Sirolimus, Tacrolimus and Low-Dose Methotrexate Based Graft-Versus-Host Disease (GVHD) Prophylaxis After Non-Ablative or Reduced Intensity Conditioning in Related and Unrelated Donor Allogeneic Stem Cell Transplantation: Decreased Severe Early aGVHD but Persistence of Late Acute Gvhd

Abstract Abstract 4194 Background: The morbidity and mortality associated with acute and chronic graft-versus-host disease (GVHD) remain significant after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Encouraging results have been reported with the combination of sirolimus, tacrolimus, and low-dose methotrexate after non-myeloablative allogeneic peripheral blood stem cell transplantation (PBSCT) (Alyea EP et al, Biol Blood Marrow Transplant 2008). We conducted a retrospective analysis of 74 patients with hematologic malignancies who underwent a non-myeloablative (NMA) or reduced intensity (RIC) allo-HSCT using sirolimus, tacrolimus, and low-dose methotrexate for GVHD prophylaxis. Methods: Between April 2008 and June 2011, 74 patients (M/F: 45/29), median age 51 years (range: 23–69) were transplanted for non-Hodgkin's lymphoma (63%), chronic lymphocytic leukemia/small lymphocytic lymphoma (20%), Hodgkin lymphoma (12%) and acute lymphoblastic leukemia or myelodysplasia (3%). At transplantation, 36 patients (49%) were in complete remission and 38 patients (51%) had chemotherapy sensitive active disease. Conditioning regimen was NMA in 59 patients and RIC in 15 patients. Donors were HLA-matched related (MRD, n = 30, 41%), matched unrelated (MUD, n = 37, 50%) or 9/10 HLA-mismatched unrelated (MMUD, n = 7). All patients received peripheral blood mobilized grafts. GVHD prophylaxis consisted of sirolimus and tacrolimus that were started on day -3 and doses were adjusted to maintain target serum trough levels of 3–12 ng/mL and 5–10 ng/mL, respectively, followed by methotrexate 5 mg/m2 on days +1, 3, 6. Tapering of sirolimus and tacrolimus began at day 60 in the absence of GVHD or relapse, with the goal of complete discontinuation of immunosuppressants by 6 months or earlier if patients were not in CR at transplant. Recipients of MUD (31 of 37) or MMUD (7 of 7) grafts were given 2 doses of anti-thymocyte globulin (ATG) on days −3, and −2. Forty-eight patients with CD20+ malignancies (65%) received rituximab at day -8 and +21, 28, 35, 42. Acute GVHD (aGVHD) was scored by IBMT Severity Index and chronic GVHD (cGVHD) based on NIH consensus criteria. Results: The cumulative incidence of Grade B-D and C-D classic aGVHD at day +100 were 14.9% and 2.7%, respectively. The cumulative incidence of aGVHD at 1-year was 31.1 % for grade B-D and 5.4 % for grade C-D, due to late-onset Grade B-D and Grade C-D aGVHD rates of 16.2% and 2.7%, respectively. The incidence of cGVHD at 1 and 2 years was 15% and 28%, respectively. The use of peri-transplant rituximab did not affect the incidence of Grade B-D aGVHD (p=0.55) or cGVHD (p=0.94). There was no difference in the incidence of Grade B-D aGVHD at day 100 between ATG (13.9%) and no ATG (15.8%) cohorts. There was a trend towards a modestly higher 2-year incidence of cGVHD in patients who did not receive ATG, despite the fact that these were predominantly recipients of MRD (37% vs. 21% in ATG cohort, p=0.12). Two patients (2.7%) developed thrombotic microangiopathy and 4 patients (5.4%) had renal toxicity, requiring modification of the immunosuppressant treatment. No sinusoidal obstructive sydrome was reported. To date, 15 patients have died; causes of death include disease recurrence (n=9) and GVHD (n=6). The cumulative incidence of non-relapse mortality and relapse at 1 year were 4% and 27%, respectively. The 1-year relapse rate in the ATG and no ATG cohorts was 11% and 28%, respectively (p=0.10). With a median follow up 2.6 (range: 0.8–3.9) years, progression-free and overall survival at 2 years were 64 % and 77 %, respectively. Conclusions: As previously reported this GVHD prophylaxis regimen is safe and effective, providing lower rates of acute GVHD compared to historical data. The incidence of chronic GVHD by NIH criteria was low due to an increase in late-onset acute GVHD. Rituximab therapy did not affect the incidence of acute and chronic GVHD. The addition of ATG in MUD and MMUD recipients resulted in a trend toward lower rates of chronic GVHD with no increase in the rate of relapse. Future strategies will need to focus on decreasing the incidence of late onset acute and chronic GVHD without increasing the risk of relapse. Disclosures: No relevant conflicts of interest to declare.

