Lenalidomide Maintenance Therapy After Toxicity-Reduced Myeloablative Allograft As Salvage Therapy for Efractory/Relapsed Myeloma Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3024-3024
Author(s):  
Nicolaus Kröger ◽  
Evgeny Klyuchnikov ◽  
Thomas Stübig ◽  
Christine Wolschke ◽  
Francis Ayuk ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Maintenance Therapy ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Myeloablative Conditioning ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade Iii

Abstract Abstract 3024FN2 Reduced-intensity conditioning (RIC) regimen followed by allogeneic stem cell transplantation (SCT) has become a reasonable treatment option for patients with multiple myeloma who are refractory or have relapse to an autograft. However, in comparison to standard myeloablative conditioning RIC resulted in higher risk of relapse. Maintenance therapy after autologous transplantation has shown to improve survival while after allogeneic SCT data are lacking so far. We here report the results of myeloablative toxicity-reduced allograft consisting of intravenous busulfan (12.2 mg/kg) and cyclophosphamide (120 mg/kg) followed by lenalidomide maintenance in 33 patients with multiple myeloma who relapsed to an autograft. A total of 32 patients had received one (n=16), two (n=15), or even three (n=1) autografts, and 1 patient was refractory to 2 induction therapies and failed to collect autologous stem cells. The median duration of remission after the autograft was 12 months. The primary endpoint of the study was non-relapse mortality at 1 year and secondary objectives were evaluation of response, incidence of acute and chronic graft-versus-host disease as well as progression and overall survival. To prevent graft-versus-host disease antithymocyte globulin (ATG Fresenius®) was given at a median dose of 20 mg/kg on day -3, -2, and -1. Lenalidomide was started earliest at day 120 after transplantation if there were no signs of infection or graft-versus-host disease. The median time between last autograft and allogeneic transplantation was 20 months. 19 patients were treated with fully HLA-matched unrelated donor, 8 patients had a mismatch donor, and 6 patients were transplanted from an HLA-identical sibling. 2 patients died of treatment-related complications resulting in a cumulative incidence of non-relapse mortality at 1 year of 6% (95% CI: 0–14%). After transplantation 27% developed grade II graft-versus-host disease, and severe grade III graft-versus-host disease was seen in 6% of the patients. Complete remission was noted in 46% of the patients, partial remission was seen in 48% and stable disease in 3%. The median interval between allogeneic transplant and start of lenalidomide was 168 days. The median starting dose was 5 mg (range 5–15 mg) without dexamethasone for 21 day followed by 1 week rest. 9 patients did not receive lenalidomide maintenance due to ongoing graft-versus-host disease, cytopenia or patient's wish. The median number of lenalidomide cycles was 6 (range 1–30). During follow-up 13 patients discontinued lenalidomide treatment due to progressive disease (n=6), GvHD (n=3), thrombocytopenia (n=2), or fatigue (n=2). In 10 patients lenalidomide dose could be increased to 10 or 15 mg, respectively. The major toxicities of lenalidomide were acute graft-versus-host disease grade I – III (21%), viral reactivation (12%), thrombocytopenia grade III-IV (12%), neutropenia grade III-IV (6%), peripheral neuropathy grade I-II (12%), or other infectious complications (6%). During follow-up 9 patients experienced relapse resulting in a cumulative incidence of relapse at 3 years of 42% (95% CI: 18–66%). The 3 year estimated probability of progression-free and overall survival was 52 % (95% CI: 28–76%) and 79 % (95% CI: 63–95%), respectively. In the current trial neither the deletion 13q14 nor the use of mismatch donor nor the chemosensitivity prior allogeneic SCT could be identified as risk factor for survival. This study showed that toxicity-reduced myeloablative conditioning regimen is feasible and highly effective in relapsed patients with multiple myeloma resulting in an acceptable treatment-related mortality. Lenalidomide as maintenance therapy is feasible early after transplantation but toxicity especially the induction of graft-versus-host disease should be considered. Disclosures: Kröger: Celgene: Research Funding. Kropff:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Malignant Neoplasms in Long-Term Survivors of Bone Marrow Transplantation – Follow up

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 453-453 ◽  
Author(s):  
Bernhard Heilmeier ◽  
Nadine Stowasser ◽  
Gerard Socie ◽  
Maria Teresa van Lint ◽  
Andre Tichelli ◽  
...  
Keyword(s):  
Risk Factors ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Marrow Transplantation ◽  
Malignant Neoplasms ◽  
Host Disease ◽  
Graft Versus Host ◽  
Long Term Survivors

