A Phase I Dose Escalation Study of Lenalidomide Following Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3954-3954 ◽  
Author(s):  
Leslie A. Andritsos ◽  
William Blum ◽  
Rebecca B. Klisovic ◽  
Sumithira Vasu ◽  
Sam Penza ◽  
...  
Keyword(s):  
Skin Rash ◽  
Dose Escalation ◽  
Acute Gvhd ◽  
Disease Risk ◽  
Risk Index ◽  
Reduced Intensity Conditioning ◽  
Dose Escalation Study ◽  
Elevated Creatinine ◽  
Very High ◽  
Reduced Intensity

Abstract Lenalidomide is an immunomodulatory drug that is FDA approved for treatment of 5q- myelodysplastic syndrome (MDS) and myeloma. It has also been tested as a salvage therapy of refractory/relapsed AML with encouraging activity, especially in patients (pts) who relapsed post allogeneic transplant (alloSCT). In this setting, it has been postulated that lenalidomide may re-activate donor immune system and enhance a graft-versus-leukemia effect. This hypothesis is also supported by evidence of increase graft-versus-disease (GVHD) observed in pts treated with lenalidomide post-alloSCT. Therefore, in order to prospectively study the safety, feasibility, and early impact on risk of disease relapse we performed a phase 1 dose escalation study of lenalidomide administered orally daily following reduced intensity conditioning (RIC) alloSCT in pts with leukemia and lymphoma eligible for transplant. Methods: Pts were enrolled on a two-step process, with initial enrollment prior to transplant followed by a re-registration evaluation post-transplant at day +60 (+/- 7 days) to ensure eligibility. At this screening, pts were required to demonstrate engraftment with ANC >1000/uL, platelet count ³50,000/uL, and T-cell chimerism ³40% by day +30. Pts were required to have a creatinine clearance ³50 mL/min, AST ²3 x ULN, and ECOG PS of 0-2. Grades 1 or 2 acute GVHD (aGVHD) were allowed if controlled on ² 20 mg of prednisone daily; pts with a history of grades 3 or 4 aGVHD were excluded. Lenalidomide was given orally daily for 28 days/cycle. Dosing escalation was performed using a standard 3 x 3 design, with dose level (DL) 1 = 5 mg , DL 2 = 10 mg, and DL 3 = 15 mg. Results: From 6/2011 to 10/2012, 17 pts with AML (n=13), CLL (n=1), and DLBCL (n=3) were enrolled (Table 1) and underwent RIC alloSCT. The majority of patients had a Disease Risk Index (Armand et al. Blood, 2014) of high or very high. Of enrolled pts, only 3 received lenalidomide. Of the pts who did not proceed to treatment at re-registration, 4 were ineligible due to relapse, 3 were ineligible due to elevated creatinine, 3 were ineligible due to GVHD, 2 declined, and 2 were not treated due to study closure. All pts who received lenalidomide were treated at DL 1. The first pt treated (00-06) received cycle 1 without toxicity. On cycle 2 day 9 he developed a skin rash consistent with acute GVHD and discontinued therapy. The second pt treated (00-11) developed skin rash and diarrhea on cycle 1 day 3 and was diagnosed with steroid refractory aGVHD of the GI tract. He expired from complications of treatment. The third pt treated (00-12) developed a skin rash and diarrhea on cycle 1 day 6. Lenalidomide was discontinued. Based on these outcomes, the study was closed due to concerns regarding the risk of severe aGVHD caused by lenalidomide. However, patients 00-06 and 00-12 remain alive and in CR days 958 and 751 post transplant, respectively. In the entire cohort, the median PFS was 103 days (range = 15-992) with median OS 103 days (range = 30-1085). Conclusion: Early administration of low-dose lenalidomide following alloSCT is not feasible due to potential increased risk of severe aGVHD and likelihood of elevated creatinine at this time point. However, 2 of 3 pts who received lenalidomide and responded to treatment for aGVHD remain in CR from their high-risk AML. Thus, an amended approach with lower/fewer dose of lenalidomide/cycle or alternatively, use in transplants that do not utilize calcineurin phosphatase inhibitors (such as T-cell depletion based approaches) warrants additional consideration. Abstract 3954. Table 1 PT Age Sex Diagnosis Disease Risk Index Comorbidity Index Lena Treatment Progression free survival (days) Overall survival (days) Cause of death 01 64 F AML High 3 Ineligible1 592 979 Relapse 02 64 M AML Very high 1 Ineligible1 140 229 Relapse 03 26 F AML High 6 Ineligible2 35 121 Relapse 04 39 M DLBCL Intermediate 0 Declined 789 1085 05 64 M DLBCL Intermediate 1 Declined 108 121 Relapse 06 36 M AML High 3 Yes 958 958 07 60 M AML High 3 Ineligible3 992 992 08 61 M CLL Low 0 Ineligible3 101 101 Acute GVHD 09 71 M AML High 1 Ineligible1 957 957 10 57 M AML High 5 Ineligible2 30 30 Regimen Related Toxicity 11 32 M AML Very High 2 Yes 103 103 Acute GVHD 12 50 F AML Very High 4 Yes 751 751 13 61 F AML Very High 4 Ineligible2 42 242 Relapse 14 60 M AML Very High 0 Ineligible2 15 160 Relapse 15 63 F AML High 3 Ineligible3 61 61 Acute GVHD 16 66 M AML High 3 Study closure 706 706 17 68 M DLBCL High 5 Study closure 72 72 Pneumonia 1 = elevated creatinine 2 = relapse 3 = GVHD Disclosures Off Label Use: Lenalidomide administration following allogeneic transplantation.. Blum:Celgene: Consultancy.

