5-Azacytidine Before or After Stem Cell Transplantation in Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndromes (MDS)

Abstract Abstract 4267 The acceptable toxic profile of 5-aza-citidine (5-aza) allows its use in fragile or elderly patients in whom intensive chemotherapy should be avoided. Whether it is possible to take advantage of this low toxicity in patients awaiting for donor search and/or stem cell transplant (SCT) and in those experiencing leukemia recurrences after the procedure remains unknown. We analysed the clinical results of using 5-aza in these two settings to define the feasibility, safety and results of this approach. Patients and methods: From 2007 to 2011, 15 patients (11 males, 4 females) received 5-aza as last treatment prior to an allogeneic SCT (n=13) or as rescue after an early post-transplant relapse (n=2) at our centre. Diagnosis was MDS in 3 cases (median age 62; range 58–63) and AML in 12 cases (median age 58; range 37–67). Patients with MDS received a median of 6 courses of 5-aza (range 3–8) as the only treatment from diagnosis, except for one patient who had received panobinostat prior to 5-aza. Amongst patients with AML, 12 patients received 5-aza either as treatment for AML (2/12) or after remission (8/12) because of the high relapse risk while awaiting for a suitable donor to be found. Two patients with AML received 5-aza as treatment for early post-SCT relapse. AML patients treated with 5-aza before SCT received a median of 5 courses (range 1–19), whilst patients receiving treatment for relapse received 1 and 3 courses, respectively. Ten patients received a nonmyeloablative conditioning regimen, 1 received a conventional conditioning regimen, 2 patients are still in the process of donor search and the other 2 patients received 5-aza after an autologous stem cell transplantation relapse. RESULTS: All MDS patients engrafted and are in complete remission (CR) after a median of 696 days of follow-up (range 377–1227). One of those patients died because of aGvHD. Nine of 12 AML patients receiving 5-aza prior to SCT are alive after a median 373 days follow-up (133–995). One patient showing refractoriness to 3 different lines of treatment died from disease progression after 211 days. All patients receiving 5-aza as treatment for early relapse are dead, 41 and 401 days after starting treatment. Most interestingly, AML patients receiving 5-aza as maintenance of an already-achieved CR while awaiting transplantation did not experience disease progression despite the median time they remained on this treatment was prolonged (9 months). Graft-versus-host disease ≥ grade II was seen in 3 patients. No graft failures were seen and all patients who received an allogeneic stem cell transplantation remain in complete response. CONCLUSION: The use of 5-aza for maintaining or achieving a response in patients with AML who are awaiting SCT is a safe procedure and adds flexibility to schedule the treatment without the need to administer potentially toxic therapy. The use of 5-aza before transplant did not appear to interfere either with engraftment, incidence of GvHD or short-term relapse after transplant. Disclosures: No relevant conflicts of interest to declare.

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Allogeneic Stem Cell Transplantation with Reduced-Intensity, Fludarabine-Based Conditioning in Relapsed and Refractory Hodgkin’s Disease: Low Transplant-Related Mortality and Impact of Intensity of Conditioning Regimen on Survival.

Blood ◽

10.1182/blood.v104.11.2135.2135 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2135-2135

Author(s):

Paolo Anderlini ◽

Rima Saliba ◽

Michele Donato ◽

Sergio Giralt ◽

Borje Andersson ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Disease Progression ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Cumulative Incidence ◽