Abstract Patients who receive allogeneic hematopoietic stem cell transplants have an increased risk for new malignancies because of several risk factors, including conditioning with radiation and chemotherapy, immune modulation, and malignant primary disease. The frequency of and risk factors for malignant neoplasm in long-term survivors should be assessed. A former analysis of the EBMT observing the 1036 patients of this study with a median observation time of 10.7 years showed older patient age and immunosuppressive treatment of chronic graft-versus-host disease as main risk factors for secondary malignancies. We have tried to determine the cumulative incidence and define potential risk factors for new malignancies in long-term survivors after marrow transplantation in a retrospective multi center follow-up study. This study of the Late Effects Working Party was performed with 45 transplantation centers cooperating in the European Cooperative Group for Blood and Marrow Transplantation. 1036 consecutive patients who underwent transplantation for leukemia, lymphoma, inborn diseases of the hematopoietic and immune systems, or severe aplastic anemia. Patients were transplanted before December 1985 and had survived more than 5 years. Reports on malignant neoplasms were evaluated, and the cumulative incidence was compared to that in the matched general population. Patient age and sex, primary disease and disease stage at transplantation, histocompatibility of the donor, conditioning regimen, type of prophylaxis of graft-versus-host disease, development of acute and chronic graft-versus-host disease, and treatment of chronic graft-versus-host disease were evaluated as variables. Univariate analysis was performed using the log rank test for the time until malignancy occurred; significant risk factors were studied in multivariate analysis (Cox regression). Median follow-up since transplantation was 17.9 years (range, 5 to 32.3 years). Malignant neoplasms were seen in 114 patients; the cumulative incidence was 4.0% at 10 years, 8.5% at 15 years, 14.0% at 20 years and 21.0% at 25 years. The rate of new malignant disease was 6-fold higher than that in an age-matched control population (P <0.001). The most frequent malignant diseases were neoplasms of the skin (23 patients), breast (16 patients), thyroid gland (13 patients), oral cavity (12 patients), uterus including cervix (7 patients), and glial tissue (3 patients). Median ages of patients and their donors at the time of transplantation were 21 years for both groups (range 0.5 – 52 years). Follow up data were avaible in 636 patients, 100 patients were deceased at the time of prior analysis, 300 patients were lost to follow up. Compared with the analysis of the same cohort of patients 10 years ago, the most striking increase in secondary malignancies was seen in breast cancer (4-fold), thyroid cancer (3-fold) and neoplasms of the skin and oral cavity (2-fold). In multivariate analysis patient age above 30 years (hazard ratio 1.8, 95% CI 1.2 – 2.6; p=0.006), radiotherapy for conditioning (hr 2.3, CI 1.2 – 4.3; p=0.01) and immunosuppression (hr 1.5, CI 1.0 – 2.2; p=0.05) (in particular cyclosporine or methotrexate) were risk factors for new malignancies after hematopoietic stem cell transplantation. In conclusion longer followup shows the continuous increase of the cumulative incidence of secondary neoplasms in long-term survivors. With longer follow-up a shift in the risk factors occurs: Until 10–15 years after allogeneic transplantation immunosuppression is the major risk factor for new malignancies, whereas more than 15 years after transplantation radiotherapy becomes the dominant risk factor.

scholarly journals Extended CCR5 Blockade in Graft-Versus-Host Disease Prophylaxis – a Phase II Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2491-2491 ◽  
Author(s):  
Ran Reshef ◽  
James K. Mangan ◽  
Selina M. Luger ◽  
Alison Wakoff Loren ◽  
Elizabeth O. Hexner ◽  
...  
Keyword(s):  
Phase Ii ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Phase Ii Study ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade 3 ◽  
Ccr5 Blockade

