. 3) This novel approach warrants further investigation in larger prospective studies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Tandem Autologous Followed By Nonmyeloablative Allogeneic Transplantation in Relapsed High Risk Follicular Lymphoma Leads to Excellent Long Term Progression-Free Survival after 8 Years of Follow-up

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4677-4677
Author(s):  
Magalie Tardif ◽  
Imran Ahmad ◽  
Nadia M. Bambace ◽  
Lea Bernard ◽  
Lambert Busque ◽  
...  
Keyword(s):  
High Risk ◽  
Follicular Lymphoma ◽  
Median Time ◽  
Progression Free Survival ◽  
Disease Status ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Free Survival

Abstract Many new therapeutic agents have been approved for follicular lymphoma (FL) but none appear to be curative. Despite novel agents, some patients (pts) experience early relapse, become chemorefractory or suffer transformation into more aggressive lymphomas. Options for these pts are limited. High dose chemotherapy with autologous stem transplant (ASCT) prolongs progression free survival (PFS) and overall survival (OS) in FL pts in first relapse and registry data shows favorable outcome with ASCT in cases of histologic transformation. However, ASCT is usually not curative. Myeloablative allogeneic transplant (MT) has produced long term PFS but is hampered by significant non relapse mortality (NRM) while nonmyeloablative transplant (NMT) has a higher relapse rate compared to MT especially in high risk pts. Finally, many transplant studies have excluded these high risk pts such as those with chemorefractory or transformed disease. We hypothesized that a tandem transplant consisting of an ASCT followed by a NMT would confer the same benefit as a MT without the associated high NRM by separating the high dose chemotherapy from graft versus host disease (GVHD) while preserving the graft versus lymphoma effect. The goal of our study was to improve long term PFS in high risk FL pts. We therefore initiated a prospective protocol in April 2003, for pts with high risk relapsed FL as defined by chemorefractory disease, early 1st relapse, >1st relapse or transformation into aggressive histology. At least one therapy was attempted to document chemosensitivity prior to ASCT. However, regardless of disease status prior to transplant, pts underwent ASCT followed 3 months later by an outpatient NMT from an HLA-identical sibling. NMT comprised 5 days of fludarabine 30 mg/m2/day and cyclophosphamide 300mg/m2/day followed by an infusion of >2x106CD34+ cells/kg. GVHD prophylaxis, chosen to take advantage of the low incidence of acute (a) GVHD and the putative protective effect of chronic (c) GVHD, consisted of tacrolimus starting on day (D) - 8 to achieve levels of 8-12 nmol/L then tapered off by D+100 or D+180 depending on disease risk and of mycophenolate mofetil 1g bid from D+2 to D+50. We previously reported on 27 pts with a follow-up (f/u) of 3 years (yrs). We now report a larger cohort of 40 pts with a median f/u of 8 yrs. Up until July 2015, 40 pts were enrolled with a median age of 50 yrs (34-65). Pts had previously been treated with a median of 3 lines of therapy (2-6). Median time from diagnosis to ASCT was 33 months. Disease status at ASCT was: 14 CR, 16 PR and 10 refractory. Conditioning for ASCT included BEAM/BEAC (n=39), and Cy-TBI (n=1). In addition, 4 pts received radiotherapy after ASCT to sites of previously bulky disease. Median time between ASCT and NMT was 138 days (75-238). Pre NMT disease status was: 25 CR, 12 PR and 3 refractory. Engraftment was prompt in all pts after ASCT and median neutrophil and platelet recovery were respectively 13 days (0-19) and 0 day (0-18) post NMT. Seven pts (18%) developed aGVHD: 2 grade II and 5 grade III. Overall, 29 pts (73%) developed cGVHD: 1 mild, 13 moderate and 15 severe according to NIH revised criteria. Median time to discontinuation of immunosuppression was 22 months. To date, 2 pts have progressed at 11 and 59 months post NMT (one died from relapse and one is now in CR after chemotherapy and DLI) and 5 pts died from either GVHD related complications (n=4) or unknown cause (n=1). All pts alive at last f/u were in CR. With a median f/u of 8 yrs in surviving pts (1-12), OS is 95% at 3 and 5 yrs and 82% at 8 yrs. PFS is 92% at 3yrs, 89% at 5 yrs and 80% at 8 yrs. NRM and relapse rate at 8 yrs are 18% and 6% respectively. Based on our current results in 40 pts, we conclude that ASCT followed by sibling NMT for high risk relapsed FL is associated with excellent disease response and PFS. Furthermore, this tandem strategy appears to be safe and well tolerated. The incidence of cGVHD remains high but could in part explain the impressive PFS in this high risk cohort. This approach should now be further explored in a multi institution setting, include matched unrelated donors and consider the addition of rituximab post-transplant to reduce the incidence and severity of cGVHD with the hope that relapse will not be increased. Figure 1 Figure 1. Disclosures Busque: Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