Hodgkin’S Disease ◽

Conditioning Regimen ◽

Related Mortality

Abstract Forty patients with relapsed or refractory Hodgkin’s disease (HD) underwent allogeneic stem cell transplantation (allo-SCT) following a fludarabine-based conditioning regimen from an HLA-identical sibling (n=20) or a matched unrelated donor (n=20). The median age was 31 years (range 18-58). The median number of chemotherapy regimens received prior to allo-SCT was five (range 2-9). Thirty (75%) and thirty (75%) patients had received prior radiotherapy or a prior autologous SCT, respectively. The median time to progression after autologous SCT was nine months (3–52). Disease status at SCT was refractory relapse (n=14) or sensitive relapse (n=26). The conditioning regimens employed were fludarabine (25 mg/m sq IV x 5 days)-cyclophosphamide (1 g/m sq IV x 3 days) ± antithymocyte globulin (30 mg/kg IV x 3 days) (FC±ATG) (n=14), a less intensive regimen, and fludarabine (25 mg/m sq IV x 5 days) -melphalan (70 mg/m sq IV x 2 days) (FM) (n=26), a more intensive one. The two groups had similar demographics and prognostic factors. Chimerism studies indicated 100% donor-derived engraftment in 26/26 (100%) FM patients and in 9/13 (69%) evaluable FC±ATG patients. Day 100 and cumulative (18-month) transplant-related mortality (TRM) were 5 % and 22%, respectively for the whole group. There was a nonsignificant trend towards a lower cumulative TRM in the FM group (18% vs. 30% at 18 months, p=0.2). The cumulative incidence of acute (grade II-IV) GVHD was 38%. The cumulative incidence of chronic GVHD at 18 months was 69%. There was a trend for a lower relapse rate after the occurrence of GVHD, however, this was not statistically significant (hazard ratio 0.8; p= 0.6). Progression rates were similar in the FM and FC patients (53% vs. 57% respectively at 18 months, p=0.4). However, disease progression occurred later in FM patients (range 2–34 months) than in FC patients (range 0.7–13 months). In addition, with comparable follow-up time after progression, the FM group experienced a lower death rate after progression. Twenty-four patients (60%) are alive (fourteen in complete remission) with a median follow-up of 13 months (4–78). Sixteen patients expired (TRM n=8, disease progression n=8). FM patients had significantly better overall survival (73% vs. 39% at 18 months; p=0.03), and a trend towards better progression-free survival (37% vs. 21% at 18 months; p=0.2). We conclude that allo-SCT with fludarabine-based, less intensive conditioning from matched related and unrelated donors are feasible in high-risk HD patients with a low TRM. The intensity of the preparative regimen affects survival.

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Allogeneic Stem Cell Transplantation (Allo-SCT) Following a Reduced-Intensity Conditioning (RIC) Regimen in Relapsed Peripheral T-Cell Lymphomas (PTCL): Results at 4 Year of Median Follow-up.

Blood ◽

10.1182/blood.v114.22.875.875 ◽

2009 ◽

Vol 114 (22) ◽

pp. 875-875

Author(s):

Anna Dodero ◽

Francesco Spina ◽

Franco Narni ◽

Francesca Patriarca ◽

Sergio Cortelazzo ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Disease Progression ◽

Cell Transplantation ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Multivariable Analysis ◽

Number Of Patients ◽

Significant Difference

Abstract Abstract 875 Conventional therapies and autologous stem cell transplantation lead to disappointing results in relapsed PTCL, therefore allo-SCT has been investigated in the last years. There are evidence supporting the existence of a “graft-versus-PTCL” effect, but the majority of the studies have a limited number of patients with a short follow-up. We conducted a retrospective analysis on 53 patients (pts) affected by relapsed/refractory PTCL who received a RIC regimen followed by allo-SCT. The main histopathological subtypes were PTCL-not otherwise specified (PTCL-NOS, n=24), anaplastic large-cell lymphoma (ALCL, n=11), and angioimmunoblastic (AILD, n=6). The remaining cases were rare subtypes (n=12). Median age was 47 years (range, 15-64 years). Patients were allografted from matched related siblings (n=34, 64%) or alternative donors (n=19, 36%). The majority of pts had chemosensitive disease (n=39, 74%), received allo-SCT more than 12 months from diagnosis (n=38, 72%) and were treated with only 1 or 2 lines of therapy before transplantation (n= 37, 70%). At last follow-up (median 49 months, range 6-118), 29 pts are alive (55%, 26 in CR) and 24 died [n=20 for disease progression, n=4 for non-relapse mortality (NRM)]. The majority of relapsing patients (20 of 25, 80%) died at median time of 7 months after allo-SCT. The crude cumulative incidence (CCI) of relapse was 32% and 50% at 6 months and at 4-year after allo-SCT. The CCI of relapse was influenced by status of disease [chemosensitive versus chemorefractory: 41% versus 77% at 4 years (p<0.001)] and number of lines [≤ 2 versus > 2: 40% versus 70% at 4 years (p<0.02)] received before allo-SCT and not by hystotype and time from diagnosis to allograft. The CCI of NRM were 4% and 10% at 6 months and 4-year, respectively; type of donor and previous auto had no significant impact on NRM. The CCI of acute (grade II-IV) and chronic GVHD were 21% and 44%, respectively. The 4-year OS and PFS were 50% (95% CI, 35% to 63%) and 47% (95% CI, 32% to 60%) for all the population, 62% (95% CI, 44% to 76%) and 15% (95% CI, 3% to 38%) as OS, 58% (95% CI, 40% to 72%) and 13% (95% CI, 1% to 41%)as PFS, for chemosensitive and chemorefractory pts, respectively. According to the histopathological subtypes, the OS and PFS were 42% and 40% for PTCL-NOS, 50% and 44% for ALCL, 67% and 80% for AILD, 58% and 48% for rare subtypes, respectively (p=ns). At multivariable analysis of OS and PFS, refractory disease prior to alloSCT and age more than 45 years were independent adverse prognostic factors [hazard ratio (HR)= 5.3, p<0.001, HR=4.8, p<0.003 for OS; HR=5.4, p<0.0007, HR=2.7, p<0.02 for PFS]. Six-teen pts received donor lymphocytes infusions (DLIs) for disease progression (n=12) or to accelerate immune reconstitution (n=4): 7 out of 12 responded to DLIs (n=3 CR, n=4 PR). In conclusion, our long-term data with a median 4-year follow-up shows that: i) only patients with chemosensitive had advantage from allo-SCT; ii) transplantation should be performed early because pts receiving less lines of therapy had a better outcome; iii) we did not observe a significant difference in outcome between the different histopathological subtypes; iv) response to DLI supports the notion of an immune mediated effect. Disclosures: No relevant conflicts of interest to declare.

