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.

Durable Remission after Prophylactic Donor Lymphocyte Transfusion Following Allogeneic Stem Cell Transplantation with Reduced Conditioning for High-Risk AML and MDS.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 299-299
Author(s):  
Michael Schleuning ◽  
Christoph Schmid ◽  
Georg Ledderose ◽  
Johanna Tischer ◽  
Meike Humann ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Allogeneic Transplantation ◽  
Chronic Infections ◽  
Term Survival

Abstract Prophylactic transfusion of donor lymphocytes (pDLT) is an attractive form of maintenance therapy after allogeneic stem cell transplantation in patients with high risk of relapse. However, clinical experience is limited, and disease response is often achieved at the expense of severe graft-versus-host disease (GvHD). We here report our data on pDLT in high-risk AML and MDS. Cells were given within a prospective protocol that contained a sequence of chemotherapy, reduced intensity conditioning for allogeneic transplantation, and pDLT (FLAMSA-regimen). For pDLT, patients had to be in CR at least 120 days from transplantation, off immunosuppression for 30 days, and free of GvHD. 22/86 patients alive at day +120 fulfilled the criteria for pDLT. They had been transplanted for refractory or relapsed leukemia (n=9 each) or in CR1 because of unfavorable cytogenetics (n=4). 14 patients had an unfavorable karyotype, 8 with complex aberrations. Reasons for withholding pDLT in 64 patients included cGvHD or prolonged immunosuppression (n=38), refractory or relapsed leukemia (n=15), refusal of patient or donor (n=4 each), a history of grade IV acute GvHD (n=2), and chronic infections (n=3). The median time from transplant to first pDLT was 167 days (range 120–297). Median follow up of transfused patients is 696 days (range 209–1341). Ten patients received 1, 6 patients received 2, and 6 patients received 3 transfusions in escalating doses, containing a median of 1x106, 5x106 and 1x107 CD3+ cells/kg at pDLT 1, 2 and 3, respectively. Reasons for giving less than 3 transfusions were GvHD, relapse or refusal of the patient. Induction of GvHD was the main complication; grade III acute GvHD developed in 1, and chronic GvHD in 7 patients. So far, 5 patients have relapsed despite pDLT. One died of refractory leukemia, whereas 2 achieved secondary CR following adoptive immunotherapy. Two patients are currently under treatment. At present, 18/22 patients are alive and in CR at a median of 423 days post DLT. The current leukemia free survival at two years from first pDLT is 79%. Nineteen patients were complete chimeras at time of pDLT. pDLT converted mixed into complete bone marrow chimerism in 1, but failed in 2 cases. In our experience, pDLT is safe after allogeneic transplantation for high risk AML, when given at low doses and to a selected group of patients. Results are encouraging, and long term survival can be achieved. However, further studies need to define more precisely the contribution of pDLT to the therapeutic effect of the entire procedure.

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

Nonmyeloablative Allogeneic Stem Cell Transplantation (NST) for Hematologic Malignancies (HM) Using Pentostatin/Low-Dose Total Body Irradiation (TBI).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3671-3671
Author(s):  
R. Gregory Bociek ◽  
James E. Talmadge ◽  
James C. Lynch ◽  
Charles A. Enke ◽  
Charles A. Kuszynski ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Allogeneic Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Unrelated Donor ◽  
Host Disease ◽  
Graft Versus Host