A Novel Reduced Intensity Conditioning Can Induce a High Incidence of Sustained Donor Engraftment After Double Unit Cord Blood Transplantation (CBT) without Anti-Thymocyte Globulin

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2351-2351
Author(s):  
Doris M Ponce ◽  
Craig Sauter ◽  
Marissa Lubin ◽  
Anne Marie Gonzales ◽  
Glenn Heller ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Gvhd ◽  
Progression Free Survival ◽  
High Dose ◽  
Free Survival ◽  
Prior Therapy ◽  
Cd34 Cells ◽  
High Incidence ◽  
Related Mortality

Abstract Abstract 2351 CBT can be curative for patients with high-risk hematologic malignancies. However, patients of older age, those with extensive prior therapy, or significant co-morbidities may not tolerate high-dose myeloablative conditioning. Reduced intensity (RI) or non-myeloablative (NMA) conditioning has been successfully used in CBT, especially in patients with lymphomas. However, patients with myeloid malignancies without extensive prior therapy have an increased risk of graft rejection following NMA CBT. Further, the addition of anti-thymocyte globulin (ATG) to enhance engraftment increases the risk of serious infections and Epstein-Barr virus post-transplant lymphoproliferative disease, and could increase the risk of relapse. Therefore, we investigated the efficacy and safety of a novel ATG-free RI conditioning prior to double unit CBT in patients with acute leukemias and myelodysplasia with the hypothesis that this regimen can induce a high incidence of sustained donor engraftment. Conditioning consisted of cyclophosphamide 50 mg/kg (day -6), fludarabine 30 mg/m2/day × 5 (days -6 to -2), thiotepa 5 mg/kg/day × 2 (days -5 and -4), and total body irradiation 200 cGy × 2 (days -2 and -1). All patients received cyclosporine-A and mycophenolate mofetil for graft-versus-host disease (GVHD) prophylaxis. Between 10/01/07-04/30/10, 20 patients were transplanted. The median age was 56 years (range 18–69). Thirteen (65%) had AML (9 CR1, 4 CR2), 4 (20%) had ALL (3 CR1, 1 CR3), and 3 (15%) had MDS (with one patient also having follicular lymphoma). The majority had high-risk disease. Indications for RI conditioning were the risk factors for transplant-related mortality (TRM) with high-dose conditioning of age ≥50 years, and/or extensive prior therapy, and/or significant co-morbidities. Thirteen patients had only 1 of these risk factors, whereas 7 had ≥2 risk factors. Units were predominantly 4–5/6 HLA-matched to the recipient (one 6/6, twenty-four 5/6, fifteen 4/6). The median infused cell doses of the larger units were 2.7 × 107 total nucleated cells/kg (range 1.46–5.56) and 0.95 × 105 CD34+ cells/kg (range 0.35–3.32), and 1.89 × 107/kg total nucleated cells/kg (range 1.42–2.47) and 0.59 × 105/kg CD34+ cells/kg (range 0.18–1.52) for the smaller units, respectively. The cumulative incidence of sustained donor engraftment at day 45 was 95% (95%CI: 81–100). The single patient with graft failure was 100% donor in the day 21 bone marrow, but died early post-transplant of multi-organ failure without count recovery. The median time to neutrophil recovery ≥0.5 × 109/l was 25 days (range 13–43). The median total donor chimerism in the day 21 bone marrow was 94% (both units combined, range 71–100), and sustained engraftment was accounted for by one unit in 18/19 engrafting patients. The incidence of grade II-IV acute GVHD at day 100 was 55% (95%CI: 32–78), and 46% (95%CI: 21–71) of patients have had late acute GVHD requiring ongoing therapy or chronic GVHD to date. The incidence of day 100 transplant-related mortality (TRM) was 20% (95%CI: 2–38). Notably, none of the 13 patients with only one risk factor died of transplant-related causes. By contrast, 5/7 (71%) patients with ≥2 risk factors died of TRM by day 100 (p=0.03, Table 1). Two additional patients died of relapse. With a median follow-up of 13 months (range 3–31), 1 year progression-free survival is 74% (95%CI: 55–94) (Figure 1). We demonstrate that this ATG-free RI conditioning is associated with a high incidence of sustained donor engraftment, and acceptable toxicities in older patients without other risk factors. While longer follow-up is needed, progression-free survival is encouraging provided multiple risk factors are not present. This conditioning combined with double unit grafts warrants further investigation, and may also be a promising alternative to high-dose conditioning in younger patients. Table 1. Day 100 TRM according to number of risk factors (age ≥50 years, extensive prior therapy, significant co-morbidities). Risk Factors Day 100 TRM P Value 1 (N = 13) 0/13 (0%) 0.03 ≥2 (N = 7) 5/7 (71%) Figure 1. Progression-Free Survival At 1 Year Figure 1. Progression-Free Survival At 1 Year Disclosures: Giralt: Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau.