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Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab

Blood ◽

10.1182/blood-2008-01-136242 ◽

2008 ◽

Vol 111 (12) ◽

pp. 5530-5536 ◽

Cited By ~ 234

Author(s):

Issa F. Khouri ◽

Peter McLaughlin ◽

Rima M. Saliba ◽

Chitra Hosing ◽

Martin Korbling ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Follicular Lymphoma ◽

Cell Transplantation ◽

Survival Rates ◽

Conditioning Regimen ◽

Human Leukocyte ◽

Progression Free Survival ◽

Nonmyeloablative Stem Cell Transplantation

Abstract Nonmyeloablative stem cell transplantation in patients with follicular lymphoma has been designed to exploit the graft-versus-lymphoma immunity. The long-term effectiveness and toxicity of this strategy, however, is unknown. In this prospective study, we analyzed our 8-year experience. Patients received a conditioning regimen of fludarabine (30 mg/m2 daily for 3 days), cyclophosphamide (750 mg/m2 daily for 3 days), and rituximab (375 mg/m2 for 1 day plus 1000 mg/m2 for 3 days). They were then given an infusion of human leukocyte antigen-matched hematopoietic cells from related (n = 45) or unrelated donors (n = 2). Tacrolimus and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. Forty-seven patients were included. All patients experienced complete remission, with only 2 relapses. With a median follow-up time of 60 months (range, 19-94), the estimated survival and progression-free survival rates were 85% and 83%, respectively. All 18 patients who were tested and had evidence of JH/bcl-2 fusion transcripts in the bone marrow at study entry experienced continuous molecular remission. The incidence of grade 2-IV acute GVHD was 11%. Only 5 patients were still undergoing immunosuppressive therapy at the time of last follow-up. We believe that the described results are a step forward toward developing a curative strategy for recurrent follicular lymphoma.

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Autologous Hematopoietic Stem Cell Transplantation for Refractory Lupus Nephritis

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.10570918 ◽

2019 ◽

Vol 14 (5) ◽

pp. 719-727 ◽

Cited By ~ 5

Author(s):

Xianghua Huang ◽

Wencui Chen ◽

Guisheng Ren ◽

Liang Zhao ◽

Jinzhou Guo ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Lupus Nephritis ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Disease Free Survival ◽

Cell Transplant ◽

Hematopoietic Stem

Background and objectivesOur study evaluated the efficiency and safety of autologous hematopoietic stem cell transplantation treatment for patients with refractory lupus nephritis.Design, setting, participants, & measurementsFrom July 2011 to January 2015, a total of 22 patients with refractory lupus nephritis were enrolled in this study. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony stimulating factor and reinfused after treatment with cyclophosphamide and antithymocyte globulin. The primary end point was the rate of remission, and secondary end points included the survival and relapse rates, changes in proteinuria, kidney function, and serology immunologic test. All complications were recorded for safety assessment.ResultsTwenty-two patients were enrolled and underwent stem cell mobilization. There were nine men and 13 women, with a median lupus nephritis duration of 46 (33–71) months. The mean number of CD34+ cells was (7.3±3.8)×106/kg. All patients had successful engraftment, and the median times of granulocyte and platelet engraftment were 8 (7–9) and 9 (6–10) days, respectively. The major complications of stem cell transplantation were fever and gastrointestinal tract symptoms. The treatment-related mortality was 5% (one of 22). After a median follow-up of 72 (60–80) months, 18 (82%) patients achieved completed remission, one (5%) patient achieved partial remission, and one patient had no response and received peritoneal dialysis at 12 months after transplantation. The 5-year overall survival and disease-free survival rates were 91% and 53%, respectively. Six patients experienced relapse during the follow-up, and the relapse rate was 27%.ConclusionsAutologous hematopoietic stem cell transplant could be used as a treatment option for refractory lupus nephritis, because it was relatively safe and associated with good outcomes.

