scholarly journals Pulsed treatment in continuation therapy improves disease-free survival in children with hematologic malignancies

2010 ◽  
Vol 7 (10) ◽  
pp. 552-552
Author(s):  
Rebecca Kirk
Keyword(s):  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Free Survival ◽  
Continuation Therapy ◽  
Pulsed Treatment ◽  
Disease Free

Chronic Graft Versus Host Disease and Pretransplant Disease Status Predict Outcomes in Patients with Hematologic Malignancies Undergoing Reduced Intensity Allogeneic Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5090-5090
Author(s):  
Megha A. Shah ◽  
Mounzer Agha ◽  
Markus Mapara ◽  
Kate Lenhart ◽  
Anastasios Raptis
Keyword(s):  
Overall Survival ◽  
Median Overall Survival ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Disease Status ◽  
Hematologic Malignancies ◽  
Free Survival ◽  
Effective Treatment Modality ◽  
Disease Free ◽  
Reduced Intensity

Abstract Reduced intensity stem cell transplantation (SCT) is an effective treatment modality for patients with hematologic malignancies who are not candidates for conventional myeloablative SCT. We conducted a retrospective review of all patients with hematologic malignancies receiving a reduced intensity allogeneic SCT from July 2002 to July 2007. Data pertaining to patient demographics, engraftment, disease status pre and post transplant, graft versus host disease (GVHD), and HLA matching was analyzed to identify factors significantly affecting the clinical outcome. Seventy three patients, with a median age of 55 (range of 19–70) and with the diagnoses of ALL (n=8), AML (n=30), CLL (n=3), CML (n=1), Hodgkin’s (n=7), non-Hodgkin’s (n=7), MDS (n=11), and MM (n=6) underwent a reduced intensity SCT using a fludarabine based conditioning regimen. Thirty nine (53%) received unrelated donor grafts and 34 (47%) received sibling donor grafts. Fifty six patients (77%) received fully matched grafts whereas 17 patients (23%) had an antigen or allele mismatch. Acute GVHD grade II-IV was observed in 27 of the 73 patients and chronic GVHD was seen in 18 of the 48 patients who could be evaluated. Seventeen patients developed transplant related fatal complications and 30 patients died from disease progression or relapse. Median time to neutrophil recovery was 15 days (range of 9–41 days) and median time to platelet recovery was 18 days (range of 9–42 days). Graft failure was observed in 6 of the 73 patients. Median overall survival and disease free survival for all patients was 7.7 and 6.6 months respectively. Median overall survival for patients with persistent disease or in remission at the time of the SCT was 5.6 and 21.8 months (p= 0.01) while that for disease free survival was 5.7 and 8.4 months (p=0.06). Median overall survival with and without chronic GVHD was 25.6 and 9.4 months (p <0.0001) while median disease free survival was 18.2 and 6.0 months (p< 0.0001). Patients with limited chronic GVHD have not yet reached median overall survival while the median disease free survival was 18.4 months. Those with no or extensive chronic GVHD had medians of 9.4 and 9.2 months for overall survival and 6.0 and 9.2 months for disease free survival (p= 0.004 and p=0.02). The source of the stem cells as well as the administration of allele or single antigen mismatch grafts did not affect the outcome. Reduced intensity SCT is an effective treatment modality in patients with hematologic malignancies, though it is most effective in patients who are in remission at the time of transplant and should be offered in this setting. Patients with limited chronic GVHD had a better outcome suggesting the presence of potent anti-tumor activity of the donor immune competent cells without the detrimental effects in clinical outcome caused by extensive chronic GVHD.

scholarly journals Allogeneic Peripheral Blood Stem-Cell Compared With Bone Marrow Transplantation in the Management of Hematologic Malignancies: An Individual Patient Data Meta-Analysis of Nine Randomized Trials

2005 ◽  
Vol 23 (22) ◽  
pp. 5074-5087 ◽  
Keyword(s):  
Late Stage ◽  
Randomized Trials ◽  
Individual Patient Data ◽  
Meta Analysis ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Free Survival ◽  
Stage Disease ◽  
Disease Free