scholarly journals Disease Risk Index Is Independently Associated with Long-Term Outcomes of Allogeneic Transplantation Post Reduced-Intensity Conditioning in Lymphoid Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5773-5773
Author(s):  
Ioanna Sakellari ◽  
Zoi Bousiou ◽  
Andriana Lazaridou ◽  
Eleni Gavriilaki ◽  
Ioannis Batsis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Disease Risk ◽  
Risk Index ◽  
Disease Stage ◽  
Reduced Intensity Conditioning ◽  
Lymphoid Malignancies ◽  
Heavily Pretreated ◽  
Very High ◽  
Reduced Intensity

Abstract Introduction: Allogeneic hematopoietic cell transplantation (alloHCT) with reduced-intensity conditioning (RIC) has been used in heavily pretreated lymphoma patients with the promise of decreased treatment-related mortality. Despite overall improvements in outcomes of patients with lymphoid malignancies, several new agents are emerging as potential therapies. However, investigation is ongoing. Therefore, we aimed to describe our long-term experience in Hodgkin (HL), non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL). Methods: In this retrospective study, we enrolled consecutive patients who underwent allo-HCT for lymphoid malignancies in our institution between 2001-2018. We performed a retrospective review of data in our prospectively acquired database. Results: In total, 50 patients (male=35, female=15, median age 36 years, range 15-64) underwent allo-HCT for HL (n=24), NHL (n=21, including mantle cell n=12, follicular n=3, aggressive B-NHL n=4, T-NHL n=2) and CLL (n=5). The majority of patients were diagnosed at stage IV (48%), 34% had bone marrow involvement and 66% had previously undergone autologous HCT. Most patients were heavily pretreated (median treatment lines=4, range 1-11), 21 of them had received more than 4 treatment lines and at the time of transplantation only 14 had complete response of the disease, while 9 had partial response and 27 were refractory. According to Disease-Risk Index (DRI), patients were stratified at low (n=11, 23.4%), intermediate (n=12, 25.5%), high (n=20, 42.6%) or very high (n=4, 8.5%) category. Among patients with Hodgkin lymphoma, Brentuximab vedotin was administered in 7, and 4 of them were effectively bridged to AHCT. All patients received RIC, mainly Fludarabine (150mg/m2)-Cyclophosphamide (2g/ m2) in CLL and NHL and Thiotepa (10mg/kg)-Fludarabine (120 mg/m2)-Cyclophosphamide (60mg/kg) in HL from matched sibling (n=27), matched unrelated (n=15) or mismatched unrelated (n=8) donor. GVHD prophylaxis consisted of cyclosporine or tacrolimus and mycophenolate mofetil or short- term methotrexate and additional low dose antithymocyte globulin (5mg/kg) in unrelated donors. Peripheral blood was the main stem cell source (only two patients received bone marrow graft) and median number of CD34+ cells infused was 6.37 x106 /kg (1.33-14.5). Two patients succumbed to advanced underlying disease before engraftment, in all other engraftment was successful. Median time until neutrophil engraftment was 10 days (7-23) and until platelet engraftment 12 days (7-28). Eighteen patients (36.7%) developed acute GVHD (grade I,n=1,grade II, n=12,grade III-IV, n=5), steroid sensitive in 10 (62.5%). Cumulative incidence (CI) of chronic extensive GVHD at first year was 78.2%, and 13 patients required more than one additional line of immunosuppression (range 1-5 lines). Ten patients presented CMV reactivation successfully treated with antiviral medication and 1 patient died from HSV7 encephalitis. With a median follow of 3 years (1-16 years), 10-year OS was 40.4%, 10-year non-relapse mortality CI 23.4% and 10-year DFS 32%. There was no difference in survival according to original disease (5yr, NHL=61.1%, HL=47.1%, CLL=30%%, p=0.67). Multivariate analysis revealed high and very high DRI as the single predicting factor for OS (HR 9.69, CI 1.55-60.55, p=0.015), when assessing impact of disease, DRI, number of prior treatment lines, cGVHD and bone marrow infiltration at diagnosis. Conclusions: Our data suggest that RIC allo-HCT provides encouraging survival rates, potentially offers the chance of cure, with acceptable 10-year TRM in selected high risk patients with lymphoid malignancies, despite high risk of chronic GVHD. Disease risk index that is mainly associated with disease stage at transplant independently affects survival. Therefore, efforts need to continue to improve clinical application of novel agents targeting specific pathways with the aim of lowering disease stage pre-transplant. These therapeutic strategies merit further investigation in prospective studies in order to select potential therapeutic targets and best regimens for individual patients. Disclosures Gavriilaki: European Hematology Association: Research Funding.