Abstract Background/Patients and Methods: NST is increasingly being used as a means of establishing a graft-versus-malignancy (GVM) effect with less regimen related toxicity. Between 9/01 and 7/04, 39 patients (pts) with high risk/relapsed/refractory HM who were not candidates for full intensity allogeneic stem cell transplantation underwent NST using Pentostatin/TBI. The median age of pts was 52 years (range 22–70). The median number of prior therapies was 4 (range 0–8) including prior autologous stem cell transplantation in 22 pts. Diseases transplanted included chronic lymphocytic leukemia/indolent non-Hodgkin’s lymphoma (NHL, n=6), aggressive NHL (n=8), mantle cell lymphoma (n=3), Hodgkin’s disease (n=6), myeloproliferative disorders (n=4), myelodysplastic syndromes (n=4), and acute myelogenous leukemia (AML, n=8). Conditioning consisted of Pentostatin 4 mg/m2 daily on day −21, −20, and −19, followed by 200 cGy TBI on day −1. Post-grafting immunosuppression consisted of cyclosporine/mycophenolate mofetil. Results: Stem cell transplantation was from matched related (n=14) or unrelated (n=25) donors. Death prior to 100 days post transplant occurred in 7 patients. Grade III/IV toxicities included hematologic (n=10 pts), infectious (n=5) and other non-infectious (n=4). The median nadir values (day −21 to day 0) for hemoglobin, neutrophil count and platelet count were 10.7 g/dl (range 7.8–12), 1056/mm3 (range 0–5336), and 174/mm3 (range 24–523) respectively. Three pts failed to engraft; two patients with myelofibrosis (both of whom had autologous reconstitution) and one patient with high risk AML (who died of complications of fungal sepsis without hematologic recovery). The median chimerism values for CD3+ cells and WBC at day 28 are 80% and 95% donor cells respectively. The median chimerism values for CD3+ and WBC at day 70 are 95% and 95% respectively. There have been no late graft failures. The cumulative incidence of all grades of acute graft-versus-host disease at day 100 was 40% and was more common in unrelated donor transplants (60% vs. 15%, P=0.012). Chronic graft-versus-host disease has developed in 69% of patients. The cumulative incidence of relapse for all patients is 30%, and is lower for unrelated donor transplants than matched related donor transplants (46% vs. 20%, P=0.02). The probability of event-free and overall survival at two years is 52% and 56% respectively. Conclusions: This regimen is associated with acceptable toxicity. Engraftment has not been an issue with the exception of two pts with myelofibrosis. Pts receiving unrelated donor grafts have a higher incidence of graft-versus-host disease and a lower relapse rate. This represents indirect support for the presence of a GVM effect. A prospective study using a modified Pentostatin schedule (starting at day − 10) is ongoing based on the nadir of host T-cells identified in this study.

Phase I Trial of High-Dose Clofarabine and Busulfan as a Myeloablative Regimen Prior to Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Relapsed or Refractory Acute Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 198-198 ◽  
Author(s):  
Sherif Farag ◽  
Lisa L Wood ◽  
Jennifer E. Schwartz ◽  
Shivani Srivastava ◽  
Robert P. Nelson ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Phase I ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Phase I Trial ◽  
High Dose ◽  
Dose Levels