Purpose Considerable uncertainty exists regarding relative effects of allogeneic peripheral blood stem cells transplantation (PBSCT) versus bone marrow transplantation (BMT) on outcomes of patients with hematologic malignancies. Patients and Methods To provide the totality of research evidence related to the effects of PBSCT versus BMT, we conducted an individual-patient data meta-analysis using data from nine randomized trials enrolling 1,111 adult patients. Results Compared with BMT, PBSCT led to faster neutrophil (odds ratio [OR] = 0.31; 95% CI, 0.25 to 0.38; P < .00001) and platelet engraftment (OR = 0.52; 95% CI, 0.44 to 0.61; P < .00001). PBSCT was associated with a significant increase in the development of grade 3-4 acute graft-versus-host disease (GVHD; OR = 1.39; 95% CI, 1.03 to 1.88) and extensive (47% v 31% at 3 years; OR = 1.89; 95% CI, 1.47 to 2.42; P < .000001) and overall chronic GVHD (68% v 52% at 3 years; OR = 1.92; 95% CI, 1.47 to 2.49; P < .000001), but not grade 2-4 acute GVHD (54% v 53%; P = .49). PBSCT was associated with a decrease in relapse (21% v 27% at 3 years; OR = 0.71; 95% CI, 0.54 to 0.93; P = .01) in both late-stage–(33% v 51% at 3 years; OR = 0.59; 95% CI, 0.38 to 0.93; P = .02) and early-stage–disease patients (16% v 20% at 3 years; OR = 0.69; 95% CI, 0.49 to 0.98; P = .04). Nonrelapse mortality was not different between groups. Overall and disease-free survival were only statistically significantly improved in patients with late-stage disease (overall survival: 46% v 31% at 3 years; OR = 0.64; 95% CI, 0.46 to 0.90; P = .01; disease-free survival: 41% v 27% at 3 years; OR = 0.63 95% CI, 0.45 to 0.87; P = .01). Conclusion PBSCT is associated with a decreased relapse rate in hematologic malignancies and improvement in overall and disease-free survival in patients with late-stage disease. PBSCT is also associated with a significant risk of extensive chronic GVHD.

Submyeloablative Allografts for Hematologic Malignancies: Validation of a Prognostic Model Based on Pre-Transplant Variables.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3036-3036
Author(s):  
Jayesh Mehta ◽  
Jane Winter ◽  
Martin Tallman ◽  
Leo Gordon ◽  
Stephanie Williams ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Prognostic Model ◽  
Reference Group ◽  
Cox Model ◽  
Performance Status ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Donor Age ◽  
Free Survival ◽  
Disease Free

Abstract Analysis of pre-transplant variables affecting the outcome of submyeloablative HSCT in 63 adult patients with hematologic malignancies identified refractory disease, poor performance status (ECOG 2/3), elevated LDH, and donor age >45 years as significant adverse prognostic factors (Mehta et al. ASH 2005, BMT 2006). The outcome of the next 28 patients treated identically was studied to see if the prognostic model developed from the first group was predictive of outcome of the second. The conditioning was 100 mg/m2 melphalan with (no prior auto) or without (prior auto) 50 mg/kg cyclophosphamide. GVHD prophylaxis comprised cyclosporine-mycophenolate (HLA-matched sibs) or tacrolimus-mycophenolate (others). G/GM-CSF were not administered routinely. All supportive care was uniform. As the table shows, the two groups of patients were comparable with reference to the major prognostic factors. Reference group (n=63) Test group (n=28) P Refractory disease 60% 64% 0.72 Performance status 2 or 3 25% 14% 0.28 Donor age >45 y 52% 61% 0.46 High LDH 44% 18% 0.21 The upper part of the first figure shows adjusted overall survival curves based on the number of adverse prognostic factors derived from the Cox model in the first 63 patients (reference group). The lower part shows actuarial overall survival of the next 28 patients by the number of adverse prognostic factors. Figure Figure Similarly, the upper part of the second figure shows adjusted disease-free survival curves based on the number of adverse prognostic factors derived from the Cox model in the first 63 patients, and the lower part shows actuarial disease-free survival of the next 28 patients by the number of adverse prognostic factors. Figure Figure As the figures show, the actual outcome of the second cohort of patients is similar to the outcome predicted by the prognostic model derived from the first cohort - validating the applicability of the model. It should be noted that the prognostic model may be different for other conditioning regimens. Also, while advanced patient age and HLA mismatch did not emerge as significant variables in this series, these variables need to explored further because the number of patients with these characteritics, expected to be adverse, was small (22% over 60 y and 12% HLA-mismatched). These data suggest that the combination of performance status, donor age, LDH, and disease chemosensitivity can be used to predict post-transplant prognosis in patients with hematologic malignancies. Identifying patients who are likely to experience a poor outcome post-transplant would then enable appropriate modification of the treatment regimen - such as reduction in the intensity of the regimen if toxicity is likely to be a concern, and intensification of the regimen and/or measures to augment graft-vs-tumor reactions if relapse is likely to be a concern.

