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 ◽  
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.

Comparison between Anti-Thymocyte Globulin and Alemtuzumab and the Possible Impact of KIR-Ligand Mismatch in Melphalan/Fludarabine Dose-Reduced Conditioning Followed by HLA-Matched and Mismatched Unrelated Stem Cell Transplantation in Patients with Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 980-980
Author(s):  
Nicolaus Kroeger ◽  
Brownen Shaw ◽  
Simona Iacobelli ◽  
Tatjana Zabelina ◽  
Karl Peggs ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Statistical Significance ◽  
High Dose ◽  
Grade Ii

Abstract We compared anti-thymocyte globulin (ATG-Fresenius median dose 60 mg/kg: n= 48) with alemtuzumab (Campath-1H 100mg: n=25) in 73 patients with multiple myeloma, who underwent dose-reduced conditioning with melphalan and fludarabine, followed by allogeneic stem cell transplantation from matched (n=63) or mismatched (n=10) unrelated donors. Patients of the ATG group had higher age (median 50 vs 47 years, p=0.05), more prior high-dose chemotherapies (p<0.001), while in the Campath group more bone marrow as stem cell source was used (p<0.001). No primary graft failure occurred in both groups. Patients receiving alemtuzumab had a significant faster engraftment of leukocyte (p=0.03) and of platelets (p=0.02) and a lower incidence of acute GvHD grade II-IV (24 vs 47%, p=0.05). However, after treatment with donor lymphocyte infusion due to persistent disease or mixed hematopoietic chimerism the difference of acute GvHD grade II-IV between alemtuzumab and ATG treated patients did not reach statistical significance (32 vs 47%, p=0.2). No difference in incidence of chronic GvHD was observed (25 vs 33%, p=0.6) More CMV seropositive patients in the alemtuzumab group experienced CMV reactivation (100% vs 47%, p=0.001). The cumulative incidence of treatment related mortality at 2 years for ATG and Campath was 29.3% (CI=17–50%) vs 28.5% (CI=15–54%), p=0.7. No significant difference could be observed in the estimated 2 years OS and PFS between ATG and Campath: 53% (CI:38–75) vs 45% (CI:28–73) and 29% (CI:16–54) and 36% (CI: 20–62), respectively. For PFS, in a multivariate analysis relapse to prior high-dose chemotherapy was the strongest negative factor: HR 2.9, p= 0.001. Including only those patients who did not experienced any relapse at time of allogeneic stem cell transplantation the Campath-group had a 2.5 fold higher risk of progression in comparison to the ATG group, but without reaching statistical significance (HR: 2.5, p=0.15). Ten out of 73 patients had KIR-ligand mismatch in GvH direction. While in patients without KIR-ligand mismatch the cumulative incidence of relapse at two years was 50%, none of the KIR-ligand mismatched patients relapsed so far (p=0.02). The immunosuppressive effect from Campath is stronger than ATG resulting in less acute GvHD, but requires more DLI procedures to control diseases and resulted in a trend to a lower PFS in chemosensitive patients. This preliminary data further implicated a major role of KIR-ligand mismatch transplantation in multiple myeloma

High-Dose Rituximab in the Conditioning Regimen Before Allogeneic Stem Cell Transplantation Reduces the Incidence of Acute Gvhd in B-Cell Lymphomas

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4546-4546
Author(s):  
Paolo Corradini ◽  
Barbara Sarina ◽  
Cristiana Carniti ◽  
Francesca Patriarca ◽  
Angelo Michele Carella ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
B Cell ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Immune Reconstitution ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
High Dose ◽  
Unrelated Donors