Abstract Abstract 198 Fludarabine in combination high-dose busulfan (Bu) is an effective myeloablative preparative regimen for allogeneic stem cell transplantation. At doses used, however, fludarabine has only modest anti-leukemic activity. Clofarabine (Clo) is a second-generation purine nucleoside antimetabolite with significant single agent activity in patients with AML and ALL. The novel combination of Clo with Bu may provide improved disease activity safely. Therefore, we conducted a phase I trial to determine the maximum tolerated dose (MTD) of Clo in combination with Bu in patients with high-risk acute leukemia. Patients received i.v. Bu (Busulfex) 0.8 mg/kg q 6 hrs on days −6 to −3 and Clo at 30–60 mg/m2/day on days −6 to −2 in successive cohorts. Stem cells were infused day 0. GvHD prophylaxis included sirolimus plus tacrolimus starting day −2 to day 100, tapering to day 180. Patients were eligible if they were 18–60 years, had primary refractory or relapsed and refractory AML or ALL, or were in CR2 or higher, had Karnofsky performance status ≥70%, and adequate organ function. Donors were HLA-matched related (5/6 or 6/6 antigen-matched) or unrelated (10/10 allele-matched). Toxicity was scored using the Common Terminology Criteria for Adverse events, version 3.0. Dose limiting toxicity (DLT) was defined as any grade 3–4 non-hematologic toxicity that did not resolve to grade 2 or less by day 30. A total of 15 patients were treated at 4 Clo dose levels, 30 (n=3), 40 (n=3), 50 (n=3), and 60 mg/m2 (n=6). Seven males and 8 females of median age 48 (30–58) years, with AML (n=13) or ALL (n=2) were treated. At transplant, leukemia was relapsed and refractory (n=8), primary refractory (n=6), or in CR2 (n=1). Median number of lines of treatment failed before transplant was 2 (1–3). Median marrow blasts at transplant was 12% (3%–83%). Hematopoietic cell transplants were from related (n=9) and unrelated (n=6) donors. All patients engrafted. Median time to neutrophils >0.5×109/l was 16 (12–20) days, and to platelets >20×109/l was 15 (10–42) days. One patient treated at the 30 mg/m2 dose level failed to achieve platelets > 20×109/l. No DLT was observed. Transient Grades 3–4 non-hematological toxicities were evenly distributed across all 4 dose levels, and included vomiting (n=3), mucositis (n=9), hand-foot syndrome (n=1), and elevation of AST/ALT (n=10). Grades 3–4 elevation of AST/ALT occurred in 2 of 3 patients treated at 30 mg/m2, 3 of 3 at 40 mg/m2, 2 of 3 at 50 mg/m2, and 3 of 6 patients at 60 mg/m2 dose levels. AST/ALT peaked at day −1 or 0 and returned to baseline in all patients by day 10, with no long-term sequelae. There was no correlation between Clo dose and peak AST/ALT. One patient developed acute renal failure at the 60 mg/m2 dose on day +12 in association with elevated tacrolimus levels, although the creatinine subsequently normalized. Two patients, both at the 30 mg/m2 dose, developed mild veno-occlusive disease of the liver which was self-limiting. One treatment-related death due to sepsis was observed at day +104 in a patient treated at the 30 mg/m2 dose. Thirteen of 15 patients were in CR by day 30; 2 patients, treated at 40 mg/m2 and 50 mg/m2, respectively, failed to achieve CR. Day 100 mortality was 0. With a median follow-up of 313 days, the 1-year relapse-free survival was 51% ± 15%, and the 1-year overall survival was 61% ± 14%. Clo at doses as high as 60 mg/m2/day × 5 days in combination with Bu 3.2 mg/kg/day × 4 days is well tolerated and demonstrates promising efficacy in a very-high risk acute leukemia population. The MTD has not been reached. We recommend Phase II testing of Clo 60 mg/m2/day × 5 days in combination with high-dose Bu as a myeloablative regimen for allogeneic stem cell transplantation in patients with acute leukemia. Disclosures: No relevant conflicts of interest to declare.

Low-dose thalidomide and donor lymphocyte infusion as adoptive immunotherapy after allogeneic stem cell transplantation in patients with multiple myeloma

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3361-3363 ◽  
Author(s):  
Nicolaus Kröger ◽  
Avichai Shimoni ◽  
Maria Zagrivnaja ◽  
Francis Ayuk ◽  
Michael Lioznov ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Allogeneic Stem Cell Transplantation ◽  
Adoptive Immunotherapy ◽  
Low Dose ◽  
Donor Lymphocyte Infusion ◽  
Graft Versus Host

Abstract To improve the antimyeloma effect of donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation in multiple myeloma, we investigated in a phase 1/2 study the effect of low-dose thalidomide (100 mg) followed by DLI in 18 patients with progressive disease or residual disease and prior ineffective DLI after allografting. The overall response rate was 67%, including 22% complete remission. Major toxicity of thalidomide was weakness grade I/II (68%) and peripheral neuropathy grade I/II (28%). Only 2 patients experienced mild grade I acute graft versus host disease (aGvHD) of the skin, while no grades II to IV aGvHD was seen. De novo limited chronic GvHD (cGvHD) was seen in 2 patients (11%). The 2-year estimated overall and progression-free survival were 100% and 84%, respectively. Adoptive immunotherapy with low-dose thalidomide and DLI induces a strong antimyeloma effect with low incidence of graft versus host disease. (Blood. 2004;104:3361-3363)