Abstract Background: Blocking lymphocyte trafficking after allogeneic stem cell transplantation (alloSCT) may prevent graft-versus-host disease (GvHD) without interfering with graft-versus-tumor (GvT) activity. We previously reported that brief (up to day+30) CCR5 blockade using maraviroc (MVC, Pfizer) after reduced-intensity conditioned (RIC) alloSCT resulted in a low incidence of acute GvHD and absence of early liver and gut GvHD, although delayed GvHD still occurred. We designed a phase II study to test the hypothesis that extended administration of MVC would be feasible, safe and provide protection against late-onset GvHD without impairing immune reconstitution or GvT responses. Patients and Methods: In April 2013 we initiated a 37-patient (pt) phase II study to test an extended course of MVC in recipients of RIC alloSCT from unrelated donors. Pts receive fludarabine 120 mg/m2 and busulfan i.v. 6.4 mg/kg followed by peripheral blood stem cells. MVC 300 mg b.i.d. is orally administered from day -3 to day +90 in addition to standard prophylaxis with tacrolimus and methotrexate. The primary endpoint is the cumulative incidence of grade 2-4 acute GvHD by day 180. As of July 2014 we enrolled 20 pts at high risk for transplant-related toxicity by virtue of age (median=64, range 55–72), donor source (matched unrelated 80%, single-antigen mismatch unrelated 20%) or comorbidities (comorbidity index: low 15%, intermediate 35%, high 50%). Underlying diseases were AML (16), MDS, MPD, ALL and CTCL (1 each). Feasibility and Safety: The median follow-up on surviving patients is 5.7 months. The 3-month course of MVC was well tolerated with no increased toxicity; two pts did not complete their treatment due to early disease relapse and one patient discontinued therapy due to a skin reaction with eosinophilia where the histological features favored a drug reaction and the attribution to MVC was possible. Postural hypotension, a known dose-dependent toxicity, was observed in one pt who completed the course with a 50% dose reduction. Engraftment and Immune Reconstitution: The median time to ANC>500/μL was 12 d (range 10-21) and platelets>20k/μL was 14 d (range 9-28). The median whole blood and T-cell donor chimerism levels at day 100 were 95% (range 12–100%) and 80% (range 23–94%) respectively, which are similar to historical rates. Median CD4 counts on day 30 were 341 (range 206-424). Only 3/16 evaluable pts had Ig levels<500 mg/dL in the first 100 days. GvHD: Sixteen pts are evaluable with > 3 mo of follow-up. The day-180 cumulative incidence rates (± s.e.) of grade 2-4 and grade 3-4 acute GvHD are 25 ± 11% and 6 ± 6% respectively (Fig. 1). Of patients who developed acute GvHD in the first 180 days, there have been no cases of liver GvHD, 2 cases of stage 1 steroid-responsive gut GvHD and 1 case of severe diarrhea with combined features of GvHD and leukemic infiltrates in the gut. These results are comparable to the GvHD rates in our phase I/II MVC study (grade 2-4: 23.6% and grade 3-4: 5.9%), which included related and unrelated donor transplants. These results also compare favorably with a 45% day-180 acute GvHD rate seen in similar patients treated with our standard GvHD prophylaxis alone. Notably, there has been no treatment-related mortality. Five patients have relapsed at a median of 2.6 months post-transplant (range 0.93 – 3.5), which is similar to our historical rates after RIC alloSCT. PD analysis: We developed a phosphoflow assay to assess in real-time the activity of MVC in fresh blood samples. The assay quantifies the activation of CCR5 by measuring the phosphorylation of C-terminal serine residues as a result of CCL4 stimulation. In 15 evaluable patients, we observed diminished pCCR5 levels with CCL4 stimulation on day 0 as compared to day -6 (Fig. 2). In summary, our preliminary results support the feasibility, safety and protective activity of the CCR5 antagonist MVC against acute GvHD, with preferential activity against visceral GvHD. Continued pt enrollment and follow-up are ongoing. Updated safety, efficacy and PD results will be presented. A multi-center study (BMT-CTN 1203) will be initiated later this year to further clarify the role of this novel strategy in improving the outcome of alloHSCT. Fig 1. Cumulative Incidence of Acute GvHD Fig 1. Cumulative Incidence of Acute GvHD Fig 2. Phosphoflow shows CCR5 unresponsiveness to CCL4 stimulation on day 0 Fig 2. Phosphoflow shows CCR5 unresponsiveness to CCL4 stimulation on day 0 Disclosures Reshef: Pfizer: Research Funding. Off Label Use: Maraviroc for graft-versus-host disease prophylaxis.

scholarly journals Allogeneic Stem Cell Transplantation (Allo-SCT) after Treatment with Programmed Cell Death-1 (PD-1) Checkpoint Inhibitors for Relapsed/Refractory Classic Hodgkin Lymphoma (R/R cHL) Is Associated with an Unprecedented Low Relapse Rate

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2185-2185
Author(s):  
Armando Santoro ◽  
Luca Castagna ◽  
Massimo Magagnoli ◽  
Stefania Bramanti ◽  
Jacopo Mariotti ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Checkpoint Inhibitors ◽  
Infectious Complications ◽  
Host Disease ◽  
Graft Versus Host ◽  
Classic Hodgkin Lymphoma ◽  
Programmed Cell Death 1