Low-Dose Decitabine Combined with Modified Bucy Is More Effective Conditioning Regimen for High-Risk Patients with Acute Myeloid Leukaemia/Myelodysplastic Syndrome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5750-5750
Author(s):  
Xiaowen Tang ◽  
Jing Cao ◽  
Xiaojing Shi ◽  
Ling Ge ◽  
Aining Sun ◽  
...  
Keyword(s):  
High Risk ◽  
Low Dose ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Advanced Stage ◽  
Free Survival ◽  
Risk Patients ◽  
Disease Free ◽  
Related Mortality

Abstract Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment options to hematologic malignancies. However, majority of patients with refractory or resistant AML/MDS can not achieve remission before transplantation. It is necessary to design a safe and effective conditioning regimen to reduce tumour burden, improve remission rates, decrease transplantation-related mortality, and improve disease-free survival (DFS) in patients with advanced acute myloid leukemia(AML) and myelodysplastic syndrom(MDS). One of the promising drugs of epigenetics is decitabine (DAC), which has a significant effect on a variety of hematologic malignancies including MDS and advanced AML. Furthermore, decitabine can not only up-modulate the tumor-associated antigen express on surface of leukemia cells to increase graft-versus-leukemia (GVL) effect but also can reduce the incidence of graft-versus-host disease (GVHD) by increase the number of regulatory T Cells (Tregs). Objective: To investigate the security and efficacy of conditioning regimen containing low-dose decitabine combined with modified BUCY regimen for advanced AML/MDS patients, explore the role of immunomodulatory activity post transplantation and compared this regimen with conventional modified BUCY regimen. Methods: Between January 2012 and March 2015, a total of 156 patients were enrolled in this retrospective study. In which, there were 46 patients who received a conditioning regimen of low-dose DAC and a modified BUCY regimen(DAC group) followed by allo-HSCT, and the second cohort consisted of 110 who only received a conventional modified BUCY regimen(Con group). Comparing the baseline of two groups, there were no significant difference except there were more advanced stage patients in DAC group(63% vs 32.7%,p=0.007). A modified BUCY conditioning regimen include semustine (250 mg/m2/d) for 1 d(-10d), cytarabine (2 g/m2 q12 h) for 2 d (-9 d to -8 d), busulfan (0.8 mg/kg/6 h) for 3 d (-7 d to -5 d), and cyclophosphamide (1.8 g/m2/d) for 2 d (-4 d to -3 d). Meanwhile, patients in the DAC group received the DAC treatment for 3 to 4 d with a total of 100 mg/m2 before modified BUCY regimen. Results: In DAC group, all patients engrafted successfully, including 29/46(63%) non-remission (NR) patients. However, there were seven patients presented graft failure in Con group. The transplantation-related mortality (TRM) rate was significantly lower in DAC group(0% vs 13.6%, p=0.019). The median time of neutrophil recovery was 12(10-21)d vs 12(10-23)d, and platelet recovery was 13(10-35)d vs 14(9-40)d, respectively in DAC and Con group, and there were no significant differences. With the median follow-up of 277.5(39-985)d and 221(3-1237)d in two groups, the cumulative relapse rate(RR) was 38.2% vs 36.8% (p=0.951). The incidence rate of aGVHD was lower in DAC group(26.7% vs 46.8%, p=0.034), while there were no diference in the incidence rate of cGVHD(68.4% vs 70.7%, p=0.598). Compared with Con group, the estimated 2-year overall survival (2yr-OS) rate and 2 year disease-free survival (2yr-DFS) rate were both higher in DAC group(2yr-OS:45.6% vs 75.3%, p=0.007, Fig 1; 2yr-DFS:39.1% vs 51.5%, p=0.076). Furtheremore, for patients in advanced stage before transplant, the estimated 2yr-OS was 37.2% vs 72.7%(p=0.009) and 2yr-DFS rate was 38.5% vs 49.8%(p=0.051), respectively. For AMLs, the estimated 2yr-OS rate in DAC and Con group was 75.0% vs 43.0%(p=0.034), and for advanced stage AMLs, the estimated 2yr-OS rate was 66.1% vs 29.7%( p=0.031). Regarding the early relapse rate(RR) of 6 months post transplant, DAC group were less than that of Con group(11.5% vs 35.3%, p=0.124). Conclusion: 1. Low-dose decitabine combined with modified BUCY is a safe and effective conditioning regimen for high-risk patients with AML/MDS with low toxicity and well tolerance. 2. 100% NR patients of DAC group achieved complete remission with full donor chimerism at d30. 3.Comparing with Con group, patients in DAC group had ralative lower incidence of aGVHD, TRM and RR but relative higher estimated 2-yr OS and DFS, especially for advanced stage patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Acute graft-versus-host disease prophylaxis with methotrexate and cyclosporine after busulfan and cyclophosphamide in patients with hematologic malignancies