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High (95%) Response Rates in Relapsed/Refractory Mantle Cell Lymphoma after R-HCVAD Alternating with R-Methotrexate/Cytarabine (R-M-A).

Blood ◽

10.1182/blood.v106.11.2446.2446 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2446-2446 ◽

Cited By ~ 1

Author(s):

Jorge Enrique Romaguera ◽

Luis E. Fayad ◽

Michael Wang ◽

Fernando Cabanillas ◽

Fredrick Hagemeister ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Stem Cell Transplant ◽

Cell Lymphoma ◽

Previous Treatment ◽

Median Number ◽

Cell Transplant ◽

Mantle Cell

Abstract Mantle cell lymphoma (MCL) has a poor prognosis. Relapsed/refractory patients must respond to salvage chemotherapy in order to receive potentially curative stem cell transplantation (SCT). A salvage regimen with higher rate of response will offer the patient a better chance of survival. We have previously reported the results of R-HCVAD alternating with R-M-A in frontline therapy of MCL (Blood, 104:40a, 2004, (Abstract #128). The current trial looked at relapsed/refractory MCL patients treated also with R-HCVAD alternating with R-M-A. Since August 2001, the trial has accrued 24 out of a planned number of 41 patients of whom 21 are evaluable for response and survival. Median age was 63 years (range 45–78) and male:female ratio was 5:1. Three patients had received previous R-HCVAD alternating with R-M-A and three patients had failed an autologous stem cell transplant. Immediate therapy prior to the study for the 21 patients included R-HCVAD/SCT (1), CHOPw/wo rituximab (8 patients), cyclophosphamide, vincristine and rituximab (1), fludarabine (1), fludarabine, mitoxantrone, dexamethasone and rituximab (2), fludarabine and cyclophosphamide (1), radiotherapy (2), gemcitabine, mitoxantrone and dexamathasone (1) ifosfamide, carboplatin, etoposide and rituximab (1), Velcade (1), gemcitabine (1), and rituximab (1). The median number of prior regimens was one (range 1–6). Responses to the previous treatment included complete response (CR; 8 patients, 38%), partial response (PR; 6 patients, 29%), and no response or progression (7 patients, 33%). Results of the trial are as follows: Median number of cycles received = 4 (range 1–7), with an overall response rate (ORR) of 95% (43% CR/Cru; 52% PR). 5/5 patients who had progressed through the previous treatment responded (1CR, 4 PR), and 2/2 patients who had no change to the prior therapy responded (2 PR’s). We evaluated 12 cases whose response in our trial was classified as PR and found that in 4 of them it was the best response achieved but another 4 were referred to transplant while the tumor was still responding and in another case treatment was still ongoing. In 3 cases toxicity precluded continuation of therapy. Five (24%) of the patients were consolidated with non-myeloablative allogeneic stem cell transplantation. Sixteen were not transplanted for the following reasons: age (2 patients), lack of donor (5), Progressive disease (2), patient refusal (4), physician’s choice (1), waiting for match (1), and lost to follow up (1). Toxicity after 81 cycles included neutropenic fever (14%), grade 4 neutropenia (58%) and grade 4 thrombocytopenia (53%). The were no deaths due to toxicity. With a median follow-up of 21 months range 5–45 months), the median failure-free survival is 18 months as compared to a median FFS of 9 months response duration with the previous therapy, with no plateau in the curve. Patients who underwent stem cell transplant were censored at the time of transplant. The high response rates achieved R-HCVAD alternating with R-M-A makes this regimen an excellent choice for induction therapy prior to stem cell transplantation.

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The Role of Autologous Stem Cell Transplantation (ASCT) in Patients with Advanced Waldenström’s Macroglobulinemia.