Abstract Introduction: Phase 1/2 trials using the programmed cell death-1 (PD-1) checkpoint inhibitors Nivolumab and Pembrolizumab in relapsed/refractory classic Hodgkin lymphoma (R/R cHL) who had failed autologous-SCT (Auto-SCT) showed high response rates and durable responses in the majority of patients. However, with extended follow-up, progression-free survival (PFS) curves from the CheckMate 205 trial failed to show a plateau, thus suggesting the need for a consolidation therapy in cHL responding to anti-PD-1. Reported here is the retrospective analysis of the outcome of 34 cHL patients who received an Allo-SCT after treatment with PD-1 inhibitors. Patients and Methods: From Nov 2014 to Apr 2017, 44 R/R cHL enrolled in the CA209-205, CA209-254 and MK3475087trials(median age, 31 years; range, 18-81) received nivolumab (n=42) or pembrolizumab (n=2) until complete remission (CR), very good partial remission (PR) defined as a tumor burden reduction >80%, or progressive disease (PD).At study entry, 30 patients (84%) had refractory disease, 39 (89%) had failed BV and 38 (86%) Auto-SCT. Tumor assessment was performed according to Cheson et al (JCO, 2014). Non-relapse mortality (NRM) was defined as death by any reason other than disease progression. Cumulative incidence of relapse, NRM, and graft-versus-host disease (GVHD) was assessed using the Kaplan-Meier method. Results: After a median duration of anti-PD-1 therapy of 10 months (range, 3-33), 18 patients (41%) experienced CR or PR whereas 26 (59%) progressed. Sixteen of 18 responding patients were allografted. Eighteen of 26 patients who progressed during anti-PD-1 therapy received additional chemotherapy and were finally allografted. Overall, 34 of 44 patients were allografted. Allografting was not performed due to age (n=1), PD (n=4), patient refusal (n=5). The median time from last nivolumab to Allo-SCT was 49 days (range, 23 - 372). At Allo-SCT, 22 patients (65%) were in CR, 11 (32%) in PR and 1 (3%) in PD. Donors were haploidentical sibling (n=23), matched sibling (n=5), or matched unrelated (n=6). Stem cell source was bone marrow (n=15) and peripheral blood (n=19).Acute graft-versus-host disease (aGVHD) was recorded in 15 patients.The cumulative incidence (CI) of grade 2-4 and grade 3-4 aGVHD at 100 days was 46% and 12%, respectively; the 2-year CI of cGVHD was 27%. Non-infectious complications including febrile syndrome, macrophage activation syndrome and cytokine release syndrome, as well as infectious complications occurring until day +100 post-allografting are detailed in a companion abstract.With a median follow-up of 18 months (range, 1.8-39.3), one patient died due to relapse and 5 to non-relapse mortality (NRM) [(acute Graft-versus-Host Disease (aGVHD) (n=1), CMV pneumonia (n=1), immune-mediated pneumonia (n=1) heart failure (n=1), post-transplant lymphoproliferative disorder (PTLD) (n=1)]. The 2-year cumulative incidence (CI) of relapse and NRM was 3.1% and 19.7%, respectively. The 2-year OS and PFS were 76% and 76%, respectively. Conclusions: With an extended follow-up, data reported herein clearly show that Allo-SCT performed after PD-1 inhibitors or the sequence PD-1 inhibitors/chemotherapy is a feasible consolidation strategy associated with an unprecedented low relapse incidence. Early transplant-related complications prompt at identification and implementation of risk-minimizing strategies. PD-1 inhibitors eventually combined with salvage chemotherapy and Allo-SCT represent a paradigm shift in the treatment of refractory cHL. Disclosures Carlo-Stella: Boehringher Ingelheim Italia: Consultancy; Sanofi: Consultancy; MSD Italia: Speakers Bureau; Amgen: Speakers Bureau; Janssen: Speakers Bureau; ADC Therapeutics: Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; Genenta Science: Speakers Bureau; Rhizen Pharmaceuticals: Research Funding; Bristol-Myers Squibb: Speakers Bureau.

Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease

2022 ◽  
Author(s):  
Marie Bleakley ◽  
Alison Sehgal ◽  
Stuart Seropian ◽  
Melinda A. Biernacki ◽  
Elizabeth F. Krakow ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Unrelated Donor ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade Iii

PURPOSE Graft-versus-host disease (GVHD) causes morbidity and mortality following allogeneic hematopoietic cell transplantation. Naive T cells (TN) cause severe GVHD in murine models. We evaluated chronic GVHD (cGVHD) and other outcomes in three phase II clinical trials of TN-depletion of peripheral blood stem-cell (PBSC) grafts. METHODS One hundred thirty-eight patients with acute leukemia received TN-depleted PBSC from HLA-matched related or unrelated donors following conditioning with high- or intermediate-dose total-body irradiation and chemotherapy. GVHD prophylaxis was with tacrolimus, with or without methotrexate or mycophenolate mofetil. Subjects received CD34-selected PBSC and a defined dose of memory T cells depleted of TN. Median follow-up was 4 years. The primary outcome of the analysis of cumulative data from the three trials was cGVHD. RESULTS cGVHD was very infrequent and mild (3-year cumulative incidence total, 7% [95% CI, 2 to 11]; moderate, 1% [95% CI, 0 to 2]; severe, 0%). Grade III and IV acute GVHD (aGVHD) occurred in 4% (95% CI, 1 to 8) and 0%, respectively. The cumulative incidence of grade II aGVHD, which was mostly stage 1 upper gastrointestinal GVHD, was 71% (95% CI, 64 to 79). Recipients of matched related donor and matched unrelated donor grafts had similar rates of grade III aGVHD (5% [95% CI, 0 to 9] and 4% [95% CI, 0 to 9]) and cGVHD (7% [95% CI, 2 to 13] and 6% [95% CI, 0 to 12]). Overall survival, cGVHD-free, relapse-free survival, relapse, and nonrelapse mortality were, respectively, 77% (95% CI, 71 to 85), 68% (95% CI, 61 to 76), 23% (95% CI, 16 to 30), and 8% (95% CI, 3 to 13) at 3 years. CONCLUSION Depletion of TN from PBSC allografts results in very low incidences of severe acute and any cGVHD, without apparent excess risks of relapse or nonrelapse mortality, distinguishing this novel graft engineering strategy from other hematopoietic cell transplantation approaches.