Blood ◽  
1993 ◽  
Vol 81 (3) ◽  
pp. 849-855 ◽  
Author(s):  
A von Bueltzingsloewen ◽  
R Belanger ◽  
C Perreault ◽  
Y Bonny ◽  
DC Roy ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Low Risk ◽  
Free Survival ◽  
Graft Versus Host ◽  
Disease Free ◽  
Acute Graft

The combination of two powerful immunosuppressive agents, methotrexate (MTX) and cyclosporine (CSP), has resulted in a significant decrease in the morbidity and mortality after allogeneic bone marrow transplantation (BMT). However, the additive toxicities from ablative preparative regimens may lead to suboptimal use of this combined immunoprophylaxis. We evaluated the efficacy and feasibility of administering MTX/CSP with busulfan (4 mg/kg/d for 4 days) and cyclophosphamide (50 mg/kg/d for 4 days) (BuCy4) in 101 consecutive patients with hematologic malignancies categorized into high- and low- risk groups receiving HLA-matched marrow grafts. Postgrafting immunosuppression consisted of MTX short course (15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and 11) and intravenous CSP (1.5 mg/kg every 12 hours). Eighty-three patients (82.1%) received 100% of MTX calculated dose and 87 (86.1%) achieved a CSP therapeutic level (250 to 600 ng/mL) within a median of 16 days. Seventy-three patients (72.2%) received optimal immunosuppressive therapy comprising a full MTX course and achieving CSP therapeutic concentrations. The Kaplan-Meier estimated incidence of grade II to IV acute graft-versus-host disease (GVHD) was 9.2% for all patients and 5.5% in patients receiving optimal GVHD prophylaxis. Eighty-nine patients (88.2%) survived > or = 100 days posttransplant and 43 (48.3%) developed chronic GVHD, the majority of which were de novo (31 of 43). The estimated incidence of relapse was 28.9% for all patients and 14.8% in the low-risk group, with a median follow-up of 24.5 months. High-risk features and the absence of chronic GVHD were significantly associated with relapse (P = .002 and .036, respectively) in multivariate analyses. Projected disease-free survival at 2 years was 52.3% for all patients and 65.2% in low-risk patients. Disease-free survival was significantly improved in optimally treated patients (P = .03) due to a lower incidence of early deaths from acute GVHD and infectious episodes. In conclusion, optimal delivery of MTX/CSP in association with BuCy4 resulted in a near complete abrogation of acute GVHD in HLA-matched transplants and a significantly improved disease-free survival.