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Evaluation of NIH Consensus Criteria for Classification of Late Acute and Chronic Gvhd in Reduce Intensity Conditioning (RIC) Stem Cell Transplantation (SCT).

Blood ◽

10.1182/blood.v114.22.1139.1139 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1139-1139 ◽

Cited By ~ 1

Author(s):

Jifang Zhou ◽

Sylvain Thepot ◽

Aurrore Perrot ◽

Marie Robin ◽

Regis Peffault de Latour ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Late Onset ◽

Chronic Gvhd ◽

Time Dependent ◽

Increased Risk ◽

Nih Consensus Criteria

Abstract Abstract 1139 Poster Board I-161 Background Chronic graft-versus-host disease (GVHD) occurs frequently after allogeneic stem cell transplantation (SCT) and has an impact on morbidity and survival. The National Institutes of Heath (NIH) consensus criteria for the diagnosis of GVHD, emphasized clinical manifestations of GVHD rather than the classical time of onset (day 100). Incidence and impact in term of relapse and no-relapse mortality (NRM) of this new classification is not well known after RIC. Methods We retrospectively reviewed 116 consecutive patients (pts) in Saint Louis' Hospital undergoing an SCT for hematologic malignancy and surviving at least day + 100 after RIC between August 2005 and December 2008. We evaluated non-relapse mortality (NRM) and recurrent malignancy. Cumulative incidence was computed using death as a competing event. Incidence of relapse and NRM was counted from 100 days post-transplant for patients without chronic GVHD or from chronic GVHD onset. Patients with relapse/progression before chronic GVHD onset were considered as not having chronic GVHD in these analyses. The association of occurrence of chronic GVHD with the risk of relapse and non-relapse death was analyzed using time-dependent covariates in cause-specific proportional hazards models. Results Among 116 pts ( M/F: 71/45), with a median age of 53 years old (19-68 years) 28 pts (24%) were transplanted for acute leukemia in, 11 pts (9%) for chronic leukemia, 27 pts (23%) for lymphoma, 30 pts (26%) for MPD/MDS and 20 pts (17%) for plasma cell disorder. Sixty-three pts (54%) received HLA-identical sibling transplantation, 53 pts (46%) received transplantation from unrelated donors. Source of stem cells was mobilized peripheral blood stem cell for 108 pts (93%), bone marrow for 4 pts (3%) and 4 cord blood (3%). After a median follow-up of 18 months (range 5-45 months), a total of 67 pts (58%) developed chronic GVHD according to the Seattle day 100 landmark criteria and when using NIH consensus criteria, 55 pts (47%) developed chronic GVHD, including 43 pts (53%) with classic chronic GVHD and 8 pts (10%) overlap syndrome. Patients reclassified included; 3 pts with late onset acute GvHD, 19 pts had recurrent and 8 had persistent acute GVHD (numbers do not to previous sentence because some of these patients latter developed chronic GvHD). The cumulative incidence of chronic GVHD at 36 months was 64% (95%CI; 53%-73%) when using Seattle criteria compared to 56% (95%CI; 45%-67%) with NIH chronic GVHD criteria. Two-year Cumulative incidences of relapse and NRM using both classifications are summarized in Table. In Cox model with GvHD as a time dependent covariate, the NRM was significantly higher in patients with late onset, persistent and recurrent acute GVHD compared to no GVHD (hazard ratio (HR) 31, 47 and 30; p = 0.005, p <0.0001, p <0.0001, respectively), whereas the NRM was statistically increased in case of chronic GVHD using Seattle day 100 criteria (HR: 2.8; P=0.034). Conclusion The cumulative incidence of chronic GVHD “decrease” about 10% when using NIH consensus criteria compared to Seattle criteria in our cohort of RIC. Most of the NRM occurred beyond 100 days after SCT was due to the increased risk of NRM in patients with late onset, recurrent or persistent acute GVHD. Disclosures No relevant conflicts of interest to declare.