scholarly journals Post-Transplant High Dose Cyclophosphamide and Bortezomib As Graft-Versus-Host Disease Prophylaxis Following Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3892-3892
Author(s):  
Benedetto Bruno ◽  
Frank Cirrone ◽  
Kelli Cole ◽  
Kelsey Stocker ◽  
Maher Abdul-Hay ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Advisory Board ◽  
High Dose ◽  
Graft Versus Host ◽  
One Year ◽  
Grade Iii

Abstract Introduction. Prevention of graft-versus-host disease (GvHD) following allogeneic hematopoietic cell transplantation (AHCT) remains a major challenge. The combination of methotrexate (MTX) and a calcineurin inhibitor has been the standard regimen for prophylaxis in patients receiving matched sibling donor (MSD) or matched unrelated donor (MUD) transplants for the past few decades. However, over 50% of patients undergoing AHCT still develop acute or chronic GvHD or even both, causing high rates of morbidity and mortality. Moreover, calcineurin inhibitors also have untoward toxic side effects. High dose post-transplant cyclophosphamide (PTCy), initially introduced for GvHD prevention in the setting of haploidentical transplantation, has now been studied in MSD and MUD transplants. We adopted a novel approach to prevent GvHD using a short course of PTCy and bortezomib. We hypothesized that such combination is safe and effective and omits the need for calcineurin or m-TOR inhibitors. Study Design. We report the outcomes of a prospective cohort of patients who received PTCy and bortezomib for GvHD prevention following MSD or MUD transplants. Twenty-eight patients were treated in a phase I-II trial and their clinical outcomes were previously reported (al-Homsi AS et al, BBMT 2019). Most of the remaining patients were treated on an extension trial. GvHD prevention consisted of PTCy 50 mg/kg IV on day +3 and +4, and bortezomib 1.3mg/m 2 IV 6 hours after transplant and again 72 hours after. Patients receiving MUD transplants also received rabbit ATG (thymoglobulin®) 5mg/kg total IV fractionated on day -4 to -2. All patients received peripheral blood grafts and standard supportive care as per Institutional policy. G-CSF was administered routinely until neutrophil engraftment. Results. Fifty-eight patients are included in this analysis. Median age was 60 (range 22-78) years. Fifty-three percent of patients were male. Underlying malignancies consisted of myeloid and lymphoid malignancies in 79.3% and 20.6%, respectively. Acute myeloid leukemia (50%) and myelodysplastic syndromes (24.1%) were the most common diseases. At transplant, disease risk index was low, intermediate, high and very high in 19.0%, 48.3%, 31.0% and 1.7% of patients, respectively. Median Pretransplant Assessment of Mortality Score (PAM) was 16.7 (5.4-29.4). Grafts were from MSD in 24.1% or MUD in 75.9% of patients. Recipient (R)/Donor (D) CMV status at transplant was as follows: R+/D+: 43%; R+/D-: 21%; R-/D+: 14% and R-/D-: 22%. Conditioning regimens consisted of reduced intensity fludarabine and busulfan in all but 2 patients who were conditioned with myeloablative fludarabine and busulfan. Overall, the regimen was remarkably well tolerated. Median times to neutrophil and platelet engraftment were 16 (13-28) and 26 (15-57) days respectively. No patient experienced primary graft failure. CMV and EBV reactivation rates were 46.6% and 24%. Cumulative incidences of grade II-IV and grade III-IV acute GVHD were 35% (95% CI: 22%-47%) and 15% (95% CI: 7%-25%) at day +120, respectively. Cumulative incidence of chronic GvHD was 14% at 1 year . Overall, 34% of patients required immunosuppression with systemic steroids after day +4 either for grade III-IV acute or chronic GvHD. Disease relapse rate was 26%. One-year cumulative incidence of transplant-related mortality was 14% (95% CI: 6%-25%). Median overall survival was 30.7 (95% CI: 15.7-not yet reached) months. One-year overall survival was 72% (95% CI: 57%-82%). One-year composite GvHD (acute and chronic) free and relapse free survival (GRFS) was 41.6% (95% CI: 28.9%-54%). Conclusion. PTCy and bortezomib combination for GvHD prophylaxis following MSD and MUD transplants is well tolerated and effective. It offers an alternative regimen to calcineurin and m-TOR inhibitor-containing regimens and may be preferred in certain settings including patients with limited resources, poor medication compliance, and with impaired renal function. A comparison of this cohort to a matched control group of patients receiving methotrexate and cyclosporine for GvHD prevention is ongoing. Disclosures Abdul-Hay: Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Other: Advisory Board, Speakers Bureau; Jazz: Other: Advisory Board, Speakers Bureau; Abbvie: Consultancy; Takeda: Speakers Bureau. Al-Homsi: Celyad: Other: Advisory Board; Daichii Sanyko: Consultancy. OffLabel Disclosure: Cyclophosphamide and Bortezomib are used for GvHD prevention

scholarly journals Post-Transplant Outcomes in AML Patients ≥ 60 Years of Age Beyond CR1