Promising Progression Free and Overall Survival Using a Novel (CY/FLU/TBI) Reduced-Intensity Conditioning (RIC) Regimen for Allogeneic Sibling Stem Cell Transplantation (SCT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2999-2999
Author(s):  
Marcie Tomblyn ◽  
Jeffrey S. Miller ◽  
Linda J. Burns ◽  
Bruce R. Blazar ◽  
Mukta Arora ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Platelet Recovery ◽  
Ventricular Ejection Fraction ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract RIC regimens permit older and less fit patients to receive allogeneic stem cell transplantation (SCT). We designed a novel RIC regimen (cyclophosphamide, fludarabine, TBI [CY/FLU/TBI]) to achieve sufficient anti-neoplastic potency for cytoreduction and adequate immunosuppression for engraftment yet have limited treatment related mortality (TRM). We report the results of 72 patients (58% male) receiving sibling donor HLA-identical (n=66; 92%) or single antigen mismatched (n=6; 8%) G-CSF mobilized peripheral blood SCT from 2002–2005. Eligible patients were >55 years or had prior SCT, ongoing but controlled infections, ventricular ejection fraction 35–45% or corrected DLCO 30–50%. All patients had chemotherapy sensitive disease or remission. Most patients had lymphoma (n=29; 40%) or acute leukemia/MDS (n=23; 32%); others (28%) had multiple myeloma, CML, CLL, aplastic anemia, or renal cell carcinoma. All acute leukemia patients were in CR (CR1=14, ≥CR2=4). All lymphoma patients were chemosensitive; 4 were in CR. All patients received conditioning with FLU 40 mg/m2/day × 5 days, CY 50 mg/kg and 200 cGy TBI. Equine ATG 90 mg/kg plus methylprednisolone were given to those without recent combination chemotherapy (29%). GVHD prophylaxis included mycophenolate mofetil 1 gm BID and cyclosporine. The median age was 55 years (range, 11–65). The median graft cell dose infused was 5.4 × 106 CD34+ cells/kg (range, 0.6–15.5). Seventeen (24%) had previous SCT (14 autologous, 3 allogeneic). Neutrophil engraftment occurred at a median of 7 days (range, 0–13) and median time to platelet recovery >20K and >50K was 9 days (range, 0–51) and 14 days (range, 0–68), respectively. Median bone marrow chimerism by day 28 was 100% (range, 50–100); only 11 patients were <90%. The cumulative incidence (95% CI) of Grade 2–4 acute GVHD was 47% (35–59) and Grade 3–4 acute GVHD was 24% (14–33). Chronic GVHD at 2 years was 48% (34–62). Treatment related mortality at 100 days and 1 year was low [100 day (95% CI): 11% (4–18%); 1 year: 17% (8–25)]. Causes of death (n=29) included relapse (52%), GVHD (21%), organ toxicity (24%), and fungal infection (3%). The cumulative incidence (95% CI) of relapse/progression for all patients was 37% (25–49) at 2 years [acute leukemia/MDS, 47% (24–71); lymphoma, 37% (18–55)]. After a median 29 months (range, 6–48) follow-up of survivors, progression-free (PFS) and overall (OS) survival were encouraging: [PFS: 1 year, 51% (39–62); 3 years, 43% (31–55); OS: 1 year 68% (57–79); 3 years, 58% (45–70)]. Importantly, almost no events (relapse or death) have occurred beyond 2 years yielding a plateau in PFS and OS. This novel CY/FLU/TBI conditioning regimen is well tolerated, effective, and associated with promising PFS and OS. Further application and testing in multi-center studies is warranted. Figure Figure

Fludarabine and Treosulfan Conditioning for Allogeneic Stem-Cell Transplantation; a Dose- Intense Regimen with Limited Toxicity.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3473-3473 ◽  
Author(s):  
Avichai Shimoni ◽  
Avital Rand ◽  
Noga Shem-Tov ◽  
Izhar Hardan ◽  
Yulia Volchek ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Graft Failure ◽  
Hematological Malignancies ◽  
Acute Gvhd ◽  
Karnofsky Score