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Multicenter, Prospective Study of Tacrolimus Plus Methotrexate As Graft-Versus-Host Disease Prophylaxis in HLA-Matched Sibling Peripheral Blood Stem Cell Transplantation: Comparison with Cyclosporine Group As Control

Blood ◽

10.1182/blood.v120.21.4177.4177 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4177-4177

Author(s):

SeungHwan Shin ◽

JaeHo Yoon ◽

SeungAh Yahng ◽

SungEun Lee ◽

ByungSik Cho ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hazard Ratio ◽

Gvhd Prophylaxis ◽

Matched Sibling ◽

Grade Ii

Abstract Abstract 4177 Background Graft-versus-host disease (GVHD) is an immunologic complication after allogeneic hematopoietic stem cell transplantation (HSCT) with significant mortality and morbidities. Allogeneic peripheral blood stem cell transplantation (PBSCT) has high risk of GVHD, especially chronic GVHD compared to bone marrow transplantation. Only limited data are available comparing the efficacy of FK506 with that of cyclosporine (CsA) in human leukocyte antigen (HLA)-matched sibling PBSCT. Methods Thirty-nine patients with various hematologic disease received PBSCT with FK506+methotrexate (MTX) as GVHD prophylaxis were compared to ninety-four historical control with CsA+MTX GVHD prophylaxis. Results The 1-year cumulative incidence of grade II-IV acute GVHD was significantly lower in patients who received FK506 than those in the CsA group (10.3% vs 28.2%, p=0.036). The female donor-male recipient pair (hazard ratio; 4.828, 95% CI; 17.84-13.06, p=0.002) and CsA prophylaxis (hazard ratio; 3.279, 95% CI; 1.14–9.43, p=0.027) were significant risk factor of acute GVHD in multivariate analysis. But, there was no difference in the 3-year cumulative incidence of chronic GVHD between the FK506 and the CsA group (77.6% vs 69.6%, p=0.793). The 3-year cumulative incidence of relapse (33.9% vs 23.1%, p=0.505) and 3-year treatment-related mortality (18.9% vs 28.4%, p=0.187) of the two groups were similar. The patients in the FK506 arm had a similar event-free survival (EFS) and overall survival (OS) with patients in the CsA arm (3-year EFS; 53.2% vs 55.1%, p=0.706, 3-year OS; 60.7 vs 61.5%, p=0.610). The age over 35 years (hazard ratio; 4.12, 95% CI; 1.95–8.70, p=0.001), female donor-male recipient pair (hazard ratio; 2.66, 95% CI; 1.52–4.65, p=0.001) and advanced pre-HSCT disease status (hazard ratio; 3.13, 95% CI; 1.72–5.71, p=0.001) were significant prognostic factors associated with OS in multivariate analysis. Conclusion These results demonstrated that the FK506+MTX can significantly reduce grade II-IV acute GVHD compared to CsA+MTX in sibling PBSCT with similar incidence of chronic GVHD, and comparable outcome in EFS, OS, relapse rate and TRM rate between two groups. Disclosures: No relevant conflicts of interest to declare.

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Impact of antithymocyte globulin (ATG)-containing conditioning regimens on patients undergoing allogeneic stem cell transplantation (allo-CST) for poor risk cytogenetic IPSS myelodysplastic syndrome (PRC-MDS): A report from the French Society of Stem Cell Transplantation and Cell Therapy (SFGM-TC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.6542 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 6542-6542

Author(s):

Ibrahim Yakoub-Agha ◽

Gandhi Laurent Damaj ◽

Marie Robin ◽

Stephane Vigouroux ◽

Alice Garnier ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

French Society ◽

Poor Risk ◽

Increased Risk

6542 Background: Due to a risk of relapse of underlying disease in patients with PRC-MDS, the use of ATG, incorporated within the conditioning regimen prior to allo-SCT, is still controversial. Methods: Inclusion criteria included patients aged over 18 (n=101) who received allo-SCT transplanted between 1999 and 2009 from either a sibling (n=68) or HLA-allele-MUD (10/10) (n=33) for PRC-MDS. HLA matching was double-checked by the national Bone Marrow Donor Registry. Results: According to the FAB/WHO classification at diagnosis, 22 pts had RA/RARS/RCMD, 40 RAEB1, 30 REAB2 and 9 RAEB-t/AML. 34 pts had progressed to a more advanced disease before allo-SCT. At diagnosis, 89 patients had an IPSS int-2 or higher. At transplant, 36 pts were responders (CR, PR, CRm) and 62 with progressive disease (relapsed/refractory, untreated or stable disease without hematological improvement). Median age at transplantation was 54 years (range, 22-69). Pts received myeloablative conditioning (n=46) and nonmyeloablative (n=55). In this series, 48 patients received ATG as part of conditioning ('ATG' group), whereas 53 did not ('no-ATG’ group). As of April 1st 2011, 44 patients died of relapse and 22 of TRM. 3-year relapse, overall and event-free survival rates were not significantly different between the two groups. In contrast, the cumulative incidence of grade 2-4 acute GVHD was 48% in the no-ATG group and 30% ATG group (P <.005). Although the cumulative incidence of chronic GVHD was similar in the no-ATG and ATG groups, a trend for a lower TRM was observed in the ATG group (p=.06). In multivariate analysis, the absence of use of ATG was associated with an increased risk of acute grade 2-4 [HR = 1.92, p=.044]. Conclusions: The addition of ATG to the conditioning regimen resulted in a decreased incidence of acute GVHD without increasing relapse rates and compromising survival of patients undergoing allo-SCT for poor risk cytogenetic MDS.