Impact Of Total Nucleated Cell and CD34+ Cell Dose On Transplant Related Outcomes In Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplants

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2048-2048 ◽  
Author(s):  
Paul Martin ◽  
Shuli Li ◽  
Edwin P. Alyea ◽  
Vincent T. Ho ◽  
Corey S. Cutler ◽  
...  
Keyword(s):  
Disease Risk ◽  
Conflicts Of Interest ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Reduced Intensity Conditioning ◽  
Allogeneic Hct ◽  
Cell Dose ◽  
The Impact ◽  
Reduced Intensity

Abstract Background Mobilized peripheral blood (PB) is the most common graft source for allogeneic hematopoietic transplantation (HCT) following reduced intensity conditioning (RIC). The impact, if any, of donor PB graft composition on major transplant outcomes in the RIC allogeneic HCT setting remains incompletely understood. Existing studies have focused primarily on CD34+ cell dose and report conflicting results, especially in relation to survival. The impact of total nucleated cell (TNC) dose has been less frequently evaluated, but limited studies with relatively small cohort sizes have reported higher TNC dose to be associated with improved survival. Methods In order to further explore the relationship between PB donor CD34+ cell dose, TNC dose and RIC HCT outcomes, we assessed 705 adult patients with hematological malignancies who underwent RIC allogeneic HCT at Dana Farber Cancer Institute/ Brigham and Women's Hospital (DFCI/BWH) between 2000 and 2010. The vast majority received a RIC regimen of fludarabine and busulfan (n=698). GVHD prophylaxis was tacrolimus based with or without sirolimus (524 vs. 171, respectively). Recipients of in vivo T-cell depletion (TCD) with antithymocyte globulin or ex-vivo TCD were excluded. The median age was 57 years (range,18-74). Patient's disease risk index (DRI) was categorized as low (n=164), intermediate (n=350), high (n=170) or very high (n=21) per Armand, et al (Blood, 2012). Transplants were categorized as matched (MRD n=273, MUD n=374) or mismatched (MMRD n=4, MMUD n=58). Results There was weak correlation between CD34+ cell dose and TNC (Spearman coefficient 0.25 [0.18-0.32]), and between CD34+/kg and TNC/kg with coefficient 0.25 [0.26, 0.39]. Cell doses for TNC effects were evaluated by quartiles. On multivariable analysis including age, DRI, donor source, gender, and CMV serostatus, higher TNC dose (top quartile, ≥10.8 x 10^10 cells) was independently associated with increased chronic GVHD (HR 1.33 [1.06-1.67], p=0.015) as well as decreased relapse (HR 0.74 [0.58-0.94], p=0.015). There was no effect on acute GVHD, engraftment, or non-relapse mortality. Importantly, higher TNC dose was associated with improved overall survival (HR 0.74 [0.59-0.94], p=0.014, Figure 1) and progression free survival, PFS (HR 0.76 [0.61-0.94], p=0.014). In contrast, although higher doses of CD34+ cells (> 10 x 10^6/kg vs. < 5 x10^6/kg) resulted in faster engraftment for both platelets and neutrophils (data not shown) and a decrease in non-relapse mortality ( HR 0.53 [0.30-0.93], p=0.027), there was no significant effect on acute or chronic GVHD incidence, relapse, PFS or survival. Conclusions These data suggest TNC dose is an important prognostic variable in T-replete RIC HCT with significant impact on survival and should, like CD34+ cell dose, be taken into consideration when planning donor graft infusions. Further studies are needed to confirm these data, and characterize the components of the PB graft that influence survival. Disclosures: No relevant conflicts of interest to declare.

Results of a Two-Arm Phase II Clinical Trial Using Post-Transplantation Cyclophosphamide for Prevention of Graft-Versus-Host Disease in Haploidentical and Mismatched Unrelated Donors Hematopoietic Stem-Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 152-152 ◽  
Author(s):  
Sameh Gaballa ◽  
Isabell Ge ◽  
Riad O. El Fakih ◽  
Jonathan E. Brammer ◽  
Sa A. Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Disease Risk ◽  
Risk Index ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Equity Ownership ◽  
Reduced Intensity

