scholarly journals Reduced Intensity Versus Myeloablative Conditioning Allogeneic HCT for Relapsed/Refractory Lymphoma: Applying Refined Disease Risk Index (DRI) to Improve Survival

2016 ◽  
Vol 22 (3) ◽  
pp. S225-S226
Author(s):  
Aleksandr Lazaryan ◽  
Veronika Bachanova ◽  
Qing Cao ◽  
Brian Lee McClune ◽  
Mukta Arora ◽  
...  
Keyword(s):  
Disease Risk ◽  
Risk Index ◽  
Myeloablative Conditioning ◽  
Allogeneic Hct ◽  
Refractory Lymphoma ◽  
Reduced Intensity

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 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.

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 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.

scholarly journals A Phase II Trial of Melphalan Based Reduced-Intensity Conditioning for Transplantation of T-Replete HLA-Haploidentical Peripheral Blood Stem Cells with Posttransplant Cyclophosphamide in Patients with Hematologic Malignancies

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Melhem M. Solh ◽  
Gabriel Hinojosa ◽  
Justin Laporte ◽  
Scott R. Solomon ◽  
Lawrence E. Morris ◽  
...  
Keyword(s):  
Phase Ii ◽  
Peripheral Blood ◽  
Cumulative Incidence ◽  
Phase Ii Trial ◽  
Disease Risk ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Myeloablative Conditioning ◽  
Peripheral Blood Stem Cells ◽  
Very High

T-replete haploidentical donor transplants using posttransplant cyclophosphamide (haplo) have greatly expanded donor availability and are increasingly utilized. Haplo were originally performed using truly nonmyeloablative conditioning and a bone marrow graft. We have also developed myeloablative conditioning and peripheral blood stem cell (PBSC) grafts for use with haplo. However, some patients may not tolerate myeloablative conditioning but may still benefit from a more dose-intensified preparative regimen to control malignancy and diminish graft rejection. To this end, we enrolled 25 patients on a prospective phase II trial utilizing a regimen of fludarabine 30 mg/m2/day × 5 days and Melphalan 140 mg/m2 on day -1 (flu/Mel) followed by infusion of unmanipulated PBSC graft from a haploidentical donor. GVHD prophylaxis included cyclophosphamide 50 mg/kg/day on days 3 and 4, mycophenolate mofetil on day 35, and tacrolimus on day 180. Median age was 57 years (range from 35 to 68). Transplantation diagnosis included AML (n = 11), ALL (n = 4), MDS/MPD (n = 6), NHL/CLL (n = 3), and MM (n = 1). Using the refined Disease Risk Index (DRI), patients were low (n = 1), intermediate (n = 13), and high/very high (n = 11). 22 out of 25 patients engrafted with a median time to neutrophil and platelet engraftment of 18 days and 36 days, respectively. All engrafting patients achieved full peripheral blood T-lymphocyte and myeloid donor chimerism at day 30. The 180-day cumulative incidence for acute GVHD grades II–IV and III-IV was seen in 20% (95% CI 8%–37%) and 8% (95% CI 2%–22%), respectively. The 2-year cumulative incidence of chronic GVHD was 16% (95% CI 5%–33%) (moderate-severe 12% (95% CI 3%–27%)). After a median follow-up of 28.3 months, the estimated 2-year OS, DFS, NRM, and relapse were 56% (95%CI 33–74%), 44% (95%CI 23%–64%), 20% (95% CI 8%–37%), and 36% (95% CI 17%–55%), respectively. Among patients with high/very high risk DRI, 2-year OS was 53% compared to 69% for low/intermediate DRI. When compared with a contemporaneous cohort of patients at our center receiving haploidentical transplant with nonablative fludarabine, Cytoxan, and total body irradiation flu/Cy/TBI regimen, the outcomes were statistically similar to the 2-year OS at 56% vs. 63% p = 0.75 and DFS at 44% vs. 46% p = 0.65 .

scholarly journals Myeloablative Conditioning Is Preferred for Allogeneic Transplantation of Acute Myeloid Leukemia and Myelodysplastic Syndromes with Low/Intermediate but Not High Disease Risk Index

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4603-4603
Author(s):  
Nelli Bejanyan ◽  
Mei-Jie Zhang ◽  
Khalid Bo-Subait ◽  
Hai-Lin Wang ◽  
Erica D. Warlick ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Disease Risk ◽  
Risk Index ◽  
Intermediate Risk ◽  
Myeloablative Conditioning ◽  
Conditioning Intensity ◽  
Very High ◽  
Risk Of Relapse

Although some data (Scott, JCO 2017) suggest that myeloablative conditioning (MAC) is preferred for allogeneic hematopoietic cell transplantation (HCT) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), these data were not informed by analysis of disease specific risk factors. We analyzed AML and MDS HCT outcomes stratified by the disease risk index (DRI) in order to identify the preferred transplant conditioning intensity (reduced-intensity conditioning [RIC] vs. MAC). In this large CIBMTR registry study we identified 4387 adult patients (age 40-65 years) who received HCT for AML (68%) or MDS (32%) between 2009 and 2015. DRI was stratified as low/ intermediate risk (1539 MAC and 999 RIC) and high/ very high risk (1121 MAC and 728 RIC). Examining the low/ intermediate risk DRI cohort (Table), RIC was associated with lower risk of TRM (HR=0.74, 95% CI 0.62-0.88; p<0.001) but significantly higher risk of relapse (HR=1.54, 95% CI 1.35-1.76; p<0.001). As a result, RFS in this cohort was significantly worse with RIC (HR=1.19, 95% CI 1.07-1.33; p=0.001). In the high/ very high risk DRI cohort, RIC resulted in similar TRM (HR=0.83, 95% CI 0.68-1.00; p=0.051) but again significantly higher risk of relapse (HR=1.23, 95% CI 1.08-1.41; p=0.002). RFS in high/ very high risk DRI cohort was similar between RIC and MAC. Adjusted outcome curves for the 3 endpoints are shown in the Figure. In this large study of HCT for AML or MDS stratified by DRI, RIC was independent predictor of lower TRM, but significantly higher risk of relapse. The MAC was an independent predictor of lower relapse in both low/ intermediate and high/very high DRI groups. However, MAC only resulted in RFS benefit in the low/ intermediate group where the magnitude of impact on relapse was not offset by the higher TRM. In adults with AML or MDS aged 40-65 years, these data support MAC as the preferred conditioning intensity for low/ intermediate risk DRI, whereas MAC does not provide significant benefit in those with high/ very high risk DRI. Safer, yet still potent MAC regimens could benefit this higher risk group. Disclosures Bejanyan: Kiadis Pharma: Other: advisory board. Brunstein:Gamida: Research Funding; Astex: Research Funding; Magenta: Research Funding. Kebriaei:Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria; Kite: Honoraria; Pfizer: Honoraria; Kite: Honoraria. Weisdorf:Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy; Incyte: Research Funding.

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