Treatment with Hypomethylating Agents before Allogeneic Stem Cell Transplant Improves Survival for Patients with Chronic Myelomonocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4347-4347 ◽  
Author(s):  
Piyanuch Kongtim ◽  
Uday R. Popat ◽  
Antonio M. Jimenez ◽  
Sameh Gabella ◽  
Riad O. El Fakih ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Progression Free Survival ◽  
Cell Transplant ◽  
Hypomethylating Agents ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Unrelated Donors ◽  
Conditioning Regimens

Abstract Introduction Allogeneic hematopoietic stem cell transplant (allo-SCT) is the only curative treatment modality for patients with CMML. Here we retrospectively reviewed the data for patients with CMML who received an all-SCT at our institution to identify factors associated with improved survival and determine whether treatment with hypomethylating agents (HMA) before transplant improves survival for these patients. Methods All 83 patients 18 years of age or older with a diagnosis of CMML confirmed at The University of Texas MD Anderson Cancer Center who underwent allo-SCT between April 1991 and December 2013 were identified through review of the institutionÕs medical records and included in this analysis. Forty, 7, and 36 patients had CMML-1, CMML-2 and CMML that had progressed to AML (CMML/AML) respectively. The median age was 57 years. CMML specific cytogenetic risk at diagnosis (Such E, hematologica, 2011) was good, intermediate, and high risk in 46, 19, and 18 patients respectively. Seventy-eight patients received induction treatment before transplant, 37 receiving HMA (either 5-azacytidine or decitabine) for at least 3 courses and 41 receiving 1-2 courses of cytotoxic chemotherapy. Among the patients who received induction therapy, 15 patients in HMA group and 9 patients in convention chemotherapy group achieved a complete remission before transplant. Thirty, 47 and 6 patients received transplants from matched related donors (MRD), matched unrelated donors (MUD), and mismatched related or unrelated donors (MMD), respectively. The sources of hematopoietic stem cells were peripheral blood for 48 patients (57.8%) and bone marrow for 35 patients (42.2%). Conditioning regimens varied; most patients received either fludarabine in combination with busulfan or fludarabine combined with melphalan. Sixty-four patients received myeloablative and 19 patients received reduced intensity conditioning regimens. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Patient and transplant characteristics did not significantly differ between the patients treated with HMA and the patients treated with conventional chemotherapy or given supportive care alone. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), Treatment related mortality (TRM), relapse incidence through last follow-up and incidences of acute GVHD and chronic GVHD. All of these outcomes were measured from the time of allo-SCT. Results Median follow up duration for 29 survivors was 48 months. Seventy-five patients engrafted (90.4%) with median time to neutrophil and platelet engraftment of 13 and 15 days respectively. Patients treated with a HMA had a significantly lower cumulative incidence (CI) of relapse at 3 years post-transplant (22%) than those treated with other agents (35%; p=0.03), whereas TRM at 1 year post-transplantdid not significantly differ between the groups (27% and 30%, respectively; p=0.84). Acute GVHD all grades and grade 2-4 were seen in 28.2% versus 35.8% (p=0.05) and 12.8% versus 11.3% (p=0.72) in patients who received a HMA compared to those who treated with other agents respectively. CI of chronic GVHD was 35% in patients treated with a HMA versus 19.2% in those treated with other agents (p=0.36) while CI of chronic extensive GVHD was seen in only 26.7% versus 19.2% respectively (p=0.64). The lower relapse rate resulted in a significantly higher 3-year PFS rate in patients treated with a HMA (43%) than in those who received other treatments (27%; p=0.04) (Figure 1). However, therapy with HMA before transplant did not significantly influence the 3-year OS rate (45% in those treated with HMA and 39% in those treated with other agents; p=0.22). The independent prognostic factors for PFS were a blast count of < 5% before transplant (HR 0.36, 95%CI 0.14-0.78), treatment with a HMA (HR 0.44, 95% CI 0.23-0.86), a transplant from an MRD (HR 0.41, 95% CI 0.22-0.94), development of grade 2-4 acute GVHD (HR 2.7, 95% CI 1.27-5.77), and development of chronic GVHD (HR 0.15, 95% CI 0.05-0.45). Conclusion We conclude that treatment with hypomethylating agents before allo-SCT may improve survival in patients with CMML. Figure 1. Progression free survival Figure 1. Progression free survival Disclosures Alousi: Therakos, Inc: Research Funding. Andersson:Otsuka Research and Development, Inc.: Consultancy.

Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplantation Cyclophosphamide in Primary Refractory Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4411-4411
Author(s):  
Sarita Rani Jaiswal ◽  
Sumita Chatterjee ◽  
Aditi Chakrabarti ◽  
Sneh Bhargava ◽  
Ray Kunal ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Peripheral Blood ◽  
Peripheral Blood Stem Cell ◽  
Chronic Gvhd ◽  
Progression Free Survival ◽  
Disease Status ◽  
Blood Stem Cell ◽  
Post Transplantation ◽  
Free Survival

Abstract In a pilot study, 75 patients with Primary Refractory (PRef) AML without matched family donors were offered post-transplantation cyclophosphamide (PTCY) based haploidentical peripheral blood stem cell (PBSC) transplantation. Twenty-seven patients (36%) opted for haploidentical transplantation with or without further chemotherapy. There was no difference in the patient or disease characteristics amongst patients undergoing transplantation or not. The conditioning regimen comprised of FluCyMel (n=5), FluBuMel (n=17) and FluTreoTBI (n=5). MMF was tapered between days 14 and 21 posttransplant in the absence of GVHD and cyclosporine A was tapered between days 60 and 90. The progression free survival at a median follow-up of 25 months was 36.6% and 0% in the transplant and the non-transplant group (p=0.0001). Prompt engraftment was noted at a median of 14 days irrespective of disease status or conditioning regimens. Cumulative incidences of acute graft-versus-host disease (GVHD) and chronic GVHD were 26.6% and 8% respectively. The overall incidence of infections remained low, with CMV reactivation and invasive aspergillosis occurring in 9 and 2 patients respectively. CMV disease was diagnosed in 2 patients. Non-relapse mortality at 1 year was 16.7%. The incidence of disease progression was 54%. Factors positively impacting progression free survival were < 15% marrow blasts at transplant and a Natural Killer Cell Ligand Mismatch (NKLMM) donor. NKLMM, Haplotype or B scores had no impact on CMV infection or GVHD. However, Bx Haplotype was associated with lower NRM (5%, 95%CI-1-9) compared to 48.6% (95%CI 28.2-69.0) in AA Haplotype (p=0.01). Disease status did not impact the overall survival (p=0.11) in the HSCT cohort. In fact, NKLMM donors with B haplotype had the greatest impact on overall survival in both the HSCT cohort (71.4%, 95%CI 54.3-88.5%) compared to 20% (95%CI 8.8-31.2, p=0.01) in those without the same. Our data suggests PTCY based Haploidentical PBSC transplantation is feasible in patients with PRef AML and donor NKLMM might improve progression free survival, provided the conditioning protocol and the post-grafting therapy offer the optimum platform for alloreactivity of NK cells. Disclosures No relevant conflicts of interest to declare.

Follicular Lymphoma International Prognostic Index 2: A New Prognostic Index for Follicular Lymphoma Developed by the International Follicular Lymphoma Prognostic Factor Project

2009 ◽  
Vol 27 (27) ◽  
pp. 4555-4562 ◽  
Author(s):  
Massimo Federico ◽  
Monica Bellei ◽  
Luigi Marcheselli ◽  
Stefano Luminari ◽  
Armando Lopez-Guillermo ◽  
...  
Keyword(s):  
High Risk ◽  
Follicular Lymphoma ◽  
Bone Marrow Involvement ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Progression Free Survival ◽  
Free Survival ◽  
Study Population ◽  
Index 2