Abstract Allogeneic stem cell transplantation offers curative therapy for many patients (pts) with high-risk hematologic malignancies. Donor availability remains a major limitation for many pts. The introduction of high-dose post-transplant cyclophosphamide (PTCy) has significantly improved the outcomes of pts undergoing haploidentical (HAPLO) stem cell transplants. The choice between a HAPLO or a one-antigen HLA mismatched unrelated donor (9/10 MUD) for pts lacking an HLA-matched donor remains unclear. Methods: We conducted a prospective non-randomized phase 2 clinical trial with two parallel arms, HAPLO (n=60) and 9/10 MUD (n=46) transplants, for pts with advanced hematologic malignancies or aplastic anemia who lacked an HLA-matched unrelated donor type at 10 loci (HLA-A, -B, -C, -DRB1, and -DQB1) using a MEL-based reduced-intensity conditioning regimen. The regimen included a single intravenous dose of MEL 140 mg/m2 (day -7), thiotepa 5 mg/kg (day -6), and four daily IV doses of fludarabine 40 mg/m2 (day -5 to day -2) (FM140). Thiotepa was intermittently available and was replaced by total body irradiation at a dose of 2 Gy on day -1. Pts >55 years (yr) old or with significant comorbidities received a lower MEL dose (100 mg/m2) (FM100). All pts with CD20-positive lymphoma received rituximab (375 mg/m2) on days -13, -6, +1 and +8. GVHD prophylaxis consisted of PTCy 50 mg/kg on day +3 and +4, and tacrolimus and mycophenolate for 6 and 3 months (mo), respectively. The stem cell source was unmodified bone marrow for both arms. Results: Patient characteristics are shown in Table 1. The median follow-up duration was 24 mo in the HAPLO arm and 29 mo in the 9/10 MUD arm. The cumulative incidence (CI) of neutrophil (ANC) recovery at day 45 was 95% and 98% in the HAPLO and 9/10 MUD arm, respectively. The median time to ANC recovery was 18 days in both arms; the median time to platelet recovery was 25 days in the HAPLO arm and 28 days in the 9/10 MUD arm. Primary graft failure developed in two pts in the HAPLO arm (one due to anti-donor HLA antibodies) and one patient in the 9/10 MUD arm. One pt in both arms developed mixed donor chimerism at day 100; otherwise, all pts in both arms achieved full (>95%) donor chimerism. Bone marrow was the graft source in all pts except 2 in the HAPLO arm and 8 in the 9/10 MUD arm who received a peripheral blood graft. The 1-yr overall and progression free survival were 70% and 60%, respectively, in the HAPLO arm (Fig. 1A) and 60% and 47%, respectively, in the 9/10 MUD arm (Fig. 1B). Day 100 CI of grade II-IV aGVHD and III-IV aGVHD were 28% and 3%, respectively, in the HAPLO arm versus 33% and 13%, respectively, in the 9/10 MUD arm; the 2-yr CI of chronic extensive GVHD was 13% and 14% in the two groups, respectively. The 1-yr CI of non-relapse mortality was 21% in the HAPLO arm and 31% in the 9/10 MUD arm, while the 1-yr relapse rate was 19% and 25% in the two groups, respectively. Conclusions: This study establishes PTCy, tacrolimus, and mycophenolate as an effective regimen for GVHD prevention in mismatched transplantation using both haploidentical and mismatched unrelated donor sources. Melphalan-based reduced-intensity conditioning is an effective regimen for a broad range of hematologic malignancies. Prospective randomized studies comparing haploidentical and unrelated donor sources are needed. Table 1. HAPLO (n=60) 9/10 MUD (n=46) Median Age, years (Range) 45 (20-63) 51 (20-64) Sex (M/F) 29/31 23/23 KPS ³90 53 (88%) 40 (87%) <90 7 (12%) 6 (13%) HCT-CI 0-3 50 (83%) 38 (83%) >3 10 (17%) 8 (17%) Disease Risk Index* Very high 5 (8%) 3 (7%) High 18 (30%) 15 (33%) Intermediate 29 (48%) 12 (26%) Low 8 (13%) 12 (26%) NA 0 4 (9%)** Conditioning Regimen FM100 20 (33) 18 (39%) FM140 40 (67%) 28 (61%) Diagnosis AML/MDS 33 (55%) 18 (39%) ALL 7 (11%) 5 (11%) Lymphoma 10 (17%) 13 (28%) Others 10 (17%) 10 (22%) Disease Stage Acute Leukemia CR1/CR2 24 (66%) 9 (56%) CR3 or higher/ CRpx 6 (17%) 5 (31%) Active disease 6 (17%) 2 (13%) Lymphoma CR 3 (30%) 8 (62%) PR 5 (50%) 3 (23%) Chemoresistant 2 (20%) 2 (15%) *Disease Risk Index by Armand et al; xCRp: Complete Remission with incomplete count recovery; **Patients had aplastic anemia. Figure 1. Figure 1. Disclosures Brammer: Celgene: Research Funding. Lee:Ziopharm: Equity Ownership; Cyto-Sen: Equity Ownership; Intrexon: Equity Ownership. Rezvani:Pharmacyclics: Research Funding. Alousi:Therakos, Inc: Research Funding.