Abstract Abstract 4546 Background: Reduced-intensity conditioning (RIC) followed by allogeneic stem cell transplantation (alloSCT) is an effective salvage therapy for relapsed lymphomas. The present GITMO study is a prospective multicenter phase II trial for patients affected by relapsed CD20 positive lymphomas. Compared with the previous thiotepa/fludarabine/cyclophosphamide GITMO protocol (Leukemia 2007), the thiotepa dose is increased, and high-dose Rituximab is included in the regimen to improve the outcome and possibly modulate the incidence of acute GVHD. Aims: Primary end-point was 1-year progression-free survival; secondary endpoints were non-relapse mortality and incidence of acute and chronic GVHD. Methods: Fifty-seven patients (pts) were enrolled so far in the study and 49 are evaluable for analysis. Treatment plan consisted of high-dose R (500 mg/ms on day -6) followed by thiotepa (12 mg/kg), fludarabine (60 mg/kg) and cyclophosphamide (60 mg/kg). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine and mini-methotrexate; ATG (7.5 mk/kg) was only added for pts allografted from one antigen mismatched sibling or unrelated donors. Histopathological subtypes included 24 aggressive (HG) (n= 17 diffuse large B-cell lymphomas, n= 7 mantle cell lymphomas) and 25 indolent lymphomas (LG) (n= 13 follicular lymphomas, n= 12 small lymphocytic/chronic lymphocytic leukemia). Patients were allografted from related siblings (SIB) (n= 32 matched, n=1 one single mismatched) or unrelated donors (UD) (n=11 matched, n=5 mismatched). All the pts had chemosensitive disease (n=20, 41% in complete remission) and 26 (53%) came from a failed autoSCT. Results: At a median follow-up of 13 months (range, 5–44 months), 36 pts are alive [n=27 (75%) in CR] and 13 died from any cause [n=6 for non-relapse mortality (NRM), n=7 for disease progression]. All the patients engrafted (94% had full donor chimerism at 3 months). The cumulative incidence (CI) of NRM was 13% at 1 year: 9% vs 19% for SIB and MUD (p=0.3), and 9% versus 16% for for LG and HG (p=0.3), respectively. In total only 11 of 49 pts had acute GVHD (n=8 grade II, n=3 grade III) with an estimated CI of 21% at 100 days. In the previous GITMO study the incidence was 35% with SIB only. Forty pts are evaluable for chronic GVHD with an estimated CI of 41% and 47% at 1 and 2 year, respectively (n=11 limited, n=3 extensive). Infections after engraftment requiring hospitalization or intravenous treatment were evaluable in 46 pts (n=3 excluded for early death). The overall incidence of infections was 58% (n=27) including 5 pts experienced sepsis and 10 pts pneumonia. Preliminary data on immune-reconstitution at 1 year showed: 1) low number of circulating B cells (median CD19+/ul: 129/ul) with an expansion of naive cells (IgD+, CD27-); 2) the median value of IgM was 89 mg/dl whereas IgG and IgA remained at low levels. The CI of relapse was 26% and 37% at 1 year and 2 years, respectively. In the indolent and aggressive groups, OS estimates at 2 years were 79% (95%CI, 52%-91%) and 61% (95 CI, 38%-77%) and PFS estimates were 53% (95%CI, 23%-76%) and 48% (95% CI, 27%-66%), respectively. Conclusions: The present data suggest that the administration of high-dose R is feasible and causes an unexpected reduction of the incidence of acute GVHD without increasing the NRM and the incidence of severe infections complications. Complete data evaluating the effects of R on immune reconstitution are ongoing. Disclosures: No relevant conflicts of interest to declare.

Allogeneic Stem Cell Transplantation For Patients With Adrenoleukodystrophy. Nationwide Retrospective Study In Japan

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2148-2148
Author(s):  
Koji Kato ◽  
Hiromasa Yabe ◽  
Shunichi Kato ◽  
Souichi Adachi ◽  
Yoshiko Hashii ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cord Blood ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Low Dose ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Transplant Outcome