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Prevention of Acute GVHD with Sirolimus Does Not Abrogate the Risk of Chronic GVHD.

Blood ◽

10.1182/blood.v104.11.3317.3317 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3317-3317

Author(s):

Corey Cutler ◽

Shuli Li ◽

Haesook T. Kim ◽

Edwin Alyea ◽

Vincent Ho ◽

...

Keyword(s):

Stem Cell ◽

Serum Level ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Peripheral Blood ◽

Acute Gvhd ◽

Tissue Injury ◽

Chronic Gvhd ◽

Effective Prevention ◽

Gvhd Prophylaxis

Abstract Chronic graft-vs.-host-disease (cGVHD) is a major cause of morbidity and mortality after allogeneic stem cell transplantation. The pathophysiology of cGVHD is poorly understood, but allogeneic T and B cells are thought to be important mediators of tissue injury. Risk factors for cGVHD include mismatched or unrelated transplantation, the use of peripheral blood stem cells, increased age and sex mismatching. Prior acute GVHD (aGVHD) is the most important risk factor and therefore strategies that reduce aGVHD are expected to reduce cGVHD as well. We have described a novel GVHD prophylaxis regimen comprised of sirolimus and tacrolimus that is effective in reducing aGVHD. Here, we report cGVHD outcomes with this novel regimen. Methods: 53 patients underwent HLA-matched sibling peripheral blood stem cell transplantation using cyclophosphamide and TBI conditioning. The GVHD prophylaxis regimen was comprised of sirolimus (target serum level 3–12 ng/ml) and tacrolimus (target serum level 5–10 ng/ml) without methotrexate. Median follow-up is 11 months from transplantation. Results: The incidence of grade II-IV aGVHD was 19%. Of the 10 patients with aGVHD, only 3 developed cGVHD. In these three patients, aGVHD had resolved entirely. In total, 21 patients developed cGVHD at a median of 231 days from transplantation, 18 of whom had no prior aGVHD. The cumulative incidence of cGVHD was 63% when relapse and death were considered as competing risks. At the time of cGVHD diagnosis, 10 patients were off all immunosuppressive medications, 6 patients were on sirolimus, either alone(2) or in combination with tacrolimus(4). 3 patients were on tacrolimus, either alone (2) or with prednisone(1), 1 patient was on prednisone alone and information was unavailable for 1 patient. cGVHD end-organ involvement included liver(13), skin(12), oral mucosa(12), eye(6), musculoskeletal(5), hematologic(1), lung(1) and serosa(1). 3 patients had isolated, limited hepatic cGVHD. Therapy included the re-institution of prednisone alone(5) or with mycophenolate(6), sirolimus(4), tacrolimus(2), rituximab(1) or multiple agents(1). One patient began on mycophenolate alone and 1 patient required no therapy. 4 patients had a complete response to immunosuppressive therapy. Only 1 patient died after the diagnosis of cGVHD while still on immunosuppression. No patient with cGVHD had malignant disease relapse. Conclusions: Despite effective prevention of aGVHD with sirolimus and tacrolimus, cGVHD was not prevented in this patient cohort. This argues that the pathophysiologic mechanisms involved in tissue injury in aGVHD and cGVHD may be different, or that methotrexate may be important in the prevention of cGVHD. Since the development of antibodies directed against minor histocompatibility antigens has been correlated with the development of cGVHD, novel strategies designed to interfere with B cell immunity after transplantation may be required to prevent cGVHD.

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Repetitively Administered Low-Dose Donor Lymphocyte Infusion for Prevention of Relapse after Allogeneic Stem Cell Transplantation in Patients with High-Risk Acute Leukemia

Cancers ◽

10.3390/cancers13112699 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2699

Author(s):

Panagiotis Tsirigotis ◽

Konstantinos Gkirkas ◽

Vassiliki Kitsiou ◽

Spiros Chondropoulos ◽

Theofilos Athanassiades ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Acute Leukemia ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Cumulative Incidence ◽