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4696-4696
Author(s):  
Dhruv Bansal ◽  
Pavan Kumar Bhamidipati ◽  
Natasha Catherine Edwin ◽  
Michael Slade ◽  
John F DiPersio ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Patient Characteristics ◽  
Study Groups ◽  
Host Disease ◽  
Graft Versus Host ◽  
Active Disease

Abstract Introduction: While 65-70 years is the median age of presentation for AML, outcomes continue to be suboptimal in patients 60 years of age or greater. This population tends to have adverse cytogenetic and molecular profiles while their medical management is often complicated by multiple co-morbidities. There is paucity of literature on the outcomes in AML patients greater than 60 years of age undergoing allogeneic hematopoietic cell transplant (allo-HCT), particularly for patients beyond complete remission 1(CR1). <> Methods: <> We retrospectively identified all patients at Washington University School of Medicine undergoing allo-HCT for AML between January 2006 and December 2012. Patients were then classified as CR1 or beyond CR1 (>CR1). The primary study endpoint was overall survival (OS). Secondary endpoints included leukemia free survival (LFS), cumulative incidence of relapse and non-relapse mortality (NRM). Patient, disease and treatment-related variables for the study groups were compared using the chi-square statistic or Fishers Exact test for categorical variables and the Kruskal-Wallis test for continuous variables. Cumulative incidence plots were generated by SAS macro %CIF and Gray's test was utilized to test equality of cumulative incidence function between study groups. Kaplan-Meier (KM) curves for OS were generated and provide unadjusted survival estimates between study groups. Differences between study groups were determined by log-rank tests. Cox proportional hazard model was used in multivariate analysis for OS and LFS. All statistical tests were two-sided using an alpha level of significance of 0.05. SAS Version 9.3 (Cary, NC) was used to perform all statistical analyses. Results: We identified 114 patients who met inclusion criteria. The patient characteristics are described in Table 1. Of these, 62 patients were beyond CR1 (24 in CR2, 17 with persistent cytogenetic abnormalities (CP) and 21 with active disease). The remaining 52 patients transplanted in CR1 were included as a control cohort. Patient characteristics in the two cohorts are described in Table 1. Three-year OS was 35.0% (95% CI 22-48) for individuals transplanted in CR1, while it was 26.6% (95% CI 16-38) in >CR1 (p=0.0504, Figure 1a). Relapse Incidence (RI) at 3-years was 43.3% (95% CI 29-57) in CR1, and 50.8% (95% CI 37-63) in >CR1 (Figure 1b). Three-year NRM in CR1 was 27.2% (95% CI 16-40) and 24.7% (95% CI 15-36) in >CR1 (Figure 1c). aGVHD (acute graft versus host disease) at 3-years of follow up in CR1 group was 50.9% (95% CI 36-64) and 41.0% (95% CI 28-53) in >CR1. cGVHD (chronic graft versus host disease) in CR1 group at 3-years of follow up was 23.8% (95% CI 13-36) and 10.6% (95% CI 4-20) in >CR1. On multivariate analysis, active disease at the time of transplant was associated with poor OS (p<0.05) (HR 3.648; CI 1.980-6.720) and poor LFS (p<0.01) (HR 3.058; CI 1.708-5.477). Conclusions: Given these findings, allo-HCT is a viable treatment option with acceptable long-term survival in AML patients 60 years of age or greater. Overall, there is a trend towards worse survival in patients transplanted beyond CR1. Specifically, active disease at transplant is associated with poor outcomes. These results underscore an unmet need to develop novel protocols associated with improved survival in these patients. Disclosures DiPersio: Incyte Corporation: Research Funding. Schroeder:Incyte Corporation: Honoraria, Research Funding.

Polymorphism in the Promoter Region of the Hemeoxygenase I Gene of the Donor Influences Overall Survival and Graft Versus Host Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2879-2879
Author(s):  
Armin Gerbitz ◽  
Patrick Hillemanns ◽  
Christoph Schmid ◽  
Andrea Wilke ◽  
Rajshri Jayaraman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Graft Versus Host Disease ◽  
Length Polymorphism ◽  
Promoter Region ◽  
Cellular Stress ◽  
Host Disease ◽  
Graft Versus Host ◽  
Unrelated Donors ◽  
Grade Iii ◽  
Related Mortality