Blood ◽

10.1182/blood.v110.11.941.941 ◽

2007 ◽

Vol 110 (11) ◽

pp. 941-941

Author(s):

Charalampia Kyriakou ◽

C. Canals ◽

A. Sureda ◽

G. Taghipour ◽

C. Gisselbrecht ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Autologous Stem Cell Transplantation ◽

Significant Proportion ◽

Safe Procedure ◽

Conditioning Regimens ◽

Retrospective Multicenter Study

Abstract Waldenström’s macroglobulinaemia (WM) is a relatively rare disorder that primarily affects elderly patients. Conventional therapies for symptomatic WM result in response rates of up to 70%. However, complete responses are rare and the disease remains incurable. Due to the indolent nature of the disease and the older age of patients the role of autologous stem cell transplantation (ASCT) in the treatment of patients with WM has not been analyzed in large series. In this retrospective multicenter study we report the outcome of 201 WM patients (132 male, 69 female), who underwent ASCT between 1992 and 2005. The median age at transplant was 53 years (22–73) and the median time from diagnosis to transplant was 18 months (3–239). Forty patients (20%) were in 1st maximum response (MR1), 24 (12%) in ≥MR2, 83 (41%) in PR1, 27 (13%) in ≥PR2 and 27(14%) were primary refractory to treatment. Conditioning regimens were BEAM (44%), TBI/Cyclophosphamide or Melphalan (28%), Melphalan (14%), BuCy (2%) and others (12%). The source of stem cells was PB in 188, BM in 10, and both in 3 patients. All patients but 3 had successful engraftment. With a median follow-up of 26 months (5–163), 112 (56%) patients are alive and free of disease, 73 (36%) patients have relapsed after a median of 14 months (1–110) post ASCT. Fifty-two patients died, 36(18%) from disease progression and 16(8%) from treatment toxicity. Non- relapse mortality was 6% at 1 year. The actuarial OS was 86% at 1 year, 75% at 3 years, and 61% at 5 years. The probability of relapse was 20% at 1 year, 38% at 3 years and 55% at 5 years with an estimated PFS of 74%, 54% and 33% at 1, 3, and 5 years respectively. Multivariate analysis revealed that, chemosensitive disease at the time of ASCT was the most important factor for NRM (p<0.001), relapse rate (p<0.01), PFS (p<0.001) and OS (p<0.001). In conclusion, this study suggests that ASCT is a safe procedure in patients with WM and that a significant proportion of heavily pre-treated patients with this disorder can respond to the procedure and achieve prolonged PFS.

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Low Relapse without Excessive Transplant-Related Mortality Following Allogeneic Stem Cell Transplantation in Patients with High Risk Secondary Acute Myeloblastic Leukaemia and Myelodysplastic Syndromes, Long-Term Outcomes in a Single Centre Experience.

Blood ◽

10.1182/blood.v114.22.4308.4308 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4308-4308

Author(s):

Jean El-cheikh ◽

Luca Castagna ◽

Sabine Furst ◽

Catherine Faucher ◽

Benjamin Esterni ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Allogenic Stem Cell Transplantation ◽

Related Mortality

Abstract Abstract 4308 Allogenic stem cell transplantation (Allo-SCT) as a therapy for secondary acute myeloid leukaemia (sAML) and myelodisplastic syndromes (MDS) is the most powerful treatment option. However, (Allo-SCT) is also complicated by a high risk for treatment-related morbidity and mortality. We analysed retrospectively the data of 70 patients transplanted at our institution from June 1995 to december 2008, 44 patients (63%) with sAML and 26 patients (37%) with MDS was treated with (Allo-SCT); median age at diagnosis was 41 years, (15-70), and the median age of 42, 5 years (16-70) at transplantation; The conditioning regimen was myeloablative combining (cyclophosphamide and TBI) in 16 patients (23%) and 54 patients (77%) was with a reduced intensity conditioning (RIC) regimens combining fludarabine, busulfan, and antithymocyte globulin; 11 patients (16%) were infused with bone marrow (BM), 55 patients (79%) peripherical blood stem cells (PBSC), and 4 patients (5%) cord blood cells; in 49 cases (70%) donor was a HLA identical sibling and in 21 (30%) was a matched unrelated donor; 41 patients (59%) carried high risk cytogenetic features, like (7q-, 5q-, > 3 alterations), while was normal in 24 patients (34%), and in 5 patients (7%) was unknown. Disease status at transplantation was as follow: CR in 24 patients (34%), 34 patients (49%) was refractory or in progression after treatment, and 12 patients (17%) was with a stable disease. With a median follow-up of 55 months (3-150), 30 patients (43%) are alive, the overall survival OS at 2 years and 5 years was 48 % and 39% respectively, and after ten years of follow up, OS was 30%, 95%CI [17.8-50.8]. We observed also that 26 % of refractory patients and 54% of patients in CR are alive at five years of transplantation. The probability of progression after transplantation at five and ten years was 31% with 95%CI [20.-46.5]. 2 years and 5 years treatment related mortality (TRM) was 23% and 26% respectively, and no modification at ten year, 95%CI [14.3-37.3]. TRM occurred in 16 patients (23%). Cause of death was; infections in 5 patients (7%), GvHD in 3 patients (4%), GvHD and infection in 3 patients (4%), multi organ failure (MOF) in 5 patients (7%). In multivariate analysis; OS, PFS or TRM, were not influenced by donor type (HLA id sibling vs others), conditioning regimen (RIC vs MAC), and stem cell source (bone marrow vs PBSC). Allogenic stem cell transplantation can be considered as a good option for the treatment of patients with high risk sAML and MDS when compared with the remission rate at five years of the other nonallogeneic SCT therapies. Disclosures: No relevant conflicts of interest to declare.