Abstract Introduction Adrenoleukodystrophy (ALD) is an autosomal recessive disorder with progressive neurodegeneration caused by the mutation of ABCD1 gene and allogeneic stem cell transplantation (SCT) at its early stage is recognized as the only effective treatment modality to control the neurological symptoms. But the transplant outcome according to the conditioning regimen is not well understood so far. Here we analyzed the transplant outcome of patients with ALD using the clinical data accumulated in the Japan Society of Hematopoietic Cell Transplantation and tried to find the favorable conditioning regimen. Methods From 1988 to 2010, 76 patients with ALD were transplanted and their age at transplant was 1-34 years old (median 8). Stem cell sources the patients received were bone marrow (sibling 26, non-sibling related donor 5, unrelated volunteer donor 17), and cord blood (sibling 1, unrelated 28). Conditioning regimen was classified into four categories of A: busulfan + cyclophosphamide +/- others, (n=25), B: melphalan + total lymphoid irradiation (TLI) / thoraco-abdominal irradiation (TAI) +/- fludarabine +/- anti-thymocyte globulin (n=23), C: fludarabine + melphalan +low dose total body irradiation (TBI) (n=18), and D: others (n=10). Results Sustained engraftment was obtained in 59 patients (77.8%) and it was significantly higher in bone marrow transplant (BMT) patients than cord blood transplant (CBT) patients (87.8% vs 60.7%, P=0.001). The incidence of acute graft-versus-host disease (GVHD), chronic GVHD and treatment related mortality of all patients were 7.9%, 19.3%, and 11.9%, respectively. Ten year overall survival (OS) and event free survival (EFS) of all patients were 83.7% and 64.1%, respectively. Ten patients died of either disease progression (n=2), or transplant related complications (n=8). Five year OS and EFS according to the conditioning regimen was A: 91.6% and 75.8%, B: 85.7% and 60.9%, C: 100% and 83.3%, D: 77.8% and 48.0%, respectively and they were not significant (P=0.379 in OS and P=0.183 in EFS, respectively). TBI was given to 22 patients with median dose of 4Gy (range 2-10.2) and sustained engraftment was obtained in 19 patients and all of 22 patients are alive. In patients who were not given TBI (n=54), 41 patients obtained engraftment and 44 patients are alive. OS according to presence or absence of TBI was 100% with TBI (n=22) and 86.1% without TBI (n=54) (P=0.091). By multivariate analysis for EFS, BMT and TBI were identified as good prognostic factors compared to CBT or non-TBI (HR 3.303, P=0.005, and HR 3.257, P=0.038, respectively), but OS of CBT was improved after 2005 compared to before 2004 (94.7% vs 68.6%, P=0.090). Conclusion Our results showed that conditioning regimen which includes TBI, even at low dose could provide better transplant outcome and the result of CBT improved after 2005 even though it was proved to be a significantly poor risk factor in the analysis of entire cohort. CBT enables urgent SCT when family donor is not available, and immediate transplant is essential for patients with ALD because of its nature. More precise assessment with brain MRI and neuropsychological examination is mandatory to evaluate the transplant outcomes of patients with ALD. Disclosures: No relevant conflicts of interest to declare.

Hyperlipidemia After Allogeneic Stem Cell Transplantation: Prevalence, Risk Factors and Impact on Prognosis.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3458-3458
Author(s):  
Yuki Kagoya ◽  
Sachiko Seo ◽  
Yasuhito Nannya ◽  
Mineo Kurokawa
Keyword(s):  
Risk Factors ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Relapse Rate ◽  
Allogeneic Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Calcineurin Inhibitors