Low Dose ◽

Acute Gvhd ◽

Donor Lymphocyte Infusion

Background: Patients with high-risk acute leukemia have a high risk of relapse after allogeneic stem cell transplantation (allo-SCT). In an effort to reduce the relapse rate, various therapeutic methods have been implemented into clinical practice. Among them, prophylactic donor lymphocyte infusion (pro-DLI) has shown significant efficacy. However, the widespread application of pro-DLI has been restricted mostly due to concerns regarding the development of graft versus host disease (GVHD). In the present study, we tested the safety and efficacy of a novel method of prophylactic-DLI based by repetitive administration of low lymphocyte doses. Methods: DLI was administered to patients with high-risk acute leukemia at a dose of 2 × 106/kg CD3-positive cells. DLI at the same dose was repeated every two months for at least 36 months post-allo-SCT, or until relapse or any clinical or laboratory feature suggested GVHD, whichever occurred first. Forty-four patients with a median age of 53 years (range 20–67) who underwent allo-SCT between 2011 and 2020 were included in our study. Thirty-three patients with high-risk acute myeloid leukemia (AML) and 11 with high-risk acute lymphoblastic leukemia (ALL) after allo-SCT from a matched sibling (MSD, no = 38 pts) or a matched-unrelated donor (MUD, no = 6 pts) received pro-DLI. Twenty-three patients were in CR1, all with unfavorable genetic features; 12 patients were in CR2 or beyond; and 9 patients had refractory disease at the time of transplant. Ten out of 23 patients in CR1 had detectable minimal residual disease (MRD) at the time of allo-SCT. Disease risk index (DRI) was high and intermediate in 21 and 23 patients, respectively. Conditioning was myeloablative (MAC) in 36 and reduced intensity (RIC) in 8 patients, while GVHD prophylaxis consisted of cyclosporine-A in combination with low-dose alemtuzumab in 39 patients or with low-dose MTX in 5 patients, respectively. Results: Thirty-five patients completed the scheduled treatment and received a median of 8 DLI doses (range 1–35). Fifteen out of 35 patients received all planned doses, while DLI was discontinued in 20 patients. Reasons for discontinuation included GVHD development in nine, donor unavailability in seven, disease relapse in three, and secondary malignancy in one patient, respectively. Nine patients were still on treatment with DLI, and they received a median of four (range 2–12) doses. Fourteen percent of patients developed transient grade-II acute GVHD while 12% developed chronic GVHD post-DLI administration. Acute GVHD was managed successfully with short course steroids, and four out of five patients with cGVHD were disease-free and off immunosuppression. With a median follow-up of 44 months (range 8–120), relapse-free (RFS) and overall survival (OS) were 74%, (95% CI, 54–87%) and 78%, (95% CI, 58–89%) respectively, while the cumulative incidence of non-relapse mortality (NRM) was 13% (95% CI, 4–28%). The cumulative incidence of relapse in patients with intermediate and high DRI is 7% and 15%, respectively. Conclusion: Prolonged—up to three years—low-dose pro-DLI administered every two months is safe and effective in reducing relapse rate in patients with high-risk acute leukemia. The low-dose repetitive administration DLI strategy reduced the risk of DLI-mediated GVHD, while the prolonged repeated administration helped in preventing relapse, possibly by inducing a sustained and prolonged immunological pressure on residual leukemic cells. This novel strategy deserves testing in larger cohort of patients with high-risk acute leukemia.

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Calcineurin Inhibitor-Free GVHD Prophylaxis with Post-Transplant Cyclophosphamide and Brief-Course Sirolimus Results in Low Rates of Non-Relapse Mortality and Chronic GVHD Following Matched Related and Unrelated Donor Peripheral Blood Stem Cell Transplantation (PBSCT)

Blood ◽

10.1182/blood.v122.21.923.923 ◽

2013 ◽

Vol 122 (21) ◽

pp. 923-923

Author(s):

Melissa Sanacore ◽

Asad Bashey ◽

Connie A. Sizemore ◽

H. Kent Holland ◽

Lawrence E. Morris ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Platelet Recovery ◽