Purpose The aim of the F2 study was to verify whether a prospective collection of data would enable the development of a more accurate prognostic index for follicular lymphoma (FL) by using parameters which could not be retrospectively studied before, and by choosing progression-free survival (PFS) as principal end point. Patients and Methods Between January 2003 and May 2005, 1,093 patients with a newly diagnosed FL were registered and 942 individuals receiving antilymphoma therapy were selected as the study population. The variables we used for score definition were selected by means of bootstrap resampling procedures on 832 patients with complete data. Procedures to select the model that would minimize errors were also performed. Results After a median follow-up of 38 months, 261 events for PFS evaluation were recorded. β2-microglobulin higher than the upper limit of normal, longest diameter of the largest involved node longer than 6 cm, bone marrow involvement, hemoglobin level lower than 12 g/dL, and age older than 60 years were factors independently predictive for PFS. Using these variables, a prognostic model was devised to identify three groups at different levels of risk. The 3-year PFS rate was 91%, 69%, and 51% for patients at low, intermediate, and high risk, respectively (log-rank = 64.6; P < .00001). The 3-year survival rate was 99%, 96%, and 84% for patients at low, intermediate, and high risk, respectively (P < .0001). Conclusion Follicular Lymphoma International Prognostic Index 2 is a simple prognostic index based on easily available clinical data and may represent a promising new tool for the identification of patients with FL at different risk in the era of immunochemotherapy.

scholarly journals Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results

Blood ◽  
2012 ◽  
Vol 119 (26) ◽  
pp. 6373-6378 ◽  
Author(s):  
Issa F. Khouri ◽  
Rima M. Saliba ◽  
William D. Erwin ◽  
Barry I. Samuels ◽  
Martin Korbling ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Survival Rates ◽  
Conditioning Regimen ◽  
Low Frequency ◽  
Progression Free Survival ◽  
Allogeneic Transplantation ◽  
Ibritumomab Tiuxetan ◽  
Free Survival ◽  
Innovative Strategies

In 2008, we reported favorable 5-year outcomes of nonmyeloablative allogeneic stem cell transplantation after fludarabine, cyclophosphamide, rituximab (FCR) conditioning for relapsed and chemosensitive follicular lymphoma. However, innovative strategies were still needed to treat patients with chemorefractory disease. We therefore subsequently performed a trial in which 90Y-ibritumomab tiuxetan (0.4 mCi/kg) was added to the fludarabine, cyclophosphamide conditioning regimen (90YFC). Here, we report updated results of the FCR trial and outcomes after 90YFC. For the FCR group (N = 47), since the last update, one patient developed recurrent disease. With a median follow-up of 107 months (range, 72-142 months), the 11-year overall survival and progression-free survival rates were 78%, and 72%, respectively. For the 90YFC group (N = 26), more patients had chemorefractory disease than did those in the FCR group (38% and 0%, P < .001). With a median follow-up of 33 months (range,17-94 months), the 3-year progression-free survival rates for patients with chemorefractory and chemosensitive disease were 80% and 87%, respectively (P = .7). The low frequency of relapse observed after a long follow-up interval of 9 years in the FCR group suggests that these patients are cured of their disease. The addition of 90Y to the conditioning regimen appears to be effective in patients with chemorefractory disease. This trial was registered at www.clinicaltrials.gov as NCT00048737.

scholarly journals Ibrutinib Dose Reduction Does Not Affect Progression-Free Survival in Patients with Waldenstrom Macroglobulinemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1598-1598
Author(s):  
Jorge J. Castillo ◽  
Joshua Gustine ◽  
Andrew Keezer ◽  
Kirsten Meid ◽  
Toni Dubeau ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Median Time ◽  
Research Funding ◽  
Regression Models ◽  
Progression Free Survival ◽  
Free Survival ◽  
Waldenstrom Macroglobulinemia ◽  
Major Response ◽  
Dose Reductions