Abstract Abstract 3473 Allogeneic stem cell transplantation (SCT) is a potentially curative approach for patients (pts) with various hematological malignancies. However, standard myeloablative conditioning (MAC) is limited to younger, medically fit pts. Reduced-intensity conditioning (RIC) is feasible in pts not eligible for MAC, allowing engraftment and limiting organ toxicity, however, relapse rates are increased, especially in pts not in remission at the time of SCT. Novel approaches are in need to deliver dose intense conditioning, yet with RIC type toxicity, to these pts. Treosulfan is a bifunctional alkylating agent with cytotoxic and immunosuppressive effects. Prior studies demonstrated the feasibility of a fludarabine-treosulfan (FT) conditioning regimen, suggesting it is effective with limited toxicity. To better define the role of FT, we analyzed outcomes of a relatively large cohort of pts, treated in a single institution. Pts were eligible for FT only if considered not eligible for MAC, due to advanced age, comorbidities or extensive prior therapy (including a prior SCT). FT included fludarabine 30 mg/m2, on days -6 to -2, and treosulfan 10–12 gr/m2 on days -6 to -4. Pts with an unrelated donor or no prior chemotherapy were also given ATG (Fresenius, total dose 15 mg/kg). The study included 105 pts, median age 57 years (range, 20–76). Diagnoses included AML (n=56), MDS (n=33), CML (n=3), lymphoid malignancies (n=12) and myelofibrosis (n=1). The donor was an HLA-matched sibling (n=50) or matched unrelated [MUD, n=55; 10/10 match (n=43), 9/10 (n=7), 8/10 (n=5)]. Disease status was defined as early (n=17), intermediate (n=24) or advanced (n=64) by standard criteria. This was a relatively high-risk pt group as only 24 pts (23%) were in CR (first or later), 30 pts had a comorbidity score ≥3 and 22 pts had a Karnofsky score ≤80 at the time of SCT. Twenty-seven pts had a prior SCT; 13 autologous and 14 allogeneic (12 from a different donor). Ninety-five pts engrafted; 7 died prior to engraftment, 3 had early primary or secondary graft failure (MUD-1, mismatched MUD- 2 pts). The median time to neutrophil and platelet engraftment was 12 (range, 9–23) and 16 (range, 10–66) days, respectively. With a median follow-up of 16 months (range, 1–73), 57 pts are alive and 48 have died. The cumulative incidence of acute GVHD and grade III-IV acute GVHD was 26% and 11%, respectively. The cumulative incidence of chronic GVHD was 53%. In all, 8 pts died of complications of GVHD and 16 from other non-relapse causes, including multi-organ failure (n=4), CNS bleeding (n=2), infections (n=7), graft failure (n=2) and suicide (n=1). The cumulative incidence of non-relapse mortality 3-years after SCT was 25% (95%CI, 18–35). Twenty-four pts died of disease recurrence, cumulative incidence 30% (95%CI, 21–44) at 3 years. Considering that only 26% of the pts were in CR at the time of SCT, this rate seems promising. The median 3-year overall (OS) and progression-free survival were 45% (95%CI, 33–57) and 37% (95%CI, 26–49), respectively. The 2 most important factors predicting for OS in multivariate analysis were advanced disease and a low Karnofsky score at the time of SCT. Hazard ratios were 3.7 (p=0.03) and 4.2 (p=0.001), respectively. The 3-year OS was 71% (95%CI, 45–96), 33% (95%CI, 6–69) and 26% (95%CI, 6–46) for low, intermediate and advanced stage, respectively (p=0.03). Best results were obtained in pts with previously untreated MDS (n=33, including 28 pts with > 10% marrow blasts at SCT) and pts with high-risk AML in first CR (n=14), with 3-year OS rates of 61% (95%CI, 42–80) and 65% (95%CI, 38–93), respectively. Interestingly, a second SCT was not associated with a worse outcome. OS was 43% (42/78 alive), 46% (8/13 alive) and 40% (7/14 alive) in first SCT, a second SCT after a prior autologous SCT or a prior allogeneic SCT, respectively. In conclusion, treosulfan-based conditioning is a promising approach in pts with advanced hematological malignancies, not eligible for standard MAC. Favorable results were observed not only in pts with early stage disease, but also in previously untreated advanced MDS. Second SCT was also feasible with FT with a relatively favorable outcome. The low relapse risk suggests that this regimen can be considered a dose-intensive regimen, with a toxicity profile that resembles RIC regimens. The role of FT should be further defined in larger prospective studies. Disclosures: No relevant conflicts of interest to declare.