Abstract Abstract 3458 Introduction: Hyperlipidemia is one of the late complications after allogeneic stem cell transplantation (SCT). Although intrahepatic cholestasis caused by chronic graft-versus host disease (GVHD) or calcineurin inhibitors has been considered to be one of the etiologies, its prevalence, risk factors, and the impact on prognosis have not been investigated well. Methods: We performed a retrospective analysis of 194 adult patients who underwent allogeneic SCT between 1995 and 2008 in our institute, and survived more than 100 days after SCT. Hypercholesterolemia or hypertriglyceridemia was defined as more than 240 mg/dl or 200 mg/dl, respectively, at two successive tests at least one week apart after the first 100 days after SCT. Cumulative incidence of hypercholesterolemia or hypertriglyceridemia was analyzed. The time to the development of hypercholesterolemia or hypertriglyceridemia was calculated and the multivariate analysis of pre- and posttransplant variables was performed by a Cox proportional hazards model. Chonic GVHD, chronic liver dysfunction (CLD; defined as more than twice the upper limit of normal for aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase, or total bilirubin >3 mg/dl over 3 months) and administration of calcineurin inhibitors were studied as posttransplant factors, which were assessed as time-dependent variables. To analyze the prognosis of patients who developed persistent hyperlipidemia, the multivariate analysis of overall survival (OS), relapse rate, and non-relapse mortality (NRM) was carried out by a landmark approach. Persistent hyperlipidemia was defined as hypercholesterolemia or hypertriglyceridemia continuing more than 3 months. Results: Overall, 83 (42.8%) and 98 (50.5%) patients developed hypercholesterolemia and hypertriglyceridemia, respectively. The median follow-up period of serum cholesterol and triglyceride values in surviving patients was 44 months. The cumulative incidence of each abnormality at 3 years after SCT was 38.1% (95% confidence interval [CI]: 31.0–45.1%), and 46.0% (95% CI: 38.8–52.9%), respectively. In a multivariate analysis, the development of chronic GVHD was independently associated with both hypercholesterolemia (hazard ratio [HR] 2.05, 95% CI: 1.23–3.43, P<0.01) and hypertriglyceridemia (HR 2.04, 95% CI: 1.30–3.18, P<0.01). Besides, CLD was significantly associated with hypercholesterolemia (HR 2.20, 95% CI: 1.39–2.50, P<0.01). Administration of calcineurin inhibitors was not an independent risk factor for the development of hypercholesterolemia (HR 1.23, 95% CI: 0.73–2.08, P=0.43) or hypertriglyceridemia (HR 1.03, 95% CI: 0.61–1.54, P=0.89). Among pretransplant factors, prior hypercholesterolemia and hypertriglyceridemia were associated with posttransplant hypercholesterolemia (HR 2.76, 95% CI: 1.07–7.17, P=0.04) and hypertriglyceridemia (HR 2.04, 95% CI: 1.27–3.27, P<0.01), respectively. Persistent hyperlipidemia was found in 49 patients (25.3%), of which 35 patients (71.4%) developed hyperlipidemia within one year. The median interval to the occurrence of hyperlipidemia of the patients was 180 days after SCT. In univariate analysis, patients with persistent hyperlipidemia had a tendency of better 3-year OS (77.3% vs 64.7%, P=0.23). Multivariate analysis showed that the development of persistent hyperlipidemia was independently associated with better OS (HR: 0.49, P=0.049). Further, although not statistically significant, patients with persistent hyperlipidemia had a tendency of lower 3-year cumulative relapse rate (15.7% vs 20.3%). There were no significant differences in 3-year NRM between patients with or without hyperlipidemia (12.3% vs 13.9%). Conclusions: Both hypercholesterolemia and hypertriglyceridemia are very common complications after SCT. Patients with persistent hyperlipidemia, however, have significantly better OS. Considering a strong association between the development of hyperlipidemia and chronic GVHD, and a tendency of lower relapse rate in patients with persistent hyperlipidemia, hyperlipidemia is regarded as one of the symptoms accompanied with chronic GVHD. Unless severe, its incidence indicates a better control of the primary disease and an improved prognosis. Disclosures: No relevant conflicts of interest to declare.

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

Cancers ◽  
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.

Reduced-Intensity Regimens for Allogeneic Stem Cell Transplantation Improve the Outcome in Advanced Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3298-3298
Author(s):  
Suzanne M. Cole ◽  
Rima Saliba ◽  
Matteo Pelosini ◽  
Floralyn L Mendoza ◽  
Donna Weber ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Opportunistic Infections ◽  
Chronic Gvhd ◽  
Progression Free Survival ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Reduced Intensity