Abstract Introduction: Ibrutinib is an oral Bruton Tyrosine Kinase inhibitor, approved for the treatment of symptomatic Waldenstrom Macroglobulinemia (WM). MYD88 and CXCR4 mutations affect progression-free survival (PFS) in patients with WM. In some cases, ibrutinib dose reductions are needed for the management of toxicity. However, it remains unclear if ibrutinib dose reductions adversely affect PFS in WM patients. Methods: We evaluated 217 consecutive patients with the clinicopathological diagnosis of WM who were symptomatic and received treatment with ibrutinib. We analyzed relevant clinical features and their association with the risk of dose reduction, using logistic regression models, as well as PFS using Cox proportional-hazard regression models. Time to events was estimated using the Kaplan-Meier method. p<0.05 were considered statistically significant. Results: All 217 patients were initiated on ibrutinib monotherapy at the approved dose of 420 mg by mouth (PO) once daily (QD). At a median follow-up of 26 months (95% CI 22-31 months), 159 patients (73%) continued ibrutinib without dose-reduction, while 58 (27%) patients had a decrease in their ibrutinib dose. There was no difference in follow-up between those with and without dose reduction. Of the 58 patients that dose reduced, 45 (78%) were reduced to 280 mg daily; 12 patients (21%) were reduced to 140 mg daily, and 1 (2%) to 140 mg every other day. The median time to ibrutinib dose reduction from 420 mg PO QD to 280 mg PO QD was 155 days (95% CI 89-282 days), and median time to dose reduction from 280 mg PO QD to 140 mg PO QD was 55 days (95% CI 24-260 days). Reasons for ibrutinib dose reduction included cytopenia(s) (n=13; 24%), arrhythmia (n=9; 17%), musculoskeletal discomfort (n=8; 15%), constitutional symptoms (n=6; 11%), skin changes/rash (n=5; 9%), mouth sores (n=4; 7%), gastrointestinal symptoms (n=3; 6%), infections (n=3; 6%), bleeding (n=2; 4%) and transaminase elevation (n=1; 2%). Patients in whom ibrutinib dose reduction was needed were more likely to be older than 65 years (76% vs. 47%; p<0.001), had higher International Prognostic Scoring System for WM (IPSSWM) at ibrutinib initiation (IPSSWM 1, 2 and 3 were 19%, 23% and 58% vs. 24%, 39% and 37%, respectively; p=0.03), and were more likely to have attained a major response (93% v. 69%; p<0.001) than patients in whom ibrutinib dose was not reduced. There were no differences in baseline characteristics including sex, hemoglobin levels, platelet counts, beta-2-microglobulin levels, serum IgM levels, bone marrow involvement, previous treatment, MYD88 and CXCR4 mutational status and time from WM diagnosis to ibrutinib initiation between those with and without dose reduction. Regression analyses showed higher odds of dose reduction occurring in patients >65 years (OR 3.6, 95% CI 1.8-7.1; p<0.001) and those who had attained a major response (OR 6.0, 95% CI 2.1-17.5; p=0.001). The median PFS for the entire group was not reached, and the 3-year PFS rate was 76% (95% CI 68-83%). Factors associated with a worse PFS were platelet count <100 K/uL (HR 3.9, 95% CI 1.8-8.7; p=0.001) and CXCR4 mutations (HR 3.0, 95% CI 1.5-6.0; p=0.001). Expression of mutated MYD88 (HR 0.01, 95% CI 0.00-0.09; p<0.001) and attainment of major response (HR 0.23, 95% CI 0.12-0.43; p<0.001) were associated with a better PFS. Importantly, those who experienced a reduction in their ibrutinib dose showed no significant difference in PFS (HR 1.19, 95% CI 0.61-2.35; p=0.61; Figure 1A). There were no differences between patients who reduced to 280 mg PO QD (HR 1.0, 95% CI 0.5-2.2; p=0.99) or 140 mg PO QD (HR 1.9, 95% CI 0.7-5.5; p=0.22) versus those without dose reduction (Figure 1B). Conclusion: Ibrutinib dose reduction occurred in 27% of patients with WM, at a median time to dose reduction of 155 days. Patients older than 65 years and those with major responses were more likely to have a dose reduction. With a median follow-up time of 26 months, ibrutinib dose reduction did not significantly impact PFS. Figure 1. Figure 1. Disclosures Castillo: Millennium: Research Funding; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Genentech: Consultancy. Hunter:Pharmacyclics: Consultancy. Treon:Johnson & Johnson: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Research Funding; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding.

scholarly journals Adding venetoclax to fludarabine/busulfan RIC transplant for high risk MDS and AML is feasible, safe, and active

2021 ◽  
Author(s):  
Jacqueline S Garcia ◽  
Haesook T Kim ◽  
H. Moses Murdock ◽  
Corey S Cutler ◽  
Jennifer Brock ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloproliferative Neoplasms ◽  
Phase 1 ◽  
Chronic Gvhd ◽  
Progression Free Survival ◽  
Platelet Recovery ◽  
Free Survival ◽  
Transplant Patients ◽  
Grade 3