Disease-Free Survival After Cord Blood (CB) Transplantation Is Not Different to That After Related or Unrelated Donor Transplantation in Patients with Hematologic Malignancies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2296-2296 ◽  
Author(s):  
Doris Ponce ◽  
Junting Zheng ◽  
Anne Marie Gonzales ◽  
H.R. Castro-Malaspina ◽  
Katharine C Hsu ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Lower Percentage ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Significant Difference ◽  
Disease Free

Abstract Abstract 2296 Poster Board II-273 CB transplantation (CB-T) may be curative for patients with high-risk or advanced hematologic malignancies. However, given there are no randomized trials comparing survival after CBT with the more traditional approach of matched related donor transplantation (MRD-T) or unrelated donor transplantation (URD-T), how CB-T compares to MRD-T and URD-T transplantation is not established. Therefore, we conducted a retrospective study comparing survival after CB-T (n=67) with MRD-T (n=96) and URD-T (n=163) performed 10/05-3/09 for the treatment of hematologic malignancies. Our hypothesis was that 1 year survival is comparable between hematopoietic stem cell (HSC) sources. Consecutive adult and pediatric recipients of first allograft for the treatment of acute leukemia in remission (CR1-3), myelodysplasia (MDS, ≤5% blasts at work-up), or non-Hodgkins or Hodgkin lymphoma were eligible for analysis. The median age of CB-T recipients (37 years, range &lt;1-66) was not different to that of MRD-T (46 years, range &lt;1-71) and URD-T (47 years, range 1-71) recipients (p=0.151). A lower percentage of CB-T recipients (n=36, 54%) had acute leukemia or MDS as compared to 69 (72%) MRD-T and 116 (71%) URD-T recipients (p=0.022), and a lower percentage received ablative conditioning (n=47, 70%) as compared to 81 (84%) MRD-T and 141 (87%) URD-T recipients (p&lt;0.001). While MRD grafts were HLA-identical, URD grafts were 8-10/10 HLA-allele matched (99 10/10, 47 9/10, 17 8/10). CB grafts were 4-6/6 HLA-A,-B antigen, DRB1 allele matched, with all CBT recipients receiving double unit grafts (median infused TNC larger unit 2.57 × 107/kg; smaller unit 1.93 × 107/kg) to augment engraftment. GVHD prophylaxis was calcineurin inhibitor based in 67 (100%) of CB-T but only 37 (39%) of MRD-T and 52 (32%) of URD-T recipients, with remaining patients receiving T cell depleted grafts. Median follow-up of survivors is 22 months (range 5-46) and was similar between HSC sources. We found no difference in the cumulative incidence (CI) of transplant-related mortality (TRM) at day 100 between HSC sources: 15% (95%CI: 6-24) in CB-T as compared to 7% (95%CI: 2-13) for MRD-T and 10% (95%CI: 5-14) for URD-T recipients (p=0.742). Further, there was no difference in the CI of relapse at 1 year: 19% (95%CI: 9-29) in CB-T as compared to 16% (95%CI: 9-24) for MRD-T and 16% (95%CI: 10-22) for URD-T recipients (p=0.930). Finally, by log-rank analysis there was no significant difference between HSC sources for either overall survival (p=0.778) or disease-free survival (DFS, p=0.381, Figure 1). While outcomes within subgroups could differ according to HSC source as well as donor-recipient HLA-match, recipient co-morbidities, diagnosis, disease risk, conditioning intensity, and GVHD prophylaxis, this encouraging preliminary data supports the use of double unit CB grafts as an alternative HSC source in patients lacking suitably HLA-matched peripheral blood HSC or marrow donors. Disclosures: No relevant conflicts of interest to declare.

Melphalan and purine analog–containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation

Blood ◽  
2001 ◽  
Vol 97 (3) ◽  
pp. 631-637 ◽  
Author(s):  
Sergio Giralt ◽  
Peter F. Thall ◽  
Issa Khouri ◽  
Xuemei Wang ◽  
Ira Braunschweig ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Reduced Intensity Conditioning ◽  
Free Survival ◽  
Purine Analog ◽  
First Remission ◽  
First Relapse ◽  
Disease Free ◽  
Reduced Intensity