Lenalidomide Followed with Donor Lymphocytes Infusion (DLI) After Allogeneic Stem-Cell Transplantation (Allo-SCT) with Reduced-Intensity Conditioning in Patients with High Risk Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4310-4310
Author(s):  
Jean El-Cheikh ◽  
Roberto Crocchiolo ◽  
Patrick Ladaique ◽  
Sabine Furst ◽  
Luca Castagna ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Donor Lymphocyte Infusion ◽  
Peripheral Blood Stem Cells

Abstract Abstract 4310 Purpose: Relapse remains the main issue after allogeneic stem cell transplantation (Allo-SCT) in high risk Multiple Myeloma (MM) patients. The aim of this study is to assess the anti-myeloma effect of lenalidomide followed by donor lymphocyte infusion (DLI) as adoptive immunotherapy after transplantation. Patients and methods: Twelve patients with refractory and high risk myeloma were analyzed. Median age at transplantation was 56 years (46–64); 6 patients (50%) received lenalidomide before Allo-SCT. All patients received a RIC including Fludarabine 30 mg/m2 5 days, ATG 2,5 mg/kg for 2 days and Busilvex 3.2 mg/kg/day (3 days in 6 patients and 2 days in 6 patients). All but one received peripheral blood stem cells (PBSC). Donor was HLA id in 6 patients and matched unrelated in 6 patients. It is our standard long term practice to consider post-transplant DLI in patients with progressive or persistent disease after day 100 if no GVHD signs were evident. In 2010, we introduced the use of lenalidomide after day 100 in patients with MM presenting the same characteristics. Doses ranged from 10 to 25 mg/day. Lenalodomide treatment could be completed with DLI, administered afterward, at least after 2 cycles. Results: The median time between Allo-SCT and lenalidomide was 10 months (3–38). The median initial dose of lenalidomide was 15 mg (10–25). Patients received a median of 6 cycles (1–10). Nine patients (60%) received an escalating dose of DLI; 1 × 107/Kg of CD3+cells for the first DLI and 1 × 108/Kg of CD3+cells for the second DLI. One patient with GVHD (after tapering of the cyclosporine A and only after 10 days of lenalidomide) and two patients with progressive disease after lenalidomide did not receive DLI. The toxicity related to lenalidomide was mainly haematological (grade II in 4 patients (33%) and grade I in 3 patients (25%); 7 patients (58%) had moderate asthenia. One patient developed a reversible renal insufficiency after 10 cycles of lenalidomide, none of our patients developed thrombo-embolism under treatment. At the last follow up, 9 patients are alive and all of them are under ongoing treatment. Four patients achieved complete remission (CR) and five patients partial remission at last evaluation. The 1 and 2 years probability of the progression-free survival (PFS) was 75% and 50% and overall survival (OS) was 83 % and 69% respectively. The median OS was not reached and the median PFS was 23 months. Conclusions: These data show that lenalidomide has an acceptable toxicity. Combination with DLI should be further evaluated in a larger cohort of patients. Disclosures: No relevant conflicts of interest to declare.

Brentuximab Vedotin in Combination with Donor Lymphocyte Infusion for Patients with Hodgkin Lymphoma Relapsing after Allogeneic Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4361-4361
Author(s):  
Panagiotis Tsirigotis ◽  
Ronit Yerushalmi ◽  
Kostantinos Gkirkas ◽  
Noga Shentov ◽  
Ivetta Danylesko ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Disease Progression ◽  
Hodgkin Lymphoma ◽  
Allogeneic Stem Cell Transplantation ◽  
Low Dose ◽  
Brentuximab Vedotin ◽  
Donor Lymphocyte Infusion ◽  
Efficacy And Safety