Abstract Background: Allogeneic hematopoietic stem cell transplantation (allo SCT) has two potential advantages over autologous SCT: a tumor-free graft and graft-versus-myeloma (GVM) effect. Allo SCT’s potential to induce long term remission has, however, been offset by high rates of transplant-related non-relapse mortality (TRM). Reduced-intensity conditioning (RIC) regimens for allo SCT are associated with lower TRM without compromising the GVM effect. Methods: We retrospectively analyzed our experience in 69 patients (30 females and 39 males) with heavily pretreated, relapsed myeloma, who received allo SCT at our institution between1985 and 2007. Eighteen patients received myeloablative regimens (MA), while 51 received RIC regimens. MA regimens were TBI-based in 5 patients, high-dose busulfan-containing in 6 patients and high-dose melphalan containing (180–200 mg/m2) in 7 patients. RIC regimens were a combination of fludarabine (90–120 mg/m2) and melphalan (100–140 mg/m2). Median age of patients at allo SCT in both groups was 51 years. Median interval from diagnosis to allo SCT was 35.4 months in MA group, and 34.2 months in RIC group. Eight (44%) patients in MA group and 36 (70%) patients in RIC group had prior autologous SCT. Six patients (33%) in the MA group and 11 (25%) in the RIC group received allo SCT from unrelated donors (p=0.3). Median number of prior treatment regimens were 5 (range 1–10) in both groups. Stem cell source was peripheral blood in 3 patients in MA group and 41 patients in the RIC group (p=0.0001). Results: Median follow-up in surviving patients was 27 months (3–98). All patients achieved engraftment. Cumulative TRM at 1 year was 56% in the MA group and 25% in the RIC group (p=0.03). Overall response rates in evaluable patients were 69% (CR=15%, PR= 54%) in MA group, and 79% (CR=23%, PR=56%) in the RIC group (p=0.47). Disease progression at 2 years was seen in 8 patients (44%) in the MA group and 25 patients (49%) in the RIC group (p=0.78). Median progression-free survival (PFS) in MA vs. RIC groups was 4.1 and 6.8 months, respectively (p=0.003) and median overall survival (OS) ) in MA vs. RIC group was 5.3 and 13.9 months, respectively (p=0.001). Cumulative Incidence of grade II–IV acute graft-vs.-host (GVHD) in MA vs. RIC groups disease was 33 vs. 27% (p=0.76); cumulative incidence of chronic GVHD in MA vs. RIC group was 54% vs. 47% (p=0.41) in evaluable patients. At the time of this analysis, 13 patients (25%) were still alive in RIC group, 7 of whom (14%) were in remission for up to 6 years post allo SCT. The most common causes of death were recurrent disease (30 patients; 43%), acute or chronic GVHD (16 patients; 23%) and opportunistic infections (5 patients: 7%). Conclusions: Allo SCT after RIC regimens is associated with longer PFS and OS and lower TRM. There was no increase in the risk of relapse, or acute or chronic GVHD. These regimens can safely replace MA regimens and may offer greater benefit if utilized earlier in the course of disease. Figure Figure

Donor Lymphocyte Infusions and Second Transplantation as Salvage Treatment for Relapsed Myelofibrosis After Reduced-Intensity allografting.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1300-1300
Author(s):  
Nicolaus Kröger ◽  
Evgeny Klyuchnikov ◽  
Daniel Wolff ◽  
Martin Bornhäuser ◽  
Guido Kobbe ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Complete Loss ◽  
Donor Lymphocyte Infusions