A Single Institution Study of Allogeneic Hematopoietic Stem Cell Transplant for MDS and AML in Patients 60 Years of Age and Older: Impact of Disease Risk Index and Secondary Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5532-5532
Author(s):  
Eva Gupta ◽  
Randi Hoffman ◽  
Thomas Colleen ◽  
William J Hogan ◽  
Mark R Litzow ◽  
...  
Keyword(s):  
Overall Survival ◽  
Older Patients ◽  
De Novo ◽  
Disease Risk ◽  
Risk Index ◽  
Cell Transplant ◽  
Reduced Intensity Conditioning ◽  
Secondary Disease ◽  
Kaplan Meier ◽  
Reduced Intensity

Abstract Background: Allogeneic Hematopoietic cell transplantation (HCT) is potentially curative therapy for MDS and AML. Although the median age at presentation is >65 years, most patients receiving HCT for these disorders are young (<60years). With the availability of Reduced Intensity Conditioning (RIC) many older patients are able to undergo HCT. The older age group is the most rapidly increasing cohort in CIBMTR registry. We analyzed the outcomes of AML and MDS patients' ≥ 60 years who received allogeneic sibling or unrelated donor HCT at our institution between 2009 and 2014. We also evaluated the influence of patient-, disease-, and transplant related factors on outcomes. Methods: Prospectively collected data available in the BMT databases at Mayo Clinic Florida, Arizona and Rochester as well as individual patient charts were reviewed after IRB approval. Patients with MDS or AML in complete remission at the time of transplant were included; those with active disease, induction failure, or prior transplant were excluded. HCT-specific comorbidity index (HCT-CI) and the disease risk index (DRI- Armand et al. Blood 2012) was noted. Survival estimates were calculated using the Kaplan Meier method. Associations with survival were explored using single variable Cox-regression modeling and log-rank tests. Results: 80 patients were included; 68 AML and 12 MDS. 31 (39%) were male. Median age 66 years (range 60-75). 33%, 52%, and 13% patients had ECOG status of 0, 1, >2, respectively. Thirty-seven patients (46%) had low or intermediate DRI and 43(54%) had high DRI. Twenty-two (28%), 24 (30%), and 34 (43%) patients had HCT-CI of 0, 1, or >2. There were equal number of sibling and unrelated donors; 85% were full HLA match and 15% with 1 or 2 mismatches; mean age of the donors was 52years (range18-74). Transplant conditioning was fludarabine-containing reduced intensity regimens in 78 (97%), 2 patients received myeloablative conditioning. The source of stem cells was peripheral blood in all patients. A median of 5.87 x10^6 CD34/kg donor cells were infused (range 1.58-10.92 X10^6). All patients received calcineurin inhibitor based GVHD prophylaxis (tacrolimus 56%, cyclosporine 44%); 6 patients also received ATG. The median follow up of survivors was 13 months. Kaplan Meier estimate of overall survival at 100 days, 1 year, and 2 years was 90%, 64%, and 55%. Cumulative incidence of relapse at 6 months, 1 year, and 2 years was 19.5%, 22.3%, and 27.1%. Relapse free survival at 2 years was 50%. The non-relapse/ treatment related mortality at 6 months, 1 year and 2 years was 11.7%, 15.9% and 15.9%. The rate of acute grade 2-4 GVHD was 30% and chronic GVHD was 39%. Univariate analysis identified secondary disease (compared to de novo) and high DRI(compared to low/intermediate) to be associated with worse mortality - HR 2.54 (1.31-4.93; P = 0.006), and 2.31 (1.13-4.73; P = 0.021), respectively. Probability of overall survival at 6 months, 1 year, and 2 years for patients with de novo disease (n=57) vs. secondary disease (n=23) was 87.1% vs. 64.5%, 71.1 vs. 45.6%, and 63.2 vs. 32.6%, respectively; P= 0.006. There was no effect of donor age, donor type or degree of mis-match on the survival. Conclusion: Allogeneic HCT is feasible in older patients with MDS and AML utilizing reduced intensity conditioning regimens with acceptable outcomes that are comparable to published results in younger patients. Patients with high DRI and secondary disease have poorer overall survival as compared to those with de novo disease and low/intermediate disease risk index. These data support other studies that age alone does not negatively influence transplant outcomes. Disclosures No relevant conflicts of interest to declare.

scholarly journals Risk Factors for Adverse Outcomes Following Haploidentical Hematopoietic Cell Transplantation with Posttransplant Cyclophosphamide: A Two-Center Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4889-4889
Author(s):  
Viviane De Jesus Torres Lima ◽  
Anderson Felipe Felipe Da Silva ◽  
Andreza Alice Feitosa Ribeiro ◽  
Mariana Nassif Kerbauy ◽  
Lucila Kerbauy ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Disease Risk ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Adverse Outcomes ◽  
Very High