Adding the selective BCL-2 inhibitor venetoclax to reduced intensity conditioning (RIC) chemotherapy (fludarabine and busulfan, FluBu2) may enhance anti-leukemic cytotoxicity and thereby reduce the risk of post-transplant relapse. This phase 1 study investigated the recommended phase 2 (RP2D) of venetoclax, a BCL-2 selective inhibitor, when added to FluBu2 in adult patients with high risk acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and MDS/myeloproliferative neoplasms (MPN) undergoing transplant. Patients received dose-escalated venetoclax (200-400 mg daily starting day -8 for 6-7 doses) in combination with fludarabine 30 mg/m2/day for four doses and busulfan 0.8 mg/kg twice daily for eight doses on day -5 to -2 (FluBu2). Transplant related-toxicity was evaluated from the first venetoclax dose on day -8 to +28. Twenty-two patients were treated. At study entry, 5 MDS and MDS/MPN patients had 5-10% marrow blasts and 18/22 (82%) had a persistent detectable mutation. Grade 3 adverse events included mucositis, diarrhea and liver transaminitis (N=3 each). Neutrophil/platelet recovery and acute/chronic GVHD rates were similar to standard FluBu2. No DLTs were observed. The RP2D of venetoclax was 400 mg daily for 7 doses. With a median follow-up of 14.7 months (8.6-24.8 months), median overall survival was not reached, and progression free survival was 12.2 months (95% CI: 6.0 months, not estimable). In high risk AML, MDS, and MDS/MPN patients, adding venetoclax to FluBu2 was feasible and safe. To further address relapse risk, assessment of maintenance therapy after venetoclax plus FluBu2 transplant is on-going. This study was registered at clinicaltrials.gov as #NCT03613532.

Extended Follow-Up of Reduced Intensity Transplantation with an Alemtuzumab-Containing Regimen for Follicular Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1666-1666
Author(s):  
Kirsty Thomson ◽  
Emma Morris ◽  
Donald Milligan ◽  
Ann Hunter ◽  
Gordon Cook ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Curative Therapy ◽  
Starting Dose ◽  
Unrelated Donors ◽  
Time To Relapse ◽  
Reduced Intensity

Abstract Allogeneic transplant with reduced intensity conditioning (RIC) is currently being investigated as potential curative therapy for patients with lymphoma. We report 64 consecutive patients with follicular lymphoma (FL) transplanted at 9 centres with a RIC regimen containing fludarabine 150mg/m2, melphalan 140mg/m2 and alemtuzumab (20–100mg). Cyclosporin A was given at 3mg/kg. Donors were HLA-matched siblings in 34 (53%), and unrelated in 30 (47%), of whom 9 (14%) were HLA-mismatched at up to 2/10 loci. Median age was 44 yrs (26–65), median lines of previous therapy was 3 (1–8) and 17 (27%) had failed a prior autograft. Fifty-five patients (86%) had chemosensitive disease pre-RIC (complete remission 11, partial remission 44), 8 (12%) were chemorefractory and 1 had untreated relapse. Median follow-up was 39 months (1–98). Non-relapse mortality (NRM) at 5 yrs was 12%, with 9% at 5 yrs for sibling donors and 15% for unrelated (p=0.41). There was no significant impact of prior autograft on NRM. Acute graft-versus-host disease (GVHD) grade II occurred in 11 (17%) with no grade III-IV, and extensive chronic GVHD occurred in 9 (16%). Relapse rate (RR) was 18% at 1 year and 32% at 5 years. Those who had failed a prior autograft had an increased RR (53% at 5 yrs) compared to those with no prior autograft (22% at 5 yrs; p=0.01). Median time to relapse from RIC was 8 months (1–43) with 15/17 events occurring within the 1st 2 years. Donor lymphocyte infusions (DLI) were given to 13 patients, at a starting dose of 1–10×106 CD3+/kg. Nine patients remitted, of whom 6 had no GVHD and 7 had received prior rituximab. Median follow-up from last DLI dose was 34 months (3–72). Overall survival (OS) for the whole cohort was 80% at 1 yr and 76% at 5 yrs. On univariate analysis, those with sibling donors had significantly improved OS (88% at 5 yrs), compared to unrelated donors (61% at 5 yrs; p=0.016), as did those with chemosensitive disease pre-RIC (80% at 5 yrs) compared to chemorefractory disease (50% at 5 yrs; p=0.028), and those who had not undergone a prior autograft (86% at 5 yrs) compared to those who had (47% at 5 yrs; p=0.001). Similarly, current progression-free survival (cPFS) for the whole cohort was 79% at 1 yr and 77% at 5 yrs, with significantly superior outcome in those with sibling donors (88% at 5 yrs) compared to unrelated donors (63% at 5 yrs; p=0.018), those with chemosensitive disease (81% at 5 yrs) compared to those with chemorefractory disease (50% at 5 yrs; p=0.0198), and those who had not failed a prior autograft (86% at 5 yrs) compared to those who had (50% at 5 yrs; p=0.001). No factor remained significant for OS or cPFS on multivariate analysis. In conclusion, RIC for FL using an alemtuzumab-containing regimen can be undertaken with relatively low rates of significant acute and chronic GVHD, and low NRM for both HLA-matched and mismatched related and unrelated donors. Responses to DLI occur, often in the absence of clinical GVHD, and appear durable so far, although further follow-up is required.