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Fludarabine, Low Dose Busulfan and Antithymocyte Globulin for Reduced-Intensity Conditioning (RIC) Prior to Allogeneic Stem Cell Transplantation (allo-SCT).

Blood ◽

10.1182/blood.v114.22.3341.3341 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3341-3341

Author(s):

F. Malard ◽

Eolia Brissot ◽

Patrice Chevallier ◽

Thierry Guillaume ◽

Jacques Delaunay ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Total Dose ◽

Disease Progression ◽

Cell Transplantation ◽

Low Dose ◽

Acute Gvhd ◽

Routine Practice ◽

Toxicity Profile

Abstract Abstract 3341 Poster Board III-229 Allo-SCT procedures are currently undergoing a profound evolution. The spectra of patients and diseases for which this approach is now considered have increased considerably over the past years. This is mainly due to the introduction in routine practice of the so-called nonmyeloablative or RIC regimens. While it is well established that fludarabine is the backbone drug to secure engraftment, there is a wide variability in the degree of myeloablation between the different RIC protocols, and the toxicity profile might vary significantly from one protocol to another. The combination of fludarabine and Busulfan (usually 8 mg/Kg total dose) with or without ATG, is among the most widely used RIC protocols worldwide. In an attempt to further decrease the toxicity of the transplant procedure, we hypothesized that further reduction (50%) of the Busulfan dose can allow improving transplant outcome. With this background, this pilot study tested the combination of Fludarabine (120 mg/m2), Busulfan (4 mg/Kg total dose administered orally over a single day) and ATG (Thymoglobuline®, 2.5 mg/Kg/d for 2 days) as a RIC regimen prior to allo-SCT in a single centre series of 46 patients. The cohort included 27 males (59%) and 19 females (41%) with a median age at time of allo-SCT of 57 (range, 12-64) y. Diagnoses included 21 cases of AML (46%), 12 NHL (26%), 6 Hodgkin diseases (13%), 3 ALL (6.5%), 2 myeloproliferative syndromes (4%), 1 MDS (2%) and 1 CLL (2%). Before allo-SCT, 23 patients (50%) underwent and failed previous stem cell transplantation (auto or allo). PBSCs were used as stem cell source in 42 patients (91%), while 4 patients (9%) received classical bone marrow. A matched-related donor was used in 18 cases (39%) and an unrelated donor in 28 cases (61%). With a median follow-up of 30.4 (range, 23.7-50.8) months, the median peripheral blood chimerism of donor origin at day 30 after allo-SCT was 99%. 20 patients (43.5%) experienced grade 2-4 acute GVHD, including 13 cases (28.3%) of grade 3-4 acute GVHD. Nine patients (19.6%) experienced some form of chronic GVHD (5 extensive and 4 limited). At time of last follow-up, 26 patients (56.5%) were still alive. Relapse or disease progression occurred in 13 patients at a median of 3.5 (range, 0.6-18) months after allo-SCT. Disease progression accounted for 7 deaths, while transplant-related causes (acute GVHD, n=5; MOF, n=3; infections, n=2; other causes, n=3) were observed in 13 cases, for a TRM rate of 28.3%. The KM estimates of disease-free survival (DFS) and overall survival (OS) at 3 years after allo-SCT were 46.9% and 56.5% respectively. Interestingly, OS was lower in the AML subgroup (n=21) as compared to the remaining 25 patients with other diagnoses (42.9% vs. 68%, p=0.09). We conclude that low dose Busulfan (4 mg/kg total dose) combined with fludarabine and ATG is a feasible RIC regimen that can allow engraftment after allo-SCT in heavily pre-treated patients. The toxicity profile of this regimen is acceptable. However, in the setting of AML, disease control may be a matter of concern, especially in the early period after allo-SCT, suggesting that this type of RIC should be reserved for patients with lymphoid or indolent malignancies. Disclosures No relevant conflicts of interest to declare.