Abstract Introduction Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for several malignant hematologic diseases. As only 30% of patients will have a matched related donor, alternative donors play a significant role in HCT. Luznik et al pioneered the use of posttransplant cyclophosphamide (PTCy) based GVHD prophylaxis in haploidentical transplantation (haplo-HCT), which greatly expanded the pool of donors and nearly revolutionized the field. Despite the increasing use of haplo-HCT with PTCy, some questions remain, namely the selection of the best donor, graft source and conditioning regimen, and risk factors for adverse outcomes. Methods Retrospective study conducted at two Brazilian centers. All patients with hematologic malignancies who underwent first HCT between 2010 and 2021, haploidentical with posttransplant cyclophosphamide, were included. The objective was to identify risk factors for adverse outcomes following haploidentical HCT with PTCy. Independent variables are detailed in table 1. Acute GVHD was graded according to the MAGIC criteria and chronic GVHD was diagnosed according to the NIH consensus criteria. Survival and cumulative incidence curves were built with the Kaplan-Meier and Gray methods, and compared with the logrank and Gray tests, respectively. Multivariate analyses were carried out with Cox models. GVHD, as an independent variable, was included as a time-dependent covariate. Results A total of 103 patients were included (table 1). In brief, median age was 39 y/o and most patients were male (58%); 71 patients had low or intermediate disease risk index, while 29 had high or very high-risk disease. Bone marrow was the preferred stem-cell (72%, followed by peripheral blood stem-cells - 28%) and reduced-intensity, the most frequent conditioning regimen (43%). Median follow-up for the whole cohort was 2.6 years. Overall survival at 2 years was 51.7% (95CI 42.4-63.0%, figure 1). Multivariable analyses are in table 2. Risk factors for death were age at transplant (HR = 1.03 for each year; 95CI 1.01-1.05; p = 0.002), high or very high disease risk index (HR = 2.73; 95CI 1.52-4.90; p = 0.0008), and compared with low or intermediate, and mother as the donor (HR = 3.50; 95CI 1.44-8.47; p = 0.006). Progression-free survival at 2 years was 45.8% (95CI 36.6-57.2%). In multivariate analysis (table 2), progression-free survival was significantly poorer for older patients (HR = 1.02; 95CI 1.01-1.04; p = 0.009), high or very high disease risk index (HR = 2.29; 95CI 1.30-4.04; p = 0.004), compared with low or intermediate, and mother as a donor (HR = 3.15; 95CI 1.37-7.22; p = 0.007; figure 2). Two-year relapse rate was 22.2% (95CI 15.2-32.5%). Risk factors for relapse (table 2) were high or very high disease risk index (HR = 3.55; 95CI 1.44-8.74; p = 0.006), compared with low or intermediate, and mother as the donor (HR = 2.85; 95CI 1.12-7.25; p = 0.007). Two-year non-relapse mortality was 32.0% (23.9-42.9%). The only risk factor we found was age at transplantation (HR = 1.03 for each year; 95CI 1.01-1.05; p = 0.02; table 2). We found no effect of GVHD, acute or chronic, on relapse, nor on non-relapse mortality. Rates of grades II-IV and III-IV acute GVHD and 2y-chronic GVHD were 30.4% (95CI 22.7-40.8%), 6.9% (95CI 3.4-14.1%) and 19.8% (95CI 13.2-29.7%), respectively. The only risk factor (table 2) identified for grades II-IV acute GVHD was tacrolimus (HR = 0.36; 95CI 0.14-0.95; p = 0.04) compared with cyclosporine. We have not carried out multivariate analysis for grades III-IV acute GVHD due to the low number of events (only 7). In multivariable analysis (table 2), peripheral blood graft was a risk factor for chronic GVHD (HR = 3.72; 95CI 1.53-9.01; p = 0.004; figure 3), compared with bone marrow, while tacrolimus was protective (HR = 0.27; 95CI 0.11-0.68; p = 0.005), compared with cyclosporine. Conclusion Our results show that mother as the donor was an important risk factor for poorer OS, PFS and relapse, and mothers might not the best choice of donor. Tacrolimus was protective for both grades II-IV aGVHD and for cGVHD, suggesting that tacrolimus may be more effective than cyclosporine in preventing GVHD. PBSC was a risk factor for cGVHD without any impact on relapse, and this result does not support the systematic use of PBSC in detriment of BM. As expected, age at transplant negatively impacted OS, PFS and NRM as well as high/very high DRI led to poorer OS, PFS and relapse. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Fludarabine Melphalan Versus Fludarabine Treosulfan As Reduced Intensity Conditioning Regimens in Allogeneic Hematopoietic Stem Cell Transplant - a Retrospective Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4493-4493
Author(s):  
Akanksha Chichra ◽  
Lingaraj Nayak ◽  
Rushabh Kothari ◽  
Siddhesh Arun Kalantri ◽  
Avinash Bonda ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Patient Characteristics ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Entire Cohort ◽  
Conditioning Regimens ◽  
Grade 3 ◽  
Haplo Group ◽  
Very High