Rituximab Added to Aggressive Chemotherapy Improves the Outcome of Patients with Follicular Lymphoma, Grade 3 and Results In Survival Comparable to Diffuse Large B-Cell Lymphoma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2810-2810
Author(s):  
Philip J. Bierman ◽  
Julie M. Vose ◽  
R. Gregory Bociek ◽  
Fausto R. Loberiza ◽  
Martin Bast ◽  
...  
Keyword(s):  
Overall Survival ◽  
Follicular Lymphoma ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Bulky Disease ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
Extranodal Disease ◽  
Grade 3

Abstract Abstract 2810 The survival of patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma is improved when rituximab is combined with chemotherapy. However, little is known about the outcome of patients with follicular lymphoma, grade 3 (FL-3), since these patients are generally excluded from DLBCL trials and often from trials evaluating treatment of follicular lymphoma. We therefore performed a retrospective study to evaluate the results of rituximab-based therapy for FL-3. An analysis of the Nebraska Lymphoma Study Group database allowed us to identify patients with FL-3 who were treated with aggressive combination chemotherapy regimens with and without the addition of rituximab. The progression-free survival (PFS) and overall survival of these patients were compared to patients with DLBCL who were treated with similar aggressive chemotherapy regimens combined with rituximab. Patients who were not treated with anthracycline-containing or mitoxantrone-containing regimens were excluded from analyses. We identified 60 FL-3 patients who were treated with aggressive chemotherapy regimens, combined with rituximab, between Feb. 1999 and Jan. 2009. The median age was 56 years (range 37–87 years). There were 27 males and 33 females. The performance status was 0–1 in 80%, the LDH was elevated in 15%, 68% had stage III-IV disease, and 13% had at least 2 sites of extranodal disease. Fifteen patients (25%) had bulky disease (≥5 cm) at diagnosis. The results of treatment for these patients were compared to 144 FL-3 patients treated with aggressive chemotherapy regimens without rituximab between June 1983 and Jan. 1999, and to 341 patients with DLBCL who were treated with aggressive chemotherapy regimens combined with rituximab between Sept. 1996 and Jan. 2009. The treatment outcomes for these three groups of patients are displayed in the table. 5-yr Estimate (95% CI) 8-yr Estimate (95% CI) Log-Rank p-value Progression-Free Survival 0.04 FL-3 with rituximab 65% (50–77) 45% (23–65) FL-3 without rituximab 42% (34–50) 33% (26–41) DLBCL with rituximab 53% (47–58) 47% (40–54) Overall Survival 0.06 FL-3 with rituximab 85% (72–92) 71% (54–82) FL-3 without rituximab 68% (59–74) 54% (46–62) DLBCL with rituximab 64% (58–69) 56% (48–63) A multivariate analysis (accounting for older patients, and more patients with elevated LDH, extranodal disease, and bulky disease in the DLBCL group) revealed that patients with FL-3 who were not treated with rituximab had a significantly higher risk of disease progression or death (RR 1.75; p=0.02). There were no significant differences in PFS when comparing patients with FL-3 and those with DLBCL who were treated with aggressive chemotherapy regimens and rituximab. Follicular lymphoma, grade 3 patients treated without rituximab had inferior overall survival, when compared to patients treated with rituximab (RR 1.58), although this difference was not significant (p=0.16). The multivariate analysis also revealed no significant differences in survival when patients with FL-3 who received rituximab were compared to similarly treated patients with DLBCL (p=0.50). In conclusion, this analysis demonstrates that the outcome of treatment for patients with FL-3 who are treated with aggressive chemotherapy regimens is improved when rituximab is added to therapy. In the “rituximab era” the outcome of patients with FL-3 is comparable to DLBCL. Disclosures: Vose: Millennium Pharmaceuticals, Inc.: Research Funding.

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