Abstract Introduction Brentuximab Vedotin (BV) has recently received approval for treatment of Hodgkin lymphoma (HL) relapse after auto-SCT. Although BV is very effective in treating relapse of HL post auto-SCT, response is usually transient. In contrast, there is a paucity of data regarding the efficacy and safety of BV, combined or not with donor lymphocyte infusion (DLI), for the treatment of relapse occurring after allo-SCT. Methods Search for patients (pts) with relapsed HL post allo-SCT was performed in our transplant data set with the aim to evaluate the efficacy and safety of BV in combination with DLI for the treatment of relapsing HL post allo-SCT. Eight pts with relapsed HL after allo-SCT that were treated with BV were included in this report. Results Patients and treatment: There were 6 males and 2 females, with a median age of 31 years (range, 23 - 40), who had previously failed an auto-SCT. Five pts had previously received BV after auto-SCT and all but one responded to treatment. All pts had chemosensitive disease before allo-SCT and were transplanted in a state of partial remission (PR). The graft source was unmanipulated peripheral blood stem cells from a matched related or an unrelated donor in 5 and 2 pts, respectively, while 1 pt received a double umbilical cord blood graft (DUCB). Five pts achieved complete remission (CR) and one PR after allo-SCT, while 2 pts had progressive disease (PD). Disease progression occurred in a median of 11 months (range, 4 - 17) after allo-SCT. All pts received BV at a dose of 1.8mg/kg every 3 weeks for a maximum of 16 doses, till disease progression or toxicity. In two pts chemotherapy was administered before BV. A median of 4.5 (range, 3 -12) BV cycles was administered. DLI was co-administered in 5 out of 7 pts (excluding one patient who received DUCB). Decision for DLI was at the discretion of the treating physician. One pt received 4 DLIs at escalating doses (5x106, 107, 5x107, 108/kg), while another one received 2 escalating DLIs (107, 108/kg) at 3 months interval. Three pts received a single DLI (107/kg). Treatment outcome: Three and two pts achieved CR and PR respectively after treatment with BV in combination with DLI. None of the pts treated only with BV responded. Four out of 5 pts developed GVHD (3 chronic, 1 acute) post DLI administration, that resolved in all cases after a short course of low dose steroids. Disease progression was observed in 3 out of 5 responders in 4, 7 and 9 months, while 2 pts remain progression free with a median follow up of 14,5 (range, 4 - 22) months. Six out of 8 pts are alive, while 2 pts died from HL. BV/DLI treatment was well tolerated and no serious adverse effects were observed in any of the patients. Conclusions In our study, we observed that administration of BV with DLI for HL relapsing post allo-SCT in pts with prior failure to auto-SCT was effective while toxicity was minimal. Notably, re-administration of BV to pts previously treated for post auto-SCT relapse did not result in additional toxicity or resistance. Furthermore, BV combined with DLI, but not BV alone, yielded anti-tumor response in 5/7 of these very high risk pts suggesting a possible synergistic effect. Of notice is the observation that one pt who was refractory to BV post auto-SCT, had a PR after re-administration of BV post allo-SCT. Our observations are in accordance with the results of a previous report, showing that BV plus DLI after allo-SCT creates a vaccination like-effect against HL [1]. Finally, in our study we observed lower than expected frequency of GVHD post DLI that was of transient duration and easily manageable with low dose steroids. We assume that this may be due to an immune-modulating effect produced by BV. Indeed previous studies have shown that CD30 is expressed on the surface of activated T-cells present in inflammatory infiltrates of GVHD lesions [2]. Administration of BV plus DLI should be tested in larger group of patients at high risk of relapse after allo-SCT. References Theurich S, Malcher J, Wennhold K, et al. Brentuximab Vedotin Combined With Donor Lymphocyte Infusions for Early Relapse of Hodgkin Lymphoma After Allogeneic Stem-Cell Transplantation Induces Tumor-Specific Immunity and Sustained Clinical Remission. J Clin Oncol. 2013; 31: 59-63. Chen Y, McDonough S, Hasserjian R, et al. Expression of CD30 in patients with acute graft-versus-host disease. Blood. 2012; 120: 691-696. Disclosures Tsirigotis: CELLTRION, Inc.: Research Funding.

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