Abstract Genetic polymorphisms of various donor and host genes have been found to be associated risk factors for graft versus host disease and transplant related mortality. Most of these genes are involved in the regulation of immune response and inflammatory reactions towards pathogens. The heme oxygenase (HO) protein is the rate limiting enzyme in heme degradation to biliverdin, free iron and carbon monoxide. Its inducible form I (HO-I) is constitutively expressed in the spleen due to the abundance of its substrate. It is inducible in a wide range of tissues upon exposure to cellular stress factors such as irradiation, bacterial lipopolysaccharide, proinflammatory cytokines and heat shock. Further, HO-I is involved in regulating inflammatory response and has been described as a “protective gene” in solid organ transplantation. In man the promoter region of HO-I displays length polymorphism due to a variable number of gt repeats within a 500bp region upstream of the TATA box. Individuals exhibiting 25 or less gt repeats express HO-I upon cellular stress at a higher level than individuals with more than 30 gt repeats. We retrospectively analysed length polymorphisms of 92 donor and host pairs undergoing allogeneic stem cell transplantation for various malignancies. We show here that donor promoter length polymorphism leading to low expression of HO-1 (>30 gt repeats) is associated with improved overall survival, relative to donors with ≤ 30 repeats (80.6% versus 54.4%, p=0.023). When subgrouped, having HLA identical siblings as donors had no influence on outcome (see figure below, right panel) whereas having matched unrelated donors strongly influenced overall survival (82.6 vs. 44.2%, p=0.015). Combination of high HO-1 expressing unrelated donors and high expressing hosts displayed a 27.8% survival (left panel, solid line vs.81.3% for individuals with one allele >30 repeats dotted line). Polymorphisms of the recipient HO-1 genes did not influence outcome after transplantation. When matched unrelated donors were used, the incidence of grade III gut GvHD was significantly higher when (p=0.032) and overall GvHD (≥ grade III) displayed a trend towards significance (p=0.098). Transplant related mortality was strongly influenced by having a donor who expresses HO-1 at a high level upon cellular stress (p=0.006). In a multivariate Cox regression analysis of pretransplant factors such as age, disease stage, sibling/unrelated donor etc. polymorphism in the donor HO-1 gene had a significant influence on overall survival (p=0.027). These data suggest a role for HO-I in GvHD pathophysiology and a possible role for HO-1 as a non MHC risk factor for unrelated transplantation. Figure Figure

scholarly journals Efficiency and Toxicity of Ruxolitinib as a Salvage Treatment for Steroid-Refractory Chronic Graft-Versus-Host Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Dong Wang ◽  
Yin Liu ◽  
Xiaoxuan Lai ◽  
Jia Chen ◽  
Qiao Cheng ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Rate ◽  
Graft Versus Host Disease ◽  
Overall Survival Rate ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
One Year ◽  
Steroid Refractory

Graft-versus-host disease (GVHD), especially steroid-refractory GVHD, remains a life-threatening complication after hematopoietic stem cell transplantation (HSCT). The effect of the JAK1/2 kinase inhibitor ruxolitinib on treating steroid-refractory acute GVHD has been verified by the REACH1/2 study; however, its safety and efficacy in patients with steroid-refractory chronic GVHD (SR-cGVHD) remain unclear. In this retrospective study, 70 patients received ruxolitinib as a salvage therapy for SR-cGVHD. Twenty-four weeks after ruxolitinib treatment, the overall response rate (ORR) was 74.3% (52/70), including 34 patients who achieved complete remission (CR) and 18 who achieved partial remission (PR). The main adverse event was cytopenia, which occurred in 51.4% (36/70) of patients. After ruxolitinib treatment, the percentage of CD4 cells increased from 18.20% to 23.22% (P&lt;0.001), while the percentages of NK (CD16+CD56+) cells and regulatory T cells (CD4+CD127 ± CD25+) decreased (P&lt;0.001, P&lt;0.001). Among the B cell subsets, the proportion of total B cells approximately tripled from 3.69% to 11.16% (P&lt;0.001). Moreover, we observed a significant increase in IL-10 levels after ruxolitinib treatment (P=0.025) and a remarkable decrease in levels of suppression of tumorigenicity 2 (ST2) from 229.90 ng/ml to 72.65 ng/ml. The median follow-up after the initiation of ruxolitinib treatment was 401 (6-1076) days. The estimated one-year overall survival rate of the whole group was 66.0% (54.4–77.6%, 95% CI), and the one-year overall survival rate of patients with mild and moderate cGVHD was 69.6% (57.4–81.8%, 95% CI), which was better than that of patients with severe cGVHD (31.3%, 0.0–66.2%, 95% CI) (P=0.002). Patients who achieved a CR and PR achieved better survival outcomes (84.5%, 73.9–95.1%, 95% CI) than those who showed NR to ruxolitinib treatments (16.7%, 0–34.3%, 95% CI) (P&lt;0.001). At the final follow-up, cGVHD relapse occurred in six patients after they reduced or continued their ruxolitinib doses. Collectively, our results suggest that ruxolitinib is potentially a safe and effective treatment for SR-cGVHD.

Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial

Blood ◽  
2002 ◽  
Vol 100 (2) ◽  
pp. 415-419 ◽  
Author(s):  
Mary E. D. Flowers ◽  
Pablo M. Parker ◽  
Laura J. Johnston ◽  
Alice V. B. Matos ◽  
Barry Storer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Host Disease ◽  
Graft Versus Host ◽  
Long Term Follow Up

Abstract In a previous multicenter phase III trial comparing peripheral blood stem cell transplantation (PBSCT) to bone marrow transplantation (BMT) from HLA-matched related donors, we found no statistically significant difference in the cumulative incidence of clinical extensive chronic graft-versus-host disease (GVHD) in the 2 groups. We have analyzed the results in more detail to determine whether the clinical characteristics of chronic GVHD after PBSCT might be distinct from those that occur after BMT. Clinical extensive chronic GVHD developed in 39 of 63 recipients of PBSCs and in 32 of 63 BM recipients who were alive and free of malignancy at day 100 after the transplantation. No significant differences were found in the time and type of onset of clinical extensive chronic GVHD or in the frequency of complications associated with severe morbidity. Involvement of skin and female genital tract was more frequent in PBSC recipients than in BM recipients. The cumulative incidence of chronic GVHD at 3 years was similar in the 2 groups, but the number of successive treatments needed to control chronic GVHD was higher after PBSCT than after BMT (P = .03), and the duration of glucocorticoid treatment was longer after PBSCT compared to BMT (P = .03). These results suggest that chronic GVHD after PBSCT may be more protracted and less responsive to current treatment than chronic GVHD after BMT. Assessment of the overall benefits of PBSCT compared to BMT will require continued long-term follow up of morbidity associated with chronic GVHD.

Early Intervention with Mesenchymal Stromal Cells for Refractory Grade III-IV Graft Versus Host Disease In Children Results In Excellent Long Term Outcome

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2336-2336
Author(s):  
Lynne Margaret Ball ◽  
Maria E. Bernardo ◽  
Jaap Jan Zwaginga ◽  
Maarten van Tol ◽  
Angela Cometa ◽  
...  
Keyword(s):  
Overall Survival ◽  
Graft Versus Host Disease ◽  
Immune Suppression ◽  
Term Survival ◽  
Long Term Survival ◽  
Host Disease ◽  
Graft Versus Host ◽  
Steroid Refractory

Abstract Abstract 2336 Mesenchymal stromal cell (MSC) infusions have been reported to be effective in patients with severe, steroid-refractory, acute graft-versus-host disease (aGVHD). However, long term comprehensive follow up data on pediatric patients is limited. We analyzed the outcome of 37 children receiving MSC for steroid-refractory aGvHD in two centers between January 2005 and December 2009 (characteristics see Table 1). A median of 2 infusions (range 1–13) were administered, with a median cell dose of 2×106/kg (range 0.9–3.0). MSC were from 3rd party HLA-mismatched donors (n=31), haploidentical relative (n=3) or both (n=3). (see Table 2) Fifteen children had either no (n=6) or partial (n=9) response to MSC. In this group, transplantation-related mortality (TRM) was 60%. Complete response (CR) was observed in 22 children, TRM being 14%. (p=0.005). Among the 28 patients with hematological malignancies, 5 relapsed, three with CR and two with PR. With a median follow-up of 2.3 years (range 7 months–4.7 years), overall survival was 62% with 87% versus 27% in patients who did or did not achieve CR after MSC respectively (p value <0.001). MSC after 2009 given at the time of steroid failure (median 8 days range 4 to 24) compared to pre 2009 (median 24 days range 5 to 85) (Maan-Whitney U = 65.5 two tailed p= 0.002) reduced fatal infections and was associated with a trend to better overall survival at 2 years post MSC infusion (p = 0.07). Although infections were evident at the time of immune suppression and mortality was high in NR/PR, response to MSC allows for reduction and eventual discontinuation of pharmacological immune suppression. Long term survival in responders is associated with eventual immune recovery, no late infections and persistent remission status. Treatment of steroid refractory aGVHD should aim to induce rapid stable control and early reduction of steroids to reduce TRM from viral reactivations. We conclude that MSC are ideal candidates for this purpose. Our results show that children responding to MSC treatment for severe steroid refractory GvHD have an excellent long term survival. Legend: ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; MDS = myelodysplastic syndrome; jMML = juvenile myelomonocytic leukemia; HLH = hemophagocytic lymphohistiocytosis; MSD = matched sibling donor; (m) MUD (mis) Matched unrelated donor; PBSC = peripheral blood stem cells; TBI = total body irradiation; CSA = Cyclosporine A; MTX = short course methrotrexate; ATG = anti-thymocyte globulin; HSCT = hematopoietic stem cell transplantation; DLI = donor lymphocyte infusion; GvHD = graft versus host disease; M=Male; F=Female. Disclosures: No relevant conflicts of interest to declare.

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