Introduction Allogeneic hematopoietic stem cell transplantation (AHSCT) has evolved as a curative therapy for various hematological malignancies. Regimen-related toxicity and transplant-related mortality (TRM) preclude the use of myeloablative conditioning (MAC) regimens in older and unfit patients. Reduced intensity conditioning (RIC) regimens have enabled AHSCT in such patients. There is a recent rise in use of RIC regimens even in younger patients in view of decreased toxicity and equal efficacy as reported in some studies. Fludarabine + Melphalan (FM) and Fludarabine + Treosulfan (FT) are 2 such regimens. There are no prospective randomised comparisons between these regimens. We retrospectively analysed these 2 regimens for toxicities and outcomes. Methods This is a retrospective single centre analysis of all consecutive patients with haematological cancers who received either FM or FT from April 2008 to December 2018. The entire cohort was divided into two groups - Matched Sibling Donor (MSD)/Matched Unrelated Donor (MUD) and Haploidentical (Haplo) transplants for analysis. We compared patient characteristics, toxicities and outcomes in both the groups based on conditioning regimen. The FT regimen consisted of fludarabine (30 mg/m2 on days − 6 to − 2) combined with treosulfan (12-14 gm/m2 on days − 6 to − 4) with or without 2 Gy TBI on day-1. The FM regimen consisted of fludarabine (30 mg/m2 on days − 7 to − 3) combined with melphalan (140 mg/m2 on day -1).Prophylaxis for GVHD consisted of calcineurin inhibitor (CNI) plus methotrexate (MTX)or mycophenolate mofetil (MMF) in MSD/MUD. Rabbit ATG (2.5-5 mg/kg) was used for MUD. Haplo transplant patients received post-transplant cyclophosphamide with CNI and MMF. Comorbidities were scored according to the HCT-CI. Disease Risk Index(DRI) and EBMT score were recorded for all patients. Neutrophil (NE) and platelet engraftment (PE) were defined as per standard criteria. Early toxicity after AHCT was graded according to CTCAE version 4. Total parenteral nutrition (TPN) was used in patients as per the physician's discretion. Acute GVHD and chronic GVHD were recorded according to standard criteria. All patients underwent chimerism studies at day 15, 30 and then monthly for 1 year. Mixed chimerism was defined as > 5% to < 95% donor chimerism. The toxicities in various arms were compared by Chi-square test or Fisher exact test, while OS was calculated by Kaplan Meier method and the survival probabilities were compared using log-rank test. Competing risk analysis was used to calculate cumulative incidence of relapse and TRM. Results The study included 138 patients, 98 males and 40 females. The diagnoses were AML- 53, ALL- 30, MDS/MPN- 49 and lymphoma -6. Patient characteristics are outlined in Table 1. MSD/MUD transplants were 105 (FM- 94; FT-11); 33 were Haplo (FM-17; FT-16) transplants. PBSC was the stem cell graft in 136 (99%) patients. In both MSD/MUD and Haplo groups, there were no significant differences in median age, gender, pre transplant CMV status, HCT-CI and EBMT score between the two conditioning regimens. In MSD/MUD group, significantly more patients had high/very high DRI in FT arm (45% vs 17%; P=0.056) Comparison of engraftment and toxicity variables of both FM and FT arms are outlined in Table 2. In MSD/MUD group, 44 (47%) patients in FM arm had grade 3/4 oral mucositis compared to 1 (9%) in FT arm (P=0.02). Corresponding numbers were 7 (41%) and 1 (6%) in Haplo group (P=0.039). Grade 3/4 diarrhoea was higher in the FM vs FT arm of Haplo group (41% vs 6%; P=0.039) but not in the MSD/MUD cohort. More patients received TPN in the FM arms of both MSD/MUD and Haplo groups (Table 2). Incidence of grade III-IV acute GVHD was higher in FT vs FM in MSD/MUD group (27% vs 17%; P=0.04). The median follow up of entire cohort was 4.8 years. The OS (figure 1) at 5 years was 62% in FM arm of MSD/MUD group vs 53% in FT arm (P=NS). Similarly OS (figure 2) at 5 years was 41% and 28 %( P=NS) in FM and FT arms respectively of Haplo group. The cumulative incidence of TRM and relapse at 2 years were not different in FM and FT arms of both MSD/MUD and Haplo groups (Table 2). Conclusion Grade 3 and 4 oral mucositis and diarrhoea were significantly less with FT than FM in both MSD/MUD and Haplo groups. FT provided comparable outcomes to FM in the MSD / MUD group in spite of having higher proportions of patients with high / very high DRI. Prospective randomised studies are required to compare various RIC regimens. Disclosures No relevant conflicts of interest to declare.

scholarly journals Poor Outcomes of HLA-Mismatched Allogeneic Hematopoietic Cell Transplantation and High Ferritin Levels after a Reduced-Intensity Conditioning Regimen in Patients with Advanced Myelofibrosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5742-5742
Author(s):  
Han Bi Lee ◽  
Jae-Ho Yoon ◽  
Gi June Min ◽  
Sung-Soo Park ◽  
Silvia Park ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Reduced Intensity Conditioning ◽  
Advisory Committees ◽  
Reduced Intensity

Allogeneic hematopoietic cell transplantation (allo-HCT) preconditioning intensity, donor choice, and graft-versus-host disease (GVHD) prophylaxis for advanced myelofibrosis (MF) have not been fully elucidated. Thirty-five patients with advanced MF were treated with reduced-intensity conditioning (RIC) allo-HCT. We searched for matched sibling (n=16) followed by matched (n=10) or mismatched (n=5) unrelated and familial mismatched donors (n=4). Preconditioning regimen consisted of fludarabine (total 150 mg/m2) and busulfan (total 6.4 mg/kg) with total body irradiation≤ 400cGy. All showed engraftments, but four (11.4%) showed either leukemic relapse (n=3) or delayed graft failure (n=1). Two-year overall survival (OS) and non-relapse mortality (NRM) was 60.0% and 29.9%, respectively. Acute GVHD was observed in 19 patients, and grade III-IV acute GVHD was higher with HLA-mismatch (70% vs. 20%, p=0.008). Significant hepatic GVHD was observed in nine patients (5 acute, 4 chronic), and six of them died. Multivariate analysis revealed inferior OS with HLA-mismatch (HR=6.40, 95%CI 1.6-25.7, p=0.009) and in patients with high ferritin level at post-HCT D+21 (HR=7.22, 95%CI 1.9-27.5, p=0.004), which were related to hepatic GVHD and high NRM. RIC allo-HCT can be a valid choice for advanced MF. However, HLA-mismatch and high post-HCT ferritin levels related to significant hepatic GVHD should be regarded as poor-risk parameters. Disclosures Kim: Handok: Honoraria; Amgen: Honoraria; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