Post Transplant ◽

Gvhd Prophylaxis ◽

Allogeneic Pbsct

Abstract Calcineurin inhibitors (CNIs) form the foundation of current GVHD prophylaxis regimens. Although advances in immunosuppressive regimens have had a significant impact on the incidence and severity of acute GVHD, it is noteworthy that CNIs have had little impact on chronic GVHD. We hypothesized that a CNI-free regimen consisting of post-transplant cyclophosphamide (Cy) and brief-course sirolimus would decrease the risk of chronic GVHD and non-relapse mortality and improve outcomes following reduced intensity allogeneic PBSCT. Twenty-seven patients with high risk hematologic malignancies were enrolled in the study: median age 61 years (25-73). All patients had a 10/10 locus matched donor; MRD=18, MUD=9. Conditioning consisted of fludarabine 30mg/m2 on days -9 to -6, IV busulfan 130 mg/m2 on days -5 to -4, and Cy 14.5 mg/kg on days -3 and -2 followed by unmanipulated PBSCT. Post-grafting immunosuppression consisted of Cy 50 mg/kg/day on days 3 and 4 and sirolimus starting day +5 and completing day+90 in the absence of GVHD. Donor engraftment occurred in all patients with a median time to neutrophil and platelet recovery of 15 and 30 days, respectively. The median day +90 donor T cell and myeloid chimerism was 94% (40-100%) and 100% (11-100%) respectively. Three patients received donor lymphocyte infusions for incomplete donor T cell chimerism. The cumulative incidence of grade II-IV acute GVHD, grade III-IV acute GVHD, all chronic GVHD, and severe chronic GVHD was 41%, 15%, and 32%, and 12% respectively. Non-relapse mortality (NRM) and relapse incidence at 2 years was 4% and 17% respectively. With a median follow-up of 18 months, the estimated 2 year overall and disease-free survival was 71% and 80% respectively for the whole cohort, while it was 87% and 89%, respectively in the subgroup of 18 patients receiving MRD transplants. Good immune reconstitution was evidenced by low cytomegalovirus reactivation rates, occurring in only 4 of 19 at-risk patients (21%). Transplant-related toxicity included BK virus-associated cystitis in 33% of patients and a non-fatal hepatotoxicity syndrome in three patients consisting of transaminase elevation and ascites, with resolution following discontinuation of sirolimus. CNI-free GVHD prophylaxis with post-transplant Cy and brief-course sirolimus achieves consistent donor engraftment, low rates of GVHD and NRM, and excellent outcomes in recipients of HLA-identical donor allogeneic PBSCT. Disclosures: Off Label Use:fludarabine, cyclophosphamide, and sirolimus are not FDA-labeled for stem cell transplantation.

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Chronic graft-versus-host disease after allogeneic blood stem cell transplantation

Blood ◽

10.1182/blood.v98.6.1695 ◽

2001 ◽

Vol 98 (6) ◽

pp. 1695-1700 ◽

Cited By ~ 165

Author(s):

Donna Przepiorka ◽

Paolo Anderlini ◽

Rima Saliba ◽

Karen Cleary ◽

Rakesh Mehra ◽

...

Keyword(s):

Risk Factors ◽

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Blood Stem Cell ◽

Gvhd Prophylaxis ◽

Blood Stem Cell Transplantation

Abstract The incidence, characteristics, risk factors for, and impact of chronic graft-vs-host disease (GVHD) were evaluated in a consecutive series of 116 evaluable HLA-identical blood stem cell transplant recipients. Minimum follow-up was 18 months. Limited chronic GVHD occurred in 6% (95% confidence interval [CI], 0%-13%), and clinical extensive chronic GVHD in 71% (95% CI, 61%-80%). The cumulative incidence was 57% (95% CI, 48%-66%). In univariate analyses, GVHD prophylaxis other than tacrolimus and methotrexate, prior grades 2 to 4 acute GVHD, use of corticosteroids on day 100, and total nucleated cell dose were significant risk factors for clinical extensive chronic GVHD. On multivariate analysis, GVHD prophylaxis with tacrolimus and methotrexate was associated with a reduced risk of chronic GVHD (hazard ratio [HR], 0.35; P = .001), whereas the risk was increased with prior acute GVHD (HR, 1.67;P = .046). When adjusted for disease status at the time of transplantation, high-risk chronic GVHD had an adverse impact on overall mortality (HR, 6.6; P < .001) and treatment failure (HR, 5.2; P < .001) at 18 months. It was concluded that there is a substantial rate of chronic GVHD after HLA-identical allogeneic blood stem cell transplantation, that clinical factors may alter the risk of chronic GVHD, and that high-risk chronic GVHD adversely affects outcome.

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Reduced risk of chronic GVHD by low-dose rATG in adult matched sibling donor peripheral blood stem cell transplantation for hematologic malignancies

Annals of Hematology ◽

10.1007/s00277-019-03884-8 ◽

2019 ◽

Vol 99 (1) ◽

pp. 167-179 ◽

Cited By ~ 1

Author(s):

Liping Dou ◽

Cheng Hou ◽

Chao Ma ◽

Fei Li ◽

Xiaoning Gao ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cumulative Incidence ◽