Abstract Abstract 1300 Introduction: Around 20–30% patients (pts) with primary myelofibrosis (PMF) experience relapses within 3 years after dose-reduced conditioning followed by allogeneic stem cell transplantation (HSCT). The prognosis for those pts is unclear, and standard treatment recommendations have not yet been proposed. Early withdrawal of post-transplant immunosuppression, use of dose escalating donor lymphocyte infusions (DLIs), and/or 2nd HSCT have been suggested as therapeutic options for pts relapsing after HSCT. Although DLIs were found to be effective in certain disease as salvage approach, the role of 2nd HSCT for non-responding patients remains controversial. Here we report on our multicenter experience on the use of a two-stage salvage strategy including DLIs and a 2nd RIC-HSCT in pts with post-transplant relapse of PMF. It was planned to start salvage therapy with DLI and only non-responding patients as well as patients with transformation to blast crisis and complete loss of donor chimerisms were assigned to receive a second allogeneic stem cell transplantation. Responses were evaluated using the International Working Group consensus criteria for treatment response in myelofibrosis. Additionally, the JAK2V617F mutation level (in 1 case, the MPLW515mut level) and donor chimerism were used to assess the molecular remission status. Patients/Methods: Thirty pts with morphologic (n=24) or molecular (n=6) relapse of PMF after 1st HSCT were proceeded to a salvage strategy, including DLIs and/or 2nd RIC-HSCT. Median time from transplantation to relapse was 9 months (range, 2–62). 26 pts received a median of 3 (range, 1–5) DLIs. The initial median dose was 1.2×106 (range, 0.3×104 – 8×107) consequently being increased up to 4×107 CD3+ cells/kg (range, 1×107 – 1.3×108). As a second stage, 13 non-responding pts as well as those who received no DLIs (transformation to blast phase, n=1; complete loss of donor chimerism, n=3) underwent a 2nd RIC-HSCT. The median interval between 1st and 2nd HSCTs was 17 months (range, 11–77). The majority of the patients received a reduced busulfan/fludarabine conditioning regimen for the 1st HSCT. Conditioning regimen at the 2nd RIC-HSCT for most pts (12/17, 71%) consisted of a combination of treosulfan (30-36 g/m2) with fludarabine (150-180 mg/m2), and anti-thymocyte globuline (Thymoglobulin®, 2.5–8 mg/kg). The majority of pts (15/17, 82%) received 2nd allografts from alternative unrelated (HLA-matched, n=8; mismatched, n=5), related (matched, n=1), and haploidentical donors (n=1). Results: After DLIs, responses were observed in 10/26 pts (39%; complete remission (CR): n=8; CRu (unconfirmed: no bone marrow histology: n=2). All pts maintain the response during a median follow-up of 31 months (range, 13–45). Acute (grade II-IV) and chronic GvHD occurred in 3/26 (12%) and 7/25 (28%) pts, respectively There were no cases of non-relapsed mortality (NRM), while 3/26 pts expired from progression. Seventeen pts received a 2nd RIC-HSCT and engraftment was documented in 16/17 pts (leukocytes: median, d +14; platelets: median, d +18). Responses were observed in 12/15 evaluable pts (80%; CR, n=8; CRu, n=1; partial remission (PR), n=3). Acute (II-IV) and chronic GvHD were observed in 8/17 (47%) and 6/14 pts (43%), respectively. The 1-year cumulative incidence of NRM was 6% (95% CI: 0%-18%). The cumulative incidence of relapse at 1 year was 24% (95% CI: 0%-50%). Overall for whole study population, after a median follow-up of 27 mo (range, 9 – 61), the 2-year probabilities of OS and PFS was 80% (95% CI: 62% - 98%) and 72% (95% CI: 52% - 92%), respectively. Conclusions: DLIs and/or 2nd HSCT are effective and well tolerated salvage approaches, which resulted in the majority of patients in long-term freedom from disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Successful Early Outcome with Low-Dose (400 cGY) Total Body Irradiation in Combination with Busulfan and Fludarabine Myeloablative Conditioning Followed By Matched Unrelated Donor Allogeneic Peripheral Blood Stem Cell Transplantation in a Patient with Non-Remission Acute Myelogeneous Leukemia with Diffuse Extramedullary Disease in Multiple Sites

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5769-5769
Author(s):  
Gorgun Akpek ◽  
Sunita Nathan ◽  
John J. Maciejewski ◽  
Deborah A. Katz ◽  
Ashley Echeverria ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Low Dose ◽  
Mediastinal Mass ◽  
High Dose ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Acute Myelogeneous Leukemia