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Dynamics of Chimerism In Regulatory T Lymphocytes (Treg; CD4+/CD25+) After Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood.v116.21.1328.1328 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1328-1328

Author(s):

Víctor Noriega ◽

Carolina Martinez-Laperche ◽

David Serrano ◽

Gabriela Rodriguez-Macias ◽

Mi Kwon ◽

...

Keyword(s):

Stem Cell ◽

T Lymphocytes ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Conflicts Of Interest ◽

Small Sample ◽

Mixed Chimerism ◽

Group 2

Abstract Abstract 1328 Introduction: CD4+CD25+ regulatory T-cells (Treg) play an important role in inducing and maintaining allogeneic tolerance and can inhibit graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). However, the dynamics of donor and recipient Treg cell populations after Allo-SCT has not been studied yet. Objective: To analyze the dynamics of chimerism in Tregs and compare it to that of T lymphocytes (TL; CD3+) and whole blood leukocytes (WBL). Material and Methods: The study includes 53 patients subjected to Allo-SCT (myeloablative and non-myeloablative). PB samples were obtained weekly during the first month and every 14 days after day +30 until complete chimerism (CC) was achieved, and at fixed time-points (+30, +60, +90, +180, +365) thereafter. TL and Tregs were purified from PB until CC was achieved using inmunomagnetic technology (Miltenyi Biotec; CD3+ Microbeads and CD4+/CD25+ Treg Isolation Kit, respectively). Chimerism analysis was performed by microsatellite PCR (STR-PCR; AmpFlSTR SGM Plus; Applied Biosystems) on genomic DNA obtained from WBL as well as on cell lysates obtained from purified TL and Tregs. Complete chimerism was considered in samples with percentage of recipient cells <1% (sensitivity of the STR-PCR) for WBL samples and <5% (minimum purity of 95% as estimated by flow cytometry) for purified cell lineages. Results: Median follow up for the whole cohort of patients was 338 days. CC was spontaneously achieved in WBL, TL and Tregs in 45/53 patients (85%) in a median time of 35.41, 38.8 and 42.5 days respectively. 5/3 patients (9%) suffered from graft failure/rejection showing mixed chimerism (MC) with increasing percentages of recipient cells both in WBL and leukocyte lineages. 3/53 patients (6%) maintained mixed chimerism (MC) in WBL and leukocyte lineages at day +180, with no signs of graft rejection or disease relapse. Analysis of the chimerism dynamics of those patients who spontaneously achieve CC revealed two different groups: Group 1 included 25/45 patients who achieved CC at the same time in WBL, TL and Tregs. Group 2 included 20/45 patients who achieved CC in WBL while maintaining MC in TL and Tregs. Interestingly enough, 9/20 patients from Group 2 maintained MC in Tregs 7–75 days after achieving CC in both WBL and TL (Figure 1). In a preliminary analysis, the small sample size precluded from obtaining statistically significant associations between the dynamics of chimerism in Tregs and the development of complications such as relapse or GVHD after SCT. Conclusions: To our knowledge, this is the first study dealing with Treg chimerism after SCT. We have shown it is feasible and can be performed on a routine basis together with standard lineage specific chimerism follow up. Although there is an association between chimerism dynamics in Tregs and TL, this is not absolute and a percentage of patients maintain residual Tregs of recipient origin after WTL and TL have become of complete donor origin. In this small cohort, Treg chimerism did not influence the development of post-SCT complications. Analysis of a larger and more homogeneous cohort would allow establishing the usefulness of Treg chimerism testing for the management of transplanted patients. Disclosures: No relevant conflicts of interest to declare.