Low Dose ◽

Peripheral Blood Stem Cell ◽

Chronic Gvhd ◽

Free Survival ◽

Gvhd Prophylaxis ◽

Matched Sibling ◽

Blood Stem Cell Transplantation

AbstractThe optimal rabbit anti-thymocyte globulin (rATG) graft-versus-host disease (GVHD) prophylaxis regimen in matched sibling donor peripheral blood stem cell transplantation (MSD-PBSCT) remains to be elucidated. In this prospective study, we used low-dose rATG for GVHD prophylaxis in patients or donors aged ≥ 40 years with hematological malignancies receiving MSD-PBSCT. rATG was administered to 40 patients at an intravenous dose of 5 mg/kg divided over day 5 and day 4 before graft infusion. No graft failure occurred. Median times to leukocyte engraftment and platelet engraftment were 11.0 days and 13.9 days. The cumulative incidence of grades 2–4 and grades 3–4 acute GVHD at day +100 was 30.0% and 2.6%. The 2-year cumulative incidence of extensive chronic GVHD and severe chronic GVHD was 11.4% and 14.7%. 93.5% (29/31) of patients had discontinued immunosuppressive medication within 3 years after transplantation. The 2-year cumulative incidence of transplant-related mortality (TRM) and relapse was 14.0% and 22.6%. The cumulative incidence of cytomegalovirus reactivation, Epstein–Barr virus reactivation, and fungal infection was 22.3%, 12.9%, and 12.5%. Kaplan–Meier estimates for overall survival, disease-free survival, and GVHD-free and relapse-free survival 3 years after transplantation were 68.9%, 68.9%, and 54.0%. rATG for GVHD prophylaxis is tolerable and efficacious at a 5 mg/kg total dose administered over 2 days (days −5 to −4) in patients receiving allogeneic MSD-PBSCT.

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Low Dose Alemtuzumab (Campath 1H) Prior to Allogeneic Stem Cell Transplantation Is Associated with Low Incidence of Acute and Chronic GVHD but Protracted Immune Recovery.

Blood ◽

10.1182/blood.v106.11.5376.5376 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5376-5376

Author(s):

Marcel P. Devetten ◽

Fausto Loberiza ◽

Robin Weisenborn ◽

Pam Bunner ◽

Jamie Brewer ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Cumulative Incidence ◽

Low Dose ◽

Chronic Gvhd ◽

High Dose ◽

Low Incidence ◽

Cmv Reactivation

Abstract Background: The administration of alemtuzumab (Campath 1H) as part of the conditioning regimen prior to allogeneic stem cell transplantation has been associated with a low incidence of acute and chronic GVHD. Initial studies employing doses of 100 mg have reported a high incidence of viral infections. Lower alemtuzumab doses combined with standard GVHD prophylaxis regimens (calcineurin inhibitor + MTX) have also resulted in a low incidence of acute GVHD in patients with CD52-positive malignancies. We investigated the effect of low-dose (40 mg) alemtuzumab on engraftment (VNTR chimerism studies), the incidence of acute and chronic GVHD, CMV reactivation, survival, and immune reconstitution (examined by TREC content at various time points after transplant). Patient and Transplant characteristics: Twenty-seven patients underwent a matched (n=24) or 1-antigen mismatched (n=3) related (n=13) or unrelated (n=14) allogeneic stem cell transplantation for various hematologic malignancies. Median age was 41 years (19–59). Disease stage at transplant was early for 48%, intermediate for 11% and late for 41%. Three patients received bone marrow and 24 received PBSC grafts. Conditioning regimen consisted of TBI 10 Gy with partial lung shielding, Thiotepa 500 mg/m2, and Alemtuzumab 20 mg IV on day -4 and day -1. GVHD prophylaxis was with cyclosporine (n=13) or tacrolimus (n=14) and full-dose MTX. High-dose viral prophylaxis with valacyclovir 2000 mg QID was given to all recipients from a CMV seropositive recipient/donor pair starting at patient #9, due to a high incidence of CMV reactivation amongst the first 8 patients. Three patients received DLI for disease relapse. Median follow-up for survivors is 13 months (6–26). Results: Of eighteen evaluable patients (3 relapsed, 5 expired, 1 not done) at day 100, 15 had ≥ 95% donor chimerism, and 3 had 90–94% donor chimerism. The cumulative incidence of acute GVHD grade II-IV at day 100 was 4% (95% CI 1–16%), and the cumulative incidence of chronic GVHD at 1 year was 31% (12–52%). Cumulative incidence of non-relapse mortality at day 100 was 18% (7–35%), and at 1 year 31% (14–49%). Cumulative incidence of relapse at 1 year was 28%, resulting in a projected 1-year disease-free survival of 41% (22–60%), and overall survival of 54% (33–71%). Amongst the first eight patients, all (5/5) at-risk recipients developed CMV reactivation. After initiation of prophylaxis with high-dose valacyclovir, 4/11 at-risk recipients developed CMV reactivation. No patient died from CMV disease. TREC analysis in a limited number of patients showed rapid increase in TREC between day 0 and day 180, but no further increment between day 180 and day 365. Conclusions: The use of low-dose alemtuzumab results in low incidences of acute and chronic GVHD. CMV reactivation is common, and can be partially prevented by use of high-dose valacyclovir. Immune reconstitution data on a small subset of patients show limited output of thymic emigrant T cells after 6 months.