Abstract Outcome after allogeneic stem cell transplantation (allo-SCT) is poor with 10-20% probability of long term survival in patients with acute myelogeneous leukemia (AML) not in remission at the time of transplant. The main cause of transplant failure in this high risk population is disease post-transplant relapse. We treated a 32 year-old male with undifferentiated AML (M0) who initially presented with leukocytosis, circulating blasts and a large anterior mediastinal mass abutting adjacent structures. A core biopsy of the mass revealed myeloid sarcoma. Patient developed respiratory distress requiring endotracheal intubation and mechanical ventilation. Cytogenetics revealed Hyperdiploid, 55, XY,+4,+6,+8,+9,+10,+11,+14,+19,+mar[12]/46,XY[14]. FLT3 ITD was positive. He did not respond to initial induction chemotherapy with 7+3 (daunorubicin 60 mg/m2/d and Cytarabine 100 mg/m2/d). He achieved morphologic and cytogenetic complete remission after re-induction with high dose cytarabine and mitoxantrone. He also received scheduled prophylactic triple intrathecal chemotherapies throughout his treatment course and started high dose cytarabine consolidation (HIDAC). His treatment courses were complicated by numerous medical problems, requiring a second prolonged hospitalization following third consolidation. He was intubated again due to diffuse alveolar hemorrhage. The patient was eventually discharged with tracheostomy collar and supplement oxygen, which was discontinued later on. A follow-up CT of chest showed increase in size of mediastinal mass but continuous CR in BM exam. While unrelated donor allogeneic SCT is in process, he received one course of decitabine. At the time of pre-transplant work-up, he relapsed of her AML first at his left conjunctivae and shortly after on his skin, presented with diffuse chloroma lesions on his trunk. He was treated with external radiation to his left eye with additional IT chemo (negative cytology). He underwent 10/10 HLA match unrelated donor allogeneic stem cell transplantation following PK-directed IV Busulfan with targeted AUC of 20,000 and Fludarabine 160 mg/m2 plus total body irradiation 200 cGY/d x 2 days. Skin lesions were active but bone marrow was in remission at the time of transplant. GVHD prophylaxis was tacrolimus and low dose methotrexate 5 mg/m2/d on days+1, +3, and +6 only. No ATG was given. His post-transplant course was relatively unremarkable. No major complications requiring re-admission to hospital occurred. His trach collar was kept thoughout his transplant and post-transplant courses due to tracheal stenosis. He achieved complete morphologic and cytogenetic remission with resolution all of his extramedullary leukemia including his mediastinal mass on day+100 evaluation. Currently he has been receving monthly 5-Azacitidine maintenance and clinically well on day+122. This case illustrates a successful early outcome after peripheral blood allogeneic stem cell transplantation using the combination of chemo-low dose radiation in a patient with non-remission AML with diffuse extra medullary disease. Optimum combination of radiation and chemotherapy in conditioning regimens may improve transplant outcomes in patients with non-remission AML and warrants prospective Phase I-II clinical trials. Disclosures No relevant conflicts of interest to declare.

Incidence, Risk Factors and Outcomes of Bronchiolitis Obliterans after Allogeneic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3365-3365
Author(s):  
Chiaki Nakaseko ◽  
Shinnichi Ozawa ◽  
Miki Nishimura ◽  
Miwa Sakai ◽  
Kumi Ohshima ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Respiratory Failure ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Bronchiolitis Obliterans ◽  
Chronic Gvhd ◽  
Time Interval

Abstract Background: Bronchiolitis obliterans (BO) after allogeneic stem cell transplantation (allo-SCT) is a late-onset, life-threatening respiratory complication which significantly reduces patients’ quality of life. Despite different therapeutic protocols, BO mortality remains high and most patients die of respiratory failure or infections. In recent practice, the source of stem cells and the conditioning regimen for allo-SCT have become more varied, but their influence on the incidence of BO is not established. Here, we retrospectively analyzed incidence of and risk factors for BO in allo-SCT protocols. Patients and methods: Between Jan 1994 and June 2005, 2692 patients underwent allo-SCT in 14 facilities of the Kanto Study Group for Cell Therapy (KSGCT) in Japan, and 2154 surviving at least 100 days after transplantation were evaluated in this study. Clinical diagnosis of BO was made by pulmonary function tests (PFT) revealing a forced expiratory volume for 1 second (FEV1) less than 70% and FEV1/forced vital capacity less than 80% of the predicted value, along with typical changes on high-resolution computed tomography. Results: BO developed in 57 patients with a cumulative incidence at 5 years post transplant of 2.6%. The Kaplan Meier estimate of median time interval from transplant to diagnosis of BO was 335 days (83–907). The cumulative incidence of BO at 5 years was 1.62% (12/691) in bone marrow transplants from related donors (R-BMT), 3.83% (16/424) in peripheral blood stem cell transplantation from related donors (R-PBSCT), 2.91% (24/808) in BMT from unrelated donors (UR-BMT), and 2.65% (5/199) in unrelated cord blood transplantation (CBT). The incidence of BO after R-PBSCT was significantly higher than after any other type of allo-SCT (p=0.02). At BO diagnosis, the mean value of FEV1% decreased to 52.1% from 82.2% pre-transplant. 94% of patients had already developed chronic GVHD before the onset of BO. Risk factors for BO by univariate analysis were R-PBSCT (p=0.019) and preceding chronic GVHD (p=0.000). Twenty eight patients died after developing BO, 21 of respiratory failure. Only one patient died of relapse of primary disease. Overall 5 yr-survival of patients with BO from the time of diagnosis was 46.5%, significantly less than for those without (76.2% from day 335, p=0.000) by semi-landmark analysis. Conclusions: The incidence of BO in CBT recipients was higher than R-BMT recipients and not significantly different with UR-BMT recipients. R-PBSCT recipients who have already developed chronic GVHD have a higher risk for developing BO and need extensive care and repeated PFT examinations.