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Phase I Study of Eltrombopag for Promoting Thrombopoiesis in Patients Undergoing Stem Cell Transplantation After Total Body Irradiation

Blood ◽

10.1182/blood.v120.21.219.219 ◽

2012 ◽

Vol 120 (21) ◽

pp. 219-219 ◽

Cited By ~ 2

Author(s):

Jane L. Liesveld ◽

Gordon L. Phillips ◽

Michael W. Becker ◽

Louis Constine ◽

Jonathan W. Friedberg ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Phase I ◽

Cell Transplantation ◽

Dose Level ◽

Stem Cell Transplant ◽

Conditioning Regimen ◽

Cell Transplant ◽

Once Daily ◽

Total Body

Abstract Abstract 219 Purpose: Prolonged intervals of thrombocytopenia are common after stem cell transplantation, and platelet transfusions are the only temporary therapy before engraftment. Risk of thrombocytopenia is greater in patients receiving total body irradiation (TBI) in their conditioning regimen. Eltrombopag is a small-molecule, nonpeptide oral agent that functions as an agonist of the thrombopoietin receptor. It is approved by the FDA for the treatment of chronic idiopathic thrombocytopenic purpura and is being developed as a treatment for thrombocytopenia of other various etiologies. We report updated results of a Phase I clinical trial assessing the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of once daily oral eltrombopag in patients undergoing stem cell transplantation with a conditioning regimen containing TBI ≥ 400 cGy. Methods: A Phase I dose-escalation clinical trial was conducted to evaluate the safety and PK of eltrombopag at 4 different dose levels: 75, 150, 225, and 300 mg given once daily for 27 days, starting 24–48 hours post stem cell transplantation to eligible patients ≥18 years old. Patients with various indications for stem cell transplantation, KPS ≥70%, and TBI ≥ 400 cGy were eligible. Patients receiving either an autologous (Auto) or allogeneic (Allo) stem cell transplantation from a sibling, related donor, or matched unrelated donor (MUD) were eligible. Stem cells from peripheral blood (PBSC) or bone marrow were permitted; however, cord blood stem cell transplantation was not permitted. Patients at risk of thromboembolism or with a history of thromboembolic disease in the preceding 6 months were excluded. PK sampling was obtained over a 24 hour period after the first dose of eltrombopag as well as during the second week of treatment (steady-state). Results: As of August 1 2012, a total of 19 subjects (7 AML, 4 lymphoma, 1 CML, 1 MDS, 1 myelofibrosis, 2 ALL, 1 APML, 1 Biphenotypic Leukemia and 1 CLL/SLL) were enrolled, and 15 completed protocol treatments. All 19 were PBSC transplants with 12 MUD, 6 Allo and 1 Auto. Three subjects were completed at each dose level up to 225 mg with six completing treatment at the highest dose of 300mg. Four subjects were replaced because drug compliance was less than 75%. To date, 11/19 are alive while 8/19 have died (3 related to graft vs. host disease (GVHD), 3 Infection-related and 2 related to disease progression (f/u interval: 5.7 – 30 months). No dose limiting toxicities (DLTs) have been observed. The most common adverse events (AEs) up to the 300 mg dose level were related to standard stem cell transplantation, which included low blood counts, fatigue, headache, diarrhea, nausea, peripheral edema, hypoalbuminemia, hyperglycemia, hypocalcemia, and hypomagnesemia. Possibly drug-related AEs were dry skin, rash, elevated creatinine, and hypokalemia; these were all grade 3 or less. There were 12 severe AEs observed in 8 subjects, which included infection (3/19), pulmonary embolism (PE) (1/19), acute renal failure (3/19), gastrointestinal (2/19), acute respiratory distress syndrome (1/19), pericarditis (1/19) and GvHD skin rash (1/19). Most SAEs were considered related to stem cell transplant, except one subject at 75 mg with PE possibly related to eltrombopag, but also possibly related to stem cell transplant and cancer diagnosis. The PE occurred 9 days after stopping eltrombopag at which time platelet count was 252K. Time to platelet engraftment and number of platelet transfusions were also documented for each enrolled patient. Median time to platelet engraftment for all subjects on this study was 16 days. PK data are summarized in Table 1 and Figure 1. A dose-dependent increase in plasma exposure of eltrombopag was observed; although some saturation of absorption is evident at the 300 mg dose level. (Figure 1). Conclusions: 27-day once daily dosing of eltrombopag to enhance platelet recovery for post-transplant thrombocytopenia is well tolerated, with no DLTs observed up to the 300 mg dose level. Most AEs were transplant related. PK showed proportional plasma concentration up to 225 mg daily dosing, with some saturation of drug absorption above 225 mg. Disclosures: Liesveld: Eisai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Ariad: Honoraria. Off Label Use: Eltrombopag not approved post-transplant. Dawson:GlaxoSmithKline: Employment.

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