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The Addition Of Sirolimus To The Gvhd Prophylaxis Regimen In Reduced Intensity Allogeneic Stem Cell Transplantation For Lymphoma: A Multicenter Randomized Trial

Blood ◽

10.1182/blood.v122.21.704.704 ◽

2013 ◽

Vol 122 (21) ◽

pp. 704-704 ◽

Cited By ~ 2

Author(s):

Philippe Armand ◽

Haesook T Kim ◽

Marie-Michele Sainvil ◽

Veronika Bachanova ◽

Steven M. Devine ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Gvhd Prophylaxis ◽

Significant Difference ◽

Reduced Intensity

Abstract The mTOR inhibitor sirolimus has been used in the prevention and treatment of GVHD after allogeneic hematopoietic stem cell transplantation (HSCT). In parallel, mTOR inhibitors have demonstrated clinical activity against various lymphoma histologies. In a retrospective study, we found that patients with lymphoma undergoing reduced intensity conditioning (RIC) HSCT who received a sirolimus-containing GVHD prophylaxis regimen had a lower rate of relapse (Armand et al, J Clin Oncol. 2008;26(35):5767). We therefore performed a multicenter, phase III, open label randomized trial comparing tacrolimus, sirolimus and methotrexate (Tac/Sir/Mtx, with sirolimus starting on day -3 of HSCT) for GVHD prophylaxis to conventional sirolimus-free regimens (tacrolimus + methotrexate (Tac/Mtx) or cyclosporine + MMF (Csa/MMF), pre-specified by center), in patients undergoing RIC HSCT for any lymphoma except Burkitt lymphoma. The primary endpoint was 2-year overall survival (OS); progression-free survival (PFS), acute and chronic GVHD were among the secondary endpoints. 139 patients were enrolled at five institutions between June 2009 and September 2012. The median age was 57 years (range, 23-70). 42 patients had aggressive B-NHL, 31 indolent B-NHL, 28 CLL, 19 T-NHL and 19 Hodgkin lymphoma. 66 were assigned to the Tac/Sir/Mtx arm, and 73 to the control arm (67 to Tac/Mtx and 7 to Csa/MMF). All patients but 1 received the allocated intervention, and all received peripheral blood stem cell products, as mandated by the protocol. Based on a planned interim analysis, the DSMB recommended reporting of the interim results at this time. Median follow-up for survivors is 22 months, and only 12% of living patients have less than 12 months of follow-up. There was no evidence of increased toxicity in the Tac/Sir/Mtx arm. At the time of this analysis, the Kaplan-Meier estimate of 2-year OS by intent to treat (Figure 1A) is 66% (95CI, 51-77) in the Tac/Sir/Mtx arm vs. 71% (95CI, 58-81) in the control arm (p=0.7); the corresponding 2-y PFS (Figure 1B) is 62% (95CI, 48-73) vs. 56% (95CI, 43-68) (p=0.9). The conditional power for finding a significant difference in the primary endpoint of 2y OS is <1%, prompting the current report. There was no significant difference in non-relapse mortality (2y cumulative incidence 14% in both groups, p=0.9) or cumulative incidence of relapse (2y incidence 25% vs. 30%, p=0.8). However, the addition of sirolimus resulted in a significant decrease in the cumulative incidence of grade 2-4 acute GVHD (6-month cumulative incidence 9% vs. 25%, p=0.014; Figure 1C), even after excluding patients who received Csa/MMF. This was apparent in both patients receiving matched related and those receiving matched unrelated grafts. There was no significant difference in the incidence of grade 3-4 acute GVHD (3% vs. 4% at 6 months, p=0.7) or chronic GVHD (2-year cumulative incidence 59% vs. 55%, p=0.5; Figure 1D).Figure 1Figure 1. In conclusion, the addition of sirolimus to the GVHD prophylaxis regimen in patients with lymphoma undergoing RIC HSCT is associated with a significant decrease in grade 2-4 acute GVHD after transplantation, without impacting toxicity, severe acute GVHD, chronic GVHD, progression-free or overall survival. These results should be broadly applicable to all recipients of RIC HSCT using T-cell-replete peripheral blood stem cells, and suggest that tacrolimus, sirolimus and methotrexate could be a preferred regimen in this patient population. Pre-specified subgroup analyses by histology and correlative studies will be performed when follow-up is complete in late 2014. Disclosures: Off Label Use: Sirolimus, tacrolimus, methotrexate, cyclosporin, mycophenolate for GVHD prophylaxis.

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