Allogeneic Stem Cell Transplantation in Multiple Myeloma: One Center Experience of 86 Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3033-3033
Author(s):  
Liisa Volin ◽  
Heli Uotinen ◽  
Eeva Juvonen ◽  
Anne Nihtinen ◽  
Tapani Ruutu
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Related Mortality ◽  
Time Point

Abstract The role of allogeneic stem cell transplantation (SCT) in the treatment of multiple myeloma (MM) is unclear. High transplant-related mortality has been regarded as a particular problem. At the Helsinki University Central Hospital 86 patients with MM have been treated with allogeneic SCT since 1995. The conditioning was at first myeloablative (MA). Since 1999 reduced intensity conditioning (RIC) after autologous SCT has been used in most cases, but a number of young patients with aggressive disease have been transplanted with MA conditioning. Of the patients 42 were male and 44 female. The median age at SCT was 50 (27–64) years. The median number of chemotherapy lines before allogeneic SCT was 1 (range 1–7). Prior autologous SCT had been performed to 55 patients. The median time from diagnosis to allogeneic SCT was 12 (4–168) months, and the time between autologous and allogeneic SCT 6 (2–146) months. At the time of allogeneic SCT 9 patients were in CR, 63 in PR, 4 had stable disease, and 10 progressive disease. 72 patients had a sibling donor: 68 were HLA-identical, one 1 antigen mismatch, 3 identical twins. 14 patients had an HLA-matched unrelated donor. The conditioning was MA in 32 and RIC in 54 patients. The MA conditioning consisted of Cy/TBI in 22, Mel/TBI in 3, and Treosulfan/Fld in 7 patients. RIC was the Seattle protocol (Fld/TBI 2 Gy) in 45, reduced Treosulfan/Fld in 8, and Fld/Cy in 1 patient. 26 patients received a BM graft and 60 patients a PB graft. As GVHD prophylaxis, 18 patients were given CsA/Mtx, 20 CsA/Mtx/MP, 45 CsA/MMF, and 3 nothing (identical twins). The median follow-up time from allogeneic SCT was 39 (2–136) months, 46 (7–136) months for the MA patients and 34 (2–92) months for the RIC patients, respectively. The OS was 50% at 61 months post SCT and there have been no deaths after this time-point. The median PFS was 31 months. After this time-point the disease has progressed in one case, at 90 months. Of the 32 MA patients 16 (50%) and of the 54 RIC patients 22 (41%) have achieved CR after SCT. The cumulative incidence of acute GVHD grade II-IV was 28%. The cumulative incidence of chronic GVHD was 72%, 58% in the MA and 83% in the RIC patients (p=0.074). The incidence of extensive chronic GVHD was significantly (p=0.012) higher in RIC than MA patients, 66% vs. 23%. There were no statistical differences in the incidence of acute or chronic GVHD by donor type (72 siblings/14 unrelated). The cumulative 100-day transplant related mortality was 4.5% and that of the whole follow-up time 14%. 26 patients have died. The cause of death was myeloma in 15, GVHD in 7, and infection in 4 patients. In conclusion, in the present material transplant-related mortality was low and the survival encouraging, supporting the use of allogeneic transplantation with curative aim in selected cases. Developing chemotherapy, given prior to transplantation, may improve the results.

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