A reduced-intensity preparative regimen consisting of melphalan and a purine analog was evaluated for allogeneic transplantation in 86 patients who had a variety of hematologic malignancies and were considered poor candidates for conventional myeloablative therapies because of age or comorbidity. Seventy-eight patients received fludarabine 25 mg/m2 daily for 5 days in combination with melphalan 180 mg/m2 (n = 66) or 140 mg/m2 (n = 12). Eight patients received cladribine 12 mg/m2 continuous infusion for 5 days with melphalan 180 mg/m2. The median age was 52 years (range, 22-70 years). Disease status at transplantation was either first remission or first chronic phase in 7 patients, untreated first relapse or subsequent remission in 16 patients, and refractory leukemia or transformed chronic myelogenous leukemia in 63 patients. Nonrelapse mortality rates on day 100 were 37.4% for the fludarabine/melphalan combination and 87.5% for the cladribine/melphalan combination. The median percentage of donor cells at 1 month in 75 patients was 100% (range, 0%-100%). The probability of grade 2-4 and 3-4 acute graft-versus-host disease was 0.49 (95% CI, 0.38-0.60) and 0.29 (95% CI, 0.18-0.41), respectively. Disease-free survival at 1 year was 57% for patients in first remission or chronic phase and 49% for patients with untreated first relapse or in a second or later remission. On multivariate analysis the strongest predictor for disease-free survival was a good or intermediate risk category. In summary, fludarabine/melphalan combinations are feasible in older patients with associated comorbidities, and long-term disease control can be achieved with reduced-intensity conditioning in this population.

scholarly journals Acute graft-versus-host disease prophylaxis with methotrexate and cyclosporine after busulfan and cyclophosphamide in patients with hematologic malignancies

Blood ◽  
1993 ◽  
Vol 81 (3) ◽  
pp. 849-855
Author(s):  
A von Bueltzingsloewen ◽  
R Belanger ◽  
C Perreault ◽  
Y Bonny ◽  
DC Roy ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Low Risk ◽  
Free Survival ◽  
Graft Versus Host ◽  
Disease Free ◽  
Acute Graft

Abstract The combination of two powerful immunosuppressive agents, methotrexate (MTX) and cyclosporine (CSP), has resulted in a significant decrease in the morbidity and mortality after allogeneic bone marrow transplantation (BMT). However, the additive toxicities from ablative preparative regimens may lead to suboptimal use of this combined immunoprophylaxis. We evaluated the efficacy and feasibility of administering MTX/CSP with busulfan (4 mg/kg/d for 4 days) and cyclophosphamide (50 mg/kg/d for 4 days) (BuCy4) in 101 consecutive patients with hematologic malignancies categorized into high- and low- risk groups receiving HLA-matched marrow grafts. Postgrafting immunosuppression consisted of MTX short course (15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and 11) and intravenous CSP (1.5 mg/kg every 12 hours). Eighty-three patients (82.1%) received 100% of MTX calculated dose and 87 (86.1%) achieved a CSP therapeutic level (250 to 600 ng/mL) within a median of 16 days. Seventy-three patients (72.2%) received optimal immunosuppressive therapy comprising a full MTX course and achieving CSP therapeutic concentrations. The Kaplan-Meier estimated incidence of grade II to IV acute graft-versus-host disease (GVHD) was 9.2% for all patients and 5.5% in patients receiving optimal GVHD prophylaxis. Eighty-nine patients (88.2%) survived > or = 100 days posttransplant and 43 (48.3%) developed chronic GVHD, the majority of which were de novo (31 of 43). The estimated incidence of relapse was 28.9% for all patients and 14.8% in the low-risk group, with a median follow-up of 24.5 months. High-risk features and the absence of chronic GVHD were significantly associated with relapse (P = .002 and .036, respectively) in multivariate analyses. Projected disease-free survival at 2 years was 52.3% for all patients and 65.2% in low-risk patients. Disease-free survival was significantly improved in optimally treated patients (P = .03) due to a lower incidence of early deaths from acute GVHD and infectious episodes. In conclusion, optimal delivery of MTX/CSP in association with BuCy4 resulted in a near complete abrogation of acute GVHD in HLA-matched transplants and a significantly improved disease-free survival.

scholarly journals A Phase II Trial of Melphalan Based Reduced Intensity Conditioning and Transplantation of Partially HLA-Mismatched Peripheral Blood Stem Cells for Patients with Hematologic Malignancies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3333-3333
Author(s):  
Melhem Solh ◽  
Scott R. Solomon ◽  
Xu Zhang ◽  
H. Kent Holland ◽  
Lawrence E Morris ◽  
...  
Keyword(s):  
Graft Failure ◽  
Phase Ii Trial ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Myeloablative Conditioning ◽  
Peripheral Blood Stem Cells ◽  
Free Survival ◽  
Blood Stem Cells ◽  
Disease Free ◽  
Very High