Fractionated gemtuzumab ozogamicin combined with intermediate-dose cytarabine and daunorubicin as salvage therapy in very high-risk AML patients: a bridge to reduced intensity conditioning transplant?

2016 ◽  
Vol 96 (3) ◽  
pp. 363-371 ◽  
Author(s):  
Etienne Paubelle ◽  
Sophie Ducastelle-Leprêtre ◽  
Hélène Labussière-Wallet ◽  
Franck Emmanuel Nicolini ◽  
Fiorenza Barraco ◽  
...  
Keyword(s):  
High Risk ◽  
Salvage Therapy ◽  
Gemtuzumab Ozogamicin ◽  
Reduced Intensity Conditioning ◽  
Very High ◽  
Reduced Intensity ◽  
Intermediate Dose

Efficacy of Reduced Intensity Conditioning (RIC) with FLU-BU-ATG and Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Pediatric ALL.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2314-2314 ◽  
Author(s):  
Reggie Duerst ◽  
David Jacobsohn ◽  
William T. Tse ◽  
Morris Kletzel
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Chronic Gvhd ◽  
High Dose ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Pediatric All ◽  
Very High ◽  
Reduced Intensity

Abstract Reduced Intensity Conditioning (RIC) regimens prior to allogeneic HSCT have gained acceptance in the treatment of adults with myelodysplasia, leukemia and multiple myeloma. RIC reduces the risk for regimen related morbidity and mortality enabling patients with pre-existing medical conditions that would have been precluded from allogeneic HSCT to attempt a curative approach. The resilience of pediatric patients (pts) following high-dose conditioning regimens and the concern that ALL cells are inherently more resistant to a graft-vs-leukemia effect have limited accrual of pediatric ALL pts to RIC protocols despite the potential benefit for reduced long-term morbidity. We report the experience of 10 pediatric ALL pts (6 M, 4 F, median age 9.5 years) treated for recurrent ALL with RIC and allogeneic HSCT. A uniform RIC regimen comprised of fludarabine, 30 mg/m2 for 6 consecutive days (days −10 through −5), followed by intravenous busulfan, 0.8 – 1 mg/kg for 8 doses or targeted AUC 4000 μMol*min for 2 doses (days −5 and −4) and equine ATG, 40 mg/kg or rabbit ATG, 2 mg/kg for 4 days (days −4 through −1) was administered. Pts with prior CNS involvement received whole brain (2400 cGy) and spinal (1800 cGy) irradiation immediately prior to the RIC. Stem cell sources included 7 unrelated donors and 3 matched sibs. 9 of 10 stem cell donations were peripheral blood stem cells (PBSC). The median cell doses infused were 6.5 x 108 MNC/kg and 4.2 x 106 CD34+ cells/kg. Graft-versus-host disease (GVHD) prophylaxis was cyclosporin A (CsA) alone in 5 patients, CsA and mycophenolate mofetil in 5 pts. Growth factor support was not used. Each of the pts had at least two very high-risk features--prior HSCT (n = 6), CR > 3/refractory disease (8), prior CNS disease (6), Ph+ (2), pre-exisiting neurologic (1) or cardiac (1) dysfunction or aspergillous infection (1). Full donor chimerism was achieved in 9 of 10 with a median time to reach an ANC >500/μl of 16 days (range 11–62) and an unsupported platelet count > 20,000/μl was achieved in 8 of 10 at a median of 25 days (15–67). 2 pts developed Gr IV acute GVHD, 2 of 5 pts surviving more than 100 days developed chronic GVHD. Only 3 patients have relapsed: 1 refractory T-ALL pt recurred day +27 and 2 Ph+ pts had a molecular relapse day +61 and +196. The latter pt is in subsequent continuous molecular remission for over 1 year on imatinib therapy. 6 pts have died, 5 in the first 100 days of HSCT from complications of GVHD (2), relapse (1), pulmonary failure (in 1 pt S/p 3 prior allogeneic HSCT) and PTLD (1). 1 pt succumbed from complications of chronic GVHD day +756. The RIC regimen and supportive care are primarily an outpatient experience. During the first 30 days post HSCT, pts spent an average of only 9 days in hospital (23 of the first 100 days). Despite very high-risk features, 4 of 10 pts survive (3 CCR) at a median of 500 days post HSCT. Thus, RIC and allogeneic HSCT also offers promise for efficacy in pediatric ALL.

Sign in / Sign up

Export Citation Format

Share Document