HLA-haploidentical (haplo) stem cell transplantation is now widely used for patients lacking a suitably matched related or unrelated donor (MUD). Conventionally, T-replete Haplo transplantation has been performed using non-myeloablative conditioning and a bone marrow graft. Subsequently, our group has developed the use of myeloablative conditioning and PBSC grafts for Haplo (Solomon et al BBMT 2015, 2019). However, some patients with hematologic malignancies who are unable to tolerate a fully myeloablative regimen may benefit from intermediate intensity conditioning. We conducted a prospective phase II trial utilizing melphalan based preparative regimen ( fludarabine 30mg/m2 days -6 to -2, melphalan 140 mg/m2 day -1) followed by infusion of unmanipulated peripheral blood stem cells (PBSCs) ,capped at 5x10 6 CD34+/kg,from a haploidentical first degree family donor. Graft-versus-host disease (GVHD) prophylaxis consisted of Cy 50mg/kg on days 3 and 4, MMF through day 35, and tacrolimus through day 180. The primary endpoint was to estimate the incidence of graft rejection following Fludarabine/Melphalan conditioning. For the graft failure endpoint we tested the hypotheses H0: p=10% versus Ha: p<10% using a one-sided exact Binomial test. Assume that none of patients undergoing the proposed regimen will have graft failure, the power for confirming p less than 15% is always 100% if the null hypothesis is rejected. The population enrolled was needed to achieve rejection of the null hypothesis at the 5% significance level. Twenty-five patients had their first allogeneic transplant on this study, and their characteristics were as follows: median age 57 years (range 35-68), male sex 44%, transplant diagnosis included AML [11], ALL [3], MDS/MPN [7], NHL [3], and multiple myeloma [1]. Using disease risk index (DRI), patients were classified as low [1], intermediate [13], or high/very high [11]. Twenty patients (80%) had a comorbidity index (HCT-CI) of ≥ 3. Median follow up for survivors was 28.3 (range 8.7-43.9) months. Post infusion fevers that subsided after receiving Cytoxan were seen in 93% and two patients had grade 2 cytokine release syndrome. Median time to ANC and platelet engraftment was 18 days (13-32) and 36 days (21-224), respectively. Three patients failed to engraft with spontaneous count recovery in one of them. Two of the three graft failures ended up engrafting after a second transplant. All engrafting patients had sustained complete donor myeloid and T cell chimerism by day 30. Acute GVHD grade II-IV and III-IV was seen in 20% and 8% respectively. The cumulative incidence of chronic GVHD was 16% (moderate-severe 12%). The estimated 2-year overall survival (OS) was 56%, disease-free survival (DFS) 44%, non-relapse mortality (NRM) 20%, relapse rate 36% and GVHD-, relapse-free survival (GRFS) 41%. For patients with high/very high DRI, the 2 year OS was 53%. For patients with HCT-CI 0-2, 2 year OS and DFS were at 75%. When compared to a contemporaneous cohort of patients receiving haplo transplant using fludarabine, Cytoxan and low dose TBI (Baltimore regimen), outcomes were not significantly different for OS, DFS, NRM and relapse. Patients receiving Flu/Mel had lower incidence of acute II-IV GVHD at 100 days (16% vs 44%). A matched pairs comparison (n=18) using matching at age range, DRI and HCT-CI between Flu/Mel and patients receiving Flu/Cy/TBI at our center, showed significant difference in OS, DFS, NRM and relapse (graph 1) between Flu/Mel and flu/Cy/TBI. All patients with primary MPD (n=4) had successful engraftment on this protocol which historically had a high graft failure rate on the non-ablative flu/Cy/TBI. Haplo transplant using fludarabine/melphalan with PBSCs is a valid option for some patients lacking a timely access to a matched donor. It is well tolerated and provides full and rapid donor myeloid and T-cell chimerism. Figure 1:Overall Survival and Disease Free Survival In Matched Cohorts of Flu/Mel versus Flu/Cy/TBI Figure 1 Disclosures No relevant conflicts of interest to declare.

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